ABSTRACT
Kallmann syndrome, a form of idiopathic hypogonadotropic hypogonadism, is characterized by developmental abnormalities of the reproductive system and abnormal olfaction. Despite association of certain genes with idiopathic hypogonadotropic hypogonadism, the genetic inheritance and expression are complex and incompletely known. In the present study, seven Kallmann syndrome pedigrees in an ethnic Han Chinese population were screened for genetic mutations. The exons and intron-exon boundaries of 19 idiopathic hypogonadotropic hypogonadism (idiopathic hypogonadotropic hypogonadism)-related genes in seven Chinese Kallmann syndrome pedigrees were sequenced. Detected mutations were also tested in 70 sporadic Kallmann syndrome cases and 200 Chinese healthy controls. In pedigrees 1, 2, and 7, the secondary sex characteristics were poorly developed and the patients' sense of smell was severely or completely lost. We detected a genetic mutation in five of the seven pedigrees: homozygous KAL1 p.R191ter (pedigree 1); homozygous KAL1 p.C13ter (pedigree 2; a novel mutation); heterozygous FGFR1 p.R250W (pedigree 3); and homozygous PROKR2 p.Y113H (pedigrees 4 and 5). No genetic change of the assayed genes was detected in pedigrees 6 and 7. Among the 70 sporadic cases, we detected one homozygous and one heterozygous PROKR2 p.Y113H mutation. This mutation was also detected heterozygously in 2/200 normal controls and its pathogenicity is likely questionable. The genetics and genotype-phenotype relationships in Kallmann syndrome are complicated. Classical monogenic inheritance does not explain the full range of genetic inheritance of Kallmann syndrome patients. Because of stochastic nature of genetic mutations, exome analyses of Kallmann syndrome patients may provide novel insights.
Subject(s)
DNA Mutational Analysis , Kallmann Syndrome/ethnology , Kallmann Syndrome/genetics , Adolescent , Adult , Amino Acid Sequence , Child , China , Codon, Nonsense , Exons , Extracellular Matrix Proteins/genetics , Family Health , Female , Genetic Association Studies , Heterozygote , Homozygote , Humans , Hypogonadism/ethnology , Hypogonadism/genetics , Introns , Male , Middle Aged , Molecular Sequence Data , Nerve Tissue Proteins/genetics , Pedigree , Phenotype , Receptor, Fibroblast Growth Factor, Type 1/genetics , Receptors, G-Protein-Coupled/genetics , Receptors, Peptide/genetics , Sequence Homology, Amino Acid , Young AdultABSTRACT
OBJECTIVE: The aim of this study was the development of a simple clinical smell test that can be applied in Jordan and its validation against one of the standard tests, the University of Pennsylvania Smell Test (UPSIT, Sensonics Inc, Haddon Heights, NJ). DESIGN: A prospective validation study of a locally designed smell test was done. SETTING: The study was conducted at the National Center for Diabetes, Endocrinology and Metabolism in Amman, Jordan. PARTICIPANTS: Fifty subjects were recruited to participate in this study. Twenty-five were normal healthy individuals, and 25 were patients with Kallmann syndrome. INTERVENTION AND MAIN OUTCOME MEASURES: All 50 participants underwent 2 tests, the UPSIT and the locally designed test (JOR test). The scores of all patients in both tests were compared. Test-retest reliability was determined in the same 50 subjects. All patients completed the study. RESULTS: Subjects who scored within normal limits on the UPSIT scored 8 to 10 on the JOR test, and people who were abnormal on the UPSIT scored between 0 and 5 on the JOR test. The correlation between the scores of both tests was almost perfect (r = 0.984, P = .000). When both tests were classified as normal and abnormal, there was a complete agreement (kappa statistic = 1). Both sensitivity and specificity were 100%. CONCLUSION: Given its highly significant correspondence to the UPSIT and the odor thresholds of Jordanians, our test proved valid and useful as a cross-cultural clinical test of olfactory function. In addition, it is an inexpensive, rapid test. Unfortunately, the data lacked persons with moderate impairment of smell. Therefore, the new test may not be used to assess this category of patients.
