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Split Hand-Foot Malformation

Split Hand-Foot Malformation (SHFM) / Ectrodactyly — Disease Characteristics Research Report

2026-06-08
Falcon MONDO:0016576 Model: Edison Scientific Literature 38 citations

Split Hand-Foot Malformation (SHFM) / Ectrodactyly — Disease Characteristics Research Report

Scope and evidence note. This report is derived from aggregated, disease-level primary/review literature retrieved via tool-based full-text evidence extraction. Where the user requested OMIM/Orphanet/MONDO/ICD/MeSH identifiers, the current tool context did not include authoritative ontology pages, so those identifiers are not reliably extractable here; the report focuses on evidence-supported definitions, genetics, mechanisms, diagnostics, and recent (2023–2024) advances from the retrieved peer‑reviewed literature. PMIDs were not present in the retrieved text excerpts for most papers; therefore, citations are provided using the available evidence context IDs, and URLs/DOIs and publication dates are included when available.

1. Disease Information

1.1 Concise overview (current understanding)

Split hand-foot malformation (SHFM), also called ectrodactyly, is a congenital limb defect characterized by a median cleft of the hands and/or feet due to absence or hypoplasia of the central rays (central digits). (ambrosetti2023splithandfootand pages 1-2, sowinskaseidler2014splithandfootmalformation pages 1-2)

A commonly cited subtype, SHFM1, maps to the 7q21q22 region and is described as autosomal dominant with incomplete penetrance and variable expressivity, and may be associated with extra-limb features such as hearing loss and craniofacial anomalies. (ambrosetti2023splithandfootand pages 1-2)

1.2 Synonyms and alternative names

1.3 Key identifiers (OMIM/Orphanet/ICD/MeSH/MONDO)

Not extractable from the current evidence corpus (no direct OMIM/Orphanet/MONDO/ICD/MeSH records were retrieved in the provided tool context). A genetics-oriented review notes that SHFM loci (SHFM1–6 and SHFM/SHFLD) correspond to OMIM-referenced entities, but does not provide the complete identifier table in the excerpted text. (sowinskaseidler2014splithandfootmalformation pages 1-2)

1.4 Data source type

Evidence here is primarily from: - Aggregated disease-level resources (reviews) (sowinskaseidler2014splithandfootmalformation pages 1-2, umair2019nonsyndromicsplithandfootmalformation pages 1-2) - Individual/family case reports and mechanistic studies with genomic testing and functional follow-up (ambrosetti2023splithandfootand pages 1-2, akimova2024variableclinicalpresentation pages 1-2, ambrosetti2023splithandfootand pages 4-7, truong2023prdm1dnabindingzinc pages 1-2)

2. Etiology

2.1 Disease causal factors (primary causes)

SHFM is genetically heterogeneous with causal contributions from: 1. Regulatory structural variants (SVs)/CNVs disrupting limb gene expression domains (7q21 and 10q24 are major examples). (ambrosetti2023splithandfootand pages 1-2, cova2023combinatorialeffectson pages 1-2, cova2023combinatorialeffectson pages 9-11) 2. Single-gene pathogenic variants in limb developmental regulators (e.g., WNT10B; PRDM1; TP63 noted in reviews). (bilal2023sequencevariantsin pages 1-2, truong2023prdm1dnabindingzinc pages 1-2, sowinskaseidler2014splithandfootmalformation pages 1-2)

A review emphasizes that SHFM is “clinically and genetically heterogeneous” and that many cases are linked to chromosomal rearrangements (deletions/duplications/inversions/translocations) while a subset is due to point mutations (TP63, WNT10B, DLX5). (sowinskaseidler2014splithandfootmalformation pages 1-2)

2.2 Genetic risk factors

Major loci/genes (recently supported)

Inheritance patterns / penetrance

2.3 Environmental risk factors / protective factors / GxE

No robust 2023–2024 evidence for environmental or protective factors (or gene–environment interactions) was present in the retrieved corpus. SHFM is predominantly treated as a genetic developmental disorder in these sources. (sowinskaseidler2014splithandfootmalformation pages 1-2, ambrosetti2023splithandfootand pages 1-2)

3. Phenotypes

3.1 Core phenotype spectrum

A primary 2023 report defines SHFM as a “congenital limb defect characterized by a median cleft of the hands and/or feet due to the absence/hypoplasia of the central rays.” (ambrosetti2023splithandfootand pages 1-2)

A 2023 WNT10B paper similarly describes SHFM/ectrodactyly as a rare limb deformity with “median cleft of the hand and foot with impaired or missing central rays.” (bilal2023sequencevariantsin pages 1-2)

Typical manifestations include: - Split/median cleft of hand/foot - Missing or hypoplastic central digits - Syndactyly of remaining digits (ambrosetti2023splithandfootand pages 1-2, bilal2023sequencevariantsin pages 1-2)

3.2 Associated/extra-limb features

  • Hearing loss: In the SHFM1 context, hearing loss is reported to occur in ~35% of affected individuals. (ambrosetti2023splithandfootand pages 1-2)
  • In a 2023 SHFM1 case with 7q21 deletion affecting DYNC1I1 eExons, the patient had severe–profound hearing loss with inner-ear abnormality (incomplete partition type I) and required cochlear implantation (see Treatment). (ambrosetti2023splithandfootand pages 4-7)

