Professional Documents
Culture Documents
Diagnostic Hipo-Statural
Diagnostic Hipo-Statural
HORMONE
RESEARCH
From Developmental Endocrinology to Clinical Research
Editor-in-Chief
Editorial Board
P. Czernichow, Paris
Associate Editors
J.-C. Carel, Paris
P.E. Clayton, Manchester
W.S. Cutfield, Auckland
O. Hiort, Lbeck
P.E. Mullis, Bern
M.A. Rivarola, Buenos Aires
P. Saenger, Bronx, N.Y.
M.O. Savage, London
O. Sder, Stockholm
G. Van Vliet, Montreal
Printed in Switzerland
on acid-free and non-aging
paper (ISO 9706) by
Reinhardt Druck, Basel
Appears monthly:
2 volumes per year
(12 issues)
S. Karger
Medical and Scientific Publishers
Basel Freiburg Paris London
New York Bangalore Bangkok
Singapore Tokyo Sydney
Disclaimer
The statements, options and data contained
in this publication are solely those of the individual authors and contributors and not of
the publisher and the editor(s). The appearance of advertisements in the journal is not
a warranty, endorsement, or approval of the
products or services advertised or of their effectiveness, quality or safety. The publisher
and the editor(s) disclaim responsibility for any
injury to persons or property resulting from
any ideas, methods, instructions or products
referred to in the content or advertisements.
Drug Dosage
The authors and the publisher have exerted
every effort to ensure that drug selection and
dosage set forth in this text are in accord with
current recommendations and practice at the
time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the
reader is urged to check the package insert for
each drug for any change in indications and
dosage and for added warnings and precautions. This is particularly important when the
recommended agent is a new and/or infrequently employed drug.
ESPE
Classi f icat ion
of
Pae diat ric E ndoc rine
Diagnoses
Edited by
Jan M. Wit
Michael B. Ranke
Christopher J.H. Kelnar
With contributions by
Hans Akerblom
Albert Aynsley-Green
Giampiero Baroncelli
Jean-Pierre Bourguignon
Henriette A. Delemarre-Van de Waal
Malcolm Donaldson
Herwig Frisch
Annette Grters-Kieslich
Lars Hagens
Eberhard Heinze
Ieuan A. Hughes
Daniel Iliev
Brygida Koehler
Klaus Kruse
Agne Larsson
Jrn Mller
Stefan Riedl
Martin Ritzn
Tomas E. Romer
Werner Rosendahl
Giuseppe Saggese
Niels Skakkebaek
Yara Smit
Gyula Soltsz
CO NTE NTS
Foreword . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . VII
User Guide. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . IX
1
SHORT STATURE
1A
1B
1C
Precocious Puberty . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Single Variations of Normal Puberty . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Contrasexual Pubertal Development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Delayed Puberty . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Menstrual Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
14
15
15
16
16
DISORDERS OF PUBERT Y
3A
3B
3C
3D
3E
1
2
5
TALL STATURE
2A
2B
2C
21
22
23
24
27
27
28
28
28
29
IV
31
31
33
33
33
THYROID DISORDERS
7A
7B
7C
7D
7E
55
56
56
57
10
44
45
46
46
47
ADRENAL DISORDERS
8A
8B
8C
8D
Hypothyroidism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Hyperthyroidism. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Goitre . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Thyroid Tumours. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Other Thyroid Disorders. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Hypergonadotrophic Hypogonadism. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Cryptorchidism/Maldescended Testes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Acquired Testicular Disorders. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Tumours of Testes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Disorders of Penis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Scrotal Disorders. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Disorders of the Epididymis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Disorders of Testicular Blood Vessels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Other Specified Disorders of the Male Genitalia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Other Disorders of the Male Genitalia, Unspecified . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
63
64
64
65
65
66
66
66
66
66
Ovary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Disorders of the Uterus and Cervix. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Disorders of the Vagina and External Female Genitalia . . . . . . . . . . . . . . . . . . . . . . . . .
Disorders of the Breast . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
68
69
70
71
11
12
13
87
87
89
90
90
14
VI
FO R EWO R D
The ESPE Classification of Paediatric Endocrine Diagnoses
One of the cornerstones of medical practice is getting the diagnosis correct. After a diagnosis is made, clinicians usually like to store the information about the diagnoses of
individual patients in their les and registries. This can then improve patient care, because it makes information about the natural history and treatment responses available
of patients that had been seen in the past. It can also be helpful for scientic research, for
example in collecting data on patient groups.
Until now, no list of paediatric endocrine diagnoses has been available. Current diagnostic classications for the whole eld of medicine lack the detail that is requested by the
subspecialist. In some countries, a specic diagnostic classication for paediatrics is available, but even that lacks the necessary detail. This was the main reason which prompted
us to produce the ESPE Classication of Paediatric Endocrine Diagnoses that forms the
body of this publication.
We believe that a classication of diagnoses is an important tool in achieving optimal
communication between paediatric endocrinologists, as it enables physicians around
the world to speak the same language. In designing a formal coding system, the following requirements should be considered: (1) it should allow classication of all patients in
question; (2) there should be room for accommodating new aetiologies and pathogenetic aspects; (3) the diagnoses listed should be well dened, making misclassications
virtually impossible; (4) the classications should follow one general principle (e.g. nosology, aetiology, pathogenesis or symptomatology); (5) it should be easy to use, and (6) it
should optimally serve the purpose for which it was designed. As each diagnosis can be
classied according to dierent aspects, for example function or anatomy, our choices
are to some extent subjective. However, we have tried to follow the logic of the paediatric endocrine clinician as much as possible, so that it would be as easy as possible to nd
the diagnosis in the structure of each chapter. We have extensively made use of the lists
of causes of disorders as presented in various (paediatric) endocrine textbooks.
This list of preconditions makes it obvious that no system for the classication of diseases
can be perfect. The authors have attempted to develop a system of diagnoses in paediatric endocrinology that serves both scientic and practical requirements. In addition to
establishing a coding system, a glossary of the most important disorders has been appended, in the form of endnotes, for the purpose of clarication and unequivocal description. Nevertheless, in areas where we are still ignorant about aetiology, any classication
will be, to an extent, arbitrary (for example idiopathic short/tall stature, familial, normal
variant). The reader should, therefore, keep in mind that in some situations a classication which is still necessarily descriptive can, if used uncritically, obscure rather than il-
VII
Reference
1
Dawkins R: Gaps in the Mind; in: A Devils Chaplain Selected Essays. London, Weidenfeld & Nicolson, 2003.
VIII
USE R GU I D E
In the preparation of this classication we have used several strategies and rules. In the
following paragraphs these are explained for the purpose of easy use.
1
The diagnostic classication is built as a tree structure, with generally up to 5 levels (rarely
going up to 6 levels). We have chosen a system of LETTERS-numbers-letters-numbers-letters(-numbers), which is easier to use than a system only consisting of numbers. The rst
number used is 1, except for the box with Disorders classied elsewhere, which gets a 0.
The rst letter is a, also for boxes with Disorders classied elsewhere.
Each diagnosis has a main site (indicated as [primary]) and can have one or more secondary sites (indicated as [secondary]). Additional information, including the footnotes,
ICD-10 codes, and OMIM codes, is only given at the primary site of classication. If the disorder is also coded in other chapters, or other segments of the same chapter, this is mentioned at the beginning of the pertinent section, under the heading: Disorders classied
elsewhere (coded as 0 or a). The diagnoses that are classied elsewhere are indicated in
italics.
Where applicable, it is indicated which diagnosis is not included in the pertinent section.
This is written as: Excluded:, followed by the diagnoses that are excluded.
Where applicable, the lists of diagnoses under a certain group end with a section called
other specied disorders (labelled as 8, 88, or y) and a section called other disorders,
unspecied (labelled as 9, 99, or z). These serve to code conditions that cannot be found
in the current classication.
With respect to spelling, we have followed the British English spelling. We have used no
s to add to the names of the discoverers of the syndromes (e.g. Turner syndrome instead
of Turners syndrome), but the s has been used for the names of Diseases (e.g. Addisons
disease).
Explanatory texts are given in the form of footnotes, and have been limited to 3 short
sections: synonyms; phenotype, including concise information about symptoms, signs,
laboratory investigations, radiology, and other further investigations, and comments. In
some instances a reference is added.
Hormonal ndings are indicated in an abbreviated form. First, hormones are abbreviated
in their usual fashion (see list of abbreviations). Second, increased is indicated as +, decreased as , and normal as N, printed immediately behind the abbreviated hormone
(e.g. T (+) means increased testosterone concentration).
If a child has a disorder that expresses itself in dierent endocrine systems, we advise to
classify the condition according to various systems. This also applies to the codes given
to Classied elsewhere. So, the short, obese, hypogonadic and diabetic child with Prader-Willi-Labhart syndrome may be coded 14B.25 (primary), 1A.1a (short), 5B.2a (obesity), 6A.3d (hypogonadotrophic hypogonadism) and 11A.3h.10 (diabetes mellitus).
J.M. Wit, M.B. Ranke, C.J.H. Kelnar
IX
ESPE Code
Diagnosis
S H O R T STATU R E 1
1A
PR I M ARY G R OW T H FAI LU R E
1A.1
1A.1a
1A.1y
1A.1z
1A.2
1A.2a
1A.2y
1A.2z
1A.3
1A.3a
1A.3a.1
1A.3a.2
OMIM
ICD-10
P05.1
Q77, Q78
Short Stature
P00.24
#100800
#146000
ESPE Code
Diagnosis
1A.3a.8
1A.3b
1A.3b.1
1A.3b.8
1A.3c
1A.3c.1
1A.3c.2
1A.3c.8
1A.3d
1A.3d.1
1A.3d.2
OMIM
ICD-10
#183900
#127300
#249700
E76
#252500
E77.0
#252600
1A.3z
1B
S E CO N DARY G R OW T H FAI LU R E
1B.1
E4046
1B.2
Q2028
J4099
1A.3d.8
1A.3e
1A.3e.1
1A.3e.8
1A.3f
1A.3f.1
1A.3f.2
1A.3f.8
1A.3y
1B.2a
1B.2b
#241500
#307800
(E84)
1B.2c
1B.2d
1B.2e
Liver disorders
Intestinal disorders, e.g. Crohns disease, malabsorption
syndromes, short bowel syndrome
Renal disorders, e.g. Fanconi syndrome, renal acidosis
K7077
K5052
K9093
N1019
N2529
1B.2f
1B.2g
Chronic anaemia
Multiorgan disorders
D5064
ESPE Code
Diagnosis
OMIM
1B.2h
G7173
1B.2i
1B.2y
1B.3
1B.3a
1B.3a.0
1B.3a.1
1B.3a.2
1B.3a.2a
1B.3a.2b
1B.3a.2c
1B.3a.2d
1B.3a.2e
1B.3a.2f
1B.3a.2g
1B.3a.2y
1B.3a.3
1B.3a.4
1B.3a.8
1B.3a.9
1B.3a.9a
1B.3a.9b
Short Stature
ICD-10
M08
E23.0
E23.0
E23.0
E23.0
*601802
*600577
*602146
*601538
+173110
*139191
+139250
Q04.4
Q37.9
O35.0
P35.0
E23.0
E23.0
ESPE Code
Diagnosis
1B.3b
1B.3b.1
1B.3b.2
1B.3b.3
OMIM
ICD-10
E23.0
D44.4
M9064/3
C71
M9400/3
M9391/3
M9380/3
M9470/3
IB.3b.4
IB.3b.5
IB.3b.6
IB.3b.7
IB.3b.8
IB.3b.9
1B.4
1B.4a
1B.4b
1B.4c
1B.4d
1B.4e
1B.4f
1B.4z
1B.5
1B.5a
1B.5b
1B.5y
1B.6
1B.6a
1B.6b
1B.6c
C9196
S06
G0108
D76
Q28
E23.0
#262650
E34.3
#262500
E34.3
#245590
E34.3
+601489
E34.3
#608747
E34.3
#270450
E34.3
E34.3
E74
E75
ESPE Code
Diagnosis
1B.6d
E7072
Psychosocial
Psychosocial (emotional) deprivation9
Anorexia nervosa
Depression
Other specified psychosocial causes
E34.3
1B.6y
1B.6z
1B.7
1B.7a
1B.7b
1B.7c
1B.7y
OMIM
ICD-10
E7683
E88
T74
F50
F32.9
E34.3
1B.8y
Iatrogenic
Systemic glucocorticoid therapy [primary 8C.1c]
Local glucocorticoid therapy (inhalation, intestinal, other)
Other medication
Treatment of childhood malignancy
Total body irradiation
Chemotherapy
Other specified iatrogenic causes
1C
I D I O P AT H I C S H O R T S T AT U R E 10
E34.3
1C.1
E34.3
E34.3
1B.8
1B.8a
1B.8b
1B.8c
1B.8d
1B.8d.1
1B.8d.2
1C.1a
1C.1b
1C.1c
1C.1d
1C.2
1C.2a
1C.2b
1C.2c
1C.2d
Short Stature
T38.0
T49.0
T3650
T66
T45.1
T78.9
Short stature
Comments: Short stature is dened as a height below 2.0 SDS (2.3rd percentile) for a given age, sex
and population. It is the result of impaired bone growth in the foregoing period, which is expressed
in terms of a reduced length/height velocity in at least some period of life (including the intrauterine
period). In some conditions growth velocity is only diminished early in life (e.g. in children born SGA
with failure of catch-up growth), in other conditions growth velocity is continuously low (e.g. in children with complete growth hormone deciency). The terms growth delay and growth retardation
are also frequently used with the same intention as short stature. In this diagnostic classication an
abnormally low height velocity is also classied under the general heading of Short stature.
The causes of short stature are varied and dier with respect to aetiology and pathogenesis. To our
present knowledge, disorders of the hormonal system account only for a minority of children with
short stature. Since growth disorders are the key symptom of many hormonal abnormalities and
since children with growth disorders are commonly presented to the paediatric endocrinologist,
disorders presenting with short/tall stature are part of this classication system.
Phenotype: Short stature and birth length and/or weight below 2 SDS (or below the 2.3rd centile)
for gestational age for the reference population.
Comments: There is some discussion about the use of the terms intrauterine growth retardation
(IUGR) and small for gestational age (SGA). There appears now some consensus that the term IUGR
implies impaired fetal growth and should be considered a prenatal diagnosis. SGA describes birth
length and/or weight in relation to gestational age and is a post-partum diagnosis. The majority of
babies born SGA (approximately 85%) catch up in height (within 23 years) and will not be short in
childhood or in adulthood, although their mean height is somewhat lower than expected for target
height. The 15% of babies who do not catch-up (height < 2 SDS after 2 or 3 years) are termed SGA
with failure to catch-up, or shortly SGA. Those who failed to catch-up by 2 years are at high risk of
remaining short in later life. Thus, the term SGA is purely descriptive, and is a working diagnosis for
children born small and continuing to be short. In most cases there is no known aetiology and/or
pathogenesis.
3 Skeletal dysplasias (constitutional disorders of bone)
Comments: Skeletal dysplasias exist in a great variety and are commonly associated with short
stature. Traditionally, the diagnosis was established based on the clinical appearance during development and conventional X-ray ndings. More recently, the classication of skeletal dysplasias
has been based upon the expanding understanding of the pathophysiology of bone development
and the discovery of the underlying molecular genetic defects. This has resulted in an International
nomenclature and classication of osteochondrodysplasias (1997) published by the International
Working Group on Constitutional Diseases of Bone [Am J Med Genet 1998;79:376382] and a more
recent update [Hall CM: International nosology and classication of constitutional disorders of bone
(2001). Am J Med Genet 2002;113:6577]. In this classication 33 groups are presented, each including various clinical entities.
For the ESPE Classication of Paediatric Endocrine Diagnoses just 6 groups out of the 33 are mentioned specically. For a more detailed classication we refer to the most recent paper on International Nosology and Classication.
4 Achondroplasia, hypochondroplasia
Phenotype: Achondroplasia and hypochondroplasia are disorders characterised by disproportionate short stature with rhizomelic limb shortening. They are commonly caused by mutations in the
tyrosine kinase domain of the broblast growth factor receptor 3 (FGFR3) gene. However, in the
absence of these mutations the diagnosis may still be conrmed by typical radiological ndings.
5 Growth hormone deciency (GHD)
Short Stature
anterior pituitary or a pituitary abnormality are not an a priori proof of a disturbed GH secretion, but
are likely to provide evidence that the biochemically established diagnosis of GHD is correct. With
greater renement in our diagnostic arsenal less cases with GHD will be classied idiopathic.
7 Neurosecretory dysfunction (NSD)
Comments: The term NSD describes a specic situation, in which GH levels observed during stimulation tests are normal, but spontaneously secreted GH is low. This situation was rst described in
children who had been treated with radiotherapy to the cranium as part of treatment for a malignancy. In this situation NSD can be seen as a special form of organic GHD. However, this situation
was also found to exist in children without such a history. Critics have emphasised that there is
a great day-to-day variation in spontaneous GH secretion, and that spontaneous GH secretion is
sometimes very low in normally growing children.
8 Bioinactive GH (Kowarski syndrome)
Comments: Bioinactive GH can be suspected in children clinically resembling classical GH, with low
circulating IGF-I levels but with normal GH secretion based on immunoassay measurements. Treatment with GH leads to an increase in IGF-I levels and a growth response to GH. It can be assumed
that one reason for bioinactive GH is a congenital structural abnormality of GH, which impairs/abolishes interaction with the GH receptor and subsequent signal transduction. Sophisticated methods
(e.g. RRA, bioassay, gene analyses) are required to prove such an entity. Up to 2006, only a few welldocumented cases have been published.
9
Psychosocial deprivation
Synonym: Emotional deprivation.
Phenotype: Behavioural abnormalities, such as apathy, watchfulness, autoerotic activity, delayed
developmental behaviour. Poor growth at home, catch-up growth in hospital or foster home. Reversible GH deciency has been described.
10
11
References: Preece MA: Horm Res 1996;45:5658; Ranke MB: Horm Res 1996;45:6466; Hermanussen M, Cole J: Horm Res 2003;59:180183; Wit JM: Horm Res 2007;67(suppl 1):5057.
