A novel rasopathy caused by recurrent de novo missense mutations in PPP1CB closely resembles Noonan syndrome with loose anagen hair.
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. © 2016 Wiley Periodicals, Inc.
Division of Medical Genetics, A. I. duPont Hospital for Children, Wilmington, Delaware.
Karen W
KW
Gripp
Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, Washington.
Kimberly A
KA
Aldinger
Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, Washington.|Department of Pediatrics, University of Washington, Seattle, Washington.
James T
JT
Bennett
Division of Medical Genetics, A. I. duPont Hospital for Children, Wilmington, Delaware.
Laura
L
Baker
Division of Medical Genetics, A. I. duPont Hospital for Children, Wilmington, Delaware.
Jessica
J
Tusi
Division of Medical Genetics, A. I. duPont Hospital for Children, Wilmington, Delaware.
Nina
N
Powell-Hamilton
Center for Applied Clinical Genomics, A. I. duPont Hospital for Children, Wilmington, Delaware.
Deborah
D
Stabley
Center for Applied Clinical Genomics, A. I. duPont Hospital for Children, Wilmington, Delaware.
Katia
K
Sol-Church
Center for Developmental Biology and Regenerative Medicine, Seattle Children's Research Institute, Seattle, Washington.
Andrew E
AE
Timms
Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, Washington.
William B
WB
Dobyns
D001921:Brain / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D003616:Dandy-Walker Syndrome / Q000175:diagnosis / Q000235:genetics; D003952:Diagnostic Imaging; D059472:Exome; D019066:Facies; D005260:Female; D056726:Genetic Association Studies; D005820:Genetic Testing; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D058247:Loose Anagen Hair Syndrome / Q000175:diagnosis* / Q000235:genetics* / Q000378:metabolism; D008297:Male; D020125:Mutation, Missense; D009634:Noonan Syndrome / Q000175:diagnosis* / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype; D054645:Protein Phosphatase 1 / Q000235:genetics*; D055815:Young Adult; D018631:ras Proteins / Q000378:metabolism
C517188:PPP1CB protein, human; D054645:Protein Phosphatase 1; D018631:ras Proteins
Dandy-Walker malformation; Noonan syndrome; PPP1CB; developmental delay; loose anagen hair; rasopathy; short stature