Endocrine Abstracts

Introduction: Kallmann syndrome (KS) is a rare congenital form of hypogonadotropic hypogonadism (HH) associated with anosmia, that occurs with an incidence of 1:48,000 (1:30,000 males). Multiple separate pituitary adenomas are also rare, identified in only 0.7 % of pituitary adenoma cases.

Case Presentation: A male Caucasian patient presented with absent puberty, small testicles (1 ml), microphalus, osteopenia and anosmia at age 15. Endocrine assessment confirmed HH. Based on concomitant olfaction dysfunction, he was diagnosed with Kallmann syndrome (KS). Hormonal replacement treatment was initiated for puberty induction with testosterone enanthate and then continued with testosterone undecanoate following local monitoring protocol. At age 26 the patient presented with mild headache. MRI revealed two separate pituitary adenomas along with the absence of the olfactory bulbs. Given the presence hyperprolactinemia (17x upper limit of the reference range) the diagnosis prolactinoma was made and treatment with cabergoline was started which resulted in complete biochemical response and in marked reduction of both adenomas in size. Hypogonadism persisted and testosterone replacement therapy was continued. Targeted genetic testing of genes associated with neuroendocrine tumors (AIP, MEN1, NF1, PRKAR1A, RET, TSC1, TSC2, VHL), and of 49 genes associated with HH and TSHZ1gene associated with isolated congenital anosmia using a next generation sequencing platform was negative. Mild concomitant hypercalcemia in accordance with familial hypocalciuric hypercalcemia (FHH) prompted mutation analysis of the CASR gene which yielded a pathogenic inactivating variant.

Discussion: Double separate prolactinoma in a patient with KS has not yet been reported in the literature. The effect of sex hormone treatment of KS patients on the possible development of prolactinoma is unknown at present. The relevance of the CASR gene mutation in our patient for the KS phenotype also needs further insights since CaSR is expressed in GnRH neurons in mouse brain and CaSR deficient mice have a reduced hypothalamic GnRH neuronal population. This would possibly point to a role for the CaSR pathogenic variant in the development of KS in our patient. On the other hand, no delayed puberty, infertility or central hypogonadism have been reported in FHH patients.

Conclusion: We are unaware of earlier reports of an ultra rare co-occurrence of KS and multiple prolactinomas and FHH. The role of an inactivating variant in CASR gene as well as the effect of sex hormone treatment on the patient’s phenotype are uncertain at this stage.