Hypogonadotropic Hypogonadism 18 With or Without Anosmia

Mendelian MONDO:0014103 Pathograph 17 Show in embeddings browser Congenital hypogonadotropic hypogonadism Disorders of puberty

HH18 is the form of congenital hypogonadotropic hypogonadism (CHH) attributed to variants in IL17RD, which encodes Sef ("similar expression to fgf genes") - not an interleukin receptor in any functional sense, despite the name, but a transmembrane feedback antagonist of FGF signalling that shares only sequence similarity with the intracellular domain of the IL-17 receptor. Sef was found in zebrafish as a member of the fgf8 synexpression group and shown to antagonise Ras/Raf/MEK/MAPK signalling downstream of FGF; in mammalian cells it associates with FGFR1 and suppresses receptor tyrosine phosphorylation and ERK activation. That places IL17RD in the same pathway as the genes that dominate CHH genetics. FGF8 and FGFR1 account for around 12% of CHH, and the hypothesis that produced HH18 was explicitly that modulators of FGFR1 signalling would also be mutated in CHH patients. Sequencing seven such genes in 386 CHH probands found IL17RD variants in eight, and an interactome-based prediction run independently ranked IL17RD among the top two candidate genes in the entire proteome. Two features make this entity different from a textbook Mendelian locus, and the entry is organised around them rather than around them being caveats. First, the variants are almost always heterozygous and inherited from an unaffected parent - in a Chinese cohort every one of five informative probands inherited the IL17RD variant from a parent with no phenotype - and most patients carry additional rare variants in other CHH genes. The cohort authors' own conclusion is that IL17RD variants act in synergy with other CHH loci rather than alone, which is why this entry types IL17RD as a susceptibility locus in an oligogenic architecture rather than as causative. Second, the extra-reproductive phenotype is unusually consistent for CHH: IL17RD variants were found only in anosmic (Kallmann) patients in the founding cohort and were strongly linked to hearing loss, which remains the most common accompanying feature across the published cases.

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Inheritance
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Pathophys.
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Phenotypes
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Gaps
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Pathograph
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Genes
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Medical Actions
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Differentials
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References
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Deep Research
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Inheritance

1
Oligogenic HP:0010983
The predominant pattern for IL17RD in CHH. Most carriers have variants in at least one other CHH-associated gene, and the reported combinations include IL17RD with PROKR2, with FGFR1 and RUVBL2, and with CPEB4. IL17RD is named in the schema sense as a contributing rather than a determining locus; see the `genetic` section, where it is typed SUSCEPTIBILITY.
Oligogenic inheritance
Show evidence (3 references)
PMID:32389901 SUPPORT Human Clinical
"Mutations in DUSP6 alone seem sufficient to cause IHH in an autosomal dominant manner, whereas IL17RD or SPRY4 mutations may cause IHH phenotypes in synergy with variants in other IHH-associated genes."
The sharpest statement of the distinction this entry turns on - and it is made against a directly comparable gene in the same pathway, DUSP6, which the same cohort does call sufficient.
PMID:23643382 SUPPORT Human Clinical
"Mutations in genes encoding components of the FGF pathway are associated with complex modes of CHH inheritance and act primarily as contributors to an oligogenic genetic architecture underlying CHH."
The founding cohort's own conclusion about the class of genes that includes IL17RD.
PMID:20301509 SUPPORT Other
"Almost all IGD-related genes have also been associated with indeterminate or oligogenic inheritance."
Places the oligogenic pattern in its clinical context: it is the norm across CHH genes, not a peculiarity of IL17RD.
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Discussions and Knowledge Gaps

3
Does an IL17RD variant increase or decrease FGF8-FGFR1 signalling in the developing olfactory-GnRH system, and how does either direction produce the same disease as FGFR1 loss of function?
KNOWLEDGE GAP hh18_direction_of_fgf_signalling_change
Attached to
pathophysiology#Dysregulated FGF8-FGFR1 Signaling in the Developing Olfactory-GnRH System
Sef is an antagonist, so impairing it should raise pathway output; but CHH is otherwise produced by FGFR1 and FGF8 loss of function, which lowers it. Both DUSP6 and the sprouties - also negative regulators - are implicated in the same disease, so this is not a peculiarity of IL17RD but a pattern that the negative-modulator class as a whole presents. No source read here measures signalling output for a patient IL17RD allele in a GnRH-lineage cell, so the node records dysregulation without a direction. Resolving it would need the patient alleles assayed in a relevant cell type, not in HEK293T.
Why is hearing loss the characteristic non-reproductive feature of IL17RD-related CHH?
KNOWLEDGE GAP hh18_hearing_loss_mechanism
Attached to
phenotypes#Sensorineural Hearing Impairment
The association is one of the most reproducible things about this entity - 6 of 8 in the founding cohort, 7 of 18 across the published carriers, and the most common accompanying symptom in both - and the human mechanism is still unaccounted for. An animal auditory phenotype does exist and is cited below: adult Sef-null mice have defective brainstem responsiveness to auditory stimuli, with Sef expressed in cochlear-nucleus astrocytes where it regulates FGF signalling from the rhombic lip. That result narrows the gap rather than closing it, in two ways. It localises the mouse defect centrally, to the cochlear nucleus, whereas the human phenotype in these carriers is reported as sensorineural hearing impairment; and no cited source connects the mouse finding to the hearing loss seen in IL17RD-related CHH, or proposes a role for Sef in cochlear or auditory-nerve development in humans. The open question is therefore whether the human deficit shares the central mechanism the mouse shows.
Show evidence (2 references)
DOI:10.1186/s12964-020-00695-7 SUPPORT Model Organism
"mice exhibited defects in the responsiveness of the brainstem to auditory stimuli."
Records the mouse auditory phenotype, which is why this gap is worded as an unexplained human mechanism rather than a total absence of animal data.
DOI:10.1186/s12964-020-00695-7 SUPPORT Model Organism
"SEF was expressed in the astrocytes of the cochlear nucleus, wherein it functioned to regulate FGF signaling from the adjacent rhombic lip"
Localises the mouse mechanism to the cochlear nucleus, which is the central-versus-cochlear distinction the gap now turns on.
Is any IL17RD variant sufficient on its own to cause congenital hypogonadotropic hypogonadism?
KNOWLEDGE GAP hh18_susceptibility_versus_causative
Attached to
pathophysiology#Oligogenic Requirement for Additional CHH Loci
Every informative proband in the largest IL17RD series inherited the variant from an unaffected parent, and oligogenicity was found in most; the same cohort concluded that DUSP6 variants are sufficient alone while IL17RD variants act in synergy. But the comparison is between small numbers, the sequencing in the earlier study did not cover every CHH gene, and an apparently isolated IL17RD case cannot be distinguished from one with an unsequenced second hit. Settling this needs genome-wide analysis of IL17RD carriers with and without disease, not more single cases. Until then the gene is typed SUSCEPTIBILITY rather than CAUSATIVE, and this discussion records that the typing is a judgement about evidence rather than a settled biological fact.
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Pathophysiology

5
IL17RD Variant Altering Sef Function
IL17RD encodes Sef, a transmembrane protein of the fgf8 synexpression group that acts as a feedback-induced antagonist of FGF signalling. In zebrafish it antagonises the Ras/Raf/MEK/MAPK arm downstream of FGF; in mammalian cells its extracellular and transmembrane domains associate with FGFR1 and inhibit receptor tyrosine phosphorylation and the ensuing Raf/MEK/ERK cascade. The CHH-associated variants are missense changes distributed across the protein, and most of those tested altered protein function in vitro. What that alteration does to signalling in a GnRH neuron is not established: the assays are heterologous, the variants are heterozygous, and no source read here measures FGF signalling output in patient-derived tissue.
IL17RD hgnc:17616 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves IL17RD (hgnc:17616). hgnc:17616 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context zygosity: HETEROZYGOUS functional_impact_category: UNKNOWN
Reported IL17RD variants in CHH are heterozygous missense changes. Most altered protein function in the founding study's in-vitro assays, but the direction of that alteration in the developing olfactory-GnRH system is not established, so the impact category is left UNKNOWN rather than being recorded as loss of function.
Sef-mediated negative feedback on FGF receptor signalling GO:0040037 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal Sef-mediated negative feedback on FGF receptor signalling, annotated with negative regulation of fibroblast growth factor receptor signaling pathway (GO:0040037). GO:0040037 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Downstream
Dysregulated FGF8-FGFR1 Signaling in the Developing Olfactory-GnRH System An altered feedback antagonist changes the gain of the pathway it regulates. The link is inferred from Sef's established role as an FGFR1-associated inhibitor plus the in-vitro demonstration that CHH variants alter protein function; it has not been measured in GnRH-lineage cells.
Sensorineural Hearing Impairment The strongest and least explained association in this disease. IL17RD variants were found only in anosmic patients in the founding cohort and were strongly linked to hearing loss, and hearing loss remains the most common accompanying feature in the published carriers. No mechanism connecting Sef to cochlear development is offered by any source read here, so this edge records a reproducible clinical association whose intermediates are unknown.
Show evidence (3 references)
PMID:11802165 SUPPORT INDIRECT Model Organism
"Here we show that in zebrafish, Sef functions as a feedback-induced antagonist of Ras/Raf/MEK/MAPK-mediated FGF signalling."
Establishes the normal function of the gene product. INDIRECT with respect to the human disease: it is zebrafish developmental biology, and it predates any link to CHH.
PMID:16603339 SUPPORT INDIRECT In Vitro
"We also showed that SefECTM associated with FGFR1, and inhibited FGF-induced ERK activation in HEK293T cells."
Places Sef physically on FGFR1 in a mammalian cell system, which is the specific pathway connection that makes IL17RD a candidate CHH gene at all.
PMID:23643382 SUPPORT Human Clinical
"Most of the FGF17 and IL17RD mutations altered protein function in vitro."
The functional evidence that the patient variants are not silent, stated with the hedge the authors used.
Oligogenic Requirement for Additional CHH Loci
An IL17RD variant on its own is usually not enough. In the IL17RD-focused Chinese cohort, every informative proband inherited the variant from an unaffected parent, and more than half carried variants in additional CHH genes; the published case reports repeat the pattern, with IL17RD paired with PROKR2, with FGFR1 plus RUVBL2, and with CPEB4. Whatever the IL17RD change does to FGF signalling, the disease appears where it is combined with a second hit. This node exists so the requirement is a step in the causal chain rather than a caveat attached to one. It is also the reason recurrence-risk counselling in HH18 cannot be run off a dominant model.
Downstream
Dysregulated FGF8-FGFR1 Signaling in the Developing Olfactory-GnRH System Co-inherited variants in other CHH genes - several of them in the same FGF8-FGFR1 axis - are what push the pathway past the threshold at which the olfactory-GnRH programme fails. The threshold model is the authors' inference from segregation and co-occurrence, not a measured quantity.
Show evidence (3 references)
PMID:32389901 SUPPORT Human Clinical
"Segregation analysis indicated that 100% (5/5) of probands inherited the IL17RD variants from their unaffected parents, and oligogenicity was found in 4/7 patients."
The segregation and oligogenicity numerators in one sentence; this is the observation the node is built on.
PMID:38628584 SUPPORT Human Clinical
"Whole-exome sequencing confirmed that the child carried both the IL17RD variant (c.2101G>A, p.Gly701Ser) inherited from the mother and the new CPEB4 variant (c.1414C>T, p.Arg472*)."
A worked instance of the pattern: a maternally inherited IL17RD variant carried by an unaffected mother, plus a de novo second-locus variant in the affected child.
PMID:38628584 SUPPORT Human Clinical
"Previous studies have demonstrated that the genetic penetrance and phenotypic expressivity of disease symptoms was dependent on factors such as zygosity of the mutation as well as mutations occurring in other genetic loci, suggesting an oligogenic mode of action"
States the oligogenic model explicitly for this gene, in the review that accompanies the case.
Dysregulated FGF8-FGFR1 Signaling in the Developing Olfactory-GnRH System
FGF8-FGFR1 signalling is required for the embryonic programme in which GnRH neurons and olfactory axons migrate together from the olfactory placode toward the forebrain, and impairment of this signalling is one of the principal causes of CHH. IL17RD joins that pathway from the regulatory side: DUSP6, IL17RD, SPRY2 and SPRY4 are all negative modulators of FGF8-FGFR1 signalling that have been implicated in the disease. The step from "the pathway is dysregulated" to a specific direction of change is not taken here. Loss of a feedback antagonist would be expected to increase signalling, which is not the direction that FGFR1 loss-of-function CHH implies, and no source read here resolves that tension for IL17RD.
FGF8-FGFR1 signalling in the olfactory-GnRH axis GO:0008543 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves dysregulated FGF8-FGFR1 signalling in the olfactory-GnRH axis, annotated with fibroblast growth factor receptor signaling pathway (GO:0008543). GO:0008543 is a biological process from the Gene Ontology. ↕ DYSREGULATED downstream ERK activation GO:0070371 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves dysregulated downstream ERK activation, annotated with ERK1 and ERK2 cascade (GO:0070371). GO:0070371 is a biological process from the Gene Ontology. ↕ DYSREGULATED
Downstream
Failure of GnRH Neuron Migration and Olfactory Bulb Development The developmental programme that FGF8-FGFR1 signalling supports is the co-migration of GnRH neurons with olfactory axons and the morphogenesis of the olfactory bulb; disturbing the signal disturbs that programme.
Show evidence (2 references)
PMID:32389901 SUPPORT Human Clinical
"FGF8-FGFR1 signalling is involved in multiple biological processes, while impairment of this signalling is one of the main reasons for isolated hypogonadotropic hypogonadism (IHH)."
Establishes the pathway as a principal cause of the disease.
PMID:32389901 SUPPORT Human Clinical
"Recently, several negative modulators of FGF8-FGFR1 signalling were also found to be involved in IHH, including DUSP6, IL17RD, SPRY2 and SPRY4."
Places IL17RD specifically among the negative modulators of that pathway implicated in the disease.
Failure of GnRH Neuron Migration and Olfactory Bulb Development
GnRH neurons originate outside the brain and reach the hypothalamus by migrating along olfactory axons; the shared route is why reproductive and olfactory deficits travel together in Kallmann syndrome. When the programme fails, the hypothalamus is left without its GnRH neuron population and the olfactory bulb is malformed or absent - in the imaged case report, bilateral olfactory nerve deficits on MRI accompanied a complete inability to identify odours.
GnRH neuron CL:0011111 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves GnRH neuron, annotated with hypothalamic gonadotropin-releasing hormone neuron (CL:0011111). CL:0011111 is a cell type from the Cell Ontology.
GnRH neuron migration GO:0001764 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal GnRH neuron migration, annotated with neuron migration (GO:0001764). GO:0001764 is a biological process from the Gene Ontology. ⚠ ABNORMAL
olfactory bulb UBERON:0002264 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in olfactory bulb (UBERON:0002264). UBERON:0002264 is an anatomical location from the Uberon multi-species anatomy ontology. hypothalamus UBERON:0001898 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in hypothalamus (UBERON:0001898). UBERON:0001898 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
GnRH-Driven Gonadotropin Deficiency Without a functioning hypothalamic GnRH neuron population there is no pulsatile GnRH signal to drive pituitary gonadotropin secretion.
Anosmia The olfactory arm of the same failed developmental programme, which is why IL17RD carriers in the founding cohort were anosmic rather than normosmic.
Abnormal Olfactory Bulb Morphology The structural correlate visible on MRI, and the imaging finding that distinguishes Kallmann syndrome from normosmic CHH.
Show evidence (2 references)
PMID:38628584 SUPPORT Human Clinical
"During embryonic development, several interacting genes are involved in olfaction establishment and the migration of GnRH neurons, implying a shared embryonic origin among these genes"
States the shared developmental origin that makes one lesion produce both the reproductive and the olfactory phenotype.
PMID:20301509 SUPPORT Other
"IGD is associated with a normal sense of smell (normosmic IGD) in approximately 40% of affected individuals and an impaired sense of smell (Kallmann syndrome) in approximately 60%."
The clinical split that the olfactory arm of this node produces, across CHH as a whole.
GnRH-Driven Gonadotropin Deficiency
Absent or insufficient hypothalamic GnRH input leaves the pituitary gonadotropes unstimulated, so LH and FSH are inappropriately low in the face of low sex steroids - the biochemical signature of the disease. The pituitary itself is structurally and functionally normal apart from this, which is what separates CHH from combined pituitary hormone deficiency, and the deficit is demonstrable as a blunted LH response to exogenous GnRH.
pituitary gonadotrope CL:0000438 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves pituitary gonadotrope, annotated with luteinizing hormone secreting cell (CL:0000438). CL:0000438 is a cell type from the Cell Ontology.
Downstream
Hypogonadotropic Hypogonadism The direct endocrine consequence, and the defining feature of the disease.
Absent or Incomplete Puberty Without gonadotropin drive the gonads do not produce the sex steroids that carry pubertal development, so puberty does not start or does not complete.
Micropenis A consequence of gonadotropin deficiency in fetal and neonatal life rather than at puberty, which is why it can be the presenting sign in an infant boy.
Cryptorchidism Testicular descent is gonadotropin-dependent in late gestation, so the same prenatal deficit that produces micropenis can leave the testes undescended.
Show evidence (2 references)
PMID:20301509 SUPPORT Other
"Isolated gonadotropin-releasing hormone (GnRH) deficiency (IGD) is characterized by inappropriately low serum concentrations of the gonadotropins LH (luteinizing hormone) and FSH (follicle-stimulating hormone) in the presence of low circulating concentrations of sex steroids."
The biochemical definition of the node.
PMID:38628584 SUPPORT Human Clinical
"Additionally, during the gonadorelin stimulation test (1-day method), LH reached a maximum of only 2.71 IU/L at 60 min."
The blunted stimulated LH response in an IL17RD carrier, which is the functional demonstration of this node in a patient with this genotype.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Hypogonadotropic Hypogonadism 18 With or Without Anosmia Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

