👪

Inheritance

3

Autosomal dominant HP:0000006

Most SHFM loci (SHFM1, SHFM3, SHFM4) are inherited in an autosomal dominant manner with reduced penetrance and variable expressivity.

Autosomal dominant inheritance

Show evidence (1 reference)

PMID:29263051 SUPPORT Human Clinical

"SHFM3 is an autosomal dominant disease, of which the pathogenesis is closely related to the genomic rearrangements at 10q24."

Documents autosomal dominant inheritance for SHFM3.

Autosomal recessive HP:0000007

SHFM6 (WNT10B) follows autosomal recessive inheritance, typically in consanguineous families.

Autosomal recessive inheritance

Show evidence (1 reference)

PMID:31050392 SUPPORT Human Clinical

"WNT10B homozygous variants have been recently identified in consanguineous families, but remain still rarely described (SHFM6; MIM225300)."

Documents autosomal recessive (homozygous WNT10B) inheritance for SHFM6.

X-linked HP:0001417

A rare X-linked form of isolated SHFM is caused by structural variants near SOX3.

X-linked inheritance

Show evidence (1 reference)

PMID:37216008 SUPPORT Human Clinical

"We describe a family with isolated X-linked SHFM, for which the causative variant could be detected after a diagnostic journey of 20 years."

Documents an X-linked SHFM family with a SOX3 regulatory variant.

◆

Subtypes

8

SHFM1 (7q21.3, DLX5/DLX6) MONDO:0008464

DLX5 hgnc:2918 DLX6 hgnc:2919 DYNC1I1 hgnc:2963 {'name': 'Autosomal dominant'}

Autosomal dominant SHFM mapping to 7q21.3, caused by deletions or chromosomal rearrangements that disrupt the DLX5/DLX6 transcription-factor genes or their long-range limb enhancers within DYNC1I1. Reduced penetrance and variable expression are characteristic. Larger 7q21 deletions involving COL1A2 can additionally cause osteogenesis imperfecta.

Show evidence (2 references)

PMID:24459211 SUPPORT Human Clinical

"This separates the DYNC1I1 exons recently identified as limb enhancers in mouse studies from their target genes, DLX5 and DLX6."

Demonstrates that SHFM1 is caused by disruption of DYNC1I1 exonic enhancers that drive DLX5/DLX6 expression in the developing limb.

PMID:38567169 SUPPORT Human Clinical

"Copy number variation in loss of 7q21 is a genetic disorder characterized by split hand/foot malformation, hearing loss, developmental delay, myoclonus, dystonia, joint laxity, and psychiatric disorders."

Confirms the 7q21 (SHFM1) deletion region and the DLX5/DLX6, COL1A2 gene content underlying this subtype.

SHFM3 (10q24 duplication, BTRC/FBXW4) MONDO:0009525

BTRC hgnc:1144 FBXW4 hgnc:10847 {'name': 'Autosomal dominant'}

Autosomal dominant SHFM caused by submicroscopic tandem duplications at 10q24, the most common molecularly defined cause of isolated SHFM. The minimal duplicated region encompasses BTRC and FBXW4 (and neighboring LBX1, POLL, TLX1); increased BTRC dosage is implicated in the limb defect.

Show evidence (3 references)

PMID:29263051 SUPPORT Human Clinical

"SHFM3 is an autosomal dominant disease, of which the pathogenesis is closely related to the genomic rearrangements at 10q24."

Establishes SHFM3 as an autosomal dominant disorder caused by 10q24 genomic rearrangements (duplications).

PMID:35908152 SUPPORT Human Clinical

"a 120 kb microduplication containing only BTRC were identified in a Chinese family affected with SHFM3."

A 120 kb duplication containing only BTRC co-segregated with SHFM3 and elevated BTRC mRNA, implicating increased BTRC dosage as the cause.

PMID:36928426 SUPPORT Model Organism

"This leads to ectopic activation of the Lbx1 and Btrc genes in the apical ectodermal ridge (AER) in an Fgf8-like pattern induced by AER-specific enhancers of Fgf8."

Transgenic mouse modeling resolves the SHFM3 mechanism: the 10q24 rearrangement restructures chromatin so AER-specific FGF8 enhancers ectopically activate LBX1/BTRC in the AER.

SHFM4 (TP63) MONDO:0011535

TP63 hgnc:15979 {'name': 'Autosomal dominant'}

Autosomal dominant SHFM caused by heterozygous variants in TP63 (p63), a master transcriptional regulator of AER and epidermal development. TP63 variants cause a spectrum from isolated SHFM (SHFM4) to syndromic forms (EEC, ADULT, AEC syndromes); this subtype refers to the non-syndromic limb-limited presentation.

Show evidence (1 reference)

PMID:33294441 SUPPORT Human Clinical

"we identified a novel missense variant (NM_003722.4:c.948G>A; p.Met316Ile) of TP63 in this family that results in a substitution of methionine with isoleucine, which is probably associated with the occurrence of SHFM."

Reports a heterozygous TP63 missense variant co-segregating with isolated SHFM, supporting TP63 as a cause of non-syndromic SHFM4.

SHFM5 (2q31, HOXD cluster / DLX1-DLX2 region) MONDO:0011709

DLX1 hgnc:2914 DLX2 hgnc:2915 HOXD13 hgnc:5136

SHFM mapping to 2q31, associated with deletions of the region. Although DLX1/DLX2 lie within the locus, genotype-phenotype analysis indicates that haploinsufficiency of the adjacent HOXD cluster, rather than DLX1/DLX2, accounts for the limb (hand/foot) anomalies; 2q31 deletions also produce a broader microdeletion phenotype with neurodevelopmental features.

Show evidence (2 references)

PMID:22140379 SUPPORT Human Clinical

"Seven subjects with deletions encompassing the HOXD cluster had hand/foot anomalies of varying severity, including syndactyly, brachydactyly, and ectrodactyly."

Maps the SHFM5 limb phenotype to 2q31 deletions encompassing the HOXD cluster.

PMID:22140379 PARTIAL Human Clinical

"The absence of hand/foot anomalies in any of the individuals with deletions of DLX1/DLX2 but not the HOXD cluster supports the hypothesis that haploinsufficiency of the HOXD cluster, rather than DLX1/DLX2, accounts for the skeletal abnormalities in subjects with 2q31.1 microdeletions."

Refines the SHFM5 mechanism: HOXD-cluster haploinsufficiency, not DLX1/DLX2 loss, drives the ectrodactyly in 2q31.1 deletions.

SHFM6 (WNT10B) MONDO:0009157

WNT10B hgnc:12775 {'name': 'Autosomal recessive'}

Autosomal recessive SHFM caused by homozygous loss-of-function variants in WNT10B, typically in consanguineous families. Feet are usually more severely affected than hands, with frequent third-fourth finger syndactyly and, in a minority, polydactyly; heterozygotes may show mild features, suggesting a dose effect.

Show evidence (2 references)

PMID:31050392 SUPPORT Human Clinical

"WNT10B homozygous variants have been recently identified in consanguineous families, but remain still rarely described (SHFM6; MIM225300)."

Establishes WNT10B homozygous loss-of-function variants as the cause of autosomal recessive SHFM6.

PMID:31050392 SUPPORT Human Clinical

"heterozygous individuals might have mild features of SHFM, suggesting a dose-effect of the WNT10B loss-of-function."

Supports a WNT10B dose effect, with mild features in heterozygotes.

