| Domain | Scope | Key Findings, Statistics & Mechanisms | Evidence Type & Ontology Terms | References |
|---|---|---|---|---|
| **Identity & Identifiers** | HH18-Specific | Hypogonadotropic hypogonadism 18 with or without anosmia (Synonym: Kallmann syndrome 18). Inheritance is complex: autosomal dominant, autosomal recessive, and digenic/oligogenic patterns reported. | MONDO:0014103 | (pqac-00000001, pqac-00000003, pqac-00000004) |
| **Gene & Variants** | HH18-Specific | Causal gene: *IL17RD* (*SEF*). Discovery cohort (2013, PMID: 23643382, DOI: 10.1016/j.ajhg.2013.04.008) screened 386 CHH probands and found 8 unrelated probands (~2%) with variants: p.Lys131Thr, p.Lys162Arg, p.Pro306Ser, p.Tyr379Cys, p.Ser468Leu, p.Pro577Gln, p.Ala735Val. Later variant reported: p.Met320Ile. | HGNC:28810; Human clinical cohorts | (pqac-00000003, pqac-00000005, pqac-00000028) |
| **Phenotypes** | HH18-Specific | In the 2013 discovery cohort (n=8): 8/8 had Kallmann syndrome (anosmia), 7/8 had absent puberty, and 6/8 had congenital hearing loss (typically unilateral). Additional findings included dental agenesis and low bone mass. | HP:0000044 (CHH), HP:0000458 (Anosmia), HP:0000365 (Hearing impairment), HP:0000806 (Absent puberty) | (pqac-00000003, pqac-00000004) |
| **Mechanism & Models** | HH18-Specific / IL17RD | IL17RD is a transmembrane inhibitor of FGF8/FGFR1c and RAS-MAPK/ERK signaling. *In vitro* reporter assays showed p.Lys131Thr, p.Pro306Ser, and p.Ser468Leu variants caused 89%, 67%, and 32% loss of inhibition, respectively. In mouse embryos (E10.5-12.5), IL17RD localizes to the olfactory placode and GnRH neurons. *Sef*-null mice exhibit auditory brainstem defects. | GO:0008543 (FGF receptor signaling), In vitro assays, Mouse models | (pqac-00000002, pqac-00000003, pqac-00000022, pqac-00000023, pqac-00000027) |
| **Diagnosis** | Broad CHH | **Neonatal:** Minipuberty window shows low LH/FSH/T, micropenis, cryptorchidism. **Adolescence:** Delayed/absent puberty; inhibin B < 60 pmol/mL helps distinguish CHH from constitutional delay. **Anosmia:** Present in 52-55% of CHH cohorts. **Genetics:** UK NHS 14 "green" gene panel includes IL17RD. | Diagnostic clinical criteria, Biomarkers | (pqac-00000010, pqac-00000011, pqac-00000013, pqac-00000032, pqac-00000036) |
| **Treatment & Statistics** | Broad CHH | **Fertility (2024 Meta-analysis, 5328 pts):** hCG+FSH induced spermatogenesis in 86% (95% CI 82-91%) vs hCG alone (40%). **Reversal (2024 study):** 10-15% spontaneous reversal rate; among 87 reversals vs 108 non-reversals, cryptorchidism significantly lowered reversal odds (OR 0.30). **Puberty Induction:** Testosterone enanthate/cypionate for males; transdermal estradiol + progestin for females. | NCIT:C64016 (Hormone Replacement Therapy), NCIT:C63740 (Fertility Treatment) | (pqac-00000016, pqac-00000018, pqac-00000019, pqac-00000037, pqac-00000038) |
| **Evidence Gaps** | Both | Few HH18-specific functional cohorts exist beyond the 2013 discovery. Human GnRH neuronal impact of IL17RD is extrapolated from animal models. No gene-targeted therapies exist for FGF/IL17RD defects. Female CHH prevalence and natural history remain under-characterized. | Expert reviews, Literature gaps | (pqac-00000012, pqac-00000026) |


*Table: A structured knowledge-base table summarizing specific genetic, phenotypic, and mechanistic findings for IL17RD-mediated HH18, alongside diagnostic and therapeutic statistics for broader congenital hypogonadotropic hypogonadism.*