Noonan Syndrome-Like Disorder With Loose Anagen Hair 2

A number sign (#) is used with this entry because of evidence that Noonan syndrome-like disorder with loose anagen hair-2 (NSLH2) is caused by heterozygous mutation in the PPP1CB gene (600590) on chromosome 2p23.

For a general phenotypic description and a discussion of genetic heterogeneity of NSLH, see NSLH1 (607721).

Clinical Features

Gripp et al. (2016) reported 4 unrelated patients who all exhibited relative or absolute macrocephaly, prominent forehead, low-set and posteriorly rotated ears, and developmental delay, as well as slow-growing, sparse, and/or unruly hair. Short stature was present in 3 patients. Feeding difficulties occurred in 3 patients, necessitating feeding tubes. One of the 2 boys had cryptorchidism, and the other had pectus excavatum. In addition, 1 patient had mitral valve thickening, and another had pulmonic valve stenosis. Brain abnormalities included mild ventriculomegaly in all 4 patients; downward displacement of cerebellar tonsils in 2 patients, progressing to Chiari I malformation in 1 of them; and classic Dandy-Walker malformation with optic nerve hypoplasia in 1 patient.

Ma et al. (2016) studied 8 unrelated individuals with mutations in the PPP1CB gene who were all either developmentally delayed or intellectually disabled, and who exhibited relative or absolute macrocephaly and variable dysmorphic features. Six patients had failure to thrive and/or short stature. Congenital heart disease was present in 6 of the 8 patients, including atrial septal defect, mitral and tricuspid valve insufficiency, hypoplastic left-sided aortic arch, coarctation of the aorta, dilated aortic root, and peripheral pulmonic stenosis. Brain abnormalities in 3 patients included septooptic dysplasia, increased white matter signal intensity in the right frontal region, and prominent subarachnoid spaces. Connective tissue abnormalities were present in 6 patients, including high-arched palate, joint hypermobility, and translucent or doughy skin consistency. Epidermal features included poor hair growth in 3 patients, neonatal teeth in 1 patient, and brittle nails in 1 patient. Three patients had delayed bone age, and pectus excavatum was present in 3.

Zambrano et al. (2017) described a 9-year-old boy who initially presented at 4 years of age with short stature and dysmorphic features, including hypertelorism, downslanting palpebral fissures, ptosis, low-set posteriorly rotated ears, short wide neck, and pectus excavatum. Echocardiography revealed a small ventricular septal defect and patent foramen ovale. Other features included mild developmental delays and unusual hair findings, with initially abundant dark hair that fell out and was replaced by slow-growing, lighter brown, coarse hair that came out easily.

Bertola et al. (2017) reported a 12-year-old Brazilian boy who presented at age 3 months with craniosynostosis involving the sagittal and bilateral partial coronal sutures, which was repaired at age 1.75 years. He also underwent surgical correction of cryptorchidism at age 6 months. Examination at 4 years of age revealed relative macrocephaly, prominent forehead, hypertelorism, downslanting palpebral fissures, low-set posteriorly rotated ears, webbed neck, pectus carinatum superiorly and excavatum inferiorly, and thin, sparse, slow-growing hair. He had delay and difficulty in speech and required support for fine motor skills in school.

Molecular Genetics

In 4 unrelated patients with Noonan syndrome-like features and hair abnormalities, Gripp et al. (2016) performed exome sequencing and identified heterozygous de novo missense mutations in the PPP1CB gene, including a recurrent P49R substitution (600590.0001), which was present in 3 patients, and an A56P substitution (600590.0002). Neither variant was found in public variant databases. The authors noted that a de novo 1-bp insertion in the PPP1CB gene, predicted to cause a frameshift and premature termination codon, had previously been identified by Hamdan et al. (2014) in 1 patient from a cohort of 41 individuals with intellectual disability; the patient's features included severe mental retardation, short stature, relative macrocephaly, large mouth, and malar hypoplasia, as well as mildly increased cerebral spinal fluid spaces.

By whole-exome sequencing in 3 cohorts involving a total of 7,763 unrelated patients with developmental delay and/or intellectual disability, with or without additional clinical features, Ma et al. (2016) identified heterozygosity for 5 different de novo missense mutations in the PPP1CB gene in 14 patients (see, e.g., 600590.0001 and 600590.0003-600590.0005), 8 of whom agreed to be included in the published report. Four of the 8 reported patients carried the recurrent P49R substitution; the authors stated that while all patients with P49R had dysmorphic features and developmental delay, there was some phenotypic variability regarding cardiac and skeletal anomalies and growth.

In a 9-year-old boy with features of Noonan syndrome and unusual hair, who was negative for mutation in 8 candidate genes, Zambrano et al. (2017) performed whole-exome sequencing and identified heterozygosity for the P49R variant in the PPP1CB gene, which was shown to have arisen de novo. The authors noted that the phenotype in patients with missense mutations in PPP1CB was similar to that of Noonan syndrome with loose anagen hair (NSLH1; 607721).

In a cohort of 40 Brazilian patients with Noonan syndrome who were negative for mutation in known Noonan syndrome-associated genes, Bertola et al. (2017) performed whole-exome sequencing and identified heterozygosity for the recurrent P49R mutation in PPP1CB in a 12-year-old boy who also exhibited hair abnormalities.