Gigantism

WW de Herder, L de Graaff, and AJ van der Lely, Erasmus MC, Rotterdam, The Netherlands
ã 2016 Elsevier Inc. All rights reserved.

Etiology 1
Growth Hormone Excess 1
Growth Hormone-Releasing Hormone Excess 2
GNAS1 Gene Mutations 3
C-Type Natriuretic Peptide Overproduction 3
MEN1 Gene Mutations 3
CDKN1B Gene Mutations 3
PRKAR1A Gene Mutations 4
AIP Gene Mutations 4
X-Linked Acrogigantism 4
GHRH Excess 5
GH Excess by Somatostatin Deficiency 5
Differential Diagnosis 5
Genetic Syndromes 5
Diagnosis 7
Acromegalic Gigantism 7
Other Causes 7
Treatment 7
Interventions Aimed at Limiting Final Height Prognosis 8
High Dose Sex Steroid Administration 8
Epiphysiodesis 8
References 8

An abnormal stature, like being too tall, has always attracted the attention of the community and doctors. In 1886, the French
neurologist Pierre Marie used the term ‘acromegaly’ for the first time and gave a full description of the characteristic clinical picture
(Marie, 1886). However, he was not the first physician to give a full record of the clinical picture of acromegaly. In 1877, Henri
Henrot published an autopsy report of a patient with gigantism, in whom a large sellar tumor was found (Henrot, 1877). At the end
of the nineteenth century, the relationship between a pituitary hyperfunction-hypertrophy, or a hyperfunctioning pituitary tumor
and acromegaly was clearly established and confirmed in many investigations. Initially, it was also believed that acromegaly and
gigantism were two totally different diseases. However, Christian F. Fritsche and Theodor Albrecht Edwin Klebs in 1884, supported
by the work of Dr. Karl Langer (1872), came to a different conclusion. They concluded that, in contrast to gigantism (which they
considered a congenital disorder), acromegaly was an acquired variety of gigantism occurring after the patient had reached final
height (Fritsche & Klebs, 1884).
Robert Pershing Wadlow, who was born on 22 February 1918 in Alton, Illinois (USA), is still considered as the tallest man on
earth from the year 1937 onwards. His birth weight was 3.8 kg (8 lb, 6 oz). His final height was 2.72 m (8’ 11.1"). Wadlow’s length
and weight have been recorded at different stages of his life (Figure 1). They clearly show that he did not stop growing till his death.
Robert Wadlow died 15 July 1940 as a result of an infected ulcer caused by pressure of a brace which he had to wear because of
peroneal nerve paralysis (drop foot) (de Herder, 2005; de Herder, 2008).
It has become clear that hypersecretion of growth hormone (GH) before epiphyseal closure leads to gigantism, whereas
thereafter GH excess causes acromegaly.

Etiology

The causes of gigantism have been classified in different ways. Pathophysiological classifications are shown in Tables 1 and 2.

Growth Hormone Excess

In all patients with an increased growth velocity and progressive upward deviation from the population reference curves, GH excess
should be considered. In young children with growth hormone excess, body proportions are normal and usually the increased
growth is the only sign of gigantism. In adolescents, the typical features of acromegaly, such as thickening of the skin, enlargement
of the lower jaw, hands, and feet, coarsening of facial features, and excessive body sweating, may be present. Later, a eunuchoid

Reference Module in Biomedical Sciences http://dx.doi.org/10.1016/B978-0-12-801238-3.06081-5 1

2 Gigantism

Figure 1 Robert Pershing Wadlow (1918–1940), the tallest man on earth. (final height: 2.72 m; 8’ 11.1"). Collection W.W. de Herder.

