Guttmacher syndrome

👪

Inheritance

1

Autosomal Dominant HP:0000006

Autosomal dominant transmission, observed in the original family in which an affected father transmitted the condition to a son and a daughter. Only one family and a few HOXA13 spectrum cases are known, so penetrance and expressivity are not formally established.

Autosomal dominant inheritance

Show evidence (2 references)

PMID:8484413 SUPPORT Human Clinical

"we conclude that this family has a hitherto unreported autosomal dominant condition"

Original report establishes autosomal dominant inheritance in the three-generation family.

PMID:11968094 SUPPORT Human Clinical

"Guttmacher syndrome, a dominantly inherited combination of distal limb and genital tract abnormalities"

Confirms the dominant inheritance of the combined distal limb and genital phenotype.

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Pathophysiology

3

HOXA13 Homeodomain Missense Variant

A heterozygous missense variant in the HOXA13 homeobox (c.1112A>T, Q50L) alters a key residue in the recognition helix of the homeodomain and is predicted to perturb the DNA-binding transcription-factor activity of HOXA13, with both a loss and a specific gain of function. The variant arose on an allele also carrying a 2-bp deletion in the gene's conserved promoter; that deletion produces no abnormality on its own but may contribute to the phenotype.

HOXA13 hgnc:5102

DNA-binding transcription factor activity GO:0003700

Downstream

Disrupted Autopod Patterning Perturbed HOXA13 transcription-factor activity disrupts patterning of the distal limb bud.

Disrupted Male Urethral Development The same HOXA13 defect disrupts development of the distal male urethra.

Show evidence (2 references)

PMID:11968094 SUPPORT Human Clinical

"affected individuals are heterozygous for a novel missense mutation in the HOXA13 homeobox (c.1112A>T; homeodomain residue Q50L)"

Identifies the causal HOXA13 homeodomain missense variant in the original family.

PMID:11968094 SUPPORT INDIRECT Human Clinical

"The missense mutation, which alters a key residue in the recognition helix of the homeodomain, is likely to perturb HOXA13's DNA-binding properties, resulting in both a loss and a specific gain of function."

States the predicted effect of the variant on HOXA13 DNA-binding transcription-factor activity.

Disrupted Autopod Patterning

Loss of normal HOXA13-dependent regionalization of the autopod produces the combined preaxial deficiency and postaxial polydactyly of the hands and the distal foot anomalies. The mechanistic link from HOXA13 dysfunction to limb patterning is inferred from HOXA13's established role in distal limb morphogenesis; the limb abnormalities themselves are observed in the family.

embryonic limb morphogenesis GO:0030326 regionalization GO:0003002

Downstream

Thumb Hypoplasia Preaxial deficiency of the hand manifests as hypoplastic thumbs.

Hallux Hypoplasia Preaxial deficiency of the foot manifests as hypoplastic great toes.

Postaxial Hand Polydactyly Abnormal ulnar-side autopod patterning produces supernumerary postaxial digits of the hands.

Short Second Toe Reduced phalangeal patterning produces uniphalangeal, shortened second toes.

Absent Toenails Distal toe patterning failure leaves the second toes without nails.

Show evidence (2 references)

PMID:11968094 SUPPORT INDIRECT Human Clinical

"HFGS is caused by mutations in the HOXA13 gene."

Establishes HOXA13 as the gene whose dysfunction underlies the distal limb (and genital) abnormalities of the HOXA13 spectrum.

PMID:36734258 SUPPORT INDIRECT BACKGROUND Human Clinical

"Mutations in HOXA genes have been linked to different human phenotypes, including developmental delay, limb anomalies, and urogenital malformations."

Supports the general role of HOXA-cluster (including HOXA13) dysfunction in limb and urogenital malformation.

Disrupted Male Urethral Development

HOXA13 also patterns the distal genitourinary tract; its dysfunction disrupts male urethral development, producing glanular hypospadias in affected males. The genital abnormality is observed; the HOXA13-dependent mechanism is inferred.

male urethra development GO:0061069

Downstream

Glanular Hypospadias Disrupted distal male urethral patterning produces glanular hypospadias.

Show evidence (1 reference)

PMID:11968094 SUPPORT Human Clinical

"Guttmacher syndrome, a dominantly inherited combination of distal limb and genital tract abnormalities, has several features in common with hand-foot-genital syndrome (HFGS), including hypoplastic first digits and hypospadias."

Links the HOXA13 defect to genital-tract abnormality (hypospadias) alongside the distal limb phenotype.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

6

Genitourinary 1

Glanular Hypospadias HP:0000807

Show evidence (1 reference)

PMID:8484413 SUPPORT Human Clinical

"Both males also had glandular hypospadias."

Glanular hypospadias in the two affected males of the original family (spelled "glandular" in the source).

Integument 1

Absent Toenails HP:0001802

Show evidence (1 reference)

PMID:11968094 SUPPORT Human Clinical

"uniphalangeal 2(nd) toes with absent nails"

Records absent nails of the second toes.

