1

Holistic approach to developmental delay: Genetic evaluation

 
(
 
(( 
 (
  (

(


(World Health Organization)

mental retardation  
 (cognitive),
(language), ( (motor), (social) 
( 
(intelligence) (http://www.who.int/mental_health/media/en/69.pdf) 
(developmental delay)  5
 (developmental specialist)

(mental retardation) ( 5 (
 (IQ test) ( 
1 
( 
(mental retardation) (( 5 (
18
  (  
 
 2


  
(
2 32, 3 40 50
  
 4
50 
(  
 
 (
( 
  

 
( 
 ( 
 

 

1.
  
(prenatal history) (birth history)
 (family history)
2. (pedigree)
(
3 (

  

3.
 3

 
  
(


 
(microcephaly) (flat occiput) 
(( (upslanting palpebral fissures) (midface hypoplasia)
 (low set ears) (small ears)
(Down syndrome) 
(hypopigmentation) (micropenis)
(cryptorchidism) (( (brachydactyly) (
(hypotonia) Prader-Wili
4.
( 

 

 


 
(

- 
- (
-
-  (
- 
- ( (
- 

 4

-  

-
( 
 ( (

- (
- 
- (protocol) (
(  

 
 3 ( 
 

( (
  

  
(  (
X (X-linked recessive
inheritance)   
 fragile X  (

  
 (anomalies)
 
 
( (broad forehead),
(periorbital fullness), (malar flattening),
(long philtrum),  (full lips), (wide mouth), (small
widely-spaced teeth) (
 5

supravalvular aortic stenosis ( Williams (Williams

syndrome)
 
411   
  

(   
5  (prospective study) 
281 150 54 1 3
1 3
  
1 3 (6 (
 

3
1. (chromosomal analysis or cytogenetics)


(
(  mitosis
metaphase
1,000 (band)
550 1 ( (conventional
karyotyping) ((
 (translocation) 

10  6
  21
( 266 ( 8.3) ( ( 
7 (
 (
 high-resolution karyotyping 
 6

( (band) 650 1
(
 (
high-resolution karyotyping 
 9-368
FISH (fluorescence in situ hybridization) 
cytogenetics probe (hybridize)  (
 
( 
Williams, del22q11 Prader-
Wili
( FISH submicroscopic
subtelomeric rearrangements 
(  (subtelomere)
  FISH
 subtelomere
probe  subtelomere
( ( (deletion duplication) subtelomere
   
Down syndrome9, 10  7.4 
 ((
( subtelomere  FISH
( FISH (recognizable syndromes) 
(  subtelomere
 111
 1  subtelomere

5
1pter deletion (growth retardation);
(mental retardation); (seizure);
(visual problems);
(large anterior fontanelle);
 7

 (asymmetric, low-set, dysplastic ears);

( (depressed nasal bridge);
(pointed chin); ( (fifth
finger clinodactyly)
1p36.3 deletion Ebstein anomaly;

1qter deletion (microcephaly);
;  corpus
callosum; ;
(hypospadias)
22qter deletion ; (
(hypotonia); (absent speech)
cytogenetics 

  
( array-based comparative genomic hybridization (array CGH)
(
(submicroscopic copy number changes) 
(  array CGH 
( (interstitial deletions duplications)
 10-1512 ( array
CGH 

2. (molecular genetic testing)
(

  
fragile X 
13 
(microphthalmos
anophthalmos), / (cleft lip with or without cleft palate),
(hypodontia), 
 8

( (ectrodactyly), ( (syndactyly) 
linear and patchy dermal hypoplasia
Goltz (Goltz syndrome focal dermal hypoplasia) ( 
(14, 15
16
 
 free T4 free T3
 TSH  thyroglobulin thyroid peroxidase (anti-
thyroglobulin anti-thyroid peroxidase) nonautoimmune
hyperthyroidism 

 ( thyrotropin receptor
(TSHR) (
(
 8 


(
-
- (
-  (
  (support
group)  

3. (metabolic testing)
(enzymatic activity)
( (substrate) (product) 
inborn errors of metabolism  (
(
 ( (attention
deficit hyperactivity disorder) 
( 
 9

3  very long chain

fatty acid (VLCFA) C26:0 C24:0
C22:0, C26:0 C22:0   X-linked adrenoleukodystrophy (X-
ALD)17 X-ALD  X (X-
linked recessive) (  
 (
Computer Tomography (CT) Magnetic Resonance Imaging (MRI)
 brain CT
  
cerebral atrophy 
 18 MRI 
  MRI
CT19 MRI 
30 MRI
3.9 
American Academy of Neurology and Child Neurology Society 
(neuro-imaging)  
  
(microcephaly)
(abnormal focal neurologic finding) MRI
CT3 
 ( (
1.
2.
3.   
4.
5. (chromosomal analysis or karyotyping)
6. FISH  subtelomere
7. Fragile X testing
8.  (Brain imaging) MRI
9.
 10

- ( :
high-resolution (>650 bands) -
- FISH 
FISH  - FISH  subtelomere
subtelomere -
-

-
- MRI
? ?


