Noonan Syndrome 6

A number sign (#) is used with this entry because this form of Noonan syndrome (NS6) is caused by heterozygous mutation in the NRAS gene (164790) on chromosome 1p13.

For a general phenotypic description and a discussion of genetic heterogeneity of Noonan syndrome, see NS1 (163950).

Cirstea et al. (2010) reported 4 unrelated probands with Noonan syndrome-6. One proband had an affected mother. The ages of the patients ranged from 3.3 to 50 years. All patients had typical and somewhat variable clinical features of Noonan syndrome, including characteristic facial features such as hypertelorism and low-set ears, short stature, webbed neck, curly hair, thorax deformities, hypotonia, and cryptorchidism in males. One had speech delay, 2 had borderline mental retardation, and 2 had normal development. Three had congenital heart defects, including hypertrophic cardiomyopathy and pulmonic stenosis. Other features included macrocephaly (in 3 patients), myopia (in 2), and hyperkeratosis (in 4). The patients were part of a larger study of 917 affected individuals who were negative for previously known Noonan-associated gene mutations.

Ekvall et al. (2015) described a 28-year-old woman who was diagnosed with Noonan syndrome at age 4 because of growth retardation, cardiomyopathy, and facial features. At age 6.5 years she was diagnosed with partial growth hormone deficiency and was treated with growth hormone. Her psychomotor development was normal. She was noted to have a broad forehead, hypertelorism, downslanting palpebral fissures, bilateral ptosis, a short and broad neck with a low hairline, and low-set ears with broad helices. She had cafe-au-lait spots on her back and many lentigines all over her body. Her 62-year-old father was noted to have sensorineural hearing impairment since birth, macrocephaly, bilateral ptosis, hypertelorism, downslanting palpebral fissures, curly hair, and lentigines on his back.

Clinical Variability

De Filippi et al. (2009) reported a boy who presented in infancy with juvenile myelomonocytic leukemia (JMML; 607785) and was later noted to have dysmorphic features suggestive of, but not diagnostic of, Noonan syndrome. Features included short stature, relative macrocephaly, high forehead, epicanthal folds, long eyebrows, low nasal bridge, low-set ears, 2 cafe-au-lait spots, and low scores on performance tasks. Cardiac studies were normal. Genetic analysis revealed a de novo germline heterozygous mutation in the NRAS gene (G13D; 164790.0003).

In 5 patients, including a mother and son, with Noonan syndrome-6, Cirstea et al. (2010) identified 1 of 2 different heterozygous mutations in the NRAS gene (T50I, 164790.0004 and G60E, 164790.0005). The mutations were de novo in 3 patients. In vitro functional expression studies showed that both mutations resulted in increased NRAS activity consistent with a gain of function.

By targeted next-generation sequencing in a father and daughter with Noonan syndrome, Ekvall et al. (2015) identified heterozygosity for G60E mutation in the NRAS gene.