Prader-Willi syndrome

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Prader-Willi syndrome is a neurogenetic disorder character- ized by hypotonia and feeding difficulties in infancy, followed by hyperphagia, hypogonadism, mental retardation, and short stature. It was the first recognized microdeletion syndrome identified with high-resolution chromosome analysis, the first recognized human genomic imprinting disorder, and the first recognized disorder resulting from uniparental disomy. The incidence of Prader-Willi syndrome is approximately 1/10,000 to 1/15,000 individuals.

GENETICS/BASIC DEFECTS

1. Inheritance

a. Usually sporadic events (de novo deletions of 15q11-q13)

b. Rare familial transmission (balanced translocations involving 15q11-q13) (<1%)

2. A contiguous gene syndrome involving multiple paternally expressed genes

3. Caused by the lack of expression of normally active pater- nally inherited genes at chromosome 15q11-q13 because of a phenomenon called genomic imprinting

a. The relevant region on chromosome 15q11-q13: nor- mally expressed on the paternally derived chromosome and imprinted on maternally derived chromosome b. The imprinted maternal allele is unable to produce

functional protein since the normally expressed pater- nal copy is often deleted in Prader-Willi syndrome 4. Molecular subclassification of Prader-Willi syndrome: all

involving loss of paternal gene expression from chromo- some 15q11-q13

a. Paternal deletion 15q11-q13 (70% of cases): micro- deletion of the actively transcribed segment on the paternally derived chromosome 15q11-q13

b. Maternal uniparental disomy (UPD15) (25–30% of cases)

i. Inheritance of two copies of the maternal chro- mosome without paternal contribution

ii. In normal individuals, the paternally donated chromosome expresses multiple genes in the Prader-Willi syndrome region while the maternal chromosome is largely silent

iii. In case of maternal uniparental disomy, without the presence of a chromosome donated from the father, normal imprinting on the 2 maternally donated chromosomes leads to the absence of gene expression in this region

c. Mutation in the imprinting control center

i. Deletion of the imprinting center (1–2% of the cases) of the SNRPN (small nuclear ribonucleo- protein polypeptide N) gene causing inability to establish the normal methylation status

ii. Without imprinting center deletion (1–2% of cases)

CLINICAL FEATURES

1. Neonatal presentation

a. Central hypotonia in infancy b. Poor feeding/sucking

c. Poor weight gain (failure to thrive) d. Genital hypoplasia/hypogonadism e. Diminished deep tendon reflexes

f. Abnormal squeaky weak cry

g. History of fetal inactivity (in utero hypotonia) 2. Developmental delay

3. Mild dysmorphic features a. Almond-shaped eyes b. Dolichocephaly

c. Narrow bifrontal diameter d. Narrow nasal bridge e. Small mandible

f. Small mouth g. High-arched palate h. Down-turned lips

i. Thick viscous saliva

4. Hyperphagia after the 1st-2nd postnatal years 5. Severe obesity without significant intervention 6. Retinal hypopigmentation

7. Small hands and feet (acromicria) 8. Mild to moderate mental retardation

9. Hypothalamic insufficiency suggested by several auto- nomic dysfunctions that affect appetite regulation, growth, pubertal development, control of breathing, and alertness

10. Behavioral and psychiatric difficulties a. Excessive food-seeking behaviors b. Obsessions

c. Compulsions d. Mood lability e. Depression 11. Other manifestations

a. Infantile lethargy

b. Sleep disturbance and/or sleep apnea c. Short stature

d. Hypopigmentation

e. Skin sores from constant picking f. Esotropia/myopia

g. Speech articulation defects h. High pain threshold

i. Ineffective thermoregulation j. Early adrenarche

k. Osteoporosis l. Kyphoscoliosis 12. Prognosis

a. Obesity: the major cause of morbidity and mortality b. Cardiopulmonary compromise (Pickwickian syn-

drome) resulting from excessive obesity

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13. Diagnostic criteria (adapted from Holm et al., 1993): 5 points for children under 3 years (3 from major criteria); 8 points for children above 3 years (4 from major criteria)

a. Major Criteria (1 points each) i. Infantile central hypotonia

ii. Infantile feeding problems/failure to thrive iii. Rapid weight gain between 1 and 6 years

iv. Characteristic facial features

v. Hypogonadism (genital hypoplasia, pubertal deficiency)

vi. Developmental delay/mental retardation b. Minor Criteria (1/2 point each)

i. Decreased fetal movement and infantile lethargy ii. Typical behavioral problems

iii. Sleep disturbance/sleep apnea

iv. Short stature for the family by age 15 years v. Hypopigmentation

vi. Small hands and feet for height age vii. Narrow hands with straight ulnar border viii. Esotropia/myopia

ix. Thick viscous saliva x. Speech articulation defects xi. Skin picking

c. Supportive Criteria (no points) i. High pain threshold ii. Decreased vomiting

iii. Temperature control problems iv. Scoliosis/kyphosis

v. Early adrenarche vi. Osteoporosis

vii. Unusual skill with jigsaw puzzles viii. Normal neuromuscular studies

DIAGNOSTIC INVESTIGATIONS

1. Cytogenetic studies

a. Microscopic or submicroscopic del(15)(q11-q13) confirmed by fluorescence in situ hybridization (FISH probe for SNRPN) (60–80%)

b. Paternally derived chromosome 15 that is deleted c. De novo events in most cases with cytogenetically

normal father’s chromosomes

d. Balanced chromosomal rearrangement with break in 15q11-q13 (<1%)

