FLRT3-Related Hypogonadotropic Hypogonadism (HH21): Research Report

Executive assessment

Hypogonadotropic hypogonadism 21 with or without anosmia (HH21) is a catalogued congenital GnRH-deficiency disorder historically attributed to heterozygous variation in FLRT3, a neural cell-adhesion and guidance gene. Its defining clinical phenotype is congenital hypogonadotropic hypogonadism (CHH)—low sex steroids with low or inappropriately normal gonadotropins—sometimes accompanied by anosmia/hyposmia, in which case it lies within the Kallmann-syndrome spectrum.

The most important contemporary qualification is that the FLRT3–HH21 relationship remains weakly supported compared with established CHH genes. Open Targets links MONDO:0014107 to four ClinVar/EVA records, principally citing PMID 23643382, but labels the records “no assertion criteria provided”; accessible evidence did not supply exact variants, segregation, population frequencies, or variant-specific functional studies. A 2023 clinical review of the UK NHS panel framework lists FLRT3 among low/moderate-evidence genes that are not part of the 14 clinically reportable “green” genes. Accordingly, HH21 should be represented as a provisional/limited-evidence Mendelian gene–disease association, not as equivalent in validity to ANOS1, FGFR1, CHD7, GNRHR, or PROKR2 disease. (OpenTargets Search: hypogonadotropic hypogonadism 21 with or without anosmia-FLRT3, sayed2023paneltestingfor pages 1-2, sayed2023paneltestingfor pages 3-5)

The following table gives a compact evidence-grade summary.

Table: Compact assessment of FLRT3-related HH21 across identifiers, validity, clinical features, mechanism, diagnostics, management, epidemiology, and models. It distinguishes direct FLRT3 evidence from broader CHH extrapolation.

1. Disease information

Definition and identifiers

• Preferred name: hypogonadotropic hypogonadism 21 with or without anosmia.
• Synonyms: HH21; FLRT3-related hypogonadotropic hypogonadism; FLRT3-related congenital hypogonadotropic hypogonadism; FLRT3-related isolated GnRH deficiency; FLRT3-related Kallmann syndrome when olfactory dysfunction is present.
• Disease OMIM: 615271.
• MONDO: MONDO:0014107.
• Gene: FLRT3, fibronectin leucine-rich transmembrane protein 3; OMIM gene 604808; Ensembl ENSG00000125848; cytogenetic location 20p12.1. (OpenTargets Search: hypogonadotropic hypogonadism 21 with or without anosmia-FLRT3, sayed2023paneltestingfor pages 1-2, sayed2023paneltestingfor pages 3-5)
• Parent concepts: congenital/isolated hypogonadotropic hypogonadism and Kallmann syndrome. CHH is defined by deficient GnRH secretion or action, producing low gonadal steroids and deficient pituitary gonadotropin output; Kallmann syndrome denotes CHH accompanied by hyposmia or anosmia. (cho2019nasalplacodedevelopment pages 1-2, sayed2023paneltestingfor pages 1-2, topaloglu2021geneticetiologyof pages 1-3)
• Orphanet, MeSH, ICD-10 and ICD-11: no FLRT3-specific identifier was established in the retrieved evidence. Broader coding generally uses hypogonadotropic hypogonadism, other testicular/ovarian dysfunction, delayed puberty, infertility, or Kallmann syndrome concepts. A knowledge base should not invent an HH21-specific ICD or Orphanet code.

This report integrates aggregated disease-level resources, published CHH cohorts and reviews, molecular/model experiments, and clinical-trial records. It does not derive from patient EHRs. Direct FLRT3 patient-level evidence is sparse and largely traces to the 2013 report indexed as PMID 23643382 and associated ClinVar records. (OpenTargets Search: hypogonadotropic hypogonadism 21 with or without anosmia-FLRT3)

2. Etiology, risk and protective factors

Causal factor

The proposed initiating lesion is a germline FLRT3 variant, historically interpreted as autosomal dominant. However, present evidence is insufficient to state that every rare damaging FLRT3 allele is causal. CHH frequently shows incomplete penetrance, variable expressivity, and di-/oligogenic inheritance; over 40 genes are recognized as causing or contributing to CHH, and fewer than half of patients in many series receive a molecular diagnosis. (sayed2023paneltestingfor pages 1-2, millar2021geneticsofhypogonadotropic pages 1-2, topaloglu2021geneticetiologyof pages 1-3)

Open Targets also associates MACROD2 with HH21 through the same four records, but the retrieved evidence does not establish whether this reflects linkage, overlapping variation, a contiguous event, or an independent causal role. MACROD2 should therefore not be asserted as an HH21 modifier without inspecting the original cases. (OpenTargets Search: hypogonadotropic hypogonadism 21 with or without anosmia-FLRT3)