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Ear 1
Sensorineural Hearing Impairment FREQUENT HP:0000407 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Sensorineural hearing impairment (HP:0000407). HP:0000407 is a phenotype from the Human Phenotype Ontology.
Numerator/denominator: 7 of 18 Kallmann-syndrome IL17RD carriers in the published review (38.9%), which sits in the FREQUENT band. The founding cohort reported a higher rate, 6 of 8, which is the source of the "strongly linked" phrasing; the band uses the larger denominator.
Show evidence (3 references)
PMID:38628584 SUPPORT Human Clinical
"Hearing loss emerged as the most common concomitant symptom (7 out of 18, 38.9%), as confirmed by our findings."
The numerator and denominator behind the band, 7 of 18 or 38.9%.
PMID:23643382 SUPPORT Human Clinical
"IL17RD mutations were found only in KS individuals and were strongly linked to hearing loss (6/8 individuals)."
The founding cohort's rate, on a smaller denominator.
PMID:38628584 SUPPORT Human Clinical
"Audiometry confirmed sensorineural hearing loss in the right ear."
Audiometric confirmation in an individual carrier, and a reminder that the deficit can be unilateral.
Endocrine 2
Hypogonadotropic Hypogonadism OBLIGATE HP:0000044 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypogonadotropic hypogonadism (HP:0000044). HP:0000044 is a phenotype from the Human Phenotype Ontology.
OBLIGATE because it is definitional rather than observed at some rate: a patient without it would not be assigned to this disease.
Sequelae: Osteoporosis
Show evidence (2 references)
PMID:20301509 SUPPORT Other
"Isolated gonadotropin-releasing hormone (GnRH) deficiency (IGD) is characterized by inappropriately low serum concentrations of the gonadotropins LH (luteinizing hormone) and FSH (follicle-stimulating hormone) in the presence of low circulating concentrations of sex steroids."
The definitional statement.
PMID:38628584 SUPPORT Human Clinical
"The basal levels of Luteinising hormone (LH), which was 0.22 IU/L (normal reference range 0.71-6.24, the same below), follicle-stimulating hormone (FSH), which was 1.63 IU/L (0.91-7.25), and testosterone (T) was 0.45 nmol/L(0.71-22.92)."
The measured values in an IL17RD carrier.
Absent or Incomplete Puberty Delayed puberty HP:0000823 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Delayed puberty (HP:0000823). HP:0000823 is a phenotype from the Human Phenotype Ontology.
No frequency band: the published IL17RD series do not report pubertal staging patient by patient, so a band would be an extrapolation from CHH in general rather than a count in this genotype.
Show evidence (2 references)
PMID:38628584 SUPPORT Human Clinical
"His pubertal development is in Tanner stage 1, with a penis length of 2 cm and a penis circumference of 1.2 cm."
The staged observation in an IL17RD carrier.
PMID:20301509 SUPPORT Other
"Adolescents and adults with IGD have clinical evidence of hypogonadism and incomplete sexual maturation on physical examination."
The general clinical description for the disease class.
Genitourinary 2
Micropenis HP:0000054 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Micropenis (HP:0000054). HP:0000054 is a phenotype from the Human Phenotype Ontology.
No frequency band. Micropenis appears in the published review only inside a list of manifestations shared by 13 of 18 carriers, without a per-feature numerator, so the denominator for micropenis specifically does not exist in these sources.
Show evidence (2 references)
PMID:38628584 SUPPORT Human Clinical
"and 72.2% (13 out of 18) of patients experienced other concomitant manifestations of KS, including cryptorchidism, micropenis, hypospadias, hearing loss, abnormal dentition, and osteoporosis."
Lists micropenis among the manifestations seen in IL17RD carriers - 13 of 18 had at least one of them, but the source gives no per-feature count, which is why no band is set.
PMID:20301509 SUPPORT Other
"Infant boys with congenital IGD often have micropenis and cryptorchidism."
Establishes micropenis as a recognised neonatal presentation of the disease class, which is the basis for the prenatal timing given in the description.
Cryptorchidism HP:0000028 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cryptorchidism (HP:0000028). HP:0000028 is a phenotype from the Human Phenotype Ontology.
No frequency band, for the same reason as micropenis: the review lists cryptorchidism inside an aggregate of 13 of 18 without a per-feature count.
Show evidence (2 references)
PMID:38628584 SUPPORT Human Clinical
"By approximately 3 years of age, the patient underwent surgery for cryptorchidism and was diagnosed with allergic rhinitis."
The individual observation in an IL17RD carrier.
PMID:20301509 SUPPORT Other
"Infant boys with congenital IGD often have micropenis and cryptorchidism."
Establishes cryptorchidism as a recognised presentation of the disease class.
Head and Neck 1
Anosmia VERY_FREQUENT HP:0000458 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Anosmia (HP:0000458). HP:0000458 is a phenotype from the Human Phenotype Ontology.
Numerator/denominator: 18 of 22 published IL17RD carriers (81.8%) had Kallmann syndrome rather than normosmic CHH, which sits at the bottom of the VERY_FREQUENT band. The founding cohort's 8 of 8 is the stronger claim but the smaller denominator; the 22-patient review is used for the band because it includes the later normosmic carriers.
Show evidence (2 references)
PMID:38628584 SUPPORT Human Clinical
"Among them, KS occurred in 18 out of 22 (81.8%) patients"
The numerator and denominator behind the band.
PMID:23643382 SUPPORT Human Clinical
"IL17RD mutations were found only in KS individuals and were strongly linked to hearing loss (6/8 individuals)."
The founding cohort's exclusive association with the anosmic form. Note the same sentence carries the hearing-loss association recorded separately below.
Musculoskeletal 1
Osteoporosis HP:0000939 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Osteoporosis (HP:0000939). HP:0000939 is a phenotype from the Human Phenotype Ontology.
No frequency band. The IL17RD source names osteoporosis only inside the same 13-of-18 list of shared manifestations that the micropenis and cryptorchidism phenotypes draw on, and gives no per-feature numerator, so a band cannot be set from it. Bound to Osteoporosis rather than the broader HP:0004349 Reduced bone mineral density because osteoporosis is the word the disease-specific source uses; the GeneReviews chapter's broader "decreased bone mass" framing is cited on the treatment and surveillance entries rather than here, so each quote sits on the claim it actually supports.
Show evidence (1 reference)
PMID:38628584 SUPPORT Human Clinical
"and 72.2% (13 out of 18) of patients experienced other concomitant manifestations of KS, including cryptorchidism, micropenis, hypospadias, hearing loss, abnormal dentition, and osteoporosis."
Names osteoporosis among the manifestations seen in IL17RD carriers. The source gives no per-feature count, which is why no frequency band is set.
Nervous System 1
Abnormal Olfactory Bulb Morphology Abnormal morphology of the olfactory bulb HP:0040327 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal morphology of the olfactory bulb (HP:0040327). HP:0040327 is a phenotype from the Human Phenotype Ontology.
No frequency band. Only one IL17RD carrier read here had olfactory imaging reported, so any band would rest on a denominator of one. The bound term is the general abnormal-morphology term rather than a hypoplasia or aplasia term, because the report describes bilateral olfactory nerve deficits without grading the bulb.
Show evidence (1 reference)
PMID:38628584 SUPPORT Human Clinical
"Plain MRI imaging of the olfactory bulb indicated bilateral olfactory nerve deficits"
The imaging finding in the one carrier for whom it is reported.
🧬

Genetic Associations

1
IL17RD
Gene: IL17RD hgnc:17616 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is IL17RD (hgnc:17616). hgnc:17616 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: SUSCEPTIBILITY
Show evidence (3 references)
PMID:23643382 SUPPORT Human Clinical
"Independently, IBAS predicted FGF17 and IL17RD as the two top candidates in the entire proteome on the basis of a statistical test of their protein-protein interaction patterns to proteins known to be altered in CHH."
The computational nomination that converged with the sequencing result, which is part of why this gene-disease relationship was taken seriously from a small number of probands.
PMID:32389901 SUPPORT Human Clinical
"Six heterozygous IL17RD variants (p.P191L, p.G35V, p.S671L, p.A221T, p.I329M and p.I329V) were found in seven patients."
The allelic spectrum and the heterozygous state, in the largest IL17RD series.
PMID:38628584 SUPPORT Human Clinical
"Currently, the prevalence of IL17RD variants remains unknown, and a definitive correlation between specific IL17RD variant types and clinical phenotypes is yet to be established"
The explicit statement that neither a prevalence nor a genotype-phenotype correlation is available, which is why this entry asserts neither.
💊

Medical Actions

3
Sex Steroid Replacement for Induction of Secondary Sexual Characteristics
Action: hormone replacement therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is hormone replacement therapy (NCIT:C15599). NCIT:C15599 is a clinical intervention from the NCI Thesaurus. Ontology label: Hormone Replacement Therapy NCIT:C15599
Agent: testosterone CHEBI:17347 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses testosterone (CHEBI:17347). CHEBI:17347 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Gradually increasing testosterone in males, or estrogen and progestin in females, to induce and then maintain secondary sexual characteristics. This substitutes for the gonadal output the absent gonadotropin drive never produced; it does not restore the axis.
Mechanism Target:
BYPASSES Absent or Incomplete Puberty — Symptomatic and downstream: exogenous sex steroid produces the pubertal changes without acting on the hypothalamic defect, so it is recorded against the phenotype rather than an upstream node.
Show evidence (1 reference)
PMID:20301509 SUPPORT Other
"To induce and maintain secondary sex characteristics, gradually increasing doses of testosterone or human chorionic gonadotropin (hCG) injections in males or estrogen and progestin in females"
The management recommendation for the disease class.
Show evidence (1 reference)
PMID:20301509 SUPPORT Other
"To induce and maintain secondary sex characteristics, gradually increasing doses of testosterone or human chorionic gonadotropin (hCG) injections in males or estrogen and progestin in females"
The recommendation, stated for isolated GnRH deficiency as a whole.
Gonadotropin or Pulsatile GnRH Therapy for Fertility
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: gonadorelin CHEBI:5520 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses gonadorelin (CHEBI:5520). CHEBI:5520 is a therapeutic agent from Chemical Entities of Biological Interest. human chorionic gonadotropin CHEBI:81570 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses human chorionic gonadotropin, annotated with Chorionic gonadotropin (CHEBI:81570). CHEBI:81570 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Peptide
Combined gonadotropin therapy (hCG with hMG or recombinant FSH), or pulsatile GnRH delivery, to drive gametogenesis when fertility is the goal. Pulsatile GnRH is the one intervention here that acts at the level of the missing signal itself, replacing the hypothalamic pulse generator rather than substituting for its end product - which is why it works only when the pituitary and gonads are otherwise intact.
Mechanism Target:
RESTORES GnRH-Driven Gonadotropin Deficiency — Pulsatile GnRH substitutes for the absent hypothalamic signal at exactly the point the pathograph breaks, which is why it is recorded against this node rather than against a phenotype. Combined gonadotropin therapy acts one step further downstream, replacing the pituitary output instead.
Show evidence (1 reference)
PMID:20301509 SUPPORT Other
"or pulsatile GnRH therapy. If conception fails despite spermatogenesis in a male or ovulation induction in a female, in vitro fertilization may be an option."
The fertility regimen for the disease class.
Show evidence (1 reference)
PMID:20301509 SUPPORT Other
"to stimulate spermatogenesis or folliculogenesis, either combined gonadotropin therapy"
The recommendation, stated for isolated GnRH deficiency as a whole.
Calcium and Vitamin D Repletion for Decreased Bone Mass
Action: calcium and vitamin D repletionNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is calcium and vitamin D repletion, annotated with Nutritional Support (NCIT:C15433). NCIT:C15433 is a clinical intervention from the NCI Thesaurus. Ontology label: Nutritional Support NCIT:C15433
Agent: calcium(2+) CHEBI:29108 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses calcium(2+) (CHEBI:29108). CHEBI:29108 is a therapeutic agent from Chemical Entities of Biological Interest. vitamin D CHEBI:27300 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses vitamin D (CHEBI:27300). CHEBI:27300 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Prevention of the skeletal secondary complication of untreated sex steroid deficiency: optimal calcium and vitamin D intake, with specific treatment of decreased bone mass where it is found. This is prevention of a complication rather than treatment of the endocrine lesion, which is why it targets the bone phenotype and not a pathophysiology node.
Mechanism Target:
INHIBITS Osteoporosis — Recorded against the bone phenotype rather than an upstream node: repletion does not act on GnRH signalling, it mitigates the skeletal consequence of the hypogonadal state.
Show evidence (1 reference)
PMID:20301509 SUPPORT Other
"Prevention of secondary complications: Optimal calcium and vitamin D intake should be encouraged and specific treatment for decreased bone mass as needed."
The GeneReviews prevention recommendation, which names both the intervention and the complication it is aimed at.
Show evidence (1 reference)
PMID:20301509 SUPPORT Other
"Optimal calcium and vitamin D intake should be encouraged and specific treatment for decreased bone mass as needed."
The recommendation, stated for isolated GnRH deficiency as a whole.
🔬

Diagnosis

6
Biochemical confirmation of hypogonadotropic hypogonadism
The diagnosis is made on the pattern, not on any single value: low sex steroid with LH and FSH that are low or inappropriately normal rather than raised, in a pituitary that is otherwise anatomically and functionally intact, and with secondary causes excluded. The "inappropriately" is the whole point - normal-range gonadotropins in the face of a low testosterone are the abnormality.
biochemical testing NCIT:C124351 NCI Thesaurus (NCIT)
Results: Low serum testosterone or estradiol with low or inappropriately normal LH and FSH.
NCIT has no clinical-action term for this panel of assays that is reachable from NCIT:C25218, so the bound term is the general Clinical Evaluation term and `preferred_term` carries the specificity.
Show evidence (2 references)
PMID:20301509 SUPPORT Other
"IGD is typically diagnosed in adolescents presenting with absent or partial puberty using biochemical testing that reveals low serum testosterone or estradiol (hypogonadism) that results from complete or partial absence of GnRH-mediated release of LH and FSH"
The diagnostic definition for the disease class.
PMID:38628584 SUPPORT Human Clinical
"The basal levels of Luteinising hormone (LH), which was 0.22 IU/L (normal reference range 0.71-6.24, the same below), follicle-stimulating hormone (FSH), which was 1.63 IU/L (0.91-7.25), and testosterone (T) was 0.45 nmol/L(0.71-22.92)."
The measured pattern in an IL17RD carrier, with reference ranges alongside.
GnRH (gonadorelin) stimulation test
A blunted LH rise after exogenous GnRH demonstrates the deficit functionally rather than inferring it from basal values. In the IL17RD carrier reported in detail, LH peaked at 2.71 IU/L at sixty minutes - a response, but far below a normal one.
gonadotropin-releasing hormone stimulation test NCIT:C124351 NCI Thesaurus (NCIT)
Results: Blunted peak LH response to exogenous GnRH.
Show evidence (1 reference)
PMID:38628584 SUPPORT Human Clinical
"Additionally, during the gonadorelin stimulation test (1-day method), LH reached a maximum of only 2.71 IU/L at 60 min."
The stimulated response in a patient with this genotype.
Formal olfactory testing
Smell is what separates Kallmann syndrome from normosmic CHH, and it has to be tested rather than asked about - patients who have never smelled normally do not report a deficit. IL17RD carriers are overwhelmingly on the anosmic side, so a positive smell test moves the diagnosis toward this gene rather than away from it.
olfactory testing NCIT:C124351 NCI Thesaurus (NCIT)
Results: Anosmia or hyposmia on formal testing.
Show evidence (1 reference)
PMID:38628584 SUPPORT Human Clinical
"During the olfactory test (water, 75% alcohol, vinegar, and perfume), the patient demonstrated an inability to discern smells."
A worked example of the bedside test and its result in an IL17RD carrier.
MRI of the olfactory bulbs and pituitary
Imaging supplies the structural counterpart of the smell deficit and simultaneously excludes the acquired pituitary causes that would make this not CHH. The reported IL17RD carrier had bilateral olfactory nerve deficits with a small pituitary and no mass lesion.
magnetic resonance imaging NCIT:C124351 NCI Thesaurus (NCIT)
Results: Absent or hypoplastic olfactory structures; a structurally unremarkable pituitary without a mass lesion.
Show evidence (2 references)
PMID:38628584 SUPPORT Human Clinical
"Plain MRI imaging of the olfactory bulb indicated bilateral olfactory nerve deficits"
The olfactory imaging finding.
PMID:38628584 SUPPORT Human Clinical
"A pituitary MRI plain scan revealed a small pituitary gland with no significant occupying lesions."
The pituitary imaging that excludes an acquired cause, which is what makes the diagnosis congenital rather than secondary.
Broad genomic testing, not single-gene testing
Single-gene testing is the wrong instrument for this disease, and the reason is the oligogenic architecture rather than a mere breadth-of-differential argument. Finding the IL17RD variant and stopping would miss the second locus that most carriers have, and it is the combination that is being counselled on. In the reported case, exome sequencing plus copy-number analysis found a maternally inherited IL17RD variant and a de novo CPEB4 variant; either alone would have told a different and wrong story.
molecular analysis NCIT:C19770 NCI Thesaurus (NCIT)
Results: A heterozygous IL17RD variant, usually with a variant in at least one other CHH-associated gene; parental testing is informative.
Show evidence (2 references)
PMID:38628584 SUPPORT Human Clinical
"Whole-exome sequencing confirmed that the child carried both the IL17RD variant (c.2101G>A, p.Gly701Ser) inherited from the mother and the new CPEB4 variant (c.1414C>T, p.Arg472*)."
The two-locus result that a single-gene test would have truncated, and the parental testing that established which variant was inherited.
PMID:20301509 SUPPORT Other
"Pathogenic variants in more than 25 genes account for about half of all IGD; the genetic cause for the remaining cases of IGD is unknown."
The locus heterogeneity that makes multi-gene testing the default, and the reminder that about half of patients will have no molecular answer at all.
Bone mineral density surveillance
Periodic measurement of bone mineral density in confirmed isolated GnRH deficiency, alongside serum sex steroid levels. It is surveillance for a secondary complication rather than a test that establishes the diagnosis, and it is what makes the decreased-bone-mass phenotype actionable.
bone mineral density measurement NCIT:C61545 NCI Thesaurus (NCIT)
Results: Reduced bone mineral density in a proportion of affected individuals.
Show evidence (1 reference)
PMID:20301509 SUPPORT Other
"In individuals with confirmed IGD, monitor at regular intervals: serum sex steroid levels (to guide optimal hormone replacement); bone mineral density."
The GeneReviews surveillance recommendation, which names bone mineral density as a monitored parameter in confirmed disease.
📈

