Split-foot malformation with mesoaxial polydactyly (SFMMP) is an autosomal recessive congenital limb malformation syndrome caused by biallelic MAP3K20 (ZAK) lesions that affect the sterile alpha motif (SAM) domain, which is present only in the long ZAK-alpha isoform. It was defined in two consanguineous families (one Pakistani family with four affected members and one Tunisian boy) with a variable split foot, partial duplication of the second toe, toe syndactyly, duplicated fingernail beds and, in the larger family, bilateral sensorineural hearing impairment. The missense allele destabilizes the isolated SAM domain and makes ZAK constitutively active in cell experiments, while a mouse SAM-domain deletion causes low-penetrance hindlimb duplication with reduced Trp63 expression. How either finding leads to the human foot defect is unresolved.
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name: Split-Foot Malformation with Mesoaxial Polydactyly
creation_date: "2026-10-09T12:00:00Z"
description: >-
Split-foot malformation with mesoaxial polydactyly (SFMMP) is an autosomal recessive congenital limb
malformation syndrome caused by biallelic MAP3K20 (ZAK) lesions that affect the sterile alpha motif (SAM)
domain, which is present only in the long ZAK-alpha isoform. It was defined in two consanguineous families
(one Pakistani family with four affected members and one Tunisian boy) with a variable split foot, partial
duplication of the second toe, toe syndactyly, duplicated fingernail beds and, in the larger family,
bilateral sensorineural hearing impairment. The missense allele destabilizes the isolated SAM domain and
makes ZAK constitutively active in cell experiments, while a mouse SAM-domain deletion causes low-penetrance
hindlimb duplication with reduced Trp63 expression. How either finding leads to the human foot defect is
unresolved.
category: Mendelian
disease_term:
preferred_term: Split-Foot Malformation with Mesoaxial Polydactyly
term:
id: MONDO:0014816
label: split-foot malformation-mesoaxial polydactyly syndrome
synonyms:
- SFMMP
- split-foot malformation-mesoaxial polydactyly syndrome
- split-foot malformation-mesoaxial polydactyly-nail abnormalities-sensorineural hearing loss syndrome
- SHFM type 7
notes: >-
No GeneReviews chapter exists for this disorder. Only two families with molecular confirmation have been
reported, so per-feature counts describe five people and are not population frequencies. SFMMP is distinct
from the MAP3K20-related congenital myopathy, caused by biallelic truncating variants that lose both
isoforms, and from the dominant MAP3K20 disorder caused by heterozygous linker-region variants with
ectodermal dysplasia and craniosynostosis. No treatment specific to SFMMP has been reported; management of
the foot anomaly and hearing loss follows general practice, so no treatment record is included.
prevalence:
- population: Published literature
measure_type: CASES_IN_LITERATURE
prevalence_class: ULTRA_RARE
notes: >-
Two consanguineous families (five affected individuals) with molecularly confirmed SFMMP have been
reported.
evidence:
- reference: PMID:38451290
reference_title: "Heterozygous MAP3K20 variants cause ectodermal dysplasia, craniosynostosis, sensorineural hearing loss, and limb anomalies."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: BACKGROUND
snippet: "Recently, biallelic variants in MAP3K20 (also known as ZAK) have been associated with SHFM type 7 (MIM # 616890), also known as split-foot malformation with mesoaxial polydactyly, in two separate consanguineous families (Spielmann 2016)."
explanation: States that the published SFMMP literature consists of two consanguineous families.
- reference: PMID:26755636
reference_title: Exome sequencing and CRISPR/Cas genome editing identify mutations of ZAK as a cause of limb defects in humans and mice.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "In a multiplex consanguineous Pakistani family with four affected individuals (family F1)"
explanation: The index family contributed four of the five described patients; the second family had one affected boy.
inheritance:
- name: Autosomal recessive inheritance
inheritance_term:
preferred_term: Autosomal recessive inheritance
term:
id: HP:0000007
label: Autosomal recessive inheritance
expressivity: VARIABLE
description: >-
Homozygous MAP3K20 lesions in two consanguineous families; the deletion was heterozygous in the unaffected
first-cousin parents of the Tunisian patient. Foot involvement ranged from bilateral to absent among
homozygous relatives.
evidence:
- reference: PMID:26755636
reference_title: Exome sequencing and CRISPR/Cas genome editing identify mutations of ZAK as a cause of limb defects in humans and mice.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Here we describe an autosomal recessive human disease in two unrelated families characterized by a split-foot defect, nail abnormalities of the hands, and hearing loss, due to mutations disrupting the SAM domain of the protein kinase ZAK."
explanation: Defines the disorder as autosomal recessive.
- reference: PMID:26755636
reference_title: Exome sequencing and CRISPR/Cas genome editing identify mutations of ZAK as a cause of limb defects in humans and mice.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "foot defects in affected individuals ranging from bilateral to unilateral foot involvement to no split foot in one individual"
explanation: Variable expressivity among homozygous affected relatives.
pathophysiology:
- name: Biallelic MAP3K20 SAM-Domain Lesions
biological_scale: MOLECULAR
mechanism_confidence: ESTABLISHED
description: >-
The initiating lesions are homozygous MAP3K20 variants affecting the C-terminal SAM domain: the missense
variant c.1103T>G p.(Phe368Cys) in the Pakistani family and a 14.7-kb intragenic deletion of exons 12-16
in the Tunisian family. The SAM domain is present only in the long ZAK-alpha isoform; the short ZAK-beta
isoform lacks it, so both lesions alter ZAK-alpha specifically.
genes:
- preferred_term: MAP3K20
term:
id: hgnc:17797
label: MAP3K20
genetic_context:
genes:
- preferred_term: MAP3K20
term:
id: hgnc:17797
label: MAP3K20
zygosity: HOMOZYGOUS
variant_origin: GERMLINE
notes: >-
One missense allele and one intragenic exon deletion; both lie in the ZAK-alpha-specific SAM domain.
The missense allele is hyperactive in cell assays, so a uniform loss-of-function category is not
assigned.
evidence:
- reference: PMID:26755636
reference_title: Exome sequencing and CRISPR/Cas genome editing identify mutations of ZAK as a cause of limb defects in humans and mice.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Notably, the missense alteration and the intragenic deletion both affect the SAM domain, which is only present in the longer ZAK-α isoform."
explanation: Both disease alleles are confined to the ZAK-alpha-specific SAM domain.
- reference: PMID:26755636
reference_title: Exome sequencing and CRISPR/Cas genome editing identify mutations of ZAK as a cause of limb defects in humans and mice.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Both variants cosegregated with the disease, were predicted to be damaging, and were absent or very rare in controls"
explanation: Cosegregation of the homozygous ZAK missense variant in the index family.
downstream:
- target: Loss of Normal ZAK-alpha SAM Domain Structure
causal_link_type: DIRECT
description: >-
The deletion removes the SAM-encoding exons; the missense variant destabilizes the domain.
evidence:
- reference: PMID:26755636
reference_title: Exome sequencing and CRISPR/Cas genome editing identify mutations of ZAK as a cause of limb defects in humans and mice.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "These results indicate that the Phe368Cys mutation strongly destabilizes the ZAK SAM domain."
explanation: Circular dichroism and thermal unfolding of purified wild-type and mutant SAM domains.