Risk factors

• Genetic: a convincingly pathogenic FLRT3 allele with phenotype concordance and segregation is the proposed risk factor. Additional CHH-gene variants could modify penetrance or severity, but no specific FLRT3 modifier pair has been validated.
• Family history: delayed/absent puberty, infertility, anosmia, micropenis, cryptorchidism, or known CHH increases suspicion.
• Sex: CHH overall is diagnosed more often in males, partly because neonatal genital signs and absent testicular enlargement are conspicuous. A 2023 review estimates a male:female ratio of approximately 3.6:1; this is not FLRT3-specific. (sayed2023paneltestingfor pages 1-2)
• Environmental/acquired: no toxin, lifestyle exposure, radiation, occupation, or infectious agent is established as a cause of FLRT3-HH21. Caloric deficit, excessive exercise, severe illness, stress, opioids, glucocorticoids, pituitary disease and iron overload can suppress the HPG axis, but these are differential causes of acquired/functional HH rather than causes of a congenital FLRT3 disorder. (abacı2024acurrentperspective pages 1-2, millar2021geneticsofhypogonadotropic pages 1-2)

Protective factors and gene–environment interaction

No genetic or environmental protective factor has been demonstrated for HH21. Healthy nutrition, adequate energy availability and avoidance of suppressive drugs may prevent superimposed functional HPG suppression but cannot correct a developmental FLRT3 lesion. A specific FLRT3-by-environment interaction has not been reported. No vaccine or infectious prophylaxis is relevant.

3. Phenotypes

Because FLRT3-specific frequencies are unavailable, the entries below are CHH-spectrum expectations, not measured HH21 penetrance estimates.

Normal puberty begins between approximately 8–13 years in girls and 9–14 years in boys. Delayed puberty is conventionally failure to initiate by age 13 or 14, respectively, or failure to complete by approximately 15–16 years in girls and 16–17 years in boys. About one-third of CHH patients may enter Tanner stage 2–3 and then arrest, illustrating that partial puberty does not exclude disease. (howard2024outcomesandexperiences pages 1-2)

Severe CHH abolishes fetal, infant “mini-puberty,” and adolescent HPG activation. A 2024 Endocrine Reviews article states that fetal deficiency manifests as micropenis and/or cryptorchidism in around 50% of affected male newborns; absent mini-puberty reduces Sertoli-cell expansion and later reproductive capacity. This percentage is disease-wide, not FLRT3-specific. (rohayem2024minipubertyphysiologicaland pages 1-2)

Quality of life

Untreated delayed puberty and hypogonadism can cause negative self-image, anxiety, depression, isolation, low energy, impaired sexual well-being, reduced bone density and infertility. Recent expert commentary emphasizes long diagnostic journeys, nonstandardized care, and adverse consequences of late or incorrect pubertal induction. No HH21-specific EQ-5D, SF-36 or PROMIS study was found. (howard2024outcomesandexperiences pages 1-2, rohayem2024minipubertyphysiologicaland pages 1-2, rohayem2024minipubertyphysiologicaland pages 10-11)

4. Genetic and molecular information

Causal gene and protein

FLRT3 encodes a type-I, single-pass plasma-membrane protein. Its extracellular portion contains ten leucine-rich repeats, cysteine-rich caps and a fibronectin type-III domain; a metalloprotease-sensitive region permits ectodomain shedding, and its short cytoplasmic tail contains conserved residues involved in Rnd-family binding and signaling. (nagel2015analysisofadhesive pages 36-41, hampel2012functionalanalysisof pages 48-52, xiaofen2019localizationandfunction pages 43-48)

Suggested annotations include GO:0005886 plasma membrane, GO:0007155 cell adhesion, GO:0007411 axon guidance, GO:0001764 neuron migration, and GO:0000165 MAPK cascade.

Pathogenic variants and classification

Four ClinVar/EVA records associated with FLRT3 and MONDO:0014107 are described as missense consequences and cite PMID 23643382. However, the retrieved records did not expose HGVS expressions, zygosity, segregation, allele frequencies, patient phenotypes or functional assays, and explicitly reported “no assertion criteria provided.” Consequently:

1. No exact FLRT3 allele can be responsibly listed here as pathogenic/likely pathogenic.
2. Population frequency in gnomAD, TOPMed, ExAC or 1000 Genomes cannot be stated without the HGVS alleles.
3. Germline origin is expected for congenital disease, but de novo versus inherited status was not recovered.
4. Loss-of-function, gain-of-function or dominant-negative action has not been established for an HH21 allele.
5. A rare FLRT3 VUS is not diagnostic on its own. (OpenTargets Search: hypogonadotropic hypogonadism 21 with or without anosmia-FLRT3)

No validated FLRT3 modifier gene, protective allele, founder mutation, germline-mosaicism series, somatic disease mechanism, repeat expansion, aneuploidy or recurrent FLRT3 structural rearrangement was identified. No disease-specific DNA methylation, histone or chromatin signature was found.

Clinical validity interpretation

The 2023 NHS-oriented review describes a 14-gene clinically reportable panel—ANOS1, CHD7, FGF8, FGFR1, FSHB, GNRHR, IL17RD, KISS1R, LHB, PROK2, PROKR2, TAC3, TACR3 and WDR11. FLRT3 appears outside this high-confidence group among genes assigned lower evidence ratings, for which variants are maintained for research rather than routinely returned. This authoritative expert appraisal is a major reason to classify HH21 cautiously. (sayed2023paneltestingfor pages 1-2, sayed2023paneltestingfor pages 3-5)

5. Environmental information

No environmental, lifestyle or infectious trigger is known for FLRT3-HH21. Environmental and behavioral factors are clinically important mainly because functional hypothalamic suppression from malnutrition, intense exercise, psychosocial stress, chronic disease or medications can phenocopy or compound CHH. Endocrine-disrupting chemicals affect pubertal timing generally, but no FLRT3-specific interaction has been demonstrated. (abacı2024acurrentperspective pages 1-2)