Progression

1
Presentation
Age: infancy to adolescence
Two presentation windows. In infancy the sign is genital: micropenis, cryptorchidism, or both. Otherwise the disease surfaces in adolescence as absent or arrested puberty - the IL17RD carrier described in detail presented at 14.4 years with a short penis and reduced olfaction.
Show evidence (2 references)
PMID:20301509 SUPPORT Other
"IGD can first become apparent in infancy, adolescence, or adulthood."
The presentation windows for the disease class.
PMID:38628584 SUPPORT Human Clinical
"A 14.4-year-old male patient presented with a complaint of “having a short penis for over 7 years and reduced olfaction for over 5 years”."
The adolescent presentation in an IL17RD carrier.
📊

Prevalence

2
Chinese men with isolated hypogonadotropic hypogonadism
Unknown Unknown
A variant detection rate within a disease-ascertained cohort - 3.38% of 148 Chinese men with IHH carried an IL17RD variant - not a population prevalence, and not a rate of HH18 as a diagnosis, since most carriers also carry variants elsewhere. `measure_type` and `prevalence_class` are left UNKNOWN rather than converted to a rate, because the quantity is not a population frequency. The same source states plainly that the prevalence of IL17RD variants is unknown.
Show evidence (1 reference)
PMID:38628584 SUPPORT Human Clinical
"which examined mutation profiles and clinical manifestations of 148 Chinese men with IHH, a mutation rate of 3.38% was identified within the IL17RD."
Numerator context and denominator for the detection rate.
Cases reported in the literature worldwide
Cases In Literature Unknown
Twenty-two published IL17RD carriers were assembled by literature review as of 2024, of whom eighteen had Kallmann syndrome. That is the size of the entire described experience with this entity.
Show evidence (1 reference)
PMID:38628584 SUPPORT Human Clinical
"Among them, KS occurred in 18 out of 22 (81.8%) patients"
The published case count for this genotype.
🔀

Differential Diagnoses

4

Conditions with similar clinical presentations that must be differentiated from Hypogonadotropic Hypogonadism 18 With or Without Anosmia:

Constitutional delay of growth and puberty
Overlapping Features The differential that cannot be settled at presentation. An adolescent with absent puberty and low gonadotropins looks the same whether the axis is permanently deficient or merely late, and the distinction is often made retrospectively.
Distinguishing Features
  • Spontaneous pubertal progression on follow-up, which does not occur in CHH
  • Anosmia, which points away from constitutional delay and toward Kallmann syndrome
Show evidence (1 reference)
PMID:20301509 SUPPORT Other
"Because of variable expressivity, a prepubertal child with a known pathogenic variant may progress through puberty in a normal or delayed fashion, or not at all; therefore, clinical reevaluation over time is necessary."
States why the distinction needs time rather than a test - even a known pathogenic variant does not settle the pubertal outcome.
Normosmic isolated GnRH deficiency
Overlapping Features The same reproductive phenotype with an intact sense of smell, and roughly 40% of isolated GnRH deficiency. It matters here because IL17RD carriers are overwhelmingly anosmic, so normosmia makes this gene a less likely explanation - though the entity's own name allows for it.
Distinguishing Features
  • Normal formal olfactory testing
  • Normal olfactory structures on MRI
Show evidence (1 reference)
PMID:20301509 SUPPORT Other
"IGD is associated with a normal sense of smell (normosmic IGD) in approximately 40% of affected individuals and an impaired sense of smell (Kallmann syndrome) in approximately 60%."
The split between the two forms, and the proportions.
Other congenital hypogonadotropic hypogonadism loci, including the FGF8-FGFR1 axis
Overlapping Features More than 25 genes cause this phenotype, and several sit in the same FGF8-FGFR1 pathway as IL17RD - FGF8 and FGFR1 themselves, and the other negative modulators DUSP6, SPRY2 and SPRY4. They are separated molecularly rather than clinically, and in this disease the separation is often not clean: the same patient may carry variants in two of them.
Distinguishing Features
  • Molecular - the variant is in the other gene rather than in IL17RD
  • DUSP6 variants appear sufficient alone, where IL17RD variants generally are not
Show evidence (2 references)
PMID:32389901 SUPPORT Human Clinical
"Recently, several negative modulators of FGF8-FGFR1 signalling were also found to be involved in IHH, including DUSP6, IL17RD, SPRY2 and SPRY4."
The pathway-mates that constitute the immediate molecular differential.
PMID:32389901 SUPPORT Human Clinical
"Mutations in DUSP6 alone seem sufficient to cause IHH in an autosomal dominant manner, whereas IL17RD or SPRY4 mutations may cause IHH phenotypes in synergy with variants in other IHH-associated genes."
The distinguishing feature that is actually actionable - the two genes differ in whether a single variant settles the diagnosis.
Acquired and structural causes of hypogonadotropic hypogonadism
Overlapping Features Pituitary or hypothalamic lesions, and other secondary causes, produce the same biochemistry without being congenital. They are excluded before CHH is diagnosed rather than considered alongside it, which is why pituitary imaging is part of the workup above.
Distinguishing Features
  • A mass lesion or other structural abnormality on pituitary imaging
  • Deficiency of other anterior pituitary hormones, which is absent in isolated GnRH deficiency
Show evidence (1 reference)
PMID:20301509 SUPPORT Other
"in the setting of otherwise normal anterior pituitary anatomy and function and in the absence of secondary causes of HH"
The exclusion clause built into the diagnostic definition, which is what this differential records.
{ }

Source YAML

click to show 
name: Hypogonadotropic Hypogonadism 18 With or Without Anosmia
category: Mendelian
creation_date: "2026-09-04T00:00:00Z"
synonyms:
- HH18
- IL17RD-related congenital hypogonadotropic hypogonadism
- IL17RD-related Kallmann syndrome
description: >-
  HH18 is the form of congenital hypogonadotropic hypogonadism (CHH) attributed to variants in
  IL17RD, which encodes Sef ("similar expression to fgf genes") - not an interleukin receptor in
  any functional sense, despite the name, but a transmembrane feedback antagonist of FGF
  signalling that shares only sequence similarity with the intracellular domain of the IL-17
  receptor. Sef was found in zebrafish as a member of the fgf8 synexpression group and shown to
  antagonise Ras/Raf/MEK/MAPK signalling downstream of FGF; in mammalian cells it associates with
  FGFR1 and suppresses receptor tyrosine phosphorylation and ERK activation.

  That places IL17RD in the same pathway as the genes that dominate CHH genetics. FGF8 and FGFR1
  account for around 12% of CHH, and the hypothesis that produced HH18 was explicitly that
  modulators of FGFR1 signalling would also be mutated in CHH patients. Sequencing seven such
  genes in 386 CHH probands found IL17RD variants in eight, and an interactome-based prediction
  run independently ranked IL17RD among the top two candidate genes in the entire proteome.

  Two features make this entity different from a textbook Mendelian locus, and the entry is
  organised around them rather than around them being caveats. First, the variants are almost
  always heterozygous and inherited from an unaffected parent - in a Chinese cohort every one of
  five informative probands inherited the IL17RD variant from a parent with no phenotype - and
  most patients carry additional rare variants in other CHH genes. The cohort authors' own
  conclusion is that IL17RD variants act in synergy with other CHH loci rather than alone, which
  is why this entry types IL17RD as a susceptibility locus in an oligogenic architecture rather
  than as causative. Second, the extra-reproductive phenotype is unusually consistent for CHH:
  IL17RD variants were found only in anosmic (Kallmann) patients in the founding cohort and were
  strongly linked to hearing loss, which remains the most common accompanying feature across the
  published cases.
disease_term:
  preferred_term: hypogonadotropic hypogonadism 18 with or without anosmia
  term:
    id: MONDO:0014103
    label: hypogonadotropic hypogonadism 18 with or without anosmia
parents:
- Congenital hypogonadotropic hypogonadism
- Disorders of puberty
notes: >-
  Identifiers. OMIM #615267 (HH18) and OMIM 606807 (IL17RD). Recorded in prose because the
  schema's `mappings` block carries `mondo_mappings` only and has no OMIM slot.

  Lump/split. This is curated as its own entry rather than as a `has_subtypes` row on
  `Kallmann_Syndrome`, following the precedent already in the KB: FGFR1-related CHH has a
  standalone entry (`FGFR1_Hypogonadotropic_Hypogonadism`) even though Kallmann syndrome 2 is
  also a gene-named subtype row inside `Kallmann_Syndrome`. The argument for a separate entry
  here is that HH18's mechanism is not "another CHH gene" but specifically the loss of *negative*
  feedback on the same FGF8-FGFR1 axis, and its inheritance is oligogenic rather than dominant -
  a different pathograph and a different counselling problem. A curator who prefers the lumped
  arrangement should fold this into `Kallmann_Syndrome` as an IL17RD subtype row rather than
  duplicating it; the two representations should not both exist.

  Why `relationship_type: SUSCEPTIBILITY` rather than `CAUSATIVE`. The published evidence does
  not support IL17RD variants being sufficient. They are heterozygous, inherited from unaffected
  parents, present in patients who also carry variants in other CHH genes, and the largest
  IL17RD-specific cohort concludes that they act in synergy with other loci. Typing this locus
  CAUSATIVE would assert something the sources decline to assert, so it is typed SUSCEPTIBILITY,
  and the oligogenic requirement is modelled as its own pathophysiology node rather than being
  buried in a caveat.

  Evidence base. Three human sources: the founding CHH cohort of 386 probands (PMID:23643382),
  an IL17RD/DUSP6/SPRY4-focused cohort of 196 Chinese IHH patients (PMID:32389901), and a single
  well-characterised case report that also reviews the 22 published IL17RD carriers
  (PMID:38628584). Mechanism comes from the zebrafish and cell-culture Sef literature
  (PMID:11802165, PMID:16603339), and general CHH management from GeneReviews (PMID:20301509).
  There is no IL17RD animal model of CHH cited here because none was found in these sources; the
  entry therefore carries no `animal_models` block rather than an empty gesture at one.

  What is not asserted. No prevalence figure is given for HH18: the case-report review states
  outright that the prevalence of IL17RD variants remains unknown, and the one available
  denominator is a variant detection rate within an ascertained IHH cohort, which is a different
  quantity. No genotype-phenotype correlation is asserted, for the same reason - the same source
  says none has been established.

  Deep research. A Falcon deep-research report is committed alongside this entry. It passed
  `just preflight-dr` against MONDO:0014103 with IL17RD mentioned 44 times and no rival gene
  close behind, and its reference validation resolved 17 of 17 citations with a confabulation
  rate of 0. Its term validation flagged one invented identifier, `HP:0000806`, which HP does not
  contain; that CURIE is not used here, and no ontology binding in this entry was taken from the
  report. The report was used as a lead source only - every snippet below is anchored to a PMID
  fetched into `references_cache/` and read directly.
references:
- reference: PMID:23643382
  title: "Mutations in FGF17, IL17RD, DUSP6, SPRY4, and FLRT3 are identified in individuals with congenital hypogonadotropic hypogonadism."
- reference: PMID:32389901
  title: Prevalence and associated phenotypes of DUSP6, IL17RD and SPRY4 variants in a large Chinese cohort with isolated hypogonadotropic hypogonadism.
- reference: PMID:38628584
  title: Clinical phenotype of a Kallmann syndrome patient with IL17RD and CPEB4 variants.
- reference: PMID:11802165
  title: Sef is a feedback-induced antagonist of Ras/MAPK-mediated FGF signalling.
- reference: PMID:16603339
  title: A role for extracellular and transmembrane domains of Sef in Sef-mediated inhibition of FGF signaling.
- reference: PMID:20301509
  title: "Isolated Gonadotropin-Releasing Hormone (GnRH) Deficiency."
  tags:
  - GeneReviews
- reference: DOI:10.1186/s12964-020-00695-7
  title: "Interleukin-17 receptor D (Sef) is a multi-functional regulator of cell signaling"
inheritance:
- name: Oligogenic
  description: >-
    The predominant pattern for IL17RD in CHH. Most carriers have variants in at least one other
    CHH-associated gene, and the reported combinations include IL17RD with PROKR2, with FGFR1
    and RUVBL2, and with CPEB4. IL17RD is named in the schema sense as a contributing rather
    than a determining locus; see the `genetic` section, where it is typed SUSCEPTIBILITY.
  inheritance_term:
    preferred_term: Oligogenic inheritance
    term:
      id: HP:0010983
      label: Oligogenic inheritance
  evidence:
  - reference: PMID:32389901
    reference_title: Prevalence and associated phenotypes of DUSP6, IL17RD and SPRY4 variants in a large Chinese cohort with isolated hypogonadotropic hypogonadism.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mutations in DUSP6 alone seem sufficient to cause IHH in an autosomal dominant manner, whereas IL17RD or SPRY4 mutations may cause IHH phenotypes in synergy with variants in other IHH-associated genes."
    explanation: >-
      The sharpest statement of the distinction this entry turns on - and it is made against a
      directly comparable gene in the same pathway, DUSP6, which the same cohort does call
      sufficient.
  - reference: PMID:23643382
    reference_title: "Mutations in FGF17, IL17RD, DUSP6, SPRY4, and FLRT3 are identified in individuals with congenital hypogonadotropic hypogonadism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mutations in genes encoding components of the FGF pathway are associated with complex modes of CHH inheritance and act primarily as contributors to an oligogenic genetic architecture underlying CHH."
    explanation: >-
      The founding cohort's own conclusion about the class of genes that includes IL17RD.
  - reference: PMID:20301509
    reference_title: "Isolated Gonadotropin-Releasing Hormone (GnRH) Deficiency."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Almost all IGD-related genes have also been associated with indeterminate or oligogenic inheritance."
    explanation: >-
      Places the oligogenic pattern in its clinical context: it is the norm across CHH genes, not
      a peculiarity of IL17RD.
pathophysiology:
- name: IL17RD Variant Altering Sef Function
  description: >-
    IL17RD encodes Sef, a transmembrane protein of the fgf8 synexpression group that acts as a
    feedback-induced antagonist of FGF signalling. In zebrafish it antagonises the
    Ras/Raf/MEK/MAPK arm downstream of FGF; in mammalian cells its extracellular and
    transmembrane domains associate with FGFR1 and inhibit receptor tyrosine phosphorylation and
    the ensuing Raf/MEK/ERK cascade.