12 Familial short stature, onset of puberty not yet known
Comments: A short prepubertal child who is not short for target height with an age below the
upper limit of the normal age at pubertal onset is classied here. In some cases, a positive family
history for pubertal delay and a delayed bone age suggest the syndrome of constitutional delay in
growth and adolescence, although in typical cases height in childhood is lower than expected for
target height. As soon as the onset of puberty (G2 or B2) is known, the patient can be classied as
1C.1a or 1C.1b.
13
14
Short Stature
TALL STATU R E
2A
2A.1
2A.1a
2A.1b
2A.1y
OMIM
ICD10
Q97.0
Q97.1
Q97.8
Q98.8
2A.1z
2A.2
Q97.9
Q98.9
2A.2a
2A.2b
2A.2c
2A.2d
2A.2y
2A.2z
2A.3
2A.3a
2A.3y
2A.3z
#154700
Q87.4
#154705
E72.1
#236250
E72.1
#236250
E88.1
Q87.3
10
2A.4z
2B
2B.1
2B.1c
2B.2
Hyperinsulinism
2B.2a
Primary
Disorders classified elsewhere:
Transient hyperinsulinism (11B.1a)
Congenital hyperinsulinism (11B.1b)
Other disorders, unspecified
Secondary
Disorders classified elsewhere:
simple obesity (5A)
Obesity with acanthosis nigricans 8 hyperlipidaemia and
sexual precocity
Other disorders, unspecified
2A.4
2A.4a
2A.4y
2B.1a
2B.1b
OMIM
ICD10
Q87.3
E22.0
#102200
#174800
Q78.1
+131100
E22.0
E15.0,
E16.1
2B.2a.1
2B.2a.9
2B.2b
2B.2b.1
2B.2b.2
2B.2b.9
2B.3
2B.4
Hyperthyroidism8
2B.5
Tall Stature
L83
E16.1
#202200
E05
11
2B.5a
2B.5y
2B.6y
2C
I D I O P AT H I C ( N O R M A L V A R I A N T T A L L S T AT U R E ) 9
2C.1
2C.2
2B.6a
2B.6b
2B.6c
ICD10
+107910
E34.9
+133430
E34.9
2B.6
OMIM
E34.4
Phenotype: Tall stature. Increased risk of variable degree of behavioural difficulties and learning
disability. Delayed menarche, and premature ovarian failure in some patients. Increased incidence
of other congenital anomalies. Ovarian function usually normal but primary ovarian impairment
seen in some individuals.
Comments: Increased risk of sex chromosome anomaly in child of 47,XXX female, therefore prenatal genetic counselling important. 48,XXXX females are tall with learning disability, radioulnar synostosis, and often incomplete puberty.
3
12
4 Homocystinuria
Phenotype: Tall stature with marfanoid habitus and osteoporosis. Learning disability common. Medial degeneration of aorta with frequent arterial and venous thromboses. Myopia and downward
subluxation of lens. Homocystine and methionine accumulation interfere in collagen formation
resulting in lens and skeletal changes, and platelet thrombosis causing vascular occlusion.
5
gigantism)
Phenotype: Inappropriately tall stature for parental heights. Enhanced height velocity. May have
headache, visual symptoms (e.g. field defect, optic nerve pallor). Elevated GH levels with failure to
suppress below 5 mU/l following oral glucose load. Abnormal overnight GH profile with loss of normal pulsatility, and failure to return to baseline. Enhanced prolactin response to TRH. May show LH,
FSH, ACTH and TSH deficiency if there is a mass effect from the adenoma.
Comments: Can be associated with McCune-Albright syndrome or MEN type 1.
7
Hyperthyroidism
Comment: Juvenile hyperthyroidism can lead to tall adult stature, but in most cases adult height is
within the normal range.
Comments: The term idiopathic tall stature is used for consistency with the classification of short
stature. Some clinicians may favour other terms (e.g. normal variant tall stature), and subclassify
children in this category in various ways, e.g. normal genetic tall stature, constitutional advance in
growth and adolescence. We prefer the term idiopathic as, even if a condition is familial, its cause
is unknown.
10
Tall Stature
13
OMIM
ICD 10
D I SO R D E R S O F PU B E R T Y
3A
P R E C O C I O U S P U B E R T Y1
E30.1
3A.1
E22.8
3A.2
E30.1 (R)
3A.2a
3A.1a
3A.1b
3A.1c
3A.1y
3A.1z
E22.8
E22.8
E22.8
E22.8
E25 (=)
3A.2b
3A.2b.1
3A.2b.2
3A.2c
3A.2c.0
3A.2c.1
3A.2c.2
3A.2c.3
3A.2d
E25.0
E30.1
E30.1
E30.1
#174800
Q78.1
E28.0
E29.0
+107910
drug code
Y42
3A.2e
3A.2f
Primary hypothyroidism10
Tumours producing androgen or estrogen steroids, not
originating from the testis or ovary
E03.9
E25.9
14
OMIM
ICD 10
3B
S I N G L E V A R I AT I O N S O F N O R M A L P U B E R T Y
3B.1
Premature adrenarche11
E27.0
3B.2
E30.8
3B.2b
Premature thelarche
In infancy (infantile mammoplasia)12
Beyond infancy (thelarche variant)13
3B.3
E30.1
3B.4
Hypertrichosis
L68.1
3B.2a
L68.9
Q84.2
3C
C O N T R A S E X U A L P U B E R TA L D E V E L O P M E N T
3C.1
3C.1a
3C.1b
3C.1b.1
3C.1b.2
3C.1c
3C.1d
3C.1e
3C.1e.1
3C.1e.2
3C.1e.9
3C.2
3C.2a
Virilisation/hirsutism (females)15
Excluded:
Virilised infant/ambiguous genitalia (4C)
Hypertrichosis (3B.4)
Due to disorders classified elsewhere:
Congenital adrenal hyperplasia (8A.1)
Cushing syndrome (8C.1)
Virilising adrenal tumours (8C.2)
Polycystic Ovary Syndrome (10B)
Germ cell tumour of the ovary (10E.4a)
Disorders of Puberty
N62
N62
E25.0
N62
E25, L68.0
15
3C.2z
Iatrogenic
Other specified disorder
Idiopathic
3D
D E L AY E D P U B E R T Y
3D.0
3C.2c
3C.2y
3D.1a
3E
MENSTRUAL DISORDERS
3E.1
Amenorrhoea
Primary amenorrhoea
Excluded:
Disorders of sex development (4)
Due to disorder classified elsewhere:
Anatomical defect female genitalia (10FG)
Hypergonadotrophic hypogonadism (10A)
Chronic anovulation with oestrogen present
Polycystic ovary syndrome (10B)
Adrenal disorders, e.g. Cushing (8C.1)
Adult-onset congenital adrenal hyperplasia (8A.1c.3)
Thyroid disease: hypothyroidism (7A), hyperthyroidism (7B)
Ovarian tumour (10E.4)
Hypogonadotrophic hypogonadism (6A.4)
Hyperprolactinaemia (6B.5)
3D.1
3D.1a
3D.1b
3E.1a
3E.1a.0
OMIM
ICD 10
E30.0
E23
E23.0
E30.0
N91.2
N91.0
E28.8
16
3E.1a.8
3E.1a.9
3E.1b
3E.1b.0
3E.1b.8
3E.1b.9
3E.2
3E.2a
3E.2b
OMIM
ICD 10
N91.1
N91.5
N91.3
N91.4
3E.3b
3E.4
Dysmenorrhoea
N94.6
3E.5
Premenstrual syndrome
N94.3
3E.8
N94.8
3E.3
3E.3a
N92
N93.9
Precocious puberty
Phenotype: Female: Breast development before the age of 8 years. Male: Genital development before the age of 9 years. Both sexes: Acceleration of growth, advancement of bone age.
Comments: Data from the United States suggest that sexual precocity should be defined by the
onset of secondary sexual development before 6 years in black girls and before 7 years in white girls
[Midyett et al., 2003]. This may be associated with the high prevalence of overweight. In Europe the
traditional age limits have been maintained by most clinicians.
Reference: Midyett LK, et al: J Pediatr 2003;111:4751.
Disorders of Puberty
17
4 Hamartoma
Comments: Presumably as a result of pressure on the hypothalamic area, a cerebral tumour may
initiate maturation of the GnRH pulse generator. Glial-derived transforming growth factor (TGF-)
may contribute to the neuro-endocrine mechanisms. Hamartoma may contain GnRH neurons functioning as an ectopic source of GnRH.
5
HCG-producing tumours
Comments: These tumours are classified by some under the heading of gonadotrophin-dependent
precocious puberty [e.g. Brook CGD, et al (eds): Clinical Pediatric Endocrinology, ed 5, 2005]. If gonadotrophin-dependent precocious puberty is defined as being caused by premature maturation
of an otherwise normal hypothalamic-pituitary system, HCG-producing tumours have a more logical place in the group of gonadotrophin-independent precocious puberty.
8 Familial testotoxicosis
18
09 Aromatase deficiency
Phenotype: Tall stature due to failure of epiphyseal closure at puberty. Elevated androgen levels
causing virilisation but not skeletal maturation in girls. Cliteromegaly, with polycystic ovaries in
pubertal females. Normal puberty in males with tall stature, eunuchoid habitus and osteoporosis
in adulthood. T (+), DHT (+), adione (+), LH (+), FSH (+), E1 (), E2 ().
10
Primary hypothyroidism
Comments: In some patients with primary hypothyroidism FSH are increased. Furthermore, TSH
has weak agonist properties at the FSH receptor.
11
Premature adrenarche
Synonym: The term premature pubarche is often used for this condition. However, strictly speaking premature pubarche means early onset of pubic hair, independent of the cause. Premature
adrenarche is the most frequent subgroup, diagnosed if other causes of premature pubarche (e.g.
late-onset congenital adrenal hyperplasia) are excluded.
Phenotype: Premature pubarche (pubic hair before the age of 8 years) and premature axillary hair,
and sweating before the age of 8 years; none or slight acceleration of growth and of bone age. No
other sex characteristics. There may be an increased prevalence of functional ovarian hyperandrogenism in mid-teenage years. Pubertal or adult levels of DHEA (S).
12
13
14
Adolescent gynaecomastia
Phenotype: Breast development in pubertal boys. E2, T, LH and FSH in early to mid-pubertal range.
By increasing T levels, the gynaecomastia usually disappears.
Comment: Galactorrhoea is extremely rare in adolescents with gynaecomastia.
15
Hirsutism
Phenotype: Excessive growth of terminal hair on the face and body of a woman in a typical male
pattern distribution. Assessment of the amount, distribution, and severity of hirsutism is by the
method of Ferriman-Gallwey.
Disorders of Puberty
19
Comment: Causes include: (1) excess androgen production by the ovary and/or the adrenal; (2) rise
in the level of biologically active free androgen, and/or (3) increased sensitivity of the hair follicle
to androgens.
Reference: Ferriman D, Gallwey JD: J Clin Endocrinol Metab 1961;21:14401447.
16
17
20
4A
OMIM
ICD 10
D I SO R D E R S O F S E X
DEVE LO PM E NT (DSD) 1
SEX CHROMOSOME DISORDERS OF SEX
DEVELOPMENT
Excluded: Disorders of gonadal differentiation that do not result
in sex reversal/virilised female infant/undervirilised male such as:
Klinefelter syndrome (14A.3)
Turner syndrome (14A.5)
46 XX gonadal agenesis/dysgenesis (10A.1b/c).
For later onset virilisation see contrasexual pubertal development
(3C)
4A.0
4A.1
Q97.8
4A.2
Q99.0
4A.8
Q99.8
(female
phenotype)
or Q98.8
(male
phenotype)
21
OMIM
ICD 10
+306100
Q97.3
4 6 , X Y D I S O R D E R S O F S E X D E V E L O P M E N T4
Excluded: Hypospadias (9E.1) or cryptorchidism (9B) without clear
underlying endocrine etiology, and Leydig cell hypoplasia if not
leading to a DSD (9A.1b)
4B.0
4B.1
4B.1a
4B.1a.1
*607102
#136680
#194080
4B.1a.2
4B.1a.3
4B.1a.4
4B.1a.5
4B.1a.6
4B.1a.7
4B.1a.8
4B.1a.9
4B.1a.10
4B.1a.88
4B.1a.99
4B.1b
4B.1c
4B.1d
4B.2
4B.2a
4B.2b
4B.2b.1
4B.2b.2
SF1
SRY
SOX-9 (campomelic dysplasia)
DHH
ATRX
ARX
DMRT1
DAX1
WNT4
Other specified causes
Other causes, unspecified
Partial gonadal dysgenesis
Gonadal regression
Ovotesticular DSD (includes 46,XY true hermaphroditism)
Disorders in androgen synthesis or action
Disorders classified elsewhere:
Enzyme defects affecting synthesis of both corticosteroids and
testosterone are primarily classified under congenital adrenal
hyperplasia (8A.1):
Lipoid CAH (cholesterol side chain cleavage deficiency, P450scc)
(8A.1a)
3beta-Hydroxysteroid dehydrogenase deficiency (8A.1b)
17alpha-Hydroxylase and 17/20 lyase deficiency (P450c17) (8A.1f)
P450 oxidoreductase deficiency (8A.1g)
Smith-Lemli-Opitz syndrome (14B.33)
Androgen biosynthesis defect
17-Hydroxysteroid dehydrogenase III deficiency6
5-Reductase deficiency7
+184757
*480000
*608160
*605423
*300032
*300382
*602424
#300018
*603490
Q99.1
Q99.1
#235600
Q99.1
E29.1
#264300
E34.5
*184753
E34.5
22
4B.3
4B.3a
4B.3b
OMIM
ICD 10
E29.1
#261550
Q56.1
*600957
Q56.1
*600956
Q56.1
E34.5
4B.4
Q56.1
4B.8
E29.8
4B.9
Idiopathic
E29.9
4C
4 6 , X X D I S O R D E R S O F S E X D E V E L O P M E N T 12
Excluded: Gonadal dysgenesis (10E.1)
4C.0
4C.1
4C.1a
4C.1b
4C.1b.1
4C.1b.2
Q99.1
278850
Q99.1
*480000
*608160
23
OMIM
ICD 10
#201750
E25.8
4C.2c.5
Androgen excess
Virilisation due to androgen production by the foetus and/or
placenta
Disorders classified elsewhere:
3beta-Hydroxysteroid dehydrogenase deficiency (8A.1b)
21-Hydroxylase deficiency (P450c21) (8A.1c)
11beta-Hydroxylase deficiency (8A.1d)
Glucocorticoid receptor defect (8A.1h)
Foetoplacental (P450-aromatase deficiency16, P450
oxidoreductase deficiency)
Maternal
Iatrogenic (specify agent)
Virilising ovarian tumour
Virilising luteoma of pregnancy
Virilising adrenal tumour
Congenital virilising adrenal hyperplasia in mother
4C.8
E25.0
4C.9
E25.0
4D
4D.1
4C.2
4C.2a
4C.2b
4C.2c
4C.2c.1
4C.2c.2
4C.2c.3
4C.2c.4
4D.1a
4D.1b
E25.0
D39.1
D27
D35.0
E25.0
Q56.4
General commentary
The LWPES/ESPE Consensus Group proposed the term Disorders of sex development (DSD), as dened by congenital conditions in which development of chromosomal, gonadal, or anatomical sex
is atypical.
Synonyms: Previously used terms: intersex disorders, genital abnormalities [Hughes IA, et al: Arch
Dis Child 2006;91:554].
24
Comments: The term MGD can be used when the above chromosomal mosaicism (or, in rare cases,
45,X/46,XY/47,XYY) is found, even if gonadal dysgenesis has not been proven anatomically.
3
Ovotesticular DSD
Synonym: This condition was previously called true hermaphrodite.
Phenotype: Baby born with ambiguous genitalia. Hypospadias, undescended testes/clitoromegaly, labial fusion. Both testicular and ovarian tissues identied in the gonads. T variable, FSH (+/N),
LH (+/N).
46,XY DSD
Synonyms: Was previously called male pseudohermaphrodite, or undervirilisation of an XY male,
or undermasculinisation of an XY male.
Phenotype: Incomplete maculinisation, hypospadias, cryptorchidism, bid scrotum.
Comments: The diagnosis incomplete masculinisation is really a symptom that may be caused by
several dierent diseases. There is no sharp line between 46,XY DSD and hypospadias. Generally,
the former term is used when at any time there has been uncertainty about the sex of rearing.
5alpha-Reductase deciency
Phenotype: Ambiguous genitalia or micropenis in XY individuals. Partial androgenisation at puberty. Defective intrauterine virilisation of male external genitalia. T (+), DHT (), possibly revealed
after hCG stimulation. T to DHT ratio (+).
25
10
11
12
46,XX DSD
Synonym: Was previously called female pseudohermaphrodite, or overvirilisation of an XX female,
or masculinisation of an XX female.
13
14
SRY+
Phenotype: External genitalia male or ambiguous. Testis or ovotestis. No Mllerian structures.
Comment: Translocation of SRY.
15
dup SOX9
Phenotype: External genitalia male or ambiguous.
16 P450-aromatase deciency
26
OVE RWE I G HT AN D O B E S IT Y
5A
S I M P L E O B E S I T Y, C O M M O N O B E S I T Y 1
5A.1
5A.1b
5A.2
5B
GENETIC CAUSES
5B.1
5A.1a
5B.1a
5B.1b
5B.1c
5B.1d
5B.1e
5B.1y
5B.2
5B.2a
5B.2y
5B.2z
5B.3
5B.3a
5B.3y
5B.3z
OMIM
ICD10
E66
E66.0
*601665
E66.8
E66.8
*164160
*601007
#609734
#600955
*155541
*601665
E66.8
E66.9
E66.8
E66.9
27
ENDOCRINE DISORDERS
5C.0
5C.8
5D
5D.0
OMIM
ICD10
E66.8
T90
G97.9
D33
G09
G99
5D.8
5E
O B E S I T Y A C C O M P A N Y I N G I M M O B I L I T Y,
M E N TA L D I S T U R B A N C E S , S O C I A L A N D
C U LT U R A L P R E S S U R E
5E.1
Muscular dystrophy6
#310200
G71.0
5E.2
and other
#182940
Q05
5E.3
T88
5E.4
Mental retardation9
F7079
5E.5
F50.2
5E.8
E66.8
5E.9
E66.9
E66.8
28
I AT R O G E N I C O B E S I T Y D U E T O M E D I C AT I O N
5F.1
Corticosteroids11
5F.2
Sodium valproate12
5F.3
Insulin13
5F.4
Phenothiazine tricyclate14
5F.5
Cyproheptadine15
5F.8
OMIM
ICD10
E66.1
Obesity
Synonyms: Severe overweight, fatness.
