Further characteristics of Noonan Syndrome type 13 caused by MAPK1 loss of function variant: Case report and literature review

Abstract

Rationale: Noonan syndrome type 13 (NS13, OMIM #619087; Orpha #648, NS13) is caused by MAPK1 gene mutations. Individuals generally present with short stature; delayed psychomotor development; attention deficit and hyperactivity; and typical dysmorphism including ptosis, hypertelorism, downslanting palpebral fissures, low-set and posteriorly rotated ears with prominent antitragus, wide nasal bridge, low posterior hairline, dental anomalies, upper lip dysmorphism, and webbed necks. Skin features include multiple pigmented lentigines and café-au-lait spots. Congenital heart defects include atrial septal defect and mitral valve insufficiency. Neurological abnormalities include hypotonia and epileptiform discharges on electroencephalography. We describe a new case of a 6-year-old boy with the clinical presentation characteristic of NS13. Patient concerns: He presented with characteristic dysmorphism, behavioral abnormalities, psychomotor and speech development delay, and global hypotonia among other symptoms. Diagnoses: A pathogenic heterozygous de novo missense variant in MAPK1 was identified upon genetic testing during the sixth year of his life. Interventions: The child is currently under multidisciplinary care. Outcomes: This case report sheds light on the rarity and clinical diversity of NS13. In comparison to other NS13 patients from the literature, our patient presented with similar dysmorphic features, joint hypermobility, and neurodevelopmental delay. In contrast, he did not present with short stature, but with downslanting palpebral fissures, epicanthal folds, micrognathia. Our patient carried a MAPK1 missense variant located close to the N-terminal. This variant could contribute to a milder phenotype by causing partial malfunction of the MAPK1 protein. Lessons: The identification of a milder form of NS13 highlights the importance of early diagnosis and targeted management. Early recognition may lead to improved patient outcomes and quality of life. It underscores the need for rapid diagnostic tools specific to NS13, emphasizing the importance of continued research.