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Hand-Foot-Genital Syndrome

Hand-Foot-Genital Syndrome (HFGS) — Comprehensive Disease Characteristics Report

2026-05-08
Falcon MONDO:0007698 Model: Edison Scientific Literature 28 citations

Hand-Foot-Genital Syndrome (HFGS) — Comprehensive Disease Characteristics Report

Executive summary

Hand-Foot-Genital Syndrome (HFGS) is a rare, autosomal dominant developmental malformation syndrome caused by pathogenic variation in HOXA13, a homeobox transcription factor essential for distal limb and urogenital tract development (goodman2000novelhoxa13mutations pages 1-2, goodman2002limbmalformationsand pages 5-6). The core phenotype is highly penetrant distal limb malformations (notably first-digit hypoplasia) with variably penetrant genitourinary anomalies (hypospadias in males; Müllerian fusion anomalies and/or urinary tract abnormalities in females) (goodman2000novelhoxa13mutations pages 1-2, utsch2002anovelstable pages 1-2). Recent (2023–2024) genomics literature emphasizes that structural variants (SVs) such as inversions can be under-ascertained by standard tests and may contribute to unresolved Mendelian phenotypes, supporting broader use of genome sequencing and SV-aware interpretation (pagnamenta2024theimpactof pages 1-2).

1. Disease information

1.1 Definition / overview (current understanding)

HFGS is “a rare, dominantly inherited condition characterized by distal limb and distal genitourinary tract malformations” (Goodman et al., 2000; published online 2000-06-05; https://doi.org/10.1086/302961) (goodman2000novelhoxa13mutations pages 1-2). Classic limb findings are typically bilateral and symmetric and include first-digit hypoplasia (thumb and hallux) with carpal/tarsal anomalies, while genitourinary findings show incomplete penetrance and variable severity (goodman2000novelhoxa13mutations pages 1-2, utsch2002anovelstable pages 1-2).

Abstract quote (primary literature): “Hand-foot-genital syndrome (HFGS) is a rare, dominantly inherited condition affecting the distal limbs and genitourinary tract.” (Goodman et al., 2000) (goodman2000novelhoxa13mutations pages 1-2).

1.2 Key identifiers

1.3 Synonyms / alternative names

  • “Hand-foot-genital syndrome”
  • “HFGS” (common abbreviation)
  • Older abbreviations in some literature include “HFG/HFU” context (as cited in a 2002 Human Genetics paper) (utsch2002anovelstable pages 1-2).

1.4 Evidence source types

The current evidence base is predominantly: - Aggregated disease-level descriptions (review-style synthesis and multi-family genetic reports) (goodman2002limbmalformationsand pages 5-6, utsch2002anovelstable pages 1-2). - Individual/family-based primary reports (case reports/series and family studies with segregation) (goodman2000novelhoxa13mutations pages 1-2, owens2013analysisofde pages 2-3).

2. Etiology

2.1 Disease causal factors

Primary cause: germline pathogenic variants affecting HOXA13 function (goodman2000novelhoxa13mutations pages 1-2, goodman2002limbmalformationsand pages 5-6).

Variant classes reported across the core literature include: - Nonsense/truncating variants (predicted loss of function) (goodman2000novelhoxa13mutations pages 1-2, goodman2002limbmalformationsand pages 5-6). - Missense variants (often in the DNA-binding homeodomain; can associate with unusually severe limb phenotypes) (goodman2000novelhoxa13mutations pages 1-2, imagawa2014severemanifestationsof pages 4-5). - In-frame polyalanine tract expansions in the N-terminus (goodman2000novelhoxa13mutations pages 1-2, innis2004polyalanineexpansionin pages 1-2). - Duplications affecting HOXA13 (reported in atypical HFGS) (frisen2003anovelduplication pages 1-1, frisen2003anovelduplication pages 5-5). - Larger structural changes including deletions affecting the HOXA cluster (discussed as part of mutational spectrum) (utsch2002anovelstable pages 1-2, frisen2003anovelduplication pages 1-1).

