A familial case of Noonan syndrome with multiple lentigines caused by a PTPN11 gene mutation: a case report

Abstract

Introduction . The differential diagnosis of hypertrophic cardiomyopathy (HCM) requires the ruling out phenocopies. Noonan syndrome with multiple lentigines (NSML) is a rare genetic disorder with an autosomal dominant inheritance pattern, classified as a RASopathies. In 85% of cases, NSML is caused by mutations in the PTPN11 gene, which encodes the key enzyme in the RAS pathway, protein tyrosine phosphatase SHP2. The remaining cases are associated with mutations in the RAF1 and BRAF genes. Like other RASopathies, NSML presents with a phenotypic triad of facial dysmorphism, cardiopathy, and growth retardation. Distinctive features of NSML include cutaneous manifestations in the form of lentigines (90%) and a high (up to 80%) incidence of HCM phenocopy. Brief description . We described a familial case of NSML caused by the Thr468Met mutation in the PTPN11 gene. The proband was a 38-year-old woman with a long-term history of HCM. Facial dysmorphism was mild, and multiple lentigines were not associated with the disease. Left ventricular hypertrophy was concentric, with a maximum myocardial thickness of 34,5 mm. The disease course was complicated by presyncope due to ventricular tachycardia episodes. All of the patient’s children inherited NSML, had a typical facial phenotype, lentigo, and a phenocopy of HCM. In addition to HCM phenocopy, the patient’s eldest son and youngest daughter had pulmonary artery stenosis of varying severity. Discussion . Diagnosis of NSML in the proband was difficult due to a decrease in the severity of external signs with age and poor awareness among cardiologists of the external syndrome manifestations. This case demonstrates the variability of cardiac pathology within families and the importance of family screening and monitoring of family members for the timely diagnosis of cardiac pathology.