Noonan syndrome: The changing phenotype

Abstract

Among the multiple congenital anomalies (MCA) syndromes, the Noonan syndrome (NS) is a cardiofacial syndrome in which affected individuals may be short and mildly mentally retarded. Autosomal dominant inheritance of Noonan syndrome with variable expressivity has been documented in many families. Genetic heterogeneity has been postulated in Noonan syndrome because of the wide phenotypic variability, the relatively high incidence, and the occasional recurrence in sibs with apparently normal parents. Clinical variability is usual in autosomal dominant disorders, and mildly affected individuals may be difficult to recognize as gene carriers. Thus, a family with two or more affected children may simulate autosomal recessive inheritance. We have studied serial and family photographs of NS individuals in order to assess the likelihood of gene carriers' being missed in genetic studies. We have confirmed wide clinical variability within families, and more importantly, we have documented marked change of phenotype with age from the newborn period, infancy, childhood, and adolescence to adulthood. Manifestations in adults may be subtle and some without a known heart defect or other medically significant problems may have been considered normal in the past. Our study, while not ruling out causal heterogeneity, suggests that the change of phenotype with age may have been falsely perceived as clinical heterogeneity. A particular and subtle phenotype must be searched for in parents of affected children.

Spectrum of mutations in PTPN11 and genotype–phenotype correlation in 96 patients with Noonan syndrome and five patients with cardio-facio-cutaneous syndrome

“…Since six out of eight affected family members are adults our findings confirm previous data showing that there is a tendency of some dysmorphic features, including hypertelorism, to normalise with increasing age. 8,9 On average, each of the craniofacial features was present in 60% of patients, i.e. less often than in previous studies.…”

Growth references for Japanese individuals with Noonan syndrome

“…Pediatric cardiologists also have an important role in NS care as it is the second most common syndromic cause of congenital heart disease, exceeded in prevalence only by trisomy 21 (7). In addition, children with NS often present to pediatric endocrinologists because of their short stature, delayed puberty, or undescended testes in males (3).…”

Clinical manifestations in patients with SOS1 mutations range from Noonan syndrome to CFC syndrome

“…Noonan syndrome (NS; MIM#163950) is an autosomaldominant developmental disorder characterized by facial dysmorphism, including hypertelorism, low-set ears, ptosis, short stature, skeletal abnormalities, and heart defects (Allanson et al 1985;Mendez and Opitz 1985). Frequently observed features in NS patients are pulmonary stenosis (PS), hypertrophic cardiomyopathy, chest deformities, a webbed and short neck, mental retardation, genitourinary defects, including cryptorchidism in males, and bleeding diathesis due to factor XI deficiency (Mendez and Opitz 1985).…”