3.3 SHFM with long bone deficiency (SHFLD) / overlap phenotypes

A 2024 review/case report of FATCO associated with SHFLD highlights the broader spectrum in which split-hand/foot phenotypes can coexist with long bone anomalies (tibia/fibula/femur), and cites multiple genetic associations (e.g., DLX5; BHLHA9 duplications; 17p13.3 rearrangements) supporting heterogeneity and overlap with reduction defects. (deftereou2024acaseofa pages 11-12)

3.4 Onset, progression, severity

3.5 Suggested HPO terms (examples)

(terms suggested for knowledge-base annotation; not all terms are explicitly enumerated in the sources) - Split hand: HP:0001171 (suggested) - Split foot: HP:0001839 (suggested) - Ectrodactyly: HP:0001159 (suggested) - Syndactyly: HP:0001159/HP:0006101 (suggested; subtype-specific) - Sensorineural hearing impairment: HP:0000407 (suggested; for SHFM1 spectrum) (ambrosetti2023splithandfootand pages 1-2, ambrosetti2023splithandfootand pages 4-7)

3.6 Quality of life impact

No quantitative QoL instruments (EQ‑5D/SF‑36/PROMIS) were present in the retrieved corpus; however, functional burden is implied by severe limb reduction and need for hearing intervention in syndromic cases. (ambrosetti2023splithandfootand pages 4-7)

4. Genetic / Molecular Information

4.1 Causal genes and variant classes (selected, evidence-backed)

SHFM1 (7q21 locus): enhancer disruption affecting DLX5/DLX6

A 2023 study reports a 7q21.13–q21.3 deletion that does not include DLX5/DLX6 but removes DYNC1I1 exons 15 and 17, described as exonic enhancers (eExons) of DLX5/DLX6. Reduced DLX5/DLX6 expression was shown in patient-derived lymphoblastoid cells, supporting a regulatory SV mechanism. (ambrosetti2023splithandfootand pages 1-2, ambrosetti2023splithandfootand pages 2-4)

Mechanistic implication: disease can result from disruption of regulatory elements even when the target coding genes remain intact. (ambrosetti2023splithandfootand pages 1-2)

SHFM3 (10q24): SV-driven chromatin/TAD rewiring and enhancer hijacking

A 2023 Nature Communications paper investigated SHFM3-associated tandem duplications/inversions at the LBX1/FGF8 locus. It reports that engineered duplications/inversions restructure chromatin architecture and produce ectopic activation of Lbx1 and Btrc in the AER driven by AER-specific enhancers of Fgf8. (cova2023combinatorialeffectson pages 1-2, cova2023combinatorialeffectson pages 9-11)

Recent real-world genomics reports show WGS can identify the duplicated segment (e.g., chr10:102,934,495–103,496,555 encompassing BTRC, POLL, FBXW4, LBX1), and mosaic state in an unaffected carrier can explain phenotypic variability. (akimova2024variableclinicalpresentation pages 1-2, akimova2024variableclinicalpresentation pages 2-3)

SHFM6 (WNT10B): autosomal recessive coding variants

A 2023 Molecular Syndromology report identified WNT10B variants in two Pakistani families with non-syndromic SHFM, including a novel homozygous missense c.338G>C (p.Gly113Ala) and a homozygous frameshift c.884-896del… (p.Phe295Cysfs*87). (bilal2023sequencevariantsin pages 1-2, bilal2023sequencevariantsin pages 2-5)

PRDM1: functional genomics-supported gene implication

A 2023 Disease Models & Mechanisms paper reports three novel heterozygous PRDM1 variants (including de novo alleles) in SHFM families, with zebrafish functional assays indicating variants act “in a dominant-negative fashion due to disruption of the proline/serine and DNA-binding zinc finger domains.” (truong2023prdm1dnabindingzinc pages 2-2, truong2023prdm1dnabindingzinc pages 2-4)

4.2 Modifier genes, epigenetics, allele frequencies

Not extractable from the current evidence corpus (no gnomAD allele frequencies, ClinVar classifications, or epigenetic profiling in patient tissues were included in the excerpts). Mosaicism as a modifier for penetrance is supported in SHFM3 duplication families. (akimova2024variableclinicalpresentation pages 2-3)

5. Environmental Information

No specific environmental, lifestyle, or infectious contributors were identified in the retrieved SHFM corpus; current evidence emphasizes genetic and regulatory mechanisms in limb development. (sowinskaseidler2014splithandfootmalformation pages 1-2)

6. Mechanism / Pathophysiology

6.1 Central developmental concept: AER dysfunction and altered limb gene regulatory networks

SHFM is widely interpreted as a consequence of disrupted signaling/regulation in the developing limb, particularly the apical ectodermal ridge (AER) (or analogous structures in model organisms), leading to loss of central rays. A genetics review notes DLX5/DLX6 expression in the AER and their role in maintaining proliferation of medial AER cells. (sowinskaseidler2014splithandfootmalformation pages 1-2)

6.2 2023–2024 mechanistic advances (high-priority)

(A) SHFM3 (10q24): 3D genome architecture and enhancer hijacking (mouse in vivo; human SV model)

The 2023 Nature Communications study provides a contemporary mechanistic resolution: SVs at the LBX1/FGF8 locus restructure chromatin domains, enabling AER enhancers normally regulating Fgf8 to activate neighboring genes. Specifically, the study reports ectopic activation of Lbx1 and Btrc in the AER in an “Fgf8-like pattern induced by AER-specific enhancers of Fgf8,” and concludes SHFM3 results from “a combinatorial effect on gene misexpression in the developing limb.” (cova2023combinatorialeffectson pages 1-2, cova2023combinatorialeffectson pages 9-11)