6. Mechanism and pathophysiology

Ordered causal chain

1. A putatively damaging germline FLRT3 variant leads to altered FLRT3 abundance, structure or signaling—the molecular consequence of actual HH21 variants remains unproven.
2. Altered FLRT3 leads to disturbed balance between homophilic cell adhesion and FLRT–UNC5-mediated repulsion, and may alter Rnd/cadherin trafficking and FGF–ERK/MAPK signaling; these functions are demonstrated in cellular and animal developmental systems. (nagel2015analysisofadhesive pages 36-41, hampel2012functionalanalysisof pages 48-52)
3. Disturbed adhesion/guidance leads to abnormal neuronal migration or axon organization; this is demonstrated for cortical populations, but its extension to human GnRH and olfactory lineages is inferred. (fleitas2021flrt2andflrt3 pages 1-2, nagel2015analysisofadhesive pages 86-92)
4. Inferred branch A: abnormal olfactory development leads to hyposmia/anosmia and possible olfactory bulb/sulcus hypoplasia.
5. Inferred branch B: impaired migration, positioning or connectivity of embryonic GnRH neurons leads to deficient hypothalamic pulsatile GnRH release. Normal GnRH neurons originate in the nasal placode and migrate along olfactory-derived/terminal-nerve pathways into the forebrain and hypothalamus. (cho2019nasalplacodedevelopment pages 1-2, millar2021geneticsofhypogonadotropic pages 1-2)
6. GnRH deficiency leads to low or inappropriately normal LH and FSH, while other pituitary axes are generally preserved.
7. Low LH/FSH leads to deficient fetal, mini-pubertal and adolescent gonadal steroidogenesis and impaired Sertoli/granulosa support.
8. Sex-steroid and gonadal maturation failure results in micropenis/cryptorchidism in severe males, delayed or arrested puberty, amenorrhea or impaired virilization, reduced bone accrual and infertility. (sayed2023paneltestingfor pages 1-2, rohayem2024minipubertyphysiologicaland pages 1-2)

Molecular and cellular detail

FLRT3 can mediate calcium-dependent homophilic adhesion, bind UNC5-family receptors through its LRR region, and after ectodomain shedding act as a chemorepellent. Model experiments also connect FLRT3 to FGFR1/ERK1/2 signaling and to Rnd1-dependent cadherin internalization. FLRT3 overexpression inhibits cortical radial migration, while disrupting homophilic binding or deleting its intracellular domain partially rescues migration. Double deletion of Flrt2/Flrt3 in mouse embryos disrupts cortical interneuron streams; UNC5B/UNC5D mutants show related defects, and FLRT proteins repel developing interneurons in vitro. (fleitas2021flrt2andflrt3 pages 1-2, nagel2015analysisofadhesive pages 86-92, nagel2015analysisofadhesive pages 104-108, hampel2012functionalanalysisof pages 48-52)

These findings establish FLRT3 as a credible developmental guidance molecule but do not demonstrate an HH21 variant disrupting GnRH neurons. Moreover, nervous-system-specific Flrt3 ablation did not produce gross brain, cortical-layer or major tract abnormalities in some analyses, suggesting redundancy, subtle phenotypes, or context dependence. (hampel2012functionalanalysisof pages 108-111)

Suggested process terms: GO:0001764 neuron migration; GO:0007411 axon guidance; GO:0007155 cell adhesion; GO:0023052 signaling; GO:0000165 MAPK cascade; GO:0030154 cell differentiation; GO:0050804 modulation of chemical synaptic transmission. Suggested cell terms include CL:0000540 neuron, CL:0000099 interneuron, CL:0000122 GnRH neuron if available in the target ontology, CL:0000163 endocrine cell, pituitary gonadotroph, Leydig cell, Sertoli cell, granulosa cell, and olfactory sensory neuron.

No disease-specific inflammatory, autoimmune, oxidative, ischemic, fibrotic, necrotic, mitochondrial, metabolic, proteostatic or ion-channel mechanism is supported. Likewise, no HH21-specific transcriptomic, single-cell, spatial, proteomic, metabolomic, lipidomic, epigenomic, organoid, iPSC, multi-omic or CRISPR-screen dataset was identified.

7. Anatomical structures affected

• Primary developmental system: nasal/olfactory placode and GnRH migratory route; suggested UBERON:0000004 nose, olfactory epithelium, terminal nerve and cribriform region.
• Central nervous system: olfactory bulb (UBERON:0002264), forebrain, preoptic area, arcuate region and hypothalamus (UBERON:0001898).
• Endocrine relay: anterior pituitary (UBERON:0000007) gonadotrophs; usually structurally normal in isolated CHH.
• Secondary target organs: testis (UBERON:0000473), ovary (UBERON:0000992), uterus, external genitalia and skeleton.
• Subcellular: plasma membrane, shed extracellular ectodomain, cytoplasmic signaling/trafficking machinery; suggested GO:0005886, GO:0005576 extracellular region, GO:0031982 vesicle.

