SMALL, SMALLER,
SMALLEST– SILVERRUSSELL TO PRIMORDIAL
DWARFISM
Dr. Judith G. Hall, OC, MD
The University of British Columbia
Vancouver, BC Canada
CAUSES OF GROWTH
RESTRICTION
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Bone disorders - chonrdrodysplasias, rickets
Nutritional - chronic infection, Celiac disease,
Crohn’s disease, malabsorption
Congenital anomalies - cardiac, renal, CNS
Metabolic - renal acidosis, glycogen storage
disease, etc.
Emotional - psychosocial dwarfism
Endocrine - hypothyroidism, hypopituitarism,
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?
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2.
3.
4.
5.
Present at birth vs. later onset (i.e.,
IUGR, SGA, primordial)
Proportionate vs. non-proportionate –
relative to what?
How short is short?
When falls off centiles in utero
Growth pattern after birth
IUGR – Intrauterine Growth Retardation
SGA – Small for Gestational Age
PRIMORDIAL – Prior to Birth
¾ IUGR
=
SGA
=
PRIMORDIAL
¾ Below the 3rd centile for gestational age
¾ How far below?
¾ Relative centiles of OFC, length, and
weight
NATURE’S RULE OF THUMB
OFC > LENGTH > WEIGHT
i.e., Preserve the brain if you
can
RELATIVE TO WHAT AT WHAT AGE?
¾ OFC, length/height, weight
FOR AGE (and to each other)
¾ OFC, length/height, weight
FOR HEIGHT AGE
¾ OFC, length/height, weight
FOR BONE AGE
PROPORTIONAL VS. NON-PROPORTIONATE
(MIDGET)
(DWARF)
¾ Length/height compared to span
¾ Upper/lower segment
¾ Proximal,
middle, distal
HERE WE ARE TALKING
ABOUT:
¾ IUGR/SGA (prenatal)
¾ Relatively proportionate short
stature postnatally
¾ Very, very small types of syndromes
Centiles have little meaning way, way,
way, below 3rd centile!
>>>3rd centile
Significant IUGR
Relatively PROPORTIONATE/POST NATAL
SHORT STATURE DISORDERS
1.
2.
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4.
5.
6.
7.
8.
Bloom*
Dubowitz
Floating Harbor
MOPD II*
Mulibrey*
Silver-Russell/Russell-Silver***
SHORT
3-M*
Also: Chromosomal, CPM, and teratogens
A
B
C
TERM DELIVERY
ADULT
HEIGHT
OFC
FLOATING
HARBOR
2460 gm
46.8 cm
130 cm-140 cm
Slow growth
OFC wnl for age
Mild MR
MULIBREY
2400 gm
45 cm
2nd best
150 cm
Relative
macrocephalic
DUBOWITZ
2300 gm
45 cm
4th best
146 cm
MR 75%
Microcephaly 100%
SHORT
2200 gm
45 cm
154 cm
Best growth
OFC about 10% for
age
3 -M
2100 gm
40 cm
120 cm-136 cm
Relative
macrocephaly
BLOOM
1850 gm
44 cm
3rd best
148 cm
Mild MR
Mild microcephaly
R -S
1200 gm – 2500 gm 150 cm males
heterogenous 35 cm – 50 cm
140 cm
females
Relative
macrocephaly
MOPD II
Start off
proportionate
become
1000 gm
35 cm
100 cm
Worst!!
