SHORT syndrome

SMALL, SMALLER,
SMALLEST– SMALLEST SILVER- SILVER
RUSSELL TO PRIMORDIAL
DWARFISM
Dr. Judith G. Hall, OC, MD
The University of British Columbia
Vancouver, BC Canada

CAUSES OF GROWTH
RESTRICTION
Bone disorders - chonrdrodysplasias, chonrdrodysplasias,
rickets
Nutritional - chronic infection, Celiac disease,
Crohn’s Crohn disease, malabsorption
Congenital anomalies - cardiac, renal, CNS
Metabolic - renal acidosis, glycogen storage
disease, etc.
Emotional - psychosocial dwarfism
Endocrine - hypothyroidism, hypopituitarism,
hypopituitarism,
Cushing’s Cushing s disease
Intrauterine growth retardation - Turner syndrome,
small for dates, many syndromes, infection,
chromosomal anomalies
Normal variation - familial short stature,
constitutional delay

HOW TO APPROACH SHORT
STATURE?
1. Present at birth vs. later onset (i.e.,
IUGR, SGA, primordial)
2. Proportionate vs. non-proportionate
non proportionate –
relative to what?
3. How short is short?
4. When falls off centiles in utero
5. Growth pattern after birth

IUGR – Intrauterine Growth Retardation
SGA – Small for Gestational Age
PRIMORDIAL – Prior to Birth
IUGR = SGA = PRIMORDIAL
Below the 3 rd centile for gestational age
How far below?
Relative centiles of OFC, length, and
weight

NATURE’S NATURE S RULE OF THUMB
OFC > LENGTH > WEIGHT
i.e., Preserve the brain if you
can

RELATIVE TO WHAT AT WHAT AGE?
OFC, length/height, weight
FOR AGE (and to each other)
OFC, length/height, weight
FOR HEIGHT AGE
OFC, length/height, weight
FOR BONE AGE

PROPORTIONAL VS. NON-PROPORTIONATE
NON PROPORTIONATE
(MIDGET) (DWARF)
Length/height compared to span
Upper/lower segment
Proximal, middle, distal

HERE WE ARE TALKING
ABOUT:
IUGR/SGA (prenatal)
Relatively proportionate short
stature postnatally
Very, very small types of syndromes
Centiles have little meaning way, way,
way, below 3 rd centile! centile
>>>3 rd centile

Significant IUGR
Relatively PROPORTIONATE/POST NATAL
SHORT STATURE DISORDERS
1. Bloom*
2. Dubowitz
3. Floating Harbor
4. MOPD II*
5. Mulibrey* Mulibrey
6. Silver-Russell/Russell
Silver Russell/Russell-Silver*** Silver***
7. SHORT
8. 3-M* M*
Also: Chromosomal, CPM, and teratogens

A
B
C
FLOATING
HARBOR
MULIBREY
DUBOWITZ
SHORT
3-M
BLOOM
R-S
heterogenous
MOPD II
TERM DELIVERY
2460 gm
46.8 cm
2400 gm
45 cm
2300 gm
45 cm
2200 gm
45 cm
2100 gm
40 cm
1850 gm
44 cm
1200 gm – 2500 gm
35 cm – 50 cm
1000 gm
35 cm
ADULT
HEIGHT
130 cm-140 cm 140 cm
Slow growth
2 nd best
150 cm
4 th
th best
146 cm
154 cm
Best growth
120 cm-136 cm 136 cm
3 rd
rd best
148 cm
150 cm males
140 cm
females
100 cm
Worst!!
OFC
OFC wnl for age
Mild MR
Relative
macrocephalic
MR 75%
Microcephaly 100%
OFC about 10% for
age
Relative
macrocephaly
Mild MR
Mild microcephaly
Relative
macrocephaly
Start off
proportionate
become

RUSSELL-SILVER/SILVER
RUSSELL SILVER/SILVER-RUSSELL RUSSELL
PHENOTYPE
Silver et al 1953, Russell 1954 (no asymmetry)
Small body compared to head; head is
normal for age; and therefore, big
relative to body
Pseudohydrocephaly,
Pseudohydrocephaly,
“macrocephaly
macrocephaly”
Relatively underweight
Asymmetry ~ 50% (hemihypotrophy
( hemihypotrophy)
Delayed bone age, but grow parallel to
centile
3 rd
rd centile

RUSSELL-SILVER/SILVER
RUSSELL SILVER/SILVER-RUSSELL RUSSELL
PHENOTYPE - 2
OFTEN PRESENT
High forehead
Triangular shaped face
Clinodactyly
Café Caf au lait spots
Special education needs 35%