No consistent lateralization is known. Cryptorchidism may be unilateral or bilateral, and olfactory bulb abnormalities may vary, but this is not FLRT3-specific. (cho2019nasalplacodedevelopment pages 1-2, millar2021geneticsofhypogonadotropic pages 1-2)

8. Temporal development

The initiating defect is presumed embryonic, during olfactory/GnRH system development. In males with severe deficiency, fetal signs include micropenis or undescended testes, and absence of postnatal mini-puberty accentuates testicular immaturity. Most patients are recognized in adolescence because puberty fails to begin or arrests; some are first diagnosed in adulthood during infertility evaluation or after reduced libido, energy or bone density. (sayed2023paneltestingfor pages 1-2, rohayem2024minipubertyphysiologicaland pages 1-2)

Untreated disease is chronic. Sex-steroid replacement induces secondary sexual characteristics but does not prove recovery of endogenous GnRH function. CHH overall shows reversal in approximately 10–20%, and relapse may occur; there are no FLRT3-specific reversal data. (topaloglu2021geneticetiologyof pages 1-3, kulvinder2016idiopathichypogonadotropichypogonadism— pages 12-14)

Critical intervention windows are infancy for recognition of mini-puberty failure and cryptorchidism, normal pubertal age for physiological induction and psychosocial/bone health, and reproductive adulthood for fertility induction. (howard2024outcomesandexperiences pages 1-2, rohayem2024minipubertyphysiologicaland pages 1-2)

9. Inheritance and population

HH21 has historically been represented as autosomal dominant, but penetrance, expressivity and monogenic sufficiency are not adequately quantified. CHH in general can be autosomal dominant, autosomal recessive, X-linked or oligogenic, with incomplete penetrance and variable expression. Oligogenic estimates vary widely—from older estimates around 10–20% to as high as 70% in selected sequencing studies—reflecting cohort and classification differences. (sayed2023paneltestingfor pages 1-2, topaloglu2021geneticetiologyof pages 1-3)

No HH21-specific prevalence, incidence, carrier frequency, founder effect, ancestry enrichment, geographic distribution, consanguinity effect or sex ratio is available. For context only, CHH overall has an estimated incidence of approximately 1:15,000–50,000 and male:female ratio near 3.6:1. Finnish estimates for Kallmann syndrome are approximately 1:30,000 males and 1:125,000 females; a 2024 review stresses that no definitive epidemiological investigation exists. (sayed2023paneltestingfor pages 1-2, abacı2024acurrentperspective pages 1-2, millar2021geneticsofhypogonadotropic pages 1-2)

No anticipation or established germline mosaicism has been reported.

10. Diagnostics

Clinical and laboratory approach

1. Document growth, Tanner stage, testicular volume, genital development, menstrual history, libido, fertility and family history.
2. Seek red flags: micropenis, bilateral cryptorchidism, anosmia/hyposmia, cleft palate, hearing loss, dental agenesis, renal anomalies, synkinesia or broader neurodevelopmental findings. These associated anomalies may point toward alternative CHH genes. (howard2024outcomesandexperiences pages 1-2, millar2021geneticsofhypogonadotropic pages 1-2)
3. Measure morning testosterone in males or estradiol in females with LH and FSH. CHH shows low steroids with low/inappropriately normal gonadotropins.
4. Assess prolactin, thyroid function, cortisol/ACTH and IGF-1 as indicated to exclude combined pituitary disease; add ferritin/iron studies and general tests for chronic illness.
5. Inhibin B and AMH can support severe gonadotropin deficiency, but neither reliably distinguishes CHH from self-limited delayed puberty. GnRH, hCG and other stimulation tests have limited discriminatory power. (howard2024outcomesandexperiences pages 1-2, sayed2023paneltestingfor pages 1-2, vezzoli2023geneticarchitectureof pages 2-3)
6. Perform standardized olfactory testing rather than relying only on self-report.
7. Obtain MRI of the hypothalamic-pituitary region when acquired/structural disease is possible and evaluate olfactory bulbs/sulci when Kallmann syndrome is suspected.
8. Semen analysis assesses adult male fertility; pelvic ultrasound can assess uterine/ovarian maturation; bone-age radiography and DXA may quantify maturational delay and skeletal morbidity.

Genetic testing

A comprehensive CHH/Kallmann multigene panel with deletion/duplication analysis is preferable to FLRT3-only testing. WES or WGS is appropriate for panel-negative, syndromic, atypical or familial cases; genome sequencing can improve detection of structural and noncoding variants. CHH’s oligogenic architecture requires analysis beyond one candidate gene. (sayed2023paneltestingfor pages 1-2, millar2021geneticsofhypogonadotropic pages 1-2, topaloglu2021geneticetiologyof pages 1-3)

For a candidate FLRT3 finding:

• confirm by an orthogonal method;
• review transcript and HGVS nomenclature;
• assess gnomAD/TOPMed frequency and regional constraint;
• perform parental and extended-family segregation;
• search for pathogenic variants/CNVs in established CHH genes;
• classify using ACMG/AMP criteria without treating phenotype match or OMIM inclusion as sufficient evidence;
• retain as VUS where functional/segregation evidence is inadequate.

CMA, karyotype and FISH are not first-line for isolated HH21 but are appropriate for multiple congenital anomalies or suspected chromosomal disease. Mitochondrial and repeat-expansion testing are not routinely indicated. No validated RNA-seq, proteomic, metabolomic, methylation or liquid-biopsy diagnostic exists.