Limbs 4

Thumb Hypoplasia Aplasia/Hypoplasia of the thumb HP:0009601

Show evidence (2 references)

PMID:8484413 SUPPORT Human Clinical

"preaxial deficiencies of the hands and feet"

Preaxial deficiency of the hands corresponds to thumb hypoplasia.

PMID:11968094 SUPPORT Human Clinical

"including hypoplastic first digits and hypospadias"

Hypoplastic first digits include the thumbs.

Hallux Hypoplasia Aplasia/Hypoplasia of the hallux HP:0008362

Show evidence (1 reference)

PMID:8484413 SUPPORT Human Clinical

"preaxial deficiencies of the hands and feet"

Preaxial deficiency of the feet corresponds to hallux hypoplasia.

Postaxial Hand Polydactyly HP:0001162

Show evidence (2 references)

PMID:8484413 SUPPORT Human Clinical

"postaxial polydactyly of the hands"

Postaxial polydactyly of the hands is a cardinal feature of the original family.

PMID:11968094 SUPPORT Human Clinical

"The presence of features not seen in HFGS, however, including postaxial polydactyly of the hands and uniphalangeal 2(nd) toes with absent nails, suggests that it represents a distinct entity."

Identifies postaxial hand polydactyly as distinguishing Guttmacher syndrome from HFGS.

Short Second Toe Short 2nd toe HP:0001885

Show evidence (1 reference)

PMID:11968094 SUPPORT Human Clinical

"uniphalangeal 2(nd) toes with absent nails"

Uniphalangeal second toes are shortened toes.

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Genetic Associations

1

HOXA13 (Causative (provisional; single family))

Gene: HOXA13 hgnc:5102 gene page variant_origin: GERMLINE

Variants (1)

p.Gln50Leu (Q50L)

single nucleotide variant

Heterozygous missense variant c.1112A>T in the HOXA13 homeobox, altering homeodomain residue 50 in the recognition helix. Found on an allele also carrying a 2-bp promoter deletion (-78_-79delGC).

Show evidence (1 reference)

PMID:11968094 SUPPORT Human Clinical

"affected individuals are heterozygous for a novel missense mutation in the HOXA13 homeobox (c.1112A>T; homeodomain residue Q50L), which arose on an allele already carrying a novel 2-bp deletion (-78-79delGC) in the gene's highly conserved promoter region"

Reports the causal missense variant and the cis promoter deletion in the original family.

💊

Medical Actions

2

Surgical Correction

Action: surgical procedure Ontology label: Surgical Procedure NCIT:C15329

Platform: Surgery

Surgical management as indicated: hypospadias repair in affected males and reconstructive or orthopaedic surgery for hand and foot anomalies.

Genetic Counseling

Action: Genetic Counseling NCIT:C15240

Genetic counseling for affected families given autosomal dominant inheritance and its recurrence risk.

📊

Prevalence

1

Worldwide

Unknown Not yet documented

No prevalence estimate is established. The condition is known from the single original family and a small number of HOXA13-spectrum case reports.

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Differential Diagnoses

1

Conditions with similar clinical presentations that must be differentiated from Guttmacher syndrome:

Hand-foot-genital syndrome MONDO:0007698

Overlapping Features Allelic HOXA13-related disorder (its own dismech entry) with overlapping distal limb and genital features, including hypoplastic first digits and hypospadias.

Distinguishing Features

Postaxial polydactyly of the hands and uniphalangeal second toes with absent nails occur in Guttmacher syndrome but not in hand-foot-genital syndrome; conversely, Mullerian (uterine) fusion anomalies in affected females are characteristic of hand-foot-genital syndrome and were not reported in the Guttmacher family. The two are increasingly viewed as one HOXA13 spectrum.

Show evidence (2 references)

PMID:11968094 SUPPORT Human Clinical

"The presence of features not seen in HFGS, however, including postaxial polydactyly of the hands and uniphalangeal 2(nd) toes with absent nails, suggests that it represents a distinct entity."

Gives the features that distinguish Guttmacher syndrome from hand-foot-genital syndrome.

PMID:24934387 SUPPORT BACKGROUND Human Clinical

"Heterozygous HOXA13 mutations have been previously reported in hand-foot-genital syndrome and Guttmacher syndrome, which are variably associated with small nails, short distal and middle phalanges, short thumbs and halluces, but not absent nails."

Frames hand-foot-genital and Guttmacher syndromes as variants of one HOXA13-related spectrum.