RUSSELL-SILVER/SILVER
RUSSELL SILVER/SILVER-RUSSELL RUSSELL
PHENOTYPE - 3
OCCASSIONAL - ? REFLECT
HETEROGENEITY
Syndactyly 20%
Hypoglycemia (45% of non UPD)
Excessive sweating, tachycardia
Congenital dislocated hip 12%
Hypospadias,
Hypospadias,
cryptorchidsm in 20% males
Scoliosis 36%
Bluish sclerae
Apparently low set ears

WEIGHT < HEIGHT < OFC
Programming
Nutrition
Fetal survival
Placental deficiency/insufficiency
Placental (CPM) mosaicism
Imprinting/epigenetic

Chromosome 7
Mat UPD 7 10%
7p11.2-13 7p11.2 13 mat dUp and other 1%
7q11q1-p14 7q11q1 p14 translocations (x 11)
7q25 translocation
Pat 7q32 disruptions
Mat 7q32 UPD
Trisomy 7 mosaicism
11p15 demethylation
Mat duplication
Opposite of BWS 30%
15q26.1 – qter deletions
Rings
17q22-q24, 17q22 q24, pat deletion 2%
17q25
1x
AR, AD families
Chromosome 8, 15, 17, 18
Discordant MZ twins _______
? All 11p15? 50%
Unknown 50%

WHAT WE HAVE LEARNED
ABOUT IMPRINTING?
Deletion
UPD (milder)
Point mutation
Duplications
Imprinting control center change
Methylation changes (LOI)
Tissue specific expression

7
UPD mat
p11.1-p14 p11.1 p14
Mat UPD (?1GFBP1↑)
(?1GFBP1
Pericentric inversion
Point mutation
q32
Mat dup and UPD
15q26.1-qter
15q26.1 qter
17q23.3-q25
17q23.3 q25
RS/SR
11p15
Mat dysfunction
Mat UPD
Loss of paternal
methylation DMR
Imprinted genes normal
expression
FOX2 pat
FOX2 pat
GRB10 pat
GRB10 pat
(C7oef10-11)
(C7oef10 11)
PEG/MIST mat
PEG/MIST
(CoPg2 Copg2AS, and
MITI, IMP3?)
H19 mat
H19
H19
IGFIR ?
CHS1 ?
KPN2
GRB2 and 7
↓
↓
--
↑
↑
Disruption

CHROMOSOME 7
Mat UPD 7
Special education 5%-10% 5% 10%
Speech delay (absence of FOXP 2) )
Fewer minor dysmorphic features
No asymmetry
Recessive disorders
Mat iso 3:5 hetero
7p11.2-p14
7p11.2 p14 – mat duplication (GRB10 paternally
imprinted – point mutations)
(3 AD families)
TX and pericentric
7q mat UPD 13 – qter (PEG1/MEST maternally
imprinted)
7q32 translocation breakpoint and ∂2-COP COP
Trisomy 7 rescue with residual T 7 cells

CHROMOSOME 11P15 – 40%
Demethylation of ICR and pat H19
regulation of IGF2 expression, biallelic
expression of H19 – with hypomethylation H19
Opposite of BWS
Asymmetry frequent (fibroblast studies important)
? Cancer risk (small)
Mat duplication 11p15 (35% of the 40%) also UPD
Discordant MZ twins

15q26.1 15q26.1-qter qter deletions and rings
apparently loss of functional
IGF1R
CHROMOSOME 15

CHROMOSOME 17
17q24.1 17q24.1-q25 q25 translocations, 2%
deletions
Apparently pat CSH1
expression lost

RS/S/R PRACTICAL ASPECTS
Early feeding problems
Hypoglycemia
? GH therapy, androgenic hormone
Leg lengthening discrepancy (> 3 cm)
Cryptorchidism for males
Speech/language development
Hundreds of cases reported
Very rarely familial

RUSSELL-SILVER/SILVER
RUSSELL SILVER/SILVER-
RUSSELL
DIFFERENTIAL DIAGNOSIS
DNA repair Fanconi anemia
Nijmegen breakage
Bloom syndrome
Partington X-linked linked with hyperpigmental skin
3-M M syndrome
Fetal alcohol syndrome
IMAGe syndrome
Chromosomal Diploid/triploid mixoploidy
Mosaic Turner syndrome
Y q deletions
Trisomy 18 and 18p -