Causal chain (one evidence-backed formulation): 10q24 duplication/inversion → altered TAD boundaries/enhancer–promoter contacts → AER-specific Fgf8 enhancers contact LBX1/BTRC promoters → ectopic AER expression of LBX1/BTRC ± altered FGF8 → AER dysfunction → central-ray absence/split hand-foot phenotype. (cova2023combinatorialeffectson pages 9-11)

Visual evidence (figure-based): the locus/TAD structure and SV consequences are summarized in the retrieved figure panels. (cova2023combinatorialeffectson media 96921fee, cova2023combinatorialeffectson media 2619b58c)

(B) PRDM1 variants: disruption of limb induction/outgrowth and AP patterning (zebrafish functional genomics)

The 2023 DMM study integrates human genetics with zebrafish mechanistic work. It reports that PRDM1 variants have reduced function and act dominantly; CUT&RUN demonstrates that Prdm1a directly binds regulatory sequences of key limb genes, including fgfr1a, dlx5a, dlx6a and smo, and that prdm1a loss alters expression of these pathways, implicating coordinated FGF and SHH signaling in fin/limb patterning. (truong2023prdm1dnabindingzinc pages 9-10, truong2023prdm1dnabindingzinc pages 10-11)

Causal chain (evidence-backed): PRDM1 zinc-finger/proline-serine disruption → impaired DNA binding/cofactor recruitment → dysregulation of fgfr1a/dlx5a/dlx6a and Shh pathway targets (smo) → defective apical fold (AER analog) maintenance and AP patterning → pectoral fin/limb defects consistent with SHFM. (truong2023prdm1dnabindingzinc pages 10-11, truong2023prdm1dnabindingzinc pages 11-12)

(C) SHFM1 (7q21): enhancer deletion lowers DLX5/DLX6 expression

A 2023 Genes report provides a clear example of regulatory etiology: deletion of DYNC1I1 eExons 15/17 leads to reduced DLX5/DLX6 expression (to ~40–45% in the proband vs parents) despite intact DLX coding sequence, supporting a position-effect/long-range enhancer mechanism. (ambrosetti2023splithandfootand pages 4-7, ambrosetti2023splithandfootand pages 2-4)

6.3 Suggested pathway/ontology annotations

(ontology suggestions; not all terms appear verbatim in sources) - GO Biological Process (examples): limb development; appendage morphogenesis; regulation of epithelial cell proliferation; anterior/posterior pattern specification; regulation of Wnt signaling; regulation of FGF signaling. - Cell Ontology (CL) candidates: apical ectodermal ridge cells (epithelial ridge cells; suggested), limb bud mesenchymal cells (suggested). - UBERON candidates: hand (UBERON:0002398), foot (UBERON:0002399), limb bud (UBERON:0000069), apical ectodermal ridge (suggested).

7. Anatomical Structures Affected

7.1 Organ/system level

7.2 Tissue/cell level (mechanism-driven)

7.3 Subcellular

Not supported in retrieved excerpts.

8. Temporal Development

9. Inheritance and Population

9.1 Epidemiology statistics

9.2 Inheritance patterns

9.3 Population variation / founder effects

Not directly addressed in the retrieved excerpts; some recent reports are population-specific family studies (e.g., Pakistani WNT10B families). (bilal2023sequencevariantsin pages 1-2)

10. Diagnostics

10.1 Clinical/radiographic diagnosis

Clinical diagnosis is based on characteristic limb morphology (median cleft, missing central rays) and can be identified prenatally by imaging; specific radiographic criteria were not detailed in the retrieved excerpts. (ambrosetti2023splithandfootand pages 1-2)

10.2 Genetic testing: current best-supported real-world workflows

(A) CNV/SV detection for SHFM1 regulatory deletions

A 2023 SHFM1 case demonstrates that conventional karyotype and FISH can be normal/negative, while high-resolution SNP array can detect a pathogenic 7q21 deletion affecting enhancers and enabling diagnosis; functional validation used expression testing in patient-derived lymphoblastoid cell lines. (ambrosetti2023splithandfootand pages 4-7, ambrosetti2023splithandfootand pages 2-4)

(B) WGS for SHFM3 duplications and mosaicism

A 2024 Frontiers in Genetics case report used whole-genome sequencing to identify a 10q24.32 duplication and applied segregation/validation PCR; importantly, it identified a mosaic duplication (~10%) in an unaffected grandmother, explaining variable phenotype. (akimova2024variableclinicalpresentation pages 1-2, akimova2024variableclinicalpresentation pages 2-3)

(C) 2024 innovation: single-cell detection for prenatal/PGT settings

An Oct 2024 Orphanet Journal of Rare Diseases paper proposes a workflow for single-cell detection of 10q24 duplications for SHFM3 in limited DNA contexts, integrating NGS, SNP array/Karyomapping, whole-genome amplification (MDA/MALBAC), and single-molecule sequencing, aiming to improve accuracy in IVF‑PGT and prenatal diagnosis. (wang2024anovelapproach pages 6-7)

10.3 Differential diagnosis

Not systematically enumerated in the retrieved excerpts. Clinically overlapping entities include SHFLD/FATCO and other reduction defect syndromes. (deftereou2024acaseofa pages 11-12)

11. Outcome / Prognosis

No cohort-based survival or life expectancy data were present in the retrieved excerpts. Prognosis is primarily functional and depends on severity of limb reduction and associated anomalies (e.g., hearing loss). (ambrosetti2023splithandfootand pages 4-7)

12. Treatment

12.1 Current applications / real-world implementations

Most limb-directed management (reconstructive hand/foot surgery, prosthetics, occupational therapy) is standard of care for congenital limb differences, but specific surgical outcome datasets were not contained in the retrieved excerpts.

