Guttmacher syndrome

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).

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.

• 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.)

1. A heterozygous HOXA13 missense variant (Q50L) changes the homeodomain recognition helix. Demonstrated as a variant; its functional effect is inferred (PMID:11968094).
2. 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.
3. Abnormal HOXA13-dependent patterning of the distal limb bud (autopod) follows. Inferred from the HOXA13 literature; not curated from a source in this session.
4. 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.
5. 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

1. Guttmacher AE et al. 1993. Am J Med Genet 46:219-222. PMID:8484413. Original family description, cited by OMIM.
2. 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.
3. 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.
4. 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
5. OMIM #140000, hand-foot-genital syndrome: https://git.lsit.ucsb.edu/publicdata/nih-gov/raw/commit/a3492137cada35c1427e5783c176e4344e6cbb56/www.ncbi.nlm.nih.gov/omim/140000
6. Orphanet/NORD summary: https://rarediseases.org/mondo-disease/guttmacher-syndrome/
7. 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.

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:

• 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.