- target: Abnormal fingernail with duplicated nail bed
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
The nail-bed duplication segregates with the SAM-domain lesions in both families; no intermediate
mechanism has been studied.
evidence:
- reference: PMID:26755636
reference_title: Exome sequencing and CRISPR/Cas genome editing identify mutations of ZAK as a cause of limb defects in humans and mice.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The patients also had duplications of the nail bed on the hands"
explanation: Genotype-phenotype association only; the step from ZAK-alpha to the nail unit is unknown.
directness: INDIRECT
- target: Bilateral sensorineural hearing impairment
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
Hearing impairment was present in the missense family; Zak is expressed in mouse cochlear hair cells,
but SAM-deleted mice showed no hearing defect on Preyer reflex screening and the auditory mechanism is
unknown.
evidence:
- reference: PMID:26755636
reference_title: Exome sequencing and CRISPR/Cas genome editing identify mutations of ZAK as a cause of limb defects in humans and mice.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "In addition to limb defects, all patients in family 1 had bilateral sensorineural hearing impairment"
explanation: Association of the homozygous missense allele with hearing impairment; mechanism not studied.
directness: INDIRECT
- name: Loss of Normal ZAK-alpha SAM Domain Structure
biological_scale: MOLECULAR
mechanism_confidence: ESTABLISHED
description: >-
p.Phe368Cys sits in the hydrophobic core of the SAM domain. The purified mutant domain loses about a
third of its alpha-helicity, loses cooperative thermal unfolding and is aggregation prone. The exon 12-16
deletion is predicted to remove the SAM domain entirely. These measurements were made on isolated
domains, not on full-length protein in limb cells.
genes:
- preferred_term: MAP3K20
term:
id: hgnc:17797
label: MAP3K20
evidence:
- reference: PMID:26755636
reference_title: Exome sequencing and CRISPR/Cas genome editing identify mutations of ZAK as a cause of limb defects in humans and mice.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "The CD spectrum of Phe368Cys showed a ∼30% loss of alpha-helicity compared with the wild-type"
explanation: Direct biophysical measurement of SAM-domain destabilization.
- reference: PMID:26755636
reference_title: Exome sequencing and CRISPR/Cas genome editing identify mutations of ZAK as a cause of limb defects in humans and mice.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "The Phe368Cys (F368C) substitution in the ZAK SAM domain causes a retarded migration, indicating protein aggregation."
explanation: Native-gel evidence that the mutant SAM domain is aggregation prone.
downstream:
- target: Constitutive ZAK-alpha Kinase Activation
causal_link_type: DIRECT
description: >-
Shown for p.Phe368Cys re-expressed in ZAK-knockout HEK293T cells; not tested for the deletion allele or
in limb tissue.
evidence:
- reference: PMID:41261136
reference_title: ZAK activation at the collided ribosome.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "The known disease-associated mutation in the SAM domain (F368C) causes a hyperactive phenotype characterized by ZAK activation similar to another previously characterized constitutively active W347S mutant"
explanation: The SFMMP missense allele is hyperactive in cell-based assays.
- target: Reduced Hindlimb Bud Trp63 Expression
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
Shown only for a mouse SAM-domain deletion that genocopies the Tunisian allele; the intermediates
between ZAK-alpha and Trp63 transcription are not known.
evidence:
- reference: PMID:26755636
reference_title: Exome sequencing and CRISPR/Cas genome editing identify mutations of ZAK as a cause of limb defects in humans and mice.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "In contrast, a deletion of the SAM domain induces a complex hindlimb defect associated with down-regulation of Trp63, a known split-hand/split-foot malformation disease gene."
explanation: Mouse SAM-domain deletion reduces hindlimb Trp63 expression.
- name: Constitutive ZAK-alpha Kinase Activation
biological_scale: MOLECULAR
mechanism_confidence: PROVISIONAL
description: >-
ZAK-alpha is normally activated when its SAM domains dimerize on collided ribosomes. The SFMMP missense
variant p.Phe368Cys is already fully autophosphorylated without induced ribosome collisions and can
bypass the ribosome requirement. Whether this hyperactivity occurs in developing limb cells, or applies
to the SAM-deletion allele, has not been tested.
genes:
- preferred_term: MAP3K20
term:
id: hgnc:17797
label: MAP3K20
molecular_functions:
- preferred_term: MAP kinase kinase kinase activity
modifier: INCREASED
term:
id: GO:0004709
label: MAP kinase kinase kinase activity
biological_processes:
- preferred_term: protein autophosphorylation
modifier: INCREASED
term:
id: GO:0046777
label: protein autophosphorylation
evidence:
- reference: PMID:41261136
reference_title: ZAK activation at the collided ribosome.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "As expected, ANS treatment induced autophosphorylation of WT ZAK but did not change the extent of phosphorylation of F368C and K387D, which were already fully activated before ANS treatment"
explanation: F368C is constitutively autophosphorylated in ZAK-knockout HEK293T cells.
- reference: PMID:41261136
reference_title: ZAK activation at the collided ribosome.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Characterization of novel SAM variants as well as a known pathogenic variant of the SAM domain of ZAK supports a key role of the SAM domain in regulating kinase activity on and off the ribosome, with some mutants bypassing the ribosome requirement for ZAK activation."
explanation: The SAM domain restrains ZAK activity; the pathogenic SAM variant escapes this control.
downstream:
- target: Disrupted Distal Hindlimb Patterning
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
Proposed link. Increased kinase activity has been associated with the SAM-domain limb phenotype, but no
experiment connects hyperactive ZAK to limb patterning.
evidence:
- reference: PMID:38451290
reference_title: "Heterozygous MAP3K20 variants cause ectodermal dysplasia, craniosynostosis, sensorineural hearing loss, and limb anomalies."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: "Thus, biallelic loss-of-function variants in the kinase domain lead to CNM6, whereas biallelic variants in the SAM domain, which have been associated with increased kinase activity (Vind 2020), have been associated with limb anomalies and hearing loss."
explanation: Authors' synthesis linking SAM-domain hyperactivity to the limb phenotype; an inference, not a test.
directness: INDIRECT
- name: Reduced Hindlimb Bud Trp63 Expression
biological_scale: TISSUE
mechanism_confidence: PROVISIONAL
description: >-
Mouse hindlimbs homozygous for a SAM-domain deletion show about a 60% decrease in Trp63 transcript at
E11.5 by qRT-PCR, although Trp63, Fgf8 and Shh in situ staining patterns appeared normal. TP63 is an
established split-hand/foot malformation gene. A reduced TP63 level has not been measured in human SFMMP
tissue, and the authors state that the ZAK-TP63 link needs further work.
genes:
- preferred_term: TP63
term:
id: hgnc:15979
label: TP63
evidence:
- reference: PMID:26755636
reference_title: Exome sequencing and CRISPR/Cas genome editing identify mutations of ZAK as a cause of limb defects in humans and mice.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Expression analysis of Zakdel/del homozygous mutant (MT) hindlimbs at E11.5 showed a 60% decrease of Trp63 expression compared with wild-type (WT) hindlimbs."
explanation: Quantitative Trp63 reduction in SAM-deleted mouse hindlimbs.
