Expanding the SHOC2 mutation associated phenotype of Noonan syndrome with loose anagen hair: structural brain anomalies and myelofibrosis

Abstract

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.

Keywords: Chiari 1 malformation; Noonan syndrome with loose anagen hair; SHOC2; heterotopia; malignancy; myelofibrosis; rasopathy.

Figure 1

Facial photograph of Patient 1 (A) at age 2 3/12 years, note sparse hair and very long eyelashes (dolichocilia); tall forehead with mild bitemporal narrowing; downslanting palpebral fissures, long and deeply grooved philtrum and low-set ears with prominent lobes. Facial photograph of Patient 4 (B) at age 5 5/12 years, note sparse hair and dolichocilia, tall forehead, long and deeply grooved philtrum, capped teeth, and low-set ears on lateral view (C). His palms (D, E) and soles (F) showed an increased number of fine wrinkles and a hyperpigmented lesion. Photographs of Patient 5 at ages 5 (G) and 8 years (H, I), showing pectus excavatum (G), tall forehead and sparse hair (H), dolichocephaly, dolichocilia and low-set ears (I). Note hair texture and light color, unusual for the family background, in Patients 4 and 5.

Figure 2

Magnetic resonance images of Patient 4 (LR12-389) at age 15 months (A–C) and 6 years (D–I). Midline sagittal images (A, D) show an unusual posterior cranial and brain configuration characterized by a small posterior fossa, a sharply angled splenium of the corpus callosum (vertical white arrows in A and D), vertical tentorium (black arrows in A and D), and large occiput that extends down well below the cerebellum. The first scan shows moderate cerebellar tonsillar ectopia (asterisk in A). The second shows a more horizontal basi-occiput and more severe tonsillar ectopia sufficient for Chiari malformation (asterisk in D). The corpus callosum appears mildly thick and the anterior commisure very thick (angled white arrow in D). Axial T2-weighted images at the level of the lateral ventricles (B and E) show enlarged extra-axial space over the frontal lobes that disappeared on the second scan. Lower T2 weighted images show the tonsils wrapping around the medulla (white arrow in C), and prominent arachnoid cysts anterior to the temporal poles (double asterisks in F). Numerous images show an unusual cluster of periventricular nodular heterotopia along the posterior right lateral ventricle that extend up into the deep subcortical white matter, not touching the ventricular wall (arrows in E, G, H and I). Comparable normal images are shown in Figure 3.

Figure 3

Magnetic resonance images of Patient 1 (LR13-109) at 12 months (A–C), Patient 2 (LR13-110) at 5 months (D–F), and Patient 5 (LR12-454) at 3 weeks (G–I), and images from a normal child at 3 years (J–L). Midline sagittal images show small posterior fossa volume with abnormal vertical tentorium (white arrows in A, D and G), borderline small cerebellar vermis hypoplasia, and mild cerebellar tonsillar ectopia without Chiari malformation (A and D). Axial images show mildly (asterisks in B and H) or moderately (asterisk in E) enlarged subarachnoid spaces over the frontal lobes, and anterior temporal lobes (asterisks in I), and tonsils wrapped partly around the low medulla (arrows in C and F). Comparable images from a 3-year-old girl are shown in the bottom row (J–L).