ESPE Abstracts

Background: Paternally expressed mono-allelic pathogenic variants in the MAGEL2 (melanoma antigen L2) gene cause Schaaf-Yang syndrome (SHFYNG), a multisystem disorder with psychomotor delay, intellectual disability, behavioral abnormalities, and obesity. Severity of the disease is highly variable, some patients may die in utero and some can live with moderate disabilities. MAGEL2 gene is located in the 15q11.2– q13 region which includes the Prader Willi Syndrome (PWS) domain hence, some of the features of this syndrome overlap with PWS.

Case report: A six-year-old girl was admitted for the evaluation of obesity. Prenatal history was uneventful. She was born at term with a birth weight of 3,300 g (0.5 SDS) to healthy second-degree cousin parents. She had no failure to thrive in infancy. She walked at 18 months and her first words were after 30 months old. She had behavioral problems and learning difficulties. The family noticed that she started to gain weight after 3 months of age. Her weight, length, and body mass index (BMI) at admission were, 38.7 kg (3.4 SDS), 116.4 cm (0.1 SDS), and 28.7 kg/m² (3.3 SDS), respectively. Coarse face, bitemporal narrowing, deep-set eyes, prominent nasal bridge, short neck, and tapering fingers were detected. She was prepubertal. Fasting blood glucose, insulin, HbA1c, transaminases and thyroid functions were normal. Her ophthalmologic, cardiac, and audiological evaluations were normal. Chromosome analysis was 46, XX, and methylation analysis for PWS was normal. At 15 years of age, her weight, height, and BMI were 115.0 kg (5.8 SDS), 157.5 cm (-0.7 SDS), and 46.3 kg/m2 (4.5 SDS), respectively. She had severe acanthosis nigricans, striae, and hypertension (155-75 mmHg, >2.3 SDS). Menses were irregular. Metformin treatment was commenced due to severe insulin resistance; however, she was non-compliant with treatment and weight gain was progressive. New treatment options such as GLP-1 analogs were considered for weight management. A novel heterozygous nonsense pathogenic variant (c.1732C>T; p. Gln578*) in MAGEL2 (NM_019066) gene was detected using Clinical Exome Sequencing (CES). This variant was not reported in gnomAD, ESP5400, or G1000. Segregation analysis in the family revealed that this variant had arisen de novo.

Conclusion: SHFYNG is among the rare monogenic causes of obesity and should be included in the differential diagnosis of PWS. The advances in molecular genetic technologies help to determine the etiology of monogenic obesity promptly and the implementation of genetic diagnosis in clinical practice may enable a personalized medicine approach.