Phenotype: Obesity is an excessive storage of body fat, relative to lean body mass. As a criterion
various parameters such as a body mass index or weight-for-height and dierent cut-o limits (e.g.
>P95) are used. A disadvantage of using percentiles of current growth studies is that cut-o levels are
changing along with the world-wide trend toward obesity. Therefore, a time- and place-independent cut-o limit has been proposed for obesity, dened as the SDS level that ends at a BMI of 30 at 18
years of age. A similar line is drawn for overweight, ending at a BMI of 25 at 18 years of age [Cole TJ, et
al: BMJ 2000;320:1240]. Obese children are frequently taller than their age- and sex-matched peers.
Bone age is usually advanced and puberty may occur earlier. Alterations in endocrine functions
are thought to be consequences of the obese state: leptin (+), insulin (+), insulin resistance, glucagon (), growth hormone (), cortisol (N), cortisol secretion rate (N/), DHEAS (+), epinephrine and
norepinephrine (N/+), IGF-I (N/+), PRL (basal (+), after stimulation ()).
29
Comments: Mutations of POMC gene on chromosome 2p22. Heterozygote condition and POMC
polymorphisms show association with obesity.
5
Muscular dystrophy
Phenenotype: Duchenne muscular dystrophy is often associated with obesity due to reduction in
physical activity. Therapeutic trials with corticoids may aggravate the situation.
Myelomeningocele
Phenotype: Risk of developing obesity by hypoactivity, subnormal tness and reduced dynamic
activities, especially in non-ambulant individuals.
Mental retardation
Phenotype: Obesity may be due to hypothalamic dysfunction or lack of understanding adequate
food ingestion. Mental retardation may aggravate the situation in syndromes where obesity is already a component of the disease (e.g. Prader-Willi syndrome).
10
11
Corticosteroids
Phenotype: In fat cells, corticosteroids increase lipolytic enzymes, resulting in hyperlipidaemia, hypercholesterolaemia and redistribution of fat with truncal obesity and moon facies.
12
Sodium valproate
Phenotype: Valproate treatment is associated with obesity, increased fasting insulin levels, hypertriglyceridaemia and hyperandrogenism. May interfere with insulin metabolism in the liver.
13
Insulin
Phenotype: Chronic hyperinsulinaemia is associated with obesity by increased ingestion of carbohydrates to prevent hypoglycaemia.
14 Phenothiazine tricyclate
Phenotype: Used in psychiatric diseases. Broad spectrum of side eects including weight gain.
15
Cyproheptadine
Phenotype: Increases appetite through its antiserotoninergic eect on 5-HT2 receptors in the brain.
Leptin (+).
30
SECTION 1
FUNCTIONAL CLASSIFICATION 1
6A
D E F I C I E N C I E S O F A N T E R I O R P I T U I TA R Y
HORMONES
6A.0
6A.1
ACTH deficiency
Congenital isolated ACTH deficiency2
Congenital ACTH deficiency in combination with other pituitary
deficiencies3
Acquired hypothalamic-pituitary ACTH deficiency, e.g. by longterm glucocorticoid therapy4
6A.1a
6A.1b
6A.1c
6A.2
6A.2a
6A.2a.1
TSH deficiency
Congenital isolated TSH deficiency5
Known genetic defect (TSH-beta, TRHR, TRH, other)6
OMIM
ICD10
E23.0
#201400
E03.9
E23.0
#275100
E23.0
+188545
+275120
6A.2a.2
6A.2b
6A.2b.1
6A.2b.2
6A.2c
6A.3
6A.3a
6A.3a.1
Unknown origin
Congenital TSH deficiency in combination with other pituitary
deficiencies7
Secondary (pituitary) hypothyroidism8
Tertiary (hypothalamic) hypothyroidism9
Acquired hypothalamic-pituitary hypothyroidism10
E23.0
E23.0
E23.0
E23.0
E23.0
E23.0
E23.0
+308700
E23.0
31
6A.3b
6A.3b.1
6A.3b.2
6A.3b.3
6A.3b.4
6A.3b.5
6A.3b.6
6A.3b.7
6A.3b.8
OMIM
ICD10
E23.0
E23.0
#147950
244200
610628
*138850
E23.0
*604161
E23.0
*603286
E23.0
600955
E23.0
*164160
E23.0
*601007
6A.3b.9
6A.3b.10
6A.3b.11
6A.3b.88
6A.3c
6A.3c.1
#228300
+152780
E23.0
#229070
E23.0
*608137
E23.0
E23.0
*601538
E23.0
*600577
*601802
6A.3c.2
6A.3d
6A.3z
6A.4
6A.4a
6A.4b
6A.4b.1
6A.4b.2
6A.4b.8
6A.4b.9
E23.0
E23.0
E23.0
264110
E23.0
E23.0
+173110
E23.0
*601538
E23.0
E23.0
E23.0
32
6B
O V E R P R O D U C T I O N O F A N T E R I O R P I T U I TA R Y
HORMONES
6B.0
6B.1
TSH-producing adenoma27
6B.2
Gonadotrophin-producing adenoma28
6B.3
Prolactin overproduction
Prolactinoma29
Hyperprolactinaemia of other cause (e.g. pituitary stalk lesion,
primary hypothyroidism)30
6A.3a
6A.3b
6C
6D
HY P OTHAL A M I C DYS FU N C TI O N , N OT
CLASSIFIED ELSEWHERE
6D.0
6D.8
6D.9
SECTION 2
AETIOLOGICAL CLASSIFICATION 1
6E
C O N G E N I TA L D I S O R D E R S
6E.1
6E.1a
6E.1b
OMIM
ICD10
E05.9
M8271/0
E22.1
E23.3
Q04
#182230
Q04.4
Q04.8
33
6E.2z
6F
ACQUIRED DISORDERS
6F.1
Neoplasms
Tumours of the pituitary/hypothalamic region
Craniopharyngioma38
Nonfunctional pituitary adenomas39
Other benign structures40
Isolated glioma41
Glioma as part of neurofibromatosis I (von Recklinghausens
disease, 14B.27)
Germinoma, dysgerminoma42
Leukaemia, lymphoma43
Other neoplasms, specified
Tumours outside the pituitary/hypothalamic region
Pinealoma44
Isolated glioma45
Glioma as part of neurofibromatosis I (von Recklinghausens
disease, 14B.27)
Germinoma, dysgerminoma
Medulloblastoma46
Leukaemia, lymphoma
Other specified neoplasms
6E.2
6E.2a
6E.2b
6E.2c
6E.2d
6E.2y
6F.1a
6F.1a.1
6F.1a.2
6F.1a.3
6F.1a.4
6F.1a.5
6F.1a.6
6F.1a.7
6F.1a.8
6F.1b
6F.1b.1
6F.1b.2
6F.1b.3
6F.1b.4
6F.1b.5
6F.1b.6
6F.1b.8
6F.2
6F.2a
Inflammatory/infiltrative
Langerhans cell histiocytosis47
OMIM
ICD10
Q04.8
241800
Q85.9
Q04.9
C71.9
604856
D76.0
D76.3
34
6F.2c
Neurosarcoidosis49
Lymphocytic neurohypophysitis50
Haemochromatosis51
OMIM
ICD10
#601744
#152700
6F.2d
6F.2e
6F.3
6F.3a
6F.3b
6F.3c
6F.3d
6F.4
6F.4a
6F.4b
6F.4c
6F.5
6F.5a
6F.5b
Infectious
Meningitis52
Encephalitis
Abscess of pituitary53
Congenital infection54
Traumatic injury
CNS surgery55
Head trauma56
Hypoxic injury57
Iatrogenic
Irradiation58
Drugs, e.g. chemotherapy59
6F.6c
6F.7
Idiopathic
6F.6
6F.6a
6F.6b
#181000
#602390
G00
G04, G05
G06.0
G09
G97
S06
G97.8
T66
E23.1
F50.0
Classication
Comments: Diagnoses are classied according to function and aetiology. In many cases, therefore,
two codes will be used for a patient with a CNS disorder.
35
traemia), hypothyroidism, growth retardation may occur in association with other brain malformations. ACTH (), cortisol (), TSH (), T4 (), GH ().
Comments: Mutations in transcription factors responsible for pituitary development. In PROP1 mutations evolving ACTH (and cortisol) deciency due to progressive pituitary degeneration.
4
10
11
36
Histologically immature gonads. LH (), FSH (), T (), inhibin-B (). Hypoplasia of the bulbus olfactorius in MRI. In severe forms hypoplastic genitalia.
Comments: Lack of GnRH neurones. X-linked mutations in KAL-1 gene (encodes anosmin-1, a protein
involved in olfactory and neuronal migration). Autosomal-dominant loss of function mutations in
FGFR-1 gene. Anosmia occurs in all KAL-1 mutations but only a small percentage of FGFR-1 mutations.
12
13
14
15
16
GPR54 mutation
Phenotype: Lack of pubertal development and fertility. LH (), FSH (), sex steroids ().
Comments: GPR54 is a G protein-coupled receptor gene, expressed by GnRH neurons. Autosomal
recessive. Patients respond to GnRH or Gn treatment.
17
KISS mutation
Phenotype: Lack of pubertal development, infertility.
Comment: Kisspeptins stimulate gonadotrophins by stimulating GnRH after activation of GPR54.
18
37
19
Leptin 1 mutation
Phenotype: Morbid obesity and hypogonadism. LH (), FSH (), sex steroids ().
Comments: Sympathetic system dysfunction, thyroid dysfunction, type 2 DM and immune dysfunction may occur. Increased mortality in obese subjects.
20
Isolated LH deciency
Synonym: Fertile eunuch.
Phenotype: Decreased virilisation and fertility. LH (), T ().
21
22
23
24
25
POU1F1 mutation
Phenotype: Symptoms related to congenital hypothyroidism and GH deciency. Prl deciency itself
has no clinical sequelae in children. GH (). Basal and TRH-stimulated TSH (). Prl (). Variable phenotype.
Comments: AD or AR. POU1F1 is expressed in lactotrophs, somatotrophs and thyrotrophs in which
it is involved in the transcription of the GH, Prl and TSHbeta genes.
26
PROP1 mutation
Phenotype: Short stature due to complete GH deciency, congenital hypothyroidism, hypogonadism. Evolving ACTH deciency in older patients (hyponatraemia, hypoglycaemia). Deciency of anterior pituitary hormones. Progressive shrinking of the pituitary gland. Occasional pituitary enlargement imposing as adenoma, which can resolve spontaneously.
Comments: PROP1 mutations were found in approximately 1/3 of patients with familial combined
pituitary hormone deciency; rare in sporadic cases.
38
27
TSH-producing adenoma
Phenotype: TSH- (and Prl-) producing micro- and macroadenomas cause symptoms of hyperthyroidism (and hyperprolactinaemia). TSH (+), T4 (+), Prl (+).
Comments: In most cases other pituitary hormones are involved as well. Carcinomas very rare.
28
Gonadotrophin-producing adenoma
Phenotype: Functioning adenomas exhibit mainly FSH hypersecretion and ovarian overstimulation.
FSH (+), E2 (+). Clinical symptoms of mass lesion (optic chiasm compression, deciency of other pituitary hormones) may occur. LH-secreting adenoma may cause precocious puberty. LH (+), T (+).
Comments: The majority of clinically nonfunctioning pituitary macroadenomas are of gonadotroph
origin, LH and FSH are rarely increased.
29
Prolactinoma
Phenotype: Prolactinomas may present with delayed puberty. Mostly girls aected: menstrual disorders and galactorrhoea. In large adenomas symptoms of intracranial mass lesion. Prl (+), pulsatile
secretion, variable response to TRH stimulation.
Comments: 40% of acromegalic patients have hyperprolactinaemia. The extent of Prl elevation may
discriminate between nonfunctioning macroadenoma and macroprolactinoma.
30
31
32
Other midline defects: cleft palate, central maxillary incisor syndrome, EEC syndrome
(ectodactyly-ectodermal dysplasia-clefting syndrome)
Phenotype: Developmental anomalies of the midline may aect the pituitary to a variable extent,
mostly GH deciency.
Comments: Common development of palate/Rathke pouch/pituitary. The central incisor syndrome
may be associated with holoprosencephaly and various other congenital anomalies.
33
39
34
Hamartoma
Phenotype: Precocious puberty of central type, psychomotor delay, seizures. Benign tumours composed of neurons, astrocytes and oligodendroncytes; appears attached to the tuber cinereum or the
oor of the 3rd ventricle. The tumour may express GnRH.
35
Chromosomal disorders
Phenotype: Turner syndrome, 18p deletion syndrome, XXXXY syndrome. Brain malformations and
pituitary hormone deciencies (mainly GH deciency) were found in a variable degree.
36
37
38
Craniopharyngioma
Phenotype: Symptoms depend on the relationship to the pituitary, hypothalamus or optic chiasma.
Hypopituitarism by compression of the adenohypophysis. Compression of the hypophyseal stalk
causes hyperprolactinaemia. Visual eld disturbance, intracranial pressure, headache, vomiting,
papilloedema, somnolence. After surgery virtually all patients show hypopituitarism. Derives from
remnant of Rathke pouch, supra- or intrasellar, calcications.
Comment: Approximately 10% of childhood tumours.
39
40
41
Isolated glioma
Phenotype: Brain tumours originating from neuroglia. Symptoms depend on impingement on local
structures (chiasmatic/hypothalamic area), hydrocephalus. Variable pituitary hormone decits.
42
Germinoma, dysgerminoma
Phenotype: Germinomas arise near the base of the hypothalamus and aect vasopressin axons
thereby causing neurohormonal diabetes insipidus. Can be very small (pituitary stalk thickening)
and undetectable for several years following the onset of polyuria. hCG (+), hCG in CSF, diabetes
insipidus. Dysgerminoma may produce gonadotrophins and give rise to precocious puberty.
40
43
Leukaemia, lymphoma
Phenotype: Most frequent causes of CNS-aecting malignant diseases. May aect hypothalamicpituitary axis by leukaemic inltration (leukaemic meningitis) or as a consequence of treatment.
Comments: Normal growth may be maintained despite biochemical GH deciency due to hypothalamic hyperphagia in children with hypothalamic disorder.
44
Pinealoma
Phenotype: Pineal parenchymal tumours (pineocytoma, pineoblastoma) or pure pineal germinomas (occur mainly in boys). Symptoms of mass lesion, obstructive hypertension. Melatonin has no
diagnostic signicance.
45
Isolated glioma
Phenotype: Tumours outside the hypothalamo-pituitary region may cause symptoms of mass lesion and obstructive hypertension and thereby aect pituitary hormone secretion.
46
Medulloblastoma
Phenotype: Embryonal tumour of the cerebellum, metastases into the CSF. Most common malignant brain tumour in children. Aection of the hypothalamus-pituitary axis as consequence of treatment (surgery, high dose irradiation, chemotherapy).
Comment: Mutations of genes encoding proteins involved in embryonic growth factors or mutations of growth factor receptors are frequently found.
47
48
49
Neurosarcoidosis
Phenotype: Inltrative granulomatous disease which may involve hypothalamic-pituitary area. Central diabetes insipidus, hypogonadism, GH deciency, hyperprolactinaemia. Thickening of the pituitary stalk. Dicult dierentiation from lymphocytic hypophysitis (biopsy).
50
Lymphocytic neurohypophysitis
Phenotype: Recent pregnancy or other autoimmune disease in 50% of cases, occasionally after pituitary surgery. Diuse destruction of pituitary and infundibulum. Aection of anterior and posterior pituitary hormone axis. Central diabetes insipidus, LH (), FSH (), T/E2 (), TSH (), T4 (),
ACTH (), cortisol (), GH ().
41
51
Haemochromatosis
Phenotype: May lead to pituitary inltration, deposits in pituitary cells. Idiopathic or secondary
(thalassaemia or sickle cell disease). Correlation with serum ferritin levels; MRI shows decreased signal intensity. Mainly gonadotrophic axis aected, delayed puberty. LH (), FSH (), T or E2 ().
52
Meningitis
Phenotype: Viral or bacterial meningoencephalitis can be associated with anterior and posterior
pituitary insuciency which may resolve after cure of the disease. Central diabetes insipidus is frequently seen in congenital meningitis of various aetiology.
53
Abscess of pituitary
Phenotype: Intrasellar infection presenting with headache, visual changes, fever, meningismus and
endocrine abnormalities. Imaging demonstrates pituitary mass. Correct diagnosis mostly only after
(surgical) treatment. Generally pituitary dysfunction does not recover after treatment.
54
Congenital infection
Phenotype: Prenatal rubella infection in the rst trimester causes dysmorphic stigmata (microphthalmos, microcephaly), cardiac anomalies, dystrophia, GH deciency has been described. Hypothyroidism was described in congenital immunodeciency syndromes. Neurohormonal diabetes
insipidus was found in congenital cytomegalovirus infection. GH deciency was found in Schwachmann-Diamond syndrome (pancreatic insuciency, recurrent infections, metaphyseal anomalies).
55
CNS surgery
Phenotype: Tumours in the sella or hypothalamus region are mostly associated with hypothalamic-pituitary hormone decits; after surgery decits will usually get worse, rarely recovery. Usually
multiple pituitary hormone decits. Brain surgery outside the hypothalamo-pituitary region may affect hormone production and secretion by pressure, blood circulatory disturbance or haemorrhage.
