Noonan syndrome is a heterogenous rasopathy typically presenting with short stature, characteristic facial features, cardiac abnormalities including pulmonic valve
stenosis, ASD and
hypertrophic cardiomyopathy (HCM),
cryptorchidism, ectodermal abnormalities, and learning differences. The phenotype is variable, and limited genotype phenotype correlation exists with SOS1 mutations often associated with normal cognition and stature, RAF1 mutations entailing a high HCM risk, and certain PTPN11 mutations predisposing to
juvenile myelomonocytic leukemia. The recently identified SHOC2 mutation (p.Ser2Gly) causes
Noonan syndrome with loose anagen hair. We report five patients with this mutation. All had skin
hyperpigmentation, sparse light colored hair, increased fine wrinkles, ligamentous laxity, developmental delay, and 4/4 had a structural cardiac anomaly.
Hypotonia and
macrocephaly occurred in 4/5 (80%); 3/5 (60%) had
polyhydramnios, increased
birth weight 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 (3/4; 75%).
Periventricular nodular heterotopia was seen in one patient with a thick and dysplastic corpus callosum. We report on the first
hematologic neoplasm,
myelofibrosis, in a 2-year-old patient with SHOC2 mutation.
Myelofibrosis is exceedingly rare in children and young adults. The absence of a somatic JAK2 mutation, seen in the majority of patients with
myelofibrosis, is noteworthy as it suggests that germline or somatic SHOC2 mutations are causally involved in
myelofibrosis.