Endocrine Abstracts

35y male presented with extreme fatigue and symptomatic hypogonadism. He had history of multiple infections since childhood due to combined immunodeficiency syndrome and hypogammaglobulinemia, autoimmune haemolytic anaemia, sensorineural deafness, cytopenias, acute hepatitis with hepatosplenomegaly. Liver biopsy (age 15y) showed chronic hepatitis with necrosis. In 2020 (age 32y) he underwent bone marrow biopsy for progressive pancytopenia demonstrating hypercellularity, but no evidence of hemophagocytosis or malignancy. Historical notes revealed history of short stature and delayed puberty presumed to chronic illness (normal pituitary MRI, LH <0.07 iu/l, FSH 0.9 iu/l, testosterone 0.3 nmol/l (10-27.6) and IGF-1 44 mg/l (75-580) at 14y). Brief testosterone replacement at 18y was followed by spontaneous recovery of gonadal axis and pubertal progression to TV 15ml, G5, PH4. Participation in 100,000 Genomes Project at age 32y designed to identify rare genetic disorders through whole genome sequencing revealed homozygosity for STXBP2 c. 1247-1G >C pathogenic variant consistent with Familial Hemophagocytic Lymphohistiocytosis type 5 (FHL5), tying up previous issues. On examination he had small stature, hypogonadal appearance, testicular volume 15 mls, height 157 cm, weight 48 kg.

Results: LH 0.5 iu/l, FSH 0.3 iu/l, testosterone <0.4 nmol/l, prolactin 802 mu/l (55.4-276), IGF-1 2.4 nmol/l (9.3-30.7), cortisol-436 nmol/l, fT4 9.2 pmol/l (7.7-15.1), Hb 76 g/l (130-170), platelets 46×10⁹/l (150-400), WBC 1.3×10⁹(4-11). Patient had no symptoms of arginine vasopressin deficiency (AVP-D). Pituitary MRI showed thickening and enhancement of infundibulum extending to hypothalamus and floor of third ventricle. Anterior gland looked normal and posterior bright spot was absent. Testosterone replacement was commenced with excellent symptomatic response. Macimorelin test to confirm growth hormone (GH) deficiency followed by GH replacement was planned but is delayed due to recent admission with decompensated liver disease.

Discussion: FHL 5 is a rare genetic hyperinflammatory syndrome caused by an uncontrolled immune response mediated by T-lymphocyte, natural killer cells and activated macrophages and infiltration of several organs by activated lymphocytes and macrophages. Pituitary involvement is well reported in other types of histiocytic disorders such as Langerhans cell histiocytosis, but rarely in familial or acquired HLH. The lack of AVP-D symptoms here is unusual. Partial hypopituitarism in this case could have contributed at least partially to significant pancytopenia and it will be interesting to observe, if his cell count improves with hormone replacement. Results three months after staring testosterone showed rise in Hb (76 to 93 g/l), but no change in platelet and white cell count to date.