RUSSELL-SILVER/SILVER
RUSSELL SILVER/SILVER-RUSSELL RUSSELL
REFERENCES
Bailey W et al. Monozygotic twins discordant for the Russell-Silver Russell Silver syndrome. Am J
Med Genet 1995;58:101-105.
1995;58:101 105.
Bliek J et al. Hypomethylation of the H19 gene causes not only Silver-Russell
Silver Russell synrome
(SRS) but also isolated asymmetry or an SRS-like SRS like phenotype. Am J Hum Genet
2006; 78:604-614.
78:604 614.
Dupont JM et al. Familial Reciprocal Translocation t(7;16) associated with maternal
uniparental disomy 7 in a Russel-Silver Russel Silver patient. Am J Med Genet 2002;111:405-
2002;111:405
408.
Font-Montgomery Font Montgomery E et al. Clinical outcome and follow-up follow up of the first reported case of
Russell-Silver Russell Silver syndrome with the unique combination of maternal uniparental
heterodisomy 7 and mosaic trisomy 7. Birth Defects Res A 2005; 73:577-582.
73:577 582.
Gicquel C et al. Epimutation of the telomeric imprinting center region on chromosome
11p15 in Silver-Russell Silver Russell syndrome Nat Genet 2005; 37:1003-1007.
37:1003 1007.
Hannula K et al. Do patients with maternal uniparental disomy for chromosome 7 have
a distinct mild Silver-Russell Silver Russell phenotype?. J Med Genet 2001;38:273-278.
2001;38:273 278.
Hitchins MP et al. Investigation of the GRB2, GRB7, and CSH1 genes as candidates candidates
for
the Silver-Russell Silver Russell syndrome (SRS) on chromosome 17q. J Med Genet 2002;39:E13.
2002;39:E13.
Kotzot D et al. Maternal uniparental disomy 7 - review and further delineation of the
phenotype. Eur J Pediatr 2000;159:247-256.
2000;159:247 256.
Matsumoto N. A 4-Mb 4 Mb critical region for intrauterine growth retardation at 15q26. Clin
Genet 2002; 62:340-342.
62:340 342.
Monk D et al. Chromosome 7p disruptions in Silver Russell syndrome: syndrome:
delineating an
imprinted candidate gene region. Hum Genet 2002;111:376-387.
2002;111:376 387.
Schonherr N et al. The centromeric 11p15 imprinting centre is also involved in Silver- Silver
Russell syndrome. J Med genet 2007; 44:59-63. 44:59 63.
Tamura T et al. Ring chromosome 15 involving deletion of the insulin insulin-like
like growth factor
1 receptor gene in a patient with features of Silver-Russell Silver Russell syndrome. Clin
Dysmorphol 1993;2:106-113.
1993;2:106 113.

MULIBREY NANISM
Muscle uscle Liver iver Brain rain Eye ye
Perhentupa et al 1970 - Finnish
Large dolicocephalic cranium with high
prominent forehead
Triangular shaped face
Depressed bridge of nose 90%
Muscle wasting
Hands & feet appear large
Yellowing of retina with yellow spots 80%
Constrictive pericarditis 35% - (congestive heart
failure)
Enlarged liver with prominent veins 45%
Long shallow sella turcica (J shaped)

MULIBREY NANISM- NANISM 2
Hypotonia 70 %
Thin long bones with narrow medullary canal 100%
Fibrous dysplasia of tibia 25%
High pitched voice 96%
Nevus flammeus 65%
Ovarian stromal tumors
Wilms tumor 4%
Incomplete breast development in females
Premature ovarian failure & subsequent infertility in
females

MULIBREY NANISM- NANISM 3
Autosomal recessive – with consanguinity
Over 80 reported cases
Finland (85%) and Egypt, France, Turkey,
Argentina, Spain
Mutations occur in TRIM 37 – 17q21 - q24
• Encodes peroxisomal protein whose function is
unknown – it shows a granular cytoplasmic
pattern in cells
• It is a RING – B – box-wild box wild-coil coil protein
• Ubiqutin E3 ligase

MULIBREY NANISM- NANISM 4
MANAGEMENT
Feeding problems early
Pericardiectomy often necessary
GH therapy little increase in ultimate weight
Females have spontaneous puberty, then
ovarian failure, oligomenorhea, oligomenorhea,
and
infertility

MULIBREY NANISM- NANISM 5
DIFFERENTIAL DIAGNOSIS
Russell-Silver Russell Silver syndrome
3-M M syndrome
Meier Gorlin syndrome

MULIBREY NANISM- NANISM 6
REFERENCES
Avela K et al. Gene encoding a new RING-B-box
RING box-Coiled Coiled coil protein is
mutated in mulibrey nanism. nanism.
Nature Genetics 2000;25:298- 2000;25:298 301.
Balg S et al. Mulibrey nanism. nanism.
Clin Dysmorphol 1995;4:63-69.
1995;4:63 69.
Hamalainen RH et al. Wilms’ Wilms tumor and novel TRIM37 mutations in an
Australian patient with mulibrey namism. namism.
Clin Genet 2006 479.
70:473- 70:473
Jagiello P et al. A novel splice site mutation in the TRIM37 gene
causes mulibrey nanism in a Turkish family with phenotypic
heterogeneity. Hum Mutat 2003; 21:630-635.
21:630 635.
Karlberg N et al. Mulibrey nanism: nanism:
clinical features and diagnostic
criteria. J Med Genet 2004;41:92-98.
2004;41:92 98.
Karlberg N e al. Failure of sexual maturation in mulibrey nanism. nanism.
NEJM 2004; 351:2559-2560.
351:2559 2560.
Lapunzina P et al. Mulibrey nanism: nanism:
three additional patients and a
review of 39 patients. Am J Med Genet 1995;55:349-355.
1995;55:349 355.