- reference: PMID:26755636
reference_title: Exome sequencing and CRISPR/Cas genome editing identify mutations of ZAK as a cause of limb defects in humans and mice.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "However, much more experimental work is needed to investigate a potential functional link between TP63 and ZAK."
explanation: The authors' own caveat that the ZAK-TP63 relationship is not established.
downstream:
- target: Disrupted Distal Hindlimb Patterning
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
Speculative link proposed by the authors, by analogy with Trp63 loss and retinoic-acid-induced limb
duplication.
evidence:
- reference: PMID:26755636
reference_title: Exome sequencing and CRISPR/Cas genome editing identify mutations of ZAK as a cause of limb defects in humans and mice.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Therefore we speculate that mutations in ZAK causing a down-regulation of Trp63 in the hindlimb give rise to a wide spectrum of lower limb phenotypes with reduced penetrance and variable expressivity."
explanation: Stated as speculation by the authors.
directness: INDIRECT
- name: Disrupted Distal Hindlimb Patterning
biological_scale: TISSUE
mechanism_confidence: PROVISIONAL
description: >-
Abnormal patterning of the central rays of the developing foot, producing the cleft, the partial
second-ray duplication, syndactyly and phalangeal hypoplasia and fusion seen on radiographs. Zak is
expressed in the developing mouse limbs, and SAM-deleted mice develop variable hindlimb duplication and
polydactyly with low penetrance (4 of 64 animals). The hands are spared apart from the nails.
biological_processes:
- preferred_term: embryonic hindlimb morphogenesis
modifier: ABNORMAL
term:
id: GO:0035116
label: embryonic hindlimb morphogenesis
locations:
- preferred_term: foot
term:
id: UBERON:0002387
label: pes
evidence:
- reference: PMID:26755636
reference_title: Exome sequencing and CRISPR/Cas genome editing identify mutations of ZAK as a cause of limb defects in humans and mice.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "we observed a spectrum of unilateral complex hindlimb duplication phenotypes with low penetrance (four out of 64 animals)"
explanation: Hindlimb patterning defect in SAM-deleted mice, at low penetrance.
- reference: PMID:26755636
reference_title: Exome sequencing and CRISPR/Cas genome editing identify mutations of ZAK as a cause of limb defects in humans and mice.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Zak was expressed in the heart and the developing limbs"
explanation: Zak expression in the developing mouse limb is consistent with a patterning role.
downstream:
- target: Split foot
causal_link_type: DIRECT
evidence:
- reference: PMID:26755636
reference_title: Exome sequencing and CRISPR/Cas genome editing identify mutations of ZAK as a cause of limb defects in humans and mice.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Here we describe an autosomal recessive human disease in two unrelated families characterized by a split-foot defect, nail abnormalities of the hands, and hearing loss, due to mutations disrupting the SAM domain of the protein kinase ZAK."
explanation: The split foot is the cardinal developmental outcome of the defect.
- target: Mesoaxial foot polydactyly
causal_link_type: DIRECT
evidence:
- reference: PMID:26755636
reference_title: Exome sequencing and CRISPR/Cas genome editing identify mutations of ZAK as a cause of limb defects in humans and mice.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "duplication of the left proximal phalanx of the second toe corresponding to mesoaxial polydactyly"
explanation: Central-ray duplication is part of the same patterning defect.
- target: 1-2 toe syndactyly
causal_link_type: DIRECT
evidence:
- reference: PMID:26755636
reference_title: Exome sequencing and CRISPR/Cas genome editing identify mutations of ZAK as a cause of limb defects in humans and mice.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Individuals F1-VI:4 and F2-VI:2 showed partial duplication of digit II in combination with syndactyly I/II"
explanation: Syndactyly accompanies the central-ray defect.
- target: 4-5 toe syndactyly
causal_link_type: DIRECT
evidence:
- reference: PMID:26755636
reference_title: Exome sequencing and CRISPR/Cas genome editing identify mutations of ZAK as a cause of limb defects in humans and mice.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "There is hypoplasia of middle and distal phalanges of toes IV and V, as well as syndactyly between these toes."
explanation: Radiographic finding in the Tunisian patient.
- target: Hypoplasia of toe phalanges
causal_link_type: DIRECT
evidence:
- reference: PMID:26755636
reference_title: Exome sequencing and CRISPR/Cas genome editing identify mutations of ZAK as a cause of limb defects in humans and mice.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "hypoplastic and misshaped phalangeal bones of toes III to V with fusions of some interphalangeal joints"
explanation: Radiographic phalangeal hypoplasia in the index family.
- target: Toe symphalangism
causal_link_type: DIRECT
evidence:
- reference: PMID:26755636
reference_title: Exome sequencing and CRISPR/Cas genome editing identify mutations of ZAK as a cause of limb defects in humans and mice.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "hypoplastic and misshaped phalangeal bones of toes III to V with fusions of some interphalangeal joints"
explanation: Interphalangeal fusions of the lateral toes.
phenotypes:
- name: Split foot
category: Skeletal
diagnostic: true
description: >-
Congenital median cleft of the foot with absent or malformed central rays. Bilateral, unilateral, or
absent in homozygous relatives: three of four affected members of the index family and the Tunisian
patient had it.
phenotype_term:
preferred_term: Split foot
term:
id: HP:0001839
label: Split foot
evidence:
- reference: PMID:26755636
reference_title: Exome sequencing and CRISPR/Cas genome editing identify mutations of ZAK as a cause of limb defects in humans and mice.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "foot defects in affected individuals ranging from bilateral to unilateral foot involvement to no split foot in one individual"
explanation: Split foot with variable laterality, and one homozygous relative without it.
- reference: PMID:26755636
reference_title: Exome sequencing and CRISPR/Cas genome editing identify mutations of ZAK as a cause of limb defects in humans and mice.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The boy presented with a very similar split-foot phenotype, including distal duplication of digit II and unilateral syndactyly I/II and IV/V"
explanation: Split foot in the second, deletion-carrying family.
- name: Mesoaxial foot polydactyly
category: Skeletal
diagnostic: true
description: >-
Partial duplication of the second toe, radiographically a duplicated proximal or rudimentary phalanx of
toe II, described in one patient from each family.
phenotype_term:
preferred_term: Partial duplication of the second toe (mesoaxial foot polydactyly)
term:
id: HP:0010112
label: Mesoaxial foot polydactyly
evidence:
- reference: PMID:26755636
reference_title: Exome sequencing and CRISPR/Cas genome editing identify mutations of ZAK as a cause of limb defects in humans and mice.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "duplication of the left proximal phalanx of the second toe corresponding to mesoaxial polydactyly"
explanation: Radiographic description of mesoaxial polydactyly in the index family.
- reference: PMID:26755636
reference_title: Exome sequencing and CRISPR/Cas genome editing identify mutations of ZAK as a cause of limb defects in humans and mice.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Individuals F1-VI:4 and F2-VI:2 showed partial duplication of digit II in combination with syndactyly I/II"
explanation: Second-toe duplication in a patient from each family.
- name: 1-2 toe syndactyly
category: Skeletal
phenotype_term:
preferred_term: 1-2 toe syndactyly
term:
id: HP:0010711
label: 1-2 toe syndactyly
evidence:
- reference: PMID:26755636
reference_title: Exome sequencing and CRISPR/Cas genome editing identify mutations of ZAK as a cause of limb defects in humans and mice.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Individuals F1-VI:4 and F2-VI:2 showed partial duplication of digit II in combination with syndactyly I/II"
explanation: Syndactyly of toes I and II in a patient from each family.
- name: 4-5 toe syndactyly
category: Skeletal
phenotype_term:
preferred_term: 4-5 toe syndactyly
term:
id: HP:0004692
label: 4-5 toe syndactyly
evidence:
- reference: PMID:26755636
reference_title: Exome sequencing and CRISPR/Cas genome editing identify mutations of ZAK as a cause of limb defects in humans and mice.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The boy presented with a very similar split-foot phenotype, including distal duplication of digit II and unilateral syndactyly I/II and IV/V"
explanation: Unilateral syndactyly of toes IV and V in the Tunisian patient.
- name: Hypoplasia of toe phalanges
category: Skeletal
phenotype_term:
preferred_term: Hypoplasia of the phalanges of the toes
term:
id: HP:0010746
label: Hypoplasia of the phalanges of the toes
evidence:
- reference: PMID:26755636
reference_title: Exome sequencing and CRISPR/Cas genome editing identify mutations of ZAK as a cause of limb defects in humans and mice.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "There is hypoplasia of middle and distal phalanges of toes IV and V, as well as syndactyly between these toes."
explanation: Radiographic phalangeal hypoplasia in the Tunisian patient.