    The CHH-associated variants are missense changes distributed across the protein, and most of
    those tested altered protein function in vitro. What that alteration does to signalling in a
    GnRH neuron is not established: the assays are heterologous, the variants are heterozygous,
    and no source read here measures FGF signalling output in patient-derived tissue.
  role: trigger
  biological_scale: MOLECULAR
  genes:
  - preferred_term: IL17RD
    term:
      id: hgnc:17616
      label: IL17RD
  biological_processes:
  - preferred_term: Sef-mediated negative feedback on FGF receptor signalling
    modifier: ABNORMAL
    term:
      id: GO:0040037
      label: negative regulation of fibroblast growth factor receptor signaling pathway
  genetic_context:
    functional_impact_category: UNKNOWN
    zygosity: HETEROZYGOUS
    description: >-
      Reported IL17RD variants in CHH are heterozygous missense changes. Most altered protein
      function in the founding study's in-vitro assays, but the direction of that alteration in
      the developing olfactory-GnRH system is not established, so the impact category is left
      UNKNOWN rather than being recorded as loss of function.
  downstream:
  - target: Dysregulated FGF8-FGFR1 Signaling in the Developing Olfactory-GnRH System
    description: >-
      An altered feedback antagonist changes the gain of the pathway it regulates. The link is
      inferred from Sef's established role as an FGFR1-associated inhibitor plus the in-vitro
      demonstration that CHH variants alter protein function; it has not been measured in
      GnRH-lineage cells.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Sensorineural Hearing Impairment
    description: >-
      The strongest and least explained association in this disease. IL17RD variants were found
      only in anosmic patients in the founding cohort and were strongly linked to hearing loss,
      and hearing loss remains the most common accompanying feature in the published carriers.
      No mechanism connecting Sef to cochlear development is offered by any source read here, so
      this edge records a reproducible clinical association whose intermediates are unknown.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  evidence:
  - reference: PMID:11802165
    reference_title: Sef is a feedback-induced antagonist of Ras/MAPK-mediated FGF signalling.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: INDIRECT
    snippet: "Here we show that in zebrafish, Sef functions as a feedback-induced antagonist of Ras/Raf/MEK/MAPK-mediated FGF signalling."
    explanation: >-
      Establishes the normal function of the gene product. INDIRECT with respect to the human
      disease: it is zebrafish developmental biology, and it predates any link to CHH.
  - reference: PMID:16603339
    reference_title: A role for extracellular and transmembrane domains of Sef in Sef-mediated inhibition of FGF signaling.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: INDIRECT
    snippet: "We also showed that SefECTM associated with FGFR1, and inhibited FGF-induced ERK activation in HEK293T cells."
    explanation: >-
      Places Sef physically on FGFR1 in a mammalian cell system, which is the specific pathway
      connection that makes IL17RD a candidate CHH gene at all.
  - reference: PMID:23643382
    reference_title: "Mutations in FGF17, IL17RD, DUSP6, SPRY4, and FLRT3 are identified in individuals with congenital hypogonadotropic hypogonadism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most of the FGF17 and IL17RD mutations altered protein function in vitro."
    explanation: >-
      The functional evidence that the patient variants are not silent, stated with the hedge the
      authors used.
- name: Oligogenic Requirement for Additional CHH Loci
  description: >-
    An IL17RD variant on its own is usually not enough. In the IL17RD-focused Chinese cohort,
    every informative proband inherited the variant from an unaffected parent, and more than half
    carried variants in additional CHH genes; the published case reports repeat the pattern, with
    IL17RD paired with PROKR2, with FGFR1 plus RUVBL2, and with CPEB4. Whatever the IL17RD change
    does to FGF signalling, the disease appears where it is combined with a second hit.

    This node exists so the requirement is a step in the causal chain rather than a caveat
    attached to one. It is also the reason recurrence-risk counselling in HH18 cannot be run off
    a dominant model.
  role: modifier
  biological_scale: ORGANISM
  downstream:
  - target: Dysregulated FGF8-FGFR1 Signaling in the Developing Olfactory-GnRH System
    description: >-
      Co-inherited variants in other CHH genes - several of them in the same FGF8-FGFR1 axis -
      are what push the pathway past the threshold at which the olfactory-GnRH programme fails.
      The threshold model is the authors' inference from segregation and co-occurrence, not a
      measured quantity.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  evidence:
  - reference: PMID:32389901
    reference_title: Prevalence and associated phenotypes of DUSP6, IL17RD and SPRY4 variants in a large Chinese cohort with isolated hypogonadotropic hypogonadism.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Segregation analysis indicated that 100% (5/5) of probands inherited the IL17RD variants from their unaffected parents, and oligogenicity was found in 4/7 patients."
    explanation: >-
      The segregation and oligogenicity numerators in one sentence; this is the observation the
      node is built on.
  - reference: PMID:38628584
    reference_title: Clinical phenotype of a Kallmann syndrome patient with IL17RD and CPEB4 variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Whole-exome sequencing confirmed that the child carried both the IL17RD variant (c.2101G>A, p.Gly701Ser) inherited from the mother and the new CPEB4 variant (c.1414C>T, p.Arg472*)."
    explanation: >-
      A worked instance of the pattern: a maternally inherited IL17RD variant carried by an
      unaffected mother, plus a de novo second-locus variant in the affected child.
  - reference: PMID:38628584
    reference_title: Clinical phenotype of a Kallmann syndrome patient with IL17RD and CPEB4 variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Previous studies have demonstrated that the genetic penetrance and phenotypic expressivity of disease symptoms was dependent on factors such as zygosity of the mutation as well as mutations occurring in other genetic loci, suggesting an oligogenic mode of action"
    explanation: >-
      States the oligogenic model explicitly for this gene, in the review that accompanies the
      case.
- name: Dysregulated FGF8-FGFR1 Signaling in the Developing Olfactory-GnRH System
  description: >-
    FGF8-FGFR1 signalling is required for the embryonic programme in which GnRH neurons and
    olfactory axons migrate together from the olfactory placode toward the forebrain, and
    impairment of this signalling is one of the principal causes of CHH. IL17RD joins that
    pathway from the regulatory side: DUSP6, IL17RD, SPRY2 and SPRY4 are all negative modulators
    of FGF8-FGFR1 signalling that have been implicated in the disease.

    The step from "the pathway is dysregulated" to a specific direction of change is not taken
    here. Loss of a feedback antagonist would be expected to increase signalling, which is not
    the direction that FGFR1 loss-of-function CHH implies, and no source read here resolves that
    tension for IL17RD.
  biological_scale: MOLECULAR
  biological_processes:
  - preferred_term: FGF8-FGFR1 signalling in the olfactory-GnRH axis
    modifier: DYSREGULATED
    term:
      id: GO:0008543
      label: fibroblast growth factor receptor signaling pathway
  - preferred_term: downstream ERK activation
    modifier: DYSREGULATED
    term:
      id: GO:0070371
      label: ERK1 and ERK2 cascade
  downstream:
  - target: Failure of GnRH Neuron Migration and Olfactory Bulb Development
    description: >-
      The developmental programme that FGF8-FGFR1 signalling supports is the co-migration of GnRH
      neurons with olfactory axons and the morphogenesis of the olfactory bulb; disturbing the
      signal disturbs that programme.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  evidence:
  - reference: PMID:32389901
    reference_title: Prevalence and associated phenotypes of DUSP6, IL17RD and SPRY4 variants in a large Chinese cohort with isolated hypogonadotropic hypogonadism.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "FGF8-FGFR1 signalling is involved in multiple biological processes, while impairment of this signalling is one of the main reasons for isolated hypogonadotropic hypogonadism (IHH)."
    explanation: Establishes the pathway as a principal cause of the disease.
  - reference: PMID:32389901
    reference_title: Prevalence and associated phenotypes of DUSP6, IL17RD and SPRY4 variants in a large Chinese cohort with isolated hypogonadotropic hypogonadism.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Recently, several negative modulators of FGF8-FGFR1 signalling were also found to be involved in IHH, including DUSP6, IL17RD, SPRY2 and SPRY4."
    explanation: >-
      Places IL17RD specifically among the negative modulators of that pathway implicated in the
      disease.
- name: Failure of GnRH Neuron Migration and Olfactory Bulb Development
  description: >-
    GnRH neurons originate outside the brain and reach the hypothalamus by migrating along
    olfactory axons; the shared route is why reproductive and olfactory deficits travel together
    in Kallmann syndrome. When the programme fails, the hypothalamus is left without its GnRH
    neuron population and the olfactory bulb is malformed or absent - in the imaged case report,
    bilateral olfactory nerve deficits on MRI accompanied a complete inability to identify odours.
  biological_scale: TISSUE
  cell_types:
  - preferred_term: GnRH neuron
    term:
      id: CL:0011111
      label: hypothalamic gonadotropin-releasing hormone neuron
  biological_processes:
  - preferred_term: GnRH neuron migration
    modifier: ABNORMAL
    term:
      id: GO:0001764
      label: neuron migration
  locations:
  - preferred_term: olfactory bulb
    term:
      id: UBERON:0002264
      label: olfactory bulb
  - preferred_term: hypothalamus
    term:
      id: UBERON:0001898
      label: hypothalamus
  downstream:
  - target: GnRH-Driven Gonadotropin Deficiency
    description: >-
      Without a functioning hypothalamic GnRH neuron population there is no pulsatile GnRH signal
      to drive pituitary gonadotropin secretion.
    causal_link_type: DIRECT
  - target: Anosmia
    description: >-
      The olfactory arm of the same failed developmental programme, which is why IL17RD carriers
      in the founding cohort were anosmic rather than normosmic.
    causal_link_type: DIRECT
  - target: Abnormal Olfactory Bulb Morphology
    description: >-
      The structural correlate visible on MRI, and the imaging finding that distinguishes
      Kallmann syndrome from normosmic CHH.
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:38628584
    reference_title: Clinical phenotype of a Kallmann syndrome patient with IL17RD and CPEB4 variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "During embryonic development, several interacting genes are involved in olfaction establishment and the migration of GnRH neurons, implying a shared embryonic origin among these genes"
    explanation: >-
      States the shared developmental origin that makes one lesion produce both the reproductive
      and the olfactory phenotype.
  - reference: PMID:20301509
    reference_title: "Isolated Gonadotropin-Releasing Hormone (GnRH) Deficiency."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "IGD is associated with a normal sense of smell (normosmic IGD) in approximately 40% of affected individuals and an impaired sense of smell (Kallmann syndrome) in approximately 60%."
    explanation: >-
      The clinical split that the olfactory arm of this node produces, across CHH as a whole.
- name: GnRH-Driven Gonadotropin Deficiency
  description: >-
    Absent or insufficient hypothalamic GnRH input leaves the pituitary gonadotropes unstimulated,
    so LH and FSH are inappropriately low in the face of low sex steroids - the biochemical
    signature of the disease. The pituitary itself is structurally and functionally normal apart
    from this, which is what separates CHH from combined pituitary hormone deficiency, and the
    deficit is demonstrable as a blunted LH response to exogenous GnRH.
  biological_scale: ORGANISM
  cell_types:
  - preferred_term: pituitary gonadotrope
    term:
      id: CL:0000438
      label: luteinizing hormone secreting cell
  downstream:
  - target: Hypogonadotropic Hypogonadism
    description: The direct endocrine consequence, and the defining feature of the disease.
    causal_link_type: DIRECT
  - target: Absent or Incomplete Puberty
    description: >-
      Without gonadotropin drive the gonads do not produce the sex steroids that carry pubertal
      development, so puberty does not start or does not complete.
    causal_link_type: DIRECT
  - target: Micropenis
    description: >-
      A consequence of gonadotropin deficiency in fetal and neonatal life rather than at puberty,
      which is why it can be the presenting sign in an infant boy.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - target: Cryptorchidism
    description: >-
      Testicular descent is gonadotropin-dependent in late gestation, so the same prenatal
      deficit that produces micropenis can leave the testes undescended.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  evidence:
  - reference: PMID:20301509
    reference_title: "Isolated Gonadotropin-Releasing Hormone (GnRH) Deficiency."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Isolated gonadotropin-releasing hormone (GnRH) deficiency (IGD) is characterized by inappropriately low serum concentrations of the gonadotropins LH (luteinizing hormone) and FSH (follicle-stimulating hormone) in the presence of low circulating concentrations of sex steroids."
    explanation: The biochemical definition of the node.
  - reference: PMID:38628584
    reference_title: Clinical phenotype of a Kallmann syndrome patient with IL17RD and CPEB4 variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Additionally, during the gonadorelin stimulation test (1-day method), LH reached a maximum of only 2.71 IU/L at 60 min."
    explanation: >-
      The blunted stimulated LH response in an IL17RD carrier, which is the functional
      demonstration of this node in a patient with this genotype.
phenotypes:
- name: Hypogonadotropic Hypogonadism
  category: Endocrine
  description: >-
    Low LH and FSH with low sex steroids - the defining feature, present by definition in every
    patient assigned to this entity.
  frequency: OBLIGATE
  phenotype_term:
    preferred_term: Hypogonadotropic hypogonadism
    term:
      id: HP:0000044
      label: Hypogonadotropic hypogonadism
  notes: >-
    OBLIGATE because it is definitional rather than observed at some rate: a patient without it
    would not be assigned to this disease.
  evidence:
  - reference: PMID:20301509
    reference_title: "Isolated Gonadotropin-Releasing Hormone (GnRH) Deficiency."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Isolated gonadotropin-releasing hormone (GnRH) deficiency (IGD) is characterized by inappropriately low serum concentrations of the gonadotropins LH (luteinizing hormone) and FSH (follicle-stimulating hormone) in the presence of low circulating concentrations of sex steroids."
    explanation: The definitional statement.
  - reference: PMID:38628584
    reference_title: Clinical phenotype of a Kallmann syndrome patient with IL17RD and CPEB4 variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The basal levels of Luteinising hormone (LH), which was 0.22 IU/L (normal reference range 0.71-6.24, the same below), follicle-stimulating hormone (FSH), which was 1.63 IU/L (0.91-7.25), and testosterone (T) was 0.45 nmol/L(0.71-22.92)."
    explanation: The measured values in an IL17RD carrier.
  sequelae:
  - target: Osteoporosis
    description: >-
      Untreated sex steroid deficiency is the reason bone mass is managed and monitored in this
      disease class. Typed with unknown intermediates deliberately: the cited sources establish
      that reduced bone mass is a recognised complication requiring prevention and surveillance,
      but none of them demonstrates the bone-loss mechanism in IL17RD carriers specifically.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:20301509
      reference_title: "Isolated Gonadotropin-Releasing Hormone (GnRH) Deficiency."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Prevention of secondary complications: Optimal calcium and vitamin D intake should be encouraged and specific treatment for decreased bone mass as needed."
      explanation: >-
        GeneReviews places decreased bone mass among the secondary complications of isolated GnRH
        deficiency requiring prevention, which is what puts it downstream of the hypogonadal state.
- name: Osteoporosis
  category: Musculoskeletal
  description: >-
    Reduced bone mass, reported among the concomitant manifestations of IL17RD-associated Kallmann
    syndrome and managed across the disease class as a secondary complication of untreated sex
    steroid deficiency.
  phenotype_term:
    preferred_term: Osteoporosis
    term:
      id: HP:0000939
      label: Osteoporosis
  notes: >-
    No frequency band. The IL17RD source names osteoporosis only inside the same 13-of-18 list of
    shared manifestations that the micropenis and cryptorchidism phenotypes draw on, and gives no
    per-feature numerator, so a band cannot be set from it. Bound to Osteoporosis rather than the
    broader HP:0004349 Reduced bone mineral density because osteoporosis is the word the
    disease-specific source uses; the GeneReviews chapter's broader "decreased bone mass" framing
    is cited on the treatment and surveillance entries rather than here, so each quote sits on the
    claim it actually supports.
  evidence:
  - reference: PMID:38628584
    reference_title: Clinical phenotype of a Kallmann syndrome patient with IL17RD and CPEB4 variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "and 72.2% (13 out of 18) of patients experienced other concomitant manifestations of KS, including cryptorchidism, micropenis, hypospadias, hearing loss, abnormal dentition, and osteoporosis."
    explanation: >-
      Names osteoporosis among the manifestations seen in IL17RD carriers. The source gives no
      per-feature count, which is why no frequency band is set.
- name: Anosmia
  category: Neurological
  description: >-
    Absent or impaired sense of smell, which is what makes most IL17RD carriers Kallmann syndrome
    rather than normosmic CHH. In the founding cohort IL17RD variants were found exclusively in
    anosmic patients.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Anosmia
    term:
      id: HP:0000458
      label: Anosmia
  notes: >-
    Numerator/denominator: 18 of 22 published IL17RD carriers (81.8%) had Kallmann syndrome
    rather than normosmic CHH, which sits at the bottom of the VERY_FREQUENT band. The founding
    cohort's 8 of 8 is the stronger claim but the smaller denominator; the 22-patient review is
    used for the band because it includes the later normosmic carriers.
  evidence:
  - reference: PMID:38628584
    reference_title: Clinical phenotype of a Kallmann syndrome patient with IL17RD and CPEB4 variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Among them, KS occurred in 18 out of 22 (81.8%) patients"
    explanation: The numerator and denominator behind the band.
  - reference: PMID:23643382
    reference_title: "Mutations in FGF17, IL17RD, DUSP6, SPRY4, and FLRT3 are identified in individuals with congenital hypogonadotropic hypogonadism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "IL17RD mutations were found only in KS individuals and were strongly linked to hearing loss (6/8 individuals)."
    explanation: >-
      The founding cohort's exclusive association with the anosmic form. Note the same sentence
      carries the hearing-loss association recorded separately below.
- name: Sensorineural Hearing Impairment
  category: Auditory
  description: >-
    The characteristic non-reproductive feature of IL17RD-related CHH, and the most common
    accompanying manifestation across the published carriers. No mechanism linking Sef to
    cochlear development has been proposed in the sources read here.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Sensorineural hearing impairment
    term:
      id: HP:0000407
      label: Sensorineural hearing impairment
  notes: >-
    Numerator/denominator: 7 of 18 Kallmann-syndrome IL17RD carriers in the published review
    (38.9%), which sits in the FREQUENT band. The founding cohort reported a higher rate, 6 of 8,
    which is the source of the "strongly linked" phrasing; the band uses the larger denominator.
  evidence:
  - reference: PMID:38628584
    reference_title: Clinical phenotype of a Kallmann syndrome patient with IL17RD and CPEB4 variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hearing loss emerged as the most common concomitant symptom (7 out of 18, 38.9%), as confirmed by our findings."
    explanation: >-
      The numerator and denominator behind the band, 7 of 18 or 38.9%.
  - reference: PMID:23643382
    reference_title: "Mutations in FGF17, IL17RD, DUSP6, SPRY4, and FLRT3 are identified in individuals with congenital hypogonadotropic hypogonadism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "IL17RD mutations were found only in KS individuals and were strongly linked to hearing loss (6/8 individuals)."
    explanation: The founding cohort's rate, on a smaller denominator.
  - reference: PMID:38628584
    reference_title: Clinical phenotype of a Kallmann syndrome patient with IL17RD and CPEB4 variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Audiometry confirmed sensorineural hearing loss in the right ear."
    explanation: >-
      Audiometric confirmation in an individual carrier, and a reminder that the deficit can be
      unilateral.
- name: Abnormal Olfactory Bulb Morphology
  category: Neurological
  description: >-
    Structural failure of the olfactory system on MRI, the imaging counterpart of the anosmia.
    Reported here in one imaged IL17RD carrier as bilateral olfactory nerve deficits.
  phenotype_term:
    preferred_term: Abnormal morphology of the olfactory bulb
    term:
      id: HP:0040327
      label: Abnormal morphology of the olfactory bulb
  notes: >-
    No frequency band. Only one IL17RD carrier read here had olfactory imaging reported, so any
    band would rest on a denominator of one. The bound term is the general abnormal-morphology
    term rather than a hypoplasia or aplasia term, because the report describes bilateral
    olfactory nerve deficits without grading the bulb.
  evidence:
  - reference: PMID:38628584
    reference_title: Clinical phenotype of a Kallmann syndrome patient with IL17RD and CPEB4 variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Plain MRI imaging of the olfactory bulb indicated bilateral olfactory nerve deficits"
    explanation: The imaging finding in the one carrier for whom it is reported.
- name: Absent or Incomplete Puberty
  category: Endocrine
  description: >-
    Puberty does not begin, or begins and does not complete, because the gonads are never driven.
    In the imaged IL17RD carrier this was Tanner stage 1 at 14.4 years with prepubertal testicular
    volumes.
  phenotype_term:
    preferred_term: Delayed puberty
    term:
      id: HP:0000823
      label: Delayed puberty
  notes: >-
    No frequency band: the published IL17RD series do not report pubertal staging patient by
    patient, so a band would be an extrapolation from CHH in general rather than a count in this
    genotype.
  evidence:
  - reference: PMID:38628584
    reference_title: Clinical phenotype of a Kallmann syndrome patient with IL17RD and CPEB4 variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "His pubertal development is in Tanner stage 1, with a penis length of 2 cm and a penis circumference of 1.2 cm."
    explanation: The staged observation in an IL17RD carrier.
  - reference: PMID:20301509
    reference_title: "Isolated Gonadotropin-Releasing Hormone (GnRH) Deficiency."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Adolescents and adults with IGD have clinical evidence of hypogonadism and incomplete sexual maturation on physical examination."
    explanation: The general clinical description for the disease class.
- name: Micropenis
  category: Genitourinary
  description: >-
    A prenatal consequence of gonadotropin deficiency, present at birth rather than emerging at
    the expected age of puberty.
  phenotype_term:
    preferred_term: Micropenis
    term:
      id: HP:0000054
      label: Micropenis
  notes: >-
    No frequency band. Micropenis appears in the published review only inside a list of
    manifestations shared by 13 of 18 carriers, without a per-feature numerator, so the
    denominator for micropenis specifically does not exist in these sources.
  evidence:
  - reference: PMID:38628584
    reference_title: Clinical phenotype of a Kallmann syndrome patient with IL17RD and CPEB4 variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "and 72.2% (13 out of 18) of patients experienced other concomitant manifestations of KS, including cryptorchidism, micropenis, hypospadias, hearing loss, abnormal dentition, and osteoporosis."
    explanation: >-
      Lists micropenis among the manifestations seen in IL17RD carriers - 13 of 18 had at least
      one of them, but the source gives no per-feature count, which is why no band is set.
  - reference: PMID:20301509
    reference_title: "Isolated Gonadotropin-Releasing Hormone (GnRH) Deficiency."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Infant boys with congenital IGD often have micropenis and cryptorchidism."
    explanation: >-
      Establishes micropenis as a recognised neonatal presentation of the disease class, which is
      the basis for the prenatal timing given in the description.
- name: Cryptorchidism
  category: Genitourinary
  description: >-
    Undescended testes, the other prenatal manifestation of gonadotropin deficiency. Present in
    the imaged IL17RD carrier, who was operated at around three years of age.
  phenotype_term:
    preferred_term: Cryptorchidism
    term:
      id: HP:0000028
      label: Cryptorchidism
  notes: >-
    No frequency band, for the same reason as micropenis: the review lists cryptorchidism inside
    an aggregate of 13 of 18 without a per-feature count.
  evidence:
  - reference: PMID:38628584
    reference_title: Clinical phenotype of a Kallmann syndrome patient with IL17RD and CPEB4 variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "By approximately 3 years of age, the patient underwent surgery for cryptorchidism and was diagnosed with allergic rhinitis."
    explanation: The individual observation in an IL17RD carrier.
  - reference: PMID:20301509
    reference_title: "Isolated Gonadotropin-Releasing Hormone (GnRH) Deficiency."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Infant boys with congenital IGD often have micropenis and cryptorchidism."
    explanation: Establishes cryptorchidism as a recognised presentation of the disease class.
genetic:
- name: IL17RD
  notes: >-
    Encodes Sef, a transmembrane feedback antagonist of FGF signalling and a member of the fgf8
    synexpression group. The gene name is misleading: the similarity to the interleukin 17
    receptor is a sequence feature of the intracellular domain, and the biology that matters here
    is FGFR1 association and suppression of the Raf/MEK/ERK cascade.