SHFLD (split hand/foot with long-bone deficiency, BHLHA9)

BHLHA9 hgnc:35126

Split hand/foot malformation with long-bone deficiency, most commonly associated with copy-number gains (duplication/triplication) at 17p13.3 that invariably encompass BHLHA9 ("Fingerin"). BHLHA9 is required for AER formation; its dysregulation causes SHFM/SHFLD via aberrant AER-related gene expression. The trait shows markedly incomplete penetrance (~50%) and variable expressivity.

Show evidence (2 references)

PMID:28324176 SUPPORT Model Organism

"These observations suggest that Bhlha9 regulates AER formation during limb/finger development by regulating the expression of some AER-formation-related genes and abnormal expression of Bhlha9 leads to SHFM and SHFLD via dysregulation of AER formation and associated gene expression."

Bhlha9-knockout mice show that BHLHA9 regulates AER formation and that its dysregulation causes SHFM/SHFLD.

PMID:36028842 SUPPORT Human Clinical

"Split-hand/ foot malformation with long bone deficiency 3 (SHFLD3) is an extremely rare condition associated with duplications located on 17p13.3, which invariably encompasses the BHLHA9 gene. The disease inherits with variable expressivity and significant incomplete penetrance as high as 50%."

Confirms 17p13.3 duplications encompassing BHLHA9 as the cause of SHFLD, with ~50% incomplete penetrance.

X-linked SHFM (SOX3 regulatory variant)

SOX3 hgnc:11199 {'name': 'X-linked'}

A rare X-linked form of isolated SHFM caused by complex structural variants near SOX3 that disrupt its regulatory landscape. Like other SHFM loci, the underlying defect is failure to maintain normal AER function during limb development.

Show evidence (1 reference)

PMID:37216008 SUPPORT Human Clinical

"We describe a family with isolated X-linked SHFM, for which the causative variant could be detected after a diagnostic journey of 20 years."

Reports a family with isolated X-linked SHFM caused by a complex structural variant near SOX3.

PRDM1-associated SHFM

PRDM1 hgnc:9346

An emerging cause of SHFM associated with de novo or segregating heterozygous variants in PRDM1, a transcription factor required for limb development. Functional studies indicate the variants disrupt the proline/serine-rich and DNA-binding zinc-finger domains and act in a dominant-negative fashion; PRDM1 directly regulates limb genes including FGFR1 and DLX5/DLX6, placing it upstream of the shared SHFM pathway.

Show evidence (2 references)

PMID:37083955 SUPPORT Human Clinical

"Through whole-exome and targeted sequencing, we detected three novel variants in a gene encoding a transcription factor, PRDM1, that arose de novo in families with SHFM or segregated with the phenotype."

Identifies PRDM1 as an SHFM gene, with de novo and segregating heterozygous variants in affected families.

PMID:37083955 SUPPORT Model Organism

"we show that the variants disrupt the proline/serine-rich and DNA-binding zinc finger domains, resulting in a dominant-negative effect."

Zebrafish rescue experiments show the PRDM1 variants act in a dominant-negative fashion via disruption of its functional domains.

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Pathophysiology

2

Apical Ectodermal Ridge Maintenance Failure

The unifying mechanism across SHFM loci is failure to maintain normal apical ectodermal ridge (AER) function during limb development. The AER is the epithelial signaling center at the distal tip of the limb bud that sustains outgrowth of the underlying mesenchyme. SHFM-associated mutations converge on dysregulation of FGF8 in the central portion of the AER, failure of AER stratification, and disruption of reciprocal Wnt-BMP-FGF signaling between the AER and progress-zone mesenchyme. The central-ray defect reflects loss of this signaling specifically in the median AER.

apical ectodermal ridge formation GO:1905139 FGF8 signaling in the AER GO:0008543 ↓ DECREASED limb development GO:0060173 ⚠ ABNORMAL

apical ectodermal ridge UBERON:0004356 limb bud UBERON:0004347

Downstream

Disrupted Wnt-BMP-FGF Signaling and Central Ray Loss

Show evidence (3 references)

PMID:30101460 SUPPORT Human Clinical

"Split-hand/foot malformation (SHFM) is caused by mutations in TP63, DLX5, DLX6, FGF8, FGFR1, WNT10B, and BHLHA9."

Lists the convergent set of SHFM-causing genes that act on a shared AER regulatory pathway.

PMID:30101460 SUPPORT Human Clinical

"The mutations in SHFM-related genes lead to dysregulation of Fgf8 in the central portion of the apical ectodermal ridge (AER) and subsequently lead to misexpression of a number of downstream target genes, failure of stratification of the AER, and thus SHFM."

States the core mechanism: central-AER FGF8 dysregulation and failed AER stratification produce SHFM.

PMID:37216008 SUPPORT Human Clinical

"SHFM is caused by failure to maintain normal apical ectodermal ridge function during limb development."

Independent confirmation that the unifying defect is failed AER maintenance.

Disrupted Wnt-BMP-FGF Signaling and Central Ray Loss

Loss of central-AER FGF8 dysregulates the reciprocal Wnt-BMP-FGF signaling loop. Disruption of canonical and non-canonical Wnt signaling, together with altered FGF-BMP-MSX signaling, drives the phenotype: median clefts with absent or hypoplastic central rays, syndactyly of the remaining digits (from dysregulated apoptotic cell death), and loss of digit identity (from misexpression of HOX genes and an abnormal SHH gradient or loss of GLI3A/GLI3R balance).

Wnt signaling pathway GO:0016055 ⚠ ABNORMAL BMP signaling pathway GO:0030509 ⚠ ABNORMAL regulation of apoptotic process GO:0042981 ⚠ ABNORMAL embryonic limb morphogenesis GO:0030326 ⚠ ABNORMAL

autopod region UBERON:0002470

Downstream

Split hand Central-ray loss in the hand produces a median cleft or split-hand malformation.

Split foot Central-ray loss in the foot produces a split-foot malformation.

Ectrodactyly Loss or hypoplasia of central digits with median clefting corresponds to ectrodactyly.

Syndactyly Dysregulated FGF-BMP-MSX signaling alters interdigital apoptosis, producing syndactyly of remaining digits.

Polydactyly SHFM-associated disruption of digit identity and patterning can include supernumerary digits in some subtypes.

Oligodactyly Central-ray absence reduces the number of digits, producing oligodactyly.

Show evidence (3 references)

PMID:30101460 SUPPORT Human Clinical

"Disruption of canonical and non-canonical Wnt signaling is involved in the pathogenesis of SHFM."

Implicates disrupted canonical and non-canonical Wnt signaling in SHFM pathogenesis.

PMID:30101460 SUPPORT Human Clinical

"Syndactyly of the remaining digits is most likely the effects of dysregulation of Fgf-Bmp-Msx signaling on apoptotic cell death."

Links syndactyly of remaining digits to dysregulated FGF-BMP-MSX signaling and altered apoptosis.

PMID:30101460 SUPPORT Human Clinical

"Loss of digit identity in SHFM is hypothesized to be the effects of misexpression of HOX genes, abnormal SHH gradient, or the loss of balance between GLI3A and GLI3R."

Attributes loss of digit identity to HOX misexpression, abnormal SHH gradient, and disturbed GLI3A/GLI3R balance.

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Pathograph

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Phenotypes

7

Ear 1

Sensorineural hearing loss Sensorineural hearing impairment HP:0000407

Show evidence (1 reference)

PMID:37628577 SUPPORT Human Clinical

"we analyzed a patient affected by SHFM1 associated with deafness and an abnormality of the inner ear (incomplete partition type I)"

Documents sensorineural deafness with inner-ear malformation in an SHFM1 patient with a 7q21 deletion affecting DLX5/6 regulation.