- reference: PMID:26755636
reference_title: Exome sequencing and CRISPR/Cas genome editing identify mutations of ZAK as a cause of limb defects in humans and mice.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "hypoplastic and misshaped phalangeal bones of toes III to V with fusions of some interphalangeal joints"
explanation: Radiographic phalangeal hypoplasia in the index family.
- name: Toe symphalangism
category: Skeletal
phenotype_term:
preferred_term: Fusion of interphalangeal joints of the lateral toes
term:
id: HP:0010179
label: Toe symphalangism
evidence:
- reference: PMID:26755636
reference_title: Exome sequencing and CRISPR/Cas genome editing identify mutations of ZAK as a cause of limb defects in humans and mice.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "hypoplastic and misshaped phalangeal bones of toes III to V with fusions of some interphalangeal joints"
explanation: Interphalangeal joint fusions of toes III to V on radiographs of one patient.
- name: Abnormal fingernail with duplicated nail bed
category: Dermatologic
diagnostic: true
description: >-
Duplication of the nail bed of the fourth finger on both hands, reported in both families, with otherwise
normal hands. No HPO term names nail-bed duplication, so the general fingernail-morphology term is bound.
phenotype_term:
preferred_term: Duplication of the fingernail bed
term:
id: HP:0001231
label: Abnormal fingernail morphology
evidence:
- reference: PMID:26755636
reference_title: Exome sequencing and CRISPR/Cas genome editing identify mutations of ZAK as a cause of limb defects in humans and mice.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The hands were normal, but the nails of both digits IV showed a duplication of the nail bed"
explanation: Nail-bed duplication in the Tunisian patient.
- reference: PMID:26755636
reference_title: Exome sequencing and CRISPR/Cas genome editing identify mutations of ZAK as a cause of limb defects in humans and mice.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The patients also had duplications of the nail bed on the hands"
explanation: Nail-bed duplication across the reported patients.
- name: Bilateral sensorineural hearing impairment
category: Auditory
description: >-
Present in all four affected members of the missense family. The Tunisian boy with the deletion passed
newborn hearing screening and had normal language development at two years, so hearing loss is not
established for every allele.
phenotype_term:
preferred_term: Bilateral sensorineural hearing impairment
term:
id: HP:0008619
label: Bilateral sensorineural hearing impairment
evidence:
- reference: PMID:26755636
reference_title: Exome sequencing and CRISPR/Cas genome editing identify mutations of ZAK as a cause of limb defects in humans and mice.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "In addition to limb defects, all patients in family 1 had bilateral sensorineural hearing impairment"
explanation: Hearing impairment in all four affected members of the index family.
- reference: PMID:26755636
reference_title: Exome sequencing and CRISPR/Cas genome editing identify mutations of ZAK as a cause of limb defects in humans and mice.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The patient had normal newborn hearing screening, and at the age of 2 yr, the psychomotor and language development was normal."
explanation: The deletion-carrying patient had no detected hearing loss at screening.
genetic:
- name: MAP3K20
gene_term:
preferred_term: MAP3K20
term:
id: hgnc:17797
label: MAP3K20
association: Causative
relationship_type: CAUSATIVE
variant_origin: GERMLINE
notes: >-
Disease alleles are confined to the SAM domain of the long ZAK-alpha isoform. Biallelic truncating
variants that remove both isoforms cause a congenital myopathy instead, and the complete mouse knockout of
both isoforms is embryonic lethal. No external gene-disease validity classification was cached for this
pair.
evidence:
- reference: PMID:26755636
reference_title: Exome sequencing and CRISPR/Cas genome editing identify mutations of ZAK as a cause of limb defects in humans and mice.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Here we describe an autosomal recessive human disease in two unrelated families characterized by a split-foot defect, nail abnormalities of the hands, and hearing loss, due to mutations disrupting the SAM domain of the protein kinase ZAK."
explanation: Homozygous ZAK SAM-domain mutations cause the disorder in two families.
- reference: PMID:38451290
reference_title: "Heterozygous MAP3K20 variants cause ectodermal dysplasia, craniosynostosis, sensorineural hearing loss, and limb anomalies."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: BACKGROUND
snippet: "It has two major isoforms, a long isoform and a short isoform, which does not contain the SAM domain"
explanation: Only the long isoform carries the SAM domain affected in SFMMP.
variants:
- name: c.1103T>G p.(Phe368Cys)
description: >-
Homozygous missense variant at a conserved hydrophobic-core residue of the SAM domain, found in the
Pakistani family. It destabilizes the isolated SAM domain and is constitutively active in cell assays.
variant_type: single nucleotide variant
evidence:
- reference: PMID:26755636
reference_title: Exome sequencing and CRISPR/Cas genome editing identify mutations of ZAK as a cause of limb defects in humans and mice.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "detected two homozygous missense variants in the linkage region: c.1247T > A (p.Phe416Tyr) in ZNF385B and c.1103T > G (p.Phe368Cys) in ZAK"
explanation: Identification of the homozygous ZAK missense variant by exome sequencing in the linkage interval.
- name: Exon 12-16 deletion
description: >-
Homozygous 14.7-kb intragenic deletion removing exons 12-16, which encode the SAM domain, in the
Tunisian patient; heterozygous in his unaffected first-cousin parents.
variant_type: deletion
evidence:
- reference: PMID:26755636
reference_title: Exome sequencing and CRISPR/Cas genome editing identify mutations of ZAK as a cause of limb defects in humans and mice.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "this 14.7-kb deletion removed exons 12–16 of ZAK"
explanation: Breakpoint sequencing defined the deletion.
animal_models:
- name: Zak SAM-domain deletion mouse
species: Mouse
genotype: Zak del/del (CRISPR/Cas deletion of the SAM-encoding region, genocopying the human exon 12-16 deletion)
publication: PMID:26755636
description: >-
Highly chimeric mice from embryonic stem cells homozygous for an in-frame 12-kb deletion of the
SAM-encoding region, with normal Zak mRNA levels in embryonic limbs.
modeled_mechanisms:
- target: Disrupted Distal Hindlimb Patterning
relationship: PARTIALLY_RECAPITULATES
fidelity: LOW
model_scale: ORGANISM
description: >-
Produces hindlimb duplication and foot polydactyly, not a cleft foot.
limitations: >-
Low penetrance (4 of 64 animals) in chimeras, and the phenotype is duplication of the hindlimb or pelvis
rather than a median cleft. No hearing defect was detected on Preyer reflex screening.
evidence:
- reference: PMID:26755636
reference_title: Exome sequencing and CRISPR/Cas genome editing identify mutations of ZAK as a cause of limb defects in humans and mice.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "we observed a spectrum of unilateral complex hindlimb duplication phenotypes with low penetrance (four out of 64 animals)"
explanation: Hindlimb patterning defect at low penetrance.
- target: Reduced Hindlimb Bud Trp63 Expression
relationship: MEASURES
fidelity: UNKNOWN
model_scale: TISSUE
readouts:
- name: Hindlimb Trp63 transcript by qRT-PCR at E11.5
target: Reduced Hindlimb Bud Trp63 Expression
direction: DECREASED
interpretation: About 60% lower than in wild-type hindlimbs.
evidence:
- reference: PMID:26755636
reference_title: Exome sequencing and CRISPR/Cas genome editing identify mutations of ZAK as a cause of limb defects in humans and mice.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Expression analysis of Zakdel/del homozygous mutant (MT) hindlimbs at E11.5 showed a 60% decrease of Trp63 expression compared with wild-type (WT) hindlimbs."
explanation: The measured reduction in Trp63 transcript.