RUSSELL-SILVER/SILVER-RUSSELL
PHENOTYPE
Silver et al 1953, Russell 1954 (no asymmetry)
¾ Small body compared to head; head is
normal for age; and therefore, big
relative to body
¾ Pseudohydrocephaly, “macrocephaly”
¾ Relatively underweight
¾ Asymmetry ~ 50% (hemihypotrophy)
¾ Delayed bone age, but grow parallel to
3rd centile
RUSSELL-SILVER/SILVER-RUSSELL
PHENOTYPE - 2
OFTEN PRESENT
¾ High forehead
¾ Triangular shaped face
¾ Clinodactyly
¾ Café au lait
spots
¾ Special education needs 35%
RUSSELL-SILVER/SILVER-RUSSELL
PHENOTYPE - 3
OCCASSIONAL - ? REFLECT
HETEROGENEITY
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Syndactyly 20%
Hypoglycemia (45% of non UPD)
Excessive sweating, tachycardia
Congenital dislocated hip 12%
Hypospadias, cryptorchidsm in 20% males
Scoliosis 36%
Bluish sclerae
Apparently low set ears
WEIGHT
<
HEIGHT
<
OFC
¾ Programming
¾ Nutrition
¾ Fetal survival
Placental deficiency/insufficiency
z Placental (CPM) mosaicism
¾ Imprinting/epigenetic
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Chromosome 7
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Mat UPD 7
z
7p11.2-13 mat dUp and other
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7q11q1-p14 translocations
z
7q25 translocation
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Pat 7q32 disruptions
z
Mat 7q32 UPD
Trisomy 7 mosaicism
11p15 demethylation
z
Mat duplication
z
Opposite of BWS
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15q26.1 – qter deletions
z
Rings
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17q22-q24, pat deletion
17q25
10%
1%
(x 11)
30%
2%
1x
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AR, AD families
Chromosome 8, 15, 17, 18
Discordant MZ twins
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? All 11p15?
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Unknown
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50%
50%
WHAT WE HAVE LEARNED
ABOUT IMPRINTING?
¾ Deletion
¾ UPD (milder)
¾ Point mutation
¾ Duplications
¾ Imprinting control center change
¾ Methylation changes (LOI)
¾ Tissue specific expression
RS/SR
Imprinted genes normal
expression
7
UPD mat
p11.1-p14
Mat UPD (?1GFBP1↑)
Pericentric inversion
Point mutation
q32
Mat dup and UPD
11p15
Mat dysfunction
Mat UPD
Loss of paternal
methylation DMR
FOX2 pat
FOX2 pat
GRB10 pat
GRB10 pat
(C7oef10-11)
PEG/MIST mat
PEG/MIST
(CoPg2 Copg2AS, and
MITI, IMP3?)
H19
mat
H19
H19
15q26.1-qter
IGFIR
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17q23.3-q25
CHS1
?
KPN2
GRB2 and 7
Disruption
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↓
--
↑
↑
CHROMOSOME 7
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Mat UPD 7
5%-10%
z Special education
z Speech delay (absence of FOXP2)
z Fewer minor dysmorphic features
z No asymmetry
z Recessive disorders
z Mat iso 3:5 hetero
7p11.2-p14 – mat duplication (GRB10 paternally
imprinted – point mutations)
z (3 AD families)
z TX and pericentric
7q mat UPD 13 – qter (PEG1/MEST maternally
imprinted)
7q32 translocation breakpoint and ∂2-COP
Trisomy 7 rescue with residual T7 cells
CHROMOSOME 11P15 – 40%
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Demethylation of ICR and pat H19
z regulation of IGF2 expression, biallelic
z 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
CHROMOSOME 15
¾ 15q26.1-qter deletions and rings
apparently loss of functional
IGF1R
CHROMOSOME 17
¾ 17q24.1-q25 translocations, 2%
deletions
z Apparently pat CSH1
expression lost
RS/S/R PRACTICAL ASPECTS
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Early feeding problems
Hypoglycemia
? GH therapy, androgenic hormone
Leg lengthening discrepancy (> 3 cm)
Cryptorchidism for males
Speech/language development
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Hundreds of cases reported
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¾ Very rarely familial
RUSSELL-SILVER/SILVERRUSSELL
DIFFERENTIAL DIAGNOSIS
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DNA repair
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Partington
3-M syndrome
Fetal alcohol syndrome
IMAGe syndrome
Chromosomal
Diploid/triploid mixoploidy
Mosaic Turner syndrome
Y q deletions
Trisomy 18 and 18p -
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Fanconi anemia
Nijmegen breakage
Bloom syndrome
X-linked with hyperpigmental skin
RUSSELL-SILVER/SILVER-RUSSELL
REFERENCES
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Bailey W et al. Monozygotic twins discordant for the Russell-Silver syndrome. Am J
Med Genet 1995;58:101-105.
