Endocrine Abstracts (2008) 16 S30.1

Reversible Kallmann syndrome associated with a novel homozygous mutation in the prokineticin receptor-2 gene

Roberta Asci1, Giuseppe Bellastella1, Luigi Maione1, Maria Chiara Quinto1, Annamaria De Bellis1, Achille Jolascon2, Antonio Bellastella1 & Antonio Agostino Sinisi1

1Endocrinology, Second University of Napoli, Napoli, Italy; 2Medical Genetics, CEINGE Scarl, Federico II University, Napoli, Italy.

Reversible Kallmann syndrome (KS) is a rare variant of hypogonadotropic hypogonadism (HH) reported in men, in which gonadotropin, testosterone (T) and fertility recover spontaneously following treatment with gonadotropins or T. In a few cases mutations of FGFR1 and KAL1 genes have been found. In this report we describe a subject with a KS carrying a new homozygous mutation of PROK-R2 gene and displaying an apparent reversal of his reproductive condition. The proband, born from first cousins, was a 19-year-old male with absent puberty, testes of 3 ml, and no sense of smell. FSH and LH basal and GNRH stimulated, and T and inhibin B levels were in the prepubertal range. MRI demonstrated absence of olfactory bulb and hypoplasia of sulci. The patient was firstly treated with gonadotropins and afterwards with T enanthate (TE). Persistence of spermatogenesis, fertility and supranormal levels of plasma T under long-term T administration, and normalization of pituitary-gonadal hormones two years off testosterone replacement therapy indicate a reversal of his HH state. Genetic analysis excluded KAL1 and FGFR1 mutation, and disclosed a T/A base substitution at codon 336 of prokineticin receptor 2 gene (Prok-R2), leading to a Val274Asp mutation in the protein. The mother with delayed menarche and normal sense of smell presented heterozygous mutation in Prok-R2 gene, suggesting that the proband inherited the trait from consanguineous parents. This study describes a novel mutation in the Prok-R2 gene and extends our understanding of the role of PROK2-PROKR2 gene pathway in the regulation of olfactory and GN-RH producing neurons development in humans. Moreover, present finding confirms that HH cannot be considered an irreversible state in the subjects harboring genetic mutations in known genes involved in the control of GnRH neuron migration and function.

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