Table 1 Causes of Gigantism

• Pituitary origin
○ Gsa gene mutation, with or without McCune-Albright syndrome
○ Pituitary adenoma due to other molecular causes
• Excess GHRH
○ Eutopic—Hypothalamic dysfunction and tumors
○ Ectopic
• Somatostatin deficiency

habitus can develop because of incomplete or absent puberty. As adenomas often secrete GH as well as prolactin, hyperprolacti-
nemia may occur, manifesting as galactorrhea. Depending on the type and expansion of the pituitary adenoma, secretion of other
pituitary hormones can be affected. Gonadotropin deficiency leads to hypogonadotropic hypogonadism and incomplete or absent
puberty. Less often, hypoadrenalism or hypothyroidism occurs. Because of compression of the optic chiasm, impaired vision and
visual field abnormalities can be presenting symptoms.

Growth Hormone-Releasing Hormone Excess

Eutopic growth hormone-releasing hormone (GHRH) excess usually results in hyperplasia of GH and prolactin-producing cells
and rarely in adenoma formation. In a case report of congenital gigantism due to GH and prolactin-producing cell hyperplasia,
high serum levels of GHRH were found. However, the lack of evidence for a hypothalamic GHRH-producing tumor was suggestive
of a congenital hypothalamic regulatory defect (Zimmerman et al., 1993). GHRH-secreting gangliocytomas within, or in close
proximity to, the sella have also been reported in conjunction with gigantism (Scheithauer et al., 1986).
Ectopic GHRH-producing neuroendocrine tumors (NETs) are rare but well-known causes of acromegaly. Thus far, only two
cases of acromegalic gigantism caused by ectopic GHRH secreting NETs have been described (Scheithauer et al., 1986).
Hereditary pituitary hyperplasia is a familial form of very early-onset gigantism with markedly elevated serum levels of GH and
prolactin, but without radiological abnormalities in the pituitary area. It has been suggested that this condition results from
retention and expansion of the GH and prolactin-producing cells, caused by paracrine or autocrine pituitary GHRH secretion
during pituitary organogenesis (Glasker et al., 2011).
 Gigantism 3

Table 2 Classification of Tall Stature

• Normal variant
○ Familial tall stature
○ Constitutional advancement of growth
• Excess or modulation of growth factors
○ IGF-1, eg, obesity
○ Insulin, eg, obesity
○ IGF-II, eg, Beckwith–Wiedemann syndrome
• Excess sex steroid production
○ Gonadotropin-dependent precocious puberty
○ Gonadotropin-independent precocious puberty
• Deficiency of factors needed to arrest linear growth
○ Hypogonadotropic hypogonadism
○ Aromatase deficiency
○ Estrogen receptor deficiency
• Deficiency of factors needed to prevent bone elongation
○ Marfan syndrome
○ Homocystinuria
• Klinefelter syndrome)
• Excess growth hormone secretion (acromegaly)
○ Pituitary tumor – somatotropinoma
○ McCune–Albright Syndrome
○ Multiple endocrine neoplasia type 1
○ Carney complex

GNAS1 Gene Mutations

McCune Albright syndrome (MIM 174800) comprises polyostotic fibrous dysplasia, café-au-lait skin pigmentation (with jagged
‘coast of Maine’ borders) and other hyperfunctional endocrinopathies.
This rare syndrome is caused by somatic activating missense mutations of GNAS1. GNAS1 is a complex gene on chromosome
20 encoding multiple proteins, of which Gsa, the alpha-subunit of the stimulatory G protein G(s), is of particular clinical interest.
Gain-of-function mutations in GNAS1 lead to constitutional activation of Gsa, causing activation of adenylate cyclase, increased
cyclic AMP formation and, finally, increased cell proliferation and secretion. Since these GNAS1 mutations occur in the post-zygotic
phase, this will result in mosaicism and, hence, a variable pattern in the variety and extent of affected tissues (Vasilev et al., 2014).
Gigantism associated with McCune-Albright syndrome results from somatotrope hyperplasia or adenoma. An activating mutation
in the Gsa encoding parts of GNAS1 in the somatotrope cells leads to constitutive activation of the Gsa protein in these cells, which
leads to GH hypersecretion (Vasilev et al., 2014).