Bliek J et al. Hypomethylation of the H19 gene causes not only Silver-Russell synrome
(SRS) but also isolated asymmetry or an SRS-like phenotype. Am J Hum Genet
2006; 78:604-614.
Dupont JM et al. Familial Reciprocal Translocation t(7;16) associated with maternal
uniparental disomy 7 in a Russel-Silver patient. Am J Med Genet 2002;111:405408.
Font-Montgomery E et al. Clinical outcome and follow-up of the first reported case of
Russell-Silver syndrome with the unique combination of maternal uniparental
heterodisomy 7 and mosaic trisomy 7. Birth Defects Res A 2005; 73:577-582.
Gicquel C et al. Epimutation of the telomeric imprinting center region on chromosome
11p15 in Silver-Russell syndrome Nat Genet 2005; 37:1003-1007.
Hannula K et al. Do patients with maternal uniparental disomy for chromosome 7 have
a distinct mild Silver-Russell phenotype?. J Med Genet 2001;38:273-278.
Hitchins MP et al. Investigation of the GRB2, GRB7, and CSH1 genes as candidates for
the Silver-Russell syndrome (SRS) on chromosome 17q. J Med Genet 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.
Matsumoto N. A 4-Mb critical region for intrauterine growth retardation at 15q26. Clin
Genet 2002; 62:340-342.
Monk D et al. Chromosome 7p disruptions in Silver Russell syndrome: delineating an
imprinted candidate gene region. Hum Genet 2002;111:376-387.
Schonherr N et al. The centromeric 11p15 imprinting centre is also involved in SilverRussell syndrome. J Med genet 2007; 44:59-63.
Tamura T et al. Ring chromosome 15 involving deletion of the insulin-like growth factor
1 receptor gene in a patient with features of Silver-Russell syndrome. Clin
Dysmorphol 1993;2:106-113.
MULIBREY NANISM
Muscle Liver Brain Eye
Perhentupa et al 1970 - Finnish
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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- 2
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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- 3
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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-coil protein
• Ubiqutin E3 ligase
MULIBREY NANISM- 4
MANAGEMENT
¾ Feeding problems early
¾ Pericardiectomy often necessary
¾ GH therapy little increase in ultimate weight
¾ Females have spontaneous puberty, then
ovarian failure, oligomenorhea, and
infertility
MULIBREY NANISM- 5
DIFFERENTIAL DIAGNOSIS
¾ Russell-Silver syndrome
¾ 3-M syndrome
¾ Meier Gorlin syndrome
MULIBREY NANISM- 6
REFERENCES
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Avela K et al. Gene encoding a new RING-B-box-Coiled coil protein is
mutated in mulibrey nanism. Nature Genetics 2000;25:298- 301.
Balg S et al. Mulibrey nanism. Clin Dysmorphol 1995;4:63-69.
Hamalainen RH et al. Wilms’ tumor and novel TRIM37 mutations in an
Australian patient with mulibrey namism. Clin Genet 2006
70:473479.
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.
Karlberg N et al. Mulibrey nanism: clinical features and diagnostic
criteria. J Med Genet 2004;41:92-98.
Karlberg N e al. Failure of sexual maturation in mulibrey nanism.
NEJM 2004; 351:2559-2560.
Lapunzina P et al. Mulibrey nanism: three additional patients and a
review of 39 patients. Am J Med Genet 1995;55:349-355.
