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Objective To correlate the presence of renal agenesis/dysgenesis to the prevalence of KAL1 gene defects in patients with sporadic Kallmann syndrome (KS). Design Prospective assessment of renal structure and DNA sequence analysis of the KAL1 gene. Setting Outpatient clinics of the divisions of endocrinology of university hospitals. Patient(s) Sixteen male patients with sporadic KS. Intervention(s) Assessment of renal structure by abdominal ultrasounds scans and DNA extraction, polymerase chain reaction amplification, and DNA sequence analysis of all 14 exons of the KAL1 gene. Main Outcome Measure(s) KAL 1 gene structure and presence of renal dysgenesis. Result(s) Renal dysgenesis was identified in only two of 16 KS patients. Genetic defects were found in only two patients with KS, that is, in those with the identified renal dysgenesis. The first gene defect was identified in a patient with associated right renal agenesis who had two point mutations in the KAL1 gene: the first was a G to A transition in exon 11, turning codon 514 encoding glutamic acid into lysine; and the second was a G to A transition in exon 13, turning codon 660 encoding alanine into threonine. The second gene defect was identified in a patient with ichthyosis, right renal agenesis, and mirror movements of the upper limbs (synkinesia) and comprised a deletion of exons 5–10 of the KAL1 gene and a complete deletion of the steroid sulphatase gene. Conclusion(s) The phenotype of renal agenesis/dysgenesis strongly indicates the existence of KAL1 gene defects in the genotype of patients with sporadic KS, providing evidence for the X-linked mode of inheritance and offering the opportunity for genetic counseling.

The study included 26 patients with idiopathic hypogonadotropic hypogonadism (24 sporadic and 2 familial). The Pro146Ser mutation was identified in the gonadotropin-releasing hormone receptor (GnRHR) gene in two sisters as well as in their mother, and one polymorphism in the GnRH1 gene (the Trp16Ser) was identified in four patients. No mutations in transcription factor–binding sites of their promoters were identified. Three patients (one male and two sisters) were found with resistance to GnRH action. No mutations were identified in the male, whereas in the females the mutation Pro146Ser in the GnRHR was identified in heterozygosity.