2.2 Risk factors

Recent development (genomics diagnostics): structural variants such as inversions can underlie rare disease and may be missed by copy-number-focused pipelines, supporting the use of genome sequencing for unsolved cases (Pagnamenta et al., 2024-06-06, AJHG; https://doi.org/10.1016/j.ajhg.2024.04.018) (pagnamenta2024theimpactof pages 1-2).

2.3 Protective factors

No evidence for genetic/environmental protective factors specific to HFGS was identified in the ingested sources (gap).

2.4 Gene–environment interactions

No direct gene–environment interaction evidence specific to HFGS was identified in the ingested sources (gap).

3. Phenotypes

3.1 Phenotype spectrum and characteristics

Distal limb phenotype (high penetrance)

Commonly described findings include: - First-digit hypoplasia: short, proximally placed thumbs and short, medially deviated halluces; hypoplastic thenar eminences (goodman2000novelhoxa13mutations pages 1-2, goodman2002limbmalformationsand pages 5-6, utsch2002anovelstable pages 1-2). - Carpal/tarsal ossification anomalies: delayed ossification, fusion, shortening of carpals and tarsals (goodman2000novelhoxa13mutations pages 1-2, utsch2002anovelstable pages 1-2). - Additional digital findings: ulnar deviation of second fingers, clinodactyly/brachydactyly (goodman2000novelhoxa13mutations pages 1-2, goodman2002limbmalformationsand pages 5-6, utsch2002anovelstable pages 1-2).

Penetrance statement: limb abnormalities are described as fully penetrant / highly penetrant in reported series (utsch2002anovelstable pages 1-2, frisen2003anovelduplication pages 1-1).

Suggested HPO terms (examples): - First digit hypoplasia: HP:0005864 (Thumb hypoplasia; approximate mapping) - Hypoplastic thenar eminence: HP:0030438 (Thenar hypoplasia; approximate) - Hallux deviation/varus/valgus: HP:0001847 (Hallux varus) / HP:0001838 (Hallux valgus; approximate) - Carpal/tarsal coalition/fusion: HP:0009702 (Carpal fusion) / HP:0008367 (Tarsal coalition; approximate)

(Exact HPO IDs should be verified during curation; the phenotype concepts are strongly supported by primary descriptions.) (goodman2000novelhoxa13mutations pages 1-2, utsch2002anovelstable pages 1-2).

Genitourinary phenotype (variable expressivity / incomplete penetrance)

Statistics (reported in a major review): - Müllerian duct fusion defects in females are described as occurring in ~50% of affected females (Goodman 2002) (goodman2002limbmalformationsand pages 5-6). - Urinary tract anomalies were described as occurring in <20% in that summary (with potential for chronic pyelonephritis and renal insufficiency) (goodman2002limbmalformationsand pages 5-6).

Suggested HPO terms (examples): - Hypospadias: HP:0000047 - Uterine didelphys / double uterus: HP:0000135 (Uterus didelphys; approximate) - Longitudinal vaginal septum: HP:0100644 (Vaginal septum; approximate) - Vesicoureteral reflux: HP:0000076 - Recurrent urinary tract infections: HP:0000010

3.2 Age of onset, progression, and natural history

HFGS is a congenital malformation syndrome with abnormalities typically evident at birth or early in life (limb phenotype), while genitourinary manifestations may be discovered during childhood/adolescence/adulthood (e.g., evaluation for UTIs, imaging of Müllerian anomalies, fertility workup) (goodman2000novelhoxa13mutations pages 1-2, owens2013analysisofde pages 2-3, jaouadi2023geneticandphenotypic pages 1-2).

3.3 Quality-of-life impact

Primary evidence indicates potential impact via: - Functional and orthopedic consequences of limb malformations (hand/foot anatomy) (goodman2000novelhoxa13mutations pages 1-2, goodman2002limbmalformationsand pages 5-6). - Urologic morbidity (recurrent UTIs, urinary leakage, renal impairment risk) and reproductive outcomes (fetal loss/neonatal death reported in at least three families in early literature) (goodman2000novelhoxa13mutations pages 1-2, goodman2002limbmalformationsand pages 5-6, owens2013analysisofde pages 2-3).