C-Type Natriuretic Peptide Overproduction

C-type natriuretic peptide (CNP) and activation of its receptor, the natriuretic peptide receptor 2 (NPR2) are essential for long bone
growth. Excessive CNP production results in tall stature, a Marfanoid phenotype, and skeletal abnormalities. A similar phenotype
was described in a family with an activating NPR2 mutation within the guanylyl cyclase domain, whereas an activating NPR2
mutation located in the kinase homology domain was found in a giant male without skeletal deformities (Hannema et al., 2013;
Miura et al., 2012).

MEN1 Gene Mutations

The multiple endocrine neoplasia type I (MEN1, MIM 131100) syndrome is an autosomal dominant disorder characterized by
varying combinations of multiple gland parathyroid hyperplasia-adenomas, clinically functioning and non-functioning pancreatic
NETs, duodenal NETs (mostly gastrinomas), and functioning or non-functioning pituitary adenomas. Less commonly associated
tumors include lung or thymic NETs (carcinoids), lipomas, angiofibromas, thyroid adenomas, adrenocortical adenomas, angio-
myolipomas, spinal cord ependymomas and breast cancer. This disorder is caused by heterozygous mutation in the MEN1 gene
(Chandrasekharappa et al., 1997; de Herder, 2012; Thakker et al., 2012).

CDKN1B Gene Mutations

Multiple endocrine neoplasia type IV (MEN4, MIM 610755) is caused by a heterozygous mutation in the CDKN1B gene, encoding
the cyclin-dependent kinase inhibitor p27(Kip1).
4 Gigantism

MEN4, which is also referred to as MENX, is characterized by the occurrence of parathyroid and anterior pituitary tumors in
possible association with tumors of the adrenals, kidneys, and reproductive organs. A germline nonsense mutation in CDKN1B was
first reported in a patient presenting with pituitary and parathyroid tumors (Pellegata et al., 2006).

PRKAR1A Gene Mutations

Carney complex type 1 (CNC1, MIM 160980) is an autosomal dominant multiple tumor syndrome (CNC) characterized by skin
pigmentary abnormalities, myxomas, endocrine tumors or hyperfunction, and schwannomas. CNC1 is caused by mutation in the
protein kinase A regulatory subunit-1-alpha gene (PRKAR1A). In some patients with CNC1, somatotrope hyperplasia precedes
the formation of the GH-secreting tumor causing acromegaly. In contrast to acromegaly, gigantism has not yet been described in
the spectrum of CNC1 (de Herder, 2012)

AIP Gene Mutations

Germline mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene have been associated with a predisposition to
familial isolated pituitary adenomas (FIPA, MIM 102200). Recently, an AIP germline mutation was found in a family with
gigantism (Urbani et al., 2014). The skeleton of the once famous Irish giant, Charles Byrne (1761–1783, 2.31 m., 7 ft. 7 in.), is
on display in the Hunterian Museum at the Royal College of Physicians in London (Figure 2). In 2010, Harvinder S. Chahal and
co-workers identified an AIP germline mutation in dental material from this giant, which was identical to a mutation found in
4 contemporary Northern Irish families who presented with gigantism, acromegaly, or prolactinoma. They, therefore, concluded
that these persons share a common ancestor who lived about 57 to 66 generations earlier (Chahal et al., 2011).

X-Linked Acrogigantism
Recently, microduplication on chromosome Xq26.3 in samples from 13 patients with gigantism was found. These microduplica-
tions are generated during chromosome replication and contain 4 protein-coding genes. Only one of these genes, GPR101, which
encodes a G-protein-coupled receptor, was overexpressed in patients’ pituitary lesions. This pediatric disorder was named X-linked
acrogigantism (X-LAG) (Trivellin et al., 2014)

Figure 2 John Kay (1742–1826) Etching, 1784. Left to right: George Fairholme, John McGowan, Charles Byrne (1761–1783, Irish giant), Alexander
Watson, and George (‘Geordie’) Cranstoun, midget, singer and beggar. Collection W.W. de Herder.
 Gigantism 5

