Endocrine Abstracts

Ulnar-mammary syndrome (UMS) is a rare autosomal dominant disorder characterised by apocrine dysfunction, upper limb abnormalities, and hypoplastic mammary glands due to variants in TBX3, a transcription factor that plays a role in pituitary tissue development. Associations with delayed puberty are observed, but TBX3 has only recently emerged as a candidate gene for hypogonadotropic hypogonadism (HH). A 14-year-old male presented with short stature associated with upper limb symphalangism and camptodactyly. He denied an altered sense of smell. His family history was significant for delayed puberty: in his father who required gonadotropin therapy at 17 years, his paternal grandfather, and his paternal aunt who had late menarche requiring hormonal treatment. Examination revealed small testes bilaterally at 3ml, stretched penis length 4.5cm, Tanner staging P1G1A1. Height was 155.1cm (predicted adult height -3.1 SD). Serum biochemistry showed undetectable luteinizing hormone (LH), follicle stimulating hormone (FSH), and testosterone concentrations, inhibin B 121pg/mL (ref. 74 - 470pg/mL), antimullerian hormone 866.5pmol/l (ref. 84.25 - 1109.52pmol/l). Peak growth hormone on insulin tolerance test was suboptimal at 5.63ug/l. MRI pituitary was declined by the patient’s mother. Whole exome sequencing demonstrated a heterozygous missense variant in TBX3 Chr12:114,674,631; c.1244C>G; p.S415*. Paternal DNA samples are awaited. Growth hormone replacement was commenced, followed by recombinant FSH and human chroionic gonadotropin. After 12 months of gonadotropin treatment, testicular volumes reached 15ml bilaterally, SPL 9cm, Tanner staging P2G3A1. Height after 18 months of growth hormone treatment had increased by 7.7cm, and 13.1cm after 30 months. TBX3 variants associated with UMS can result in congenital, normosmic HH and an associated hypoplastic pituitary gland. In mouse models, Tbx3 defines a specific progenitor domain during hypothalamic development, thus establishing and maintaining the identity of kisspeptin-neurokinin-dynorphin (KNDy) neurons, vital for pubertal commencement. TBX3 loss-of-function should be considered in patients presenting with normosmic HH with phenotypic features of UMS.