3 – M
Miller iller McKusick cKusick Malvaux alvaux et al. 1975
Relatively large head, dolicocephaly, dolicocephaly,
with
frontal bossing, 50 th centile for age
Short broad neck with prominent trapezius, trapezius,
square shoulders
Deformed sternum, short thorax
Transverse grooves on anterior chest, flaring
of bottom of chest, transverse ribs
Square shoulders with winged scapulae
Triangular face, hypoplastic midface, midface,
long
philtrum, philtrum,
prominent lips, “gloomy gloomy facies”
facies

3 – M – (2)
Full eyebrows
Prominent ears
Fleshy nose tip
Crowded teeth, V-shaped V shaped dental arch
Short fifth finger
Hypospadius and hypogonadism in males

3 – M – (3)
Miller iller McKusick cKusick Malvaux alvaux et al. 1975
Hyperlordosis
Loose joints
Slender long bone with diaphyseal
constriction and flared metaphyses
Tall vertebrae
Thoracic kyphoscoliosis
? CNS aneurysms

3 – M – (4)
TREATMENT
Feeding problems
Male cryptorchidism, cryptorchidism,
infertility
Watch for kyphoscolosis

3 – M – (5)
Autosomal recessive, increased
consanguinity
Heterozygotes may have minor clinical
features
About 100 cases reported
Cullin 7 gene, 25 different mutations in
29 families
CUL7 assembles an E3 ubiquitin ligase
complex

3 – M – (6)
Miller iller McKusick cKusick Malvaux alvaux et al. 1975
DIFFERENTIAL DIAGNOSIS
Russell-Silver Russell Silver syndrome
Bloom syndrome
Mulibrey Nanism

3 – M – (7)
REFERENCES
Hennekam RCM et al. Further delineation of the 3-M 3 M syndrome with
review of the literature. Am J Med Genet 1987;28:195-209.
1987;28:195 209.
Huber C et al. Identification of mutations in CUL7 in 3-M 3 M syndrome.
Nature Genet 2005;37:1119-1124.
2005;37:1119 1124.
Le Merrer M et al. Dwarfism with gloomy face: a new syndrome with
features of 3-M 3 M syndrome. J Med Genet 1991;28:186-191.
1991;28:186 191.
Maksimova N et al. Clinical, molecular and histopathological
features of short stature syndrome with novel CUL7 mutation
in Yakuts: Yakuts:
new population isolate in Asia. J Med genet
2007;44:772-778.
2007;44:772 778.
Miller JD et al. The 3-M 3 M syndrome: a heritable low birthweight
dwarfism. BDOAS 1975;11(5):39-47.
1975;11(5):39 47.
Mueller RF et al. The 3-M 3 M syndrome: risk of intracerebral
aneurysm?. J Med Genet 1992;29:425-427.
1992;29:425 427.
van der Wal G et al. 3-M 3 M syndrome: description of six new patients
with review of the literature. Clin Dysmorphol 2001;10:241-252.
2001;10:241 252.
Winter RM et al. The 3-M 3 M syndrome. J Med Genet 1984;21:124-128.
1984;21:124 128.

SHORT SYNDROME
(Gorlin Gorlin et al and Sensenbrenner et al, 1975)
Short stature
Hyperextensible joints/inguinal hernia
Ocular depression (deep set, large
appearing eyes)
Rieger anomaly (megalocornea
( megalocornea, ,
anterior segment dystrophy,
glaucoma, and lens opacities)
Teething delay (small teeth, enamel
hypoplasia, hypoplasia,
malocclusion)

SHORT SYNDROME - 2
Speech delay (36 months) with normal
intelligence
Triangular shaped face
Broad forehead, small chin, small facial bones
Telecanthus, Telecanthus,
deep set eyes, Reiger anomaly
Hypoplastic alae, alae,
broad nasal bridge
Micrognathia, Micrognathia,
dimple in chin
Dental eruption delay and bone age delay

