Clinical and molecular characterization of a large sample of patients with hypogonadotropic hypogonadism.
OBJECTIVE
To characterize the phenotype, modes of inheritance, karyotype, and molecular basis of patients with idiopathic hypogonadotropic hypogonadism (IHH).


METHODS
Review of medical records, karyotyping, and collation of gene mutation analysis.


METHODS
University molecular reproductive endocrinology laboratory.


METHODS
Patients with IHH.


METHODS
Review of medical records, laboratory studies, and molecular studies.


METHODS
Sense of smell, severity of IHH (complete vs. incomplete), associated anomalies, karyotype, mutation analysis, and genotype/phenotype correlations were studied.


RESULTS
Of 315 patients with IHH, 6.3% had one or more affected relatives. Autosomal recessive inheritance was likely in most of these familial cases, but autosomal-dominant and X-linked recessive inheritance patterns were likely in some families. Complete IHH was more commonly found in males (62%), whereas incomplete IHH was more commonly observed in females (54.3%). Anosmia was present in 31.3% of males and 27.9% of females. The karyotype was normal in all 19 females tested, but was abnormal in 3 of 57 (5.3%) of males tested. Although cryptorchidism did not differ among those who were anosmic vs. normosmic, it was approximately four times more common in patients with complete IHH than incomplete IHH (15.3% vs. 3.9%). Approximately 10% of the IHH patients tested had mutations in either the GNRHR or KAL1 gene.


CONCLUSIONS
Idiopathic hypogonadotropic hypogonadism is a heterogeneous disorder affecting fertility, in which the number of familial cases is probably underestimated. Further study of genes that regulate hypothalamic-pituitary development and function will likely reveal important information regarding the development of normal puberty in humans.
Bhagavath
Balasubramanian
B
Division of Reproductive Endocrinology, Infertility, and Genetics, Department of Obstetrics and Gynecology, Medical College of Georgia, Augusta, Georgia 30912-3360, USA.
Podolsky
Robert H
RH
Ozata
Metin
M
Bolu
Erol
E
Bick
David P
DP
Kulharya
Anita
A
Sherins
Richard J
RJ
Layman
Lawrence C
LC
D000293:Adolescent; D003456:Cryptorchidism / Q000235:genetics; D016326:Extracellular Matrix Proteins / Q000235:genetics; D005260:Female; D006801:Humans; D007006:Hypogonadism / Q000235:genetics* / Q000503:physiopathology; D015994:Incidence; D017436:Kallmann Syndrome / Q000453:epidemiology / Q000235:genetics*; D007621:Karyotyping; D008297:Male; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics; D011966:Receptors, LHRH / Q000235:genetics; D012189:Retrospective Studies; D012720:Severity of Illness Index; D012727:Sex Characteristics; D017678:Sex Distribution
C076266:ANOS1 protein, human; D016326:Extracellular Matrix Proteins; C484844:GNRHR protein, human; D009419:Nerve Tissue Proteins; D011966:Receptors, LHRH