-
-
-



- 
 
(family members at risk)
 11

  


(Down syndrome)
(Down syndrome trisomy 21) 

 21 1 800

 95  Down syndrome
 21  (trisomy 21)
3-4   21 
(translocation)  21 
(acrocentric chromosome)  14, 21  1-2
 2  
 trisomy 21 ( (mosaic)
 (
- Brachycephaly
- Epicanthal folds
- Upward slanting palpebral fissures
- Flat nasal bridge
- Small ears
- Open and small mouth
- Excessive skin at the nape of the neck
- Brachydactyly
- Broad hands
- Fifth finger clinodactyly
- Single transverse palmar crease
- Wide 1-2 toe gap
- Hypotonia
- Short stature
(
   (
 12

( 40), ( 60), ( 75), (

( 50-75), (
(obstructive sleep apnea) ( 50-75), ( 20),
( 12), (leukemia) ( 3-5) Hirschsprung (
1)20 ( 
 ( 




 
 21  (translocation)  (
  (carrier)
 (balanced
translocation)  21 
(
  
(pedigree) 
 (

 (
( (
  2
 2 ( (recurrence risk)

Trisomy 21 1 + maternal age-related risk (

 )
Translocation ( 21

 13

(acrocentric chromosome) 
14, 22)
-  10-15
-  1-2
21q21q translocation 100


(duodenal stenosis/atresia), (annular pancreas), Hirschsprung
(anal stenosis/atresia)
(duodenal atresia) 
( (
  
((
(gastroesophageal reflux, GER)
(duodenal stenosis) ( GER
duodenal stenosis 
GER  duodenal stenosis ( 
 (

( 
( (
( ( ( (overweight)
(obesity)  (
body mass index (BMI)
 (21, 22

(   
(( 

 
23 ( 

 14

 free T4
TSH 
(neonatal thyroid screen) (
 (


  (
( ( 


( (

50 
( ( conductive
sensorineural 
conductive (  ( ( ( (otitis media with
effusion)   (
 
( 3 

& (obstructive sleep apnea)

 (
 (nasopharynx) ((
(hypotonia) ( ( 
obstructive sleep apnea OSA ( 
    
(
(  
(  

 ( (early
 15

intervention)    
((

  (
(
(   
  (

(health supervision for children with Down syndrome)
American Academy of Pediatrics (AAP)  3 
AAP24
 16

 3

2 4 6 9 12 15 18 24 3 4 5-13 13-21
( ) ( )

- X
- X
-  X

- X X X X X X X X X X X X X
- X X X X X X X X
- T O O O O S S O O O O
- O S O O S O S O O O O
- X
-Echocardiogram X
- X
(CBC)
--- X X X X X X X X X X X X X
(, ,

)
- X X

X
T
O
S :

:: ::
 17

FGFR-related craniosynostosis
FGFR-related craniosynostosis 8  
fibroblast growth factor receptors
(FGFRs) FGFR1, 2 3 ( Pfeiffer syndrome, Apert
syndrome, Crouzon syndrome, Beare-Stevenson syndrome, FGFR2-related isolated coronal
synostosis, Jackson-Weiss syndrome, Crouzon syndrome with acanthosis nigricans
Muenke syndrome
(  Crouzon, Apert,
Pfeiffer
( 3 ( 

 (craniosynostosis or premature closure of
cranial sutures)  coronal ( 2 (bilateral coronal
craniosynostosis) (brachycephaly)
  lambdoid sagittal sutures 
( ( (ridging)  
(skull radiograph) head CT examination (
( (ocular
proptosis) ( (shallow orbits) (hypertelorism)
(maxillary or midface hypoplasia) 
( 3  4
(http://www.genetests.org/)
 4 

D D
Crouzon
Apert ( ( ( (
( (syndactyly) ( (syndactyly)
Pfeiffer (( ((
(brachydactyly) (brachydactyly)
(broad, medially (broad, medially
deviated) deviated)
 18

(
Crouzon
- :
- : (proptosis), (external strabismus), 
(mandibular prognathism)
- :
- : ( (hydrocephalus)
Apert
- :
- : (turribrachycephaly)
(midface hypoplasia)
- : (( (mitten glove)
- : ( (hydrocephalus)
 C5-C6 (fused cervical vertebrae)

Pfeiffer
Pfeiffer 3   2 3
 1
Pfeiffer type 1
- :
- : (midface hypoplasia)
- : ((
(broad, medially deviated thumbs and great toes) ((
(brachydactyly)
- : ( (hydrocephalus)
(hearing loss)
Pfeiffer type 2
- :
 19

- :  (cloverleaf skull)

- : ((
(broad, medially deviated thumbs and great toes) ((
(brachydactyly) (ankylosis of elbows and knees)
Pfeiffer type 3
- :
- : (turribrachycephaly)