    Reported CHH variants are heterozygous missense changes spread across the protein - p.P191L,
    p.G35V, p.S671L, p.A221T, p.I329M and p.I329V in the Chinese cohort, p.Gly701Ser in the case
    report and in two previously published patients. The recurrent p.Gly701Ser is instructive
    about the oligogenic pattern: of the three reported carriers, one also carried PROKR2 p.Y113H
    and one carried FGFR1 p.Gly348Glu with RUVBL2 p.Arg71Trp.

    No genotype-phenotype correlation has been established, and the variant detection rate in
    ascertained IHH cohorts is a few per cent - 3.38% in one series of 148 Chinese men. That is a
    detection rate within a disease cohort and says nothing about population frequency.
  relationship_type: SUSCEPTIBILITY
  gene_term:
    preferred_term: IL17RD
    term:
      id: hgnc:17616
      label: IL17RD
  evidence:
  - reference: PMID:23643382
    reference_title: "Mutations in FGF17, IL17RD, DUSP6, SPRY4, and FLRT3 are identified in individuals with congenital hypogonadotropic hypogonadism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Independently, IBAS predicted FGF17 and IL17RD as the two top candidates in the entire proteome on the basis of a statistical test of their protein-protein interaction patterns to proteins known to be altered in CHH."
    explanation: >-
      The computational nomination that converged with the sequencing result, which is part of
      why this gene-disease relationship was taken seriously from a small number of probands.
  - reference: PMID:32389901
    reference_title: Prevalence and associated phenotypes of DUSP6, IL17RD and SPRY4 variants in a large Chinese cohort with isolated hypogonadotropic hypogonadism.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Six heterozygous IL17RD variants (p.P191L, p.G35V, p.S671L, p.A221T, p.I329M and p.I329V) were found in seven patients."
    explanation: The allelic spectrum and the heterozygous state, in the largest IL17RD series.
  - reference: PMID:38628584
    reference_title: Clinical phenotype of a Kallmann syndrome patient with IL17RD and CPEB4 variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Currently, the prevalence of IL17RD variants remains unknown, and a definitive correlation between specific IL17RD variant types and clinical phenotypes is yet to be established"
    explanation: >-
      The explicit statement that neither a prevalence nor a genotype-phenotype correlation is
      available, which is why this entry asserts neither.
diagnosis:
- name: Biochemical confirmation of hypogonadotropic hypogonadism
  description: >-
    The diagnosis is made on the pattern, not on any single value: low sex steroid with LH and
    FSH that are low or inappropriately normal rather than raised, in a pituitary that is
    otherwise anatomically and functionally intact, and with secondary causes excluded. The
    "inappropriately" is the whole point - normal-range gonadotropins in the face of a low
    testosterone are the abnormality.
  diagnosis_term:
    preferred_term: biochemical testing
    term:
      id: NCIT:C124351
      label: Clinical Evaluation
  results: Low serum testosterone or estradiol with low or inappropriately normal LH and FSH.
  evidence:
  - reference: PMID:20301509
    reference_title: "Isolated Gonadotropin-Releasing Hormone (GnRH) Deficiency."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "IGD is typically diagnosed in adolescents presenting with absent or partial puberty using biochemical testing that reveals low serum testosterone or estradiol (hypogonadism) that results from complete or partial absence of GnRH-mediated release of LH and FSH"
    explanation: The diagnostic definition for the disease class.
  - reference: PMID:38628584
    reference_title: Clinical phenotype of a Kallmann syndrome patient with IL17RD and CPEB4 variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The basal levels of Luteinising hormone (LH), which was 0.22 IU/L (normal reference range 0.71-6.24, the same below), follicle-stimulating hormone (FSH), which was 1.63 IU/L (0.91-7.25), and testosterone (T) was 0.45 nmol/L(0.71-22.92)."
    explanation: The measured pattern in an IL17RD carrier, with reference ranges alongside.
  notes: >-
    NCIT has no clinical-action term for this panel of assays that is reachable from NCIT:C25218,
    so the bound term is the general Clinical Evaluation term and `preferred_term` carries the
    specificity.
- name: GnRH (gonadorelin) stimulation test
  description: >-
    A blunted LH rise after exogenous GnRH demonstrates the deficit functionally rather than
    inferring it from basal values. In the IL17RD carrier reported in detail, LH peaked at 2.71
    IU/L at sixty minutes - a response, but far below a normal one.
  diagnosis_term:
    preferred_term: gonadotropin-releasing hormone stimulation test
    term:
      id: NCIT:C124351
      label: Clinical Evaluation
  results: Blunted peak LH response to exogenous GnRH.
  evidence:
  - reference: PMID:38628584
    reference_title: Clinical phenotype of a Kallmann syndrome patient with IL17RD and CPEB4 variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Additionally, during the gonadorelin stimulation test (1-day method), LH reached a maximum of only 2.71 IU/L at 60 min."
    explanation: The stimulated response in a patient with this genotype.
- name: Formal olfactory testing
  description: >-
    Smell is what separates Kallmann syndrome from normosmic CHH, and it has to be tested rather
    than asked about - patients who have never smelled normally do not report a deficit. IL17RD
    carriers are overwhelmingly on the anosmic side, so a positive smell test moves the diagnosis
    toward this gene rather than away from it.
  diagnosis_term:
    preferred_term: olfactory testing
    term:
      id: NCIT:C124351
      label: Clinical Evaluation
  results: Anosmia or hyposmia on formal testing.
  evidence:
  - reference: PMID:38628584
    reference_title: Clinical phenotype of a Kallmann syndrome patient with IL17RD and CPEB4 variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "During the olfactory test (water, 75% alcohol, vinegar, and perfume), the patient demonstrated an inability to discern smells."
    explanation: >-
      A worked example of the bedside test and its result in an IL17RD carrier.
- name: MRI of the olfactory bulbs and pituitary
  description: >-
    Imaging supplies the structural counterpart of the smell deficit and simultaneously excludes
    the acquired pituitary causes that would make this not CHH. The reported IL17RD carrier had
    bilateral olfactory nerve deficits with a small pituitary and no mass lesion.
  diagnosis_term:
    preferred_term: magnetic resonance imaging
    term:
      id: NCIT:C124351
      label: Clinical Evaluation
  results: Absent or hypoplastic olfactory structures; a structurally unremarkable pituitary without a mass lesion.
  evidence:
  - reference: PMID:38628584
    reference_title: Clinical phenotype of a Kallmann syndrome patient with IL17RD and CPEB4 variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Plain MRI imaging of the olfactory bulb indicated bilateral olfactory nerve deficits"
    explanation: The olfactory imaging finding.
  - reference: PMID:38628584
    reference_title: Clinical phenotype of a Kallmann syndrome patient with IL17RD and CPEB4 variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A pituitary MRI plain scan revealed a small pituitary gland with no significant occupying lesions."
    explanation: >-
      The pituitary imaging that excludes an acquired cause, which is what makes the diagnosis
      congenital rather than secondary.
- name: Broad genomic testing, not single-gene testing
  description: >-
    Single-gene testing is the wrong instrument for this disease, and the reason is the
    oligogenic architecture rather than a mere breadth-of-differential argument. Finding the
    IL17RD variant and stopping would miss the second locus that most carriers have, and it is
    the combination that is being counselled on. In the reported case, exome sequencing plus
    copy-number analysis found a maternally inherited IL17RD variant and a de novo CPEB4
    variant; either alone would have told a different and wrong story.
  diagnosis_term:
    preferred_term: molecular analysis
    term:
      id: NCIT:C19770
      label: Molecular Analysis
  results: A heterozygous IL17RD variant, usually with a variant in at least one other CHH-associated gene; parental testing is informative.
  evidence:
  - reference: PMID:38628584
    reference_title: Clinical phenotype of a Kallmann syndrome patient with IL17RD and CPEB4 variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Whole-exome sequencing confirmed that the child carried both the IL17RD variant (c.2101G>A, p.Gly701Ser) inherited from the mother and the new CPEB4 variant (c.1414C>T, p.Arg472*)."
    explanation: >-
      The two-locus result that a single-gene test would have truncated, and the parental testing
      that established which variant was inherited.
  - reference: PMID:20301509
    reference_title: "Isolated Gonadotropin-Releasing Hormone (GnRH) Deficiency."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Pathogenic variants in more than 25 genes account for about half of all IGD; the genetic cause for the remaining cases of IGD is unknown."
    explanation: >-
      The locus heterogeneity that makes multi-gene testing the default, and the reminder that
      about half of patients will have no molecular answer at all.
- name: Bone mineral density surveillance
  description: >-
    Periodic measurement of bone mineral density in confirmed isolated GnRH deficiency, alongside
    serum sex steroid levels. It is surveillance for a secondary complication rather than a test
    that establishes the diagnosis, and it is what makes the decreased-bone-mass phenotype
    actionable.
  diagnosis_term:
    preferred_term: bone mineral density measurement
    term:
      id: NCIT:C61545
      label: Bone Mineral Density Test
  results: Reduced bone mineral density in a proportion of affected individuals.
  evidence:
  - reference: PMID:20301509
    reference_title: "Isolated Gonadotropin-Releasing Hormone (GnRH) Deficiency."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "In individuals with confirmed IGD, monitor at regular intervals: serum sex steroid levels (to guide optimal hormone replacement); bone mineral density."
    explanation: >-
      The GeneReviews surveillance recommendation, which names bone mineral density as a
      monitored parameter in confirmed disease.
differential_diagnoses:
- name: Constitutional delay of growth and puberty
  description: >-
    The differential that cannot be settled at presentation. An adolescent with absent puberty and
    low gonadotropins looks the same whether the axis is permanently deficient or merely late, and
    the distinction is often made retrospectively.
  distinguishing_features:
  - Spontaneous pubertal progression on follow-up, which does not occur in CHH
  - Anosmia, which points away from constitutional delay and toward Kallmann syndrome
  evidence:
  - reference: PMID:20301509
    reference_title: "Isolated Gonadotropin-Releasing Hormone (GnRH) Deficiency."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Because of variable expressivity, a prepubertal child with a known pathogenic variant may progress through puberty in a normal or delayed fashion, or not at all; therefore, clinical reevaluation over time is necessary."
    explanation: >-
      States why the distinction needs time rather than a test - even a known pathogenic variant
      does not settle the pubertal outcome.
- name: Normosmic isolated GnRH deficiency
  description: >-
    The same reproductive phenotype with an intact sense of smell, and roughly 40% of isolated
    GnRH deficiency. It matters here because IL17RD carriers are overwhelmingly anosmic, so
    normosmia makes this gene a less likely explanation - though the entity's own name allows for
    it.
  distinguishing_features:
  - Normal formal olfactory testing
  - Normal olfactory structures on MRI
  evidence:
  - reference: PMID:20301509
    reference_title: "Isolated Gonadotropin-Releasing Hormone (GnRH) Deficiency."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "IGD is associated with a normal sense of smell (normosmic IGD) in approximately 40% of affected individuals and an impaired sense of smell (Kallmann syndrome) in approximately 60%."
    explanation: The split between the two forms, and the proportions.
- name: Other congenital hypogonadotropic hypogonadism loci, including the FGF8-FGFR1 axis
  description: >-
    More than 25 genes cause this phenotype, and several sit in the same FGF8-FGFR1 pathway as
    IL17RD - FGF8 and FGFR1 themselves, and the other negative modulators DUSP6, SPRY2 and SPRY4.
    They are separated molecularly rather than clinically, and in this disease the separation is
    often not clean: the same patient may carry variants in two of them.
  distinguishing_features:
  - Molecular - the variant is in the other gene rather than in IL17RD
  - DUSP6 variants appear sufficient alone, where IL17RD variants generally are not
  evidence:
  - reference: PMID:32389901
    reference_title: Prevalence and associated phenotypes of DUSP6, IL17RD and SPRY4 variants in a large Chinese cohort with isolated hypogonadotropic hypogonadism.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Recently, several negative modulators of FGF8-FGFR1 signalling were also found to be involved in IHH, including DUSP6, IL17RD, SPRY2 and SPRY4."
    explanation: The pathway-mates that constitute the immediate molecular differential.
  - reference: PMID:32389901
    reference_title: Prevalence and associated phenotypes of DUSP6, IL17RD and SPRY4 variants in a large Chinese cohort with isolated hypogonadotropic hypogonadism.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mutations in DUSP6 alone seem sufficient to cause IHH in an autosomal dominant manner, whereas IL17RD or SPRY4 mutations may cause IHH phenotypes in synergy with variants in other IHH-associated genes."
    explanation: >-
      The distinguishing feature that is actually actionable - the two genes differ in whether a
      single variant settles the diagnosis.
- name: Acquired and structural causes of hypogonadotropic hypogonadism
  description: >-
    Pituitary or hypothalamic lesions, and other secondary causes, produce the same biochemistry
    without being congenital. They are excluded before CHH is diagnosed rather than considered
    alongside it, which is why pituitary imaging is part of the workup above.
  distinguishing_features:
  - A mass lesion or other structural abnormality on pituitary imaging
  - Deficiency of other anterior pituitary hormones, which is absent in isolated GnRH deficiency
  evidence:
  - reference: PMID:20301509
    reference_title: "Isolated Gonadotropin-Releasing Hormone (GnRH) Deficiency."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "in the setting of otherwise normal anterior pituitary anatomy and function and in the absence of secondary causes of HH"
    explanation: >-
      The exclusion clause built into the diagnostic definition, which is what this differential
      records.
prevalence:
- population: Chinese men with isolated hypogonadotropic hypogonadism
  measure_type: UNKNOWN
  prevalence_class: UNKNOWN
  notes: >-
    A variant detection rate within a disease-ascertained cohort - 3.38% of 148 Chinese men with
    IHH carried an IL17RD variant - not a population prevalence, and not a rate of HH18 as a
    diagnosis, since most carriers also carry variants elsewhere. `measure_type` and
    `prevalence_class` are left UNKNOWN rather than converted to a rate, because the quantity is
    not a population frequency. The same source states plainly that the prevalence of IL17RD
    variants is unknown.
  evidence:
  - reference: PMID:38628584
    reference_title: Clinical phenotype of a Kallmann syndrome patient with IL17RD and CPEB4 variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "which examined mutation profiles and clinical manifestations of 148 Chinese men with IHH, a mutation rate of 3.38% was identified within the IL17RD."
    explanation: Numerator context and denominator for the detection rate.
- population: Cases reported in the literature worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: UNKNOWN
  notes: >-
    Twenty-two published IL17RD carriers were assembled by literature review as of 2024, of whom
    eighteen had Kallmann syndrome. That is the size of the entire described experience with this
    entity.
  evidence:
  - reference: PMID:38628584
