Endocrine Abstracts (2009) 20 OC3.3

Variable phenotype of PROKR2 and PROK2 mutations in central hypogonadism

Marco Bonomi1,2, Domenico Libri1, Francesco Antonica1, Marta Busnelli1, Paolo Beck-Peccoz1, Roberto Maggi2,3, Csilla Krausz4 & Luca Persani1,2

1Dipartimento di Scienze Mediche, Istituto Auxologico Italiano IRCCS e Fondazione Ospedale Policlinico di Milano IRCCS, Università di Milano, Milano, Italy; 2Centro Interuniversitario per la Ricerca delle basi Molecolari delle Malattie della Riproduzione (CIRMAR), Milano, Italy; 3Istituto di Endocrinologia, Università di Milano, Milano, Italy; 4Dipartimento di Fisiopatologia Clinica, Unità di Andrologia, Università di Firenze, Firenze, Italy.

Idiopathic central hypogonadism (ICH) is a rare and heterogeneous disease due to defects of GnRH secretion or action. Depending on the association with a normal or defective sense of smell, ICH could be respectively identified as normosmic ICH (nICH) or Kallmann’s syndrome (KS). Recent experimental evidences indicate the involvement of the new PROK2/PROKR2 pathway in GnRH neuron maturation and function and mutations affecting these two genes have been described in some ICH cases. We analyzed by direct automatic sequencing the genes encoding the ligand PROK2 and its related G protein-coupled receptor (PROKR2) in a series of ICH patients: 19 KS (16M, 3F) and 31 nICH (26M,5F). Only one case is familiar, while all other presented as sporadic. We found 4 new (15fsX45, V158I, T260M, V334) and 1 known mutation (20fsX43) in PROKR2 gene and 1 new mutation (G62D) in PROK2. These variations are present in the heterozygous state in the patients according to the reported mechanism of haplo-insufficiency. While most of the carriers of these mutations exhibited typical ICH manifestations, two of them presented a particular phenotype. The nonsense mutation 15fsX45 was found in a nICH male patients, who was diagnosed with delayed puberty at 18 years and was then put on testosterone treatment. After 6 years, the medication was discontinued for revaluation and the patient presented a reversal of the ICH phenotype, with a spontaneous normal secretion of LH/FSH and testosterone. The mutation 20fsX43 was instead found in a 58 years old man who was referred to us for obesity accompanied by loss of libido. He reported a normal pubertal development at 13 years and fathered 2 daughters.

At physical examination, he presented signs of normal sexual development and testes volume. Biochemically, he had a typical nICH hormone profile in the absence of any traumatic brain injury and hypothalamic–pituitary lesion at MRI.

These two particular cases demonstrate the extreme variability in the expression of PROKR2 heterozygous mutations and the existence of ICH cases with adult onset that have a recognized genetic origin.

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