Limbs 4

Split hand Split hand HP:0001171

Show evidence (1 reference)

PMID:30101460 SUPPORT Human Clinical

"This implies that in normal situations these SHFM-associated genes share an underlying regulatory pathway that is involved in the development of the central parts of the hands and feet."

Identifies the central hand/foot rays as the developmental territory affected, the basis of the split-hand phenotype.

Ectrodactyly Ectrodactyly HP:0100257

Show evidence (1 reference)

PMID:38567169 SUPPORT Human Clinical

"We report a Turkish girl with ectrodactyly, joint laxity, multiple bone fractures, blue sclera, early teeth decay, mild learning disability, and depression."

Documents ectrodactyly as the limb manifestation in a SHFM1 (7q21 deletion) patient.

Syndactyly FREQUENT Syndactyly HP:0001159

Show evidence (1 reference)

PMID:31050392 SUPPORT Human Clinical

"Syndactyly of third-fourth fingers was a frequent finding (62%)."

Quantifies third-fourth finger syndactyly as a frequent SHFM feature.

Polydactyly OCCASIONAL Polydactyly HP:0010442

Show evidence (1 reference)

PMID:31050392 SUPPORT Human Clinical

"Polydactyly, which was classically described in SHFM6, was only present in 27% of patients."

Documents polydactyly in a minority (27%) of WNT10B-related SHFM6 patients.

Other 2

Split foot Split foot HP:0001839

Show evidence (1 reference)

PMID:31050392 SUPPORT Human Clinical

"The feet are more severely affected than the hands and there is a frequent asymmetry without obvious side-bias."

Documents foot involvement and the frequent foot-predominant asymmetry seen in SHFM (here WNT10B-related SHFM6).

Oligodactyly VERY_FREQUENT Oligodactyly HP:0012165

Show evidence (1 reference)

ORPHA:2440 SUPPORT Other

"HP:0012165 | Oligodactyly | Very frequent (99-80%)"

Orphadata lists oligodactyly as a very frequent isolated SHFM phenotype.

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Genetic Associations

2

SHFM is genetically heterogeneous with a shared AER regulatory pathway (Causative)

Show evidence (1 reference)

PMID:30101460 SUPPORT Human Clinical

"The clinical features of SHFM caused by mutations of these genes are not distinguishable."

Establishes that the multiple SHFM genes produce clinically indistinguishable phenotypes, consistent with a shared pathway.

BHLHA9 dosage and AER formation (Causative)

Gene: BHLHA9 hgnc:35126

Show evidence (1 reference)

PMID:28324176 SUPPORT Model Organism

"some apical ectodermal ridge (AER) formation related genes, including Trp63, exhibited an aberrant expression pattern in the limb bud of Bhlha9-knockout mice; TP63 (Trp63) was regulated by Bhlha9 on the basis of in vitro analysis."

Places BHLHA9 upstream of TP63 in AER formation, linking it to the shared SHFM pathway.

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Medical Actions

3

Reconstructive orthopedic surgery

Action: orthopedic surgical procedure Ontology label: Orthopedic Surgical Procedure NCIT:C16186

Multi-stage reconstructive and corrective orthopedic surgery is the mainstay of SHFM management, addressing the cleft, digital deficiency, and associated long-bone anomalies (e.g., tibial aplasia) to improve hand function and achieve weight-bearing and ambulation. Management is individualized and supportive; there is no disease-modifying therapy.

Show evidence (2 references)

PMID:24647283 SUPPORT Human Clinical

"Reconstruction of these patients required multiple surgical procedures and orthoprosthesis was mandatory."

Documents multi-stage reconstructive orthopedic surgery as the primary management approach for SHFM with associated tibial aplasia.

PMID:24647283 SUPPORT Human Clinical

"The main goal of treatment was to achieve walking."

Establishes restoration of ambulation as the functional goal of surgical management in severe SHFM.

Prosthetics and orthotics

Action: prosthetic and orthotic fitting Ontology label: Rehabilitation NCIT:C15315

Custom prosthetic and orthotic fitting complements surgical reconstruction, stabilizing deformed limbs and enabling ambulation and use of the affected hands and feet.

Show evidence (1 reference)

PMID:24647283 SUPPORT Human Clinical

"walking was achieved with simultaneous designation of orthotic fitting."

Documents orthotic/prosthetic fitting as an adjunct to surgery that enabled ambulation in SHFM with tibial aplasia.

Genetic counseling

Action: Genetic Counseling NCIT:C15240

Because SHFM is genetically heterogeneous with autosomal dominant (often reduced-penetrance), autosomal recessive, and X-linked forms, molecular diagnosis and genetic counseling inform recurrence-risk assessment and reproductive decision-making for affected families.

Show evidence (1 reference)

PMID:37216008 SUPPORT Human Clinical

"We describe a family with isolated X-linked SHFM, for which the causative variant could be detected after a diagnostic journey of 20 years."

Illustrates the diagnostic complexity of SHFM that genetic counseling and molecular testing address, supporting their role in family management.

{ }

Source YAML

click to show

name: Split Hand-Foot Malformation
creation_date: "2026-06-08T19:07:49Z"
category: Mendelian
description: >-
  Split hand-foot malformation (SHFM, ectrodactyly) is a genetically and
  clinically heterogeneous congenital limb malformation characterized by
  hypoplasia or absence of the central rays of the hands and feet, median
  ("lobster-claw") clefts, and variable syndactyly, oligodactyly, and
  aplasia. SHFM may occur as an isolated (non-syndromic) limb defect or as a
  feature of syndromes such as EEC and ADULT syndrome; this entry models the
  non-syndromic limb-malformation entity. The shared developmental mechanism
  is failure to maintain normal apical ectodermal ridge (AER) function during
  limb development: SHFM-associated genes converge on dysregulation of FGF8 in
  the central portion of the AER, with disruption of the Wnt-BMP-FGF signaling
  loop and the p63-DLX5/6 axis. Six classic loci (SHFM1-SHFM6) plus a
  split-hand/foot with long-bone-deficiency form (SHFLD, BHLHA9) and an
  X-linked SOX3-associated form have been defined. Inheritance is most often
  autosomal dominant with reduced penetrance and variable expressivity, with
  autosomal recessive and X-linked forms also described.
disease_term:
  preferred_term: split hand-foot malformation
  term:
    id: MONDO:0016576
    label: split hand-foot malformation
parents:
- limb malformation
- congenital limb malformation

inheritance:
- name: Autosomal dominant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    Most SHFM loci (SHFM1, SHFM3, SHFM4) are inherited in an autosomal dominant
    manner with reduced penetrance and variable expressivity.
  evidence:
  - reference: PMID:29263051
    reference_title: "Microduplications of 10q24 Detected in Two Chinese Patients with Split-hand/foot Malformation Type 3."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "SHFM3 is an autosomal dominant disease, of which the pathogenesis is closely related to the genomic rearrangements at 10q24."
    explanation: Documents autosomal dominant inheritance for SHFM3.
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    SHFM6 (WNT10B) follows autosomal recessive inheritance, typically in
    consanguineous families.
  evidence:
  - reference: PMID:31050392
    reference_title: "WNT10B variants in split hand/foot malformation: Report of three novel families and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "WNT10B homozygous variants have been recently identified in consanguineous families, but remain still rarely described (SHFM6; MIM225300)."
    explanation: Documents autosomal recessive (homozygous WNT10B) inheritance for SHFM6.
- name: X-linked
  inheritance_term:
    preferred_term: X-linked inheritance
    term:
      id: HP:0001417
      label: X-linked inheritance
  description: >-
    A rare X-linked form of isolated SHFM is caused by structural variants near
    SOX3.
  evidence:
  - reference: PMID:37216008
    reference_title: "A complex structural variant near SOX3 causes X-linked split-hand/foot malformation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We describe a family with isolated X-linked SHFM, for which the causative variant could be detected after a diagnostic journey of 20 years."
    explanation: Documents an X-linked SHFM family with a SOX3 regulatory variant.