- name: Zak complete knockout mouse
species: Mouse
genotype: Zak -/- (CRISPR/Cas frameshift in exon 2, both isoforms)
publication: PMID:26755636
description: >-
Frameshift inactivation of both Zak isoforms; homozygous embryos die at E9.5 with cardiac edema, and
heterozygotes are normal.
modeled_mechanisms:
- target: Disrupted Distal Hindlimb Patterning
relationship: FAILS_TO_RECAPITULATE
fidelity: LOW
description: >-
Whole-gene loss is lethal before limb patterning can be assessed, unlike the viable SAM-specific human
disease.
limitations: >-
Removes both isoforms rather than only the ZAK-alpha SAM domain, so it models a different allele class.
evidence:
- reference: PMID:26755636
reference_title: Exome sequencing and CRISPR/Cas genome editing identify mutations of ZAK as a cause of limb defects in humans and mice.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "The CRISPR/Cas-mediated inactivation of Zak resulted in fully penetrant lethality at E9.5 due to severe cardiac edema and growth retardation"
explanation: Embryonic lethality prevents modeling of the limb phenotype.
Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.
Create: Split-Foot_Malformation_with_Mesoaxial_Polydactyly · 2026-10-09T21:14:12Z · View source
New entry for MONDO:0014816, curated from the Perplexity deep-research report (research/Split-Foot_Malformation_with_Mesoaxial_Polydactyly-deep-research-perplexity.md). just preflight-dr returned WARN only because the report cites the MAP3K20 gene OMIM number 609479 alongside the phenotype number 616890; the report is about this disease (MAP3K20 mentioned 13 times). The off-topic flagged reference (PMC11805609, ribosomes and UV) was not used. Evidence comes from the original Genome Research report (PMID:26755636, full text), the 2025 ZAK collided-ribosome study (PMID:41261136, full text) for p.Phe368Cys hyperactivity, and the 2024 heterozygous MAP3K20 report (PMID:38451290) for isoform structure and a literature count. The disease alleles affect the SAM domain of the long ZAK-alpha isoform, not ZAK-beta. Pathophysiology is a five-node chain with two unresolved branches (constitutive kinase activation in cells, and reduced Trp63 in SAM-deleted mouse hindlimbs); the links from either branch to limb patterning are INDIRECT_UNKNOWN_INTERMEDIATES. No Orphanet cache could be generated for ORPHA:488232 and no GeneReviews chapter exists. Validated with just validate, count-verified-snippets (47/47), validate-terms, check-entity-refs, check-causal-targets, check-genereviews and validate-disorders.
Split-foot malformation with mesoaxial polydactyly (SFMMP) is an exceptionally rare, congenital, autosomal-recessive disorder caused by biallelic variants affecting the sterile alpha motif (SAM) domain of the long MAP3K20/ZAK protein isoform. Its defining clinical combination is variable split-foot malformation, abnormal fingernails, and—in one reported family—bilateral sensorineural hearing loss. The original molecular study described five affected people in two families; consequently, most apparent phenotype percentages are descriptions of those five people, not reliable population estimates. PMID: 26755636.[46][101]
The original abstract states: “Here we describe an autosomal recessive human disease in two unrelated families characterized by a split-foot defect, nail abnormalities of the hands, and hearing loss, due to mutations disrupting the SAM domain of the protein kinase ZAK.” PMID: 26755636; published online January 11, 2016.[46]
SFMMP is a developmental limb-patterning disorder, not an acquired or progressive degeneration of an initially normal foot. “Split foot” describes a cleft appearance caused by deficiency of central foot structures; “mesoaxial polydactyly” refers to an extra, centrally positioned toe. Neither finding alone establishes this molecular diagnosis. The 2023 international skeletal-disorder nosology places SFMMP in its split-hand/foot group as NOS 39-0100, with recessive ZAK inheritance. PMIDs: 26755636, 36779427.[90][196][272][278]
| Identifier or name | Disease-level value |
|---|---|
| MONDO | MONDO:0014816.[1] |
| OMIM phenotype | 616890; distinct from 609479, the MAP3K20 gene entry.[69] |
| Orphanet | ORPHA:488232.[2] |
| ICD-10 | Q74.8, a broad congenital-limb-malformation category rather than an SFMMP-specific code.[2] |
| ICD-11 / disease-specific MeSH descriptor | No specific identifier established in the reviewed disease records; do not substitute a gene/protein MeSH term for a disease descriptor.[2][94] |
| Other terminology | SFMMP; “split-foot malformation-mesoaxial polydactyly syndrome”; “split-foot malformation-mesoaxial polydactyly-nail abnormalities-sensorineural hearing loss syndrome”; sometimes SHFM7.[2][69] |
| Other identifiers | UMLS C5567487; SNOMED CT 1172635005.[2][106] |
Evidence provenance: This is an aggregated disease-level entry derived principally from published, individually described patients and family studies, supplemented by curated OMIM, Orphanet, HPO, and ClinVar records. It is not an EHR-derived population cohort. ClinVar additionally contains submitted individual-variant observations and literature-derived assertions; those should not be mistaken for independent disease cohorts.[46][106][113][web:EX7zcFJZkZRVQY5N1HGJM6Hx]
Established cause: Homozygosity for either MAP3K20 c.1103T>G, p.(Phe368Cys) or an approximately 14.7-kb intragenic deletion removing exons 12–16 was identified in the two original families. Both lesions affect the SAM-containing long isoform, ZAKα. The missense allele segregated with disease in the Pakistani family, was absent from 180 Pakistani controls and then-available public databases, and affected a structurally important SAM residue. The deletion was homozygous in an affected Tunisian boy and heterozygous in his unaffected first-cousin parents. PMID: 26755636.[46][web:64dmrzKYw3F8wQLZlMe7VIVX][web:hd5SRXfhsDlQUuWJemN2EHyg]
Established risk factor: Having two disease-causing alleles. Consanguinity occurred in both reported families and increases the chance that relatives inherit the same rare allele; it is not itself a separate molecular cause. Family history is therefore clinically useful. Neither variant has an established founder prevalence, carrier frequency, or population-specific risk estimate. No sex-dependent susceptibility, environmental toxin, infection, parental-age effect, protective allele, protective diet, or demonstrated gene–environment interaction has been established for SFMMP. General knowledge about teratogens or ribotoxic stress should not be entered as an SFMMP-specific exposure association. PMID: 26755636.[46][web:64dmrzKYw3F8wQLZlMe7VIVX]
Denominators matter. The initial report included four affected relatives in family 1 and one affected boy in family 2. Three of four affected family-1 members had a split foot—two bilateral and one unilateral—while the fourth, despite being homozygous, did not. The Tunisian boy had bilateral involvement. All four affected family-1 members had bilateral sensorineural hearing impairment; the boy passed newborn hearing screening and had normal reported language development at age two, not a documented comprehensive lifetime exclusion of hearing loss. These yield descriptive counts of 4/5 with split foot and 4/5 with reported hearing impairment, without justifying precise penetrance estimates. PMID: 26755636.[46][web:64dmrzKYw3F8wQLZlMe7VIVX][web:dbKj8JkWy7gE7ebDykFfDuZX]
The table distinguishes directly reported findings from additional Orphanet-curated HPO associations. Curated frequency bands should not be converted into numerical percentages from five cases.[web:hwHbfWnxra0B7zX87KwzsLuY][web:pwBpm7Vg3MOVPYeEasOb1gKg]