SHORT SYNDROME - 3
Feeding problems (V & D) and FTT
Decreased subcutaneous fat, lipodystrophy –
dystrophy of face & upper limbs and
subcutaneous pits in elbows, and
buttocks
DM related to insulin resistance after
puberty & GH RX
Thin hair & skin transparent
Occasional neurosensory deafness
Ears – relatively larger, parallel creases,
apparently posterior angle

SHORT SYNDROME - 4
Hyperextensible
Hyperextensible hands
Clinodactyly
Clinodactyly 5 th
Large Large & cone shaped epiphyses
Thin, Thin, gracile, gracile,
long bones

SHORT SYNDROME - 5
20 cases
? 2 AR families; ?4 AD with non penetrance
Equal males and females
Translocation 1q31.2/4q25, ? PITX2 mutation

SHORT SYNDROME – 6
DIFFERENTIAL DIAGNOSIS
GMS
DeHawere syndrome
Russell-Silver Russell Silver syndrome
Polycystic ovary disease

SHORT SYNDROME – 7
REFERENCES
Bankier A et al. Absent iris stroma, stroma,
narrow body build and small facial
bones: a new association or variant of SHORT syndrome?. Clin
Dysmorphol 1995;4:304-312.
1995;4:304 312.
Brodsky MC et al. Rieger anomaly and congenital glaucoma in the SHORT
syndrome. Arch Ophthal 1996;114:1146-1147.
1996;114:1146 1147.
Haan E et al. SHORT syndrome: distinctive radiographic features. Clin
Dysmorphol 1998;7:103-107.
1998;7:103 107.
Joo SH et al. Case report on SHORT syndrome. Clin Dysmorphol
1999;8:219-221.
1999;8:219 221.
Koenig R et al. SHORT syndrome. Clin Dysmorphol 2003;12:45-50.
2003;12:45 50.
Lipson AH et al. The SHORT syndrome: further delineation and natural natural
history. J Med Genet 1989;26:473-475.
1989;26:473 475.
Schwingshandl J et al. SHORT syndrome and insulin resistance. Am J
Med Genet 1993;47:907-909.
1993;47:907 909.
Sorge G et al. SHORT syndrome: a new case with probable autosomal
dominant inheritance. Am J Med Genet 1996;61:178-181.
1996;61:178 181.

FLOATING HARBOR SYNDROME
Boston Floating Hospital – Harbor General
Hospital
(Pelletier et al 1973, Leisti et al 1974)
Developmental delay, particularly speech 100%
Mild MR, some with hyperactivity
Craniofacial – triangular face (round in infancy)
triangular face (round in infancy)
Broad nose, bulbous with prominent nasal bridge
Broad nose, bulbous with prominent nasal bridge
Prominent eyes early, deep set later
Prominent eyes early, deep set later
Wide mouth, thin lips
Broad columella
Smooth and short philtrum
Large nares, nares,
hypoplastic alae
Posteriorly rotated ears, appear lowset
Head circumference normal for age

FLOATING HARBOR SYNDROME - 2
Clinodactyly of 5 th (nail hypoplasia),
hypoplasia),
brachydactyly, brachydactyly,
broad thumbs,
Appear proportionate
Decreased subcutaneous tissue
Short neck, with low hairline
Hirsuitism and long eye lashes
Joint laxity – 50%
Trigonencephaly
Celiac disease
Occasional high pitched voice
Tethered cord x1

FLOATING HARBOR SYNDROME - 3
Delayed BA 100% - but puberty on time
Clinodactyly of 5 th in 75% and coned
epiphyses
Brachydactyly 50%
Finger clubbed 45%
Pseudoarthrosis of clavicle

FLOATING HARBOR SYNDROME – 4
About 20 cases
Mostly sporadic M:F – 1:2
Consanguinity, 1 set of female sibs
Advanced paternal age in most
x 3 mother daughter affected – doubtful
Gene Unknown

FLOATING HARBOR SYNDROME – 5
DIFFERENTIAL DIAGNOSIS
Silver – Russell syndrome
Shprintzen syndrome
3-M M syndrome
Dubowitz syndrome
Rubinstein – Taybi syndrome