4. Genetic / molecular information

4.1 Causal gene

4.2 Pathogenic variant spectrum (types and interpreted effects)

Evidence supports at least two broad mechanistic categories: 1) Loss-of-function / haploinsufficiency-like outcomes (notably truncating variants; and some polyalanine expansions with reduced protein abundance) (innis2004polyalanineexpansionin pages 1-2, goodman2000novelhoxa13mutations pages 1-2). 2) Dominant-negative and/or gain-of-function possibilities for certain missense variants and some polyalanine expansions, discussed as explaining unusually severe phenotypes compared with null alleles (utsch2002anovelstable pages 6-7, imagawa2014severemanifestationsof pages 4-5, frisen2003anovelduplication pages 5-5).

Key variant categories documented in the ingested primary literature: - Truncating/nonsense variants leading to truncated proteins (Goodman 2000) (goodman2000novelhoxa13mutations pages 1-2). - Polyalanine expansions in HOXA13 (Innis 2004; Utsch 2002) (innis2004polyalanineexpansionin pages 1-2, utsch2002anovelstable pages 1-2). - Abstract quote (Innis 2004): “Polyalanine expansions … can cause HFGS.” and “Mutant limb buds had … reduced levels of steady-state protein… loss of function is secondary to a reduction in the in vivo abundance of the expanded protein likely due to degradation.” (Innis et al., 2004-11; https://doi.org/10.1093/hmg/ddh306) (innis2004polyalanineexpansionin pages 1-2). - Duplications (including “novel HOXA13 duplication” associated with atypical HFGS) (frisen2003anovelduplication pages 1-1, frisen2003anovelduplication pages 5-5). - De novo polyalanine expansions with molecular evidence consistent with replication slippage (Owens 2013) (owens2013analysisofde pages 2-3).

4.3 Inheritance, penetrance, expressivity

4.4 Modifier genes / dual diagnoses

The phenotype can be complicated by additional variants in other genes in some individuals, consistent with “phenotypic blending” / multiple diagnoses in modern genomics (concept supported by rare disease genome sequencing studies and reported dual diagnoses including HOXA13 plus another gene in case literature) (wallis2016dualgeneticdiagnoses pages 6-7, pagnamenta2024theimpactof pages 1-2).

4.5 Epigenetic information

No disease-specific epigenetic mechanisms for HFGS were identified in the ingested sources (gap).

4.6 Chromosomal abnormalities

The mutational spectrum discussed in the HFGS literature includes HOXA cluster deletions and other SV mechanisms (utsch2002anovelstable pages 1-2, frisen2003anovelduplication pages 1-1). Separately, recent large-cohort genome sequencing indicates inversions are an under-recognized disease mechanism in general and can act via gene disruption or altered regulatory landscapes (pagnamenta2024theimpactof pages 1-2).

5. Environmental information

No established non-genetic environmental or infectious contributors were identified for HFGS in the ingested sources; HFGS is treated as a Mendelian developmental disorder (goodman2000novelhoxa13mutations pages 1-2, goodman2002limbmalformationsand pages 5-6).

6. Mechanism / pathophysiology

6.1 Causal chain (from gene defect to phenotype)

1) Upstream trigger: germline pathogenic variant affecting HOXA13 (goodman2000novelhoxa13mutations pages 1-2). 2) Molecular consequence: altered transcription factor function (via reduced protein abundance/degradation for some polyalanine expansions; altered DNA-binding for homeodomain missense; truncation removing key domains) (innis2004polyalanineexpansionin pages 1-2, imagawa2014severemanifestationsof pages 4-5, goodman2002limbmalformationsand pages 5-6). 3) Developmental pathway disruption: impaired patterning and morphogenesis of distal limbs and urogenital tract derivatives (goodman2002limbmalformationsand pages 5-6, utsch2002anovelstable pages 1-2). 4) Organ-level manifestations: first-digit hypoplasia/carpal-tarsal defects and hypospadias/Müllerian anomalies/urinary anomalies (goodman2000novelhoxa13mutations pages 1-2, goodman2002limbmalformationsand pages 5-6).

