Family case of Noonan syndrome with multiple lentigines caused by a mutation in the PTPN11 gene: clinical observation

Introduction. The differential diagnosis of hypertrophic cardiomyopathy (HCM) requires exclusion of phenocopies. Noonan syndrome with multiple lentigines (NSML) is a rare genetic disease with an autosomal dominant type of inheritance, belonging to RASopathies. In 85% of cases, NSML is caused by mutations in the PTPN11 gene, which encodes a key enzyme of the RAS pathway — the protein tyrosine phosphatase SHP2; the remaining cases are associated with mutations in the RAF1 and BRAF genes. Like other RASopathies, NSML is manifested by a phenotypic triad — facial dysmorphism, cardiopathy, and growth retardation. Distinctive features of NSML are skin manifestations in the form of lentigines in 90% of cases and a high (up to 80%) frequency of development of HCM phenocopies.

Brief description. We described a family case of NSML caused by the Thr468Met mutation in the PTPN11 gene. The proband is a 38-year-old woman with a long history of HCM. Facial dysmorphism was mildly expressed, and multiple lentigines were not associated with the disease. Left ventricular hypertrophy was concentric with a maximum myocardial thickness of 34.5 mm. The course of the disease was complicated by presyncope due to paroxysms of ventricular tachycardia. All children of our patient inherited NSML and had a typical phenotype: facial dysmorphism, lentigines, and HCM phenocopy. In addition to HCM phenocopy, the eldest son and the youngest daughter had pulmonary artery stenosis of varying severity.

Discussion. The diagnosis of NSML in the proband was difficult due to the decrease in the severity of external features with age and poor awareness of cardiologists regarding the external manifestations of the syndrome. This case demonstrates the variability of cardiac pathology within a family and the importance of family screening and follow-up of family members for timely diagnosis of cardiac pathology.

Key points

1. Noonan syndrome with multiple lentigines (NSML), previously called LEOPARD syndrome, is a rare genetic disease with an autosomal dominant type of inheritance, belonging to RASopathies, the main phenotypic manifestations of which are skin manifestations in the form of lentigines and café-au-lait spots, hypertrophic cardiomyopathy (HCM), and growth retardation.
2. HCM in NSML is observed in 80% of cases, usually develops in childhood, more often has a concentric pattern, biventricular hypertrophy is frequently observed, partial regression of hypertrophy in childhood is possible, and a progressive course is associated with an unfavorable prognosis.
3. The proband is a 38-year-old woman with a long history of HCM. Diagnosis of NSML in the proband was difficult due to the decrease in the severity of external features with age and poor awareness of cardiologists regarding the external manifestations of the syndrome.
4. All children of the proband inherited NSML and had a characteristic phenotype: facial dysmorphism, lentigines, café-au-lait spots, and HCM phenocopy.
5. Characteristic external features allow suspicion of NSML at early stages, and cardiac examination over time is necessary for timely diagnosis of HCM and congenital heart defects. List of abbreviations

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