    reference_title: Clinical phenotype of a Kallmann syndrome patient with IL17RD and CPEB4 variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Among them, KS occurred in 18 out of 22 (81.8%) patients"
    explanation: The published case count for this genotype.
progression:
- phase: Presentation
  age_range: infancy to adolescence
  notes: >-
    Two presentation windows. In infancy the sign is genital: micropenis, cryptorchidism, or
    both. Otherwise the disease surfaces in adolescence as absent or arrested puberty - the
    IL17RD carrier described in detail presented at 14.4 years with a short penis and reduced
    olfaction.
  evidence:
  - reference: PMID:20301509
    reference_title: "Isolated Gonadotropin-Releasing Hormone (GnRH) Deficiency."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "IGD can first become apparent in infancy, adolescence, or adulthood."
    explanation: The presentation windows for the disease class.
  - reference: PMID:38628584
    reference_title: Clinical phenotype of a Kallmann syndrome patient with IL17RD and CPEB4 variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A 14.4-year-old male patient presented with a complaint of “having a short penis for over 7 years and reduced olfaction for over 5 years”."
    explanation: The adolescent presentation in an IL17RD carrier.
treatments:
- name: Sex Steroid Replacement for Induction of Secondary Sexual Characteristics
  description: >-
    Gradually increasing testosterone in males, or estrogen and progestin in females, to induce
    and then maintain secondary sexual characteristics. This substitutes for the gonadal output
    the absent gonadotropin drive never produced; it does not restore the axis.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: hormone replacement therapy
    term:
      id: NCIT:C15599
      label: Hormone Replacement Therapy
    therapeutic_agent:
    - preferred_term: testosterone
      term:
        id: CHEBI:17347
        label: testosterone
  target_mechanisms:
  - target: Absent or Incomplete Puberty
    treatment_effect: BYPASSES
    description: >-
      Symptomatic and downstream: exogenous sex steroid produces the pubertal changes without
      acting on the hypothalamic defect, so it is recorded against the phenotype rather than an
      upstream node.
    evidence:
    - reference: PMID:20301509
      reference_title: "Isolated Gonadotropin-Releasing Hormone (GnRH) Deficiency."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "To induce and maintain secondary sex characteristics, gradually increasing doses of testosterone or human chorionic gonadotropin (hCG) injections in males or estrogen and progestin in females"
      explanation: The management recommendation for the disease class.
  notes: >-
    No treatment evidence specific to IL17RD carriers was found in the sources read here;
    management is the general CHH regimen and is cited as such, from GeneReviews rather than from
    an IL17RD series.
  evidence:
  - reference: PMID:20301509
    reference_title: "Isolated Gonadotropin-Releasing Hormone (GnRH) Deficiency."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "To induce and maintain secondary sex characteristics, gradually increasing doses of testosterone or human chorionic gonadotropin (hCG) injections in males or estrogen and progestin in females"
    explanation: The recommendation, stated for isolated GnRH deficiency as a whole.
- name: Gonadotropin or Pulsatile GnRH Therapy for Fertility
  description: >-
    Combined gonadotropin therapy (hCG with hMG or recombinant FSH), or pulsatile GnRH delivery,
    to drive gametogenesis when fertility is the goal. Pulsatile GnRH is the one intervention here
    that acts at the level of the missing signal itself, replacing the hypothalamic pulse
    generator rather than substituting for its end product - which is why it works only when the
    pituitary and gonads are otherwise intact.
  therapeutic_modality: PEPTIDE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: gonadorelin
      term:
        id: CHEBI:5520
        label: gonadorelin
    - preferred_term: human chorionic gonadotropin
      term:
        id: CHEBI:81570
        label: Chorionic gonadotropin
  target_mechanisms:
  - target: GnRH-Driven Gonadotropin Deficiency
    treatment_effect: RESTORES
    description: >-
      Pulsatile GnRH substitutes for the absent hypothalamic signal at exactly the point the
      pathograph breaks, which is why it is recorded against this node rather than against a
      phenotype. Combined gonadotropin therapy acts one step further downstream, replacing the
      pituitary output instead.
    evidence:
    - reference: PMID:20301509
      reference_title: "Isolated Gonadotropin-Releasing Hormone (GnRH) Deficiency."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "or pulsatile GnRH therapy. If conception fails despite spermatogenesis in a male or ovulation induction in a female, in vitro fertilization may be an option."
      explanation: The fertility regimen for the disease class.
  notes: >-
    As above, no IL17RD-specific outcome data exist in the sources read here: the regimen is the
    general one for isolated GnRH deficiency, and it is cited from GeneReviews rather than from
    any IL17RD series.
  evidence:
  - reference: PMID:20301509
    reference_title: "Isolated Gonadotropin-Releasing Hormone (GnRH) Deficiency."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "to stimulate spermatogenesis or folliculogenesis, either combined gonadotropin therapy"
    explanation: The recommendation, stated for isolated GnRH deficiency as a whole.
- name: Calcium and Vitamin D Repletion for Decreased Bone Mass
  description: >-
    Prevention of the skeletal secondary complication of untreated sex steroid deficiency:
    optimal calcium and vitamin D intake, with specific treatment of decreased bone mass where it
    is found. This is prevention of a complication rather than treatment of the endocrine lesion,
    which is why it targets the bone phenotype and not a pathophysiology node.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: calcium and vitamin D repletion
    term:
      id: NCIT:C15433
      label: Nutritional Support
    therapeutic_agent:
    - preferred_term: calcium(2+)
      term:
        id: CHEBI:29108
        label: calcium(2+)
    - preferred_term: vitamin D
      term:
        id: CHEBI:27300
        label: vitamin D
  target_mechanisms:
  - target: Osteoporosis
    treatment_effect: INHIBITS
    description: >-
      Recorded against the bone phenotype rather than an upstream node: repletion does not act on
      GnRH signalling, it mitigates the skeletal consequence of the hypogonadal state.
    evidence:
    - reference: PMID:20301509
      reference_title: "Isolated Gonadotropin-Releasing Hormone (GnRH) Deficiency."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Prevention of secondary complications: Optimal calcium and vitamin D intake should be encouraged and specific treatment for decreased bone mass as needed."
      explanation: >-
        The GeneReviews prevention recommendation, which names both the intervention and the
        complication it is aimed at.
  notes: >-
    As with the other treatments here, no IL17RD-specific outcome data exist in the sources read:
    this is the general recommendation for isolated GnRH deficiency, cited from GeneReviews. The
    modality is SMALL_MOLECULE rather than BEHAVIORAL because the intervention named is repletion
    with two specific compounds, not a dietary pattern change - the distinction CLAUDE.md draws
    for NCIT:C15433.
  evidence:
  - reference: PMID:20301509
    reference_title: "Isolated Gonadotropin-Releasing Hormone (GnRH) Deficiency."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Optimal calcium and vitamin D intake should be encouraged and specific treatment for decreased bone mass as needed."
    explanation: The recommendation, stated for isolated GnRH deficiency as a whole.
discussions:
- discussion_id: hh18_direction_of_fgf_signalling_change
  kind: KNOWLEDGE_GAP
  prompt: >-
    Does an IL17RD variant increase or decrease FGF8-FGFR1 signalling in the developing
    olfactory-GnRH system, and how does either direction produce the same disease as FGFR1
    loss of function?
  attaches_to:
  - pathophysiology#Dysregulated FGF8-FGFR1 Signaling in the Developing Olfactory-GnRH System
  rationale: >-
    Sef is an antagonist, so impairing it should raise pathway output; but CHH is otherwise
    produced by FGFR1 and FGF8 loss of function, which lowers it. Both DUSP6 and the sprouties -
    also negative regulators - are implicated in the same disease, so this is not a peculiarity
    of IL17RD but a pattern that the negative-modulator class as a whole presents. No source read
    here measures signalling output for a patient IL17RD allele in a GnRH-lineage cell, so the
    node records dysregulation without a direction. Resolving it would need the patient alleles
    assayed in a relevant cell type, not in HEK293T.
- discussion_id: hh18_hearing_loss_mechanism
  kind: KNOWLEDGE_GAP
  prompt: >-
    Why is hearing loss the characteristic non-reproductive feature of IL17RD-related CHH?
  attaches_to:
  - phenotypes#Sensorineural Hearing Impairment
  rationale: >-
    The association is one of the most reproducible things about this entity - 6 of 8 in the
    founding cohort, 7 of 18 across the published carriers, and the most common accompanying
    symptom in both - and the human mechanism is still unaccounted for. An animal auditory
    phenotype does exist and is cited below: adult Sef-null mice have defective brainstem
    responsiveness to auditory stimuli, with Sef expressed in cochlear-nucleus astrocytes where it
    regulates FGF signalling from the rhombic lip. That result narrows the gap rather than closing
    it, in two ways. It localises the mouse defect centrally, to the cochlear nucleus, whereas the
    human phenotype in these carriers is reported as sensorineural hearing impairment; and no
    cited source connects the mouse finding to the hearing loss seen in IL17RD-related CHH, or
    proposes a role for Sef in cochlear or auditory-nerve development in humans. The open question
    is therefore whether the human deficit shares the central mechanism the mouse shows.
  evidence:
  - reference: DOI:10.1186/s12964-020-00695-7
    reference_title: "Interleukin-17 receptor D (Sef) is a multi-functional regulator of cell signaling"
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "mice exhibited defects in the responsiveness of the brainstem to auditory stimuli."
    explanation: >-
      Records the mouse auditory phenotype, which is why this gap is worded as an unexplained
      human mechanism rather than a total absence of animal data.
  - reference: DOI:10.1186/s12964-020-00695-7
    reference_title: "Interleukin-17 receptor D (Sef) is a multi-functional regulator of cell signaling"
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "SEF was expressed in the astrocytes of the cochlear nucleus, wherein it functioned to regulate FGF signaling from the adjacent rhombic lip"
    explanation: >-
      Localises the mouse mechanism to the cochlear nucleus, which is the central-versus-cochlear
      distinction the gap now turns on.
- discussion_id: hh18_susceptibility_versus_causative
  kind: KNOWLEDGE_GAP
  prompt: >-
    Is any IL17RD variant sufficient on its own to cause congenital hypogonadotropic
    hypogonadism?
  attaches_to:
  - pathophysiology#Oligogenic Requirement for Additional CHH Loci
  rationale: >-
    Every informative proband in the largest IL17RD series inherited the variant from an
    unaffected parent, and oligogenicity was found in most; the same cohort concluded that
    DUSP6 variants are sufficient alone while IL17RD variants act in synergy. But the comparison
    is between small numbers, the sequencing in the earlier study did not cover every CHH gene,
    and an apparently isolated IL17RD case cannot be distinguished from one with an unsequenced
    second hit. Settling this needs genome-wide analysis of IL17RD carriers with and without
    disease, not more single cases. Until then the gene is typed SUSCEPTIBILITY rather than
    CAUSATIVE, and this discussion records that the typing is a judgement about evidence rather
    than a settled biological fact.
📚

References & Deep Research

References

7
PMID:23643382
Mutations in FGF17, IL17RD, DUSP6, SPRY4, and FLRT3 are identified in individuals with congenital hypogonadotropic hypogonadism.
No top-level findings curated for this source.
PMID:32389901
Prevalence and associated phenotypes of DUSP6, IL17RD and SPRY4 variants in a large Chinese cohort with isolated hypogonadotropic hypogonadism.
No top-level findings curated for this source.
PMID:38628584
Clinical phenotype of a Kallmann syndrome patient with IL17RD and CPEB4 variants.
No top-level findings curated for this source.
PMID:11802165
Sef is a feedback-induced antagonist of Ras/MAPK-mediated FGF signalling.
No top-level findings curated for this source.
PMID:16603339
A role for extracellular and transmembrane domains of Sef in Sef-mediated inhibition of FGF signaling.
No top-level findings curated for this source.
PMID:20301509
Isolated Gonadotropin-Releasing Hormone (GnRH) Deficiency.
No top-level findings curated for this source.
DOI:10.1186/s12964-020-00695-7
Interleukin-17 receptor D (Sef) is a multi-functional regulator of cell signaling
No top-level findings curated for this source.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (1)

Record notes

Identifiers. OMIM #615267 (HH18) and OMIM 606807 (IL17RD). Recorded in prose because the schema's `mappings` block carries `mondo_mappings` only and has no OMIM slot. Lump/split. This is curated as its own entry rather than as a `has_subtypes` row on `Kallmann_Syndrome`, following the precedent already in the KB: FGFR1-related CHH has a standalone entry (`FGFR1_Hypogonadotropic_Hypogonadism`) even though Kallmann syndrome 2 is also a gene-named subtype row inside `Kallmann_Syndrome`. The argument for a separate entry here is that HH18's mechanism is not "another CHH gene" but specifically the loss of *negative* feedback on the same FGF8-FGFR1 axis, and its inheritance is oligogenic rather than dominant - a different pathograph and a different counselling problem. A curator who prefers the lumped arrangement should fold this into `Kallmann_Syndrome` as an IL17RD subtype row rather than duplicating it; the two representations should not both exist. Why `relationship_type: SUSCEPTIBILITY` rather than `CAUSATIVE`. The published evidence does not support IL17RD variants being sufficient. They are heterozygous, inherited from unaffected parents, present in patients who also carry variants in other CHH genes, and the largest IL17RD-specific cohort concludes that they act in synergy with other loci. Typing this locus CAUSATIVE would assert something the sources decline to assert, so it is typed SUSCEPTIBILITY, and the oligogenic requirement is modelled as its own pathophysiology node rather than being buried in a caveat. Evidence base. Three human sources: the founding CHH cohort of 386 probands (PMID:23643382), an IL17RD/DUSP6/SPRY4-focused cohort of 196 Chinese IHH patients (PMID:32389901), and a single well-characterised case report that also reviews the 22 published IL17RD carriers (PMID:38628584). Mechanism comes from the zebrafish and cell-culture Sef literature (PMID:11802165, PMID:16603339), and general CHH management from GeneReviews (PMID:20301509). There is no IL17RD animal model of CHH cited here because none was found in these sources; the entry therefore carries no `animal_models` block rather than an empty gesture at one. What is not asserted. No prevalence figure is given for HH18: the case-report review states outright that the prevalence of IL17RD variants remains unknown, and the one available denominator is a variant detection rate within an ascertained IHH cohort, which is a different quantity. No genotype-phenotype correlation is asserted, for the same reason - the same source says none has been established. Deep research. A Falcon deep-research report is committed alongside this entry. It passed `just preflight-dr` against MONDO:0014103 with IL17RD mentioned 44 times and no rival gene close behind, and its reference validation resolved 17 of 17 citations with a confabulation rate of 0. Its term validation flagged one invented identifier, `HP:0000806`, which HP does not contain; that CURIE is not used here, and no ontology binding in this entry was taken from the report. The report was used as a lead source only - every snippet below is anchored to a PMID fetched into `references_cache/` and read directly.

