Inherited Reproductive Disorders
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. In particular, hypogonadotropic hypogonadism (HH) exists
 along a genetic and phenotypic spectrum that includes milder forms of GnRH dysregulation,
 precocious and delayed puberty, and onset of reproductive dysfunction after puberty.

 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. We will use both candidate gene and whole exome approaches, as
 well as linkage analysis.

 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.
-  INCLUSION CRITERIA:

 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 (due to substantial
 variability among patient presentations, this will be based on the clinical judgement
 of the Investigator), 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).

 -  Patients who are taking medications known to affect GnRH secretion, such as
 corticosteroids or continuous opiate administration (or were taking them at the time
 of diagnosis).