FLOATING HARBOR SYNDROME - 6
REFERENCES
Ala-Mello Ala Mello S et al. The first Finnish patient with the Floating-Harbor
Floating Harbor syndrome:
the follow-up follow up of eight years. Am J Med Genet 2004;130A:317-319.
2004;130A:317 319.
Davalos IP et al. Floating-Harbor Floating Harbor syndrome. A neuropsychological approach.
Genetic Counseling 1996;7:283-288.
1996;7:283 288.
Feingold M. Thirty-two Thirty two year follow-up follow up of the first patient reported with the
Floating-Harbor Floating Harbor syndrome. Am J Med Genet 2006;140A: 782-784. 782 784.
Hersh JH et al. Changing phenotype in Floating-Harbor Floating Harbor syndrome. Am J Med
Genet 1998;76:58-61.
1998;76:58 61.
Lacombe D et al. Floating-Harbor
Floating Harbor Syndrome: description of a further patient,
review of the literature, and suggestion of autosomal dominant
inheritance. Eur J Pediatr 1995;154:658-661.
1995;154:658 661.
Patton MA et al. Syndrome of the month: Floating-Harbor Floating Harbor syndrome. J Med
Genet 1991;28:201-204.
1991;28:201 204.
Rosen AC et al. A further report on a case of Floating-Harbor Floating Harbor Syndrome in a
mother and daughter. J Clin Exp Neuropsychol 1998;20:483-495.
1998;20:483 495.
Wiltshire E et al. Floating-Harbor
Floating Harbor syndrome complicated by tethered cord: A
new association and potential contribution from growth hormone therapy. therapy.
Am J Med Genet 2005;136A:81-83.
2005;136A:81 83.

BLOOM SYNDROME
(Bloom 1954, German F/U)
Microcephaly – mildly/small for size
Malar mypoplasia
Telangiectasia and erythema of face
(butterfly distribution)
Pigment abnormalities and atrophic
scars (photosensitivity by 2 years)
Increased risk of tumors: tumors:
leukemia,
lymphoma, adenocaricoma,
adenocaricoma,
squamous cell, carcinoma, and Wilm’s Wilm
(at least 44% affected, mean age of onset
25 years)

BLOOM SYNDROME – 2
High squeaky voice
Immune deficiency and reduced 1gA,
1gG, 1gM
Chronic infections (particularly chronic
lungs 20%)
Male infertility with small testes, females
fertile with premature menopause

BLOOM SYNDROME - 3
Delayed puberty (and BA)
DM 16% - type 2 after puperty
Mild MR – normal IQ with learning
disability
Feeding problems in infancy
Male infertility with small testes,
females fertile with early menopause

BLOOM SYNDROME - 4
Increase Increase sister chromatid
exchange (SCE) breakage,
dicenrics, dicenrics,
tetraradials

BLOOM SYNDROME - 5
Autosomal recessive
Mutations in BML (15q26.1) which is a
protein homolous to REC Q helicase
64 mutations, 2 Ashkenazi mutations
Ashkenazi Jew carrier rate about 1%
Unwinds DNA in 3’ 3 to 5’ 5 direction along
bound strand, nuclear cell cycle
regulator
Other DNA helicase disorders - Werner,
Rothman Thompson

Bloom syndrome registry ~ 150
patients maintained by
German & Passarge
- Helps to clarify the natural
history

BLOOM SYNDROME - 7
DIFFERENTIAL DIAGNOSIS
Russell Silver syndrome
Rothmund Thompson syndrome
Cockayne syndrome
Ataxia Teliangectasia
Fanconi Anemia

BLOOM SYNDROME - 8
REFERENCES
Auerbach AD et al. Disorders of DNA replication and repair.
Curr Opin Pediatr 1997;9:600-616.
1997;9:600 616.
Chisholm CA et al. Successful pregnancy in a woman with
Bloom syndrome. Am J Med Genet 2001;102:136-138.
2001;102:136 138.
Ellis NA et al. Molecular genetics of Bloom's syndrome.
Hum Mol Genet 1996;5:1457-1463.
1996;5:1457 1463.
Ellis NA et al. The Bloom's sydrome gene product is
homologous to RecQ helicases. helicases.
Cell 1995;83:655-666.
1995;83:655 666.
Mohaghegh P et al. DNA helicase deficiencies associated
with cancer predisposition and premature ageing
disorders. Hum Mol Genet 2001;10:741-746.
2001;10:741 746.
Passarge E. Bloom's syndrome: the German experience.
Ann Genet (Paris) 1991;34:179-197.
1991;34:179 197.

DUBOWITZ SYNDROME - 1
Dubowitz 1965
DD & MR – mild – moderate (72%)
Hyperactivity 70%
Shy, short attention span
Speech delay 67%
High pitched voice 55%, hoarse cry 30%
Microcephaly, Microcephaly,
high sloping forehead 80%, flat
superorbital ridges 90%, present at birth
Exzema – like skin disorder on face & flexion areas,
60% from birth, clears 2 – 4 years
Space hair, especially frontal 70% and lateral
eyebrows 45%

DOBOWITZ SYNDROME – 2
FTT - Muscular hypotonia 40%
Delayed BA 50%
Faces become triangular
Broad nasal tip 50% and broad base to
nose
Telecanthis with prominent epicanthal folds,
ptosis 65%, blepharophimosis 80%
Apparently low set, prominent, dysmorphic
ears 75%