{ }

Source YAML

click to show

name: Guttmacher syndrome
synonyms:
- Preaxial deficiency-postaxial polydactyly-hypospadias syndrome
creation_date: "2026-10-12T13:10:00Z"
category: Mendelian
description: >
  Guttmacher syndrome is an extremely rare, autosomal dominant malformation
  syndrome of the distal limbs and the distal genitourinary tract, allelic to
  hand-foot-genital syndrome (both caused by HOXA13, a homeobox transcription
  factor patterning the distal limb bud and the genital tract). It was described
  in 1993 in a single three-generation family (a man, his son, and his daughter)
  presenting with preaxial deficiencies of the hands and feet together with
  postaxial polydactyly of the hands, with glanular hypospadias in the affected
  males. Re-investigation of that family identified a heterozygous HOXA13
  homeodomain missense variant (Q50L). Postaxial polydactyly of the hands and
  uniphalangeal second toes with absent nails are features not seen in
  hand-foot-genital syndrome, and on that basis the condition was judged a
  distinct entity, though the two disorders are increasingly regarded as ends of
  one HOXA13 phenotypic spectrum.
disease_term:
  preferred_term: Guttmacher syndrome
  term:
    id: MONDO:0008301
    label: Guttmacher syndrome
parents:
- Limb Development Disorders
inheritance:
- name: Autosomal Dominant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >
    Autosomal dominant transmission, observed in the original family in which an
    affected father transmitted the condition to a son and a daughter. Only one
    family and a few HOXA13 spectrum cases are known, so penetrance and
    expressivity are not formally established.
  evidence:
  - reference: PMID:8484413
    reference_title: "Autosomal dominant preaxial deficiency, postaxial polydactyly, and hypospadias."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we conclude that this family has a hitherto unreported autosomal dominant condition"
    explanation: Original report establishes autosomal dominant inheritance in the three-generation family.
  - reference: PMID:11968094
    reference_title: "A HOXA13 allele with a missense mutation in the homeobox and a dinucleotide deletion in the promoter underlies Guttmacher syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Guttmacher syndrome, a dominantly inherited combination of distal limb and genital tract abnormalities"
    explanation: Confirms the dominant inheritance of the combined distal limb and genital phenotype.
pathophysiology:
- name: HOXA13 Homeodomain Missense Variant
  biological_scale: MOLECULAR
  description: >
    A heterozygous missense variant in the HOXA13 homeobox (c.1112A>T, Q50L)
    alters a key residue in the recognition helix of the homeodomain and is
    predicted to perturb the DNA-binding transcription-factor activity of
    HOXA13, with both a loss and a specific gain of function. The variant arose
    on an allele also carrying a 2-bp deletion in the gene's conserved promoter;
    that deletion produces no abnormality on its own but may contribute to the
    phenotype.
  genes:
  - preferred_term: HOXA13
    term:
      id: hgnc:5102
      label: HOXA13
  molecular_functions:
  - preferred_term: DNA-binding transcription factor activity
    term:
      id: GO:0003700
      label: DNA-binding transcription factor activity
  evidence:
  - reference: PMID:11968094
    reference_title: "A HOXA13 allele with a missense mutation in the homeobox and a dinucleotide deletion in the promoter underlies Guttmacher syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "affected individuals are heterozygous for a novel missense mutation in the HOXA13 homeobox (c.1112A>T; homeodomain residue Q50L)"
    explanation: Identifies the causal HOXA13 homeodomain missense variant in the original family.
  - reference: PMID:11968094
    reference_title: "A HOXA13 allele with a missense mutation in the homeobox and a dinucleotide deletion in the promoter underlies Guttmacher syndrome."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "The missense mutation, which alters a key residue in the recognition helix of the homeodomain, is likely to perturb HOXA13's DNA-binding properties, resulting in both a loss and a specific gain of function."
    explanation: States the predicted effect of the variant on HOXA13 DNA-binding transcription-factor activity.
  downstream:
  - target: Disrupted Autopod Patterning
    description: Perturbed HOXA13 transcription-factor activity disrupts patterning of the distal limb bud.
  - target: Disrupted Male Urethral Development
    description: The same HOXA13 defect disrupts development of the distal male urethra.
- name: Disrupted Autopod Patterning
  biological_scale: TISSUE
  description: >
    Loss of normal HOXA13-dependent regionalization of the autopod produces the
    combined preaxial deficiency and postaxial polydactyly of the hands and the
    distal foot anomalies. The mechanistic link from HOXA13 dysfunction to limb
    patterning is inferred from HOXA13's established role in distal limb
    morphogenesis; the limb abnormalities themselves are observed in the family.
  biological_processes:
  - preferred_term: embryonic limb morphogenesis
    term:
      id: GO:0030326
      label: embryonic limb morphogenesis
  - preferred_term: regionalization
    term:
      id: GO:0003002
      label: regionalization
  evidence:
  - reference: PMID:11968094
    reference_title: "A HOXA13 allele with a missense mutation in the homeobox and a dinucleotide deletion in the promoter underlies Guttmacher syndrome."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "HFGS is caused by mutations in the HOXA13 gene."
    explanation: Establishes HOXA13 as the gene whose dysfunction underlies the distal limb (and genital) abnormalities of the HOXA13 spectrum.
  - reference: PMID:36734258