has_subtypes:
- name: SHFM1
  display_name: SHFM1 (7q21.3, DLX5/DLX6)
  subtype_term:
    preferred_term: split hand-foot malformation 1
    term:
      id: MONDO:0008464
      label: split hand-foot malformation 1
  description: >-
    Autosomal dominant SHFM mapping to 7q21.3, caused by deletions or
    chromosomal rearrangements that disrupt the DLX5/DLX6 transcription-factor
    genes or their long-range limb enhancers within DYNC1I1. Reduced
    penetrance and variable expression are characteristic. Larger 7q21
    deletions involving COL1A2 can additionally cause osteogenesis imperfecta.
  inheritance:
  - name: Autosomal dominant
  genes:
  - preferred_term: DLX5
    term:
      id: hgnc:2918
      label: DLX5
  - preferred_term: DLX6
    term:
      id: hgnc:2919
      label: DLX6
  - preferred_term: DYNC1I1
    term:
      id: hgnc:2963
      label: DYNC1I1
  evidence:
  - reference: PMID:24459211
    reference_title: "Next generation sequencing of chromosomal rearrangements in patients with split-hand/split-foot malformation provides evidence for DYNC1I1 exonic enhancers of DLX5/6 expression in humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This separates the DYNC1I1 exons recently identified as limb enhancers in mouse studies from their target genes, DLX5 and DLX6."
    explanation: >-
      Demonstrates that SHFM1 is caused by disruption of DYNC1I1 exonic
      enhancers that drive DLX5/DLX6 expression in the developing limb.
  - reference: PMID:38567169
    reference_title: "Osteogenesis Imperfecta and Split Foot Malformation due to 7q21.2q21.3 Deletion Including COL1A2, DLX5/6 Genes: Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Copy number variation in loss of 7q21 is a genetic disorder characterized by split hand/foot malformation, hearing loss, developmental delay, myoclonus, dystonia, joint laxity, and psychiatric disorders."
    explanation: >-
      Confirms the 7q21 (SHFM1) deletion region and the DLX5/DLX6, COL1A2 gene
      content underlying this subtype.

- name: SHFM3
  display_name: SHFM3 (10q24 duplication, BTRC/FBXW4)
  subtype_term:
    preferred_term: split hand-foot malformation 3
    term:
      id: MONDO:0009525
      label: split hand-foot malformation 3
  description: >-
    Autosomal dominant SHFM caused by submicroscopic tandem duplications at
    10q24, the most common molecularly defined cause of isolated SHFM. The
    minimal duplicated region encompasses BTRC and FBXW4 (and neighboring
    LBX1, POLL, TLX1); increased BTRC dosage is implicated in the limb defect.
  inheritance:
  - name: Autosomal dominant
  genes:
  - preferred_term: BTRC
    term:
      id: hgnc:1144
      label: BTRC
  - preferred_term: FBXW4
    term:
      id: hgnc:10847
      label: FBXW4
  evidence:
  - reference: PMID:29263051
    reference_title: "Microduplications of 10q24 Detected in Two Chinese Patients with Split-hand/foot Malformation Type 3."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "SHFM3 is an autosomal dominant disease, of which the pathogenesis is closely related to the genomic rearrangements at 10q24."
    explanation: >-
      Establishes SHFM3 as an autosomal dominant disorder caused by 10q24
      genomic rearrangements (duplications).
  - reference: PMID:35908152
    reference_title: "Microduplication of BTRC detected in a Chinese family with split hand/foot malformation type 3."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a 120 kb microduplication containing only BTRC were identified in a Chinese family affected with SHFM3."
    explanation: >-
      A 120 kb duplication containing only BTRC co-segregated with SHFM3 and
      elevated BTRC mRNA, implicating increased BTRC dosage as the cause.
  - reference: PMID:36928426
    reference_title: "Combinatorial effects on gene expression at the Lbx1/Fgf8 locus resolve split-hand/foot malformation type 3."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "This leads to ectopic activation of the Lbx1 and Btrc genes in the apical ectodermal ridge (AER) in an Fgf8-like pattern induced by AER-specific enhancers of Fgf8."
    explanation: >-
      Transgenic mouse modeling resolves the SHFM3 mechanism: the 10q24
      rearrangement restructures chromatin so AER-specific FGF8 enhancers
      ectopically activate LBX1/BTRC in the AER.

- name: SHFM4
  display_name: SHFM4 (TP63)
  subtype_term:
    preferred_term: split hand-foot malformation 4
    term:
      id: MONDO:0011535
      label: split hand-foot malformation 4
  description: >-
    Autosomal dominant SHFM caused by heterozygous variants in TP63 (p63), a
    master transcriptional regulator of AER and epidermal development. TP63
    variants cause a spectrum from isolated SHFM (SHFM4) to syndromic forms
    (EEC, ADULT, AEC syndromes); this subtype refers to the non-syndromic
    limb-limited presentation.
  inheritance:
  - name: Autosomal dominant
  genes:
  - preferred_term: TP63
    term:
      id: hgnc:15979
      label: TP63
  evidence:
  - reference: PMID:33294441
    reference_title: "A Novel Missense Variant of TP63 Heterozygously Present in Split-Hand/Foot Malformation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we identified a novel missense variant (NM_003722.4:c.948G>A; p.Met316Ile) of TP63 in this family that results in a substitution of methionine with isoleucine, which is probably associated with the occurrence of SHFM."
    explanation: >-
      Reports a heterozygous TP63 missense variant co-segregating with
      isolated SHFM, supporting TP63 as a cause of non-syndromic SHFM4.

- name: SHFM5
  display_name: SHFM5 (2q31, HOXD cluster / DLX1-DLX2 region)
  subtype_term:
    preferred_term: split hand-foot malformation 5
    term:
      id: MONDO:0011709
      label: split hand-foot malformation 5
  description: >-
    SHFM mapping to 2q31, associated with deletions of the region. Although
    DLX1/DLX2 lie within the locus, genotype-phenotype analysis indicates that
    haploinsufficiency of the adjacent HOXD cluster, rather than DLX1/DLX2,
    accounts for the limb (hand/foot) anomalies; 2q31 deletions also produce a
    broader microdeletion phenotype with neurodevelopmental features.
  genes:
  - preferred_term: DLX1
    term:
      id: hgnc:2914
      label: DLX1
  - preferred_term: DLX2
    term:
      id: hgnc:2915
      label: DLX2
  - preferred_term: HOXD13
    term:
      id: hgnc:5136
      label: HOXD13
  evidence:
  - reference: PMID:22140379
    reference_title: "Refinement of the Region for Split Hand/Foot Malformation 5 on 2q31.1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Seven subjects with deletions encompassing the HOXD cluster had hand/foot anomalies of varying severity, including syndactyly, brachydactyly, and ectrodactyly."
    explanation: >-
      Maps the SHFM5 limb phenotype to 2q31 deletions encompassing the HOXD
      cluster.
  - reference: PMID:22140379
    reference_title: "Refinement of the Region for Split Hand/Foot Malformation 5 on 2q31.1."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "The absence of hand/foot anomalies in any of the individuals with deletions of DLX1/DLX2 but not the HOXD cluster supports the hypothesis that haploinsufficiency of the HOXD cluster, rather than DLX1/DLX2, accounts for the skeletal abnormalities in subjects with 2q31.1 microdeletions."
    explanation: >-
      Refines the SHFM5 mechanism: HOXD-cluster haploinsufficiency, not
      DLX1/DLX2 loss, drives the ectrodactyly in 2q31.1 deletions.