DOBOWITZ SYNDROME – 3
Small chin 80%, with age becomes long
square chin
Clinodactyly of fifth - 50% and
syndactyly 20%
Males hypospadias,
hypospadias,
cryptorchidism 50%
Leukemia, lymphoma, neuroblastoma,
neuroblastoma,
and aplastic anemia have been
reported

DOBOWITZ SYNDROME – 4
150 cases
AR many with consanguinity
? Subtypes
• ? Anorectal & craniosynostosis
subtypes
• Immune deficiency and frequent
infection
• Low cholesterol
Gene unknown

DOBOWITZ SYNDROME – 5
DIFFERENTIAL DIAGNOSIS
FAS syndrome
Bloom syndrome
Smith-Lemli
Smith Lemli-Opitz Opitz syndrome
22q- 22q syndrome

DOBOWITZ SYNDROME – 6
REFERENCES
Hansen KE et al. Dubowitz syndrome: long-term long term follow-up follow up of an original
patient. Am J Med Genet 1995;55:161-164.
1995;55:161 164.
Ilyina HG et al. Dubowitz syndrome: possible evidence for a clinical
subtype. Am J Med Genet 1990;35:561-565.
1990;35:561 565.
Moller KT et al. The Dubowitz syndrome: a retrospective. J Cranio Gen
Dev Bio 1985;5:283-286.
1985;5:283 286.
Parrish JA et al. Studies of the density and the properties of the the
hair in a
new inherited syndrome of hypotrichosis. hypotrichosis.
Ann Hum Genet
1972;35:349-356.
1972;35:349 356.
Tsukahara M et al. Dubowitz syndrome: review of 141 cases including 36
previously unreported patients. Am J Med Genet 1996;63:277-289.
1996;63:277 289.
Winter RM. Syndrome of the month: Dubowitz syndrome. J Med Genet
1986;23:11-13.
1986;23:11 13.

MAJEWSKI (MICROCEPHALIC)
OSTEODYSPLASTIC PRIMORDIAL
DWARFISM II
Majewski et al 1982
Severe IUGR < 1000 gm at term
Severe postnatal short stature – around 100
cm as adult
At birth, proportionate OFC (28 weeks at term)
Progressive relative true microcephaly
Forehead lacks posterior slant, in fact tall,
forehead
Small dysplastic teeth (or absent) compared to
mouth size
High squeaky voice
Prominent nose and eyes

MOPD II - 2
Progressive bony changes and loose
jointedness with disproportionate
shortening of mesomelic segment
Brachydactyly
Bowed legs
Develop café caf au lait spots
May have depigmentation spots
Develop dark pigment with some
acanthesis around neck & axilla
Far sighted, short globe
Pleasant personality

MOPD II - 3
Develop intracranial aneurysm
Develop truncal obesity
Rarely DM
Cutis mamorata seen
Males cryptorchidism,
cryptorchidism,
hypospadias,
hypospadias,
micropenis
Reduced life expectancy – oldest 40 years
old
No increase in cancer noted

MOPD II – 4
MANAGEMENT
Feeding problems
Little or no response to GH
Scoliosis may develop
CNS aneurysm need to be screened for
Avoid sun
Watch for dislocation radius & knees
Danger from being so small
Watch for DM

MOPD II - 5
Autosomal recessive with consanguinity
Increase among Mediterranean countries
Variability in same family
About 100 cases reported

MOPD II - 6
Percentrin (PCNT) mutations
Component of centrosome complex
Role in cell division (mitosis)
Helps to organize mitotic spindle for
segregation and anchoring of
spindle
Giant coiled coil protein localized to
centrosome througout cell cycle
21q22.3

MOPD II - 7
Meier-Gorlin
Meier Gorlin syndrome
Floating Harbor syndrome
3 – M syndrome
SHORT syndrome
Seckels syndrome
MOPD I and III

MOPD II – 8
REFERENCES
Brancati F et al. Majewski osteodysplastic primordial dwarfism type II
(MOPD II) complicated by stroke: Clinical report and review of
cerebral vascular anomalies. Am J Med Genet 2005;139A:212-215.
2005;139A:212 215.
Hall JG et al. Majewski osteodysplastic primordial dwarfism type II
(MOPD II): natural history and clinical findings. Am J Med Genet
2004;130A:55-72.
2004;130A:55 72.
Kannu P et al. Microcephalic osteodysplastic primordial dwarfism type
II: a child with cafe au lait lesions, cutis marmorata, marmorata,
and
moyamoya disease. Am J Med Genet 2004;128A:98-100.
2004;128A:98 100.
Nishimura G et al. Microcephalic osteodysplastic primordial short
stature type II with cafe-au cafe au-lait lait spots and moyamoya disease. Am J
Med Genet 2003;117A:299-301.
2003;117A:299 301.
Ozawa H et al. Pachygyria in a girl with microcephalic osteodysplastic
primordial short stature type II. Brain Dev 2005;27:237-240.
2005;27:237 240.
Rauch A et al. Mutations in the pericentrin (PCNT PCNT) ) gene cause
primoridal dwarfism. Science 2008;319:816-819.
2008;319:816 819.
Young ID et al. Microcephalic osteodysplastic primordial short stature
type II with cafe-au cafe au-lait lait spots and moyamoya disease: another
patient. Am J Med Genet 2004;127A:218-220.
2004;127A:218 220.