    reference_title: "Genetic and phenotypic continuum of HOXA genes: A case with double HOXA9/HOXA13 mutations."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Mutations in HOXA genes have been linked to different human phenotypes, including developmental delay, limb anomalies, and urogenital malformations."
    explanation: Supports the general role of HOXA-cluster (including HOXA13) dysfunction in limb and urogenital malformation.
  downstream:
  - target: Thumb Hypoplasia
    description: Preaxial deficiency of the hand manifests as hypoplastic thumbs.
  - target: Hallux Hypoplasia
    description: Preaxial deficiency of the foot manifests as hypoplastic great toes.
  - target: Postaxial Hand Polydactyly
    description: Abnormal ulnar-side autopod patterning produces supernumerary postaxial digits of the hands.
  - target: Short Second Toe
    description: Reduced phalangeal patterning produces uniphalangeal, shortened second toes.
  - target: Absent Toenails
    description: Distal toe patterning failure leaves the second toes without nails.
- name: Disrupted Male Urethral Development
  biological_scale: TISSUE
  description: >
    HOXA13 also patterns the distal genitourinary tract; its dysfunction
    disrupts male urethral development, producing glanular hypospadias in
    affected males. The genital abnormality is observed; the HOXA13-dependent
    mechanism is inferred.
  biological_processes:
  - preferred_term: male urethra development
    term:
      id: GO:0061069
      label: male urethra development
  evidence:
  - reference: PMID:11968094
    reference_title: "A HOXA13 allele with a missense mutation in the homeobox and a dinucleotide deletion in the promoter underlies Guttmacher syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Guttmacher syndrome, a dominantly inherited combination of distal limb and genital tract abnormalities, has several features in common with hand-foot-genital syndrome (HFGS), including hypoplastic first digits and hypospadias."
    explanation: Links the HOXA13 defect to genital-tract abnormality (hypospadias) alongside the distal limb phenotype.
  downstream:
  - target: Glanular Hypospadias
    description: Disrupted distal male urethral patterning produces glanular hypospadias.
phenotypes:
- name: Thumb Hypoplasia
  category: Limbs
  description: >
    Preaxial deficiency of the hands, with hypoplastic first digits (thumbs).
  phenotype_term:
    preferred_term: Aplasia/Hypoplasia of the thumb
    term:
      id: HP:0009601
      label: Aplasia/Hypoplasia of the thumb
  evidence:
  - reference: PMID:8484413
    reference_title: "Autosomal dominant preaxial deficiency, postaxial polydactyly, and hypospadias."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "preaxial deficiencies of the hands and feet"
    explanation: Preaxial deficiency of the hands corresponds to thumb hypoplasia.
  - reference: PMID:11968094
    reference_title: "A HOXA13 allele with a missense mutation in the homeobox and a dinucleotide deletion in the promoter underlies Guttmacher syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "including hypoplastic first digits and hypospadias"
    explanation: Hypoplastic first digits include the thumbs.
- name: Hallux Hypoplasia
  category: Limbs
  description: >
    Preaxial deficiency of the feet, with hypoplastic great toes.
  phenotype_term:
    preferred_term: Aplasia/Hypoplasia of the hallux
    term:
      id: HP:0008362
      label: Aplasia/Hypoplasia of the hallux
  evidence:
  - reference: PMID:8484413
    reference_title: "Autosomal dominant preaxial deficiency, postaxial polydactyly, and hypospadias."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "preaxial deficiencies of the hands and feet"
    explanation: Preaxial deficiency of the feet corresponds to hallux hypoplasia.
- name: Postaxial Hand Polydactyly
  category: Limbs
  description: >
    Postaxial (ulnar-side) polydactyly of the hands, a feature not seen in
    hand-foot-genital syndrome and taken as a distinguishing feature.
  phenotype_term:
    preferred_term: Postaxial hand polydactyly
    term:
      id: HP:0001162
      label: Postaxial hand polydactyly
  evidence:
  - reference: PMID:8484413
    reference_title: "Autosomal dominant preaxial deficiency, postaxial polydactyly, and hypospadias."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "postaxial polydactyly of the hands"
    explanation: Postaxial polydactyly of the hands is a cardinal feature of the original family.
  - reference: PMID:11968094
    reference_title: "A HOXA13 allele with a missense mutation in the homeobox and a dinucleotide deletion in the promoter underlies Guttmacher syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The presence of features not seen in HFGS, however, including postaxial polydactyly of the hands and uniphalangeal 2(nd) toes with absent nails, suggests that it represents a distinct entity."
    explanation: Identifies postaxial hand polydactyly as distinguishing Guttmacher syndrome from HFGS.
- name: Short Second Toe
  category: Limbs
  description: >
    Uniphalangeal, shortened second toes.
  phenotype_term:
    preferred_term: Uniphalangeal second toe
    term:
      id: HP:0001885
      label: Short 2nd toe
  evidence:
  - reference: PMID:11968094
    reference_title: "A HOXA13 allele with a missense mutation in the homeobox and a dinucleotide deletion in the promoter underlies Guttmacher syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "uniphalangeal 2(nd) toes with absent nails"
    explanation: Uniphalangeal second toes are shortened toes.
- name: Absent Toenails
  category: Limbs
  description: >
    Absent nails of the affected (second) toes.
  phenotype_term:
    preferred_term: Absent toenail
    term:
      id: HP:0001802
      label: Absent toenail
  evidence:
  - reference: PMID:11968094
    reference_title: "A HOXA13 allele with a missense mutation in the homeobox and a dinucleotide deletion in the promoter underlies Guttmacher syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "uniphalangeal 2(nd) toes with absent nails"
