Hypogonadotropic hypogonadism 24 without anosmia

Summary

Hypogonadotropic hypogonadism 24 without anosmia (MONDO:0009239) is a disease caused by FSHB (GenCC Strong), with 2 cohort genes.

At a glance

• Prevalence: Unknown (Worldwide)
• Causal gene: FSHB (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 31
• Phenotypes (HPO): 22

Clinical features

Signs & symptoms

Clinical features (HPO)

22 HPO clinical features (Orphanet curated; top 22 by frequency):

HPO ID	Term	Frequency
HP:0000026	Male hypogonadism	Obligate (100%)
HP:0000134	Female hypogonadism	Obligate (100%)
HP:0008213	Gonadotropin deficiency	Obligate (100%)
HP:0000044	Hypogonadotropic hypogonadism	Very frequent (80-99%)
HP:0000786	Primary amenorrhea	Very frequent (80-99%)
HP:0000823	Delayed puberty	Very frequent (80-99%)
HP:0002215	Sparse axillary hair	Very frequent (80-99%)
HP:0002225	Sparse pubic hair	Very frequent (80-99%)
HP:0002750	Delayed skeletal maturation	Very frequent (80-99%)
HP:0008214	Decreased serum estradiol	Very frequent (80-99%)
HP:0008734	Decreased testicular size	Very frequent (80-99%)
HP:0012569	Delayed menarche	Very frequent (80-99%)
HP:0040171	Decreased serum testosterone concentration	Very frequent (80-99%)
HP:0000027	Azoospermia	Frequent (30-79%)
HP:0000029	Testicular atrophy	Frequent (30-79%)
HP:0000798	Oligozoospermia	Frequent (30-79%)
HP:0000876	Oligomenorrhea	Frequent (30-79%)
HP:0010791	Hyperplasia of the Leydig cells	Frequent (30-79%)
HP:0012814	Bilateral breast hypoplasia	Frequent (30-79%)
HP:0012864	Abnormal sperm morphology	Frequent (30-79%)
HP:0030018	Decreased female libido	Frequent (30-79%)
HP:0000458	Anosmia	Excluded (0%)

Identifiers

Disease identifiers

Field	Value
Canonical name	hypogonadotropic hypogonadism 24 without anosmia
Mondo ID	MONDO:0009239
MeSH	C537070
OMIM	229070
Orphanet	52901
DOID	DOID:0090088
SNOMED CT	758664007
UMLS	C5574957
MedGen	1806136
GARD	0010128
Is cancer (heuristic)	no

Also known as: FSHB hypogonadotropic hypogonadism · HH24 · hypogonadotropic hypogonadism 24 without anosmia · hypogonadotropic hypogonadism caused by mutation in FSHB · isolated follicle-stimulating hormone (FSH) deficiency · isolated FSH deficiency

Data availability: 31 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › reproductive system disorder › gonadal disorder › hypogonadism › hypogonadotropic hypogonadism › hypogonadotropic hypogonadism 24 without anosmia

Related subtypes (9): hypogonadotropic hypogonadism 23 with or without anosmia, hypogonadotropic hypogonadism 10 with or without anosmia, hypogonadotropic hypogonadism 12 with or without anosmia, hypogonadotropic hypogonadism 13 with or without anosmia, congenital hypogonadotropic hypogonadism, Kallmann syndrome, hypogonadotropic hypogonadism 25 with anosmia, hypogonadotropic hypogonadism 26 with or without anosmia, hypogonadotropic hypogonadism 27 without anosmia

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

31 retrieved; paginated sample, class counts are floors:

