Genetics of Reproductive Disorders (Including Kallmann Syndrome) and Cleft Lip and/or Palate

The Genetics of Neuroendocrine Reproductive Disorders and of the Cleft Lip and/or Palate

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

Study Overview

• Status: Recruiting
• Conditions: Kallmann Syndrome; Hypogonadotropic Hypogonadism; Hypothalamic Amenorrhea; Polycystic Ovarian Syndrome; Precocious Puberty; Cleft Lip and Palate; Cleft Palate; Cleft Lip

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

• Study Type: Observational
• Enrollment (Anticipated): 2000

Contacts and Locations

• Study Contact: Name: Emmanuelle Paccou; Phone Number: +41 79 556 60 13; Email: emmanuelle.paccou@chuv.ch
• Study Contact Backup: Name: Michela Adamo, MD; Phone Number: +41 079 556 85 14; Email: michela.adamo@chuv.ch

Study Locations

• Switzerland
  • Vaud
    • Lausanne, Vaud, Switzerland, 1011
      • Recruiting
      • Centre Hospitalier Universitaire Vaudois (CHUV)
      • Contact: Emmanuelle Paccou; Phone Number: +41 79 556 60 13; Email: emmanuelle.paccou@chuv.ch
      • Contact: Michela Adamo, MD; Phone Number: +41 079 556 85 14; Email: michela.adamo@chuv.ch
      • Principal Investigator: Nelly Pitteloud, M.D.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• 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.

Description

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

Study Plan

How is the study designed?

Design Details

• Observational Models: Case-Control
• Time Perspectives: Other

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort
Patients; Patients with reproductive disorders with or without cleft lip/palate will be recruited for: completion of medical questionnaire and review of medical records; family tree (including questions on reproductive disorders and cleft lip/palate); specimen collection (DNA/RNA) from: serum/plasma/saliva/urine/buccal swab/hair follicles/sperm/skin biopsy; smell testing; hearing test; bone density; brain MRI; kidney, testicular/ovarian ultrasound
Family members; Family members of Patients will be recruited for: completion of medical questionnaire; specimen collection (DNA/RNA) from: serum/plasma/saliva/urine/buccal swab/hair follicles/sperm/skin biopsy; smell testing

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
rare sequence variant(s) in gene(s)	The investigators aim to discover genes associated with reproductive disorders by identifying rare sequence variants (mutations) in patients	1 year (ongoing if no variants are identified)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
functionality of identified rare sequence variants (mutations)	The investigators will use a variety of scientific approaches to assess the functional impact of the identified rare sequence variants (mutations)	1 year (following variant identification)
mode of inheritance	The investigators will examine family pedigrees and study family members to determine the inheritance patterns (how the disorder is transmitted in the family)	1 year (following variant identification)
genotype-phenotype correlation	The investigators will study the phenotypic spectrum (how the disorder presents clinically) in patients with identified rare sequence variants (mutations)	1 year (following variant identification)

Collaborators and Investigators

• Sponsor: Centre Hospitalier Universitaire Vaudois
• Collaborators: Swiss National Science Foundation
• Investigators: Principal Investigator: Nelly Pitteloud, M.D., Centre Hositalier Universitaire Vaudois (CHUV)

Publications and helpful links

General Publications

• 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.
• 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.

Helpful Links

• Web page for the Principal Investigator Nelly Pitteloud's research group

Study record dates

Study Major Dates

• Study Start: March 1, 2012
• Primary Completion (Anticipated): March 1, 2025
• Study Completion (Anticipated): March 1, 2030

Study Registration Dates

• First Submitted: May 15, 2012
• First Submitted That Met QC Criteria: May 16, 2012
• First Posted (Estimate): May 17, 2012

Study Record Updates

• Last Update Posted (Actual): June 21, 2022
• Last Update Submitted That Met QC Criteria: June 17, 2022
• Last Verified: June 1, 2022

More Information

Terms related to this study

• Keywords: GnRH deficiency; hypogonadism; anosmia; infertility; cleft lip; cleft palate; cryptorchidism; microphallus
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms; Endocrine System Diseases; Disease; Ovarian Cysts; Cysts; Ovarian Diseases; Adnexal Diseases; Gonadal Disorders; Disorders of Sex Development; Urogenital Abnormalities; Congenital Abnormalities; Genetic Diseases, Inborn; Musculoskeletal Diseases; Stomatognathic Diseases; Mouth Diseases; Lip Diseases; Mouth Abnormalities; Stomatognathic System Abnormalities; Jaw Abnormalities; Jaw Diseases; Maxillofacial Abnormalities; Craniofacial Abnormalities; Musculoskeletal Abnormalities; Menstruation Disturbances; Disorder of Sex Development, 46,XY; Polycystic Ovary Syndrome; Syndrome; Cleft Palate; Cleft Lip; Kallmann Syndrome; Hypogonadism; Puberty, Precocious; Amenorrhea
• Other Study ID Numbers: 345/11

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No