Differential diagnosis

Key alternatives are self-limited delayed puberty; functional hypothalamic suppression; pituitary/hypothalamic tumor or infiltrative disease; hyperprolactinemia; hemochromatosis; medication-induced HH; combined pituitary hormone deficiency; CHARGE and other syndromic CHH; primary gonadal failure, which instead raises LH/FSH; and other established monogenic CHH forms. CDGP accounts for approximately 60% of delayed puberty in boys and 30% in girls in a 2024 review, making longitudinal assessment and genetic interpretation important. (abacı2024acurrentperspective pages 1-2)

Screening

HH21 is not included in newborn population screening. Targeted early evaluation is justified in male infants with micropenis and/or bilateral cryptorchidism and in relatives of a person with a convincingly pathogenic familial variant. Cascade testing should not be predictive when the familial allele remains a VUS.

11. Outcome and prognosis

CHH is generally compatible with normal life expectancy, and no disease-specific mortality signal is established. No HH21 survival, mortality or life-expectancy cohort exists. Major morbidity arises from absent puberty, infertility, sexual dysfunction, low bone density, unfavorable body composition and psychosocial distress. (rohayem2024minipubertyphysiologicaland pages 1-2, rohayem2024minipubertyphysiologicaland pages 10-11)

Sex-steroid replacement usually induces and maintains secondary sexual characteristics. Fertility is often achievable because the gonads can respond to GnRH or gonadotropins; the 2023 clinical review reports restoration in approximately 75% of treated CHH patients overall. Poorer male fertility predictors include cryptorchidism, very small pretreatment testes, absent prior sexual maturation and low inhibin B. (sayed2023paneltestingfor pages 1-2, kulvinder2016idiopathichypogonadotropichypogonadism— pages 12-14)

Endogenous HPG recovery occurs in a minority and can relapse, so supervised treatment withdrawal and lifelong reassessment are appropriate. No FLRT3 genotype-specific prognostic biomarker exists. (topaloglu2021geneticetiologyof pages 1-3, kulvinder2016idiopathichypogonadotropichypogonadism— pages 12-14)

12. Treatment and current implementation

No treatment targets FLRT3 itself; management follows CHH/Kallmann practice.

Puberty and maintenance

• Males: gradually escalating testosterone induces virilization, penile growth, muscle mass, bone accrual, libido and sexual function. Suggested NCIT concept: Testosterone (NCIT:C2300). Testosterone does not induce spermatogenesis and suppresses intratesticular gonadotropin-dependent function.
• Females: low-dose estradiol, slowly escalated, induces breast and uterine development; cyclic progesterone is added after adequate estrogenization or breakthrough bleeding. Suggested terms: Estradiol (NCIT:C483) and Progesterone (NCIT:C2302). (abacı2024acurrentperspective pages 1-2, rohayem2024minipubertyphysiologicaland pages 10-11)
• Monitor growth and bone age during induction, clinical pubertal progression, testosterone/estradiol, hematocrit and prostate-related parameters where age-appropriate, blood pressure/metabolic health, menstrual response, bone density, adherence and psychosocial well-being.

Fertility induction

• Pulsatile GnRH can restore physiological LH/FSH secretion when pituitary gonadotroph function is intact; suggested NCIT:C614.
• Men: hCG, commonly combined sequentially or concurrently with recombinant FSH, stimulates Leydig-cell testosterone production and Sertoli-cell/spermatogenic maturation; suggested NCIT:C644 and NCIT:C717. FSH priming may help men with severe CHH and very small testes. (millar2021geneticsofhypogonadotropic pages 1-2, rohayem2024minipubertyphysiologicaland pages 19-20, NCT00064987 chunk 2)
• Women: pulsatile GnRH or exogenous gonadotropins can induce follicular maturation and ovulation, with ultrasound and estradiol monitoring to limit multiple pregnancy and ovarian hyperstimulation.

Disease-wide trials include NCT00064987 (FSH pretreatment before GnRH-induced fertility), NCT02880280 (hMG plus hCG), NCT01403532 (sequential therapy), NCT03687606 (long-term hCG versus hCG+hMG), and NCT00392756 (IHH/Kallmann natural-history/interventional program). None is FLRT3-stratified. (NCT00392756 chunk 3, NCT00064987 chunk 2)

Infancy and surgery

Short-course low-dose testosterone or topical DHT can treat micropenis but does not expand Sertoli cells or promote testicular descent. Physiological gonadotropin replacement during mini-puberty may increase penile and testicular size and support descent, but evidence comes from small case series; 2022 Endo-ERN guidance did not recommend routine use, and long-term fertility benefit remains uncertain. Reported adverse effects include injection pain, irritation, scarring, lipohypertrophy, rare abscess/blistering, gynecomastia, increased estradiol and rare anti-hCG antibodies. (rohayem2024minipubertyphysiologicaland pages 19-20, rohayem2024minipubertyphysiologicaland pages 22-23)

Orchidopexy is recommended at approximately 6–12 months for congenital cryptorchidism. Disease-wide data cited in the 2024 review indicate roughly 90% surgical success and approximately 2% testicular atrophy; hormonal descent produces only about 15% final success after re-ascent. Suggested intervention term: NCIT:C15218 Orchidopexy. (rohayem2024minipubertyphysiologicaland pages 19-20)

Advanced and experimental therapy

No FLRT3-directed small molecule, gene replacement/editing, ASO, siRNA, mRNA, cell therapy, immunotherapy or validated pharmacogenomic algorithm exists. Kisspeptin and neurokinin-B biology is an active reproductive-neuroendocrine research area, but there is no evidence that these approaches correct a developmental FLRT3 lesion.