| Phenotype type and characteristic | Onset, severity, course, and observed frequency | Functional or quality-of-life implications | Suggested HPO term |
|---|---|---|---|
| Physical sign: split foot, unilateral or bilateral; a homozygous affected relative can lack it | Congenital; anatomically variable; 4/5 described patients, with bilateral, unilateral, and absent presentations; structural defect expected to persist without correction | Footwear fit, support, walking, and appearance may be affected; no SFMMP-specific functional score was reported | Split foot — HP:0001839.[46][web:64dmrzKYw3F8wQLZlMe7VIVX][web:hwHbfWnxra0B7zX87KwzsLuY] |
| Physical sign: central/partial second-toe duplication, described in individuals from both families | Congenital; variable; at least two individually identified presentations, not a validated prevalence | May complicate footwear or foot reconstruction; no quantified SFMMP-specific impact | Mesoaxial foot polydactyly — HP:0010112, when its precise anatomical definition is met; record “partial duplication of second toe” separately where appropriate.[46][196] |
| Physical signs: first–second and/or fourth–fifth toe syndactyly | Congenital; individually reported, including in the Tunisian boy; severity and total frequency insufficiently characterized | May affect toe configuration and surgical planning; specific functional effect unmeasured | 1–2 toe syndactyly — HP:0010711; 1–2 toe complete cutaneous syndactyly — HP:0005767; 4–5 toe syndactyly — HP:0004692. Use “complete” only when documented.[web:dbKj8JkWy7gE7ebDykFfDuZX][web:hwHbfWnxra0B7zX87KwzsLuY] |
| Physical sign: abnormal fingernails, including duplicated nail beds of fourth fingers | Congenital; characteristic in both families; exact person-level frequency and severity not securely tabulated | Potential appearance or fine-manipulation implications; no measured nail-specific quality-of-life effect | Abnormality of the nail — HP:0001597; describe the documented duplicated nail bed in free text rather than equating it with all nail dysplasia.[46][web:64dmrzKYw3F8wQLZlMe7VIVX][web:hwHbfWnxra0B7zX87KwzsLuY] |
| Clinical sign: bilateral sensorineural hearing impairment | 4/4 in family 1; 4/5 across the initial report as recorded. Age at diagnosis, audiometric severity, and progression were not established; family-2 newborn screening was normal | Potential effects on speech and language access; early assessment matters, but no SFMMP-specific outcome scale exists | Bilateral sensorineural hearing impairment — HP:0008619.[web:dbKj8JkWy7gE7ebDykFfDuZX][241] |
| Additional curated structural signs: toe-phalangeal hypoplasia/aplasia and proximal second-toe symphalangism | Congenital associations in Orphanet; no independently verified person-by-person counts for each feature | Depends on resultant foot anatomy; no phenotype-specific measurements | HP:0010413 second-toe distal phalanx; HP:0010076 hallux distal phalanx; HP:0010359, HP:0010371, HP:0010383 third–fifth toe phalanges; HP:0100483 second-toe proximal phalanx–metatarsal symphalangism.[web:hwHbfWnxra0B7zX87KwzsLuY] |
Not established as SFMMP features: behavioral or psychiatric changes, a characteristic blood/urine chemistry abnormality, and the broad skin, dental, craniosynostosis, and eye phenotype described in a different, heterozygous MAP3K20-associated disorder. A reported Tunisian child’s psychomotor and language development were normal at age two. PMIDs: 26755636, 38451290.[web:dbKj8JkWy7gE7ebDykFfDuZX][web:ZJvgk4cm9d9MxYGCAItMHt2j]
Causal gene: MAP3K20 (HGNC:17797; NCBI Gene:51776; OMIM:609479), historically ZAK, at 2q31.1. ZAKα contains an N-terminal kinase domain, leucine zipper, and C-terminal SAM domain; the shorter ZAKβ lacks that SAM domain. PMIDs: 26755636, 27816943.[95][91][46][web:Scoq7tGuP1xNmfWOudXb3Z3b]
| SFMMP-associated germline allele | Class, evidence, and molecular consequence | Frequency and interpretation |
|---|---|---|
| NM_016653.3:c.1103T>G; NP_057737.2:p.Phe368Cys; rs863225437; ClinVar VCV000218144 | Homozygous missense SAM-domain allele. ClinVar aggregates two pathogenic submissions, but its review status is “no assertion criteria provided”—not an independently documented ACMG expert-panel classification. Structural tests found approximately 30% less SAM-domain α-helicity, loss of cooperative unfolding, and aggregation propensity. PMID: 26755636.[web:EX7zcFJZkZRVQY5N1HGJM6Hx][web:EOAnxlclgg6vjWe7CeaEheqH] | Absent from 180 tested Pakistani controls, EVS, and ExAC in the original investigation. The retrieved ClinVar record gives no current numerical gnomAD allele frequency; absence from those older datasets is not a measured zero frequency today.[web:EX7zcFJZkZRVQY5N1HGJM6Hx] |
| NM_016653.2:c.988-4814_1359+60del; approximately 14.7 kb, exons 12–16; ClinVar RCV000210488 | Homozygous intragenic structural deletion affecting the SAM domain; ClinVar pathogenic, one literature-based submission without stated assertion criteria. A 31-bp insertion at the junction was also reported; preserve the source’s breakpoint notation when recording this complex allele. PMID: 26755636.[web:hd5SRXfhsDlQUuWJemN2EHyg] | Absent from the investigators’ more than 600 in-house samples and consulted CNV databases; no validated numerical population allele frequency. Unaffected parents were heterozygous.[web:hd5SRXfhsDlQUuWJemN2EHyg][web:dbKj8JkWy7gE7ebDykFfDuZX] |
Important 2025 mechanistic refinement: The original protein-folding findings do not prove simple loss of kinase activity. In a later cell-based, in-vitro/structural study, disease-associated p.Phe368Cys showed constitutive ZAK activation even without induced ribosome collisions or normal ribosome interaction. The authors did not show that this activity causes the human limb phenotype in vivo. Thus, annotate “disrupted SAM structure; constitutive kinase activation demonstrated in an experimental cellular system; developmental consequence unresolved,” rather than an unqualified “kinase loss of function.” The abstract describes “a known pathogenic variant of the SAM domain” among mutants that can bypass the ribosome requirement. PMID: 41261136; online November 19, 2025.[web:q7a1jL9GGAgGvNRUfGEUIrwd]
Do not conflate MAP3K20 disorders. A 2024 primary report found five people with de novo heterozygous linker-region variants and a different spectrum involving craniosynostosis, ectodermal findings, hearing loss, and limb anomalies. Its abstract specifies “five individuals” with “heterozygous de novo variants in the linker region between the kinase domain and leucine zipper domain.” Separately, biallelic truncating, kinase-domain alleles cause MAP3K20-related centronuclear myopathy, with muscle weakness rather than the characteristic SFMMP foot defect. PMIDs: 38451290, 27816943.[web:ZJvgk4cm9d9MxYGCAItMHt2j][web:Scoq7tGuP1xNmfWOudXb3Z3b]
Modifiers and other genomic findings: The original linkage analysis found a 9.1-Mb chromosome-2 interval, maximum LOD 3.5. A later patient with split-hand/foot malformation had homozygous ZAK p.Ala505Ser and an approximately 2.01-Mb 7q21.3–q22.1 deletion encompassing established SHFM-related genes; its authors favored the deletion as the principal cause and proposed p.Ala505Ser only as a possible modifier. Do not register that deletion or p.Ala505Ser as established SFMMP-causing alleles or an established SFMMP modifier. No SFMMP-specific methylation signature, pathogenic aneuploidy, translocation, or inversion has been established. PMIDs: 26755636, 32266845.[web:EOAnxlclgg6vjWe7CeaEheqH][web:jQuU0ZAeiLluYP1hDlcbWWz7]