3–M
Miller McKusick Malvaux et al. 1975
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Relatively large head, dolicocephaly, with
frontal bossing, 50th centile for age
Short broad neck with prominent 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, long
philtrum,
prominent lips, “gloomy facies”
3 – M – (2)
¾ Full eyebrows
¾ Prominent ears
¾ Fleshy nose tip
¾ Crowded teeth, V-shaped dental arch
¾ Short fifth finger
¾ Hypospadius and hypogonadism in males
3 – M – (3)
Miller McKusick Malvaux et al. 1975
¾ Hyperlordosis
¾ Loose joints
¾ Slender long bone with diaphyseal
constriction and flared metaphyses
¾ Tall vertebrae
¾ Thoracic kyphoscoliosis
¾ ? CNS aneurysms
3 – M – (4)
TREATMENT
¾ Feeding problems
¾ Male
cryptorchidism, infertility
¾ Watch for kyphoscolosis
3 – M – (5)
¾ Autosomal recessive, increased
consanguinity
¾ Heterozygotes may have minor clinical
features
¾ About 100 cases reported
¾ Cullin 7 gene, 25 different mutations in
29 families
¾ CUL7 assembles an E3 ubiquitin ligase
complex
3 – M – (6)
Miller McKusick Malvaux et al. 1975
DIFFERENTIAL DIAGNOSIS
¾ Russell-Silver syndrome
¾ Bloom syndrome
¾ Mulibrey Nanism
3 – M – (7)
REFERENCES
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Hennekam RCM et al. Further delineation of the 3-M syndrome with
review of the literature. Am J Med Genet 1987;28:195-209.
Huber C et al. Identification of mutations in CUL7 in 3-M syndrome.
Nature Genet 2005;37:1119-1124.
Le Merrer M et al. Dwarfism with gloomy face: a new syndrome with
features of 3-M syndrome. J Med Genet 1991;28:186-191.
Maksimova N et al. Clinical, molecular and histopathological
features of short stature syndrome with novel CUL7 mutation
in Yakuts: new population isolate in Asia. J Med genet
2007;44:772-778.
Miller JD et al. The 3-M syndrome: a heritable low birthweight
dwarfism. BDOAS 1975;11(5):39-47.
Mueller RF et al. The 3-M syndrome: risk of intracerebral
aneurysm?. J Med Genet 1992;29:425-427.
van der Wal G et al. 3-M syndrome: description of six new patients
with review of the literature. Clin Dysmorphol 2001;10:241-252.
Winter RM et al. The 3-M syndrome. J Med Genet 1984;21:124-128.
SHORT SYNDROME
(Gorlin et al and Sensenbrenner et al, 1975)
¾ Short stature
¾ Hyperextensible joints/inguinal hernia
¾ Ocular depression (deep set, large
appearing eyes)
¾ Rieger anomaly (megalocornea,
anterior segment dystrophy,
glaucoma, and lens opacities)
¾ Teething delay (small teeth, enamel
hypoplasia, malocclusion)
SHORT SYNDROME - 2
Speech delay (36 months) with normal
intelligence
¾ Triangular shaped face
z Broad forehead, small chin, small facial bones
z Telecanthus, deep set eyes, Reiger anomaly
z Hypoplastic alae, broad nasal bridge
¾ Micrognathia, dimple in chin
¾ Dental eruption delay and bone age delay
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SHORT SYNDROME - 3
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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
¾ Hyperextensible hands
¾ Clinodactyly 5th
¾ Large
& cone shaped epiphyses
¾ Thin, gracile, long bones
SHORT SYNDROME - 5
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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
¾ GMS
¾ DeHawere syndrome
¾ Russell-Silver syndrome
¾ Polycystic ovary disease
SHORT SYNDROME – 7
REFERENCES
Bankier A et al. Absent iris stroma, narrow body build and small facial
bones: a new association or variant of SHORT syndrome?. Clin
Dysmorphol 1995;4:304-312.
Brodsky MC et al. Rieger anomaly and congenital glaucoma in the SHORT
syndrome. Arch Ophthal 1996;114:1146-1147.
Haan E et al. SHORT syndrome: distinctive radiographic features. Clin
Dysmorphol 1998;7:103-107.
Joo SH et al. Case report on SHORT syndrome. Clin Dysmorphol
1999;8:219-221.
Koenig R et al. SHORT syndrome. Clin Dysmorphol 2003;12:45-50.
Lipson AH et al. The SHORT syndrome: further delineation and natural
history. J Med Genet 1989;26:473-475.
