Noonan syndrome-like disorder with loose anagen hair

The phenotype overlaps clinically with but is distinguished by a characteristic ectodermal, growth and cardiac constellation. Affected individuals present with easily pluckable, sparse, thin and slow-growing hair (loose anagen hair), darkly pigmented skin frequently associated with eczema or ichthyosis, and a hypernasal voice. Short stature attributable to growth hormone deficiency is observed at higher frequency than in classic Noonan syndrome. Cardiac involvement is common, with mitral valve dysplasia and septal defects over-represented relative to classic Noonan syndrome. Hyperactive behaviour during childhood is described in many individuals and tends to improve with age. Clinical presentation usually emerges in infancy or early childhood. Inter- and intra-familial variability is marked, with the phenotype ranging from features that resemble classic Noonan syndrome to the distinctive constellation of loose anagen hair, hyperpigmented skin, growth hormone deficiency and cardiac involvement.

Due to insufficient data, no reliable statement on prevalence can currently be made. The condition is considered ultra-rare and represents well under 1% of the Noonan syndrome spectrum disorders.

Noonan syndrome-like disorder with loose anagen hair is caused by heterozygous germline pathogenic variants in SHOC2 (NSLH1) or PPP1CB (NSLH2). SHOC2 encodes a scaffold protein and PPP1CB encodes a catalytic subunit of phosphoprotein phosphatase 1; both participate in regulation of the RAS-MAPK signalling cascade. Disease-associated variants result in dysregulated activation of RAS-MAPK signalling, consistent with the wider RASopathy mechanism. A recurrent pathogenic missense variant in SHOC2 has been characterised at the molecular level.

Noonan syndrome-like disorder with loose anagen hair follows an autosomal dominant pattern of inheritance. Each child of an affected individual has a 50% risk of inheriting the germline pathogenic variant.

There are no established clinical or biochemical diagnostic criteria. The diagnosis is established by identification of a germline pathogenic variant in SHOC2 or PPP1CB by molecular genetic testing.

Main differential diagnoses include:

• : classic phenotype without loose anagen hair or mitral valve dysplasia over-representation; PTPN11, SOS1, RAF1 and others
• : more severe intellectual disability, coarser facies and prominent ectodermal pathology; BRAF, KRAS, MAP2K1, MAP2K2
• : failure to thrive, coarse facies, papillomata and deep palmar/plantar creases; HRAS

• Establishing the molecular diagnosis confirms the clinical suspicion and ends the diagnostic odyssey for affected individuals and their families.
• Identification of the causative pathogenic variant informs individualised clinical management decisions and is a prerequisite for targeted medical care that can be tailored by the treating physicians in consultation with the affected individual.
• Once the familial pathogenic variant has been identified, predictive testing can be offered to at-risk relatives in the context of human-genetic counselling.