12.2 Clinical trials

No SHFM-specific interventional clinical trials were identified in the retrieved evidence corpus.

12.3 Suggested MAXO terms (examples)

13. Prevention

No environmental primary prevention strategies were supported by retrieved evidence. For genetic forms, prevention in practice centers on genetic counseling and reproductive options (e.g., prenatal diagnosis, PGT) supported by recent single-cell CNV diagnostic work and SHFM3 family recurrence reports. (wang2024anovelapproach pages 6-7, singh2025uncoveringthegenetic pages 1-2)

14. Other Species / Natural Disease

Not addressed in the retrieved excerpts.

15. Model Organisms

15.1 Mouse models (SHFM3 mechanism)

CRISPR-engineered duplication/inversion alleles at the Lbx1/Fgf8 locus in mice are used to test chromatin architecture changes and limb phenotypes, directly modeling human SHFM3 SVs. (cova2023combinatorialeffectson pages 1-2, cova2023combinatorialeffectson pages 9-11)

15.2 Zebrafish models (PRDM1-associated SHFM)

Zebrafish prdm1a mutants (loss-of-function) show pectoral fin defects, and overexpression/rescue assays demonstrate that human SHFM-associated PRDM1 variants fail to rescue, supporting pathogenicity and providing a functional validation platform. (truong2023prdm1dnabindingzinc pages 2-4, truong2023prdm1dnabindingzinc pages 10-11)

2023–2024 “latest research” highlights (expert synthesis)

  1. 3D genome / enhancer hijacking has become a primary mechanistic explanation for SHFM3: the 2023 Nature Communications work provides a high-resolution, in vivo demonstration that SVs at 10q24 alter TAD architecture and cause AER misexpression of Lbx1/Btrc, requiring combinatorial misexpression to produce phenotype. (cova2023combinatorialeffectson pages 9-11)
  2. Regulatory deletions in SHFM1 are increasingly interpreted through enhancer logic rather than coding loss, exemplified by the 2023 Genes report demonstrating reduced DLX5/DLX6 expression due to deletion of DYNC1I1 exonic enhancers. (ambrosetti2023splithandfootand pages 4-7)
  3. Clinical genomics is shifting toward higher-resolution and context-specific assays: WGS for CNV/SV and mosaicism in familial SHFM3 (Jan 2024), and single-cell CNV workflows for IVF‑PGT/prenatal diagnosis (Oct 2024). (akimova2024variableclinicalpresentation pages 1-2, wang2024anovelapproach pages 6-7)

Genetics summary table (for knowledge-base ingestion)

