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Noonan syndrome-like disorder with loose anagen hair
A Noonan-related syndrome, characterized by facial anomalies suggestive of Noonan syndrome, loose anagen hair, frequent congenital heart defects, distinctive skin features (darkly pigmented skin, keratosis pilaris, eczema or ichtyosis), and short stature that is often associated with a growth hormone deficiency. Psychomotor delay with attention deficit/hyperactivity disorder (ADHD) is frequently observed.
ORPHA:2701Classification level: Disorder
To date, more than 70 cases have been reported in the literature.
At birth and during childhood, the clinical features generally observed in Noonan syndrome appear more severe, but the phenotype generally improves with age. In particular, macrocephaly, high and prominent forehead, loose anagen hair and diffuse dark skin pigmentation are the features that may be observed early at birth or in infancy. The facial features, reminiscent of Noonan syndrome, include high broad forehead, hypertelorism, palpebral ptosis and downward slanting palpebral fissures, low-set, thick, posteriorly rotated ears, deep philtrum, micrognathia, and short neck. Hair is sparse, thin, easily plucked and slow growing despite being in the anagen phase. The roots lack inner and outer sheaths. Other ectodermal anomalies, include darkly pigmented and hairless skin, eczema and occasionally neonatal ichthyosis. The voice is hypernasal. Congenital heart abnormalities are common and predominated by mitral valve dysplasia and septal defects; hypertrophic cardiomyopathy (HCM) is observed in approximately 25% of cases. Short stature is often associated with proven growth hormone (GH) deficiency. Patients benefit from long-term GH-therapy, although they do not show the characteristic catch-up growth of isolated GH deficiency. Pubertal development is variable, showing a prolonged and delayed puberty or rapid pubertal progression that could impair the final height. A mild psychomotor delay with attention deficit/hyperactivity disorder (ADHD) is frequent. Sporadic neurological abnormalities such as ventriculomegaly, focal epilepsy, chronic complex tics, moyayamoya syndrome and neuroblastoma have been reported.
SHOC2 gene encodes a protein that is a positive modulator of the RAS-MAPK signaling pathway. The p.Ser2Gly change in SHOC2 creates an N-myristoylation site, resulting in constitutive targeting of the mutated protein to the plasma membrane and enhanced signaling through the MAPK cascade. PPP1CB gene is a component of RAS/MAPK pathway and missense mutations in PPP1CB have also been identified in patients with this phenotype.
Diagnosis is suspected on clinical presentation and confirmed by molecular testing.
The principal differential diagnosis includes Noonan syndrome and the other related disorders.
Prenatal diagnosis is possible where the pathogenic variant has previously been identified in a family member. It may also be suspected prenatally due to ultrasound abnormalities.
Transmission is autosomal dominant; however, most cases arise de novo and thus the risk of sibling recurrence is low.
Management and treatment
A multidisciplinary approach is mandatory. Regular evaluations by a pediatrician, endocrinologist, cardiologist, dermatologist, neurologist, psychologist should be recommended. GH therapy is a possible approach for short stature.
No longitudinal data are available for the estimation of life expectancy. The phenotype often improves with age. Quality of life depends on the degree of multiorgan and cognitive impairment and on the rehabilitation program adopted.