GHRH Excess
Eutopic growth hormone-releasing hormone (GHRH) excess usually results in GH and prolactin-producing cell hyperplasia and
rarely in adenoma formation. In a case report of congenital gigantism due to GH and prolactin-producing cell hyperplasia, high
serum levels of GHRH were found. However, no evidence for a hypothalamic GHRH-producing tumor was found, which was
suggestive for a congenital hypothalamic regulatory defect (Zimmerman et al., 1993). GHRH-secreting gangliocytomas within or in
close proximity to the sella have also been reported in conjunction with gigantism (Scheithauer et al., 1986).
Ectopic GHRH-producing NETs are rare but well-known causes of acromegaly. Thus far, only two cases of acromegalic gigantism
caused by ectopic GHRH secreting tumors have been described (Scheithauer et al., 1986).
Hereditary pituitary hyperplasia is described as a familial form of very early onset gigantism associated with abnormally high
serum levels of GH and prolactin, but absence of radiological abnormalities in the pituitary area. It has been suggested that this
condition results from embryonic pituitary maldevelopment with retention and expansion of the GH and prolactin-producing cells
caused by paracrine or autocrine pituitary GHRH secretion during pituitary development (Glasker et al., 2011).

GH Excess by Somatostatin Deficiency

A few cases have been documented in which GH excess is found in children with neurofibromatosis and optic gliomas or
astrocytomas. It has been suggested that in these cases an inhibition in the somatostatin tone had led to increased GH secretion
(Drimmie et al., 2000).

Differential Diagnosis (Table 3)

Tall stature in childhood and adolescence can be classified in 3 main groups: constitutional tall stature, primary growth disorders
and secondary growth disorders.
The most common reason for hospital referral because of tall stature is constitutional (familial) tall stature. The physical
examination is normal and the presenting height is usually within the target percentile range calculated from the parent’s heights.
An increase in height velocity may be observed until about the age of 4 years and usually will remain normal thereafter. The bone
age may be advanced and can be used for adult height prediction. The parents and child should be reassured that the growth pattern
is normal.
Obese children can also be taller than expected during childhood but their final height is usually not increased. There is an
increased predisposition to premature adrenarche, a relatively early puberty, hyperinsulinism and an advanced bone age, all of
which contribute to increased height velocity and taller stature during childhood. Early puberty results in subsequent reduced linear
growth as compared with normal weight controls finally resulting in normal adult height.

Genetic Syndromes
Klinefelter syndrome (47, XXY) is the most frequent sex chromosome-related disorder associated with tall stature. The prevalence is
approximately 1 in 500–1000 males. Usually, boys with this syndrome are not exceptionally tall in childhood, but adolescents and
adults can be tall due to increased leg length. They often have eunuchoid body proportions and relatively small testes in
combination with gonadal failure and infertility.
In Beckwith-Wiedemann syndrome (MIM 130650), birth weight and length, and postnatal growth are increased. In 30–50% of
newborns with this syndrome, hypoglycemia is reported. Adult height is often within the normal range due to advanced bone
maturation. Patients with this syndrome may also manifest with hemihypertrophy and/or macroglossia, abdominal wall defects
and renal anomalies (nephrocalcinosis, nephrolithiasis and medullary dysplasia). There is also a predisposition to embryonic

Table 3 Overgrowth syndromes associated with tall stature

• Marfan syndrome.
• Beckwith–Wiedemann syndrome.
• Sotos syndrome - MIM ID #117550.
• Weaver syndrome - MIM ID #130650.
• Marshall–Smith syndrome.
• Homocystinuria.
• Acromegaly.
• Leontiasis ossea / hyperostosis frontalis interrna.
• Elephantiasis.
• Proteus syndrome - OMIM ID #176920.
• Klinefelter syndrome.
6 Gigantism

Figure 3 Left to right: Peter Wessels, Matthew McGrory (7 ft 6 in. (228.6 cm, 17 May 1973 – 9 August 2005, movie actor, Proteus syndrome, size
29 shoes), and Georg Wessels. Collection W.W. de Herder, with courtesy of G. and P. Wessels.