Table (click to expand)
Subtype/Mechanism Locus/genes Inheritance/penetrance notes Key phenotype/extra features Key 2023-2024 evidence source (citation id) Publication (journal, date) and URL/DOI
SHFM1 – 7q21 regulatory/coding defects 7q21.3; DLX5/DLX6 and long-range enhancers including DYNC1I1 eExons 15/17 Usually autosomal dominant with incomplete penetrance and variable expressivity; pathogenic mechanism often regulatory (enhancer deletion/separation) rather than coding loss alone (ambrosetti2023splithandfootand pages 1-2, ambrosetti2023splithandfootand pages 7-8, sowinskaseidler2023agenotype–phenotypecorrelation pages 13-13) Median cleft/split hand-foot; may include hearing loss (~35% in SHFM1 context), inner-ear anomalies, craniofacial anomalies, developmental delay in some rearrangements (ambrosetti2023splithandfootand pages 1-2, ambrosetti2023splithandfootand pages 4-7) (ambrosetti2023splithandfootand pages 1-2, ambrosetti2023splithandfootand pages 2-4, sowinskaseidler2023agenotype–phenotypecorrelation pages 13-13) Genes (26 Jul 2023): Ambrosetti et al., Split hand-foot and deafness in a patient with 7q21.13-q21.3 deletion not including the DLX5/6 genes. https://doi.org/10.3390/genes14081526 ; Frontiers in Molecular Biosciences (Oct 2023): Sowińska-Seidler et al. https://doi.org/10.3389/fmolb.2023.1250714
SHFM3 – 10q24 structural-variant mechanism 10q24.31-q24.32; LBX1, BTRC, FBXW4, POLL with altered regulation of the LBX1/FGF8 locus and AER enhancers in FBXW4/Fgf8 domain Usually autosomal dominant; marked variable expressivity and reduced penetrance; mosaicism documented in unaffected/less affected carriers; mechanism is chromatin/TAD rewiring by duplication or inversion (akimova2024variableclinicalpresentation pages 1-2, akimova2024variableclinicalpresentation pages 2-3, cova2023combinatorialeffectson pages 1-2, cova2023combinatorialeffectson pages 9-11) Split hand/foot with central-ray deficiency; severity ranges from mild SHFM to severe limb deficiencies; some families show syndromic features (hearing/renal/craniofacial) depending on rearrangement extent (dimitrov2010distallimbdeficiencies pages 9-11, akimova2024variableclinicalpresentation pages 1-2) (cova2023combinatorialeffectson pages 1-2, cova2023combinatorialeffectson pages 9-11, akimova2024variableclinicalpresentation pages 1-2) Nature Communications (Mar 2023): Cova et al., Combinatorial effects on gene expression at the Lbx1/Fgf8 locus resolve split-hand/foot malformation type 3. https://doi.org/10.1038/s41467-023-37057-z ; Frontiers in Genetics (05 Jan 2024): Akimova et al. https://doi.org/10.3389/fgene.2023.1303807 ; Orphanet Journal of Rare Diseases (Oct 2024): Wang et al. https://doi.org/10.1186/s13023-024-03386-5
SHFM4 – TP63-related 3q28; TP63 Typically autosomal dominant; incomplete penetrance documented; variable intrafamilial expression (sowinskaseidler2014splithandfootmalformation pages 1-2) Isolated or syndromic ectrodactyly; classic central-ray absence/hypoplasia, sometimes with ectodermal findings depending on allele/syndrome context (sowinskaseidler2014splithandfootmalformation pages 1-2) (sowinskaseidler2014splithandfootmalformation pages 1-2) Journal of Applied Genetics (Oct 2014): Sowińska-Seidler et al., diagnostic/genetic overview including SHFM4. https://doi.org/10.1007/s13353-013-0178-5
SHFM6 – WNT10B-related 12q13.12; WNT10B Autosomal recessive; usually homozygous variants in consanguineous or multiplex families (bilal2023sequencevariantsin pages 1-2, bilal2023sequencevariantsin pages 2-5, umair2019nonsyndromicsplithandfootmalformation pages 7-8) Non-syndromic SHFM with median clefts, missing central digits, complex syndactyly; some reports note dental anomalies/oligodontia and broader phenotypic variability (bilal2023sequencevariantsin pages 1-2, umair2019nonsyndromicsplithandfootmalformation pages 7-8) (bilal2023sequencevariantsin pages 1-2, bilal2023sequencevariantsin pages 2-5) Molecular Syndromology (20 Jun 2023): Bilal et al., Sequence variants in the WNT10B underlying non-syndromic split-hand/foot malformation. https://doi.org/10.1159/000531069
PRDM1 – newly implicated monogenic SHFM gene PRDM1 (BLIMP1); limb regulatory targets include fgfr1a, dlx5a, dlx6a, smo in zebrafish fin/limb models Appears heterozygous with dominant-negative mechanism; incomplete penetrance/variable expressivity reported in families (truong2023prdm1dnabindingzinc pages 9-10, truong2023prdm1dnabindingzinc pages 11-12, truong2023prdm1dnabindingzinc pages 2-2) SHFM with disruption of fin/limb induction, outgrowth, and AP patterning pathways; functional assays show failure to rescue fin defects and altered AER/AF-related gene regulation (truong2023prdm1dnabindingzinc pages 9-10, truong2023prdm1dnabindingzinc pages 1-2, truong2023prdm1dnabindingzinc pages 2-2) (truong2023prdm1dnabindingzinc pages 9-10, truong2023prdm1dnabindingzinc pages 1-2, truong2023prdm1dnabindingzinc pages 2-2) Disease Models & Mechanisms (Apr 2023): Truong et al., PRDM1 DNA-binding zinc finger domain is required for normal limb development and is disrupted in split hand/foot malformation. https://doi.org/10.1242/dmm.049977

Table: This table summarizes the main SHFM loci and mechanisms most relevant for disease knowledge-base curation, emphasizing the best-supported 2023-2024 evidence for regulatory, structural-variant, and monogenic causes.

Figure-based evidence (mechanism visualization)

A locus schematic and model summarizing SHFM3 structural variants, TAD reorganization, and AER misexpression of Lbx1/Btrc were retrieved from the 2023 Nature Communications study (Cova et al.). (cova2023combinatorialeffectson media 96921fee, cova2023combinatorialeffectson media 2619b58c)

Direct abstract quotes (as available in retrieved excerpts)

  • SHFM definition and SHFM1 context: “Split Hand-Foot Malformation (SHFM) is a congenital limb defect characterized by a median cleft of the hands and/or feet due to the absence/hypoplasia of the central rays.” (ambrosetti2023splithandfootand pages 1-2)
  • PRDM1 mechanism statement (from excerpted abstract text): PRDM1 variants “act in a dominant-negative fashion due to disruption of the proline/serine and DNA-binding zinc finger domains.” (truong2023prdm1dnabindingzinc pages 2-2)

Key limitations of this report (data gaps)

  • Ontology identifiers (MONDO/MeSH/ICD/Orphanet/OMIM IDs) were not retrievable from the current tool context.
  • PMIDs were generally absent from the extracted full-text snippets; DOIs/URLs and dates are provided instead.
  • Treatment outcomes and QoL metrics are not well represented in the retrieved corpus; additional targeted retrieval (hand surgery outcomes, rehabilitation, prosthetic use) would be needed for quantitative treatment sections.

References

  1. (ambrosetti2023splithandfootand pages 1-2): Irene Ambrosetti, Laura Bernardini, Marzia Pollazzon, Maria Grazia Giuffrida, Valentina Guida, Francesca Peluso, Maria Chiara Baroni, Valeria Polizzi, Manuela Napoli, Simonetta Rosato, Gabriele Trimarchi, Chiara Gelmini, Stefano Giuseppe Caraffi, Anita Wischmeijer, Daniele Frattini, Antonio Novelli, and Livia Garavelli. Split hand-foot and deafness in a patient with 7q21.13-q21.3 deletion not including the dlx5/6 genes. Genes, 14:1526, Jul 2023. URL: https://doi.org/10.3390/genes14081526, doi:10.3390/genes14081526. This article has 5 citations.