2. Molecular analyses

a. Uniparental disomy identified by using microsatellite repeat sequences of chromosome 15 in the patient and both parents

i. Maternal uniparental disomy for chromosome 15 in most of non-deletion cases (20–40%)

ii. Inheriting both copies of chromosome 15 from the mother

iii. Absence of the paternally inherited copy of chro- mosome 15q11-q13

b. Rare familial Prader-Willi syndrome: associated with very small mutations in 15q11-q13 region leading to the loss of expression of multiple genes from the paternal chromosome

c. DNA methylation analyses (by Southern blotting and PCR) of the SNRPN or PW71 (D15S63) loci to detect

absence of paternal methylation patterns on the basis of deletion, uniparental disomy, or defective methyla- tion: detects over 99% of cases and is highly specific

GENETIC COUNSELING

1. Recurrence risks

a. De novo deletion or maternal uniparental disomy in an affected child: a low recurrence risk ≤1% due to possible paternal balanced insertion or gonadal mosaicism)

b. Imprinting center mutation in an affected child: recur- rence risk up to 50%

c. Presence of a parental balanced chromosomal re- arrangement: up to 25% recurrence risk

2. Prenatal diagnosis a. High risk pregnancies

i. Parents who have had a previous child with Prader-Willi syndrome, caused by deletion or uniparental disomy, for assurance purpose ii. Parents who have had a previous child with

Prader-Willi syndrome, caused by a defect in the imprinting control center, because of the high recurrence risk

iii. Inherited translocation involving chromosome 15 and resulting in a deletion, because of the theoretical 25% risk of Prader-Willi syndrome in the offspring

b. Low risk pregnancies in which no family history of Prader-Willi syndrome exists

c. Cytogenetic study to detect del(15q11-q13) from amniocytes or CVS cells, complemented by FISH probe

d. Molecular studies of uniparental disomy 15 using microsatellite dinucleotide polymorphism analysis of amniocytes and parental DNA

e. DNA methylation analysis of amniocytes 3. Management

a. Manage feeding problems with special nipples or gavage feeding if needed to assure adequate nutrition, to avoid failure to thrive, and to improve hypotonia b. Early intervention programs with speech, physical,

and occupational therapies after careful educational, behavioral, and psychological assessments

c. Dietary control

i. Monitoring of weight and nutritional counseling ii. Low-calorie and well-balanced diet combined

with a regular exercise program iii. Limit access to food

iv. Close supervision to minimize food stealing d. Management of endocrine problems

i. Growth hormone replacement in patients with deficient growth hormone

ii. Testosterone treatment in males to improve changes in voice and body hair, beard growth, genital size, body mass and strength, and self- image

iii. Treatment with estrogen, cycling hormones or

birth control pills in females has resulted in

increasing breast size and menstrual periods

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e. Management of scoliosis as in the general population f. Behavioral management

i. Firm limit setting and enforcement

ii. Consult with a behavioral psychologist or other behavior specialist for behavioral management programs

g. Psychiatric management i. Psychosis

ii. Manic-depressive illness iii. Obsessive-compulsive disorder

h. Treatment of complications resulting from excessive obesity

i. Cardiopulmonary compromise ii. Type II diabetes mellitus iii. Thrombophlebitis

iv. Management of skin picking, chronic skin changes, and peripheral edema

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Fig. 1. A 10-month old girl with Prader-Willi syndrome showing severe hypotonia, strabismus, and small hands and feet. Parent-of-origin specific DNA methylation studies at 15q11-q13 for Prader-Willi syndrome revealed the presence of maternal 4.2 kb hybridization band only but not paternal 0.9 kb band consistent with Prader-Willi syndrome. Uniparental disomy DNA analysis revealed that the patient has only maternal alleles based on the Mendelian inheritance of 2 informative markers (D15S205 and D15S1002) and 2 partial informative markers (D15S130 and D15S1007), indicative of uniparental disomy for chromosome 15.

Fig. 3. A girl with Prader-Willi syndrome [del(15)(q11-q13)] showing obesity, short stature, almond-shaped eyes, and small hands and feet.

Fig. 2. An infant with Prader-Willi syndrome [del(15)(q11-q13)]

showing hypotonia and failure to thrive.

Fig. 4. A boy with Prader-Willi syndrome [del(15)(q11-q13)] showing almond-shaped eyes, bitemporal narrowing, obesity, hypogenitalism, and small hands and feet.

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Fig. 5. A girl with Prader-Willi syndrome [del(15)(q11-q13)] showing extreme obesity, characteristic facial appearance, small hands and feet, and multiple skin sores from constant picking.

Fig. 6. Sore on the hand in a patient with Prader-Willi syndrome [del(15)(q11-q13)] (shown by partial karyotypes and ideogram) and trimethylaminuria.

Fig. 7. A woman with Prader-Willi syndrome [del(15)(q11-q13)] and neurofibromatosis 1 showing obesity and axillary freckles.