Hypogonadotropic Hypogonadism/Kallmann Syndrome via the FGF8 Gene

Hypogonadotropic hypogonadism (HH), also known as gonadotropin-releasing hormone (GnRH) deficiency, 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 et al. 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 et al. 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 et al. 2017. PubMed ID: 20301509).

Most patients harboring heterozygous FGF8 pathogenic variants have been reported to exhibit KS, although normosmic HH has also been reported. Individuals with FGF8 variants present a broad spectrum of pubertal development ranging from absent to partial to complete puberty (in males with adult-onset HH). The associated nonreproductive phenotypes include hearing loss and a range of skeletal features (high arched palate, cleft lip/palate, severe osteoporosis, camptodactyly, and hyperlaxity of the digits). Variable expressivity is evident in family members harboring the identical variant (Falardeau et al. 2008. PubMed ID: 18596921; Trarbach et al. 2010. PubMed ID: 20463092).

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 FGF8, account for about half of all HH ((Marino et al. 2014. PubMed ID: 25254043; Balasubramanian et al. 2017. PubMed ID: 20301509). These genes are known to be involved in the formation and migration of GnRH and olfactory neurons. Pathogenic variant in these genes haven been reported to disrupt the migratory pathway of GnRH and olfactory neurons from the nasal region into the hypothalamus.

Heterozygous loss-of-function variants in FGFR8 including frameshift, splicing and missense variants have been reported to be causative for KS and normosmic HH (Falardeau et al. 2008. PubMed ID: 18596921; Trarbach et al. 2010. PubMed ID: 20463092; Suzuki et al. 2014. PubMed ID: 24280688). De novo frameshift variants have been documented (Suzuki et al. 2014. PubMed ID: 24280688). Exon-level large deletions or duplications have not been reported in this gene (Human Gene Mutation Database). The most commonly reported pathogenic variant is c.385C>T (p.Arg129*) with an allele frequency of 0.003% (Genome Aggregation Database).

FGF8 encodes fibroblast growth factor 8. It was discovered as the critical ligand for FGFR1 in GnRH ontogeny. Mice homozygous for a hypomorphic Fgf8 allele lacked GnRH neurons in the hypothalamus, while heterozygous mice showed substantial decreases in the number of GnRH neurons and hypothalamic GnRH peptide concentration (Falardeau et al. 2008. PubMed ID: 18596921).

Pathogenic variants in FGF8 have been identified in 1-2% of KS patients (Falardeau et al. 2008. PubMed ID: 18596921).

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This test provides full coverage of all coding exons of the FGF8 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).