13. Prevention

Primary prevention of a de novo or inherited developmental allele is not possible through lifestyle or vaccination. Appropriate measures are:

• Secondary prevention: early recognition of micropenis, bilateral cryptorchidism, anosmia and pubertal arrest; timely endocrine referral; family cascade evaluation for a proven pathogenic allele.
• Tertiary prevention: timely physiological puberty induction, bone-health monitoring, fertility-preserving treatment, orchidopexy, and psychological/sexual-health support.
• Reproductive counseling: discuss uncertain penetrance and gene validity; once a familial pathogenic allele is firmly established, prenatal diagnosis or PGT-M may be technically possible. These options should not be based on an unresolved VUS.

No population carrier screening, newborn biochemical screening, public-health environmental intervention or prophylactic medication is indicated.

14. Other species and natural disease

The principal comparative species is Mus musculus, NCBI Taxon 10090, carrying the ortholog Flrt3. No naturally occurring veterinary syndrome equivalent to FLRT3-HH21 was identified, and no breed-specific VBO association is established. There is no infectious transmission, zoonotic potential or cross-species contagion.

FLRT adhesion/guidance biology is evolutionarily conserved and has also been studied in Xenopus embryos and cultured mammalian cells. These systems illuminate morphogenesis and signaling but do not constitute natural HH21 disease. (nagel2015analysisofadhesive pages 36-41, hampel2012functionalanalysisof pages 48-52)

15. Model organisms

Available systems

• Conventional Flrt3-null mouse: early morphogenetic defects, including ventral closure/headfold and endoderm abnormalities, with embryonic lethality around E10.5; useful for morphogenesis but poorly suited to postnatal reproductive phenotyping. (nagel2015analysisofadhesive pages 36-41, hampel2012functionalanalysisof pages 48-52)
• Conditional nervous-system Flrt3 deletion: no gross brain, cortical-layer or major tract defect in reported analyses, suggesting subtle functions or redundancy. (hampel2012functionalanalysisof pages 108-111)
• Flrt2/Flrt3 double conditional deletion: abnormal cortical interneuron-stream distribution and altered postnatal somatostatin-interneuron layering; mechanistically linked to UNC5-dependent repulsion. This is direct neuronal-migration evidence, not a GnRH model. (fleitas2021flrt2andflrt3 pages 1-2)
• Embryonic cortical electroporation/overexpression: FLRT3 overexpression retains neurons in the intermediate zone; homophilic-binding and intracellular-domain mutants partly rescue migration. (nagel2015analysisofadhesive pages 86-92, nagel2015analysisofadhesive pages 104-108)
• Cell, neuronal-culture and Xenopus assays: useful for FLRT3–FGFR1, FLRT3–UNC5, Rnd/cadherin, adhesion, ectodomain shedding, repulsion and neurite studies. (nagel2015analysisofadhesive pages 36-41, hampel2012functionalanalysisof pages 48-52, xiaofen2019localizationandfunction pages 43-48)

Limitations and priority models

No existing model was shown to reproduce the combined human endpoints of GnRH deficiency, absent puberty/infertility and optional anosmia. Priority experiments are patient-variant knock-in mice with GnRH-neuron counts, migration mapping, olfactory testing, LH pulsatility and fertility phenotyping; nasal-placode/GnRH lineage organoids; and isogenic iPSC models with rescue by wild-type FLRT3. These would directly test whether reported human alleles are loss-of-function, altered adhesion/repulsion, or incidental variants.

Recent developments and evidence gaps

1. Clinical genetics, 2023: UK NHS implementation demonstrates the move from broad candidate lists toward evidence-curated reportable panels. FLRT3’s exclusion from the 14 “green” genes highlights its unresolved clinical validity. DOI: https://doi.org/10.1038/s41431-022-01261-0; published online 15 December 2022, journal issue 2023. The abstract states: “The genetic complexity of CHH is further increased by the observation of di- and oligogenic, as well as classic monogenic, inheritance and incomplete penetrance.” (sayed2023paneltestingfor pages 1-2, sayed2023paneltestingfor pages 3-5)
2. Mini-puberty, 2024: a major Endocrine Reviews synthesis identifies infancy as a diagnostic and potential therapeutic window but emphasizes limited evidence and uncertain long-term fertility benefit. DOI: https://doi.org/10.1210/endrev/bnae003; typeset 4 March 2024. Its essential points state that CHH disrupts mini-puberty, “resulting in testicular immaturity.” (rohayem2024minipubertyphysiologicaland pages 1-2, rohayem2024minipubertyphysiologicaland pages 22-23)
3. Delayed-puberty management, 2024: current reviews favor more physiological hCG/FSH or pulsatile-GnRH strategies where fertility is a goal but acknowledge absence of consensus on protocols and long-term outcomes. DOI: https://doi.org/10.4274/jcrpe.galenos.2024.2024-2-7; epub 5 April 2024. (abacı2024acurrentperspective pages 1-2)
4. FLRT biology: mouse and in-vitro work confirms FLRT2/3–UNC5 control of developmental neuronal migration. The primary 2021 study states that FLRT proteins are “chemorepellent ligands for developing interneurons in vitro,” partly dependent on FLRT–UNC5 interaction. DOI: https://doi.org/10.1523/JNEUROSCI.0380-20.2021. (fleitas2021flrt2andflrt3 pages 1-2)
5. Unmet need: no independently replicated 2023–2024 FLRT3-HH21 cohort, variant-specific GnRH assay, reproductive animal model, prevalence estimate, natural-history study or targeted therapy was found. The highest-priority research task is rigorous re-evaluation of the original PMID 23643382 alleles under current ACMG/AMP and gene-validity standards.