- name: SHFM6
  display_name: SHFM6 (WNT10B)
  subtype_term:
    preferred_term: split hand-foot malformation 6
    term:
      id: MONDO:0009157
      label: split hand-foot malformation 6
  description: >-
    Autosomal recessive SHFM caused by homozygous loss-of-function variants in
    WNT10B, typically in consanguineous families. Feet are usually more
    severely affected than hands, with frequent third-fourth finger syndactyly
    and, in a minority, polydactyly; heterozygotes may show mild features,
    suggesting a dose effect.
  inheritance:
  - name: Autosomal recessive
  genes:
  - preferred_term: WNT10B
    term:
      id: hgnc:12775
      label: WNT10B
  evidence:
  - reference: PMID:31050392
    reference_title: "WNT10B variants in split hand/foot malformation: Report of three novel families and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "WNT10B homozygous variants have been recently identified in consanguineous families, but remain still rarely described (SHFM6; MIM225300)."
    explanation: >-
      Establishes WNT10B homozygous loss-of-function variants as the cause of
      autosomal recessive SHFM6.
  - reference: PMID:31050392
    reference_title: "WNT10B variants in split hand/foot malformation: Report of three novel families and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "heterozygous individuals might have mild features of SHFM, suggesting a dose-effect of the WNT10B loss-of-function."
    explanation: >-
      Supports a WNT10B dose effect, with mild features in heterozygotes.

- name: SHFLD
  display_name: SHFLD (split hand/foot with long-bone deficiency, BHLHA9)
  description: >-
    Split hand/foot malformation with long-bone deficiency, most commonly
    associated with copy-number gains (duplication/triplication) at 17p13.3
    that invariably encompass BHLHA9 ("Fingerin"). BHLHA9 is required for AER
    formation; its dysregulation causes SHFM/SHFLD via aberrant AER-related
    gene expression. The trait shows markedly incomplete penetrance (~50%) and
    variable expressivity.
  genes:
  - preferred_term: BHLHA9
    term:
      id: hgnc:35126
      label: BHLHA9
  evidence:
  - reference: PMID:28324176
    reference_title: "Bhlha9 regulates apical ectodermal ridge formation during limb development."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "These observations suggest that Bhlha9 regulates AER formation during limb/finger development by regulating the expression of some AER-formation-related genes and abnormal expression of Bhlha9 leads to SHFM and SHFLD via dysregulation of AER formation and associated gene expression."
    explanation: >-
      Bhlha9-knockout mice show that BHLHA9 regulates AER formation and that
      its dysregulation causes SHFM/SHFLD.
  - reference: PMID:36028842
    reference_title: "SHFLD3 phenotypes caused by 17p13.3 triplication/ duplication encompassing Fingerin (BHLHA9) invariably."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Split-hand/ foot malformation with long bone deficiency 3 (SHFLD3) is an extremely rare condition associated with duplications located on 17p13.3, which invariably encompasses the BHLHA9 gene. The disease inherits with variable expressivity and significant incomplete penetrance as high as 50%."
    explanation: >-
      Confirms 17p13.3 duplications encompassing BHLHA9 as the cause of SHFLD,
      with ~50% incomplete penetrance.

- name: X-linked SHFM
  display_name: X-linked SHFM (SOX3 regulatory variant)
  description: >-
    A rare X-linked form of isolated SHFM caused by complex structural
    variants near SOX3 that disrupt its regulatory landscape. Like other SHFM
    loci, the underlying defect is failure to maintain normal AER function
    during limb development.
  inheritance:
  - name: X-linked
  genes:
  - preferred_term: SOX3
    term:
      id: hgnc:11199
      label: SOX3
  evidence:
  - reference: PMID:37216008
    reference_title: "A complex structural variant near SOX3 causes X-linked split-hand/foot malformation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We describe a family with isolated X-linked SHFM, for which the causative variant could be detected after a diagnostic journey of 20 years."
    explanation: >-
      Reports a family with isolated X-linked SHFM caused by a complex
      structural variant near SOX3.

- name: PRDM1-associated SHFM
  display_name: PRDM1-associated SHFM
  description: >-
    An emerging cause of SHFM associated with de novo or segregating
    heterozygous variants in PRDM1, a transcription factor required for limb
    development. Functional studies indicate the variants disrupt the
    proline/serine-rich and DNA-binding zinc-finger domains and act in a
    dominant-negative fashion; PRDM1 directly regulates limb genes including
    FGFR1 and DLX5/DLX6, placing it upstream of the shared SHFM pathway.
  genes:
  - preferred_term: PRDM1
    term:
      id: hgnc:9346
      label: PRDM1
  evidence:
  - reference: PMID:37083955
    reference_title: "PRDM1 DNA-binding zinc finger domain is required for normal limb development and is disrupted in split hand/foot malformation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Through whole-exome and targeted sequencing, we detected three novel variants in a gene encoding a transcription factor, PRDM1, that arose de novo in families with SHFM or segregated with the phenotype."
    explanation: >-
      Identifies PRDM1 as an SHFM gene, with de novo and segregating
      heterozygous variants in affected families.
  - reference: PMID:37083955
    reference_title: "PRDM1 DNA-binding zinc finger domain is required for normal limb development and is disrupted in split hand/foot malformation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "we show that the variants disrupt the proline/serine-rich and DNA-binding zinc finger domains, resulting in a dominant-negative effect."
    explanation: >-
      Zebrafish rescue experiments show the PRDM1 variants act in a
      dominant-negative fashion via disruption of its functional domains.

pathophysiology:
- name: Apical Ectodermal Ridge Maintenance Failure
  description: >-
    The unifying mechanism across SHFM loci is failure to maintain normal
    apical ectodermal ridge (AER) function during limb development. The AER is
    the epithelial signaling center at the distal tip of the limb bud that
    sustains outgrowth of the underlying mesenchyme. SHFM-associated mutations
    converge on dysregulation of FGF8 in the central portion of the AER,
    failure of AER stratification, and disruption of reciprocal Wnt-BMP-FGF
    signaling between the AER and progress-zone mesenchyme. The central-ray
    defect reflects loss of this signaling specifically in the median AER.
  locations:
  - preferred_term: apical ectodermal ridge
    term:
      id: UBERON:0004356
      label: apical ectodermal ridge
  - preferred_term: limb bud
    term:
      id: UBERON:0004347
      label: limb bud
  biological_processes:
  - preferred_term: apical ectodermal ridge formation
    term:
      id: GO:1905139
      label: apical ectodermal ridge formation
  - preferred_term: FGF8 signaling in the AER
    term:
      id: GO:0008543
      label: fibroblast growth factor receptor signaling pathway
    modifier: DECREASED
  - preferred_term: limb development
    term:
      id: GO:0060173
      label: limb development
    modifier: ABNORMAL
  evidence:
  - reference: PMID:30101460
    reference_title: "Genetic regulatory pathways of split-hand/foot malformation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Split-hand/foot malformation (SHFM) is caused by mutations in TP63, DLX5, DLX6, FGF8, FGFR1, WNT10B, and BHLHA9."
    explanation: >-
      Lists the convergent set of SHFM-causing genes that act on a shared AER
      regulatory pathway.
  - reference: PMID:30101460
    reference_title: "Genetic regulatory pathways of split-hand/foot malformation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The mutations in SHFM-related genes lead to dysregulation of Fgf8 in the central portion of the apical ectodermal ridge (AER) and subsequently lead to misexpression of a number of downstream target genes, failure of stratification of the AER, and thus SHFM."
    explanation: >-
      States the core mechanism: central-AER FGF8 dysregulation and failed AER
      stratification produce SHFM.
  - reference: PMID:37216008
    reference_title: "A complex structural variant near SOX3 causes X-linked split-hand/foot malformation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "SHFM is caused by failure to maintain normal apical ectodermal ridge function during limb development."
    explanation: >-
      Independent confirmation that the unifying defect is failed AER
      maintenance.
  downstream:
  - target: Disrupted Wnt-BMP-FGF Signaling and Central Ray Loss
    causal_link_type: DIRECT