6.2 Pathways, processes, and targets (evidence-based highlights)

  • Polyalanine expansion mechanism: evidence indicates decreased steady-state HOXA13 protein with expanded tract, with inferred degradation leading to functional loss (mouse model and molecular assays) (innis2004polyalanineexpansionin pages 1-2).
  • Homeodomain missense and developmental processes: HOXA13 is reported to bind targets such as Bmp2 and Bmp7 and to regulate “interdigital programmed cell death, digit mesenchymal condensation, and digit chondrogenesis” (Imagawa 2014) (imagawa2014severemanifestationsof pages 4-5).
  • De novo expansion mechanism: evidence supports replication slippage/unequal sister chromatid exchange as plausible mechanisms rather than unequal crossing-over in at least one de novo expansion analysis (owens2013analysisofde pages 2-3).

6.3 Ontology suggestions

GO biological process (examples to curate/validate): - Pattern specification process (GO:0007389) - Limb development / appendage development (e.g., GO:0060173 / GO:0048736) - Urogenital system development (GO:0001655) - Regulation of programmed cell death (for interdigital apoptosis; GO:0043067)

Cell types (CL) likely involved (developmental): - Limb bud mesenchymal cell (CL term requires curator selection) - Urogenital sinus / genital tubercle mesenchyme (developmental CL terms require curator selection)

These ontology mappings are consistent with the mechanistic descriptions but require formal term validation during curation (imagawa2014severemanifestationsof pages 4-5, innis2004polyalanineexpansionin pages 1-2).

7. Anatomical structures affected

7.1 Organ and system level

Suggested UBERON terms (examples): - UBERON:0002398 (hand), UBERON:0002108 (foot) - UBERON:0000945 (uterus), UBERON:0000996 (vagina) - UBERON:0001255 (urinary bladder), UBERON:0000056 (ureter)

7.2 Subcellular level

HOXA13 is a transcription factor (nuclear localization implied), and polyalanine expansions can alter protein abundance; specific organelle-level pathology beyond this is not described in the ingested sources (innis2004polyalanineexpansionin pages 1-2).

8. Temporal development

9. Inheritance and population

9.1 Epidemiology (available statistics)

Robust population prevalence/incidence estimates were not found in the ingested sources (gap).

A frequently cited early aggregation reported: “nine families and three sporadic cases” totaling “52 affected individuals (34 males, 18 females)” (Utsch et al., 2002-04; https://doi.org/10.1007/s00439-002-0712-8) (utsch2002anovelstable pages 1-2). This is not a prevalence estimate but provides early ascertainment scale.

9.2 Inheritance pattern

Founder effects, consanguinity, carrier frequency: not identified in ingested sources (gap).

10. Diagnostics

10.1 Clinical recognition

Suspicion is based on the combination of: - Typical bilateral distal limb pattern (thumb/hallux hypoplasia, carpal/tarsal anomalies) (goodman2000novelhoxa13mutations pages 1-2, utsch2002anovelstable pages 1-2). - Genitourinary anomalies (hypospadias; Müllerian fusion anomalies; urinary anomalies) with variable penetrance (goodman2000novelhoxa13mutations pages 1-2, goodman2002limbmalformationsand pages 5-6).

10.2 Imaging and clinical tests

10.3 Genetic testing (current practice implications)

Evidence across time supports a tiered approach: - Targeted HOXA13 sequencing (PCR/Sanger validation) has been used in classic families (goodman2000novelhoxa13mutations pages 1-2, imagawa2014severemanifestationsof pages 4-5, owens2013analysisofde pages 2-3). - WES can identify novel HOXA13 missense variants in syndromic presentations (Jaouadi 2023; received 2022-10-04; accepted 2022-11-30; https://doi.org/10.3892/mmr.2023.12946) (jaouadi2023geneticandphenotypic pages 1-2). - Genome sequencing with SV-aware analysis is increasingly important because inversion and other complex SV classes can be missed by copy-number-focused pipelines; large rare disease cohort work shows inversions are a “small but notable” contributor and can resolve prolonged diagnostic odysseys (Pagnamenta 2024) (pagnamenta2024theimpactof pages 1-2).

