ESPE2022 Poster Category 1 Sex Differentiation, Gonads and Gynaecology, and Sex Endocrinology (56 abstracts)
Monoallelic variants in Myelin Regulatory Factor (MYRF) associated with 46,XY DSD – two cases and first report of inheritance through parental mosaicism
Abhidhamma Kaninde 1,2 , Harish Chandran 3 , Liam McCarthy 3 , Arun Ghose 4 , David Ellis 4 , Piers Fulton 2,5 , Julie Vogt 2,5 , Rebecca Igbokwe 5 , Jeremy Jeremy Kirk 1,2 , Zainaba Mohammed 1,2 & Jan Idkowiak 1,2,6
1Department of Endocrinology and Diabetes, Birmingham Children’s Hospital, Birmingham Women’s and Children’s NHS Foundation Trust, Birmingham, United Kingdom; 2Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, University of Birmingham and University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom; 3Department of Paediatric Urology, Birmingham Children’s Hospital, Birmingham Women’s and Children’s NHS Foundation Trust, Birmingham, United Kingdom; 4Department of Paediatric Intensive Care, Birmingham Children’s Hospital, Birmingham Women’s and Children’s NHS Foundation Trust, Birmingham, United Kingdom; 5Department of Clinical Genetics, Birmingham Women’s and Children’s NHS Foundation Trust, Birmingham, United Kingdom, Birmingham, United Kingdom; 6Institute of Metabolism and Systems Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom
Background: Haplo-insufficiency of the Myelin-Regulatory Factor (MYRF) gene causes cardiac-urogenital syndrome (CUGS) and Differences in Sexual Development (DSD) in 46,XY and 46,XX (OMIM #618280). The gene product, a transcription factor, is involved in development of Coelomic epithelium derived cells, and likely causative for DSD. To date, only a few MYRF de novo variants are reported in children with DSD and associated CUGS symptoms.
Aims and objectives: To report the clinical, hormonal and genetic findings in two infants with CUGS and DSD from a single centre.
Patients: Case 1 (46,XY) presented at term birth with diaphragmatic hernia and was commenced on extracorporeal membrane oxygenation due severe lung hypoplasia. The external genitalia were significantly under-masculinised (1 cm phallus, single opening, penoscrotal hypospadias, no gonads palpable) with non-detectable Mullerian structures but gonads identified in the iliac fossa on pelvic ultrasound. Gender was assigned female at birth. A rapid trio whole exome sequencing analysis identified a heterozygous frameshift variant in the MYRF gene [p.(Ser878Profs*20)]. Parental analysis detected the variant at a low-level mosaicism (estimated 10%) in mother. Sadly, the infant passed away at day 21 of life due to severe respiratory failure. Case 2 (46,XY) presented at term birth with diaphragmatic eventration, Scimitar Syndrome and partial anomalous pulmonary venous drainage. The external genitalia were highly ambiguous with small phallus (2 cm), single opening, penoscrotal hypospadias, underdeveloped scrotum and impalpable gonads. An ultrasound of the pelvis did not detect gonads or Mullerian structures. A testosterone level after birth was low (0.2 nmol/L), there were no other hormonal abnormalities with normal adrenal and thyroid function tests. Gender was assigned as male. Genetic analysis of the MYRF gene revealed a novel missense variant p.(Arg478Gln), which occurred de novo.
Discussion and conclusions: Our cases expand the clinical and genetic spectrum of MYRF-associated CUGS and provides further evidence on its causative role in 46,XY DSD. We report the first case of MYRF haplo-insufficiency inherited through low-grad mosaicism from an asymptomatic mother, which has important implications for genetic counselling. We recommend genetic testing of the MYRF gene, in particular when cardiovascular and renal abnormalities are present in infants with DSD.
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