Schwingshandl J et al. SHORT syndrome and insulin resistance. Am J
Med Genet 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.
FLOATING HARBOR SYNDROME
Boston Floating Hospital – Harbor General
Hospital
(Pelletier et al 1973, Leisti et al 1974)
Developmental delay, particularly speech 100%
z Mild MR, some with hyperactivity
¾ Craniofacial – triangular face (round in infancy)
z Broad nose, bulbous with prominent nasal bridge
z Prominent eyes early, deep set later
z Wide mouth, thin lips
z Broad columella
z Smooth and short philtrum
z Large nares, hypoplastic alae
z Posteriorly rotated ears, appear lowset
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Head circumference normal for age
FLOATING HARBOR SYNDROME - 2
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Clinodactyly of 5th (nail hypoplasia),
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
¾ Delayed BA 100% - but puberty on time
¾ Clinodactyly of 5th
in 75% and coned
epiphyses
¾ Brachydactyly 50%
¾ Finger clubbed 45%
¾ Pseudoarthrosis of clavicle
FLOATING HARBOR SYNDROME – 4
¾ About 20 cases
¾ Mostly sporadic M:F – 1:2
¾ Consanguinity, 1 set of female sibs
¾ Advanced paternal age in most
¾ x 3 mother daughter affected – doubtful
¾ Gene Unknown
FLOATING HARBOR SYNDROME – 5
DIFFERENTIAL DIAGNOSIS
¾ Silver – Russell syndrome
¾ Shprintzen syndrome
¾ 3-M syndrome
¾ Dubowitz syndrome
¾ Rubinstein – Taybi syndrome
FLOATING HARBOR SYNDROME - 6
REFERENCES
Ala-Mello S et al. The first Finnish patient with the Floating-Harbor syndrome:
the follow-up of eight years. Am J Med Genet 2004;130A:317-319.
Davalos IP et al. Floating-Harbor syndrome. A neuropsychological approach.
Genetic Counseling 1996;7:283-288.
Feingold M. Thirty-two year follow-up of the first patient reported with the
Floating-Harbor syndrome. Am J Med Genet 2006;140A: 782-784.
Hersh JH et al. Changing phenotype in Floating-Harbor syndrome. Am J Med
Genet 1998;76:58-61.
Lacombe D et al. 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.
Patton MA et al. Syndrome of the month: Floating-Harbor syndrome. J Med
Genet 1991;28:201-204.
Rosen AC et al. A further report on a case of Floating-Harbor Syndrome in a
mother and daughter. J Clin Exp Neuropsychol 1998;20:483-495.
Wiltshire E et al. Floating-Harbor syndrome complicated by tethered cord: A
new association and potential contribution from growth hormone therapy.
Am J Med Genet 2005;136A:81-83.
BLOOM SYNDROME
(Bloom 1954, German F/U)
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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: leukemia,
lymphoma, adenocaricoma,
squamous cell, carcinoma, and Wilm’s
(at least 44% affected, mean age of onset
25 years)
BLOOM SYNDROME – 2
¾ High squeaky voice
¾ Immune deficiency and reduced 1gA,
1gG, 1gM
¾ Chronic infections (particularly chronic
lungs 20%)
¾ Male infertility with small testes, females
fertile with premature menopause
BLOOM SYNDROME - 3
¾ Delayed puberty (and BA)
¾ DM 16% - type 2 after puperty
¾ Mild MR – normal IQ with learning
disability
¾ Feeding problems in infancy
¾ Male infertility with small testes,
females fertile with early menopause
BLOOM SYNDROME - 4
¾ Increase sister chromatid
exchange (SCE) breakage,
dicenrics, tetraradials
BLOOM SYNDROME - 5
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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’ to 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
¾ Russell Silver syndrome
¾ Rothmund Thompson syndrome
¾ Cockayne syndrome
¾ Ataxia Teliangectasia
¾ Fanconi Anemia
BLOOM SYNDROME - 8
REFERENCES
Auerbach AD et al. Disorders of DNA replication and repair.