10.4 Differential diagnosis (examples mentioned in primary literature)

In severe limb phenotypes due to HOXA13 missense, differential diagnoses discussed include brachydactyly type B1 and Cook syndrome (imagawa2014severemanifestationsof pages 4-5).

10.5 Screening

No newborn screening or population screening programs were identified for HFGS in the ingested sources; however, family-based cascade testing is implied by autosomal dominant inheritance and de novo possibility (goodman2000novelhoxa13mutations pages 1-2, owens2013analysisofde pages 2-3).

11. Outcome / prognosis

HFGS is not presented as a life-shortening disorder per se in the ingested sources; morbidity primarily reflects urogenital complications (reflux, UTIs, renal insufficiency) and reproductive outcomes in affected females (goodman2002limbmalformationsand pages 5-6, goodman2000novelhoxa13mutations pages 1-2). Severe urologic dysfunction can require major reconstructive interventions in some cases (owens2013analysisofde pages 2-3).

12. Treatment

12.1 Current applications and real-world implementations (management)

Management is individualized and typically includes: - Urologic evaluation and treatment of reflux/obstruction/UTIs; in severe cases, reconstructive procedures. - Example of high-intensity management reported: bladder augmentation and creation of a Mitrofanoff channel for urinary leakage and small bladder, in a patient with HOXA13 polyalanine expansion (Owens 2013) (owens2013analysisofde pages 2-3). - Surgical repair of hypospadias when indicated (not quantified in ingested sources, but repeatedly listed as a key manifestation) (goodman2000novelhoxa13mutations pages 1-2, innis2004polyalanineexpansionin pages 1-2). - Orthopedic/hand-foot care as needed for function and footwear (not detailed quantitatively in ingested sources) (goodman2000novelhoxa13mutations pages 1-2, goodman2002limbmalformationsand pages 5-6).

12.2 Pharmacotherapy

No disease-specific pharmacologic therapy targeting HOXA13 mechanisms was identified (gap).

12.3 Experimental / clinical trials

ClinicalTrials.gov searches retrieved observational studies related to hypospadias and other conditions, but no HFGS-specific interventional clinical trials were identified in the retrieved trial set (gap; based on current tool results).

12.4 MAXO term suggestions (examples)

  • Genetic counseling (MAXO term to curate)
  • Surgical repair of hypospadias (MAXO)
  • Urologic reconstructive surgery (e.g., urinary diversion, bladder augmentation) (MAXO)
  • Renal/urinary tract surveillance (MAXO)

13. Prevention

Primary prevention is not applicable for inherited HFGS beyond reproductive planning.

13.1 Genetic counseling and reproductive options

Autosomal dominant inheritance supports: - Cascade testing of at-risk relatives once a familial HOXA13 variant is known (goodman2000novelhoxa13mutations pages 1-2). - Prenatal diagnosis or preimplantation genetic testing may be considered for known familial variants (not directly described in ingested sources, but standard for AD Mendelian disorders; should be treated as an implementation inference).

13.2 Secondary/tertiary prevention

14. Other species / natural disease

No naturally occurring veterinary analogs were identified in the ingested sources (gap).

15. Model organisms

Mouse models provide functional evidence linking HOXA13 disruptions to the phenotype: - A mouse HOXA13 polyalanine expansion model showed phenotypes indistinguishable from null mice and demonstrated that loss of function can arise from reduced in vivo abundance of the expanded protein (Innis 2004) (innis2004polyalanineexpansionin pages 1-2). - Review-level summaries note that homozygous loss of Hoxa13 is lethal and produces severe urinary/genital tract malformations, supporting developmental essentiality (Goodman 2002) (goodman2002limbmalformationsand pages 5-6).

2023–2024 “latest research” highlights (prioritized)

1) Expanded syndromic context and penetrance framing (2023): A 2023 case-based paper reiterates HFGS (OMIM 140000) as a HOXA13-related autosomal dominant disorder with fully penetrant limb defects and partially penetrant genitourinary anomalies, and emphasizes variable fertility implications (Jaouadi 2023; https://doi.org/10.3892/mmr.2023.12946) (jaouadi2023geneticandphenotypic pages 1-2). 2) Structural variants and diagnostic implementation (2024): A large rare disease genome sequencing analysis highlights how inversions and complex SVs contribute to Mendelian diagnoses and can be missed by routine approaches, supporting broader implementation of WGS/SV detection for unresolved phenotypes (Pagnamenta 2024-06-06; https://doi.org/10.1016/j.ajhg.2024.04.018) (pagnamenta2024theimpactof pages 1-2).