Falcon ▸
Hypogonadotropic Hypogonadism 18 With or Without Anosmia: Research Report
Edison Scientific Literature 48 citations 2026-09-04T14:04:06.476715

Hypogonadotropic Hypogonadism 18 With or Without Anosmia: Research Report

Executive summary and evidence boundaries

Hypogonadotropic hypogonadism 18 with or without anosmia (HH18) is an IL17RD-associated form of congenital hypogonadotropic hypogonadism (CHH). CHH results from deficient gonadotropin-releasing hormone (GnRH) secretion or action and causes low sex steroids with low or inappropriately normal luteinizing hormone (LH) and follicle-stimulating hormone (FSH). Disease accompanied by anosmia or hyposmia is conventionally called Kallmann syndrome (KS); patients with preserved smell have normosmic CHH. The strongest HH18-specific evidence remains the 2013 discovery study of only eight unrelated IL17RD-positive probands. Accordingly, subtype-specific prevalence, penetrance, prognosis, and treatment-response estimates are unavailable; broader CHH evidence is identified explicitly below rather than presented as HH18-specific evidence. (miraoui2013mutationsinfgf17 pages 7-10, miraoui2013mutationsinfgf17 pages 6-7, oleari2021thedifferentialroles pages 2-4)

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 (OpenTargets Search: hypogonadotropic hypogonadism 18 with or without anosmia, miraoui2013mutationsinfgf17 pages 6-7, miraoui2013mutationsinfgf17 pages 14-15)
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 (miraoui2013mutationsinfgf17 pages 6-7, cannarella2023geneticanalysisof pages 5-8, miraoui2013mutationsinfgf17 pages 4-6)
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) (miraoui2013mutationsinfgf17 pages 6-7, miraoui2013mutationsinfgf17 pages 14-15)
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 (miraoui2013mutationsinfgf17 pages 7-10, miraoui2013mutationsinfgf17 pages 6-7, pande2021interleukin17receptord pages 1-2, pande2021interleukin17receptord pages 2-4)
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 (swee2019congenitalhypogonadotrophichypogonadism pages 2-3, young2019clinicalmanagementof pages 17-18, young2019clinicalmanagementof pages 10-11, sayed2023paneltestingfor pages 3-5)
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) (dwyer2024classesandpredictors pages 6-8, alexander2024gonadotropinsforpubertal pages 1-2, dwyer2024classesandpredictors pages 1-3, young2019clinicalmanagementof pages 23-24, young2019clinicalmanagementof pages 24-25)
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 (young2019clinicalmanagementof pages 7-8, pande2021interleukin17receptord pages 13-14)

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.

1. Disease information

Definition. HH18 is a rare Mendelian neurodevelopmental reproductive disorder in which pathogenic or contributory IL17RD variants disrupt development or function of the GnRH neuronal system. The defining endocrine phenotype is absent, partial, or arrested puberty and infertility caused by central gonadotropin deficiency. Olfactory dysfunction is variable by disease definition, although all eight probands in the original IL17RD series had KS. (miraoui2013mutationsinfgf17 pages 6-7, vezzoli2023geneticarchitectureof pages 3-5)

Identifiers and terminology. The principal mappings are MONDO:0014103 and OMIM phenotype 615267; the causal gene is IL17RD (interleukin-17 receptor D; synonym SEF, “similar expression to FGF”; HGNC:17616; OMIM gene 606807). Common names include “hypogonadotropic hypogonadism 18 with or without anosmia,” “HH18,” “IL17RD-related congenital hypogonadotropic hypogonadism,” and “Kallmann syndrome 18.” Open Targets maps MONDO:0014103 specifically to IL17RD and cites PMID 23643382 as foundational evidence. (OpenTargets Search: hypogonadotropic hypogonadism 18 with or without anosmia)

No dedicated Orphanet, MeSH, ICD-10, or ICD-11 code reliably distinguishes HH18 from other CHH forms. Practical aggregate mappings include ICD-10-CM E23.0 (“hypopituitarism,” encompassing hypogonadotropic hypogonadism) and broader Kallmann/CHH concepts in Orphanet and MeSH. These coding systems should not be treated as genotype-specific identifiers.

The evidence is aggregated disease-level literature and curated-resource evidence, not an individual EHR extraction. The primary human evidence consists of deeply phenotyped research probands and families. (OpenTargets Search: hypogonadotropic hypogonadism 18 with or without anosmia, miraoui2013mutationsinfgf17 pages 4-6)

2. Etiology, risk, and protective factors

Causal and genetic factors

The 2013 primary study screened 386 CHH probands—199 with KS and 187 with normosmic CHH—and 155 controls. Eight unrelated probands carried heterozygous or homozygous IL17RD missense variants. Reported alleles were c.392A>C (p.Lys131Thr), c.485A>G (p.Lys162Arg), c.916C>T (p.Pro306Ser), c.1136A>G (p.Tyr379Cys), c.1403C>T (p.Ser468Leu), c.1730C>A (p.Pro577Gln), and c.2204C>T (p.Ala735Val). Across the screened FGF-network genes, individual genes explained approximately 1–4% of cases; this is not an HH18 population-prevalence estimate. (miraoui2013mutationsinfgf17 pages 6-7, miraoui2013mutationsinfgf17 pages 4-6)

Inheritance can appear autosomal dominant, autosomal recessive, or oligogenic. A heterozygous IL17RD allele may be insufficient by itself: some severe cases also carried an FGFR1 or KISS1R variant. For example, p.Tyr379Cys was inherited from an anosmic mother, while the proband additionally carried de novo FGFR1 p.Gly348Arg and had complete absent puberty, dental agenesis, hearing loss, and osteoporosis. This illustrates incomplete penetrance, variable expressivity, and locus–locus interaction rather than simple deterministic Mendelian transmission. (miraoui2013mutationsinfgf17 pages 7-10, miraoui2013mutationsinfgf17 pages 14-15)

A 2023 case series identified heterozygous IL17RD c.960G>A (p.Met320Ile) together with FGF17 p.Gly70Arg in a man with KS. Both were VUS-level findings; modeling did not demonstrate a major structural effect, so they should not be regarded as independently established pathogenic alleles. (cannarella2023geneticanalysisof pages 5-8, cannarella2023geneticanalysisof pages 4-5)

Environmental, infectious, and protective factors

No toxin, infection, diet, occupation, or lifestyle exposure is established as a cause of germline HH18, and no validated genetic or environmental protective factor has been reported. Energy deficiency, excessive exercise, stress, chronic systemic illness, obesity, diabetes, opioids, glucocorticoids, hyperprolactinemia, iron overload, tumors, inflammation, surgery, and radiotherapy can cause acquired or functional hypogonadotropic hypogonadism, but these are differential diagnoses rather than demonstrated HH18 modifiers. (vezzoli2023geneticarchitectureof pages 2-3)

A plausible gene–environment interaction is that reduced developmental reserve from an incompletely penetrant allele could make the reproductive axis more vulnerable to illness, undernutrition, or stress; however, this remains unproven for IL17RD. There is likewise no evidence that avoiding a particular exposure prevents expression in a carrier.

3. Phenotypes

The discovery cohort provides the best HH18-specific frequencies: KS/anosmia in 8/8, absent puberty in 7/8, and congenital hearing loss in 6/8, often unilateral. Dental abnormalities and low bone mass occurred in selected patients. The ascertainment strategy and very small cohort make these frequencies vulnerable to selection bias and unsuitable as population estimates. (miraoui2013mutationsinfgf17 pages 6-7)

Suggested knowledge-base phenotypes are:

  • Central hypogonadism: low testosterone or estradiol with low/inappropriately normal LH and FSH; congenital, usually recognized in adolescence; severity ranges from absent to partial/arrested puberty. HPO: Hypogonadotropic hypogonadism (HP:0000044), Delayed puberty (HP:0000823), Absent puberty (HP:0000805).
  • Olfactory dysfunction: congenital anosmia or hyposmia, generally stable. HPO: Anosmia (HP:0000458), Hyposmia (HP:0004409), Abnormality of the olfactory bulb (HP:0002033). In a broader IHH referral cohort of 286 patients, 31.5% were anosmic, 33.6% hyposmic, and 34.9% normosmic, demonstrating a continuum rather than a binary phenotype. (lewkowitzshpuntoff2012olfactoryphenotypicspectrum pages 1-2)
  • Male neonatal signs: micropenis and cryptorchidism reflect deficient fetal/neonatal gonadotropin action. Broader CHH series report cryptorchidism in approximately 30–50% of males. HPO: Micropenis (HP:0000054), Cryptorchidism (HP:0000028). (swee2019congenitalhypogonadotrophichypogonadism pages 2-3)
  • Male adolescent/adult manifestations: small prepubertal testes, absent virilization, sparse body/facial hair, high-pitched voice, reduced libido, erectile dysfunction, azoospermia/infertility, and gynecomastia. HPO suggestions include Small testis (HP:0000050), Azoospermia (HP:0000027), Infertility (HP:0000789), and Gynecomastia (HP:0000771). (oleari2021thedifferentialroles pages 2-4, fanis2023gonadotropinreleasinghormonereceptor pages 14-15)
  • Female manifestations: absent or limited breast development, primary amenorrhea, anovulation, and infertility. HPO: Primary amenorrhea (HP:0000786), Absent breast development (HP:0010311), Female infertility (HP:0008222). (oleari2021thedifferentialroles pages 2-4)
  • Auditory phenotype: congenital, sometimes unilateral hearing impairment was unusually prominent in the original HH18 cohort. HPO: Hearing impairment (HP:0000365), Unilateral hearing impairment (HP:0000369). (miraoui2013mutationsinfgf17 pages 7-10)
  • Secondary consequences: low bone mineral density/osteoporosis, adverse body composition, reduced muscle mass, anemia, fatigue, and metabolic risk arise downstream of untreated sex-steroid deficiency. HPO: Osteoporosis (HP:0000939), Decreased bone mineral density (HP:0004349). (oleari2021thedifferentialroles pages 2-4, vezzoli2023geneticarchitectureof pages 3-5)

Quality-of-life effects documented across CHH include anxiety, depression, low self-esteem, altered body image, social withdrawal, impaired psychosexual development, sexual distress, and infertility-related burden. Delayed diagnosis—often around age 18–19 years—prolongs these effects. No validated HH18-specific EQ-5D, SF-36, or PROMIS study was identified. (swee2019congenitalhypogonadotrophichypogonadism pages 2-3, young2019clinicalmanagementof pages 7-8)

4. Genetic and molecular information

IL17RD lies at chromosome 3p14.3 and encodes a 739-amino-acid type-I single-pass transmembrane signaling regulator. The extracellular region contains a signal peptide, immunoglobulin-like domain, fibronectin type-III region, conserved cysteines, and potential N-glycosylation sites. The cytoplasmic region includes Tyr330, a SEFIR domain, TIR-like motifs, a putative TRAF6-binding site, and a proline-rich putative SH3-binding region. Full-length IL17RD is mainly at the plasma membrane but also occurs in Golgi and endosomal compartments; alternative translation produces cytosolic isoforms. (pande2021interleukin17receptord pages 1-2, pande2021interleukin17receptord pages 2-4)

The established HH18 alleles are germline, not somatic. Most reported founding alleles are missense variants. Functional evidence is allele-specific: p.Lys131Thr, p.Pro306Ser, and p.Ser468Leu impaired suppression of an FGF8/FGFR1c-responsive AP-1 reporter; p.Tyr379Cys and p.Pro577Gln had weaker borderline effects, while p.Lys162Arg and p.Ala735Val behaved similarly to wild type in that assay. Reduced cell-surface expression was observed for several mutants. Variant classification should therefore be performed allele by allele under ACMG/AMP criteria rather than assuming that every rare IL17RD missense substitution is pathogenic. (miraoui2013mutationsinfgf17 pages 7-10, miraoui2013mutationsinfgf17 pages 6-7)

Population allele frequencies were not supplied in the retrieved primary passages and should be obtained directly from the current gnomAD release for each transcript-normalized variant. Absence or rarity in gnomAD is supporting—not sufficient—evidence. No validated recurrent structural rearrangement, repeat expansion, mitochondrial defect, somatic event, disease-specific methylation signature, or epigenetic biomarker has been established for HH18.

Probable modifiers include other FGF/GnRH-network genes, especially FGFR1 and KISS1R in reported families. Broad CHH studies also demonstrate oligogenicity, but specific modifier penetrance estimates for IL17RD are unavailable. (miraoui2013mutationsinfgf17 pages 7-10, dwyer2024classesandpredictors pages 1-3)

5. Environmental information

Environmental toxins, radiation, pollution, occupational exposures, smoking, alcohol, diet, or infectious agents have no demonstrated etiologic role in HH18. These factors may affect general reproductive health but should not be entered as HH18 causes without direct evidence. Functional hypothalamic suppression from low energy availability, illness, medications, or stress must instead be excluded diagnostically. HH18 is not infectious, transmissible, or zoonotic. (vezzoli2023geneticarchitectureof pages 2-3)

6. Mechanism and pathophysiology

Ordered causal chain

  1. A functionally deleterious germline IL17RD allele leads to altered abundance, trafficking, or signaling activity of IL17RD/SEF at the cell membrane.
  2. Defective IL17RD regulation leads to dysregulated FGF8–FGFR1 signaling through FRS2 and RAS–RAF–MEK–ERK/related MAPK pathways; the exact direction, timing, and cell-specific consequence in human embryos remain partly inferred.
  3. In the embryonic olfactory placode/GnRH developmental field, mistimed FGF signaling is inferred to lead to abnormal GnRH-neuron specification, survival, differentiation, or migration into the forebrain/hypothalamus. Mouse colocalization supports this location, but direct human embryonic proof is absent.
  4. Reduced or dysfunctional hypothalamic GnRH neurons lead to deficient pulsatile GnRH release.
  5. Deficient GnRH stimulation of anterior-pituitary gonadotropes leads to low or inappropriately normal LH and FSH.
  6. Low LH/FSH lead to insufficient Leydig/Sertoli or ovarian follicular stimulation, causing low testosterone/estradiol, deficient gametogenesis, absent or arrested puberty, and infertility.
  7. Olfactory branch: disturbed olfactory-system development leads to hyposmia/anosmia and olfactory-bulb abnormalities.
  8. Auditory branch: IL17RD-dependent developmental/signaling abnormalities are inferred to lead to congenital hearing impairment; knockout-mouse auditory-brainstem abnormalities support this branch, but the human mechanism is unresolved.
  9. Chronic sex-steroid deficiency leads to reduced bone mineralization, adverse body composition, sexual dysfunction, and psychosocial morbidity. (miraoui2013mutationsinfgf17 pages 7-10, oleari2021thedifferentialroles pages 2-4, pande2021interleukin17receptord pages 1-2, miraoui2013mutationsinfgf17 pages 6-7)

IL17RD is a feedback regulator and scaffold rather than a classical metabolic enzyme. It can bind FGFR1/2 and inhibit FGFR kinase activity, FRS2α phosphorylation, ERK/AKT signaling, or MEK–ERK nuclear trafficking depending on isoform and cellular context. It also interacts with IL17RA, TLR3/4, TNFR2, and EGFR and can regulate JNK, p38, NF-κB, ACT1, and TRAF6 outputs. These inflammatory roles are biologically established in other tissues but have not been shown to cause HH18; immune-mediated tissue injury is therefore not part of the demonstrated reproductive mechanism. (pande2021interleukin17receptord pages 2-4, pande2021interleukin17receptord pages 4-6, pande2021interleukin17receptord pages 6-8)

Suggested annotations include GO:0008543 (fibroblast growth factor receptor signaling pathway), GO:0000165 (MAPK cascade), GO:0007218 (neuropeptide signaling pathway), GO:0007399 (nervous-system development), GO:0030154 (cell differentiation), GO:0050900 (leukocyte migration; only for immune studies), and GO:0005886 (plasma membrane). Relevant cell concepts include GnRH neuron, olfactory sensory neuron, anterior-pituitary gonadotroph, Leydig cell (CL:0000178), Sertoli cell (CL:0000216), ovarian granulosa cell (CL:0000501), and cochlear-nucleus astrocyte. No validated HH18-specific transcriptomic, proteomic, metabolomic, lipidomic, spatial-transcriptomic, organoid, iPSC, or CRISPR-screen signature was identified.

