Clinical trial NCT01601171: Genetics of Reproductive Disorders (Including Kallmann Syndrome) and Cleft Lip and/or Palate
Official title: The Genetics of Neuroendocrine Reproductive Disorders and of the Cleft Lip and/or Palate
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Kallmann Syndrome
Hypogonadotropic Hypogonadism
Hypothalamic Amenorrhea
Polycystic Ovarian Syndrome
Precocious Puberty
Cleft Lip and Palate
Cleft Palate
Cleft Lip
Keywords: GnRH deficiency
hypogonadism
anosmia
infertility
cleft lip
cleft palate
cryptorchidism
microphallus
Lead sponsor: Centre Hospitalier Universitaire Vaudois
Sponsor class: OTHER
Collaborators: name: Swiss National Science Foundation
First posted: 2012-05-17
Enrollment: 2000
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Observational model: CASE_CONTROL
Time perspective: OTHER
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Study participants will be a convenience sample of those patients with reproductive disorders (and their family members), with or without cleft lip/palate, who are interested in participating in this genetic study.

Brief summary: The purpose of this study is to explore the genetic basis of reproductive disorders and cleft lip and/or palate.

Detailed description: The World Health Organization estimates approximately 10% of couples experience some sort of infertility problem.

In humans, puberty is the process through which we develop reproductive capacity.

The timing of puberty varies greatly in the general population and is influenced by both genetic and environmental factors. In extreme cases of pubertal delay, puberty progresses only partially or not at all and results in the clinical picture of congenital hypogonadotropic hypogonadism (CHH), either accompanied by anosmia in 50% of cases (Kallmann syndrome \[KS\]) or by normal sense of smell (nCHH), with a male: female ratio of 4:1.

CHH is due to GnRH deficiency (incidence 1: 4,000-10,000) and result in the failure of sexual maturation and infertility. It is genetically heterogeneous, with multiple patterns of inheritance and several associated loci. In the clinical spectrum of GnRH deficiency, CHH may also be associated with a cleft lip/palate (CL/P) in 5 to 7% of cases. However, this prevalence increases up to 40% in CHH patients carrying a mutation in a CL/P gene, suggesting a genetic overlap between CHH and CL/P.

Disorders of puberty have provided insight into the biology of reproduction and genetic technologies have enabled us to deepen understanding in this field. The focus of this study is to better understand the genetic control of puberty and human reproduction as well as its link with CL/P.

Increasing understanding of the molecular basis (genes) of inherited reproductive disorders and CL/P may enable investigators to:

* improve diagnostic testing and treatments for these problems
* develop new diagnostic tests and therapies for patients
* enhance counseling for patients and families with reproductive disorders
* enhance counseling for patients and families with cleft lip/palate

Eligibility criteria: Inclusion Criteria:(any of the following conditions)

* hypogonadotropic hypogonadism
* Kallmann syndrome
* adult-onset hypogonadotropic hypogonadism
* hypothalamic amenorrhea
* polycystic ovarian syndrome
* primary gonadal failure
* precocious puberty
* cleft lip/palate
* family members of the above groups

Exclusion Criteria:

* acute illness/hospitalization
* pituitary tumors
* iron overload (hemochromatosis)
* infiltrative diseases (sarcoidosis)
* chronic alcohol abuse
* illicit drug use
* anabolic steroid abuse

Primary outcomes:
measure: rare sequence variant(s) in gene(s)
timeFrame: 1 year (ongoing if no variants are identified)
Secondary outcomes:
measure: functionality of identified rare sequence variants (mutations)
timeFrame: 1 year (following variant identification)
measure: mode of inheritance
timeFrame: 1 year (following variant identification)
measure: genotype-phenotype correlation
timeFrame: 1 year (following variant identification)
Other outcomes:
Locations:
city: Lausanne
country: Switzerland
facility: Centre Hospitalier Universitaire Vaudois (CHUV)
state: Vaud
Study officials:
affiliation: Centre Hositalier Universitaire Vaudois (CHUV)
name: Nelly Pitteloud, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Miraoui H, Dwyer AA, Sykiotis GP, Plummer L, Chung W, Feng B, Beenken A, Clarke J, Pers TH, Dworzynski P, Keefe K, Niedziela M, Raivio T, Crowley WF Jr, Seminara SB, Quinton R, Hughes VA, Kumanov P, Young J, Yialamas MA, Hall JE, Van Vliet G, Chanoine JP, Rubenstein J, Mohammadi M, Tsai PS, Sidis Y, Lage K, Pitteloud N. Mutations in FGF17, IL17RD, DUSP6, SPRY4, and FLRT3 are identified in individuals with congenital hypogonadotropic hypogonadism. Am J Hum Genet. 2013 May 2;92(5):725-43. doi: 10.1016/j.ajhg.2013.04.008.
citation: Villanueva C, Jacobson-Dickman E, Xu C, Manouvrier S, Dwyer AA, Sykiotis GP, Beenken A, Liu Y, Tommiska J, Hu Y, Tiosano D, Gerard M, Leger J, Drouin-Garraud V, Lefebvre H, Polak M, Carel JC, Phan-Hug F, Hauschild M, Plummer L, Rey JP, Raivio T, Bouloux P, Sidis Y, Mohammadi M, de Roux N, Pitteloud N. Congenital hypogonadotropic hypogonadism with split hand/foot malformation: a clinical entity with a high frequency of FGFR1 mutations. Genet Med. 2015 Aug;17(8):651-9. doi: 10.1038/gim.2014.166. Epub 2014 Nov 13.