Genotype phenotype correlation in children with noonan syndrome

Noonan syndrome (NS, OMIM 163950) is a clinically and genetically variable autosomal dominant syndrome characterized by congenital heart defects, short stature, development delay, and characteristic facial features. It affects 1/1000-1500 newborns. Congenital heart defects, especially pulmonary stenosis and hypertrophic cardiomyopathy, are common. Characteristic facial features have been reported such as a broad forehead, ptosis, low-set ears, deeply grooved philtrum, hypertelorism, depressive nasal bridge, triangular face shape, and a webbed neck. Polyhydramnios, increased nuchal translucency, and hydrops fetalis may occur in the prenatal period. Feeding difficulties, short stature, delayed early development milestones, intellectual disability, epilepsy, refractive errors, strabismus, and hearing loss have been reported. Coagulation defects, malignancies of the hematopoietic system, particularly JMML, and other system malignancies have been reported. Varied lymphatic abnormalities such as lymphodema and lymphangioma, urinary system disorders, genital system disorders such as cryptorchidism and infertility, dermatological disorders such as xerosis, hair loss, curly and wavy hair, café au lait macules, hyperkeratosis have been reported. Many genes have been described in the etiology of Noonan syndrome such as PTPN11 (%50), SOS1 (%10-13), LZTR1 (%8), RAF1 (%5), RIT1 (%5), KRAS (<%5), SOS2 (<%4), BRAF (%2), MAP2K1 (<%2), MRAS (<%1), NRAS (<%1), RRAS2 (<%1), RASA2, RRAS2, A2ML1, SHOC2, CBL, HRAS, MAP2K2, SPRED1, PPP1CB, and MAPK1. Based on the phenotype-genotype correlation, PTPN11 variants have been associated with typical facial appearance, PS, easy bruising, cryptorchidism, short stature, decreased IGF-1 levels and low responses to provocation tests, mild intellectual disabilities, and malignancies of the hematopoietic system (esp. JMML). SOS1 variants have been associated with ectodermal features, PS, macrocephaly, and rhabdomyosarcoma in various studies. RAF1 variants have commonly been associated with hypertrophic cardiomyopathy (HCM), short stature, and multiple nevi, lentigines, and café au lait macules. RIT1 variants have been associated with prenatal findings, lymphatic defects, congenital heart defects, and HCM. KRAS variants have been associated with congenital heart 78 defects, PS, short stature, macrocephaly, and thorax deformities. SHOC2 variants have been described with Noonan-like syndrome with loose anagen hair. Serious development delay, thin and slow-growing hair, hyperpigmentation on the skin, eczema, central nervous system findings, mitral valve dysplasia, and growth hormone deficiency have been described along with typical facial characteristics of NS. BRAF variants have been associated with developmental delay, feeding difficulties, hypotonia, intellectual disabilities, and dysmorphic facial features. Our study evaluated the genotype-phenotype correlation in 24 patients diagnosed with Noonan syndrome and a patient diagnosed with Noonan-like syndrome with loose anagen hair via clinical examination and molecular tests. 32% of the patients were women and 68% percent were men. The patients's mean age, height, and weight were calculated to be 102.76±60.37 months, 117±24 cm, and 23,83±12,12 kg, respectively. Polyhydramnios and an increase in nuchal translucency were calculated as 16%. Delays were found in head control in 36%, sitting in 16%, walking in 24%, and speaking in 40% of the cases. Congenital heart defects were seen in 68% of cases. Patients were diagnosed with PS in 48%, ASD in 24%, VSD in 8%, and HCM in 4% of cases A statistically significant genotype-phenotype correlation with a triangular face shape was found in patients with variants in the PTPN11 gene (p=0.04). Another statistically significant finding was that short stature occurred more frequently in cases with variants in the PTPN11 gene than in cases with variants in other genes (p=0.04). Microcephaly and PTPN11 variants were statistically correlated (p=0.017). Dermatological findings such as thin hair and xerosis were seen to occur less often in PTPN11 variants (p<0.05) which is similar to the literature. Only PS was detected in SOS1 variants. As our study group contained slightly few patients especially with rare variants, further studies are necessary to understand genotype- phenotype correlations in NS.