7. Anatomical structures affected

The primary axis comprises the olfactory placode/nasal embryonic compartment, olfactory nerves and bulbs, hypothalamic GnRH neuronal network, pituitary gonadotropes, and gonads. Secondary structures include testes, penis, ovaries, uterus, breast, skeleton, muscle, and adipose tissue. Hearing impairment implicates auditory pathways, although its precise lesion is uncertain. (young2019clinicalmanagementof pages 10-11, pande2021interleukin17receptord pages 1-2)

Suggested UBERON mappings include olfactory placode (UBERON:0009950), olfactory bulb (UBERON:0002264), hypothalamus (UBERON:0001898), pituitary gland (UBERON:0000007), anterior pituitary (UBERON:0002196), testis (UBERON:0000473), ovary (UBERON:0000992), uterus (UBERON:0000995), and cochlea (UBERON:0001844). Relevant subcellular GO terms are plasma membrane (GO:0005886), Golgi apparatus (GO:0005794), endosome (GO:0005768), and cytoplasm (GO:0005737). Olfactory and hearing abnormalities may be bilateral or asymmetric; unilateral hearing loss was common in the original series. (miraoui2013mutationsinfgf17 pages 7-10, pande2021interleukin17receptord pages 2-4)

8. Temporal development

The initiating defect is congenital and acts during embryonic GnRH/olfactory development. In males, severe disease can be detected during fetal life or neonatal “minipuberty” through micropenis, cryptorchidism, absent erections, and low LH/FSH/testosterone. Childhood may be clinically silent because the reproductive axis is normally quiescent. Adolescence reveals absent, partial, or arrested puberty; adult presentation may be infertility, sexual dysfunction, or osteoporosis. (swee2019congenitalhypogonadotrophichypogonadism pages 2-3, young2019clinicalmanagementof pages 10-11)

Untreated endocrine deficiency is chronic, but severity is variable. Across CHH—not specifically HH18—approximately 5–20% recover endogenous reproductive-axis activity, and relapse can occur. A 2024 six-center study compared 87 men with reversal against 108 non-reversal controls; cryptorchidism reduced reversal odds (OR 0.30), while larger testes and less severe phenotypes favored reversal. Long-term periodic reassessment is therefore appropriate even after apparent recovery. (dwyer2024classesandpredictors pages 6-8, dwyer2024classesandpredictors pages 1-3)

Critical intervention windows are neonatal minipuberty, timely adolescent pubertal induction, and the period before prolonged sex-steroid deficiency causes skeletal and psychosocial morbidity. (swee2019congenitalhypogonadotrophichypogonadism pages 2-3, swee2019managingcongenitalhypogonadotrophic pages 7-8)

9. Inheritance and population

HH18 is exceedingly rare; neither incidence nor prevalence has been measured. Broader male CHH estimates range from approximately 1:4,000 to 1:30,000, with a historical French estimate near 1:10,000 men and a Sardinian KS estimate near 1:86,000. The reported male:female ratio is roughly 4:1, probably reflecting ascertainment and the greater neonatal visibility of male disease. These figures must not be assigned directly to HH18. (oleari2021thedifferentialroles pages 2-4, young2019clinicalmanagementof pages 7-8)

Both dominant and recessive IL17RD genotypes have been reported, often against an oligogenic background. Penetrance is incomplete and expressivity variable. No anticipation mechanism is known. Germline mosaicism is theoretically possible but not established; no founder allele, population-specific enrichment, carrier frequency, or robust consanguinity effect has been demonstrated. Cascade testing should account for mildly affected or apparently unaffected relatives and should not use genotype alone to predict severity. (miraoui2013mutationsinfgf17 pages 7-10, miraoui2013mutationsinfgf17 pages 14-15)

10. Diagnostics

Diagnosis requires: (1) absent, partial, or arrested puberty or adult reproductive symptoms; (2) repeatedly low testosterone/estradiol with low or inappropriately normal LH/FSH; and (3) exclusion of functional, structural, systemic, medication-related, and combined-pituitary causes. There is no single gold-standard test distinguishing CHH from self-limited delayed puberty at age 14–16. (vezzoli2023geneticarchitectureof pages 2-3, young2019clinicalmanagementof pages 10-11)

Recommended evaluation includes:

  • neonatal LH, FSH, testosterone and, when useful, inhibin B/AMH during approximately 4–12 weeks of life;
  • morning testosterone on two occasions in adult males; estradiol, LH, and FSH in females; prolactin, TSH/free T4, morning cortisol, and IGF-1 when broader pituitary disease is possible;
  • testicular volume, genital examination, Tanner staging, menstrual history, semen analysis, and bone age/BMD where indicated;
  • formal smell testing rather than self-report; coronal T2-weighted MRI may assess olfactory bulbs and sulci;
  • pituitary/brain MRI when structural disease, neurological findings, or combined pituitary deficiency is suspected;
  • renal, reproductive-tract, auditory, dental, skeletal, and ophthalmic assessment guided by phenotype. A stimulated LH cutoff of 4.3 IU/L was reported with 100% sensitivity and 75% specificity for severe CHH in one study, and inhibin B below 60 pmol/mL may support severe GnRH deficiency, but neither is definitive. (young2019clinicalmanagementof pages 17-18, vezzoli2023geneticarchitectureof pages 2-3)

Genetic testing. A multigene CHH/KS panel is preferable to isolated IL17RD sequencing because oligogenicity and phenotypic overlap are common. The 2023 UK NHS PanelApp R148 “green” panel included ANOS1, CHD7, FGF8, FGFR1, FSHB, GNRHR, IL17RD, KISS1R, LHB, PROK2, PROKR2, TAC3, TACR3, and WDR11. Exome or genome sequencing is appropriate when panel testing is negative, syndromic features are atypical, or structural/noncoding variation is suspected; parental testing assists segregation and de novo assessment. CMA is reasonable for multiple congenital anomalies or developmental delay, but karyotyping, FISH, mitochondrial sequencing, and repeat-expansion testing are not routine HH18 tests unless another diagnosis is suspected. (sayed2023paneltestingfor pages 2-2, sayed2023paneltestingfor pages 3-5)

Differentials include constitutional/self-limited delayed puberty, functional hypothalamic amenorrhea, chronic illness/undernutrition, hyperprolactinemia, pituitary tumors or infiltration, combined pituitary hormone deficiency, CHARGE, Waardenburg, Bardet–Biedl, adrenal hypoplasia congenita, septo-optic dysplasia, and neurodegenerative hypogonadism syndromes. (vezzoli2023geneticarchitectureof pages 2-3, kim2015congenitalhypogonadotropichypogonadism pages 5-7)

11. Outcome and prognosis

Life expectancy and disease-specific mortality have not been quantified for HH18; isolated CHH is not generally considered directly life-limiting. Major untreated morbidity includes infertility, sexual dysfunction, osteoporosis/fracture risk, adverse body composition, anemia, and substantial psychological burden. Hearing loss adds communication and educational consequences in affected HH18 patients. (oleari2021thedifferentialroles pages 2-4, young2019clinicalmanagementof pages 7-8)

Puberty and sex-steroid-dependent health are usually medically restorable, and fertility can often be induced. Prognosis is less favorable for spermatogenesis in males with cryptorchidism, micropenis, complete absent puberty, or very small baseline testes. Apparent reversal requires monitoring because relapse is documented. No IL17RD-specific prognostic biomarker exists. (dwyer2024classesandpredictors pages 6-8, young2019clinicalmanagementof pages 26-26)

12. Treatment and current applications

There is no approved IL17RD-targeted, gene, RNA, cell, CRISPR, or immunotherapy. Treatment replaces downstream hormones and is genotype-independent.

  • Male puberty/maintenance: gradually escalating testosterone enanthate or cypionate—often beginning near 50 mg monthly and increasing over 24–36 months—or age-appropriate transdermal/injectable adult replacement. Testosterone induces virilization and supports bone, muscle, libido, and well-being but does not enlarge testes or induce spermatogenesis. Monitor testosterone, growth/bone age, hematocrit, acne, gynecomastia, and psychosocial health. Excess dosing can cause erythrocytosis or premature epiphyseal closure. Suggested NCIt concepts: Testosterone Replacement Therapy and Hormone Replacement Therapy. (young2019clinicalmanagementof pages 23-24, lee2022treatmentofcongenital pages 3-4)
  • Female puberty/maintenance: low-dose oral or transdermal 17β-estradiol, slowly escalated; add cyclic progestin after adequate estrogenization/bleeding to protect the endometrium. Continue physiologic replacement to the usual menopausal age unless contraindicated. Suggested NCIt concepts: Estrogen Replacement Therapy and Progestin Therapy. (young2019clinicalmanagementof pages 23-24, young2019clinicalmanagementof pages 24-25)
  • Male fertility: pulsatile GnRH when pituitary function and specialist infrastructure permit, or hCG plus FSH/hMG. FSH priming before hCG may expand Sertoli-cell mass in severe prepubertal disease. A 2024 systematic review included 103 studies, 5,328 patients, and 21 countries; more than 98% of analyses showed increased testicular size, penile size, or testosterone. Pooled spermatogenesis was 86% with hCG+FSH (95% CI 82–91%), 76% with hCG+hMG, 76% with pulsatile GnRH, and 40% with hCG alone. The authors’ abstract states: “This systematic review provides convincing evidence of the efficacy of gonadotropins for pubertal induction,” while emphasizing major regimen heterogeneity. (alexander2024gonadotropinsforpubertal pages 3-5, alexander2024gonadotropinsforpubertal pages 1-2)
  • Female fertility: pulsatile GnRH is physiologic where available; alternatively use FSH with LH activity followed by hCG/recombinant LH, with estradiol and ultrasound monitoring to limit ovarian hyperstimulation and multiple pregnancy. (young2019clinicalmanagementof pages 24-25, young2019clinicalmanagementof pages 26-26)
  • Neonatal management: orchidopexy is generally undertaken by 6–12 months for persistent cryptorchidism. Short-course testosterone treats micropenis but not testicular maturation. Recombinant LH/FSH “minipuberty replacement” can increase penile length, testicular volume, testosterone, and inhibin B, but protocols remain specialized and long-term fertility benefit is not definitively established. (lee2022treatmentofcongenital pages 3-4, swee2019managingcongenitalhypogonadotrophic pages 5-7, lee2022treatmentofcongenital pages 2-3)
  • Supportive care: bone-health assessment, adequate calcium/vitamin D and weight-bearing activity, hearing services, fertility counseling, sexual-health care, and psychological support.

In the 2024 meta-analysis, pooled gynecomastia rates were 8% with hCG+FSH, 15% with hCG+hMG, and 4% with GnRH; acne rates were 8%, 16%, and 5%, respectively. Injection-site pain/reaction was 9% with hCG+FSH and 42% with pump-delivered GnRH. These are broader HH data and not HH18-specific rates. (alexander2024gonadotropinsforpubertal pages 6-8)

Representative registered studies include NCT00064987 (FSH to improve testicular development), NCT02880280 (hCG+hMG in CHH), NCT01403532 (sequential therapy), and NCT03687606 (long-term hCG versus hCG+hMG). None is an IL17RD-specific interventional trial.

13. Prevention

The congenital germline lesion cannot currently be prevented by vaccination, medication, diet, or exposure modification. Primary prevention consists only of informed reproductive options after genetic counseling: cascade testing, partner testing where recessive risk is plausible, prenatal diagnosis, and preimplantation genetic testing for a familial pathogenic variant. Counseling must explain incomplete penetrance, oligogenicity, and uncertain phenotype prediction.

Secondary prevention is targeted early detection: examine male infants with bilateral cryptorchidism or micropenis during minipuberty, assess children from affected families, and investigate delayed puberty promptly rather than waiting until late adolescence. Tertiary prevention includes timely sex-steroid replacement, orchidopexy, fertility-preserving gonadotropin strategies, bone protection, hearing support, and mental-health care. Population newborn screening is not available or justified by present evidence. (swee2019congenitalhypogonadotrophichypogonadism pages 2-3, swee2019managingcongenitalhypogonadotrophic pages 7-8)

14. Other species and natural disease

No naturally occurring veterinary disease specifically established as orthologous IL17RD-HH18 was identified. IL17RD is evolutionarily conserved across vertebrates, and FGF-feedback functions have been studied in zebrafish, frog, chick, and mouse. These are experimental comparative systems, not evidence of transmissible or zoonotic disease. NCBI Taxonomy suggestions include Homo sapiens 9606, Mus musculus 10090, Danio rerio 7955, and Gallus gallus 9031. (pande2021interleukin17receptord pages 1-2)

15. Model organisms

  • Mouse embryonic localization: at E10.5–E12.5, IL17RD was examined in the olfactory placode and in relation to GnRH neurons. Expression was FGF8-dependent and supports a role in early GnRH ontogeny, but localization is not itself proof that a patient allele causes migratory failure. (miraoui2013mutationsinfgf17 pages 7-10, miraoui2013mutationsinfgf17 pages 4-6)
  • Mouse knockout: Sef/Il17rd-null mice have comparatively mild gross developmental findings but abnormal auditory-brainstem responses, supporting the human hearing phenotype. They do not fully reproduce the human reproductive syndrome, indicating redundancy and species/context dependence. (pande2021interleukin17receptord pages 2-4)
  • Zebrafish/frog/chick systems: overexpression and loss-of-function studies establish IL17RD as an FGF-feedback regulator during morphogenesis. These models are useful for signaling, developmental patterning, and variant assays but do not recapitulate the full human HPG axis. (pande2021interleukin17receptord pages 1-2)
  • Cellular models: HEK293/HEK293T, NIH3T3, PC12, mouse embryonic fibroblasts, macrophages, and keratinocytes have been used to study FGFR, ERK, AKT, JNK, p38, IL-17, TLR, and NF-κB regulation. The HH18 discovery study’s FGF8–FGFR1c/AP-1 assay provides the most direct patient-variant functional evidence. Major limitations are non-neuronal cellular context, overexpression, isoform differences, and incomplete correspondence to embryonic human GnRH neurons. (pande2021interleukin17receptord pages 4-6, pande2021interleukin17receptord pages 6-8, miraoui2013mutationsinfgf17 pages 6-7)

Recent developments and expert assessment

Three developments are most relevant. First, the 2023 NHS-oriented review moved CHH testing toward curated multigene panels and explicitly included IL17RD, while stressing incomplete penetrance and oligogenicity. Second, the 2024 international reversal study showed that detailed phenotype plus genotype can identify patients warranting trials off treatment and continued surveillance, although no IL17RD-specific predictor emerged. Third, the 2024 meta-analysis supplied the strongest quantitative synthesis for gonadotropin-based male pubertal and fertility induction, favoring hCG+FSH over hCG alone while calling for standardized protocols and randomized trials. (dwyer2024classesandpredictors pages 6-8, alexander2024gonadotropinsforpubertal pages 1-2, sayed2023paneltestingfor pages 1-2)

The principal expert conclusion is therefore cautious: HH18 is a credible IL17RD/FGF-network disorder supported by human segregation, functional assays, and developmental-model evidence, but its gene–disease relationship is more complex than a fully penetrant single-gene syndrome. Rare missense alleles—especially VUSs—require segregation, population-frequency assessment, phenotype concordance, and preferably functional evidence. Clinical management should follow comprehensive CHH practice rather than depend on IL17RD genotype. (miraoui2013mutationsinfgf17 pages 7-10, cannarella2023geneticanalysisof pages 5-8, pande2021interleukin17receptord pages 12-13)

Key primary and recent sources

  1. Miraoui H, et al. “Mutations in FGF17, IL17RD, DUSP6, SPRY4, and FLRT3…” American Journal of Human Genetics. Published May 2013. PMID: 23643382. https://doi.org/10.1016/j.ajhg.2013.04.008. (miraoui2013mutationsinfgf17 pages 7-10)
  2. Cannarella R, et al. “Genetic Analysis of Patients with Congenital Hypogonadotropic Hypogonadism: A Case Series.” International Journal of Molecular Sciences. Published April 2023. https://doi.org/10.3390/ijms24087428. (cannarella2023geneticanalysisof pages 5-8)
  3. Al Sayed Y, Howard SR. “Panel testing for the molecular genetic diagnosis of congenital hypogonadotropic hypogonadism.” European Journal of Human Genetics. 2023;31:387–394. https://doi.org/10.1038/s41431-022-01261-0. (sayed2023paneltestingfor pages 3-5)
  4. Dwyer AA, et al. “Classes and predictors of reversal…” Lancet Diabetes & Endocrinology. Published April 2024. https://doi.org/10.1016/S2213-8587(24)00028-7. (dwyer2024classesandpredictors pages 6-8)
  5. Alexander EC, et al. “Gonadotropins for pubertal induction in males…” European Journal of Endocrinology. Published 2024. https://doi.org/10.1093/ejendo/lvad166. (alexander2024gonadotropinsforpubertal pages 1-2)
  6. Young J, et al. “Clinical Management of Congenital Hypogonadotropic Hypogonadism.” Endocrine Reviews. Published April 2019. https://doi.org/10.1210/er.2018-00116. (young2019clinicalmanagementof pages 17-18)

Major unresolved gaps: no reliable HH18 prevalence or penetrance; no prospective natural-history cohort; no female-specific HH18 series; incomplete ClinVar/ACMG functional resolution for many alleles; no validated molecular biomarker; no IL17RD-specific treatment trial; and no human GnRH-neuron single-cell, spatial, organoid, or multi-omics model demonstrating the complete causal chain.

References

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Artifacts

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome Count
References checked 17
Resolved 17
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 17
On topic 5
Off topic 0

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome Count
Terms checked 47
Resolved 44
Unresolved (possible confabulation) 1
Obsolete 0
Unverifiable 2
Terms whose name was checked 7
Terms named correctly 5
Terms named as a different term 0
Terms whose name is worth a second look 2

Unresolved terms

These identifiers do not exist in an ontology that resolved other terms from the same prefix, so they were most likely invented:

  • HP:0000806 (1 mention) - HP does not contain this term

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

  • GO:0008543 (2 mentions) - the report calls it "FGF receptor signaling", "fibroblast growth factor receptor signaling pathway"; GO calls it fibroblast growth factor receptor signaling pathway, and lists "FGF receptor signaling pathway" among its other names
  • GO:0050900 (1 mention) - the report calls it "leukocyte migration; only for immune studies"; GO calls it leukocyte migration

Terms named inconsistently

The report gives these identifiers more than one name of its own:

  • GO:0008543 - called "FGF receptor signaling", "fibroblast growth factor receptor signaling pathway"