Clinical Utility of Testing

Diagnostic Testing

Prader-Willi syndrome is a disorder with many manifestations related to hypothalamic insufficiency. The major features include infantile hypotonia, hypogonadism, dysmorphic appearance, small hands and feet, hyperpha-gia and obesity, developmental delay and MR, and characteristic behavior such as temper outbursts, rigidity, and repetitive thoughts and behavior. In infancy, the differential diagnosis includes neuromuscular disorders associated with hypotonia such as congenital myotonic dystrophy. The differential diagnosis in children and adults includes disorders with MR and obesity such as Bardet-Biedl, Cohen, and fragile X syndromes as well as acquired hypothalmic injury.

AS is characterized by microcephaly, gait ataxia, seizures, severe speech impairment, severe development delay or MR, and characteristic behavior, such as inappropriate laughter and excitability. The differential diagnosis in infancy includes cerebral palsy, inborn errors of metabolism, mitochondrial encephalopathy, and Rett syndrome. Infants with AS sometimes have been clinically misdiagnosed as PWS because of hypotonia, feeding difficulties, and developmental delay, or because the distinctive features of AS are not apparent until later in development.

Prenatal Testing

The risk of recurrence and the type of prenatal testing vary according to the chromosome or molecular defect found in the proband. For this reason, prenatal diagnosis should be undertaken only after the genetic mechanism in the proband has been determined and the parents have received genetic counseling. A low risk of recurrence is associated with PWS and AS due to a deletion or UPD, if the parents' chromosomes are normal; however, prenatal testing may be offered for reassurance. Since mosaicism has been reported in mothers of AS patients with UBE3A mutations, prenatal testing should be offered even if the mother is negative for a mutation. Prenatal testing is also appropriate for families without a child with PWS or AS if a deletion of chromosome 15q11-q13 is suspected on chromosome analysis of CVS or amniotic fluid, if trisomy 15 is noted on CVS but a normal karyotype is found on amniotic fluid, and if a de novo chromosome 15 translocation or supernumerary marker chromosome is found by karyotyping.

Testing Parents and Other Family Members of a Proband

Parents of patients with deletions, specifically fathers of PWS patients and mothers of AS patients, should have chromosome and FISH analysis to determine whether they carry balanced subtle chromosome rearrangements or deletions not expressed as an abnormal phenotype in that parent. Chromosome analysis also is appropriate for parents of patients with UPD combined with a Robertson-ian translocation to determine whether the translocation is inherited or de novo. Parents also should be tested for mutations that are identified in the proband such as IC deletions or UBE3A mutations. If a parent of a PWS or AS patient is a carrier of a mutation or a chromosomal translocation, then the siblings of that parent should be offered testing.

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