Knowledge-base recommendation

Represent MONDO:0014107 / OMIM 615271 as a catalogued, ultra-rare CHH entity with limited/provisional FLRT3 causality. Store CHH clinical features as expected spectrum annotations with evidence qualifiers rather than FLRT3-specific frequencies. Do not label an FLRT3 allele pathogenic without current variant-level evidence, segregation, rarity and functional support. Treatment and prognosis should be inherited from the broader CHH/Kallmann clinical model, explicitly noting the absence of genotype-specific evidence.

References

1. (OpenTargets Search: hypogonadotropic hypogonadism 21 with or without anosmia-FLRT3): Open Targets Query (hypogonadotropic hypogonadism 21 with or without anosmia-FLRT3, 4 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.

2. (sayed2023paneltestingfor pages 1-2): Yasmin Al Sayed and Sasha R. Howard. Panel testing for the molecular genetic diagnosis of congenital hypogonadotropic hypogonadism – a clinical perspective. European Journal of Human Genetics, 31(4):387-394, Dec 2023. URL: https://doi.org/10.1038/s41431-022-01261-0, doi:10.1038/s41431-022-01261-0. This article has 39 citations and is from a domain leading peer-reviewed journal.

3. (sayed2023paneltestingfor pages 3-5): Yasmin Al Sayed and Sasha R. Howard. Panel testing for the molecular genetic diagnosis of congenital hypogonadotropic hypogonadism – a clinical perspective. European Journal of Human Genetics, 31(4):387-394, Dec 2023. URL: https://doi.org/10.1038/s41431-022-01261-0, doi:10.1038/s41431-022-01261-0. This article has 39 citations and is from a domain leading peer-reviewed journal.

4. (howard2024outcomesandexperiences pages 1-2): Sasha R. Howard and Richard Quinton. Outcomes and experiences of adults with congenital hypogonadism can inform improvements in the management of delayed puberty. Journal of Pediatric Endocrinology and Metabolism, 37:1-7, Nov 2024. URL: https://doi.org/10.1515/jpem-2023-0407, doi:10.1515/jpem-2023-0407. This article has 11 citations and is from a peer-reviewed journal.

5. (rohayem2024minipubertyphysiologicaland pages 1-2): Julia Rohayem, Emma C Alexander, Sabine Heger, Anna Nordenström, and Sasha R Howard. Mini-puberty, physiological and disordered: consequences, and potential for therapeutic replacement. Endocrine Reviews, 45:460-492, Mar 2024. URL: https://doi.org/10.1210/endrev/bnae003, doi:10.1210/endrev/bnae003. This article has 135 citations and is from a domain leading peer-reviewed journal.

6. (topaloglu2021geneticetiologyof pages 1-3): Ali Kemal Topaloglu and Ihsan Turan. Genetic etiology of idiopathic hypogonadotropic hypogonadism. Endocrines, 3:1-15, Dec 2021. URL: https://doi.org/10.3390/endocrines3010001, doi:10.3390/endocrines3010001. This article has 12 citations.

7. (nagel2015analysisofadhesive pages 36-41): Analysis of adhesive and repulsive functions of FLRT proteins in central nervous system development This article has 0 citations.

8. (hampel2012functionalanalysisof pages 48-52): Functional analysis of FLRT proteins in nervous system development This article has 1 citations.

9. (xiaofen2019localizationandfunction pages 43-48): Li Xiaofen and Hyosun Park. Localization and function of tmc1, lhfpl5 and flrt3 in mammalian auditory hair cells. ArXiv, 2019. URL: https://doi.org/10.14711/thesis-991012753255603412, doi:10.14711/thesis-991012753255603412. This article has 0 citations.

10. (cho2019nasalplacodedevelopment pages 1-2): Hyun-Ju Cho, Yufei Shan, Niteace C. Whittington, and Susan Wray. Nasal placode development, gnrh neuronal migration and kallmann syndrome. Frontiers in Cell and Developmental Biology, Jul 2019. URL: https://doi.org/10.3389/fcell.2019.00121, doi:10.3389/fcell.2019.00121. This article has 96 citations.

11. (millar2021geneticsofhypogonadotropic pages 1-2): Adam C. Millar, Hanna Faghfoury, and Jared M. Bieniek. Genetics of hypogonadotropic hypogonadism. Mar 2021. URL: https://doi.org/10.21037/tau.2020.03.33, doi:10.21037/tau.2020.03.33. This article has 43 citations and is from a peer-reviewed journal.

