Endocrine Abstracts

JOINT1951

Introduction: The MED12 gene is located on the X chromosome and encodes a protein involved in the initiation of gene transcription. Pathogenic variants in MED12 have been reported to cause three X-linked recessive syndromes (FG syndrome type 1, Lujan-Fryns syndrome and X-linked Ohdo syndrome) and one X-linked dominant syndrome (Hardikar syndrome). Pathogenic variants in MED12 have been reported to cause nonspecific intellectual disability (NSID) and other neurological features as hypotonia, behavior issues, seizures as well as growth delays. Here, we report the case of an infant with precocious obesity and neurodevelopmental delay.

Case presentation: A 19-month-old female was seen in our outpatient clinic for pediatric obesity. She was the second child of Venezuelan parents, born at 38 weeks by caesarian section with a birth weight of 2.9kg (-0.75SDS). Her 5-year-old sister, was healthy and not overweight. At the referral, the patient weighted 13.4 kg (2.37SDS) for a length of 82 cm (0.1SDS), BMI 19.9kg/m² (2.63SDS). She had some dysmorphic features: prominent forehead, tented upper lip, protruding and backwardly rotated ears. At the clinical examination, she had a mild global hypotonia and was not yet walking. A blood analysis revealed normal cortisol, TSH and fT4. Genetic analysis, CGH and methylation profile of the 15q11q13 region were normal. Trio- exome sequencing revealed a de novo heterozygous mutation in the MED12 gene (c.4453G>T, p.(Val1485Leu)). This variant is considered likely pathogenic by two prediction tools (Polyphen and SIFT).

Conclusion: Pathogenic variants in MED12 have been already reported to cause various neurological symptoms and some have been also implicated as oncogenic in tumour tissue for leiomyoma or leiomyosarcoma. So far, only one female patient has been reported with a de novo MED12 variant (c.4669T>C, p.Trp1557Arg) and severe obesity. This patient had obesity, neurodevelopmental delay and abnormalities of the corpus callosum. Some recent studies in Human adipose-derived stem cells hASCs and in murine models suggest that MED12 could promote adipogenesis by acting as transcriptional coactivator for adipogenic genes and by repressing inhibitory pathways like Wnt signaling. Here we report another patient with a MED12 de novo variant, presenting with precocious obesity and neurodevelopmental delay. Genetic counseling is very helpful in pediatric obesity clinics and exome sequencing is a powerful tool for identifying novel rare variants and understanding the pathogenesis of obesity in a subset of patients.