Noonan Syndrome 8

A number sign (#) is used with this entry because of evidence that Noonan syndrome-8 (NS8) is caused by heterozygous mutation in the RIT1 gene (609591) on chromosome 1q22.

Description

Noonan syndrome-8 is an autosomal dominant disorder characterized by short stature, distinctive facial features, and a high incidence of congenital heart defects and hypertrophic cardiomyopathy. A subset of patients show intellectual disabilities (summary by Aoki et al., 2013).

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

Clinical Features

Aoki et al. (2013) reported 17 unrelated individuals with Noonan syndrome-8 who ranged in age from a few months to 15 years. Patients had a distinctive facial appearance with relative macrocephaly, hypertelorism, downslanting palpebral fissures, ptosis, epicanthal folds, and low-set ears. Many had skin and hair anomalies, such as curly hair, hyperelastic skin, and hyperkeratosis. Other features included short stature and short or webbed neck. Twelve individuals (71%) developed hypertrophic cardiomyopathy, 11 (65%) had pulmonic stenosis, and 5 (29%) had atrial septal defects. At least 4 patients had documented intellectual disability. Nine patients showed perinatal abnormalities, including polyhydramnios, nuchal translucency, and chylothorax. One infant with cardiomyopathy and pleural effusion died at age 53 days, and 1 child developed acute lymphoblastic leukemia at age 5 years.

Bertola et al. (2014) reported 6 unrelated Brazilian patients with Noonan syndrome-8. The patients had a high frequency of abnormal findings on prenatal ultrasound, mainly polyhydramnios and fetal hydrops, high birthweight (mean of 4,342 g), relative macrocephaly, left ventricular hypertrophy, and ectodermal findings such as curly hair, hyperpigmentation, and wrinkled palms and soles. Short stature and pectus deformity were less frequent than in patients with other forms of Noonan syndrome. The majority of patients did not show apparent intellectual disability, but formal testing was not performed. One patient developed severe and progressive scoliosis; another patient, who also had factor XI deficiency (612416), developed aggressive giant cell lesions in the mandible at age 15 years. Two other patients had autoimmune disorders, Graves disease and systemic lupus erythematosus, respectively.

Gos et al. (2014) reported 4 unrelated Polish patients with Noonan syndrome-8. Dysmorphic craniofacial features included hypertelorism, downslanting palpebral fissures, epicanthal folds, low-set ears with thickened helix, and short neck with low posterior hairline. All patients had pulmonary valve stenosis, 3 had septal defects, and 2 had hypertrophic cardiomyopathy. Only 1 patient had short stature. All had mild cognitive impairment manifest as learning difficulties or delayed speech.

Using a standardized form, Kouz et al. (2016) recorded clinical features of all 33 RIT1 mutation-positive patients from 28 families. Clinical and genotype data from 36 individuals with RIT1 mutation reported previously were reviewed. In relation to Noonan syndrome of other genetic etiologies, prenatal abnormalities, cardiovascular disease, and lymphatic abnormalities were common in individuals with RIT1 mutation, whereas short stature, intellectual problems, pectus anomalies, and ectodermal findings were less frequent. RIT1 is one of the major genes for Noonan syndrome. The RIT1-associated phenotype differs from other Noonan syndrome subtypes, with a high prevalence of cardiovascular manifestations, especially hypertrophic cardiomyopathy, and lymphatic problems.

Calcagni et al. (2016) concurred with the observations of Kouz et al. (2016) and reported that the RIT1 gene was responsible for Noonan syndrome in 6% of the patients they sequenced. All 9 of their Noonan syndrome patients with RIT1 mutations had congenital cardiac defects. Four also had hypertrophic cardiomyopathy, which in 1 case was severe.

Zenker and Kutsche (2016) replied and added observations from Cave et al. (2016) and Yaoita et al. (2016), noting that 94% of the more than 120 RIT1 mutation-positive patients had cardiac abnormalities, with pulmonic stenosis (64%), hypertrophic cardiomyopathy (45%), and septal defects (39%) being the most frequent.

Inheritance

The RIT1 mutations identified by Aoki et al. (2013) in 16 patients with NS8 occurred de novo, consistent with sporadic occurrence of the disorder. One additional patient inherited a heterozygous mutation from a mother with a similar phenotype, suggesting rare autosomal dominant inheritance.

DNA was available from the parents of only 2 of the 6 patients with NS8 reported by Bertola et al. (2014); study showed that it was an apparently de novo event in both.

Molecular Genetics

In 17 (9%) of 180 unrelated patients suspected of having Noonan syndrome but without mutation in selected exons of any known Noonan syndrome-causing genes, Aoki et al. (2013) identified heterozygous mutations in the RIT1 gene (see, e.g., 609591.0001-609591.0004). The first mutations were found by exome sequencing, and subsequent mutations were identified from a larger cohort of patients screened for the RIT1 gene. A total of 9 missense mutations were found. The mutations tended to cluster in the switch II region, and in vitro functional expression studies of 3 of the mutations showed that they resulted in a gain of function. Transfection of 2 of the mutations into zebrafish embryos resulted in a variety of developmental defects, including gastrulation defects, craniofacial abnormalities, pericardial edema, and elongated yolk sac. A smaller percentage of mutant embryos showed even more disorganized growth and abnormal cardiogenesis. The findings were similar to those observed with mutations in other RAS genes (see, e.g., PTPN11, 176876; SOS1, 182530; NRAS, 164790) causing other forms of Noonan syndrome.

In 6 (9%) of 70 Brazilian patients with Noonan syndrome but without mutation in selected exons of any known Noonan syndrome-causing genes, Bertola et al. (2014) identified 4 heterozygous missense mutations in the RIT1 gene, all of which had previously been identified in patients with NS8 by Aoki et al. (2013). The mutations were identified by exome sequencing. Bertola et al. (2014) suggested possible hotspots at residues 57 and 95 of the protein due to recurrent mutations, and recommended that RIT1 be added to gene panels for the molecular diagnosis of Noonan syndrome.

In 4 unrelated Polish girls with NS8, Gos et al. (2014) identified 3 different heterozygous missense mutations in the RIT1 gene (609591.0004-609591.0006). The mutations in the first 2 patients were found by whole-exome sequencing after mutations in common Noonan syndrome genes were excluded. The mutations in the second 2 patients were found by direct sequencing of the RIT1 gene in 64 patients with Noonan syndrome. Functional studies of the variants were not performed. The RIT1 mutation rate in this study was estimated at 3.8% (4 of 106 Noonan syndrome patients).

Kouz et al. (2016) sequenced RIT1 in 310 mutation-negative individuals with a suspected RASopathy and prospectively in individuals who underwent genetic testing for Noonan syndrome. Eleven different RIT1 missense mutations, 3 of which were novel, were identified in 33 subjects from 28 families; codons 57, 82, and 95 represent mutation hotspots. RIT1 is 1 of the 4 most common genes mutated in Noonan syndrome.