Trans-sphenoidal surgery frequently followed by SIADH (hyponatraemia, elevated vasopressin).
56
57
Hypoxic injury
Phenotype: Hypoxic brain injury, especially in the neonate, can produce irreversible tissue damage.
Predominantly diabetes insipidus as a sign of severe brain damage. Anterior pituitary hormone decits may develop with some delay.
58
Irradiation
Phenotype: Cranial irradiation for prophylaxis or treatment of leukaemic meningitis or for treatment of various brain tumours. Radiotherapy has a dose-dependent eect on hypothalamic-pituitary hormone secretion, GH secreting cells being most sensitive. Hormone decits occur years after
treatment.
Comment: May also aect cartilage plates and bone growth.
42
59
60
Anorexia nervosa
Phenotype: Amenorrhoea, weight loss, behavioural changes (fear of gaining weight, disturbance of
self-evaluation of body shape, hyperactivity, sleep disturbance). Endocrine abnormalities represent
an adaptation to starvation. LH (), FSH (), E2 (), T4 (), TSH (N), Prl (N), basal GH (+), IGF1 (). Generally in young women under age 25. Female:male ratio 9:1.
61
43
THYRO I D D I SO R D E R S
7A
HYPOTHYROIDISM1
7A.1
7A.1a
7A.1b
7A.1b.1
7A.1b.2
7A.1b.3
7A.1c
7A.1c.1
7A.1c.2
OMIM
ICD10
E03.1
#218700
E03.1
#218700
E03.1
#218700
Q89.2
E07.1
#274400
#274500
#274600
#607200
7A.1c.3
7A.1c.4
7A.1d
+188450
%274800
#218700
E07.9
#275200
7A.1y
7A.1z
7A.2b.1
7A.2b.2
7A.2b.3
7A.2b.8
7A.2b.9
7A.2c
7A.2
7A.2a
7A.2b
E00
P72.2
E03.2
P72.2
E03.2
P72.2
E03.2
P72.2
E03.2
P72.2
E03.2
P72.2
44
7A.2y
7A.2z
7A.3z
7B
H Y P E R T H Y R O I D I S M 23
7B.1
7A.3
7A.3a
7A.3b
7A.3c
7A.3d
7A.3d.1
7A.3d.2
7A.3e
7A.3f
7A.3g
7A.3y
7B.1a
7B.1b
7B.1c
7B.1d
7B.1d.1
7B.1d.2
7B.2
7B.2a
7B.2b
7B.2c
OMIM
Thyroid Disorders
ICD10
P72.2
P72.2
P72.2
%140300
E06.3
E01
E89.0
E03.2
E03.2
E03.8
E03.8
E03.9
P72.1
#609152
E05.8
E05.8
#174800
E05.8
E05.8
%140300
E05.0
45
OMIM
7B.2z
7C
GOITRE
7C.0
7C.1
Euthyroid goitre
Disorders classified elsewhere:
Non-autoimmune thyroiditis (7E.4)
Dyshormonogenetic
Iodine transport defect30
#274400
Organification defects due to an abnormality in the TPO enzyme #274500
or in the H2O2 generating system (includes Pendred syndrome)31 #274600
7B.2c.1
7B.2c.2
7B.2y
7C.1a
7C.1b
7C.1b.1
7C.1b.2
ICD10
E05.4
E05.4
E05.9
E05.9
E04
E07.1
#607200
7C.1b.3
7C.1b.4
7C.1c
+188450
%274800
#218700
E07.9
#275200
7C.1z
Iodine deficiency34
Autoimmune/Hashimotos thyroiditis with normal thyroid
function35
Drug-induced/goitrogen exposure
Nodular goitre due to cysts or haemorrhage36
Other specified disorder
Idiopathic (juvenile goitre, adolescent goitre, simple goitre)37
7D
THYROID TUMOURS
7D.1
Adenomas38
7D.2
Carcinomas
Papillary39
Follicular40
7C.1d
7C.1e
7C.1f
7C.1g
7C.1y
7D.2a
7D.2b
E01, E02
%140300
E06.3
E04.8
E04.8
E04.9
D34
C73, D44
#188550
46
OMIM
ICD10
7D.2c.2
#171400
D44.8
7D.2c.3
#162300
7D.2c.4
#155240
7D.2c
7D.2c.1
M8360/1
D44.8
M8360/1
7D.2d
7D.2y
7D.2z
7D.8
7D.9
D44
D44.0, C73
C73
D34
7E
7E.1
Sick-euthyroid syndrome
Excluded: Thyroid dysfunction in prematurity (7A.2d)
7E.2
7E.2a
7E.2b
7E.2c
7E.2d
7E.3
7E.3a
7E.3b
7E.3c
7E.4c
Non-autoimmune thyroiditis
Non-autoimmune thyroiditis due to viral or bacterial agents
Acute suppurative thyroiditis44
Subacute thyroiditis
7E.5
7E.4
7E.4a
7E.4b
Thyroid Disorders
E07.8
E07.8
+314200
+176300
+176300
E07.9
#188570
#145650
#188570
E06.0
E06.0
E06.1
47
Hypothyroidism
Phenotype: Decreased activity, dry skin and hair, excessive weight gain secondary to uid retention,
growth failure, retarded bone age. TSH (+ in primary; /N in secondary/tertiary hypothyroidism),
FT4 (), FT3 ().
Athyrosis/agenesis
Phenotype: Most pronounced form of hypothyroidism. Remnants of brotic tissue might be detectable.
Hypoplasia/hypogenesis
Phenotype: Similar as in athyrosis. Remnants of normal tissue can be visualised, but of smaller size
than normal.
Ectopy
Phenotype: Hypothyroidism usually milder than in athyrosis. Normal tissue can be visualised in an
abnormal location.
Organication defect
Phenotype: Normal or enlarged gland in ultrasound, rapid uptake of radioactive iodine, but also
rapid discharge after perchlorate administration (perchlorate discharge test).
48
Comment: Defect of iodine organication (thyroidperoxidase and H2O2 generation defects have
been identied).
10
11
12
13
Iodine deciency
Synonym: Endemic cretinism.
Phenotype: Enlarged, normal or hypoplastic thyroids, symptoms of CH varying from severe to mild.
Tg (+), urinary iodine excretion ().
Comments: Congenital hypothyroidism due to iodine deciency is common in developing countries. It is preventable by iodine prophylaxis. In some industrialised countries with lesser degrees
of iodine deciency, the incidence of congenital hypothyroidism and hyperthyrotropinaemia is increased as well.
14
15
Iodine excess
Phenotype: Enlarged or normal thyroids, symptoms of CH usually mild, however, long-term sequelae are possible. Tg (+), extremely elevated urinary iodine excretion.
Comments: Administration of large amounts of iodide, e.g. disinfectants or contrast media to the
mother or infant leads to transient suppression of thyroid function (Wol-Chaiko eect). Transient
hypothyroidism due to iodine excess is frequent in newborns and premature infants in intensive
care.
Thyroid Disorders
49
16
17
18
Iodine deciency
Phenotype: Enlarged or normal thyroids, symptoms of CH usually mild, short stature is the most
prominent feature in infants and children. Tg (+), low urinary iodine excretion.
Comment: Hypothyroidism due to iodine deciency caused by inadequate nutritional supply or
substances which inhibit iodine uptake, e.g. soy, cassava.
19
Iatrogenic
Phenotype: Absent or diminished thyroid tissue, symptoms of hypothyroidism.
Comment: Hypothyroidism following the surgical or radiotherapy treatment of hyperthyroidism,
cancer or nodular goitre.
20
Iodine excess
Phenotype: Enlarged or normal thyroid, symptoms of CH usually mild. Tg (+), extremely elevated
urinary iodine excretion.
Comment: Administration of large amounts of iodide, e.g. disinfectants or contrast media, infrequently leads to transient suppression of thyroid function in an older child (Wol-Chaiko eect).
21
Drug-induced
Phenotype: Thyroid enlarged or normally sized, mild to severe symptoms of hypothyroidism, short
stature.
Comment: Hypothyroidism due to administration of drugs which block thyroid function (perchlorate, carbimazole, methimazole) or iodine uptake (perchlorate, amiodarone) or cause autoimmune
inammation (interferon).
22
Systemic diseases
Phenotype: Hypothyroidism, storage of iron, cystin, etc., in the thyroid, usually small glands.
Comment: Hypothyroidism as a symptom of systemic disease (e.g. cystinosis, -thalassemia), usually caused by storage of non-thyroidal material or inammation in the thyroid.
50
23
Hyperthyroidism (thyrotoxicosis)
Phenotype: Rapid growth associated with restlessness, tremor, heat intolerance, diarrhea, polydipsia and poor concentration. T4 (+), FT4 (+), T3 (+), TSH (). TSH suppressed despite TRH stimulation.
24
25
26
27
G-protein mutations
Phenotype: Thyroid normally sized, rarely enlarged, normal echo pattern in ultrasound investigation, severe symptoms of hyperthyroidism, failure to thrive, tachycardia, relatively resistant to antithyroid drug treatment. T4 (+), T3 (+), TSH (), no measurable auto-antibodies.
Comment: Hyperthyroidism due to constitutively activating mutations of the G-protein signalling
pathway, sometimes combined with dysfunction of other endocrine cells, e.g. precocious pseudopuberty, hypo- or hyperparathyroidism (McCune-Albright).
28
Graves disease
Synonym: Hashitoxicosis.
Phenotype: Thyroid enlarged, abnormal echo pattern in ultrasound investigation, mild to severe
symptoms of hyperthyroidism, tachycardia, weight loss, nervousness, increased blood pressure, exophthalmos, most severe symptoms evident in thyroid storm. T4 (+), T3 (+), TSH (), measurable
stimulating auto-antibodies (anti-TSH receptor (TRab) and anti-TPO, and anti-thyroglobulin (Tg) autoantibodies).
Comment: Increased familial occurrence.
29
Thyroid Disorders
51
31
Organication defect
Phenotype: Goitre, enlarged gland in ultrasound, rapid uptake of radioactive iodine, but also rapid
discharge after perchlorate administration (perchlorate discharge test). T4 (N/), T3 (N), TSH (N/+).
Comment: Defect of iodine organication (thyroid peroxidase and H2O2 generation defects have
been identied).
32
33
34
Iodine deciency
Phenotype: Enlarged thyroid. Increased radioactive iodine uptake. There can be a cold nodule. T4
(N), TSH (N), Tg (+), urinary iodine excretion ().
Comments: Congenital cases: goitre due to iodine deciency caused by inadequate nutritional supply or substances which inhibit iodine uptake, e.g. soy, cassava. Acquired cases: goitre development
due to iodine deciency is common in many developing countries but also in some industrialised
countries with lesser degrees of iodine deciency. Possible inuence of IGF-1, the incidence of juvenile goitre ranges from 0 to 60% in correlation to iodine supply. Can be associated with nodular
goitre.
35
52
36
37
38
Adenomas
Phenotype: Thyroid not enlarged, thyroid nodule demonstrable in ultrasound. In cases with hyperthyroidism a hot nodule is found in scintigraphy, and there are mild to severe symptoms of hyperthyroidism, tachycardia, weight loss, nervousness, increased blood pressure. Thyroid function can
also be normal. Histology: single or multiple nodules without inammatory signs or lymphocytic
inltration.
Comment: Hyperthyroidism due to a hyperfunctioning thyroid nodule carrying a somatic mutation
of the TSH receptor gene or G-proteins causing constitutive activation of the thyroid cells.
39
Papillary carcinoma
Phenotype: Single or multiple nodules in ultrasound, usually representing as cold, very rarely as
warm nodules in scintigraphy, frequently early lymph node metastases, bilateral occurrence, favourable prognosis. T4 (N), TSH (N).
Comments: Most common thyroid tumour in children, relatively dierentiated due to rearrangements of ret-proto-oncogenes. More frequent after neck irradiation.
40
Follicular carcinoma
Phenotype: Single or multiple nodules in ultrasound, usually representing as cold, very rarely as
warm nodules in scintigraphy, infrequently lymph node metastases, bilateral occurrence, vascular
invasion common. T4 (N), TSH (N).
Comment: Rare, hard to distinguish from follicular adenoma. More frequent after neck irradiation.
41
Thyroid Disorders
53
42
43
44
54
AD R E NAL D ISO R D E R S
8A
8A.1
8A.1a
8A.1b
OMIM
ICD10
#201710
E25
E25.0
+201810
E25.0
*109715
8A.1c
8A.1c.1
8A.1c.2
8A.1c.3
8A.1d
8A.1e
8A.1e.1
8A.1e.2
8A.1e.3
8A.1f
8A.1g
8A.1h
8A.1z
8A.2z
8A.3
8A.2
8A.2a
8A.2a.1
8A.2a.2
8A.2b
8A.2c
8A.2d
8A.2e
8A.2f
Adrenal Disorders
+201910
E25.0
#202010
E25.0
*124080
E25.0
E25.0
E25.0
#103900
E25.0
#202110
#201750
E25.0
E25.0
+138040
E25.0
E25.9
#300200
Q89.1
#202370
E71.3
+278000
Q89.1
#202200
Q89.1
#231550
Q89.1
#264350
Q89.1
Q89.1
E27.1
55
8A.3a
8A.3b
8A.4
8A.4a
8A.4b
8A.4c
8A.4d
8A.4y
Infections
Tuberculosis21
Fungal infections22
Bacterial sepsis23
AIDS24
Other specified infections
8A.5z
8A.9
Idiopathic
8B
8A.5a
8A.5y
ICD10
Haemorrhage
Associated with meningococcal infection
(Waterhouse-Friedrichsen syndrome)25
Other specified causes26
Idiopathic
8A.5
OMIM
E27.8
A18.7, E35.1
E27.4
E27.4
E27.4
A39.1,
E35.1
E27.4
E27.4
E27.4
8C
ADRENAL EXCESS
8C.1
8C.1a
8C.1a.1
8C.1a.2
8C.1a.3
8C.1b
8C.1b.1
8C.1b.2
8C.1b.3
E24
E24.0
219090
E24.0
E24.3
E24.3
E24.8
#219080
E24.8
#160980
E24.8
E24.8
56
8C.1c.z
Adrenal carcinoma33
Glucocorticoids from other sources
Iatrogenic Cushing syndrome34
Other
8C.2
8C.3
8C.3b
Mineralocorticoid excess
Conn syndrome36
Substances with mineralocorticoid action (liquorice)37
8D
8D.1
8C.1b.4
8C.1c
8C.1c.1
8C.3a
8D.1a
8D.1b
8D.1c
8D.1z
8D.2
8D.2a
8D.2b
OMIM
ICD10
E24.8
E24.8
E24.2
E24.2
E26.0
E26.0
E26.0
A39.1, E35.1
E35.1
E35.1
E35.1
M8700/0
M9500/3
Adrenal Disorders
57
Salt-wasting 21-OHD
Phenotype: Most severe form of CAH with total deciency of enzymes of cortisol and aldosterone
biosynthesis. In female newborns masculinised external genitalia (ambiguous genitalia with clitoral
enlargement and urogenital sinus). Life-threatening salt wasting crises, Na (), K (+), cortisol (),
ACTH (+), 17OHP (+), androstenedione (+). Accelerated growth and advanced bone age, peripheral
precocious puberty, early epiphyseal closure and reduced nal height.
Comments: CYP21 gene deletion/conversion that totally ablates enzyme activity. Approximately
30% of CAH cases. Autosomal-recessive inheritance.
10
58
Phenotype: Hypertension, undervirilised genitalia in males, lack of pubertal development, salt retention. Cortisol (), ACTH (+), deoxycorticosterone (+), T (), estrogens (), renin (), K (), alkalosis.
Comment: Mutations in CYP17 gene, autosomal recessive.
12
13
14
Phenotype: Inherited neurometabolic disease associated with demyelination of the central nervous
system, adrenal insuciency, and accumulation of very long chain fatty acids in plasma and tissues.
Clinically heterogeneous disorder ranging from severe childhood cerebral form to asymptomatic
persons. Adrenomyeloneuropathy and adrenoleukodystrophy are dierent presentations of the
same single gene disorder. Frequently associated with adrenal insuciency (Addisons disease)
which may remain the only clinical expression of ALD.
Comment: Mutations in the ABCD1 gene encoding the adrenoleukodystrophy protein.
16
Adrenal Disorders
59
Phenotype: Partial end-organ resistance to glucocorticoids; variable phenotype from asymptomatic to severe hyperandrogenism (sex reversal in females), fatigue and/or mineralocorticoid excess,
hypertension. Cortisol (+), ACTH (+), mineralocorticoids (+), androgens (+).
Comment: Mutations in the glucocorticoid receptor-alpha (hGRalpha) which impair normal glucocorticoid signal transduction, familial and sporadic cases.
18 Triple A (Allgrove) syndrome
Phenotype: Severe salt loss by a defect in one of the subunits of the epithelial sodium channel
(autosomal recessive). An autosomal-dominant form is caused by a defect in the mineralocorticoid
receptor gene NR3C2.
20Autoimmune adrenalitis (Addisons disease)
Phenotype: Weakness, fatigue, weight loss, hyperpigmentation of the skin and/or mucosae, anorexia, vomiting, hypotension, hypoglycaemia. Glucocorticoid and mineralocorticoid deciency.
ACTH (+), PRA (+). May be associated with other autoimmune diseases (Hashimotos thyroiditis, coeliac disease, etc., autoimmune polyglandular diesease, Schmidt syndrome).
Comment: Adrenal autoantibodies may be transferred transplacentally from an aected mother to
the baby.
21
Tuberculosis
Phenotype: Impairment of adrenal function may occur in active tuberculosis. Also primary adrenal
tuberculosis.
Comment: Rifampicin treatment has an eect on adrenal steroid metabolism.
22
Fungal infections
Phenotype: Histoplasmosis or coccidiomycosis may cause Addisons disease.
23
Bacterial sepsis
Phenotype: Adrenal crisis may occur during an acute meningococcal, pneumococcal, streptococcal
or Haemophilus infection. Waterhouse-Friderichsen syndrome in meningococcal sepsis with meningitis: massive adrenal haemorrhage with very poor prognosis.