12. (rohayem2024minipubertyphysiologicaland pages 19-20): Julia Rohayem, Emma C Alexander, Sabine Heger, Anna Nordenström, and Sasha R Howard. Mini-puberty, physiological and disordered: consequences, and potential for therapeutic replacement. Endocrine Reviews, 45:460-492, Mar 2024. URL: https://doi.org/10.1210/endrev/bnae003, doi:10.1210/endrev/bnae003. This article has 135 citations and is from a domain leading peer-reviewed journal.

13. (rohayem2024minipubertyphysiologicaland pages 22-23): Julia Rohayem, Emma C Alexander, Sabine Heger, Anna Nordenström, and Sasha R Howard. Mini-puberty, physiological and disordered: consequences, and potential for therapeutic replacement. Endocrine Reviews, 45:460-492, Mar 2024. URL: https://doi.org/10.1210/endrev/bnae003, doi:10.1210/endrev/bnae003. This article has 135 citations and is from a domain leading peer-reviewed journal.

14. (rohayem2024minipubertyphysiologicaland pages 10-11): Julia Rohayem, Emma C Alexander, Sabine Heger, Anna Nordenström, and Sasha R Howard. Mini-puberty, physiological and disordered: consequences, and potential for therapeutic replacement. Endocrine Reviews, 45:460-492, Mar 2024. URL: https://doi.org/10.1210/endrev/bnae003, doi:10.1210/endrev/bnae003. This article has 135 citations and is from a domain leading peer-reviewed journal.

15. (abacı2024acurrentperspective pages 1-2): A. Abacı and Ö. Besci. A current perspective on delayed puberty and its management. Journal of Clinical Research in Pediatric Endocrinology, 16:379-400, Apr 2024. URL: https://doi.org/10.4274/jcrpe.galenos.2024.2024-2-7, doi:10.4274/jcrpe.galenos.2024.2024-2-7. This article has 17 citations.

16. (fleitas2021flrt2andflrt3 pages 1-2): Catherine Fleitas, Pau Marfull-Oromí, Disha Chauhan, Daniel del Toro, Blanca Peguera, Bahira Zammou, Daniel Rocandio, Rüdiger Klein, Carme Espinet, and Joaquim Egea. Flrt2 and flrt3 cooperate in maintaining the tangential migratory streams of cortical interneurons during development. Jul 2021. URL: https://doi.org/10.1523/jneurosci.0380-20.2021, doi:10.1523/jneurosci.0380-20.2021. This article has 19 citations.

17. (hampel2012functionalanalysisof pages 108-111): Functional analysis of FLRT proteins in nervous system development This article has 1 citations.

18. (nagel2015analysisofadhesive pages 86-92): Analysis of adhesive and repulsive functions of FLRT proteins in central nervous system development This article has 0 citations.

19. (nagel2015analysisofadhesive pages 104-108): Analysis of adhesive and repulsive functions of FLRT proteins in central nervous system development This article has 0 citations.

20. (kulvinder2016idiopathichypogonadotropichypogonadism— pages 12-14): Idiopathic Hypogonadotropic Hypogonadism— An Update on the Aetiopathogenesis, Management of IHH in Both Males and Females—An Exhaustive Review This article has 7 citations.

21. (vezzoli2023geneticarchitectureof pages 2-3): Valeria Vezzoli, Faris Hrvat, Giovanni Goggi, Silvia Federici, Biagio Cangiano, Richard Quinton, Luca Persani, and Marco Bonomi. Genetic architecture of self-limited delayed puberty and congenital hypogonadotropic hypogonadism. Frontiers in Endocrinology, Jan 2023. URL: https://doi.org/10.3389/fendo.2022.1069741, doi:10.3389/fendo.2022.1069741. This article has 27 citations.

22. (NCT00064987 chunk 2): William Crowley. Follicle Stimulating Hormone (FSH) to Improve Testicular Development in Men With Hypogonadism. Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD). 2001. ClinicalTrials.gov Identifier: NCT00064987

23. (NCT00392756 chunk 3): Stephanie B. Seminara, MD. Examination of Idiopathic Hypogonadotropic Hypogonadism (IHH)and Kallmann Syndrome (KS). Massachusetts General Hospital. 1989. ClinicalTrials.gov Identifier: NCT00392756

Artifacts

• Edison artifact artifact-00

Reference Validation

Checked with linkml-reference-validator 0.2.1.

All extracted references resolved successfully.

Term Validation

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

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

• MONDO:0014107 (7 mentions) - the report calls it "if available"; MONDO calls it hypogonadotropic hypogonadism 21 with or without anosmia
• HP:0000044 (2 mentions) - the report calls it "Laboratory/endocrine abnormality; congenital, recognized in infancy or adolescence; usually persistent but variable"; HP calls it Hypogonadotropic hypogonadism
• HP:0000054 (2 mentions) - the report calls it "Congenital physical sign in severely affected 46,XY infants"; HP calls it Micropenis
• HP:0000028 (2 mentions) - the report calls it "Congenital sign, unilateral or bilateral; may persist and compromise fertility"; HP calls it Cryptorchidism
• HP:0004349 (1 mention) - the report calls it "Secondary complication of delayed or untreated sex-steroid deficiency"; HP calls it Reduced bone mineral density

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: Taxon.