Expanding the SHOC2 mutation associated phenotype of Noonan syndrome with loose anagen hair: structural brain anomalies and myelofibrosis.

Authors:
Karen W Gripp
Karen W Gripp
A. I. duPont Hospital for Children
Wilmington | United States
Dina J Zand
Dina J Zand
The Children's Hospital of Philadelphia
United States
Laurie Demmer
Laurie Demmer
Slone Epidemiology Center at Boston University
United States
Carol E Anderson
Carol E Anderson
Drexel University College of Medicine
United States
William B Dobyns
William B Dobyns
University of Washington
Seattle | United States
Elaine H Zackai
Elaine H Zackai
The Children's Hospital of Philadelphia
Philadelphia | United States
Elizabeth Denenberg
Elizabeth Denenberg
A. I. duPont Hospital for Children
Kim Jenny
Kim Jenny
St Mary's Hospital
United Kingdom

Am J Med Genet A 2013 Oct 5;161A(10):2420-30. Epub 2013 Aug 5.

Division of Medical Genetics, A. I. duPont Hospital for Children, Wilmington, Delaware.

Noonan syndrome is a heterogenous rasopathy typically presenting with short stature, characteristic facial features, cardiac abnormalities including pulmonic valve stenosis, ASD and hypertrophic cardiomyopathy (HCM), cryptorchidism, ectodermal abnormalities, and learning differences. The phenotype is variable, and limited genotype phenotype correlation exists with SOS1 mutations often associated with normal cognition and stature, RAF1 mutations entailing a high HCM risk, and certain PTPN11 mutations predisposing to juvenile myelomonocytic leukemia. The recently identified SHOC2 mutation (p.Ser2Gly) causes Noonan syndrome with loose anagen hair. We report five patients with this mutation. All had skin hyperpigmentation, sparse light colored hair, increased fine wrinkles, ligamentous laxity, developmental delay, and 4/4 had a structural cardiac anomaly. Hypotonia and macrocephaly occurred in 4/5 (80%); 3/5 (60%) had polyhydramnios, increased birth weight or required use of a feeding tube. Distinctive brain abnormalities included relative megalencephaly and enlarged subarachnoid spaces suggestive of benign external hydrocephalus, and a relatively small posterior fossa as indicated by a vertical tentorium. The combination of a large brain with a small posterior fossa likely resulted in the high rate of cerebellar tonsillar ectopia (3/4; 75%). Periventricular nodular heterotopia was seen in one patient with a thick and dysplastic corpus callosum. We report on the first hematologic neoplasm, myelofibrosis, in a 2-year-old patient with SHOC2 mutation. Myelofibrosis is exceedingly rare in children and young adults. The absence of a somatic JAK2 mutation, seen in the majority of patients with myelofibrosis, is noteworthy as it suggests that germline or somatic SHOC2 mutations are causally involved in myelofibrosis.

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http://dx.doi.org/10.1002/ajmg.a.36098DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3787995PMC
October 2013
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