- name: Disrupted Wnt-BMP-FGF Signaling and Central Ray Loss
  description: >-
    Loss of central-AER FGF8 dysregulates the reciprocal Wnt-BMP-FGF signaling
    loop. Disruption of canonical and non-canonical Wnt signaling, together
    with altered FGF-BMP-MSX signaling, drives the phenotype: median clefts
    with absent or hypoplastic central rays, syndactyly of the remaining
    digits (from dysregulated apoptotic cell death), and loss of digit
    identity (from misexpression of HOX genes and an abnormal SHH gradient or
    loss of GLI3A/GLI3R balance).
  locations:
  - preferred_term: autopod region
    term:
      id: UBERON:0002470
      label: autopod region
  biological_processes:
  - preferred_term: Wnt signaling pathway
    term:
      id: GO:0016055
      label: Wnt signaling pathway
    modifier: ABNORMAL
  - preferred_term: BMP signaling pathway
    term:
      id: GO:0030509
      label: BMP signaling pathway
    modifier: ABNORMAL
  - preferred_term: regulation of apoptotic process
    term:
      id: GO:0042981
      label: regulation of apoptotic process
    modifier: ABNORMAL
  - preferred_term: embryonic limb morphogenesis
    term:
      id: GO:0030326
      label: embryonic limb morphogenesis
    modifier: ABNORMAL
  evidence:
  - reference: PMID:30101460
    reference_title: "Genetic regulatory pathways of split-hand/foot malformation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Disruption of canonical and non-canonical Wnt signaling is involved in the pathogenesis of SHFM."
    explanation: >-
      Implicates disrupted canonical and non-canonical Wnt signaling in SHFM
      pathogenesis.
  - reference: PMID:30101460
    reference_title: "Genetic regulatory pathways of split-hand/foot malformation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Syndactyly of the remaining digits is most likely the effects of dysregulation of Fgf-Bmp-Msx signaling on apoptotic cell death."
    explanation: >-
      Links syndactyly of remaining digits to dysregulated FGF-BMP-MSX
      signaling and altered apoptosis.
  - reference: PMID:30101460
    reference_title: "Genetic regulatory pathways of split-hand/foot malformation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Loss of digit identity in SHFM is hypothesized to be the effects of misexpression of HOX genes, abnormal SHH gradient, or the loss of balance between GLI3A and GLI3R."
    explanation: >-
      Attributes loss of digit identity to HOX misexpression, abnormal SHH
      gradient, and disturbed GLI3A/GLI3R balance.
  downstream:
  - target: Split hand
    causal_link_type: DIRECT
    description: >-
      Central-ray loss in the hand produces a median cleft or split-hand
      malformation.
    evidence:
    - reference: ORPHA:2440
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0001171 | Split hand | Occasional (29-5%)"
      explanation: Orphadata lists split hand as an isolated SHFM phenotype.
  - target: Split foot
    causal_link_type: DIRECT
    description: >-
      Central-ray loss in the foot produces a split-foot malformation.
    evidence:
    - reference: ORPHA:2440
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0001839 | Split foot | Frequent (79-30%)"
      explanation: Orphadata lists split foot as a frequent isolated SHFM phenotype.
  - target: Ectrodactyly
    causal_link_type: DIRECT
    description: >-
      Loss or hypoplasia of central digits with median clefting corresponds to
      ectrodactyly.
    evidence:
    - reference: ORPHA:2440
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "A rare, congenital, bone development disorder characterized by a spectrum of terminal limb malformations including hypoplasia/absence of central rays of the hands and feet"
      explanation: Orphadata definition supports ectrodactyly as central-ray absence in isolated SHFM.
  - target: Syndactyly
    causal_link_type: DIRECT
    description: >-
      Dysregulated FGF-BMP-MSX signaling alters interdigital apoptosis,
      producing syndactyly of remaining digits.
    evidence:
    - reference: PMID:30101460
      reference_title: "Genetic regulatory pathways of split-hand/foot malformation."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Syndactyly of the remaining digits is most likely the effects of dysregulation of Fgf-Bmp-Msx signaling on apoptotic cell death."
      explanation: The SHFM pathway review directly links syndactyly to dysregulated FGF-BMP-MSX signaling.
  - target: Polydactyly
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      SHFM-associated disruption of digit identity and patterning can include
      supernumerary digits in some subtypes.
    evidence:
    - reference: PMID:31050392
      reference_title: "WNT10B variants in split hand/foot malformation: Report of three novel families and review of the literature."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Polydactyly, which was classically described in SHFM6, was only present in 27% of patients."
      explanation: WNT10B-related SHFM6 shows polydactyly as an occasional digit-patterning outcome.
  - target: Oligodactyly
    causal_link_type: DIRECT
    description: >-
      Central-ray absence reduces the number of digits, producing oligodactyly.
    evidence:
    - reference: ORPHA:2440
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0012165 | Oligodactyly | Very frequent (99-80%)"
      explanation: Orphadata lists oligodactyly as a very frequent isolated SHFM phenotype.

phenotypes:
- name: Split hand
  category: Skeletal
  description: >-
    Median cleft of the hand with absent or hypoplastic central rays,
    producing a lobster-claw appearance.
  phenotype_term:
    preferred_term: Split hand
    term:
      id: HP:0001171
      label: Split hand
  evidence:
  - reference: PMID:30101460
    reference_title: "Genetic regulatory pathways of split-hand/foot malformation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This implies that in normal situations these SHFM-associated genes share an underlying regulatory pathway that is involved in the development of the central parts of the hands and feet."
    explanation: >-
      Identifies the central hand/foot rays as the developmental territory
      affected, the basis of the split-hand phenotype.

- name: Split foot
  category: Skeletal
  description: >-
    Median cleft of the foot with absent or hypoplastic central rays; in many
    SHFM forms the feet are more severely affected than the hands.
  phenotype_term:
    preferred_term: Split foot
    term:
      id: HP:0001839
      label: Split foot
  evidence:
  - reference: PMID:31050392
    reference_title: "WNT10B variants in split hand/foot malformation: Report of three novel families and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The feet are more severely affected than the hands and there is a frequent asymmetry without obvious side-bias."
    explanation: >-
      Documents foot involvement and the frequent foot-predominant asymmetry
      seen in SHFM (here WNT10B-related SHFM6).