Structured identifiers/nomenclature artifact

Table (click to expand)
Disease name Synonyms / alternative names OMIM number Causal gene Inheritance Key phenotypic hallmarks: hands/feet Key phenotypic hallmarks: genitourinary Key references (year; DOI / URL)
Hand-Foot-Genital Syndrome HFGS; hand-foot-genital syndrome; hand–foot–genital syndrome OMIM 140000 HOXA13 Autosomal dominant Distal limb malformations with first-digit hypoplasia; short, proximally placed thumbs; hypoplastic thenar eminences; short, medially deviated halluces; delayed ossification/fusion/shortening of carpals and tarsals; clinodactyly/brachydactyly may occur (goodman2000novelhoxa13mutations pages 1-2, goodman2002limbmalformationsand pages 5-6, utsch2002anovelstable pages 1-2, jaouadi2023geneticandphenotypic pages 1-2, innis2004polyalanineexpansionin pages 1-2) Distal genitourinary tract malformations with variable expressivity; hypospadias in males; Müllerian duct fusion defects in females (e.g., vaginal septum, double uterus with double cervix, bicornuate uterus); urinary anomalies can include vesicoureteric reflux, ectopic ureteric orifices, pelvi-ureteric/ureteropelvic junction obstruction, recurrent UTIs, and risk of renal insufficiency (goodman2000novelhoxa13mutations pages 1-2, goodman2002limbmalformationsand pages 5-6, utsch2002anovelstable pages 1-2, jaouadi2023geneticandphenotypic pages 1-2, innis2004polyalanineexpansionin pages 1-2) Goodman 2000; doi:10.1086/302961; https://doi.org/10.1086/302961 (goodman2000novelhoxa13mutations pages 1-2)
Hand-Foot-Genital Syndrome HFGS; HFG syndrome / HFU syndrome (older abbreviation in literature) OMIM 140000; OMIM 142959 also cited in older literature context HOXA13 Autosomal dominant Limb defects are described as fully penetrant / highly penetrant in reported series; bilateral and symmetrical in typical cases (utsch2002anovelstable pages 1-2, jaouadi2023geneticandphenotypic pages 1-2) Genitourinary anomalies are incompletely penetrant / partially penetrant and variably severe, with fertility implications in some affected females (goodman2000novelhoxa13mutations pages 1-2, utsch2002anovelstable pages 1-2, jaouadi2023geneticandphenotypic pages 1-2) Goodman 2002; doi:10.1002/ajmg.10776; https://doi.org/10.1002/ajmg.10776 (goodman2002limbmalformationsand pages 5-6)
Hand-Foot-Genital Syndrome HFGS OMIM 140000 HOXA13 Autosomal dominant Typical phenotype can result from nonsense mutations and polyalanine tract expansions; missense variants may produce more severe limb phenotypes (goodman2000novelhoxa13mutations pages 1-2, imagawa2014severemanifestationsof pages 4-5) Typical phenotype includes hypospadias, Müllerian anomalies, and urinary tract abnormalities; severity is variable across families (goodman2000novelhoxa13mutations pages 1-2, imagawa2014severemanifestationsof pages 4-5) Utsch 2002; doi:10.1007/s00439-002-0712-8; https://doi.org/10.1007/s00439-002-0712-8 (utsch2002anovelstable pages 1-2, utsch2002anovelstable pages 6-7)
Hand-Foot-Genital Syndrome HFGS OMIM 140000 HOXA13 Autosomal dominant Polyalanine expansions in all three major HOXA13 polyalanine repeats can cause HFGS; common phenotype includes bilaterally symmetrical shortening of thumbs and halluces with clinobrachydactyly (innis2004polyalanineexpansionin pages 1-2) Genitourinary anomalies may include hypospadias, ureteral reflux, and incomplete Müllerian fusion (innis2004polyalanineexpansionin pages 1-2) Innis 2004; doi:10.1093/hmg/ddh306; https://doi.org/10.1093/hmg/ddh306 (innis2004polyalanineexpansionin pages 1-2)
Hand-Foot-Genital Syndrome HFGS OMIM 140000 HOXA13 Autosomal dominant Recent review/case literature reiterates bilateral, symmetrical distal limb anomalies centered on first-digit hypoplasia and wrist/foot ossification defects (jaouadi2023geneticandphenotypic pages 1-2) Recent review/case literature reiterates genitourinary malformations with variable penetrance; females do not necessarily have infertility (jaouadi2023geneticandphenotypic pages 1-2) Jaouadi 2023; doi:10.3892/mmr.2023.12946; https://doi.org/10.3892/mmr.2023.12946 (jaouadi2023geneticandphenotypic pages 1-2)
Hand-Foot-Genital Syndrome HFGS OMIM 140000 HOXA13 Autosomal dominant Structural variant studies expand the mutational spectrum affecting HOXA13-related disease; inversions can contribute to rare disease diagnosis where targeted prior testing was negative (pagnamenta2024theimpactof pages 1-2) Structural rearrangements near/disrupting developmental genes such as HOXA13 may alter regulatory landscape and contribute to disease phenotypes, relevant to unresolved HFGS-like presentations (pagnamenta2024theimpactof pages 1-2) Pagnamenta 2024; doi:10.1016/j.ajhg.2024.04.018; https://doi.org/10.1016/j.ajhg.2024.04.018 (pagnamenta2024theimpactof pages 1-2)

