Hypogonadotropic Hypogonadism/Kallmann Syndrome via the IL17RD Gene

Hypogonadotropic hypogonadism (HH), also known as gonadotropin-releasing hormone (GnRH) deficiency (IGD), is a genetic condition that is characterized by delayed or absent sexual development and infertility due to an impaired secretion of gonadotropins. Hypogonadotropic hypogonadism is divided into two major clinical phenotypes depending on the presence of an intact sense of smell: anosmic hypogonadotropic hypogonadism (Kallmann syndrome, KS) and normosmic hypogonadotropic hypogonadism (nHH) (Marino et al. 2014. PubMed ID: 25254043; Boehm et al. 2015. PubMed ID: 26194704; Kim. 2015. PubMed ID: 26790381; Balasubramanian and Crowly. 2017. PubMed ID: 20301509). The prevalence of HH has been estimated to range from 1:10,000 to 1:86,000 individuals depending on different populations (for example 1:10,000 in French and 1:86,000 in Sardinian). A recent study in Finland showed a minimal incidence of KS which accounts for nearly two thirds of individuals with HH of 1:30,000 in males and 1:125,000 in females (Laitinen et al. 2011. PubMed ID: 21682876). Males predominate in HH with a male-to-female ratio of nearly 4:1 (Seminara et al. 1998. PubMed ID: 9793755).

HH is typically diagnosed in patients presenting with absent or incomplete puberty, low serum testosterone or estradiol due to absence of circulating gonadotropins LH (luteinizing hormone) and FSH (follicle-stimulating hormone), but no other abnormalities of the hypothalamic-pituitary axis (Balasubramanian and Crowley. 2017. PubMed ID: 20301509). Infant boys with HH often demonstrate micropenis and cryptorchidism. Adult males with HH present failure to undergo normal puberty and absence of secondary sexual characteristics. Females with HH usually have little or no breast development, primary amenorrhea or infertility. In addition to reproductive symptoms, many KS patients exhibit a wide variety of additional signs and symptoms. Commonly recognized non-reproductive features that may be present in KS patients include: digital synkinesia, unilateral renal agenesis, cleft lip and/or palate, dental agenesis, hearing loss, and abnormal eye movements (Kaplan et al. 2010. PubMed ID: 20949504; Layman 2013. PubMed ID: 23650337; Balasubramanian and Crowley. 2017. PubMed ID: 20301509).

Hormone replacement with testosterone in males and estrogen in females is the classic treatment for hypogonadism. Hypogonadotropic hypogonadism is one of the rare conditions in which specific medical treatment can reverse infertility. Early intervention can promote the development of and maintain secondary sexual characteristics and normal sexual function, prevent low bone density and related complications, and also provides the opportunity for fertility (Boehm et al. 2015. PubMed ID: 26194704).

HH is a clinically and genetically heterogeneous disorder. To date, pathogenic variants in more than 35 genes, including IL17RD, account for about half of all HH. These genes are known to be involved in the formation and migration of GnRH and olfactory neurons. Pathogenic variants in these genes have been reported to disrupt the migratory pathway of GnRH and olfactory neurons from the nasal region into the hypothalamus.

Homozygous missense variants in IL17RD have been reported in HH/KS individuals and were strongly linked to hearing loss, indicating autosomal recessive inheritance (Miraoui et al. 2013. PubMed ID: 23643382). However, heterozygous missense variants in IL17RD have also been reported in HH/KS individuals, indicating autosomal dominant inheritance ( Miraoui et al. 2013. PubMed ID: 23643382 ; Zhou et al. 2018. PubMed ID: 30098700; Cassatella et al. 2018. PubMed ID: 29419413).

IL17RD encodes a single transmembrane glycoprotein belonging to the interleukin -17 receptor protein family. It is one of the major antagonists of FGF downstream signaling. IL17RD is coexpressed with FGF8 in the olfactory placode during embryogenesis, suggesting a potential role in the early development of both GnRH and olfactory neurons (Miraoui et al. 2013. PubMed ID: 23643382).

Pathogenic variants in IL17RD have been reported in ~3.4% of individuals with Kallmann syndrome/Hypogonadotropic hypogonadism (Zhou et al. 2018. PubMed ID: 30098700).

This test provides full coverage of all coding exons of the IL17RD gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).