malignancies, like Wilms tumor and hepatoblastoma. Beckwith-Wiedemann syndrome is caused by mutations or deletions of
imprinted genes within the chromosome 11p15.5 region.
Patients with Sotos syndrome (MIM 117550) have distinctive facial characteristics (prominent forehead, hypertelorism, down
slanting palpebral fissures, pointed chin), a large dolicephalic head, excessive growth and learning difficulties. The overgrowth is
prenatal and postnatal during the first 4 years. Hereafter, the growth is normal or height-appropriate. Patients with this syndrome
usually have disproportionately long limbs. The height velocity is increased of life and is normal or height-appropriate thereafter.
Some adults can reach an excessive height and gigantism. There may be delayed motor development, delayed speech and learning
difficulties, although up to 10% if patients have a normal intelligence. Deletions in the NSD1 gene account for the majority of cases
and there is an autosomal dominant transmission.
Proteus syndrome (MIM 176920) is a mosaic disorder with variable features including asymmetric, distorted and dispropor-
tionate overgrowth of body parts, cerebriform connective tissue nevi, epidermal nevi consisting of acanthosis and hyperkeratosis in
early life, deregulated adipose tissue including lipomas, lipohypoplasia, fatty overgrowth, and localized fat deposits, and vascular
malformations of the capillary, venous, or lymphatic types. Some patients may have intellectual disability with facial deformities.
Deep vein thrombosis is common. Many features of Proteus syndrome overlap with other overgrowth syndromes. This syndrome is
associated with mosaicism for a somatic activating mutation in the AKT1 gene (Cohen, 2014) (Figure 3).
Simpson-Golabi-Behmel syndrome type 1 (MIM 312870) is an X-linked condition characterized by pre- and postnatal
overgrowth, coarse facial features, congenital heart defects, and other congenital abnormalities. It shows phenotypic similarities
to Beckwith-Wiedemann syndrome. This syndrome is caused by mutations in the gene encoding glypican-3 (GPC3).
Weaver syndrome (MIM 277590) is also characterized by prenatal and postnatal overgrowth, typical facies (hypertelorism, large
ears, depressed nasal bridge, down slanting of palpebral fissures, broad face, dimpled chin, prominent wide philtrum, micro-
gnathy), hypo- or hypertonia, advanced skeletal maturation and deformities of the fingers (camptodactyly). Many have delayed
development and learning difficulties. This syndrome is caused by a mutation in the EZH2 gene.
Marfan syndrome (MIM 154700) is an autosomal dominant inherited disorder, in which tall stature is the most prominent
feature. Associated symptoms are arachnodactyly, joint hyperlaxity, aortic root dilatation, and lens dislocation (ectopia lentis).
A fibrillin-1 (FBN1) gene mutation is found in the majority of cases.
Homocystinuria (MIM 236200) is an autosomal recessive disorder due to mutation in the cystathionine b-synthase gene. Its
clinical features are similar to those of Marfan’s syndrome, but with associated learning difficulties, an increased predisposition to
psychiatric disorders and a tendency to thrombosis and thrombotic embolisms.
 Gigantism 7

In infants, hyperinsulinism (due to diabetes mellitus of the mother or due to nesidioblastosis), can result in overgrowth in terms
of weight and length, but this usually normalizes shortly afterwards.
Sex hormone excess, from either gonadotropin-dependent or gonadotropin-independent causes, may lead to accelerated linear
growth and tall stature. Sex hormones act on the growth plates to cause chondrocyte maturation and longitudinal bone growth.
Although children may be tall or relatively tall for family size, there is advanced skeletal maturation with premature fusion of the
epiphyses and the final height will usually be compromised in the absence of intervention.
Sex hormone deficiency or resistance leads to delayed fusion of the epiphyses with prolonged prepubertal linear growth and tall
stature in adolescence and beyond. The phenotype is characterized by long legs and low upper segment ratio (eunuchoid
proportions). Causes of sex hormone deficiency include hypogonadotrophic hypogonadism and absence of estrogen effects due
to aromatase deficiency or due to estrogen receptor a gene mutations (which are both extremely rare).