- name: Ectrodactyly
  category: Skeletal
  description: >-
    Absence of one or more central digits with median clefting, the defining
    limb defect of SHFM.
  phenotype_term:
    preferred_term: Ectrodactyly
    term:
      id: HP:0100257
      label: Ectrodactyly
  evidence:
  - reference: PMID:38567169
    reference_title: "Osteogenesis Imperfecta and Split Foot Malformation due to 7q21.2q21.3 Deletion Including COL1A2, DLX5/6 Genes: Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report a Turkish girl with ectrodactyly, joint laxity, multiple bone fractures, blue sclera, early teeth decay, mild learning disability, and depression."
    explanation: >-
      Documents ectrodactyly as the limb manifestation in a SHFM1 (7q21
      deletion) patient.

- name: Syndactyly
  category: Skeletal
  description: >-
    Fusion of remaining digits, frequently affecting the third and fourth
    fingers, attributed to dysregulated apoptotic cell death in the
    interdigital mesenchyme.
  phenotype_term:
    preferred_term: Syndactyly
    term:
      id: HP:0001159
      label: Syndactyly
  evidence:
  - reference: PMID:31050392
    reference_title: "WNT10B variants in split hand/foot malformation: Report of three novel families and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Syndactyly of third-fourth fingers was a frequent finding (62%)."
    explanation: >-
      Quantifies third-fourth finger syndactyly as a frequent SHFM feature.
  frequency: FREQUENT

- name: Polydactyly
  category: Skeletal
  description: >-
    Supernumerary digits, classically described in SHFM6 (WNT10B) though
    present in only a minority of patients.
  phenotype_term:
    preferred_term: Polydactyly
    term:
      id: HP:0010442
      label: Polydactyly
  evidence:
  - reference: PMID:31050392
    reference_title: "WNT10B variants in split hand/foot malformation: Report of three novel families and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Polydactyly, which was classically described in SHFM6, was only present in 27% of patients."
    explanation: >-
      Documents polydactyly in a minority (27%) of WNT10B-related SHFM6
      patients.
  frequency: OCCASIONAL

- name: Oligodactyly
  category: Skeletal
  description: >-
    Reduced digit number reflects hypoplasia or absence of central rays in
    split hand-foot malformation.
  phenotype_term:
    preferred_term: Oligodactyly
    term:
      id: HP:0012165
      label: Oligodactyly
  evidence:
  - reference: ORPHA:2440
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0012165 | Oligodactyly | Very frequent (99-80%)"
    explanation: Orphadata lists oligodactyly as a very frequent isolated SHFM phenotype.
  frequency: VERY_FREQUENT

- name: Sensorineural hearing loss
  category: Audiologic
  subtype: SHFM1
  description: >-
    Sensorineural hearing impairment, sometimes with inner-ear malformation,
    is an extra-limb feature associated with the SHFM1 (7q21, DLX5/DLX6) locus.
  phenotype_term:
    preferred_term: Sensorineural hearing impairment
    term:
      id: HP:0000407
      label: Sensorineural hearing impairment
  evidence:
  - reference: PMID:37628577
    reference_title: "Split Hand-Foot and Deafness in a Patient with 7q21.13-q21.3 Deletion Not Including the DLX5/6 Genes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we analyzed a patient affected by SHFM1 associated with deafness and an abnormality of the inner ear (incomplete partition type I)"
    explanation: >-
      Documents sensorineural deafness with inner-ear malformation in an SHFM1
      patient with a 7q21 deletion affecting DLX5/6 regulation.

genetic:
- name: SHFM is genetically heterogeneous with a shared AER regulatory pathway
  association: Causative
  notes: >-
    SHFM is caused by mutations across at least seven loci (SHFM1-SHFM6 plus
    SHFM/SHFLD) involving TP63, DLX5, DLX6, FGF8, FGFR1, WNT10B, and BHLHA9,
    which converge on a single AER regulatory pathway. Inheritance is most
    often autosomal dominant with reduced penetrance and variable expression,
    with autosomal recessive (WNT10B) and X-linked (SOX3) forms also reported.
  evidence:
  - reference: PMID:30101460
    reference_title: "Genetic regulatory pathways of split-hand/foot malformation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The clinical features of SHFM caused by mutations of these genes are not distinguishable."
    explanation: >-
      Establishes that the multiple SHFM genes produce clinically
      indistinguishable phenotypes, consistent with a shared pathway.

- name: BHLHA9 dosage and AER formation
  association: Causative
  gene_term:
    preferred_term: BHLHA9
    term:
      id: hgnc:35126
      label: BHLHA9
  notes: >-
    BHLHA9 ("Fingerin") regulates AER formation, in part by regulating Trp63
    (TP63); copy-number gains at 17p13.3 encompassing BHLHA9 cause SHFM/SHFLD.
  evidence:
  - reference: PMID:28324176
    reference_title: "Bhlha9 regulates apical ectodermal ridge formation during limb development."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "some apical ectodermal ridge (AER) formation related genes, including Trp63, exhibited an aberrant expression pattern in the limb bud of Bhlha9-knockout mice; TP63 (Trp63) was regulated by Bhlha9 on the basis of in vitro analysis."
    explanation: >-
      Places BHLHA9 upstream of TP63 in AER formation, linking it to the
      shared SHFM pathway.

treatments:
- name: Reconstructive orthopedic surgery
  description: >-
    Multi-stage reconstructive and corrective orthopedic surgery is the
    mainstay of SHFM management, addressing the cleft, digital deficiency, and
    associated long-bone anomalies (e.g., tibial aplasia) to improve hand
    function and achieve weight-bearing and ambulation. Management is
    individualized and supportive; there is no disease-modifying therapy.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: orthopedic surgical procedure
    term:
      id: NCIT:C16186
      label: Orthopedic Surgical Procedure
  evidence:
  - reference: PMID:24647283
    reference_title: "Reconstruction of bilateral tibial aplasia and split hand-foot syndrome in a father and daughter."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Reconstruction of these patients required multiple surgical procedures and orthoprosthesis was mandatory."
    explanation: >-
      Documents multi-stage reconstructive orthopedic surgery as the primary
      management approach for SHFM with associated tibial aplasia.
  - reference: PMID:24647283
    reference_title: "Reconstruction of bilateral tibial aplasia and split hand-foot syndrome in a father and daughter."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The main goal of treatment was to achieve walking."
    explanation: >-
      Establishes restoration of ambulation as the functional goal of surgical
      management in severe SHFM.
- name: Prosthetics and orthotics
  description: >-
    Custom prosthetic and orthotic fitting complements surgical reconstruction,
    stabilizing deformed limbs and enabling ambulation and use of the affected
    hands and feet.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: prosthetic and orthotic fitting
    term:
      id: NCIT:C15315
      label: Rehabilitation
  evidence:
  - reference: PMID:24647283
    reference_title: "Reconstruction of bilateral tibial aplasia and split hand-foot syndrome in a father and daughter."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "walking was achieved with simultaneous designation of orthotic fitting."
    explanation: >-
      Documents orthotic/prosthetic fitting as an adjunct to surgery that
      enabled ambulation in SHFM with tibial aplasia.
- name: Genetic counseling
  description: >-
    Because SHFM is genetically heterogeneous with autosomal dominant
    (often reduced-penetrance), autosomal recessive, and X-linked forms,
    molecular diagnosis and genetic counseling inform recurrence-risk
    assessment and reproductive decision-making for affected families.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:37216008
    reference_title: "A complex structural variant near SOX3 causes X-linked split-hand/foot malformation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We describe a family with isolated X-linked SHFM, for which the causative variant could be detected after a diagnostic journey of 20 years."
    explanation: >-
      Illustrates the diagnostic complexity of SHFM that genetic counseling and
      molecular testing address, supporting their role in family management.

references:
- reference: PMID:30101460
  title: "Genetic regulatory pathways of split-hand/foot malformation."