Curr Opin Pediatr 1997;9:600-616.
Chisholm CA et al. Successful pregnancy in a woman with
Bloom syndrome. Am J Med Genet 2001;102:136-138.
Ellis NA et al. Molecular genetics of Bloom's syndrome.
Hum Mol Genet 1996;5:1457-1463.
Ellis NA et al. The Bloom's sydrome gene product is
homologous to RecQ helicases. Cell 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.
Passarge E. Bloom's syndrome: the German experience.
Ann Genet (Paris) 1991;34:179-197.
DUBOWITZ SYNDROME - 1
Dubowitz 1965
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DD & MR – mild – moderate (72%)
Hyperactivity 70%
Shy, short attention span
Speech delay 67%
High pitched voice 55%, hoarse
cry 30%
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
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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
¾ Small chin 80%, with age becomes long
square chin
¾ Clinodactyly of fifth - 50% and
syndactyly 20%
¾ Males hypospadias, cryptorchidism 50%
¾ Leukemia, lymphoma, neuroblastoma,
and aplastic anemia have been
reported
DOBOWITZ SYNDROME – 4
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150 cases
AR many with consanguinity
? Subtypes
• ? Anorectal & craniosynostosis
subtypes
• Immune deficiency and frequent
infection
• Low cholesterol
Gene unknown
DOBOWITZ SYNDROME – 5
DIFFERENTIAL DIAGNOSIS
¾ FAS syndrome
¾ Bloom syndrome
¾ Smith-Lemli-Opitz syndrome
¾ 22q- syndrome
DOBOWITZ SYNDROME – 6
REFERENCES
Hansen KE et al. Dubowitz syndrome: long-term follow-up of an original
patient. Am J Med Genet 1995;55:161-164.
Ilyina HG et al. Dubowitz syndrome: possible evidence for a clinical
subtype. Am J Med Genet 1990;35:561-565.
Moller KT et al. The Dubowitz syndrome: a retrospective. J Cranio Gen
Dev Bio 1985;5:283-286.
Parrish JA et al. Studies of the density and the properties of the hair in a
new inherited syndrome of hypotrichosis. Ann Hum Genet
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.
Winter RM. Syndrome of the month: Dubowitz syndrome. J Med Genet
1986;23:11-13.
MAJEWSKI (MICROCEPHALIC)
OSTEODYSPLASTIC PRIMORDIAL
DWARFISM II
Majewski et al 1982
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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
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Progressive bony changes and loose
jointedness with disproportionate
shortening of mesomelic segment
Brachydactyly
Bowed legs
Develop café 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
¾ Develop intracranial aneurysm
¾ Develop truncal obesity
¾ Rarely DM
¾ Cutis mamorata seen
¾ Males cryptorchidism, hypospadias,
micropenis
¾ Reduced life expectancy – oldest 40 years
old
¾ No increase in cancer noted
MOPD II – 4
MANAGEMENT
¾ Feeding
problems
¾ Little or no response to GH
¾ Scoliosis may develop
¾ CNS aneurysm need to be screened for
¾ Avoid sun
¾ Watch for dislocation radius & knees
¾ Danger from being so small
¾ Watch for DM
MOPD II - 5
¾ Autosomal recessive with consanguinity
¾ Increase among Mediterranean countries
¾ Variability in same family
¾ About
100 cases reported
MOPD II - 6
¾ Percentrin (PCNT) mutations
¾ Component of centrosome complex
¾ Role in cell division (mitosis)
¾ Helps to organize mitotic spindle for
segregation and anchoring of
spindle
¾ Giant coiled coil protein localized to
centrosome througout cell cycle
¾ 21q22.3
MOPD II - 7
¾ Meier-Gorlin syndrome
¾ Floating Harbor syndrome
¾ 3 – M syndrome
¾ SHORT syndrome
¾ Seckels syndrome
¾ MOPD I and III
MOPD II – 8
REFERENCES
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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.
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.
