SHORT syndrome

istituti.unicatt.it

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

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