    explanation: Records absent nails of the second toes.
- name: Glanular Hypospadias
  category: Genitourinary
  description: >
    Glanular hypospadias (ventrally displaced urethral opening at the glans) in
    affected males.
  phenotype_term:
    preferred_term: Glanular hypospadias
    term:
      id: HP:0000807
      label: Glanular hypospadias
  evidence:
  - reference: PMID:8484413
    reference_title: "Autosomal dominant preaxial deficiency, postaxial polydactyly, and hypospadias."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Both males also had glandular hypospadias."
    explanation: Glanular hypospadias in the two affected males of the original family (spelled "glandular" in the source).
genetic:
- name: HOXA13
  gene_term:
    preferred_term: HOXA13
    term:
      id: hgnc:5102
      label: HOXA13
  association: Causative (provisional; single family)
  variant_origin: GERMLINE
  variants:
  - name: p.Gln50Leu (Q50L)
    description: >
      Heterozygous missense variant c.1112A>T in the HOXA13 homeobox, altering
      homeodomain residue 50 in the recognition helix. Found on an allele also
      carrying a 2-bp promoter deletion (-78_-79delGC).
    variant_type: single nucleotide variant
    evidence:
    - reference: PMID:11968094
      reference_title: "A HOXA13 allele with a missense mutation in the homeobox and a dinucleotide deletion in the promoter underlies Guttmacher syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "affected individuals are heterozygous for a novel missense mutation in the HOXA13 homeobox (c.1112A>T; homeodomain residue Q50L), which arose on an allele already carrying a novel 2-bp deletion (-78-79delGC) in the gene's highly conserved promoter region"
      explanation: Reports the causal missense variant and the cis promoter deletion in the original family.
  notes: >
    The gene-disease link rests on a single re-investigated family (Innis et al.
    2002, PMID:11968094) and is marked provisional in OMIM (#176305); no
    independent validity tier is recorded here because no external body has
    classified HOXA13 for Guttmacher syndrome specifically. The only ClinGen
    gene-disease validity assertion for HOXA13
    (CGGV:assertion_a138effd-f406-4791-b0eb-1f7f89c381d7-2025-07-22T160000.000Z,
    Definitive) is for hand-foot-genital syndrome (MONDO:0007698), a distinct
    MONDO entity, so it is not copied onto this entry. relationship_type is left
    unset and the free-text association records the provisional status.
prevalence:
- population: Worldwide
  measure_type: UNKNOWN
  prevalence_class: NOT_YET_DOCUMENTED
  notes: >
    No prevalence estimate is established. The condition is known from the
    single original family and a small number of HOXA13-spectrum case reports.
differential_diagnoses:
- name: Hand-foot-genital syndrome
  disease_term:
    preferred_term: hand-foot-genital syndrome
    term:
      id: MONDO:0007698
      label: hand-foot-genital syndrome
  description: >
    Allelic HOXA13-related disorder (its own dismech entry) with overlapping
    distal limb and genital features, including hypoplastic first digits and
    hypospadias.
  distinguishing_features:
  - >-
    Postaxial polydactyly of the hands and uniphalangeal second toes with absent
    nails occur in Guttmacher syndrome but not in hand-foot-genital syndrome;
    conversely, Mullerian (uterine) fusion anomalies in affected females are
    characteristic of hand-foot-genital syndrome and were not reported in the
    Guttmacher family. The two are increasingly viewed as one HOXA13 spectrum.
  evidence:
  - reference: PMID:11968094
    reference_title: "A HOXA13 allele with a missense mutation in the homeobox and a dinucleotide deletion in the promoter underlies Guttmacher syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The presence of features not seen in HFGS, however, including postaxial polydactyly of the hands and uniphalangeal 2(nd) toes with absent nails, suggests that it represents a distinct entity."
    explanation: Gives the features that distinguish Guttmacher syndrome from hand-foot-genital syndrome.
  - reference: PMID:24934387
    reference_title: "Severe manifestations of hand-foot-genital syndrome associated with a novel HOXA13 mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Heterozygous HOXA13 mutations have been previously reported in hand-foot-genital syndrome and Guttmacher syndrome, which are variably associated with small nails, short distal and middle phalanges, short thumbs and halluces, but not absent nails."
    explanation: Frames hand-foot-genital and Guttmacher syndromes as variants of one HOXA13-related spectrum.
treatments:
- name: Surgical Correction
  description: >
    Surgical management as indicated: hypospadias repair in affected males and
    reconstructive or orthopaedic surgery for hand and foot anomalies.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: surgical procedure
    term:
      id: NCIT:C15329
      label: Surgical Procedure
- name: Genetic Counseling
  description: >
    Genetic counseling for affected families given autosomal dominant
    inheritance and its recurrence risk.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
notes: >
  Guttmacher syndrome is curated as its own dismech Disease entry because it is a
  distinct MONDO/OMIM/Orphanet entity (MONDO:0008301; OMIM #176305; ORPHA:2957)
  with features - notably postaxial polydactyly of the hands and uniphalangeal
  second toes with absent nails - not seen in the allelic hand-foot-genital
  syndrome (MONDO:0007698), which has its own entry. The whole clinical picture
  derives from one three-generation family, and the HOXA13 gene-disease link is
  marked provisional in OMIM; later literature treats the two HOXA13 disorders as
  one phenotypic spectrum (PMID:24934387).