24 AIDS
60
Phenotype: Acute adrenal insuciency occurring with meningococcaemia. High fever, circulatory
collapse, skin haemorrhage, subcapsular adrenal haemorrage. Very high mortality.
26 Haemorrhage other specied causes
Phenotype: Adrenal haemorrhage of the newborn may occur after prolonged labour and traumatic
delivery. Acute shock, hypoglycaemia, hyponatraemia, hyperkalaemia, acidosis.
27 Glucocorticoid excess (Cushing syndrome)
Phenotype: Truncal obesity and moon facies, acne, hypertension, striae, loss of muscle mass, decreased growth velocity, emotional instability. Cortisol (+), androgens (+), estrogens (N/+), aldosterone (+), ACTH (+/N/). Elevated blood glucose, hyperlipidaemia, insulin-resistant diabetes.
Comment: Symptoms of hypercortisolism are similar whatever its cause.
28 Cushings disease (ACTH-producing pituitary adenoma)
Phenotype: See 8C.1. ACTH (+), cortisol (+), adrenal androgens (+), urinary 17-hydroxycorticosteroid (+), urinary free cortisol (+). ACTH and cortisol response to CRH stimulation and suppression
to dexamethasone indicates pituitary-dependent disease. MRI of the brain, eventually with sinus
petrosus sampling for exact localisation of the tumour. May occur as a rare manifestation of MEN1.
29 CRF excess
Phenotype: See 8C.1. ACTH (+), cortisol (+). Ectopic tumors secreting CRH (e.g. phaeochromocytoma, ganglioneuroblastoma). Most CRH-producing tumours also secrete ACTH.
30 Ectopic ACTH syndrome (EAS)
Phenotype: See 8C.1. Ectopic, nonpituitary ACTH secretion. ACTH (+), cortisol (+). Dynamic tests not
very reliable. Bilateral inferior sinus petrosus sampling shows absent central gradient. Imaging discovers 2/3 of cases. Bronchial carcinoid, neuroendocrine tumors, gastrinomas, etc. In 20% no source
of EAS detectable.
31 Multinodular adrenal hyperplasia, isolated or as part of the Carney complex.
Phenotype: Primary adrenocortical hyperplasias leading to Cushing syndrome include primary pigmented nodular adrenocortical disease and ACTH-independent macronodular adrenal hyperplasia.
Carney complex is a familial multiple endocrine neoplasia syndrome characterised by spotty skin
pigmentation, myxomas, endocrine overactivity and schwannomas. Cortisol (+), ACTH (), impaired
response to CRH stimulation and dexamethasone suppression.
Comments: Carney complex inherits autosomal dominant. Mutations in the PRKAR1A gene coding
for protein kinase A. Somatic mutations in adrenal neoplasms.
32 Adrenal adenoma
Phenotype: See 8C.1. Autonomous production of cortisol by an adrenal adenoma. Cortisol (+), adrenal androgens (+), ACTH (). No response of ACTH and cortisol to CRH stimulation and dexamethasone suppression.
Comment: Adrenal masses may be detected incidentally by imaging procedures (incidentaloma),
approximately 10% produce glucocorticoids.
Adrenal Disorders
61
33 Adrenal carcinoma
Phenotype: See 8C.1. Hormonally active tumours. Cortisol (+), ACTH ().
34 Iatrogenic Cushing syndrome
Phenotype: See 8C.1. Oral, parenteral, inhaled, topical or intra-articular administration of glucocorticoids causes Cushing syndrome in a dose-dependent manner. Adrenal suppression, osteoporosis,
growth retardation. Cortisol (+ or ), ACTH ().
35 Virilising and feminising adrenal tumours
Phenotype: Virilising tumours: peripheral precocious puberty, virilisation, accelerated growth. T (+),
cortisol (N/+). LH, FSH (N), but no response to LHRH stimulation. Diagnostic imaging. Adenoma or
carcinoma. Feminising tumours: peripheral precocious puberty, gynaecomastia in boys. E2 (+), unresponsiveness of LH and FSH to GnRH stimulation.
36 Conn syndrome (primary hyperaldosteronism)
Phenotype: Hypertension, pollakisuria, muscular weakness, tetany. Na (+), K (N/), metabolic alkalosis. Aldosterone (+), renin (). Primary aldosteronism is caused by bilateral hyperplasia in 2/3 cases
and by aldosterone-producing adenoma in 1/3. Imaging and adrenal vein sampling to distinguish
unilateral and bilateral adrenal aldosterone production.
Comment: Subtype of glucocorticoid-suppressible aldosteronism. Elevated aldosterone synthase
which increases 18-hydroxycortisol in plasma. See 8A.1e.3.
37
38 Phaeochromocytoma
Phenotype: Hypertension and ushing are found rarely. Symptoms and signs depend largely on size
and localisation of the tumour and whether it has metastasised (lymph nodes, liver, skin, bone, bone
marrow). Excretion of catecholamines (+), dopamine (+), vanillylmandelic acid (+). Localisation by
imaging procedures. High rate of spontaneous regression. Mainly in children <5 years.
Comments: Several chromosomal loci show loss of heterozygosity, indicative of a tumour suppressor
gene. Gain of the long arm of chromosome 17q is the most frequent chromosomal abnormality.
62
OMIM
ICD10
TESTI CU L AR D ISO R D E R S/
D I SO R D E R S O F M ALE G E N ITAL S
Excluded: Testicular hyperfunction/testotoxicosis (3A.2c.2)
Congenital defects with malformation of external genitalia
resulting in sexual ambiguity (4B.1, 4B.2)
9A
HYPERGONADOTROPHIC HYPOGONADISM
(primary testicular failure)
E29
9A.1
9A.1a
9A.1b
9A.1c
9A.1d
9A.1e
9A.1y
9A.1z
9A.2
E29.8
E29.8
#400042
E29.8
#300068
E34.5
273250
Q55.0
E29.8
E29.9
63
9A.2z
9B
CRYPTORCHIDISM/MALDESCENDED TESTES7
9A.2a
9A.2b
9A.2c
9A.2d
9A.2e
9A.2e.1
9A.2e.2
9A.2e.3
9A.2y
OMIM
ICD10
E29.1,
E89.5
E29.8
E29.8
E29.8
E29.1
E89.5
E89.5
E89.5
E29.1
E29.1
#219050
Q53
Q53.1
Q53.2
9B.2e
Bilateral
Suprascrotal
Inguinal
Abdominal
Ectopic
Combination of various locations
9B.3
Retractile testes
Q55.2
9B.4
Acquired cryptorchidism
(testis has definitely been in scrotum on previous examinations,
but later found to be suprascrotal or inguineal, needing treatment)
Q53.9
9C
9C.1
Orchitis
If associated with testicular failure then also give code 9A.2b
9B.1
9B.1a
9B.1b
9B.1c
9B.1d
9B.2
9B.2a
9B.2b
9B.2c
9B.2d
N45
64
Testicular torsion8
If associated with testicular failure also give code 9A.2c
9C.8
OMIM
ICD10
75
N44
S30.8
S39.9
9D
TUMOURS OF TESTES
Benign:
D29.2
Malignant:
C62
9D.1
M906M909
M859M867
9D.1a
9D.1b
9D.1b.1
9D.1b.2
9D.1b.3
9D.1b.4
9D.2
9D.2a
9D.2b
9D.2c
9D.3
9D.3a
9D.3z
Mixed tumours
Gonadoblastomas
Other mixed testicular tumours
9D.8
9E
DISORDERS OF PENIS
M9073/1
C62.9
C62.9
Hypospadias9
Glandular hypospadias
Penile hypospadias
Penoscrotal hypospadias
Q54
Q54.0
Q54.1
Q54.2
65
OMIM
ICD10
9E.1z
Other
Q54.8
9E.2
Epispadias
Q64.0
9E.3
Q43.7
9E.4
Microphallus (micropenis)10
Q55.6
9F
S C R O TA L D I S O R D E R S
9F.1
Bifid scrotum
Q55.2
9F.2
Shawl scrotum
(if part of Aarskog-Scott syndrome, use 14B.1 as [primary], and 9F.2
as [secondary])
N50.9
9G
D I SO R D E R S O F TH E E PI D I DYM I S
9G.1
Epididymitis
N45
9G.2
Spermatocele
Q55.4
9G.3
Q55.4
9H
9H.1
Varicocele
9H.9
9Y
Q55.8
9Z
O T H E R D I S O R D E R S O F T H E M A L E G E N I TA L I A ,
UNSPECIFIED
Q55.9
I86.2
66
Spermatogenic arrest
Phenotype: Infertility, small to normal sized testes in adulthood. Histology: Seminiferous tubules of
reduced diameter; arrest of spermatogenesis at spermatogonial, spermatocytic or spermatid level;
no secondary spermatids. Adulthood: FSH (+).
Phenotype: Normal or small penis. Infertility, small to normal sized testes in adulthood. Histology:
Quantitative and qualitative defect of spermatogenesis. Adulthood: FSH (N, +, ), LH (N, +), T (N, +).
4
Phenotype: Reduced fertility. Atrophy of seminiferous tubules; Leydig cells intact. Adulthood:
FSH (+).
6
Cryptorchidism/maldescended testes
Synonym: Retentio testis, undescended testes, cryptorchism.
Phenotype: Unilateral or bilateral empty scrotum.
Comment: Retractile testes are classied under the general heading of cryptorchidism, although
some may consider this as a variant of normal.
Testicular torsion
Phenotype: Painful swelling of the testis. Occlusion of blood supply to the testis.
Comment: Bilateral intrauterine torsion results in anorchia; postnatal torsion results in primary testicular failure.
Hypospadias
Phenotype: Glandular, penile or penoscrotal hypospadias.
Comment: Occurs in higher frequency in hypogonadotrophic hypogonadism.
10 Microphallus (micropenis)
Phenotype: Small but otherwise normally shaped penis, measuring less than 2 SDS (25 mm at
birth) in stretched length from the pubic bone to the tip of the glans penis. For review of anthropometric measurements, see Hughes et al. [Arch Dis Child 2006;91:554563].
67
OMIM
ICD10
10
OVAR I ES , FE MALE
R E PRODUC TIVE TR AC T AN D
B R E A STS
10A
OVARY
E28.3
10A.1
E28.3
10A.1a
10A.1b
10A.1c
10A.1c.1
10A.1c.2
10A.1c.3
10A.1c.8
600171
Q99.1
Q99.1
Q99.1
Q99.8
Q97.0
Q97.1
Q97.2
Q97.8
10A.1c.9
Q98.9
10A.1d
E89.4
10A.1z
10A.2
10A.1e
10A.1y
E28.3
*136435
E28.3
E28.3
E28.3
E28.1
68
OMIM
ICD10
#184700
E28.2
E28.2
N83.0
N83.1
N83.2
Benign:
D27
Malignant:
C56
10A.3e
Benign:
D27
Malignant:
C56
10A.3e.2
Granulosa tumour8
Other specified tumours
10B
10A.3e.1
10B.1b
10B.1c
10B.1d
10B.1y
Congenital malformations
Agenesis and aplasia of the uterus (Mllerian agenesis/MayerRokitansky-Kuster-Hauser syndrome, Mllerian-renal-cervical
spine (MURCS) syndrome)9
Congenital absence of the cervix (isolated)
Endometrial hypoplasia/aplasia
Incomplete Mllerian fusion [includes: double uterus (uterus
didelphy), half uterus (uterus unicornis), partial duplication
(uterus bicornis, Fryns syndrome), partial or complete uterine
septum (uterus septus and subseptus)]
Other specified congenital malformations of uterus and cervix
Q51
#277000
Q51.0
Q51.5
Q51.8
192050
Q51.2
Q51.4
Q51.8
Q51.6
Q51.7
Q51.1
10B.1z
Q51.9
10B.2
N85.6
10B.2a
10B.2b
N88.2
69
10B.2z
10B.3
10B.2y
OMIM
ICD10
Benign:
D25, D26
Malignant:
10B.8
10B.9
10C
D I S O R D E R S O F T H E VAG I N A AN D E X T E R N AL
F E M A L E G E N I TA L I A
C53, C54
N84.0
N84.1
10C.1y
10C.1z
10C.2
10C.2a
Congenital malformations
Vaginal agenesis (isolated)
Imperforate hymen (can be part of McKusick-Kaufman
syndrome)
Transverse vaginal septum
Labial fusion/agglutination
Congenital malformation of the clitoris
Excluded: Clitoromegaly due to endocrine causes/virilisation
(4C.2)
Other specified congenital malformations of the female external
genitalia and vagina
Congenital malformations of female external genitalia and
vagina, unspecified
Acquired disorders of the vagina and external female
genitalia
Adhaesions (vaginal, labial, vulval)
Q52
Q52.0
#236700
Q52.3
Q52.8
Q52.5
Q52.6
Q52.8
Q52.9
N89.5
N90.8
10C.2b
10C.2c
10C.2z
N90.8
S30.2
S30.2
70
OMIM
ICD10
Benign:
D28.0
D28.1
D28.7
D28.9
Malignant:
C51, C52
10C.8
10C.9
10D
10D.1
10D.2
Disorders of size
Hypoplasia/aplasia/hypomastia/micromastia
Macromastia
10D.2a
10D.2b
10D.3b
Disorders in numbers
Polythelia, polymastia
Absence of breast and nipple (athelia)
10D.4
Tumours of breasts
10D.3
10D.3a
N84.2
N84.9
N64.3
Q83.8
N62
%163700
Q83.1
113700
Q83.0
Benign:
D24
Malignant:
C50
10D.8
N60, N61
N63
N64.8
Q83.2
Q83.3
Q83.8
10D.9
N64.9
Q83.9
71
72
ESPE Code
Diagnosis
OMIM
ICD10
11
D ISO R D E R S O F G LUCOSE
AN D TR I G LYCE R I D E
M E TABO LISM
11A
DIABETES ME LLITUS1
11A.1
+222100
E10
11A.1a
11A.1b
11A.2
#125853
E11
11A.3
11A.3a
11A.3a.1
11A.3a.2
11A.3a.3
11A.3a.4
11A.3a.5
11A.3a.6
11A.3a.7
11A.3a.8
11A.3b
11A.3b.1
11A.3b.2
11A.3b.3
11A.3b.4
11A.3b.5
11A.3c
11A.3c.1
11A.3c.2
11A.3c.3
11A.3c.4
11A.3c.5
11A.3c.6
11A.3c.7
#606391
#600496
#125851
#125850
#606392
*142410
#600394
#500002
*147670
#246200
#262190
#269700
#269700
#151660
*147670
#219700
+235200
#608189
73
ESPE Code
Diagnosis
11A.3c.9
11A.3d
11A.3d.1
11A.3d.2
11A.3d.3
11A.3d.4
11A.3d.5
11A.3d.6
11A.3d.7
11A.3d.8
11A.3d.9
11A.3e
11A.3e.1
11A.3e.2
11A.3e.3
11A.3e.4
11A.3e.5
11A.3e.6
11A.3e.7
11A.3e.8
11A.3e.9
11A.3e.10
11A.3e.11
11A.3f
11A.3f.1
11A.3f.2
11A.3f.3
11A.3g
11A.3g.1
11A.3g.2
11A.3g.3
11A.3h
11A.3h.1
11A.3h.2
11A.3h.3
11A.3h.4
OMIM
ICD10
#102200
+131100
#171300
#275000
+131100
184850
#190685
#222300
#598500
11A.3h.5
11A.3h.6
#229300
+143100
74
ESPE Code
Diagnosis
OMIM
11A.3h.7
245800
11A.3h.8
11A.3h.11
11A.4
11A.5
11A.6
11A.7
Diabetic complications
11A.7a
11A.7d
Diabetic ketoacidosis
Diabetic nephropathy
Diabetic retinopathy
Diabetic neuropathy
11B
H Y P O G LY C A E M I A
11B.1
Hyperinsulinism
Excluded: Hyperinsulinism or impaired glucose tolerance
secondary to other conditions, e.g. simple obesity (5A), PCOS
(10A.2a)
Transient hyperinsulinism
Infant of diabetic mother12
Perinatal asphyxia
Rhesus disease
Intrauterine growth retardation
Beckwith-Wiedemann syndrome [primary 14B.5]
Idiopathic
Congenital (permanent) hyperinsulinism13
SUR1 mutations
KIR6.2 mutations
Glucokinase mutations
glutamate dehydrogenase mutations
Defects in the metabolism of fatty acids (SCHAD)
(3alpha-hydroxyacyl-CoA dehydrogenase)
Carbohydrate-deficient glycoprotein syndrome (CDG)
ICD10
#209900
11A.3h.9
11A.3h.10
11A.7b
11A.7c
11B.1a
11B.1a.1
11B.1a.2
11B.1a.3
11B.1a.4
11B.1a.5
11B.1a.9
11B.1b
11B.1b.1
11B.1b.2
11B.1b.3
11B.1b.4
11B.1b.5
11B.1b.6
#160900
#176000
#176270
#201800
E10.1
E10.2
E10.3
E10.4
P70.4
P70.1
P70.4
P70.4
P70.4
#130650
Q87.3
P70.9
E16.1
#256450
#256450
#256450
*138130
*601609
#212065
75
ESPE Code
Diagnosis
11B.1b.7
Insulinomas14
Other specified causes
Other causes, unspecified
11B.1b.8
11B.1b.9
11B.2
11B.2a
11B.2b
11B.3
11B.3a
11B.3b
11B.3c
11B.3d
11B.3e
11B.3f
11B.3g
11B.3z
11B.4
11B.4a
11B.4b
OMIM
M8151/0
E16.1
E16.1
Hormonal deficiency
Disorders classified elsewhere:
Growth hormone deficiency (1B.3)
Cortisol deficiency: primary (adrenal defect) (8A)
Secondary (ACTH deficiency) (8B and 6A.1)
Noradrenaline (epinephrine) deficiency (8D.1)
Glucagon deficiency15
Defects in hepatic glycogen release/storage (glycogen
storage diseases)
Glucose-6-phosphatase deficiency16
Glucose-6-phosphatase translocase deficiency17
Amylo 1-6 glucosidase deficiency18
Branching enzyme deficiency19
Liver phosphorylase deficiency20
Phosphorylase kinase deficiency21
Hepatic glycogen synthase deficiency22
Other defects, unspecified
Defects in gluconeogenesis
Hereditary fructose intolerance, fructose-1,6-bisphosphatase
deficiency23
Phosphoenolpyruvate carboxykinase (PEPCK) deficiency24
ICD10
E16.1
E74.0
+232200
+232400
+232400
#232500
+306000
+306000
#240600
E74.1
+229600
+261680
+261650
11B.4c
11B.4z
11B.5
11B.5a
11B.5b
11B.5c
11B.5d
11B.5e
11B.5f
11B.5g
#266150
E16.2
#201475
#201450
#201470
#609015
#212140
#255120
#255110
#608836
#600649
76
ESPE Code
Diagnosis
OMIM
11B.5h
+212138
11B.5z
11B.6
11B.6a
11B.6b
11B.6c
11B.6z
11B.7
11B.7a
ICD10
E16.2
#605911
#245050
*138571
E71.1
#606054
#251000
11B.7b
11B.7c
11B.7d
11B.7e
11B.7f
Galactosaemia33
Maple syrup disease34
3-Hydroxy 3-methylglutaryl-CoA lyase deficiency35
3-Methylcrotonyl-CoA carboxylase deficiency36
Tyrosinaemia
#230400
#248600
+246450
#210200
+276700
+276600
#276710
11B.7g
11B.7h
11B.7z
11B.8
11B.8a
11B.8b
11B.8z
11B.9
11B.9a
11B.9b
11B.9c
11B.9d
11B.9e
11B.9f
11B.9y
11B.9z
11C
#231680
#256000
Drug induced
E.g. sulphonylureas, insulin, beta-blockers, salicylates, alcohol
Ethanol toxicity38
Salicylate toxicity39
Toxicity from other sources, unspecified
E16.0
Miscellaneous causes
Idiopathic ketotic hypoglycaemia (diagnosis of exclusion)40
Infections (e.g. septicaemia, malaria)
Congenital heart disease
Fulminant hepatic failure 41
Reye syndrome42
Jamaican vomiting sickness 43
Other specified disorders
Other disorders, unspecified
E16.1
77
ESPE Code
Diagnosis
11C.1
Genetic hyperlipoproteinaemias
Familial hypercholesterolaemia (type IIa
hyperlipoproteinaemia)45
Heterozygous familial hypercholesterolaemia
Homyzygous familial hypercholesterolaemia
Familial defective apolipoprotein B-10046
Polygenic hypercholesterolaemia47
Familial combined hypercholesterolaemia (hyperlipidaemia)
(type IIa)48
Familial hypertriglyceridaemia49
11C.1a
11C.1a.1
11C.1a.2
11C.1b
11C.1c
11C.1d
11C.1e
11C.2
11C.2a
11C.2b
11C.2b.1
11C.2b.2
11C.2b.3
11C.2c
11C.2d
11C.2d.1
11C.2d.2
11C.2d.3
11C.2e
11C.3
11C.3a
11C.3b
11C.3c
11C.3d
11C.3e
11C.4
11C.4a
11C.4b
11C.4c
11C.4d
11C.4e
11C.4y
11C.4z
Disorders of apolipoproteins
Apolipoprotein A disorders: familial APOA-I deficiency and
structural APOA-I mutations50
Apolipoprotein B disorders
Abetalipoproteinaemia51
Familial hypobetalipoproteinaemia52
Chylomicron retention disease53
Apolipoprotein C disorders (apolipoprotein C-II deficiency)
(type Ib)54
Apolipoprotein E disorders
Familial dysbetalipoproteinaemia (type III
hyperlipoproteinaemia)55
Type V hyperlipoproteinaemia (HLP)56
Other apolipoprotein E disorders
Lp(a) disorders57
Other disorders of lipoprotein metabolism
Tangier disease58
Lipoprotein lipase deficiency (type Ia)59
Hepatic lipase deficiency
Familial lecithin-cholesterol acyltransferase deficiency60
Cholesterol ester transfer protein deficiency
Other disorders of lipid and cholesterol metabolism
Disorders classified elsewhere:
Smith-Lemli-Opitz syndrome (14B.33)
Cerebrotendinous xanthomatosis61
Phytosterolaemia (beta-sitosterolaemia)62
Cholesterol ester storage disease and Wolman disease
Niemann-Pick C disease
Other specified disorders
Other disorders, unspecified
OMIM
ICD10
#143890
E78.0
#144010
E78.8
E78.2
#144250
E78.0
#145750
E78.1
*107680
E78.8
+107730
E78.8
#200100
E78.6
%605019
E78.6
#246700
E78.3
#207750
E78.3
+107741
E78.1
+107741
E78.2
#144650
E78.3
+107741
E78.8
+152200
E78.8
#205400
E78.6
246650
E78.3
246650
E78.3
#245900
E78.6
#607322
E78.8
#213700
E75.5
#210250
E78.8
+278000
E75.5
#257220
E75.2
E78.8
E78.9
78
Diabetes mellitus
Comments: For this classication the most recent updated Etiologic classication of diabetes mellitus is used [American Diabetes Association: Diagnosis and classication of diabetes mellitus. Diabetes Care 2007;30(suppl 1);S4247].
