Noonan Syndrome: A Syndrome with Wide Clinical Spectrum

Noonan syndrome (NS) is a genetic disorder with an estimated incidence of 1/1000–2500 live births. Owing to multiple organ involvement, a wide spectrum of symptoms and signs may occur in this syndrome as well as a high variable expressivity.

We present two cases of NS with different presentations.

4-year-old boy, with prenatal diagnosis of cystic hygroma, pleural effusion and bilateral hydronephrosis. Amniocentesis was performed at 21 weeks for extended genetic and infectious study including Noonan Syndrome and Noonan spectrum mutation panel, which was negative. Admitted at birth due to prematurity of 32 weeks. During hospitalization, craniofacial dysmorphisms (CD) suggestive of NS were observed as well as multiple organ involvement hence he performed genetic study detecting a pathogenic heterozygosity variant c.1391G>T (p.G464V) exon 11 in the BRAF gene. He is currently medicated with propanolol for hypertrophic cardiomyopathy. Maintains delayed psychomotor development and feeding problems, exclusively fed through gastrostomy and growing below -2SDS (NS Growth Charts).

16-year-old girl, referred to hospital consultation at 3 years of age due to CD. Performed a metabolic study, karyotype, muscle biopsy and mitochondrial DNA study that were normal. Subsequently she abandoned follow-up and was referral again at age 13 due to pubertal delay and short stature. She presented CD, unilateral mammary bud, very scarce pubic hair, pulmonary stenosis, syndactyly, interventricular comunication, pielic ectasia and intellectual disability. NS was suspected and confirmed by the finding of a heterozygosity variant c.4A>G(pSer2Gly) in the SHOC2 gene.

The severity of NS varies widely, from presentations that are lethal prenatally to mildly affected individuals. Because presentation can be mild and the typical facial features recede with age, the diagnosis might be overlooked, while in severe cases the diagnosis is made sooner and multidisciplinary approach is often needed to address the medical and developmental complications.