PPP1CB-Related Noonan Syndrome with Loose Anagen Hair: A Systematic Review

Background: PPP1CB-related Noonan syndrome-like disorder with loose anagen hair type 2 (NSLH2; OMIM #617506) is a rare RASopathy caused by pathogenic variants in PPP1CB, encoding the catalytic beta subunit of protein phosphatase 1 (PP1C). Since its first description in 2016, only a limited number of patients have been reported, leaving the full phenotypic spectrum and genotype-phenotype correlations largely undefined. Objectives: To systematically review the clinical, molecular, and functional characteristics of NSLH2, we define its phenotypic spectrum, explore genotype-phenotype correlations, and summarize current evidence on therapeutic management. Methods: A systematic literature search was conducted across PubMed/MEDLINE, Embase, Web of Science, and Google Scholar, supplemented by searches of Orphanet, OMIM, and ClinVar, from 2016 to 2026. Studies reporting patients with pathogenic or likely pathogenic variants in PPP1CB were included. Individual patient-level data were extracted and analyzed descriptively. Additionally, we report a novel patient identified at our institution. Results: Thirty patients from 14 publications were included, harboring nine distinct PPP1CB variants. The most frequently identified variant was p.Pro49Arg (n = 17, 56.7%), followed by p.Met182Lys (n = 4, 13.3%) and p.Glu183Ala (n = 3, 10.0%). The majority of variants arose de novo (n = 26, 86.7%). Ectodermal anomalies, predominantly slow-growing and structurally abnormal hair consistent with loose anagen hair, were present in 79.3% of patients. Congenital heart defects were identified in 75.9%, with pulmonary stenosis and atrial septal defect representing the most common lesions. Short stature was documented in 69.2% of cases, and neurodevelopmental delay-encompassing motor and language delay-affected the majority of patients (72.4-84.6%). Brain structural anomalies were detected in 35.7%. Facial dysmorphic features were universal. Macrocephaly was present in 58.6% of cases, intellectual disability was reported in 26.9%, and epilepsy in 6.7%. Three familial cases with inherited p.Met182Lys transmission from an affected mother to three children are described, representing the largest reported familial cluster. Conclusions: NSLH2 is a clinically recognizable RASopathy with a consistent core phenotype comprising loose anagen hair, congenital heart defects, short stature, macrocephaly, and neurodevelopmental delay. The p.Pro49Arg variant accounts for the majority of reported cases and appears associated with a broad phenotypic expression. Larger cohorts and functional studies are needed to fully delineate genotype-phenotype correlations and guide therapeutic strategies.