Type 1 diabetes
Synonyms: Insulin-dependent diabetes mellitus (IDDM), juvenile insulin-dependent diabetes.
Phenotype: Polyuria, polydipsia, nocturia, polyphagia, weight loss, or symptoms of frank diabetic
ketoacidosis: air hunger, Kussmaul breathing, acetone on the breath, vomiting, dehydration, abdominal pain, obtundation of consciousness or coma. Loss of insulin secretion, acquired deciencies
of the secretion of some counterregulatory hormones (glucagon, adrenalin). Auto-antibodies: islet
cells (ICA), insulin (IAA), glutamate-decarboxylase (GAD II), etc.
Comment: Caused by beta-cell destruction, usually leading to absolute insulin deciency.
Type 2 diabetes
Synonyms: Type II diabetes, non-insulin-dependent diabetes mellitus (NIDDM).
Phenotype: Non-characteristic. May be suspected in obese patients, family history positive, glycosuria, no ketonuria. Many aected children are asymptomatic, some have signs of hyperglycaemia
(polyuria, polydipsia) without ketosis; the majority are overweight. Insulin insuciency and insulin
resistance (may range from predominantly insulin resistance with relative insulin deciency to predominantly secretory defect with insulin resistance). Auto-antibodies (ICA, IAA, GAD II, etc.) usually
negative.
Comments: Probably multifactorial, familial aggregation is common. Uncommon in children, most
patients are adolescents. Strongly associated with obesity of the population.
Mitochondrial diabetes
Synonym: Maternally transmitted diabetes with deafness.
Phenotype: Similar to type I or type II diabetes, deafness. Impaired insulin secretion.
Comment: Maternally transmitted trait.
79
Berardinelli syndrome
Synonyms: Congenital generalised lipodystrophy (CGL), total lipodystrophy, Lawrence-Seip syndrome, Berardinelli-Seip syndrome.
Phenotype: Lack of adipose tissue, hypertrophy of muscle. Tall stature, large hands and feet. Phallic/
clitoral hypertrophy. Elevated basal metabolic rate. Hypertrophic cardiomyopathy. Hepatomegaly
leading to cirrhosis. Acanthosis nigricans, insulin resistance, polycystic ovaries. Corneal opacities.
Hyperinsulinism with insulin resistance and hyperlipidaemia.
Cystic brosis
Phenotype: Typical symptoms of diabetes, ketoacidosis is rare. Chronic pancreatic inammation.
Insulin insuciency or deciency.
10
11
12
80
commonly than in normal infants. Increased incidence of prematurity, and congenital malformations (58%), specically sacral agenesis.
Comment: Features of IDM can be minimised if good metabolic control of diabetes mellitus can be
achieved during pregnancy.
13
Congenital hyperinsulinism
Synonyms: Nesidioblastosis, hyperinsulinaemia of infancy, neonatal hyperinsulinism.
Phenotype: Persistent hypoglycaemia usually beginning in the neonatal period, associated with
elevated/inappropriate insulin levels.
Comments: Medical therapy involves oral diazoxide and chlorothiazide (acting on KATP channel),
nifedipine (acting on calcium channel). Subcutaneous somatostatin and glucagon infusions are
helpful in acute management and can be given long term. 95% pancreatectomy is required for diffuse hyperinsulinism resistant to medical treatment, partial pancreatectomy for focal hyperinsulinism. Surgery should only be performed in designated specialist centres.
14
Insulinomas
Phenotype: Fasting hypoglycaemia, obesity.
15
Glucagon deciency
Phenotype: Symptoms of recurrent neonatal hypoglycaemia.
16
Glucose-6-phosphatase deciency
Synonyms: Glycogenosis type Ia, von Gierkes disease, glycogen storage disease type 1a (GSD Ia).
Phenotype: Hepatomegaly, hypoglycaemia and lactic acidaemia; long-term: growth failure, osteoporosis, anaemia, gout, hyperlipidaemia, insulin resistance, hepatic adenomas, renal disease, pulmonary hypertension.
17
Glucose-6-phosphatase translocase
Synonym: Glycogenosis type Ib (GSD Ib).
Phenotype: As for GSD type Ia, recurrent infections, neutropenia, impaired neutrophil function, inammatory bowel disease.
18
Amylo 1-6 glucosidase deciency (glycogenosis type IIIa and type IIIb)
Synonyms: Type IIIa: liver and muscle debrancher deciency, limit dextrinosis, Cori or Forbes disease. Type IIIb: liver debrancher deciency (GSD III).
Phenotype: Type IIIa: hepatomegaly, hypoglycaemia, growth failure, muscle weakness, cardiomyopathy, hyperlipidaemia. Type IIIb: no muscle symptoms.
19
Branching enzyme
Synonyms: Glycogen storage disease type IV, branching enzyme deciency, amylopectinosis, Andersens disease (GSD IV).
Phenotype: Failure to thrive, hepatosplenomegaly, portal hypertension, muscle weakness, cardiomyopathy, progressive stenosis, elevated transaminase levels.
81
20
21
22
23
24
25
26
27
28
82
29
Carnitine deciency
Synonym: Carnitine transport defect.
Phenotype: Cardiomyopathy, muscle weakness, fasting hypoglycaemia.
Comment: Secondary carnitine deciency occurs in many -oxidation defects.
30
31
32
33
Galactosaemia
Phenotype: Diarrhoea, vomiting, failure to thrive, cataracts, liver disease, intellectual retardation
(especially aecting speech). Ovarian failure.
Comment: Probably only causes hypoglycaemia as a complication of severe liver failure.
34
35
36
37
38
Ethanol toxicity
Phenotype: In children, alcohol can cause hypoglycaemia after relatively short fasts. Other symptoms of ethanol ingestion: confusion, vomiting, inebriation.
83
39
Salicylate toxicity
Synonym: Aspirin toxicity.
Phenotype: Hypoglycaemia can occur with overdoses or with therapeutic doses in young children
(<3 years), especially if fasting. Other symptoms of toxicity: tinnitus, vomiting, tremor, sweating,
confusion, hyperventilation.
40
41
42
Reyes syndrome
Phenotype: Vomiting; encephalopathy, seizures; hepatic dysfunction with hyperammonaemia and
coagulopathy; hypoglycaemia; preceding viral illness and/or aspirin exposure.
Comment: This is a diagnosis of exclusion, many suspected cases actually having inborn errors of
metabolism (-oxidation or urea cycle defects or organic acidaemias).
43
44
45
84
46
47
Polygenic hypercholesterolaemia
Phenotype: Cholesterol and LDL are moderately elevated, lipoprotein electrophoretic pattern usually IIa type, or IIb.
Comments: Multifactorial etiology. Occurs in 5% of the adult population.
48
49
Familial hypertriglyceridaemia
Phenotype: In the mild forms of this condition symptoms usually not evident during childhood. Environmental factors may potentiate symptoms in aected adults. Plasma triglycerides are elevated
moderately. VLDL is elevated, but cholesterol is not. Lipoprotein electrophoretic patterns of type IV
or occasionally type V. The severe form presents also in childhood, and is characterised by elevated
triglycerides, fasting chylomicronaemia, eruptive xanthomas, recurrent abdominal pain and pancreatitis, and a type V lipoprotein pattern.
Comments: Mild forms: Autosomal dominant that aects 0.20.3% of the population, associated
with mutations in the HTGS gene. Severe forms: Autosomal dominant, resulting from mutations at
the apoE gene locus that lead to defective binding with the LDL receptor and other LDL receptorrelated proteins.
50
Apolipoprotein A disorders
Phenotype: Severe coronary atherosclerosis, cutaneous and tendinous xanthomas, and corneal
clouding, low levels of HDL, normal LDL and cholesterol.
Comment: Familial apoA-I deciency is a rare autosomal-recessive disorder.
51
Abetalipoproteinaemia
Synonym: Bassen Kornzweig disease.
Phenotype: Steatorrhoea; failure to thrive; spinocerebellar ataxia, peripheral neuropathy, pigmentary retinopathy, ceroid myopathy; absent VLDL and LDL, absent apoB-48 and apoB-100 in plasma.
Comment: Due to absence of a microsomal triglyceride transfer protein (MTP) involved in the assembly, processing, or secretion of apoB-containing lipoproteins.
52
Familial hypobetalipoproteinaemia
Phenotype: Homozygotes: steatorrhoea; failure to thrive; spinocerebellar ataxia, peripheral neuropathy, pigmentary retinopathy, ceroid myopathy; absent VLDL and LDL; heterozygotes: sometimes
ataxia or pigmentary retinopathy; low LDL and cholesterol levels.
53
85
54
55
56
57
Lp(a) disorders
Comments: Lp(a), a variant of LDL, consists of an LDL-like molecule that has one or two copies of
the glycoprotein Lp(a) attached to its apoB-100. Approximately 20% of the general population have
high levels of Lp(a) that double the risk for premature atherosclerosis.
58
Tangier disease
Synonym: Familial high-density lipoprotein deciency.
Phenotype: Hyperplastic orange tonsils; splenomegaly, relapsing neuropathy; low plasma cholesterol and HDL.
59
60
61
Cerebrotendinous xanthomatosis
Phenotype: Tuberous and tendon xanthomas; dementia, ataxia, paraparesis; atherosclerosis; cataracts.
62
Sitosterolaemia
Synonym: Phytosterolaemia.
Phenotype: Tuberous and tendon xanthomas; premature coronary atherosclerosis.
86
OMIM
ICD10
12
D I SO R D E R S O F BO N E
M E TABO LISM , I N CLU D I N G
C ALCI UM/ PH OS PHATE
M E TABO LISM
12A
T R A N S I E N T H Y P O C A L C A E M I A ( N E O N AT A L )
E83.5
12A.1
Early neonatal1
Prematurity 2
Asphyxia
Infant of diabetic mother
Perinatal stress or trauma
P71.1
Late neonatal3
Disorders classified elsewhere:
Conditions classified under permanent hypocalcaemia,
hypomagnesaemia
High milk phosphate load
P71.1
12A.1a
12A.1b
12A.1c
12A.1d
12A.2
12A.2a
12A.2b
P71.0,
P71.1
12A.2h
Parenteral nutrition
Exchange transfusions
Chronic alkalosis or bicarbonate treatment
Maternal hypercalcaemia
Maternal vitamin D deficiency
Transient hypoparathyroidism
12B
PERMANENT HYPOCALCAEMIA
12B.1
12A.2c
12A.2d
12A.2e
12A.2f
12A.2g
12B.1a
12B.1b
12B.2
12B.2a
12B.2b
Hypoparathyroidism
Disorders classified elsewhere:
DiGeorge syndrome types 1 and 2 (14B.10)
Autoimmune polyglandular syndrome type 1 (APECED syndrome)
(14C.4a)
X-linked hypoparathyroidism
P71.4
#146200
+601199
E20.9
E20.8
%307700
E20.8
87
Mitochondrial disorders
Kearns-Sayre
MELAS
Pearson marrow-pancreas syndrome
tRNA-Leu mutation
Other
Hypoparathyroidism, deafness and renal anomalies (Barakat
syndrome)
Long-chain hydroxyacyl-CoA dehydrogenase deficiency (LCHAD
deficiency) [primary 11B.5d]
Other familial syndromes
Kenny-Caffey syndrome type 1
Sanjad-Sakati
Other specified syndromes
Acquired hypoparathyroidism
Parathyroid surgery
Isolated autoimmune hypoparathyroidism
Iron overload
Other specified acquired forms
Idiopathic
12B.3
PTH defects
(autosomal-dominant or autosomal-recessive familial isolated
hypoparathyroidism)
12B.4
12B.4a
12B.4z
12B.5
12B.5a
12B.5b
12B.5c
12B.5d
12B.6
12B.6a
12B.6b
12B.6c
12B.6d
Post-receptor defects
Classified elsewhere:
Pseudohypoparathyroidism type Ia (Albrights hereditary
osteodystrophy, 14B.2)
Pseudohypoparathyroidism type Ic
Pseudohypoparathyroidism type II
Pseudohypoparathyroidism with testotoxicosis
Magnesium deficiency5
Familial primary hypomagnesaemia
Familial hypomagnesaemia with hypercalciuria,
nephrocalcinosis, and severe ocular involvement
Isolated renal magnesium wasting
Hypomagnesaemia with secondary hypocalcemia
OMIM
ICD10
#530000
#540000
#557000
*590050
#146255
*600890
E20.8
#244460
#241410
E20.0
#146200
E20.8
#603233
E20.1
#103580
E20.1
%203330
E20.1
#176410
E20.1
E83.4
#248250
#248190
#154020
#602014
88
12B.7
12B.8
12B.8z
12C
RICKETS
12C.1
Calciopenic rickets
Nutritional (vitamin D deficiency)
Malabsorption
Liver disease
Anticonvulsant treatment (phenobarbital, phenytoin)
Renal osteodystrophy6
Calcium deficiency rickets7
Genetic
Vitamin D 1-hydroxylase deficiency (formerly known as
pseudo-vitamin D-deficiency rickets, vitamin D-dependent
rickets type I)
Hereditary 1,25(OH)2D-resistant rickets (formerly known as
pseudo-vitamin D-deficiency rickets type II, vitamin
D-dependent rickets type II, calcitriol-resistant rickets)
12B.8a
12B.8b
12B.8c
12B.8y
12C.1a
12C.1a.1
12C.1a.2
12C.1a.3
12C.1a.4
12C.1a.5
12C.1b
12C.1b.1
12C.1b.2
12C.2
12C.2a
12C.2b
12C.2b.1
12C.2b.2
12C.2b.3
12C.2b.4
12C.2c
12C.2d
12C.3
Phosphopenic rickets
Classified elsewhere:
McCune-Albright syndrome (14B.22)
Renal tubular disorders Fanconi renotubular syndrome (14B.13)
Familial hypophosphataemic rickets
X-linked hypophosphataemic rickets8
Autosomal-dominant hypophosphataemic rickets9
Hereditary hypophosphataemic rickets with hypercalciuria10
Hypophosphataemic nonrachitic bone disease
Tumour-induced osteomalacia11
Decreased phosphate intake12
Hypopophosphatasia
(if not associated with rickets, classify under 12E.5l)
OMIM
ICD10
#263800
N25.0
E55.0
N25.0
#264700
E83.3
#277400
E83.3
E83.3
#307800
#193100
#241530
%146350
#146300
E83.3
#241500
89
12D
OSTEOPOROSIS
12D.1
Genetic defects
Classified elsewhere:
Ehlers-Danlos syndrome (14B.11)
Marfan syndrome [primary 14B.20, other secondary 2A.2a]
12D.1a
12D.1b
OMIM
ICD10
M81.9
#166200
#166210
#166220
#166240
#259420
12D.1d
12D.2
Chromosomal defects
M82.8
12D.3
Endocrine disorders
M82.0
12D.4
Iatrogenic causes
M81.4
12D.5
Nutritional disorders
M81.3
12D.6
Chronic diseases
M82.8
12D.7
Malignancies
M82.8
12D.8
Disuse
M81.2
12D.9
M81.8
12D.10
M81.5
12E
HYPERCALCAEMIA
E83.5
12E.1
12D.1c
12E.1a
12E.1b
12E.1c
+236200
#145980
#239200
90
12E.2b
12E.2c
12E.2d
12E.2e
12E.2f
12E.2y
12E.3
12E.3a
12E.4y
12E.4
12E.4a
12E.4b
12E.5
12E.5a
12E.5b
12E.5c
12E.5d
12E.5e
12E.5f
12E.5g
12E.5h
12E.5i
12E.5j
12E.5k
12E.5l
12E.5m
12E.5y
12E.5z
OMIM
#145000
#156400
ICD10
E21
#145001
E21.0
E21.0
E21.4
E21.4
E21.4
E21.4
Q78.9
#19405
E83.5
E67.3
D86.9
E83.5
E83.5
#223000
#222900
#190685
Q90
B24
300290
#241500
E83.3
91
Magnesium deciency
Comment: Only some conditions, such as familial primary hypomagnesaemia and hypomagnesaemia with secondary hypocalcaemia, show hypocalcaemia.