Table: This table summarizes the core identifiers, naming, inheritance, causal gene, and hallmark clinical features of Hand-Foot-Genital Syndrome using only the specified evidence sources. It is useful as a compact disease knowledge base seed for nomenclature and phenotype curation.

Evidence limitations and curation gaps

  • MONDO, Orphanet, ICD-10/ICD-11, and MeSH identifiers were not extractable from the currently ingested texts; this report therefore anchors coding primarily to OMIM and primary literature (gap).
  • Population prevalence/incidence estimates were not found; available numeric data are from early aggregated case counts and phenotype-frequency statements in review summaries (utsch2002anovelstable pages 1-2, goodman2002limbmalformationsand pages 5-6).
  • HPO/GO/CL/UBERON/MAXO term IDs listed are partially inferential and require curator verification; however, the underlying phenotype/process/anatomy concepts are strongly supported by cited sources.

References

  1. (goodman2000novelhoxa13mutations pages 1-2): Frances R. Goodman, Chiara Bacchelli, Angela F. Brady, Louise A. Brueton, Jean-Pierre Fryns, Douglas P. Mortlock, Jeffrey W. Innis, Lewis B. Holmes, Alan E. Donnenfeld, Murray Feingold, Frits A. Beemer, Raoul C.M. Hennekam, and Peter J. Scambler. Novel hoxa13 mutations and the phenotypic spectrum of hand-foot-genital syndrome. The American Journal of Human Genetics, 67:197-202, Jul 2000. URL: https://doi.org/10.1086/302961, doi:10.1086/302961. This article has 288 citations.

  2. (goodman2002limbmalformationsand pages 5-6): Frances R. Goodman. Limb malformations and the human hox genes. American journal of medical genetics, 112 3:256-65, Oct 2002. URL: https://doi.org/10.1002/ajmg.10776, doi:10.1002/ajmg.10776. This article has 294 citations.

  3. (utsch2002anovelstable pages 1-2): Boris Utsch, Karl Becker, Detlef Brock, Michael J. Lentze, Frank Bidlingmaier, and Michael Ludwig. A novel stable polyalanine [poly(a)] expansion in the hoxa13 gene associated with hand-foot-genital syndrome: proper function of poly(a)-harbouring transcription factors depends on a critical repeat length? Human Genetics, 110:488-494, Apr 2002. URL: https://doi.org/10.1007/s00439-002-0712-8, doi:10.1007/s00439-002-0712-8. This article has 74 citations and is from a peer-reviewed journal.