- : ((
(broad, medially deviated thumbs and great toes) ((
(brachydactyly) (ankylosis of elbows and knees)
- : ( (hydrocephalus)
(laryngotracheal abnormalities)
Pfeiffer  1  
2 3
Crouzon, Apert, Pfeiffer 
(autosomal dominant inheritance) fibroblast growth factor
receptors (FGFRs) Pfeiffer  1 FGFR1
Crouzon, Apert, Pfeiffer  2 3 FGFR2
 (sporadic) (
(( ( 
(de novo mutation)   (
(advanced paternal age)   (
(
((   50 
(genetic testing) 
 25
( 
  

 20



Neural tube defects (NTD)
(neural tube defects)
 
( 0.2  1

(anencephaly)   neural fold (
 neural tube defects  
meningoceles, myeloceles, meningoencephaloceles, meningomyeloceles
 neural folds   anencephaly
 
2 3 ( (spina
bifida)  (vertebral arches) 26
(spina bifida) ( (lumbar)
( spina bifida occulta  (
spina bifida aperta  meningocele
meningomyelocele
neural tube defects (
-Chromosome abnormalities
Trisomy 13 or 18
Triploidy
-Single gene mutations
Walker-Walburg syndrome
Jarco-Levin syndrome
Meckel-Gruber syndrome
- Teratogens
Thalidomide
Valproic acid
- Maternal diabetes mellitus
- Multifactorial inheritance
 21

neural tube defects 

(multifactorial) ( 
neural tube defects  
(folic acid)27 (DNA
synthesis) (cell division) (  (tissue growth)
 folic acid 400
 ( 1 ( 3 (
neural tube defects 7528
neural tube defects
folic acid ( 
(  MTHFR folic acid 
folic acid 400-800
  neural tube defects
75
( (  NTD
( folic acid 
 10 4,000 4  ( 1
( ( (
alpha-fetoprotein (AFP) ( anencephaly open
spina bifida (prenatal ultrasonography) 
 NTD AFP
 ( (  folic acid
AFP NTD
 
((
 
(
websites
 
(
  
 22


(  
  
(  
 23

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8 Schreppers-Tijdink, G.A., Curfs, L.M., Wiegers, A., Kleczkowska, A. & Fryns, J.P.
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9 Knight, S.J., Regan, R., Nicod, A., Horsley, S.W., Kearney, L., Homfray, T., Winter,
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unexplained mental retardation. Lancet 354, 1676-1681.
 24

10 Biesecker, L.G. (2002) The end of the beginning of chromosome ends. Am J Med
Genet 107, 263-266.
11 Moeschler, J.B. & Shevell, M. (2006) Clinical genetic evaluation of the child with
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12 Stankiewicz, P. & Beaudet, A.L. (2007) Use of array CGH in the evaluation of
dysmorphology, malformations, developmental delay, and idiopathic mental retardation. Curr
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13 Maddalena, A., Richards, C.S., McGinniss, M.J., Brothman, A., Desnick, R.J., Grier,
R.E., Hirsch, B., Jacky, P., McDowell, G.A., Popovich, B., Watson, M. & Wolff, D.J. (2001)
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14 Grzeschik, K.H., Bornholdt, D., Oeffner, F., Konig, A., del Carmen Boente, M.,
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Szalai, Z., Tadini, G., Traupe, H. & Happle, R. (2007) Deficiency of PORCN, a regulator of
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15 Wang, X., Reid Sutton, V., Omar Peraza-Llanes, J., Yu, Z., Rosetta, R., Kou, Y.C.,
Eble, T.N., Patel, A., Thaller, C., Fang, P. & Van den Veyver, I.B. (2007) Mutations in X-linked
PORCN, a putative regulator of Wnt signaling, cause focal dermal hypoplasia. Nat Genet 39,
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16 Leoyklang, P., Suphapeetiporn, K., Wananukul, S. & Shotelersuk, V. (2008) Three
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17 Moser, A.B., Kreiter, N., Bezman, L., Lu, S., Raymond, G.V., Naidu, S. & Moser,
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 25

19 Gabrielli, O., Salvolini, U., Coppa, G.V., Catassi, C., Rossi, R., Manca, A., Lanza, R. &
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22 Rubin, S.S., Rimmer, J.H., Chicoine, B., Braddock, D. & McGuire, D.E. (1998)
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25 Shotelersuk, V., Mahatumarat, C., Ittiwut, C., Rojvachiranonda, N., Srivuthana, S.,
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Crouzon and Apert syndromes. J Craniofac Surg 14, 101-104; discussion 105-107.
26 Botto, L.D., Moore, C.A., Khoury, M.J. & Erickson, J.D. (1999) Neural-tube defects. N
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27 Wenstrom, K.D., Johanning, G.L., Owen, J., Johnston, K.E., Acton, S., Cliver, S. &
Tamura, T. (2000) Amniotic fluid homocysteine levels, 5,10-methylenetetrahydrafolate
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28 Berry, R.J., Li, Z., Erickson, J.D., Li, S., Moore, C.A., Wang, H., Mulinare, J., Zhao,
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