Noonan Syndrome-Like Disorder With Loose Anagen Hair 1

A number sign (#) is used with this entry because of evidence that Noonan syndrome-like disorder with loose anagen hair-1 (NSLH1) is caused by heterozygous mutation in the SHOC2 gene (602775) on chromosome 10q25.

Description

Noonan syndrome-like disorder with loose anagen hair is characterized by facial features similar to those observed in Noonan syndrome (163950), including hypertelorism, ptosis, downslanting palpebral fissures, low-set posteriorly angulated ears, and overfolded pinnae. In addition, patients display short stature, frequently with growth hormone (GH; see 139250) deficiency; cognitive deficits; relative macrocephaly; small posterior fossa resulting in Chiari I malformation; hypernasal voice; cardiac defects, especially dysplasia of the mitral valve and septal defects; and ectodermal abnormalities, in which the most characteristic feature is the hair anomaly, including easily pluckable, sparse, thin, slow-growing hair (summary by Bertola et al., 2017).

Genetic Heterogeneity of Noonan Syndrome-Like Disorder with Loose Anagen Hair

NSLH2 (617506) is caused by mutation in the PPP1CB gene (600590) on chromosome 2p23.

Clinical Features

Tosti et al. (1991, 1997) reported 2 unrelated children with loose anagen hair in association with Noonan syndrome (see 163950). Mazzanti et al. (2003) restudied these children and described a third unrelated child. All 3 children had short stature, the same facial phenotype, macrocephaly, enlarged cerebrospinal fluid spaces, short neck with redundant skin, severe growth hormone deficiency, mild psychomotor delay with attention deficit/hyperactivity disorder, mild dilatation of the pulmonary root in 2 of them, and a unique combination of ectodermal abnormalities. The skin was generally darkly pigmented and hairless. The hair of the head had the characteristics of loose anagen hair syndrome (600628). The hair was easily pluckable, sparse, thin, slow growing, and generally silver-blond. Mazzanti et al. (2003) suggested that the disorder in these children is distinct from Noonan syndrome.

Cordeddu et al. (2009) studied 25 patients with Noonan syndrome-like disorder with loose anagen hair and observed facial features that were typical of Noonan syndrome, including macrocephaly, high forehead, hypertelorism, palpebral ptosis, and low-set and posteriorly rotated ears, in addition to short and webbed neck and pectus anomalies. These features were associated with reduced growth that was frequently associated with proven growth hormone (GH; 139250) deficiency, cognitive deficits, distinctive hyperactive behavior that improved with age in most subjects, and hair anomalies including easily pluckable, sparse, thin, slow-growing hair. In 12 individuals, a diagnosis of loose anagen hair was confirmed by microscopic examination. Most of the patients also had darkly pigmented skin with eczema or ichthyosis. Cardiac anomalies were observed in the majority of the subjects, with mitral valve and septal defects overrepresented compared to the general population of Noonan syndrome patients. The affected individuals' voices were characteristically hypernasal.

Gripp et al. (2013) reported 5 unrelated children with molecularly confirmed Noonan syndrome-like disorder and loose anagen hair. All had skin hyperpigmentation, sparse light-colored hair that was slow-growing and unruly in texture, increased fine wrinkles, ligamentous laxity, and developmental delay; 4 also had documented structural cardiac anomalies. Hypotonia and macrocephaly were present in 4, and 3 had polyhydramnios, high birth weight, and/or required use of a feeding tube. Distinctive brain abnormalities included relative megalencephaly and enlarged subarachnoid spaces suggestive of benign external hydrocephalus, and a relatively small posterior fossa as indicated by a vertical tentorium. The combination of a large brain with a small posterior fossa likely resulted in the high rate of cerebellar tonsillar ectopia (3 of 5 patients).

Molecular Genetics

Based on a systems biology approach that identified SHOC2 (602775) as a candidate gene, Cordeddu et al. (2009) sequenced SHOC2 coding exons in a Noonan syndrome cohort that included 96 individuals who were negative for mutations in known disease genes and identified a heterozygous mutation (S2G; 602775.0001) in 4 unrelated individuals. They then analyzed the SHOC2 gene in a cohort of 410 mutation-negative patients with Noonan syndrome or a related phenotype and identified 21 individuals with the same S2G mutation. All 25 patients with the S2G mutation had a relatively consistent Noonan syndrome-like phenotype with loose anagen hair. Functional studies of S2G-mutant SHOC2 demonstrated introduction of an N-myristoylation site, resulting in aberrant localization and signaling.

Hoban et al. (2012) reported a male infant with typical dysmorphic facial features and other signs of Noonan syndrome, including thickened nuchal folds, generalized perinatal edema, hepatosplenomegaly, coagulopathy, hypertrophic cardiomyopathy (CMH), leukocytosis, thrombocytopenia, bleeding dyscrasia, hearing loss, and cryptorchidism, who was found to have the recurrent S2G mutation in the SHOC2 gene. The infant had rapidly progressive CMH and died of congestive heart failure at 4 months of age. Hoban et al. (2012) stated that the 'loose anagen hair' phenotype 'was not clinically noted' in the patient, who also had not developed any of the previously reported skin features in patients with the S2G mutation. They noted that the cardiac anomaly expanded the clinical phenotype associated with the SHOC2 mutation.

In 5 unrelated children with Noonan syndrome-like disorder and loose anagen hair, Gripp et al. (2013) identified heterozygosity for the S2G mutation in the SHOC2 gene. One of the patients was a 2-year-old boy who developed myelofibrosis (254450), which the authors noted is exceedingly rare in children and young adults; he was negative for the V617F JAK2 mutation (147796.0001) seen in the majority of myelofibrosis patients, suggesting that germline or somatic SHOC2 mutations might be involved in myelofibrosis.