SUMMARY 1
ALL PROPORTIONATE, IUGR, AND POST- POST
NATAL SHORT STATURE
Bloom syndrome
Mild microcephaly,
microcephaly,
malar hypoplasia
Telangectasia erythemations rash on cheeks and with sun
exposure
Floating Harbor syndrome
Speech delay - mild MR
Changing face – prominent nose, short philtrum
BA delay, but puberty on time
SHORT
Riegers (lens opacity, glaucoma), eyes large appearing, then
deepset
Lipodystrophy of face and upper torso
Speech delay – IQ okay
Hypoplastic alae, alae,
prominent nose as adults

SUMMARY 2
ALL PROPORTIONATE, IUGR, AND POST- POST
NATAL SHORT STATURE
Dubowitz syndrome
Relative microcephaly
Eczema
Sparce lateral eyebrows
Telecanthus, Telecanthus,
prominent epicanthal folds
Russell-Silver/Silver
Russell Silver/Silver-Russell Russell
Normal size head (pseudohydrocephaly
( pseudohydrocephaly)
Relatively underweight
50% asymmetric
BA delay, late puberty
Mulibrey Nanism
Large, long head with triangular face with depressed bridge of
nose
Constructive pericarditis and heart failure with liver
enlargement
Yellow pigment and spots in retina
Fibrosis of ovaries, fibrodysplasia of tibia

SUMMARY 3
ALL PROPORTIONATE, IUGR, AND POST- POST
NATAL SHORT STATURE
3-M
Short thorax with sternal deformity, transverse ribs, rib groove
Broad neck, square shoulders, prominent trapezius
Triangular face, full lips, hypoplastic midface, midface,
long philtrum
MOPD II
Severe pre & postnatal growth
Progressive microcephaly, microcephaly,
high forehead
Prominent nose, small teech, teech,
squeaky voice
Progressive boney dysplasia

SEVERE IUGR
Epigenetic control of growth
Ubiquinoation
Peroxisomal function
Centrosomal functiion – mitotic spindle
DNA repair
Chromosomal aberrations
Teratogens
Placental function

COMMON AND OVERLAPPING
FEATURES
Large appearing head
Triangular shaped face
Decreased subcutaneous fat
Delayed bone age
Feeding difficulties as an infant
High pitched voice
Infertility
Clinodactyly of the fifth finger
Pigment abnormalities
Bone changes of disuse (tall vertebrae,
dolicocephaly, dolicocephaly,
thin ribs, and long bones)

“A” LIST
1. Bloom*
2. Dubowitz
3. Floating Harbor
4. MOPD II*
5. Mulibrey* Mulibrey
6. Silver-Russell/Russell
Silver Russell/Russell-Silver*** Silver***
7. SHORT
8. 3-M* M*
Also: Chromosomal, CPM, and teratogens

Gorlin/Smith/Jones
Gorlin/Smith/Jones
Aarskog Sx
de Lange Sx
Hallerman Streiff Sx
Meire-gorlin
Meire gorlin Sx
Rubinstein Taybi Sx
Seckel’s Seckel Sx
“B” LIST
Hall 2004 article on MOPD II
Toriello 1986
Saul Wilson Hersh 1990 & 1994
Hurst 1988
Sdfs
Bangstad 1989, Salerno 2003, Scott 1969
Bluebel 1996
Cervenka 1979
Frias 2005

REFERENCES
Gorlin RJ, Cohen Jr. MM, Hennekam RCM. Syndromes of
the head and neck, 4 th ed. Oxford University Press, Press,
NY,
2001. 2001.
Jones KL. Smith’s Smith s recognizable patterns of human
malformations, 6th edition. WB Saunders,
Philadelphia, 2006.
Winter-Baraitser
Winter Baraitser Dysmorphology Database, version 1.0.
In Winter RM & Baraitser M (eds.) London
Medical Databases, Oxford University Press, Oxford,
UK, 2005.
OMIM (Online Mednelian Inheritance in Man)
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db
http:// www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=OMIM =OMIM
Genetest/GeneClinics
http://www.genetests.org
http:// www.genetests.org