📚

References & Deep Research

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)

Create: Guttmacher_Syndrome · 2026-10-12T14:28:28Z · View source

De-novo curation of Guttmacher syndrome (MONDO:0008301, HOXA13), claim #13929. Curated as its own DISEASE entry: distinct MONDO/OMIM(#176305)/Orphanet(ORPHA:2957) entity, allelic to and distinguished from hand-foot-genital syndrome (MONDO:0007698, own entry) by postaxial hand polydactyly and uniphalangeal 2nd toes with absent nails. Four PMIDs quoted (8484413 Guttmacher 1993 original family; 11968094 Innis 2002 HOXA13 Q50L; 24934387 Imagawa 2014 severe-spectrum; 36734258 Jaouadi 2023 HOXA continuum background). Deep-research report used as leads only (thin, no verbatim quotes). Pathograph: 3 nodes (HOXA13 missense variant -> autopod patterning + male urethral development) wiring all 6 phenotypes via bare-name downstream edges; gene node grounded with GO:0003700 molecular_functions. gene_disease_validity omitted - only HOXA13 ClinGen assertion is for HFGS, not Guttmacher; recorded in genetic.notes. Validation: validate-disorders passed, 18/18 snippets verified, validate-terms passed, check-gene-activity-grounding clean, 6/6 phenotypes connected.

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1. Disease Information

claude-haiku-5-5, claude-sonnet-5-5 4 citations 2026-10-12T14:12:12.499577

1. Disease Information

Overview. Guttmacher syndrome is an extremely rare, dominantly inherited malformation syndrome of the distal limbs and the distal genitourinary tract. Orphanet's definition, reproduced by NORD, lists these features: - hypoplastic thumbs and halluces - 5th-finger clinobrachydactyly - postaxial polydactyly of the hands - short or uniphalangeal 2nd toes with absent nails - hypospadias

Guttmacher described it in 1993 in one family (a father, a son and a daughter). He judged it distinct from hand-foot-genital syndrome (HFGS). He took postaxial polydactyly as the distinguishing feature (OMIM #176305, which cites Guttmacher 1993, PMID:8484413).

Identifiers (from the sources below; confirm each in a lookup step before binding).

Source	Identifier
OMIM phenotype	#176305, "Preaxial deficiency, postaxial polydactyly, and hypospadias" (Guttmacher syndrome is an alternative title)
Orphanet	ORPHA:2957
MONDO	MONDO:0008301 (reported by one search summary; verify)
Disease Ontology	DOID:0111544
SNOMED CT	722452004
MedGen	401304
Gene	HOXA13 (OMIM 142959), 7p15.2; HGNC ID not retrieved. In the KB it is written lowercase as `hgnc:NNNN`, copied from a lookup.

Do not confuse these with hand-foot-genital syndrome (HFGS, also called hand-foot-uterus syndrome), which is OMIM #140000 and ORPHA:2438. It is a separate entry.

Synonyms. Preaxial deficiency–postaxial polydactyly–hypospadias syndrome (GUTTS); Guttmacher syndrome.

Level of data. The data are aggregated, disease-level resources and one family-level report. No EHR-derived data were found.

Curation implication. Under the lump/split rules this is probably a DISEASE entry. It is a distinct OMIM and Orphanet entity with its own MONDO term. Overlap with HFGS must be recorded, and a note should say that HFGS has its own entry. The gene–disease link is provisional (see §4).

2. Etiology

Causal factor. Genetic. Heterozygous HOXA13 missense variant, Q50L, found in the original family (Innis et al. 2002, PMID:11968094).
Genetic risk factors. None beyond the HOXA13 variant. The reported allele also carried a 2-bp deletion in the HOXA13 promoter. It caused no detectable abnormality by itself but "may contribute" (OMIM, summarizing Innis 2002). Treat this as a possible cis-modifier, not an established one.
Environmental, protective and gene–environment factors. Nothing found. Not applicable or not documented.

3. Phenotypes

All of this comes from one family (OMIM #176305, Guttmacher 1993). Frequencies cannot be given, so use qualitative terms only.

Phenotype	HPO (OMIM synopsis; others need lookup)	Notes
Short thumbs (preaxial hypoplasia)	HP:0009778	Thumb hypoplasia; "preaxial deficiencies" in all 3 affected
Postaxial polydactyly of hands	HP:0001162	Distinguishing feature versus HFGS
5th-finger brachydactyly/clinodactyly	HP:0001156 (mild brachydactyly of the 5th finger)	Orphanet: clinobrachydactyly
Glanular hypospadias	HP:0000807	Father and son
Rudimentary or hypoplastic halluces	Lookup needed
Uniphalangeal or short 2nd toes	Lookup needed
Absent nails of halluces and 2nd toes	Lookup needed
Limited interphalangeal joint motion	Lookup needed

Onset. Congenital or neonatal (Orphanet).
Progression. Static malformations (inference; not stated).
Severity. Variable in the HOXA13 spectrum. One severe, de novo HOXA13 case with absent nails, absent halluces and genitourinary malformations was placed by the authors at the severe end of the HFGS/Guttmacher spectrum (Imagawa 2014, PMID:24934387).
Quality of life. No data.
Uterine anomalies. These belong to HFGS, not to the Guttmacher family as described. The one female case in that family was a daughter, and a uterine anomaly is not recorded for her. Do not add a uterine phenotype.