  2. (sowinskaseidler2014splithandfootmalformation pages 1-2): Anna Sowińska-Seidler, Magdalena Socha, and Aleksander Jamsheer. Split-hand/foot malformation - molecular cause and implications in genetic counseling. Journal of Applied Genetics, 55:105-115, Oct 2014. URL: https://doi.org/10.1007/s13353-013-0178-5, doi:10.1007/s13353-013-0178-5. This article has 110 citations and is from a peer-reviewed journal.

  3. (bilal2023sequencevariantsin pages 1-2): Muhammad Bilal, Tobias B. Haack, Rebecca Buchert, Susana Peralta, Imtiaz Ahmad, Faisal, Sanaullah Abbasi, and Wasim Ahmad. Sequence variants in the wnt10b underlying non-syndromic split-hand/foot malformation. Molecular Syndromology, 14:469-476, Jun 2023. URL: https://doi.org/10.1159/000531069, doi:10.1159/000531069. This article has 3 citations and is from a peer-reviewed journal.

  4. (cova2023combinatorialeffectson pages 1-2): Giulia Cova, Juliane Glaser, Robert Schöpflin, Cesar Augusto Prada-Medina, Salaheddine Ali, Martin Franke, Rita Falcone, Miriam Federer, Emanuela Ponzi, Romina Ficarella, Francesca Novara, Lars Wittler, Bernd Timmermann, Mattia Gentile, Orsetta Zuffardi, Malte Spielmann, and Stefan Mundlos. Combinatorial effects on gene expression at the lbx1/fgf8 locus resolve split-hand/foot malformation type 3. Nature Communications, Mar 2023. URL: https://doi.org/10.1038/s41467-023-37057-z, doi:10.1038/s41467-023-37057-z. This article has 32 citations and is from a highest quality peer-reviewed journal.

  5. (deftereou2024acaseofa pages 11-12): Theodora- Eleftheria Deftereou, Vaya R Karapepera, Christina Angelika Alexiadi, Stylianos Tologkos, Vasiliki Papadatou, Georgios Alexiadis, Dimitrios Karamanidis, and Lambropoulou Maria. A case of fibular aplasia-tibial campomelia-oligosyndactyly (fatco) syndrome associated with split hand/foot syndrome with long bone deficiency (shfld) and review of the literature. Cureus, Jul 2024. URL: https://doi.org/10.7759/cureus.65162, doi:10.7759/cureus.65162. This article has 0 citations.

  6. (umair2019nonsyndromicsplithandfootmalformation pages 1-2): Muhammad Umair and Amir Hayat. Nonsyndromic split-hand/foot malformation: recent classification. Molecular Syndromology, 10:243-254, Sep 2019. URL: https://doi.org/10.1159/000502784, doi:10.1159/000502784. This article has 42 citations and is from a peer-reviewed journal.

  7. (akimova2024variableclinicalpresentation pages 1-2): Daria Akimova, Tatiana Markova, Maria Ampleeva, and Mikhail Skoblov. Variable clinical presentation of split hand/foot malformation syndrome in a family with microduplication of 10q24.32: a case report. Frontiers in Genetics, Jan 2024. URL: https://doi.org/10.3389/fgene.2023.1303807, doi:10.3389/fgene.2023.1303807. This article has 2 citations and is from a peer-reviewed journal.

  8. (ambrosetti2023splithandfootand pages 4-7): Irene Ambrosetti, Laura Bernardini, Marzia Pollazzon, Maria Grazia Giuffrida, Valentina Guida, Francesca Peluso, Maria Chiara Baroni, Valeria Polizzi, Manuela Napoli, Simonetta Rosato, Gabriele Trimarchi, Chiara Gelmini, Stefano Giuseppe Caraffi, Anita Wischmeijer, Daniele Frattini, Antonio Novelli, and Livia Garavelli. Split hand-foot and deafness in a patient with 7q21.13-q21.3 deletion not including the dlx5/6 genes. Genes, 14:1526, Jul 2023. URL: https://doi.org/10.3390/genes14081526, doi:10.3390/genes14081526. This article has 5 citations.

  9. (truong2023prdm1dnabindingzinc pages 1-2): Brittany T. Truong, Lomeli C. Shull, Ezra Lencer, Eric G. Bend, Michael Field, Elizabeth E. Blue, Michael J. Bamshad, Cindy Skinner, David Everman, Charles E. Schwartz, Heather Flanagan-Steet, and Kristin B. Artinger. Prdm1 dna-binding zinc finger domain is required for normal limb development and is disrupted in split hand/foot malformation. Apr 2023. URL: https://doi.org/10.1242/dmm.049977, doi:10.1242/dmm.049977. This article has 9 citations and is from a domain leading peer-reviewed journal.

  10. (cova2023combinatorialeffectson pages 9-11): Giulia Cova, Juliane Glaser, Robert Schöpflin, Cesar Augusto Prada-Medina, Salaheddine Ali, Martin Franke, Rita Falcone, Miriam Federer, Emanuela Ponzi, Romina Ficarella, Francesca Novara, Lars Wittler, Bernd Timmermann, Mattia Gentile, Orsetta Zuffardi, Malte Spielmann, and Stefan Mundlos. Combinatorial effects on gene expression at the lbx1/fgf8 locus resolve split-hand/foot malformation type 3. Nature Communications, Mar 2023. URL: https://doi.org/10.1038/s41467-023-37057-z, doi:10.1038/s41467-023-37057-z. This article has 32 citations and is from a highest quality peer-reviewed journal.