92
93
10
11
12
13
94
14
15
Vitamin D intoxication
Synonym: Hypervitaminosis D.
Phenotype: Asymptomatic or symptoms of hypercalcaemia/hypercalciuria. Excessive storage of vitamin D in adipose tissue and voluntary muscle. Serum-Ca (+), P (N/+), PTH (), 25-OHD (+ if vitamin
D or 25-OHD is ingested), 1,25(OH)2D (N), urine-Ca (+).
Comment: Increased action of vitamin D metabolites on intestinal Ca absorption and Ca mobilisation from bone.
16
Immobilisation
Synonyms: Immobilisation-induced hypercalciuria, immobilisation-induced hypercalcaemia and
osteopenia.
Phenotype: Asymptomatic or symptoms related to hypercalcaemia/hypercalciuria. Osteopenia. Serum-Ca (N/+), alkaline phosphatase (N/+), PTH (N), 1,25(OH)2D (), urine-Ca (+), urine-P (+), GFR (),
metabolic alkalosis.
Comment: Uncoupling of bone cells activity for increased osteoclastic bone resorption and decreased osteoblastic bone formation.
95
13
D I SO R D E R S O F WATE R
BAL ANCE
13A
D I S O R D E R S C H A R A C T E R I S E D B Y P O LY D I P S I A
A N D P O LY U R I A
13A.1
13A.1a
13A.1a.1
13A.1a.1a
13A.1a.1b
13A.1a.2
13A.1b
13A.1b.1
13a.1b.2
13a.1b.3
13a.1b.4
13A.1c
13A.1c.1
13A.1c.2
13A.1c.3
13A.1c.4
13A.1c.9
13A.1d
13A.2
13A.2a
13A.2a.1
13A.2a.2
13A.2a.3
13A.2b
13A.2b.1
13A.2b.2
13A.2b.3
OMIM
ICD10
E23.2
#125700
#222300
#182230
%236100
N25.1
#304800
#125800
#125800
96
OMIM
ICD10
Primary polydipsia9
Psychogenic10
Dipsogenic11
Iatrogenic12
R63.1
13B
E87.0
13B.1
13B.2
Adipsic hypernatraemia13
13B.3
13B.4
13B.5
13A.3
13A.3a
13A.3b
13A.3c
13B.5a
13B.5b
13C
E87.1
13C.1
E22.2
13C.1a
13C.1b
13C.1c
13C.1d
13C.1e
13C.1f
13C.1g
13C.1h
13C.2
13C.2a
13C.2a.1
#300539
E87.1
97
OMIM
ICD10
13C.2b
13C.3
Water intoxication
E87.7
13C.4
E87.1
13C.2a.2
Holoprosencephalic syndromes
Phenotype: Etiologically heterogeneous entity which varies widely from cyclopia to almost no manifestation except perhaps a single middle incisor.
Comments: Frequency of about 1 in 16,000 live births and about 1 in 200 spontaneous abortions.
There are teratogenic causes, maternal diabetes being the most signicant, giving a 200-fold increased risk. Genetic factors are indicated by familial occurrence, the occurrence of holoprosencephaly in some mendelian genetic syndromes, and the association with non-random chromosomal aberrations. One of the genetic syndromes that includes holoprosencephaly as a feature is
98
Smith-Lemli-Opitz syndrome. Several loci for holoprosencephaly have been mapped to specic
chromosomal sites and the molecular defects in some cases of HPE have been identied. Holoprosencephaly-1 (HPE1) maps to 21q22.3, HPE2 is caused by a mutation in the SIX3 gene, HPE3 is caused
by a mutation in the sonic hedgehog gene (SHH), HPE4 is caused by a mutation in the TGIF gene,
HPE5 is caused by a mutation in the ZIC2 gene, HPE6 maps to 2q37.1, HPE7 is caused by a mutation
in the PTCH1 gene, HPE8 maps to 14q13, and HPE9 is caused by a mutation in the GLI2 gene.
6
Primary polydipsia
Synonym: Primary polyuria.
Phenotype: Excessive water drinking, resulting in decrease of plasma osmolality. Normalisation of
renal concentrating capacity by stepwise reduction of water intake. Hypernatraemia is never seen.
Therapy with dDAVP may cause water intoxication to develop rapidly.
10
Psychogenic polydipsia
Phenotype: Can occur as part of a general cognitive defect associated with schizophrenia or other
psychiatric disorder or compulsive water drinking.
11
Dipsogenic polydipsia
Phenotype: Increased water consumption is due to an increase in thirst, e.g. in diseases involving
the hypothalamus.
.
12
Iatrogenic polydipsia
Phenotype: Primary polydipsia can also be prompted by incorrect advice or incorrect understanding of advice oered by physicians, etc.
99
13
Adipsic hypernatraemia
Phenotype: Primary adipsia is usually caused by lesions in the anterior hypothalamus. The water
intake associated with a normal diet is insucient to match obligate renal, bowel, and insensible
water losses, and absent thirst can lead to hypernatraemic dehydration.
14
15
16
100
OMIM
ICD10
14
14A
CHROMOSOMAL ABNORMALITIES
(deletions or duplications of complete or half chromosomes)
14A.1
#601808
Q93.5
14A.2
#190685
Q90
14A.3
Q98.0
14A.4
Q99.9
14A.5
Q96.9
14A.6
XYY syndrome7
If associated with tall stature: also classify as 2A.1a
Q98.5
101
OMIM
ICD10
14B
C O N G E N I TA L DY S M O R P H I C S Y N D R O M E S
14B.1
Aarskog-Scott syndrome8
If associated with short stature: also classify as 1A.1a
If associated with shawl scrotum: also classify as 9F.2
100050
Q87.1
14B.2
#103580
E20.1
14B.3
Alstrm syndrome10
If associated with obesity: also classify as 5A.2a
If associated with diabetes mellitus: also classify as 11A.3h.11
#203800
Q87.8
14B.4
Bannayan-Riley-Ruvalcaba syndrome11
If associated with tall stature: also classify as 2A.3a
#153480
Q87.3
14B.5
Beckwith-Wiedemann syndrome12
If associated with tall length/stature: also classify as 2A.4a
If associated with hypoglycaemia: also classify as 11B.1a.5
#130650
Q87.3
14B.6
Bloom syndrome13
If associated with short stature: also classify as 1A.1a
#210900
Q82.8
14B.7
Carpenter syndrome14
If associated with obesity: also classify as 5B.2a
%201000
Q87.0
14B.8
Cohen syndrome15
If associated with obesity: also classify as 5B.2a
#216550
Q87.8
14B.9
#122470
Q87.1
#300590
#610759
14B.10
#188400
Q87.1
102
14B.11
Ehlers-Danlos syndrome18
If associated with osteoporosis: also classify as 12D.1a
OMIM
ICD10
#130000
Q79.6
(to 80)
#225400
%229200
%305200
14B.12
Elejalde syndrome19
If associated with tall stature: also classify as 2A.3a
200995
Q87.3
14B.13
%134600
E72.0
14B.14
Fragile X syndrome21
If associated with tall stature: also classify as 2A.3a
#300624
Q99.2
14B.15
Gitelman syndrome22
If associated with hypocalcaemia: classify as 12B.6e
#263800
14B.16
Kallmann syndrome23
Primarily classified as 6A.3a.1
If associated with tall stature: also classify as 2B.6a
+308700
14B.17
Klippel-Trenaunay-Weber syndrome24
If associated with tall stature: also classify as 2A.4a
%149000
Q87.2
14B.18
Laurence-Moon-Bardet-Biedl syndrome25
If associated with obesity: also classify as 5B.2a
If associated with hypogonadism: also classify as 9A.0
If associated with diabetes mellitus: also classify as 11A.3h.7
245800
Q87.8
14B.19
Leri-Weill dyschondrosteosis26
If associated with short stature: also classify as 1A.1a
#127300
Q77.8
14B.20
Marfan syndrome27
If associated with tall stature: also classify as 2A.2a
If associated with osteoporosis: also classify as 12D.1a
#154700
Q87.4
14B.21
Marshall-Smith syndrome28
If associated with tall stature: also classify as 2A.3a
602535
E23.0
#147950
#244200
#209900
103
OMIM
ICD10
14B.22
McCune-Albright syndrome29
#174800
If associated with tall stature: also classify as 2B.1b
If associated with pseudoprecocious puberty: also classify as 3A.2c.0
If associated with hyperthyroidism: also classify as 7B.1d.1
If associated with phosphogenic rickets: also classify as 12C.2a
Q87.1
14B.23
Nevo syndrome30
If associated with tall stature: also classify as 2A.3a
#601451
E87.3
14B.24
Noonan syndrome31
If associated with short stature: also classify as 1A.1a
If associated with hypogonadism: also classify as 9A.0
#163950
Q87.1
14B.25
Prader-Willi(-Labhart) syndrome32
If associated with short stature: also classify as 1A.1a
If associated with obesity: also classify as 5B.2a
If associated with hypogonadotrophic hypogonadism: also classify
as 6A.3d
If associated with hypothalamic-pituitary disorders: also classify as
6E.2a
If associated with diabetes mellitus: also classify as 11A.3h.10
#176270
Q87.1
14B.26
Proteus syndrome33
If associated with tall stature: also classify as 2A.4a
#176920
Q87.3
14B.27
+162200
Q85.0
14B.28
Rieger syndrome35
If associated with growth hormone deficiency: also classify as
1B.3a.0
If associated with ACTH deficiency: also classify as 6A.1
If associated with TSH deficiency: also classify as 6A.2
If associated with gonadotrophin deficiency: also classify as 6A.3d
#180500
Q87.1
14B.29
Rubinstein-Taybi syndrome36
If associated with short stature: also classify as 1A.1a
#180849
Q87.2
104
OMIM
ICD10
14B.30
Septo-optic dysplasia37
Primarily classified as 6E.1a
If associated with short stature: also classify as 1B.3a.3
If associated with diabetes insipidus: also classify as 13A.1b.1
#182230
Q04.4
14B.31
Silver-Russell syndrome38
If associated with short stature: also classify as 1A.1a
If associated with precocious or delayed puberty: also classify
according to the codes in chapter 3
%180860
Q87.1
14B.32
#312870
Q87.3
14B.33
Smith-Lemli-Opitz syndrome40
If associated with a disorder of sex development: also classify as
4B.2a
If associated with low cholesterol level: also classify as 11C.4a
#270400
Q87.1
14B.34
Sotos syndrome41
If associated with tall stature: also classify as 2A.3a
#117550
Q87.3
14B.35
#160900
G71.1
14B.36
Weaver syndrome43
If associated with tall stature: also classify as 2A.3a
#277590
Q87.3
14B.37
Williams-Beuren syndrome44
If associated with short stature: also classify as 1A.1a
If associated with hypercalcaemia: also classify as 12E.4a
#194050
Q87.1
14B.38
#222300
E10
E23.2
105
14C
N O N - DYSM O R PH I C SY N D RO M E S
14C.1
Cushing syndrome46
Primarily classified as 8C.1
If associated with short stature: also classify as 1B.5a
If associated with diabetes mellitus: also classify as 11A.3d.2
14C.2
Mauriac syndrome47
Primarily classified as 11A
If associated with short stature: also classify as 1B.5a
If associated with obesity: also classify as 5C.0
14C.3
14C.4
14C.4a
14C.4b
14C.4c
14C.4d
14C.4e
OMIM
ICD10
E24
#184700
E28.2
M35.9
#240300
M35.9
269200
M35.9
M35.9
#304790
M35.9
#601859
M35.9
106
OMIM
ICD10
%147920
M35.9
14C.4f
14C.5
14C.5a
14C.5b
14C.5c
M8360/1
M8360/1
M8360/1
107
Down syndrome
Synonyms: Trisomy 21, trisomy-21-syndrome, mongolism.
Phenotype: (1) Dysmorphic features (brachycephaly, Brusheld spots, simian crease, gap between
1st and 2nd toe, high arched palate, strabismus, broad short neck, small teeth, short broad hands,
hypoplasia of the middle phalange V); (2) psycho-motor (mental retardation, hypotonia); (3) short
stature (approximately 100%); (4) cardiac anomalies (40% atrio-ventricularis communis); (5) infertility (100%); (6) frequent obesity, leukaemia (1%), urinary tract malformations and hypothyroidism.
Comments: Trisomy of chromosome 21, additional (maternal) chromosome free or translocated
(3%) mosaicism (2%). Full clinical picture in trisomy 21p22. Mostly sporadic except for maternal
translocation. Incidence 1:650, increasing with age of mother.
XYY syndrome
Phenotype: Often no specic symptoms, sometimes behavioural problems. Adulthood: FSH (N/+),
reduced fertility. Histology: quantitatively reduced spermatogenesis.
Comment: 1/900 newborn males.
108
Aarskog-Scott syndrome
Phenotype: Short stature, hypertelorism, shawl scrotum, delayed puberty, cryptorchidism, stretchable skin.
Comment: X-linked recessive inheritance or autosomal dominant.
10
Alstrm syndrome
Phenotype: Although this disorder bears many similarities (retinitis pigmentosa, progressive nerve
deafness, obesity, and diabetes mellitus) to the Bardet-Biedl syndrome there is no mental defect,
polydactyly, or hypogonadism. The retinal lesion causes nystagmus and early loss of central vision in
contrast to loss of peripheral vision rst, as in other pigmentary retinopathies. Hypogonadotrophic
hypogonadism (FSH (), LH ()), insulin resistance (insulin (+)), acanthosis nigricans, glomerulosclerotic renal disease.
Comment: Caused by mutation in the ALMS1 gene.
11
Bannayan-Riley-Ruvalcaba syndrome
Synonyms: Bannayan-Zonana, Ruvalcaba-Myhre, Riley-Smith, Bannayan-Riley-Ruvalcaba.
Phenotype: Prenatal overgrowth with large birth weight and length. Developmental delay with hypotonia and macrocephaly with frontal bossing. Downslanting palpable ssures. Pigmented macules on penis. Mesodermal hamartomas with angiolipomas/lipomas in GI tract, cranium, bone. Lipid
storage myopathy.
Comment: Caused by mutations in the PTEN gene.
12
109
Comments: Genetic lesion probably causes imbalance between maternally imprinted IGF-2 growth
enhancer gene and paternally imprinted H19 growth suppressor gene, leading to foetal overgrowth.
Aected infants require clinical, ultrasound, and alpha-foetoprotein monitoring until growth is completed to pre-empt tumour development, particularly Wilms.
13
Bloom syndrome
Phenotype: Bloom syndrome is an autosomal-recessive disorder characterised by proportionate
pre- and postnatal growth deciency; sun-sensitive, telangiectatic, hypo- and hyperpigmented skin;
predisposition to malignancy; and chromosomal instability.
Comment: Caused by mutations in the gene encoding DNA helicase RecQ protein-like-3.
14
Carpenter syndrome
Synonym: Acrocephalopolysyndactyly.
