A 31-year-old female was referred to Endocrinology clinic for review of her hypergonadotrophic-hypogonadism. She had cleft palate operation at age 3. At age 15y lack of pubertal signs prompted investigations showing XX genotype, FSH:120 IU/L, LH:32 IU/L and low E2. She was started on cyclo-progynova (elsewhere). She has tall stature, span 2.5 cm longer than height, bifid uvula, arachnodactyly with positive wrist sign, mild scoliosis, pectus excavatum and reduced muscle mass. There are no joint laxity, delayed wound healing, muscle hypotonia and reduced subcutaneous fat. Normal smell and hearing is reported. There is no family history of similar body habitus or fertility issues. While hypogonadotrophic-hypogonadism is well-known to be associated with cleft palate, this has not been described in hypergonadotrophic-hypogonadism. Exome sequencing identified a transforming growth factor-β3 (TGFB3) missense variant of a well-conserved amino-acid (NM_003239:exon7:c.C1118A:p.S373Y, not present in gnomAD) resulting in a predicted probably-damaging change (PolyPhen2). Mutations in TGFB3 cause Loeys-Dietz syndrome type-5 (LDS5, Rienhoff-syndrome) characterised by skeletal overgrowth, arterial tortuosity, aneurysms, hypertelorism, bifid uvula, cleft palate, mitral valve disease, cervical spine instability and clubfoot deformity (not all features occur in all patients). TGFB3 plays key role in development of skeletal muscle, blood vessels, bone growth, wound healing and gonadal development as demonstrated in mouse models. While several families are described with male/female transmission of the disease, more recently, variants of TGFB3 gene have been associated with male infertility. There is no reported case associated with female hypogonadism. Gonadal failure could be an inconsistent feature of LDS5. Cardiac MRI, performed due to this new diagnosis, shows normal aorta and no significant valvular disease. Her parents are invited for genetic screening. Further studies are needed to prove the pathogenic role of this variant and establish the link, if any, to human female primary gonadal failure.
19 Nov 2018 - 21 Nov 2018