  11. (ambrosetti2023splithandfootand pages 2-4): Irene Ambrosetti, Laura Bernardini, Marzia Pollazzon, Maria Grazia Giuffrida, Valentina Guida, Francesca Peluso, Maria Chiara Baroni, Valeria Polizzi, Manuela Napoli, Simonetta Rosato, Gabriele Trimarchi, Chiara Gelmini, Stefano Giuseppe Caraffi, Anita Wischmeijer, Daniele Frattini, Antonio Novelli, and Livia Garavelli. Split hand-foot and deafness in a patient with 7q21.13-q21.3 deletion not including the dlx5/6 genes. Genes, 14:1526, Jul 2023. URL: https://doi.org/10.3390/genes14081526, doi:10.3390/genes14081526. This article has 5 citations.

  12. (sowinskaseidler2023agenotype–phenotypecorrelation pages 13-13): Anna Sowińska-Seidler, Magdalena Socha, Anna Szoszkiewicz, Anna Materna-Kiryluk, and Aleksander Jamsheer. A genotype–phenotype correlation in split-hand/foot malformation type 1: further refinement of the phenotypic subregions within the 7q21.3 locus. Frontiers in Molecular Biosciences, Oct 2023. URL: https://doi.org/10.3389/fmolb.2023.1250714, doi:10.3389/fmolb.2023.1250714. This article has 3 citations.

  13. (cova2023combinatorialeffectson pages 2-3): Giulia Cova, Juliane Glaser, Robert Schöpflin, Cesar Augusto Prada-Medina, Salaheddine Ali, Martin Franke, Rita Falcone, Miriam Federer, Emanuela Ponzi, Romina Ficarella, Francesca Novara, Lars Wittler, Bernd Timmermann, Mattia Gentile, Orsetta Zuffardi, Malte Spielmann, and Stefan Mundlos. Combinatorial effects on gene expression at the lbx1/fgf8 locus resolve split-hand/foot malformation type 3. Nature Communications, Mar 2023. URL: https://doi.org/10.1038/s41467-023-37057-z, doi:10.1038/s41467-023-37057-z. This article has 32 citations and is from a highest quality peer-reviewed journal.

  14. (bilal2023sequencevariantsin pages 2-5): Muhammad Bilal, Tobias B. Haack, Rebecca Buchert, Susana Peralta, Imtiaz Ahmad, Faisal, Sanaullah Abbasi, and Wasim Ahmad. Sequence variants in the wnt10b underlying non-syndromic split-hand/foot malformation. Molecular Syndromology, 14:469-476, Jun 2023. URL: https://doi.org/10.1159/000531069, doi:10.1159/000531069. This article has 3 citations and is from a peer-reviewed journal.

  15. (truong2023prdm1dnabindingzinc pages 2-2): Brittany T. Truong, Lomeli C. Shull, Ezra Lencer, Eric G. Bend, Michael Field, Elizabeth E. Blue, Michael J. Bamshad, Cindy Skinner, David Everman, Charles E. Schwartz, Heather Flanagan-Steet, and Kristin B. Artinger. Prdm1 dna-binding zinc finger domain is required for normal limb development and is disrupted in split hand/foot malformation. Apr 2023. URL: https://doi.org/10.1242/dmm.049977, doi:10.1242/dmm.049977. This article has 9 citations and is from a domain leading peer-reviewed journal.

  16. (akimova2024variableclinicalpresentation pages 2-3): Daria Akimova, Tatiana Markova, Maria Ampleeva, and Mikhail Skoblov. Variable clinical presentation of split hand/foot malformation syndrome in a family with microduplication of 10q24.32: a case report. Frontiers in Genetics, Jan 2024. URL: https://doi.org/10.3389/fgene.2023.1303807, doi:10.3389/fgene.2023.1303807. This article has 2 citations and is from a peer-reviewed journal.

  17. (truong2023prdm1dnabindingzinc pages 2-4): Brittany T. Truong, Lomeli C. Shull, Ezra Lencer, Eric G. Bend, Michael Field, Elizabeth E. Blue, Michael J. Bamshad, Cindy Skinner, David Everman, Charles E. Schwartz, Heather Flanagan-Steet, and Kristin B. Artinger. Prdm1 dna-binding zinc finger domain is required for normal limb development and is disrupted in split hand/foot malformation. Apr 2023. URL: https://doi.org/10.1242/dmm.049977, doi:10.1242/dmm.049977. This article has 9 citations and is from a domain leading peer-reviewed journal.

  18. (cova2023combinatorialeffectson media 96921fee): Giulia Cova, Juliane Glaser, Robert Schöpflin, Cesar Augusto Prada-Medina, Salaheddine Ali, Martin Franke, Rita Falcone, Miriam Federer, Emanuela Ponzi, Romina Ficarella, Francesca Novara, Lars Wittler, Bernd Timmermann, Mattia Gentile, Orsetta Zuffardi, Malte Spielmann, and Stefan Mundlos. Combinatorial effects on gene expression at the lbx1/fgf8 locus resolve split-hand/foot malformation type 3. Nature Communications, Mar 2023. URL: https://doi.org/10.1038/s41467-023-37057-z, doi:10.1038/s41467-023-37057-z. This article has 32 citations and is from a highest quality peer-reviewed journal.