4. Genetic/Molecular Information

Gene. HOXA13, a homeobox transcription factor. OMIM marks the gene–phenotype link as provisional ("?").
Variant. c.1112A>T, p.Gln50Leu (homeodomain residue 50; OMIM allelic variant 142959.0005). It was found in the original family (Innis et al. 2002).
Mechanism. The missense change alters a key residue in the recognition helix of the homeodomain. Innis et al. suggest this may affect DNA binding, with both loss and gain of function (my summary; verify against the full text).
Classification. The OMIM source is a single family. Under ACMG, only the original report supports it, and ClinVar and ClinGen status was not retrieved. No ClinGen gene–disease validity record was checked. Do not fill gene_disease_validity unless a CGGV record turns up for this disease.
Origin. Germline (familial).
Allele frequency, epigenetic and chromosomal data. Not retrieved.
Related variants. Other HOXA13 variants cause HFGS (OMIM #140000). Imagawa 2014 reports a de novo HOXA13 variant in a severe case. One search summary gave p.Ile368Phe for it (also written c.1102A>T), but that comes from a search summary only and must be checked against the paper.

5. Environmental Information

No environmental, lifestyle or infectious factors are documented. Not applicable.

6. Mechanism / Pathophysiology

Causal chain (the HOXA13 steps are inferred from the general HOXA13 literature and the Innis 2002 interpretation. The patient-level steps are observed in the family.)

A heterozygous HOXA13 missense variant (Q50L) changes the homeodomain recognition helix. Demonstrated as a variant; its functional effect is inferred (PMID:11968094).
This is predicted to alter DNA binding by the HOXA13 transcription factor, with possible loss and gain of function. Inferred. A promoter 2-bp deletion on the same allele may modulate expression. Hypothesised.
Abnormal HOXA13-dependent patterning of the distal limb bud (autopod) follows. Inferred from the HOXA13 literature; not curated from a source in this session.
The patterning defect produces preaxial hypoplasia of thumbs and halluces, 5th-finger shortening, postaxial polydactyly, and hypoplastic nails and phalanges. Observed in the family; the link from step 3 is inferred.
A parallel defect in genital tubercle development produces hypospadias. Observed in males; mechanism inferred.

Suggested ontology terms. Verify each by lookup before binding. - GO: pattern specification process; embryonic limb morphogenesis; DNA-binding transcription factor activity. - Cell types: limb bud mesenchymal cells and distal limb progenitors (CL term to look up). - Anatomy: autopod, hand, foot, nail, penis/urethra (UBERON IDs to look up).

Molecular profiling, single-cell and multi-omics data for this disease were not found.

7. Anatomical Structures Affected

Primary: hands (thumb, 5th finger, ulnar side), feet (hallux, 2nd toe), nails, and the distal male urethra (glanular hypospadias).
Pattern: bilateral involvement is not stated in the sources I read, so lateralization is unknown.
Subcellular site: nucleus (the HOXA13 transcription factor).

8. Temporal Development

Congenital, with neonatal recognition (Orphanet).
Static course; there is no source for progression.
No stages, remission, or critical periods are documented, apart from embryonic limb and genital development (inference).

9. Inheritance and Population

Inheritance. Autosomal dominant (HP:0000006). In the family, a father transmitted it to a son and a daughter, consistent with dominant inheritance.
Penetrance and expressivity. Not formally assessed. Only one family has been described.
Prevalence. Orphanet gives no prevalence data. One aggregator mentions an estimate of about 1,000 US cases. I could not verify it and do not recommend using it. The class is probably NOT_YET_DOCUMENTED, or CASES_IN_LITERATURE with measure_type set accordingly.
Founder effect, consanguinity, carrier frequency, ancestry, sex ratio. Not documented.

10. Diagnostics

Clinical. Examination of the hands, feet and genitalia, plus limb radiographs. No criteria were retrieved.
Differential. HFGS (OMIM #140000): no postaxial polydactyly, and uterine anomalies in women. Also consider other HOXA13-related phenotypes and other syndromic limb malformations (not reviewed).
Genetic testing. Single-gene HOXA13 sequencing or a limb-malformation gene panel (no panel contents retrieved). HOXA13 contains a polyalanine tract, so check how the laboratory handles repeat-region variants and deletions. This is general knowledge, not from a retrieved source.
Biomarkers and screening. None known.

11. Outcome/Prognosis

No survival, life expectancy or quality-of-life data were found. Morbidity is presumably functional (hand and foot use, hypospadias repair), which is an inference. Not documented.

12. Treatment

No disease-specific literature was found. Management is supportive and surgical, which is an inference rather than a sourced claim: - Hypospadias repair: NCIT surgical procedure terms (verify the CURIE by lookup). - Hand and foot reconstructive or orthopaedic surgery (NCIT:C16186 Orthopedic Surgical Procedure appears in the repository guidance). - Genetic counseling (NCIT:C15240).