Diagnosis (Table 4)
Acromegalic Gigantism
As in acromegaly, serum GH and IGF-1 levels of patients with acromegalic gigantism are higher than age and gender references (see
chapter on acromegaly diagnosis). Adult patients with acromegalic gigantism show a paradoxical increase of GH in the oral glucose
tolerance test. However, in children and adolescents, the oral glucose tolerance test is less useful for diagnosing GH excess, as absent
GH suppression is also common in healthy tall children and adolescents. GHRH measurement can be helpful in differentiating
GHRH excess from primary GH hypersecretion.

Other Causes
In the work-up, the other pituitary hormones should also be assessed and hyperprolactinemia and gonadotropin, ACTH or TSH
deficiency can be found. Basal gonadotropins and sex hormone levels should be measured in those with an abnormal pubertal
development. Serum homocysteine levels should be measured in children with mental retardation or marfanoid features.
Bone age should be assessed, but is usually not advanced, or only slightly advanced, during childhood.
When GH excess is confirmed, magnetic resonance imaging of the sellar and perisellar areas are required for tumor localization
and extension.
The clinical evaluation will determine the subsequent investigations and an assessment by a geneticist may be merited in some
cases. As trisomy X (XXX female) and an XYY male may have tall stature as the only clinical feature, a karyotype is indicated to detect
these conditions.
If Marfan syndrome is suspected, then a cardiac assessment including echocardiography with assessment of aortic root
dimensions should be obtained and ophthalmologic examinations might be needed.

Treatment

If a GH secreting pituitary adenoma is present, transsphenoidal (endoscopic) surgery is the treatment of choice. Irradiation can
cause permanent damage to the pituitary and its surrounding tissues and is therefore not desirable in children. Primary or adjuvant
pharmacotherapy is used pre- and postoperatively and in cases of pituitary hyperplasia. Dopamine agonists (bromocriptine,
quinagolide and cabergoline) can suppress GH hypersecretion in some patients with gigantism. The response to this therapy
depends on the expression of dopamine D2 receptors on the tumor cells. In cases with pituitary hyperplasia or in cases with an
insufficient response to transsphenoidal surgery, somatostatin analogs (octreotide, lanreotide) are frequently applied. The somato-
statin receptor subtypes 2 and 5 mediate the inhibitory effect of the currently available somatostatin analogues. A new multi-target

Table 4 Investigations for tall stature (on indication)

• Karyotype.
• T4 and TSH.
• IGF-1.
• Bone age.
• If concerns about puberty consider:
○ LH, FSH, estradiol or testosterone.
○ Consider AFP, HCG in precocious puberty.
• If marfanoid features consider:
○ Plasma homocysteine.
○ DNA for FBN1 mutation.
• Store DNA if tall stature syndrome suspected.
8 Gigantism

somatostatin analog, Pasireotide, is tested in phase 3 trials. Pegvisomant is a growth hormone (GH) antagonist which interferes
with GH action by competitive binding to receptor and blocking signal transduction.

Interventions Aimed at Limiting Final Height Prognosis

Height prediction algorithms have been devised to predict final height in the otherwise healthy child. Unfortunately, the SD
associated with a given prediction is usually considerable and this tends to hamper their value. The majority of tall children will
require no intervention to limit height and an explanation and reassurance will suffice.

High Dose Sex Steroid Administration

Administration of high dose estradiol or testosterone has been used to limit final height prognosis by promoting closure of the
epiphyseal plates. However, their use has declined over the last 30 years because of side-effects during treatment and social
acceptance of taller stature (Rayner et al., 2010). Of concern is the fact that girls treated with high dose estrogen appear to have a
dose-dependent influence on fertility in adulthood with a depleted follicular pool and the development of primary ovarian
insufficiency (Hendriks et al., 2012). To date, high dose testosterone treatment has not been shown to affect male fertility in
adulthood (Hendriks et al., 2010).

Epiphysiodesis
Epiphysiodesis is a surgical intervention that destroys the growth plates around the knee (distal femur, proximal tibia and fibula),
thus preventing further longitudinal bone growth. This intervention remains controversial for the treatment of tall stature. However
it still has a role in the treatment of limb length discrepancy.

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