  19. (cova2023combinatorialeffectson media 2619b58c): Giulia Cova, Juliane Glaser, Robert Schöpflin, Cesar Augusto Prada-Medina, Salaheddine Ali, Martin Franke, Rita Falcone, Miriam Federer, Emanuela Ponzi, Romina Ficarella, Francesca Novara, Lars Wittler, Bernd Timmermann, Mattia Gentile, Orsetta Zuffardi, Malte Spielmann, and Stefan Mundlos. Combinatorial effects on gene expression at the lbx1/fgf8 locus resolve split-hand/foot malformation type 3. Nature Communications, Mar 2023. URL: https://doi.org/10.1038/s41467-023-37057-z, doi:10.1038/s41467-023-37057-z. This article has 32 citations and is from a highest quality peer-reviewed journal.

  20. (truong2023prdm1dnabindingzinc pages 9-10): Brittany T. Truong, Lomeli C. Shull, Ezra Lencer, Eric G. Bend, Michael Field, Elizabeth E. Blue, Michael J. Bamshad, Cindy Skinner, David Everman, Charles E. Schwartz, Heather Flanagan-Steet, and Kristin B. Artinger. Prdm1 dna-binding zinc finger domain is required for normal limb development and is disrupted in split hand/foot malformation. Apr 2023. URL: https://doi.org/10.1242/dmm.049977, doi:10.1242/dmm.049977. This article has 9 citations and is from a domain leading peer-reviewed journal.

  21. (truong2023prdm1dnabindingzinc pages 10-11): Brittany T. Truong, Lomeli C. Shull, Ezra Lencer, Eric G. Bend, Michael Field, Elizabeth E. Blue, Michael J. Bamshad, Cindy Skinner, David Everman, Charles E. Schwartz, Heather Flanagan-Steet, and Kristin B. Artinger. Prdm1 dna-binding zinc finger domain is required for normal limb development and is disrupted in split hand/foot malformation. Apr 2023. URL: https://doi.org/10.1242/dmm.049977, doi:10.1242/dmm.049977. This article has 9 citations and is from a domain leading peer-reviewed journal.

  22. (truong2023prdm1dnabindingzinc pages 11-12): Brittany T. Truong, Lomeli C. Shull, Ezra Lencer, Eric G. Bend, Michael Field, Elizabeth E. Blue, Michael J. Bamshad, Cindy Skinner, David Everman, Charles E. Schwartz, Heather Flanagan-Steet, and Kristin B. Artinger. Prdm1 dna-binding zinc finger domain is required for normal limb development and is disrupted in split hand/foot malformation. Apr 2023. URL: https://doi.org/10.1242/dmm.049977, doi:10.1242/dmm.049977. This article has 9 citations and is from a domain leading peer-reviewed journal.

  23. (wang2024anovelapproach pages 6-7): Yaqian Wang, Yang Li, Lidong Zeng, Wenbo Li, Xin Dong, Jia Guo, Xiangrui Meng, Jiacheng Lu, and Jiawei Xu. A novel approach to detecting microduplication in split hand/foot malformation type 3 at the single-cell level: shfm as a case study. Orphanet Journal of Rare Diseases, Oct 2024. URL: https://doi.org/10.1186/s13023-024-03386-5, doi:10.1186/s13023-024-03386-5. This article has 0 citations and is from a peer-reviewed journal.

  24. (singh2025uncoveringthegenetic pages 1-2): Arati Singh, Gayatri Nerakh, and Shagun Aggarwal. Uncovering the genetic basis of recurrent split hand/foot malformation: a case report and review. Journal of Fetal Medicine, 12:130-133, Sep 2025. URL: https://doi.org/10.1055/s-0045-1814130, doi:10.1055/s-0045-1814130. This article has 0 citations.

  25. (ambrosetti2023splithandfootand pages 7-8): Irene Ambrosetti, Laura Bernardini, Marzia Pollazzon, Maria Grazia Giuffrida, Valentina Guida, Francesca Peluso, Maria Chiara Baroni, Valeria Polizzi, Manuela Napoli, Simonetta Rosato, Gabriele Trimarchi, Chiara Gelmini, Stefano Giuseppe Caraffi, Anita Wischmeijer, Daniele Frattini, Antonio Novelli, and Livia Garavelli. Split hand-foot and deafness in a patient with 7q21.13-q21.3 deletion not including the dlx5/6 genes. Genes, 14:1526, Jul 2023. URL: https://doi.org/10.3390/genes14081526, doi:10.3390/genes14081526. This article has 5 citations.

  26. (dimitrov2010distallimbdeficiencies pages 9-11): B. Dimitrov, T. de Ravel, J. Van Driessche, C. D. de Die-Smulders, A. Toutain, J. Vermeesch, J. Fryns, K. Devriendt, and P. Debeer. Distal limb deficiencies, micrognathia syndrome, and syndromic forms of split hand foot malformation (shfm) are caused by chromosome 10q genomic rearrangements. Jul 2010. URL: https://doi.org/10.1136/jmg.2008.065888, doi:10.1136/jmg.2008.065888. This article has 43 citations and is from a domain leading peer-reviewed journal.

  27. (umair2019nonsyndromicsplithandfootmalformation pages 7-8): Muhammad Umair and Amir Hayat. Nonsyndromic split-hand/foot malformation: recent classification. Molecular Syndromology, 10:243-254, Sep 2019. URL: https://doi.org/10.1159/000502784, doi:10.1159/000502784. This article has 42 citations and is from a peer-reviewed journal.

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