No specific toxin, radiation exposure, pollution, occupation, smoking pattern, diet, exercise pattern, alcohol exposure, or infectious agent is implicated as a cause or reproducible modifier of this Mendelian syndrome. Chemical induction of ribosome collisions in a laboratory is an experimental tool, not evidence that an exposed pregnancy will develop SFMMP. There is no infectious transmission or zoonotic risk. PMIDs: 26755636, 41261136.[46][web:q7a1jL9GGAgGvNRUfGEUIrwd]
Pathway detail and evidence boundaries: ZAK is a MAP kinase kinase kinase. A 2025 primary biochemical/cryo-electron-microscopy study showed that ribosome collisions position ZAK on neighboring RACK1 proteins, promote SAM-domain dimerization and activation, and engage downstream p38/JNK stress signaling; SERBP1 opposes inappropriate activation. That work explains how p.Phe368Cys can be hyperactive experimentally, not whether ordinary embryonic ribosome collisions cause SFMMP. The 2016 mouse experiments found normal Fgf8, Shh, and Trp63 spatial staining patterns in a tested context, whereas quantitative testing found reduced Trp63 amount in SAM-mutant hindlimbs. A WNT, FGF8, or SHH defect should therefore not be recorded as a directly established SFMMP molecular abnormality. PMIDs: 26755636, 41261136.[web:dbKj8JkWy7gE7ebDykFfDuZX][web:q7a1jL9GGAgGvNRUfGEUIrwd]
Ontology-ready mechanism annotations: Suggested biological-process terms are protein phosphorylation (GO:0006468), embryonic limb morphogenesis (GO:0030326), and limb development (GO:0060173); these are annotation suggestions, not claims that each process was individually measured in patients. The experimental subcellular context includes cytoplasm and ribosome; the structural target is a protein SAM domain, not a demonstrated mitochondrial, lysosomal, or metabolic defect. Suggested relevant cells are mesenchymal cell (CL:0000134), chondrocyte (CL:0000138), and keratinocyte (CL:0000312), with limb-bud ectoderm and auditory hair cells named anatomically; involvement of each particular cell class in human SFMMP has not been independently proven. No disease-specific single-cell, spatial-transcriptomic, proteomic, metabolomic, lipidomic, or validated epigenomic signature was identified in the reviewed evidence. The decisive functional-genomics application was CRISPR/Cas editing of mouse Zak. PMIDs: 26755636, 41261136.[46][web:q7a1jL9GGAgGvNRUfGEUIrwd][210][227]
Primary sites: distal lower limbs, especially the foot (UBERON:0002387), toes, phalanges/metatarsals and their developmental precursors; fingernail units are also affected. An apical ectodermal ridge (UBERON:0004356) is a useful developmental-context annotation, not a directly sampled lesion in a patient. Secondary/associated site: the auditory system and ear (UBERON:0001690); a cochlear cellular mechanism remains unconfirmed. Relevant tissue classes include developing ectoderm/epithelium, mesenchyme, and developing connective/skeletal tissues. Involvement may be unilateral or bilateral and asymmetric; one genetically affected person had no split foot. Do not assign the mouse knockout’s severe embryonic cardiac phenotype as an established organ manifestation of surviving humans with SFMMP. PMID: 26755636.[46][202][280]
Suggested cellular-component annotation: cytoplasm and ribosome for the experimentally studied ZAK stress-response machinery; not a patient-specific subcellular pathology diagnosis. PMID: 41261136.[web:q7a1jL9GGAgGvNRUfGEUIrwd]
The malformations are congenital; Orphanet specifies neonatal onset. The defensible natural-history description is persistent structural differences with variable severity, rather than an acute, episodic, staged, or relapsing disease. Neither a progression rate nor formal early/intermediate/end stages, spontaneous anatomical remission, or long-term audiometric trajectory has been established. Embryonic limb patterning is the biologically relevant vulnerability period; after birth, the clinically actionable period is early assessment of hearing and function. The Tunisian child’s normal hearing screen and development at two years must not be extrapolated to lifelong outcome. PMID: 26755636.[2][web:dbKj8JkWy7gE7ebDykFfDuZX]
Autosomal recessive. When both biological parents carry the same established pathogenic allele, the standard Mendelian risk per pregnancy is 25% affected, 50% carrier, and 25% inheriting neither familial allele; counseling should confirm the actual familial genotypes. Variable expressivity is directly observed: one homozygous affected relative lacked a split foot, while another had unilateral involvement. That observation alone cannot yield a population penetrance percentage. No anticipation, germline mosaicism rate, founder effect, or carrier frequency has been established. PMID: 26755636.[46][web:64dmrzKYw3F8wQLZlMe7VIVX]
Orphanet’s estimate is prevalence <1 per 1,000,000, not a measured national incidence. Annual incidence, population age distribution, geographic prevalence, and population sex ratio are unknown. The original cases were from families in Pakistan and Tunisia; their locations do not establish ethnic restriction or an endemic region. A later comparison table records three males and one female in the original Pakistani family and one male in the Tunisian family, but 4:1 is a five-person report count, not a disease sex ratio. PMIDs: 26755636, 38451290.[2][web:ZJvgk4cm9d9MxYGCAItMHt2j]
Clinical suspicion: congenital split/atypical feet, central toe duplication or syndactyly, characteristic fingernails, and potentially bilateral sensorineural hearing loss, especially with similarly affected relatives or consanguinity. Examine all four limbs and nails, obtain a pedigree, and arrange foot radiographs to define skeletal anatomy when management requires it. Obtain age-appropriate formal audiology even if an initial newborn screen was passed, because the molecular syndrome can include hearing loss and a normal screen is not a complete lifelong audiological evaluation. Foot imaging and audiology are phenotype-directed clinical recommendations, not validated SFMMP-specific diagnostic criteria. PMID: 26755636.[46][web:dbKj8JkWy7gE7ebDykFfDuZX][76]
Molecular confirmation: seek biallelic pathogenic/likely pathogenic MAP3K20 variants, considering SNVs and intragenic exon deletions. An appropriate limb-malformation/SHFM panel with deletion–duplication analysis, exome sequencing plus reliable CNV calling, or genome sequencing can be selected according to the phenotype and laboratory capabilities. Single-gene sequencing is reasonable when a familial allele is known, but sequencing alone may miss the documented exon 12–16 deletion; use validated copy-number or breakpoint assessment. The original study used linkage, exome sequencing, array-CGH, qPCR, breakpoint PCR, and segregation analysis; GTR lists tests associated with MAP3K20 and this condition. PMID: 26755636.[web:EOAnxlclgg6vjWe7CeaEheqH][web:RjRxYfl6gV7WymF9gF9gk2y6]
Differential diagnosis: other molecular forms of split-hand/foot malformation, including 7q21/DLX5–DLX6 abnormalities and other SHFM loci; heterozygous MAP3K20 linker-associated disease, particularly if craniosynostosis or broad ectodermal findings predominate; and biallelic kinase-domain MAP3K20 myopathy, if generalized weakness, hypotonia, or abnormal muscle biopsy dominates. These are distinct molecular diagnoses despite overlap in gene or limb appearance. PMIDs: 32266845, 38451290, 27816943.[web:jQuU0ZAeiLluYP1hDlcbWWz7][web:ZJvgk4cm9d9MxYGCAItMHt2j][web:Scoq7tGuP1xNmfWOudXb3Z3b]
Tests without an established routine SFMMP role: characteristic blood/urine biomarkers, enzyme assays, biopsy, ECG/EEG/EMG, mitochondrial sequencing, repeat-expansion testing, liquid biopsy, and clinical metabolomic/proteomic/epigenomic assays. Chromosomal microarray or cytogenetic testing can be useful for a broader unresolved differential diagnosis, not because the two established SFMMP alleles are aneuploidies. There are no demonstrated SFMMP-specific formal diagnostic-score criteria or population newborn molecular-screening program. PMIDs: 26755636, 32266845.[web:EOAnxlclgg6vjWe7CeaEheqH][web:jQuU0ZAeiLluYP1hDlcbWWz7]
