Noonan syndrome is a rasopathy caused by mutations in multiple genes encoding components of the RAS/MAPK pathway. Despite its variable phenotype, limited genotype–phenotype correlations exist. Noonan syndrome with loose anagen hair (NS-LAH) is characterized by its distinctive hair anomalies, developmental differences, and structural brain abnormalities and is caused by a single recurrent missense SHOC2 mutation. SHOC2 forms a complex with protein phosphatase 1 (PP1C). Protein phosphatases counterbalance kinases and control activation of signaling proteins, such as the mitogen-activated protein kinases of the RAS/MAPK pathway. Here we report four patients with de novo missense mutations in protein phosphatase one catalytic subunit beta (PPP1CB), sharing a recognizable phenotype. Three individuals had the recurrent PPP1CB c.146G>C, p.Pro49Arg mutation, the fourth had a c.166G>C, p.Ala56Pro change. All had relative or absolute macrocephaly, low-set and posteriorly angulated ears, and developmental delay. Slow growing and/or sparse hair and/or an unruly hair texture was present in all. Three individuals had feeding difficulties requiring feeding tubes. One of two males had cryptorchidism, another had pectus excavatum. Short stature was present in three. A female with the recurrent mutation had a Dandy–Walker malformation and optic nerve hypoplasia. Mild ventriculomegaly occurred in all, cerebellar tonsillar ectopia was seen in two and progressed to Chiari 1 malformation in one individual. Based on the combination of phenotypic findings and PPP1CB's effect on RAF dephosphorylation within the RAS/MAPK pathway, this novel condition can be considered a rasopathy, most similar to NS-LAH. Collectively, these mutations meet the standardized criteria for pathogenicity.
Bibliographical noteFunding Information:
We thank the patients and their families for sharing this information. Genematcher (genematcher.org) was instrumental in establishing the connection between the investigators. Research reported in this publication was supported by an Institutional Development Award (IDeA) from the National Institute of General Medical Sciences of the National Institutes of Health under grant numbers P30GM114736 (COBRE) and P20GM103446 (INBRE), the National Institute of Neurological Disorders and Stroke (NINDS) of the National Institutes of Health under award number R01NS050375 (to W.B.D.), an internal award from Seattle Children's Research Institute and a Burroughs Wellcome Fund Career Award for Medical Scientists (to J.T.B.), and by the Dandy–Walker Alliance. The content is solely the responsibility of the authors, and does not necessarily represent the official views of the National Institutes of Health. The funding sources had no role in the design and conduct of the study, collection, management, analysis and interpretation of the data, preparation, review or approval of the article, or decision to submit the article for publication.
© 2016 Wiley Periodicals, Inc.
- Dandy–Walker malformation
- Noonan syndrome
- developmental delay
- loose anagen hair
- short stature