Inherited Reproductive Disorders

Background:

- During puberty, children begin to develop into adults. Problems with the hormones released during puberty can affect the reproductive system. Some people have low hormone levels that severely delay or prevent puberty. Others start puberty abnormally early. Other people may have a normal puberty but develop reproductive disorders later in life. Researchers want to study people with reproductive disorders to learn more about how these disorders may be inherited.

Objectives:

- To learn how reproductive system disorders may be inherited.

Eligibility:

• People with one of the following problems:
• Abnormally early puberty
• Abnormally late or no puberty
• Normal puberty with hormonal problems that develop later in life
• People who have not yet had puberty but have symptoms that indicate low hormone levels.

Design:

• Participants will provide a blood sample for testing. They will complete a questionnaire about their symptoms. They will also have a scratch-and-sniff test to study any problems with their ability to smell.
• Participant medical records will be reviewed. Participants will also provide a family medical history.
• Family members of those in the study may be invited to participate.
• Treatment will not be provided as part of this study.

The key initiating factors for reproductive development remain among the great mysteries of pediatric and reproductive endocrinology. The onset of puberty is initiated by pulsatile secretion of gonadotropin-releasing hormone (GnRH) from the hypothalamus. The neuroendocrine events leading to increased GnRH secretion and the resultant onset of puberty remain largely unknown.

Isolated deficiency of GnRH results in the rare clinical syndrome of idiopathic hypogonadotropic hypogonadism (IHH), where decreased secretion of GnRH results in impaired gonadotropin secretion. The resultant hypogonadism presents with delayed, incomplete, or absent sexual maturation. Human and animal models have identified a number of genes responsible for IHH, but more than half of patients with clinical evidence of the disorder do not have a detectable mutation. In addition, there is significant clinical heterogeneity among affected individuals, including members of the same family harboring the same mutations. Careful human phenotyping of such patients and families has expanded our understanding of this spectrum of disorders to include oligo-digenic inheritence, as well as reversibility of the condition, and has provided insight into developmental pathways involved in the ontogeny of GnRH neurons.

Genetic analysis of subjects with unknown mutations is likely to yield important insights into additional pathways involved in the regulation of GnRH secretion. Here, we propose a genetic investigation of subjects with IHH to characterize further the phenotypic effect of previously described genetic variants, as well as to identify novel genes involved in congenital GnRH deficiency. In collaboration with the Reproductive Endocrine Unit at the Massachusetts General Hospital, we will use both candidate gene and whole exome approaches, as well as linkage analysis. The collaboration will allow for sufficient statistical power to conduct such an investigation.

This protocol will utilize the disease model of IHH to increase our understanding of the physiology of GnRH secretion, including the neuroendocrine regulation of GnRH pulsatility. Examining the genetic characteristics of subjects with isolated GnRH deficiency will reveal insights into the mechanisms underlying the reawakening of the hypothalamic-pituitary-gonadal axis at puberty, providing opportunities for new diagnostic capabilities and therapeutic interventions for disorders of puberty and fertility.

• Endocrine Diseases
• Genetic Disorder
• Infertility
• Hypogonadism
• Amenorrhea

• Donahoe PK, Noonan KM, Lage K. Genetic tools and algorithms for gene discovery in major congenital anomalies. Birth Defects Res A Clin Mol Teratol. 2009 Jan;85(1):6-12. No abstract available.
• Zeggini E, Damcott CM, Hanson RL, Karim MA, Rayner NW, Groves CJ, Baier LJ, Hale TC, Hattersley AT, Hitman GA, Hunt SE, Knowler WC, Mitchell BD, Ng MC, O'Connell JR, Pollin TI, Vaxillaire M, Walker M, Wang X, Whittaker P, Xiang K, Jia W, Chan JC, Froguel P, Deloukas P, Shuldiner AR, Elbein SC, McCarthy MI; International Type 2 Diabetes 1q Consortium. Variation within the gene encoding the upstream stimulatory factor 1 does not influence susceptibility to type 2 diabetes in samples from populations with replicated evidence of linkage to chromosome 1q. Diabetes. 2006 Sep;55(9):2541-8. Erratum in: Diabetes. 2006 Nov;55(11):3197. Kunsun, Xiang [corrected to Xiang, Kunsan].
• Alkuraya FS. Homozygosity mapping: one more tool in the clinical geneticist's toolbox. Genet Med. 2010 Apr;12(4):236-9. Review.

• The essential inclusion criteria include:

  1. failure to go through a normal, age-appropriate, spontaneous puberty and low sex steroid levels in the setting of low/normal gonadotropins, or
  2. abnormally early development of puberty, or
  3. normal puberty with subsequent development of low gonadotropin levels, or
  4. pre-pubertal individuals with features suggestive of hypogonadotropic hypogonadism.

  5. Family members: both affected and unaffected family members are strongly encouraged to participate.

     EXCLUSION CRITERIA:

     Since hypogonadotropic hypogonadism is a rare condition, this protocol remains open to enrollment so that we may study all subjects that are both qualified and interested in participating.

     Because HH represents a spectrum, where associated clinical findings may provide phenotypic clues to the assessment of inheritability and underlying physiology, exclusion criteria are very limited:

• Patients who have additional pituitary deficiencies, effectively ruling out isolated GnRH deficiency, whether these deficiencies are congenital or acquired (e.g. secondary to malignancy, infection, or irradiation).