Phenotype: Acrocephaly, peculiar facies, brachysyndactyly of the ngers, preaxial polydactyly
and syndactyly of the toes, hypogenitalism, obesity and mental retardation, short stature. LH (),
FSH ().
15
Cohen syndrome
Phenotype: Nonprogressive mild to severe psychomotor retardation, motor clumsiness, microcephaly, characteristic facial features, childhood hypotonia and joint laxity, progressive retinochoroidal
dystrophy, myopia, intermittent isolated neutropenia, and a cheerful disposition. Characteristic
facial features include high-arched or wave-shaped eyelids, a short philtrum, thick hair, and low
hairline.
Comments: Rare autosomal-recessive disorders that are overrepresented in the Finnish population.
Some patients with Cohen syndrome have mutations in the COH1 gene.
16
17
DiGeorge syndrome
Synonym: 22q11.2 deletion syndrome, hypoplasia of thymus and parathyroids, third and fourth
pharyngeal pouch syndrome, takao vcf syndrome, catch22.
Phenotype: DiGeorge syndrome (DGS) comprises hypocalcaemia arising from parathyroid hypoplasia, thymic hypoplasia, and outow tract defects of the heart. Disturbance of cervical neural crest
migration into the derivatives of the pharyngeal arches and pouches can account for the phenotype. Most cases result from a deletion of chromosome 22q11.2 (the DiGeorge syndrome chromosome region, or DGCR). Several genes are lost including the putative transcription factor TUPLE1
110
which is expressed in the appropriate distribution. This deletion may present with a variety of phenotypes: Shprintzen or velocardiofacial syndrome; conotruncal anomaly face (or Takao syndrome);
and isolated outow tract defects of the heart including tetralogy of Fallot, truncus arteriosus, and
interrupted aortic arch. A collective acronym CATCH22 has been proposed for these diering presentations. A small number of cases of DGS have defects in other chromosomes, notably 10p13.
Comments: DiGeorge syndrome is caused by a 1.5- to 3.0-Mb hemizygous deletion of chromosome
22q11.2. Haploinsuciency of the TBX1 gene in particular is responsible for most of the physical malformations. There is evidence that point mutations in the TBX1 gene can also cause the disorder.
18
Ehlers-Danlos syndrome
Phenotype: The main features of classic Ehlers-Danlos syndrome, which includes EDS I and EDS
II, are loose-jointedness and fragile, bruisable skin that heals with peculiar cigarette-paper scars.
Most persons are born prematurely due to premature rupture of foetal membranes. A spontaneous
carotid-cavernous stula and rupture of large vessels, hiatus hernia, spontaneous rupture of the
bowel, diverticula of the bowel and retinal detachment have been reported.
Comments: According to the classication used by McKusick, 11 types of EDS were distinguished.
In a later classication major and minor diagnostic criteria were dened for each type and complemented whenever possible with laboratory ndings. Six main descriptive types were substituted for
earlier types numbered with Roman numerals: classic type (EDS I and II), hypermobility type (EDS
III), vascular type (EDS IV), kyphoscoliosis type (EDS VI), arthrochalasia type (EDS VIIA and VIIB), and
dermatosparaxis type (EDS VIIC). Six other forms were listed, including a category of unspecied
forms. At least some cases of the syndrome are caused by mutation in the collagen alpha-1(V) gene
(COL5A1), the collagen alpha-2(V) gene (COL5A2), or the collagen alpha-1(I) gene (COL1A1).
19
Elejalde syndrome
Synonyms: Acrocephalopolydactylous dysplasia, acrocephalopolydactyly renal dysplasia syndrome.
Phenotype: Excessive birth weight, a swollen globular body with thick skin, apparently short limbs,
polydactyly, craniosynostosis with acrocephaly, omphalocele, and abnormal face. At autopsy abdominal organomegaly, ascites, and cystic renal dysplasia, with excessive amounts of connective
tissue and perivascular proliferation of nerve bers in many organs.
Comment: Not to be confused with Elejaldes disease (neuroectodermal melanolysosomal disease).
20
111
metabolic acidosis. Most commonly it is idiopathic, or related to genetically transmitted inborn errors of metabolism (cystinosis, fructose intolerance, galactosaemia, glycogenosis, Lowe syndrome,
tyrosinaemia, Wilsons disease), or acquired. FS may be associated with renal tubular acidosis.
21
Fragile X syndrome
Phenotype: Moderate to severe mental retardation (possibly worse with age); particularly delayed
speech development; behavioural changes; seizures. Large forehead and head (circumference
>97th centile), prominent chin, long nose and ears; increased birth weight, tall stature in childhood
but adult height tends to shortness; macro-orchidism in males (15% prepubertally, 80% by adulthood up to 120 ml); increased risk of mitral valve prolapse, aortic root dilatation and hernias; soft
skin; joint hypermobility. Testes are usually histologically and functionally normal; increased size
may be due to interstitial oedema or connective tissue; normal size penis. Generally normal gonadal
function, normal GH axis, no precocious puberty. Chromosomal analysis: Xq27 folate-sensitive fragile site in 520% of cells.
Comments: Basically inherited as an X-linked recessive disorder, i.e. a female may carry the trait and
pass it on to her sons; only 50% of obligatory female carriers demonstrate fragile sites. 1/1,000
1,500 males; 5% of autistic males; second commonest cause of mental retardation (after Down
syndrome); up to one third of female heterozygotes may show some manifestation of the disorder
(<10% of all female mild mental retardation).
22
Gitelman syndrome
Phenotype: It has been proposed that Bartter syndrome, dened generically as an autosomal-recessive disorder featuring hypokalaemic metabolic alkalosis with salt wasting, is a heterogeneous
entity with at least 2 subsets, Gitelman syndrome and true Bartter syndrome. Gitelman syndrome
refers to the numerically predominant subset of patients with hypokalaemic alkalosis in conjunction
with hypocalciuria and hypomagnesaemia, while true Bartter syndrome refers to patients with normal or hypercalciuria and typically normal magnesium levels. True Bartter patients usually present
under the age of 5 years with signs of vascular volume depletion, while Gitelman syndrome patients
typically present at older ages without overt hypovolaemia.
Comment: The Gitelman variant of Bartter syndrome is caused by mutation in the thiazide-sensitive
Na-Cl cotransporter (SLC12A3).
23
24
Klippel-Trenaunay-Weber syndrome
Phenotype: Triad of (1) cutaneous vascular naevus; (2) varicosity over trunk or limbs (usually lower)
in asymmetrical distribution; (3) hypertrophy of soft tissue and bone. Naevus formation and bone
hypertrophy do not always overlap. Occasional neurological involvement with meningocortical angiomata.
112
Comments: Somatic mutation aecting factor involved in embryonic vascular development. Usually sporadic but increased familial incidence of hemi-hypertrophy in some families.
25
Laurence-Moon-Bardet-Biedl syndrome
Synonyms: Laurence-Moon syndrome; Bardet-Biedl syndrome (it is assumed that these may be two
separate entities).
Phenotype: Retinal dystrophy (retinitis pigmentosa), polydactyly or syndactyly, increased appetite,
mental retardation, mild obesity, hypogonadism, defective pubertal development. Renal abnormalities are frequent in the Bardet-Biedl syndrome. FSH (N, ), LH (N, ), T ().
Comment: Mutations have been found in genes at the BBS1, BBS2, BBS3, BBS4, BBS5, BBS6, BBS7,
BBS8, BBS9, BBS10, BBS11, and BBS12 loci.
26
Leri-Weill dyschondrosteosis
Synonym: Leri-Weill syndrome.
Phenotype: Mesomelic (shortening of forearms and lower legs) short stature, with Madelungs deformity. Heterogeneity of the clinical expression, e.g. short fourth metacarpals, scoliosis, exostoses.
Adult height of males 156171 cm, females 135164 cm.
Comments: DNA: haploinsuciency of SHOX. A complete (homozygous) defect of SHOX causes
Langer mesomelic dwarsm. Heterozygous SHOX mutations or deletions have been described in
2.5% of short children previously labeled idiopathic short stature.
27
Marfan syndrome
Phenotype: A heritable disorder of brous connective tissue, Marfan syndrome shows striking pleiotropism and clinical variability. The cardinal features occur in 3 systems skeletal, ocular, and cardiovascular. Increased height, disproportionately long limbs and digits, anterior chest deformity,
mild to moderate joint laxity, vertebral column deformity (scoliosis and thoracic lordosis), and a
narrow, highly arched palate with crowding of the teeth are frequent skeletal features. Tall stature
with characteristic phenotype arachnodactyly, long face, high palate. Hyperextensible joints with
hypotonia, kyphoscoliosis, pes planus. Upward lens subluxation, myopia, retinal detachment. Aortic
root dilatation leading to rupture, mitral valve prolapse. Aortic histology shows swelling and fragmentation of elastic bres. Microbrillopathy with abnormal and reduced microbril production in
connective tissues.
Comments: All cases of the true Marfan syndrome appear to be due to mutation in the brillin-1
gene (FBN1) gene. Incidence: 1 in 20,000. Variable phenotype reects dierent mutations. Cardiac
ultrasonography is a useful screening test in children with unexplained tall stature/mildly marfanoid
habitus. NB: Several rare syndromes described with marfanoid habitus and other features (e.g. mental retardation, craniosynostosis, X linked inheritance).
28
Marshall-Smith syndrome
Phenotype: Prenatal onset acceleration in linear growth with failure to thrive, developmental delay,
unusual facies, including prominent forehead, shallow orbits, blue sclerae, depressed nasal bridge,
and micrognathia. Respiratory diculties causing early death from pneumonia. Radiology: accelerated skeletal maturation, broad proximal and middle, with narrow distal, phalanges. Cerebral anomalies (macrogyria, cerebral atrophy, absent corpus collosum, cerebellar hypoplasia).
113
29
30
Nevo syndrome
Phenotype: Increased growth, kyphosis, prominent forehead, volar oedema, spindle-shaped ngers, wrist drop, talipes, hyperbilirubinemia, and generalised hypotonia. Developmental delay in
some but not all cases reported. Long face, large extremities, cryptorchidism.
Comment: Mutation in the gene encoding lysyl hydroxylase (PLOD1) and is therefore allelic with, or
in the view of some identical to, the kyphoscoliotic type of Ehlers-Danlos syndrome.
31
Noonan syndrome
Phenotype: Autosomal-dominant dysmorphic syndrome characterised by Turner-like dysmorphic
features (chest deformity, a short neck with webbing or redundancy of skin, hypertelorism, epicanthic folds, ptosis, downslanting palpebral ssures, and low-set posteriorly rotated ears). Other
features include short stature (50%), cardiac malformations (typically: pulmonary artery stenosis),
deafness, motor delay, moderate mental retardation, behavioural problems, a bleeding diathesis,
visual disturbance, hearing impairment, often cryptorchidism, anorchia, testicular atrophy, defective pubertal development, decreased fertility occurrence in males and females (1:1). In adulthood
FSH (N, +), LH (N, +), T (N, ).
Comments: One form of Noonan syndrome, that which maps to 12q24.1, is due to mutations in
PTPN11, a gene encoding the nonreceptor protein tyrosine phosphatase SHP2, which contains 2 Src
homology-2 (SH2) domains. Mutations in the PTPN11 gene account for about half the patients studied. Mutations in the neurobromin gene (NF1), which is the site of mutations causing classic neurobromatosis type I, have been found in neurobromatosis-Noonan syndrome (NFNS). De novo
germline mutations of the KRAS gene have also been found in individuals with Noonan syndrome
(NS3), but account for less than 5% of Noonan syndrome cases. A form of Noonan syndrome (NS4) is
caused by mutation in the SOS1 gene. Sporadic (80%) or autosomal dominant (20%). 1:1,0002,500
livebirths.
32
114
Contiguous gene syndrome resulting from deletion of the paternal copies of the imprinted SNRPN
gene, the necdin gene, and possibly other genes.
33
Proteus syndrome
Phenotype: Hemihypertrophy/partial gigantism particularly aecting hands and feet; exostoses of
skull, ear canals, nasal bridge, alveolar ridge; macrocephaly, skull asymmetry; vascular abnormalities
(verrucous hamartomas, haemangiomas, lymphangiomas). Developmental delay in 50%. The skin
changes are papillomatous epidermal nevi.
Comments: Somatic mosaicism with alterations in genes aecting muscle dierentiation/paracrine
growth factors. Imaging studies useful in distinguishing from hemihyperplasia. A germline mutation in the tumour suppressor gene PTEN was found in 1 patient with Proteus syndrome.
34
35
Rieger syndrome
Phenotype: Hypodontia (partial anodontia), malformation of the anterior chamber of the eye (microcornea with opacity, hypoplasia of the iris, and anterior synechiae), myotonic dystrophy, anal
stenosis, characteristic facies. It has been suggested to label the combination of short stature, facial
anomalies, Rieger anomaly, midline anomalies, and enamel defects the short-FRAME syndrome.
Comments: There may be more than one genetic form of Rieger syndrome. Rieger syndrome type
1 is caused by mutations in a homeobox transcription factor gene, PITX2. Linkage studies indicated
that a second type of Rieger syndrome maps to chromosome 13q14 (RIEG2). Autosomal dominant
inheritance.
36
Rubinstein-Taybi syndrome
Phenotype: Mental retardation, broad halluces, broad thumbs, facial abnormalities, congenital or
juvenile glaucoma, persistent foetal pads of the ngers, shawl scrotum, frequent fractures, constipation, diculties in sleep and anaesthesia by easily collapsible laryngeal walls, short upper lip, pouting lower lip, high slit-like palate.
Comment: Can be caused by mutation in the gene encoding the transcriptional coactivator CREBbinding protein (CREBBP) or in the EP300 gene.
115
37
38
39
Simpson-Golabi-Behmel syndrome
Phenotype: Pre- and postnatal overgrowth with mild-to-moderate psychomotor delay. Hypotonia
with macrocephaly. Postaxial polydactyly, partial syndactyly. Macroglossia, cleft lip/palate, hypertelorism. Cardiac conduction defects. Gastro-intestinal defects. Ambiguous genitalia. Renal defects
with enlarged cystic kidneys, dysplasia, duplex systems, hydronephrosis, increased risk of embryonal
tumours. Lab: Increased maternal alphafoetoprotein. Disorder of glypican (GPC3 + 4) metabolism.
Comment: Similar to Beckwith-Wiedemann syndrome but distinguished by facial dysmorphism,
broad thumb and great toe, and polydactyly.
40
Smith-Lemli-Opitz syndrome
Phenotype: Hypospadias, failure to thrive, mental retardation, photosensitivity, abnormal sleep pattern, microcephaly, short or proximally placed thumbs, syndactyly, second-third toe syndactyly, congenital cardiac abnormalities (e.g. atrioventricular septal defect), visceral abnormalities. The typical
facial appearance (coarse facies) becomes less obvious with age. Variable phenotype of the external
genitalia. Serum 7-dehydrocholesterol level does not correlate with clinical severity.
Comments: Caused by mutations in the sterol delta-7-reductase gene (DHCR7). This syndrome is the
rst true metabolic syndrome of multiple congenital malformations. Frequency: Approximately 1 in
20,000 to 30,000 births in populations of northern and central European background.
41
42
116
3-prime untranslated region of the protein kinase gene. Disease severity varies with the number
of repeats: normal individuals have 530 repeats, mildly aected persons have 5080 repeats, and
severely aected individuals have 2,000 or more copies. Amplication is frequently observed after
parent-to-child transmission, but extreme amplications are not transmitted through the male line.
This mechanism explains genetic anticipation and the occurrence of the severe congenital form
almost exclusively in the ospring of aected women. Dystrophia myotonica-2 (DM2l) is caused by
mutation in the ZNF9 gene.
43
Weaver syndrome
Phenotype: Primordial overgrowth syndrome with prenatal and infantile growth acceleration; hypertonia and developmental delay. Camptodactyly, with thin, deep-set nails and prominent nger
tip pads. Craniofacial dysmorphism (round face, hypertelorism, long philtrum, micrognathia, large
ears, down-slanting palpebral ssures). Talipes equinovarus. Radiology: Accelerated skeletal maturation, broad distal femur and ulna.
Comment: Some patients have a mutation in the NSD1 gene.
44
Williams-Beuren syndrome
Phenotype: Supravalvular aortic stenosis, multiple peripheral pulmonary arterial stenoses, eln face,
mental and statural deciency, characteristic dental malformation, and infantile hypercalcaemia.
Comment: The disorder is a contiguous gene syndrome, autosomal-dominant inheritance. GTF2IRD1
and GTF2I are responsible for the main aspects of WBS, but other genes may also be involved (LIMK1,
RFC2, CYLN2).
45
46
47
Mauriac syndrome
Phenotype: Short stature and glycogen-loaded liver in poorly controlled diabetes mellitus.
117
48
49
50
51
52
53
118
54
55
MEN1
Synonyms: Multiple endocrine neoplasia, type Ia (MEN1a, MEN I); multiple endocrine adenomatosis
(MEA I), Wermer syndrome.
Phenotype: Autosomal-dominant disorder characterised by a high frequency of peptic ulcer disease and primary endocrine abnormalities involving the pituitary, parathyroid, and pancreas.
Comments: MEN1A is caused by a mutation in the MEN1 gene. MEN1B is caused by a mutation in
the CDKN1B gene.
56
MEN2A
Phenotype: Multiple endocrine neoplasia, type IIA, is an autosomal-dominant syndrome of multiple
endocrine neoplasms, including medullary thyroid carcinoma, phaeochromocytoma, and parathyroid adenomas.
Comment: Caused by a mutation in the RET oncogene.
57
MEN2B
Phenotype: Multiple true neuromas, phaeochromocytoma, thyroid carcinoma (medullary type),
sometimes caf-au-lait spots. The neuromas occur as pedunculated nodules on the eyelid margins,
lips and tongue. The lips are diusely hypertrophied. Features of Marfan syndrome (high arched palate, pectus excavatum, bilateral pes cavus, high patella and scoliosis), nodular goitre, pigmentation
of hands, feet and circumoral area, proximal myopathy, loose motions, and ushing attacks.
Comment: MEN2B is caused by a mutation in the RET gene.
119