Overgrowth & Premature Aging: 100 Genetic Syndromes

Front 1

Beckwith Wiedemann Syndrome: Type, Inheritance, Genes, Chromosome

Back 1

Overgrowth
Autosomal Dominant (15%)
CDKN1C, H19, KCNQ1OT1
11p15.5

Front 2

Sotos Syndrome: Type, Inheritance, Gene

Back 2

Overgrowth
Autosomal Dominant
NSD1
5q35

Front 3

Diagnosis and Mechanism in Beckwith Wiedemann

Back 3

Clinical Tests: AFP, abdominal CT

Molecular Tests: Cytogenetically detectable abnormalities of 11p15 (<1%);
Loss of methylation at DMR2 (50%);
Gain of methylation at DMR1 (2% -7%);
Pat. UPD for 11p15 (10-20%);
Mutations in the CDKN1C (40% of familial cases and 5-10% of sporadic cases)

Disease Mechanism: imprinted genes including growth factors and tumor suppressor genes in the 11p15.5 region

Front 4

Features of Beckwith Wiedemann

Back 4

Features:
Hemihyperplasia
Macrosomia (FAT)
Macroglossia
Omphalocele
Viceromegaly
Renal Abnormalities
Embryonal Tumors (Wilm's, hepatoblast, neuroblas, abdomosarcoma)
Neonatal Hypoglycemia
EarCreases, Ear Pits

Front 5

Diagnosis and Mechanism in Sotos Syndrome

Back 5

Molecular Tests: MLPA or FISH for 5q35 microdeletion including NSD1: ~15% (70% in Japanese).
NSD1 sequencing: 27-93% (12% in Japanese)

Disease Mechanism: Haploinsufficiency of NSD1. May be related to genes affecting growth.

Front 6

Features of Sotos Syndrome

Back 6

Classic: macrocephaly, pointed chin, tall stature and increased body mass, delayed motor skills, delayed cognitive, verbal, and social development, advanced BA.
Less common: phobias, aggression, OCD, ADD, abnormal EEG and seizure, chronic OM and constipation, congenital heart defects, strabismus, hyper/hypothyroidism, possible inc risk of tumors (saccrococcygeal teratoma and neuroblastoma).

Front 7

Ataxia with Oculomotor Apraxia
Types 1 & 2:
Type
Inheritance
Gene
Chromosome

Back 7

Premature Aging Syndrome
Autosomal Recessive
APTX, SETX
9p13.3, 9q34

Front 8

Ataxia with Oculomotor Apraxia
Types 1 & 2: Features

Back 8

Childhood onset of slowly progressive cerebellar ataxia,
followed by oculomotor apraxia and a severe primary motor peripheral axonal motor neuropathy.
Oculomotor apraxia progresses to external ophthalmoplegia.

Front 9

Ataxia with Oculomotor Apraxia
Types 1 & 2: Diagnosis and Mechanism

Back 9

Sequencing APTX (Inc incidence in Portugal and Japan)
and SETX.
Mutation detection rate unknown.

Disease Mechanism: There is direct involvement of aprataxin in the DNA single-strand break repair mechanisms; mutations in the APTX gene destabilize aprataxin and cells from individuals with AOA1 are characterized by enhanced sensitivity to agents that cause single-strand breaks in DNA

Front 10

COCKAYNE SYNDROME (CS):
Type
Inheritance
Gene
Chromosome

Back 10

Premature Aging Syndrome
Autosomal Recessive
ERCC6, ERCC8, ERCC-8
10q11, Chromosome 5

Front 11

COCKAYNE SYNDROME (CS): Features

Back 11

CS Type I: normal prenatal growth, severe FTT in first 2 years, progressive deterioration of vision, hearing, CNS, and peripheral nervous syndrome.
Type II: growth failure at birth, little or no postnatal neurological development, kyphosis, scoliosis, joint contracture.
Type III: normal growth and development or late onset. Xeroderma Pigmentosum-CS: facial freckling, early skin cancer, ID, spasticity, short stature, hypogonadism (no demyelination).

Front 12

COCKAYNE SYNDROME (CS): Testing and Mechanism

Back 12

Gene sequencing ERCC6 (75%), ERCC8 (25%)

Disease Mechanism: Abnormal transcription-coupled nucleotide excision repair (preferential removal of UV-induced pyrimidine dimers and other transcription blocking lesions)

Front 13

HUTCHINSON-GILFORD PROGERIA SYNDROME:
Type
Inheritance
Gene
Chromosome

Back 13

Premature Aging Syndrome
All de novo, (paternal age effect)
Lamin-A/C
Cytogenetic locus: 1q21.2

Front 14

HUTCHINSON-GILFORD PROGERIA SYNDROME: Features

Back 14

Short Stature, wt<<ht, head large for face, diminished sc fat, prominent scalp veins, generalized alopecia, delayed and crowded teeth, delayed fontanelle closure, pear shaped thorax, small chin, thin limbs, tight joints, wide based shuffling gate. Sclerodermatous skin changes over lower abdomen and thighs

Front 15

HUTCHINSON-GILFORD PROGERIA SYNDROME: Testing and Mechanism

Back 15

LMNA G608G Exon 11 (100%)
Disease Mechanism: G608G leads to abnl splicing and the mutant form of prelamin A that results is thought have a dominant negative effect leading to progressive defects in nuclear architecture