18 uncertain significance, 4 benign, 3 pathogenic, 2 conflicting classifications of pathogenicity, 1 association, 1 pathogenic/likely pathogenic, 1 likely benign, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
16240	NM_001382289.1(FSHB):c.236_237del (p.Val79fs)	ARL14EP-DT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
16241	NM_001382289.1(FSHB):c.205T>G (p.Cys69Gly)	ARL14EP-DT	Pathogenic	no assertion criteria provided
16242	NM_001382289.1(FSHB):c.282C>A (p.Tyr94Ter)	ARL14EP-DT	Pathogenic	no assertion criteria provided
189329	NM_001382289.1(FSHB):c.298T>C (p.Cys100Arg)	ARL14EP-DT	Pathogenic	no assertion criteria provided
375419	NM_001382289.1(FSHB):c.343C>T (p.Arg115Ter)	ARL14EP-DT	Likely pathogenic	no assertion criteria provided
304276	NM_001382289.1(FSHB):c.59G>T (p.Ser20Ile)	ARL14EP-DT	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
880521	NM_001382289.1(FSHB):c.312G>A (p.Lys104=)	ARL14EP-DT	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
139460	NM_000510.2(FSHB):c.-280G>T	ARL14EP-DT	association	no assertion criteria provided
2627786	NM_001382289.1(FSHB):c.83T>C (p.Ile28Thr)	ARL14EP-DT	Uncertain significance	no assertion criteria provided
304273	NM_001382289.1(FSHB):c.-66C>G	ARL14EP-DT	Uncertain significance	criteria provided, single submitter
304274	NM_001382289.1(FSHB):c.-38+2T>C	ARL14EP-DT	Uncertain significance	criteria provided, single submitter
304275	NM_001382289.1(FSHB):c.30C>G (p.Phe10Leu)	ARL14EP-DT	Uncertain significance	criteria provided, single submitter
304277	NM_001382289.1(FSHB):c.327C>A (p.Ser109Arg)	ARL14EP-DT	Uncertain significance	criteria provided, multiple submitters, no conflicts
304278	NM_001382289.1(FSHB):c.*212T>C	ARL14EP-DT	Uncertain significance	criteria provided, single submitter
304279	NM_001382289.1(FSHB):c.*303C>A	ARL14EP-DT	Uncertain significance	criteria provided, single submitter
304282	NM_001382289.1(FSHB):c.*551G>A	ARL14EP-DT	Uncertain significance	criteria provided, single submitter
304284	NM_001382289.1(FSHB):c.*663G>C	ARL14EP-DT	Uncertain significance	criteria provided, single submitter
304285	NM_001382289.1(FSHB):c.*872C>T	ARL14EP-DT	Uncertain significance	criteria provided, single submitter
304286	NM_001382289.1(FSHB):c.*898T>C	ARL14EP-DT	Uncertain significance	criteria provided, single submitter
304288	NM_001382289.1(FSHB):c.*1009G>A	ARL14EP-DT	Uncertain significance	criteria provided, multiple submitters, no conflicts
877745	NM_001382289.1(FSHB):c.*610C>T	ARL14EP-DT	Uncertain significance	criteria provided, single submitter
878778	NM_001382289.1(FSHB):c.*841C>A	ARL14EP-DT	Uncertain significance	criteria provided, single submitter
878779	NM_001382289.1(FSHB):c.*1337G>A	ARL14EP-DT	Uncertain significance	criteria provided, single submitter
878780	NM_000510.2(FSHB):c.*1430T>C	ARL14EP-DT	Uncertain significance	criteria provided, single submitter
880520	NM_001382289.1(FSHB):c.245C>T (p.Pro82Leu)	ARL14EP-DT	Uncertain significance	criteria provided, single submitter
880522	NM_001382289.1(FSHB):c.344G>A (p.Arg115Gln)	ARL14EP-DT	Uncertain significance	criteria provided, multiple submitters, no conflicts
257061	NM_001382289.1(FSHB):c.228C>T (p.Tyr76=)	ARL14EP-DT	Benign	criteria provided, multiple submitters, no conflicts
304280	NM_001382289.1(FSHB):c.*476A>G	ARL14EP-DT	Benign	criteria provided, multiple submitters, no conflicts
304281	NM_001382289.1(FSHB):c.*520C>G	ARL14EP-DT	Benign	criteria provided, multiple submitters, no conflicts
304283	NM_001382289.1(FSHB):c.*635A>G	ARL14EP-DT	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 1 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
FSHB	Strong	Autosomal recessive	hypogonadotropic hypogonadism 24 without anosmia	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
FSHB	Orphanet:52901	Isolated follicle stimulating hormone deficiency

Cohort genes → proteins

2 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
FSHB	HGNC:3964	ENSG00000131808	P01225	Follitropin subunit beta	gencc
ARL14EP-DT	HGNC:55517	ENSG00000254532		ARL14EP divergent transcript	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
FSHB	Follitropin subunit beta	Together with the alpha chain CGA constitutes follitropin, the follicle-stimulating hormone, and provides its biological specificity to the hormone heterodimer.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Other/Unknown	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
FSHB	Other/Unknown	no		Gonadotropin_bsu, Glyco_hormone_CN, Gonadotropin_bsu_CS
ARL14EP-DT	Other/Unknown	no

Expression context

Cohort genes with no expression data: 0.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
male germ line stem cell (sensu Vertebrata) in testis	2
adenohypophysis	1
pituitary gland	1
prefrontal cortex	1
primordial germ cell in gonad	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
FSHB	52	tissue_specific	yes	adenohypophysis, pituitary gland, male germ line stem cell (sensu Vertebrata) in testis
ARL14EP-DT	99		yes	primordial germ cell in gonad, male germ line stem cell (sensu Vertebrata) in testis, prefrontal cortex

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
FSHB	1,333
ARL14EP-DT	0

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
FSHB	P01225	6

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. Enrichment computed across 2 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Glycoprotein hormones	1	951.7×	0.002	FSHB
Hormone ligand-binding receptors	1	951.7×	0.002	FSHB
G alpha (s) signalling events	1	73.2×	0.014	FSHB

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
positive regulation of steroid biosynthetic process	1	8426.0×	0.001	FSHB
follicle-stimulating hormone signaling pathway	1	5617.3×	0.001	FSHB
progesterone biosynthetic process	1	3370.4×	0.001	FSHB
Sertoli cell proliferation	1	2808.7×	0.001	FSHB
regulation of osteoclast differentiation	1	1532.0×	0.002	FSHB
positive regulation of bone resorption	1	991.3×	0.003	FSHB
female gamete generation	1	802.5×	0.003	FSHB
female pregnancy	1	210.7×	0.009	FSHB
transforming growth factor beta receptor signaling pathway	1	159.0×	0.010	FSHB
positive regulation of cell migration	1	61.7×	0.024	FSHB
positive regulation of gene expression	1	38.7×	0.032	FSHB
G protein-coupled receptor signaling pathway	1	36.2×	0.032	FSHB
spermatogenesis	1	35.2×	0.032	FSHB
positive regulation of cell population proliferation	1	33.6×	0.032	FSHB
positive regulation of transcription by RNA polymerase II	1	14.9×	0.067	FSHB

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 0 of 2 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
FSHB	0	0
ARL14EP-DT	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	FSHB, ARL14EP-DT

Undrugged target profiles

2 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
FSHB	0	—
ARL14EP-DT	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.