Outreach &Education Core (Core C) Background In our previous grant cycles, this Center has assembled a considerable amount of valuable information regarding the genotypes and phenotypes of GnRH deficient patients including those with isolated GnRH deficiency both with anosmia, i.e. Kallmann Syndrome (KS) and with normosmic Idiopathic Hypogonadotropic Hypogonadism (nIHH). We have also: a) described novel clinical variations on this theme such as reversal of GnRH deficiency (PI 9) and adult onset variety (Nachtigall et. al. N Engl J Med 1997 &P42); b) documented that digenicity/oligogenicity is evident in a significant proportion of cases (PI 4, P45); c) begun exploring the role of mutations in these genes in more common reproductive disorders such as precocious puberty (P22), and hypothalamic amenorrhea (P46). Thus, through the incremental work of this Center and other investigators around the world, the collective understanding of the genetics of this condition has advanced considerably. From completely lacking a genetic explanation in 1990 to now accounting for 33% of patients having an identifiable genetic defect (cf. Introductory Overview/ Fig 1 page 93) this striking change represents a rather remarkable gain in information. These findings have not only propelled several areas of neuroendocrine research but have also made significant contributions to the care and genetic counseling of patients and families with these disorders. As a direct consequence of this rapid progress, we have now amassed the world?s largest and most thoroughly phenotyped and genotyped cohort of patients with GnRH deficiency and their family members (cf. Introductory Overview, pg. 93). Over 400 of these probands now undergone complete sequencing of all known genes that are causative for this disease (publication P45). In addition, we also have assembled DNA samples from large and growing populations of the more common reproductive conditions in which some abnormality of GnRH secretion has been documented as described in the introductory Overview

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Specialized Center--Cooperative Agreements (U54)
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Special Emphasis Panel (ZHD1-DSR-L (32))
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Massachusetts General Hospital
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