There is no pharmacotherapy, gene therapy or clinical trial. I did not search ClinicalTrials.gov.

13. Prevention

Genetic counseling for autosomal dominant recurrence (50% risk for offspring of an affected parent, from the standard dominant model).
Prenatal or preimplantation testing is possible in a family with a known variant (general principle).
No other prevention data.

14. Other Species / Natural Disease

No natural disease is documented in the sources read. OMIA was not searched. The OMIM page links to Alliance Genome and MGI resources but gives no animal model description.

15. Model Organisms

I did not retrieve any Guttmacher-specific model.
General knowledge, unsourced here: mouse Hoxa13 mutants show distal limb and genital phenotypes, and Mortlock and colleagues linked HOXA13 mutation to the hand-foot-genital phenotype (Mortlock 1996, cited in one search result as the HFGS origin; the PMID was not retrieved). Verify through MGI before adding any animal_models entry.
No Q50L knock-in model was found.

Key References

Guttmacher AE et al. 1993. Am J Med Genet 46:219-222. PMID:8484413. Original family description, cited by OMIM.
Innis JW, Goodman FR, Bacchelli C, Williams TM, Mortlock DP, Sateesh P, Scambler PJ, McKinnon W, Guttmacher AE. Hum Mutat 2002;19(5):573-574. PMID:11968094. Title as returned: a HOXA13 allele with a missense mutation in the homeobox and a dinucleotide deletion in the promoter underlies Guttmacher syndrome. Q50L; re-examination of the original family.
Imagawa E, Kayserili H, Nishimura G, Nakashima M, Tsurusaki Y, Saitsu H, Ikegawa S, Matsumoto N, Miyake N. Am J Med Genet A 2014;164A(9):2398-2402. PMID:24934387. Severe HFGS manifestations with a novel de novo HOXA13 variant. Its authors mention Guttmacher syndrome as part of the spectrum.
OMIM #176305 (the page text was read; its last ~8 kB was not): https://git.lsit.ucsb.edu/publicdata/nih-gov/raw/branch/main/www.ncbi.nlm.nih.gov/omim/176305
OMIM #140000, hand-foot-genital syndrome: https://git.lsit.ucsb.edu/publicdata/nih-gov/raw/commit/a3492137cada35c1427e5783c176e4344e6cbb56/www.ncbi.nlm.nih.gov/omim/140000
Orphanet/NORD summary: https://rarediseases.org/mondo-disease/guttmacher-syndrome/
MalaCards, Preaxial deficiency, postaxial polydactyly, and hypospadias: https://www.malacards.org/card/preaxial_deficiency_postaxial_polydactyly_and_hypospadias_2

A search also turned up PMID:36734258, a case with a HOXA9/HOXA13 deletion whose background reviews Guttmacher syndrome. I did not read it, so use it only as a lead.

Gaps and Cautions for Curation

Single family. The whole phenotype list rests on one family, and the gene–disease link is provisional in OMIM. Say so in notes. Do not assign a validity tier that no external body has given.
Quotes. I have no verbatim snippets. Fetch the cache entries and quote from them.
IDs. HGNC, UBERON, CL and GO identifiers and the remaining HPO terms have not been looked up. Do not bind any from this report without a lookup.
HFGS overlap. Orphanet and OMIM keep Guttmacher syndrome and HFGS separate, while the literature treats them as one spectrum (PMID:24934387). Record this overlap in the entry.
Possible merge. If MONDO later merges the two, the entry would be affected. A mondo_replaced_by check is cheap.

Reference Validation

Checked with linkml-reference-validator 0.3.0.

Outcome	Count
References checked	4
Resolved	4
Unresolved (possible confabulation)	0
Unverifiable	0
References weighed for topical relevance	4
On topic	4
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	11
Resolved	9
Unresolved (possible confabulation)	0
Obsolete	0
Unverifiable	2
Terms whose name was checked	6
Terms named correctly	2
Terms named as a different term	1
Terms whose name is worth a second look	3

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:

DOID:0111544 (1 mention) - the report calls it "Disease Ontology"; DOID calls it Guttmacher syndrome

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:

HP:0009778 (1 mention) - the report calls it "Short thumbs (preaxial hypoplasia)"; HP calls it Short thumb, and lists "Thumb hypoplasia" among its other names
HP:0001162 (1 mention) - the report calls it "Postaxial polydactyly of hands"; HP calls it Postaxial hand polydactyly, and lists "Postaxial polydactyly of hand" among its other names
HP:0001156 (1 mention) - the report calls it "mild brachydactyly of the 5th finger"; HP calls it Brachydactyly, and lists "Brachydactyly syndrome" among its other names

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: ORPHA.

Guttmacher syndrome

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Prevalence

Differential Diagnoses

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References & Deep Research

Deep Research

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic/Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome/Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Key References

Gaps and Cautions for Curation

Reference Validation

Term Validation

Terms the report names something else

Terms whose name is worth a second look

Prefixes with no resolver