  4. (pagnamenta2024theimpactof pages 1-2): Alistair T. Pagnamenta, Jing Yu, Susan Walker, Alexandra J. Noble, Jenny Lord, Prasun Dutta, Mona Hashim, Carme Camps, Hannah Green, Smrithi Devaiah, Lina Nashef, Jason Parr, Carl Fratter, Rana Ibnouf Hussein, Sarah J. Lindsay, Fiona Lalloo, Benito Banos-Pinero, David Evans, Lucy Mallin, Adrian Waite, Julie Evans, Andrew Newman, Zoe Allen, Cristina Perez-Becerril, Gavin Ryan, Rachel Hart, John Taylor, Tina Bedenham, Emma Clement, Ed Blair, Eleanor Hay, Francesca Forzano, Jenny Higgs, Natalie Canham, Anirban Majumdar, Meriel McEntagart, Nayana Lahiri, Helen Stewart, Sarah Smithson, Eduardo Calpena, Adam Jackson, Siddharth Banka, Hannah Titheradge, Ruth McGowan, Julia Rankin, Charles Shaw-Smith, D. Gareth Evans, George J. Burghel, Miriam J. Smith, Emily Anderson, Rajesh Madhu, Helen Firth, Sian Ellard, Paul Brennan, Claire Anderson, Doug Taupin, Mark T. Rogers, Jackie A. Cook, Miranda Durkie, James E. East, Darren Fowler, Louise Wilson, Rebecca Igbokwe, Alice Gardham, Ian Tomlinson, Diana Baralle, Holm H. Uhlig, and Jenny C. Taylor. The impact of inversions across 33,924 families with rare disease from a national genome sequencing project. The American Journal of Human Genetics, 111:1140-1164, Jun 2024. URL: https://doi.org/10.1016/j.ajhg.2024.04.018, doi:10.1016/j.ajhg.2024.04.018. This article has 36 citations.

  5. (jaouadi2023geneticandphenotypic pages 1-2): Hager Jaouadi, Alexis Theron, Giulia Norscini, Jean-François Avierinos, and Stéphane Zaffran. Genetic and phenotypic continuum of hoxa genes: a case with double hoxa9/hoxa13 mutations. Molecular Medicine Reports, Jan 2023. URL: https://doi.org/10.3892/mmr.2023.12946, doi:10.3892/mmr.2023.12946. This article has 3 citations and is from a peer-reviewed journal.

  6. (owens2013analysisofde pages 2-3): Kailey M. Owens, Shane C. Quinonez, Peedikayil E. Thomas, Catherine E. Keegan, Nanci Lefebvre, Diane Roulston, Christine A. Larsen, H. Scott Stadler, and Jeffrey W. Innis. Analysis of de novo hoxa13 polyalanine expansions supports replication slippage without repair in their generation. American Journal of Medical Genetics Part A, 161:1019-1027, May 2013. URL: https://doi.org/10.1002/ajmg.a.35843, doi:10.1002/ajmg.a.35843. This article has 11 citations.

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  9. (frisen2003anovelduplication pages 1-1): L. Frisén, K. Lagerstedt, M. Tapper-Persson, Ingrid Kockum, and A. Nordenskjöld. A novel duplication in the hoxa13 gene in a family with atypical hand-foot-genital syndrome. Journal of Medical Genetics, 40:e49-e49, Apr 2003. URL: https://doi.org/10.1136/jmg.40.4.e49, doi:10.1136/jmg.40.4.e49. This article has 37 citations and is from a domain leading peer-reviewed journal.

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  11. (utsch2002anovelstable pages 6-7): Boris Utsch, Karl Becker, Detlef Brock, Michael J. Lentze, Frank Bidlingmaier, and Michael Ludwig. A novel stable polyalanine [poly(a)] expansion in the hoxa13 gene associated with hand-foot-genital syndrome: proper function of poly(a)-harbouring transcription factors depends on a critical repeat length? Human Genetics, 110:488-494, Apr 2002. URL: https://doi.org/10.1007/s00439-002-0712-8, doi:10.1007/s00439-002-0712-8. This article has 74 citations and is from a peer-reviewed journal.

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