📚

References & Deep Research

References

1

PMID:30101460

Genetic regulatory pathways of split-hand/foot malformation.

No top-level findings curated for this source.

Deep Research

1

Falcon ▸

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

Edison Scientific Literature 38 citations 2026-06-08T12:32:43.783751

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

Split-hand/split-foot malformation (SHFM) (ambrosetti2023splithandfootand pages 1-2)
Ectrodactyly (bilal2023sequencevariantsin pages 1-2, sowinskaseidler2014splithandfootmalformation pages 1-2)
“Split hand-foot malformation type 1/3/4/6” depending on locus (sowinskaseidler2014splithandfootmalformation pages 1-2, ambrosetti2023splithandfootand pages 1-2, cova2023combinatorialeffectson pages 1-2, bilal2023sequencevariantsin pages 1-2)
SHFM with long bone deficiency (SHFLD) for phenotypes with tibia/fibula/femur involvement (deftereou2024acaseofa pages 11-12, umair2019nonsyndromicsplithandfootmalformation pages 1-2)

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)

SHFM1 (7q21): disruptions affecting DLX5/DLX6 and/or their tissue-specific enhancers at 7q21.3; enhancer mechanisms include DYNC1I1 exonic enhancers (eExons 15/17). (ambrosetti2023splithandfootand pages 1-2, ambrosetti2023splithandfootand pages 2-4, sowinskaseidler2023agenotype–phenotypecorrelation pages 13-13)
SHFM3 (10q24): tandem duplications/inversions at the LBX1/FGF8 locus encompassing genes such as LBX1, BTRC, POLL, FBXW4 (duplications often exclude FGF8 coding sequence). (cova2023combinatorialeffectson pages 2-3, akimova2024variableclinicalpresentation pages 1-2)
SHFM6 (12q13.12): biallelic (autosomal recessive) WNT10B variants. (bilal2023sequencevariantsin pages 1-2, bilal2023sequencevariantsin pages 2-5)
PRDM1 (newer implication with functional validation): heterozygous PRDM1 variants with dominant-negative features in zebrafish assays. (truong2023prdm1dnabindingzinc pages 1-2, truong2023prdm1dnabindingzinc pages 2-2)

Inheritance patterns / penetrance

A genetics-focused review states SHFM “shows mostly autosomal dominant inheritance with variable expressivity and reduced penetrance; autosomal recessive and X-linked inheritance are very uncommon.” (sowinskaseidler2014splithandfootmalformation pages 1-2)
For SHFM1 specifically, a 2023 primary report reiterates autosomal dominant inheritance with incomplete penetrance and variable expressivity. (ambrosetti2023splithandfootand pages 1-2)
For SHFM3 (10q24 duplications), 2024 WGS-based family study documents mosaicism in an unaffected carrier as a plausible explanation for absence of phenotype, illustrating reduced penetrance/variable expressivity. (akimova2024variableclinicalpresentation pages 1-2, akimova2024variableclinicalpresentation pages 2-3)

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

Onset: congenital (implied across sources describing SHFM as congenital limb defect). (ambrosetti2023splithandfootand pages 1-2, sowinskaseidler2014splithandfootmalformation pages 1-2)
Severity: highly variable, including intrafamilial variability (notably with SHFM3 duplications and mosaicism). (akimova2024variableclinicalpresentation pages 2-3)

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

Primary: hands and feet (autopod), central rays/digits (ambrosetti2023splithandfootand pages 1-2, bilal2023sequencevariantsin pages 1-2)
Secondary (in SHFM1 spectrum): inner ear structures (hearing loss; malformed cochlea) (ambrosetti2023splithandfootand pages 4-7)

7.2 Tissue/cell level (mechanism-driven)

Limb ectoderm/AER (ectodermal ridge signaling center) implicated by mechanistic studies (cova2023combinatorialeffectson pages 1-2, truong2023prdm1dnabindingzinc pages 10-11)

7.3 Subcellular

Not supported in retrieved excerpts.

8. Temporal Development

Typical onset: congenital (ambrosetti2023splithandfootand pages 1-2)
Course: structural, generally non-progressive limb anatomy; however, associated features like hearing loss may be progressive in some cases (reported “progressive sensorineural hearing loss” in one SHFM1 regulatory-deletion case). (ambrosetti2023splithandfootand pages 4-7)

9. Inheritance and Population

9.1 Epidemiology statistics

SHFM prevalence is reported as ~1:18,000 live births in a 2023 SHFM1-focused paper. (ambrosetti2023splithandfootand pages 1-2)
A 2019 review reports prevalence as 1 per 90,000 live births, reflecting variability in estimates across sources/populations/definitions. (umair2019nonsyndromicsplithandfootmalformation pages 1-2)

9.2 Inheritance patterns

Predominantly autosomal dominant for common subtypes (SHFM1/3/4/5), often with reduced penetrance and variable expressivity (review-level). (sowinskaseidler2014splithandfootmalformation pages 1-2)
Autosomal recessive forms exist (e.g., WNT10B SHFM6). (bilal2023sequencevariantsin pages 1-2)

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

In an SHFM1 case with severe hearing impairment, cochlear implantation was performed (real-world intervention for syndromic feature). (ambrosetti2023splithandfootand pages 4-7)

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)

MAXO:0000015 Surgical procedure (suggested)
MAXO:0000767 Genetic testing (suggested)
MAXO:0000504 Cochlear implantation (suggested; supported by case) (ambrosetti2023splithandfootand pages 4-7)

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)

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)
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)
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)

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

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

1. Disease Information

1.1 Concise overview (current understanding)

1.2 Synonyms and alternative names

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

1.4 Data source type

2. Etiology

2.1 Disease causal factors (primary causes)

2.2 Genetic risk factors

Major loci/genes (recently supported)

Inheritance patterns / penetrance

2.3 Environmental risk factors / protective factors / GxE

3. Phenotypes

3.1 Core phenotype spectrum

3.2 Associated/extra-limb features

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

3.4 Onset, progression, severity

3.5 Suggested HPO terms (examples)

3.6 Quality of life impact

4. Genetic / Molecular Information

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

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

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

SHFM6 (WNT10B): autosomal recessive coding variants

PRDM1: functional genomics-supported gene implication

4.2 Modifier genes, epigenetics, allele frequencies

5. Environmental Information

6. Mechanism / Pathophysiology

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

6.2 2023–2024 mechanistic advances (high-priority)

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

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

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

6.3 Suggested pathway/ontology annotations

7. Anatomical Structures Affected

7.1 Organ/system level

7.2 Tissue/cell level (mechanism-driven)

7.3 Subcellular

8. Temporal Development

9. Inheritance and Population

9.1 Epidemiology statistics

9.2 Inheritance patterns

9.3 Population variation / founder effects

10. Diagnostics

10.1 Clinical/radiographic diagnosis

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

(A) CNV/SV detection for SHFM1 regulatory deletions

(B) WGS for SHFM3 duplications and mosaicism

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

10.3 Differential diagnosis

11. Outcome / Prognosis

12. Treatment

12.1 Current applications / real-world implementations

12.2 Clinical trials

12.3 Suggested MAXO terms (examples)

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

15.1 Mouse models (SHFM3 mechanism)

15.2 Zebrafish models (PRDM1-associated SHFM)

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

Genetics summary table (for knowledge-base ingestion)

Figure-based evidence (mechanism visualization)

Direct abstract quotes (as available in retrieved excerpts)

Key limitations of this report (data gaps)

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