Kannu P et al. Microcephalic osteodysplastic primordial dwarfism type
II: a child with cafe au lait lesions, cutis marmorata, and
moyamoya disease. Am J Med Genet 2004;128A:98-100.
Nishimura G et al. Microcephalic osteodysplastic primordial short
stature type II with cafe-au-lait spots and moyamoya disease. Am J
Med Genet 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.
Rauch A et al. Mutations in the pericentrin (PCNT) gene cause
primoridal dwarfism. Science 2008;319:816-819.
Young ID et al. Microcephalic osteodysplastic primordial short stature
type II with cafe-au-lait spots and moyamoya disease: another
patient. Am J Med Genet 2004;127A:218-220.
SUMMARY 1
ALL PROPORTIONATE, IUGR, AND POSTNATAL SHORT STATURE
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Bloom syndrome
z Mild microcephaly, malar hypoplasia
z Telangectasia erythemations rash on cheeks and with sun
exposure
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Floating Harbor syndrome
z Speech delay - mild MR
z Changing face – prominent nose, short philtrum
z BA delay, but puberty on time
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SHORT
z Riegers (lens opacity, glaucoma), eyes large appearing, then
deepset
z Lipodystrophy of face and upper torso
z Speech delay – IQ okay
z Hypoplastic alae, prominent nose as adults
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SUMMARY 2
ALL PROPORTIONATE, IUGR, AND POSTNATAL SHORT STATURE
Dubowitz syndrome
z Relative microcephaly
z Eczema
z Sparce lateral eyebrows
z Telecanthus, prominent epicanthal folds
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Russell-Silver/Silver-Russell
z Normal size head (pseudohydrocephaly)
z Relatively underweight
z 50% asymmetric
z BA delay, late puberty
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Mulibrey Nanism
z Large, long head with triangular face with depressed bridge of
nose
z Constructive pericarditis and heart failure with liver
enlargement
z Yellow pigment and spots in retina
z Fibrosis of ovaries, fibrodysplasia of tibia
SUMMARY 3
ALL PROPORTIONATE, IUGR, AND POSTNATAL SHORT STATURE
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3-M
z Short thorax with sternal deformity, transverse ribs, rib groove
z Broad neck, square shoulders, prominent trapezius
z Triangular face, full lips, hypoplastic midface, long philtrum
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MOPD II
z Severe pre & postnatal growth
z Progressive microcephaly, high forehead
z Prominent nose, small teech, squeaky voice
z Progressive boney dysplasia
SEVERE IUGR
¾ Epigenetic control of growth
¾ Ubiquinoation
¾ Peroxisomal function
¾ Centrosomal functiion – mitotic spindle
¾ DNA repair
¾ Chromosomal aberrations
¾ Teratogens
¾ Placental function
COMMON AND OVERLAPPING
FEATURES
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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, thin ribs, and long bones)
“A” LIST
1.
2.
3.
4.
5.
6.
7.
8.
Bloom*
Dubowitz
Floating Harbor
MOPD II*
Mulibrey*
Silver-Russell/Russell-Silver***
SHORT
3-M*
Also: Chromosomal, CPM, and teratogens
“B” LIST
Gorlin/Smith/Jones
¾ Aarskog Sx
¾ de Lange Sx
¾ Hallerman Streiff Sx
¾ Meire-gorlin Sx
¾ Rubinstein Taybi Sx
¾ Seckel’s Sx
Hall 2004 article on MOPD II
¾ Toriello 1986
¾ Saul Wilson Hersh 1990 & 1994
¾ Hurst 1988
¾ Sdfs
¾ Bangstad 1989, Salerno 2003, Scott 1969
¾ Bluebel 1996
¾ Cervenka 1979
¾ Frias 2005
REFERENCES
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Gorlin RJ, Cohen Jr. MM, Hennekam RCM. Syndromes of
the head and neck, 4th ed. Oxford University Press, NY,
2001.
Jones KL. Smith’s recognizable patterns of human
malformations, 6th edition. WB Saunders,
Philadelphia, 2006.
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=OMIM
Genetest/GeneClinics
http://www.genetests.org