Wallach's Interpretation of Diagnostic Tests: Pathways to Arriving at a Clinical Diagnosis (444 page)

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PRADER-WILLI SYNDROME (PWS)

MIM #176270

   Definition

Prader-Willi syndrome (PWS) results from deletion of the paternal copies of the imprinted SNRPN gene, the necdin gene, and possibly other genes within the chromosome region 15q11-q13.

   Who Should Be Suspected?

Prader-Willi syndrome is characterized by diminished fetal activity, obesity, muscular hypotonia, mental retardation, short stature, hypogonadotropic hypogonadism, and small hands and feet. There are three genetic reasons of PWS: (1) paternal deletion—about 70% of all cases of PWS, (2) maternal uniparental disomy (UPD)— about 25% of cases, and (3) imprinting defect—<5% of cases

   Relevant Tests and Diagnostic Value

   Molecular testing:

   FISH—typical deletions, large and small, can be detected—if the FISH test is positive (a deletion is found), the diagnosis of PWS is confirmed.

   DNA methylation test—confirms or rules out PWS as a diagnosis with over 99% accuracy. Normal results show both paternal and maternal DNA imprinting pattern. In PWS, there is only a maternal pattern, but the positive result does not tell whether the cause of PWS is deletion, uniparental disomy (UPD), or an imprinting defect.

   DNA polymorphism study is done to confirm UPD. It requires blood samples from both parents and child. If both chromosomes are from the mother, the PWS is confirmed.

Suggested Readings

Driscoll DJ, Miller JL, Schwartz S, et al. Prader-Willi syndrome. In: Pagon RA, Adam MP, Bird TD, et al., eds.
GeneReviews
^™
[Internet]
. Seattle, WA: University of Washington, Seattle; 1998: 1993– 2013 Oct 6 [Updated 2012 Oct 11]. Available from:
http://www.ncbi.nlm.nih.gov/books/NBK1330

http://www.pwsausa.org/syndrome/Genetics_of_PWS.htm

www.faseb.org/genetics/acmg/pol-22htm

RETT SYNDROME

MIM #312750

   Definition

The majority of females presenting with clinical consensus criteria for Rett Syndrome have mutations in the transcription repressor MECP2 gene (Xq28). However, not all patients with MECP2 mutations have all the necessary clinical criteria for Rett syndrome diagnosis, and MECP2 mutations have not been found in some Rett patients.

Who Should Be Suspected?

Classic Rett syndrome is characterized by abnormal psychomotor development usually beginning in the first 6 months of life, followed by loss of purposeful hand skills and spoken language, gait abnormalities, and appearance of stereotypic hand movements.

   Relevant Tests and Diagnostic Value

Sequence analysis of entire coding region, especially C-terminal; deletion/insertion analysis.

Suggested Reading

Neul JL, Kaufmann WE, Glaze DG, et al. Rett syndrome: revised diagnostic criteria and nomenclature.
Ann Neurol.
2010;68:944–950.