Life expectancy, 5-/10-year survival, mortality rates, disease-specific deaths, EQ-5D/SF-36 scores, and validated prognostic biomarkers are unavailable for SFMMP. No progressive multiorgan failure has been established. The main plausible long-term burdens are those of persistent foot anatomy and potentially hearing impairment; their individual severity, footwear needs, and hearing trajectory require assessment, not prediction from genotype alone. The single reported two-year-old Tunisian child had normal psychomotor and language development at that examination. There are no reliable genotype-specific response rates or natural-history cohorts. PMID: 26755636.[46][web:dbKj8JkWy7gE7ebDykFfDuZX]
There is no established medication or molecular treatment that reverses the congenital SFMMP lesion. Management is individualized and function-oriented; the table separates general clinical practice or evidence from other cleft-foot cases from outcomes demonstrated in genetically confirmed SFMMP.[46][76][256]
| Intervention and suggested NCIt term | Practical role and evidence boundary |
|---|---|
| Orthopedic/foot assessment; footwear adaptation, orthoses, and rehabilitation. Suggested broad intervention vocabulary: Physical Therapy where applicable; verify any more specific local NCIt code before loading it. | Assess balance, walking, pressure, pain, and shoe fit; treat observed problems. No SFMMP-specific treatment-response percentage exists. This is supportive care, not alteration of embryonic anatomy.[46][256] |
| Individualized foot reconstruction, potentially including cleft closure, correction of selected duplicated structures, or syndactyly procedures; broad Surgical Procedure — NCIT:C15329. | Consider only after imaging and assessment of expected function and patient/family goals. A 2020 cleft-foot case without an established SFMMP genotype reported improved support and appearance maintained two years after surgery; it does not demonstrate efficacy or risk rates in SFMMP. PMID: 32190557.[256][211] |
| Audiological assessment, hearing technology when indicated, and early communication/language intervention; use appropriately verified device-specific NCIt terms, rather than a generic surgery code for every hearing intervention. | Follow general pediatric hearing-loss practice: screen by 1 month, diagnose identified loss by 3 months, and initiate intervention by 6 months; hearing aids or cochlear implants depend on measured hearing and clinical assessment. These are general hearing-care benchmarks, not SFMMP trial results.[76][77] |
| Genetic counseling — NCIT:C15240. | Explain recessive recurrence risk, variable foot expression, carrier testing of relatives when appropriate, and reproductive options after familial variants are confirmed.[46][211] |
Not established for this disorder: disease-modifying pharmacotherapy or pharmacogenomic dosing rules; gene, cell, RNA, immune, or targeted therapy; a validated genotype-guided treatment algorithm; an SFMMP-specific interventional trial or NCT identifier; treatment response rates or disease-specific adverse-event rates. In particular, experimental ZAK inhibition used to interrogate a cellular p.Phe368Cys mechanism is not an indicated treatment for a congenital limb malformation. PMID: 41261136.[web:q7a1jL9GGAgGvNRUfGEUIrwd]
Primary prevention of the underlying allele is not possible through vaccination, diet, or avoidance of a known SFMMP-specific exposure. For a family with established variants, genetic counseling, targeted carrier testing, and discussion of prenatal or preimplantation genetic testing can support reproductive decisions; these are options, not evidence of environmental prevention or a population screening recommendation. Secondary prevention means identifying an affected child’s hearing or functional needs early; tertiary prevention means managing footwear, mobility, and communication-related consequences. Routine immunizations remain appropriate but do not prevent SFMMP. PMID: 26755636.[46][76]
Human: Homo sapiens, NCBI Taxon:9606; mouse: Mus musculus, NCBI Taxon:10090, ortholog Map3k20, NCBI Gene:65964; MGI:2443258. Other species have MAP3K20 orthologs, but an authenticated, naturally occurring veterinary equivalent caused by the human SFMMP SAM-domain alleles was not established in the reviewed evidence. Naturally occurring polydactyly in an animal should not be equated with this molecular syndrome. Cross-species conservation supports experimental comparison; there is no zoonotic transmission. PMID: 26755636.[121][126][128][130][134]
| Model or system | What it reproduces or demonstrates | Principal limitation and research application |
|---|---|---|
| Mouse Zak disruption of both isoforms, produced with CRISPR/Cas-edited embryonic stem cells | Homozygous knockout caused fully penetrant embryonic lethality around E9.5, with severe cardiac edema and growth retardation; heterozygotes appeared morphologically normal. PMID: 26755636.[web:EOAnxlclgg6vjWe7CeaEheqH] | Models an extreme whole-gene loss, not the viable, SAM-region-specific human SFMMP phenotype; demonstrates why variant domain/isoform matters. |
| Mouse SAM-region deletion, generated using a roughly 12-kb engineered deletion | 4/64 animals had variable hindlimb duplication/polydactyly phenotypes; homozygous mutant hindlimbs showed approximately 60% less Trp63 expression by qRT-PCR. PMID: 26755636.[web:EOAnxlclgg6vjWe7CeaEheqH][web:dbKj8JkWy7gE7ebDykFfDuZX] | Low penetrance; phenotypes can include substantial hindlimb/pelvic duplication rather than a close copy of a human cleft foot. No obvious ear abnormality or Preyer-reflex difference was found. Useful for developmental mechanism, not for estimating human penetrance or hearing outcomes. |
| Purified wild-type and p.Phe368Cys SAM domains, structural/biophysical assays | Demonstrated missense-domain destabilization, reduced helicity, altered unfolding, and aggregation propensity. PMID: 26755636.[web:EOAnxlclgg6vjWe7CeaEheqH] | Isolated protein cannot establish the full embryonic phenotype or net cellular kinase output. |
| Human ZAK-knockout HEK293T cells re-expressing ZAK variants; cryo-EM/biochemistry of ribosome complexes | Demonstrated RACK1-associated collision sensing and constitutive, ribosome-interaction-independent activation of p.Phe368Cys in the tested cellular system. PMID: 41261136.[web:q7a1jL9GGAgGvNRUfGEUIrwd] | These are not developing human limb or auditory cells; no p.Phe368Cys human-limb rescue experiment or corresponding knock-in developmental outcome was established in that study. |
Knowledge-base interpretation: Record the human biallelic genotype–phenotype association as established; record the mouse SAM-deletion/Trp63 result and cellular p.Phe368Cys hyperactivity as different, complementary mechanistic evidence types. The exact link between those results—and the cause of hearing impairment—remains unresolved. PMIDs: 26755636, 41261136.[46][web:q7a1jL9GGAgGvNRUfGEUIrwd]
Checked with linkml-reference-validator 0.3.0.
| Outcome | Count |
|---|---|
| References checked | 15 |
| Resolved | 15 |
| Unresolved (possible confabulation) | 0 |
| Unverifiable | 0 |
| References weighed for topical relevance | 15 |
| On topic | 1 |
| Off topic | 1 |
These identifiers resolve, so they are not fabrications, but the records they resolve to share almost none of this report's vocabulary. That is a clue and not a verdict - a paper can be relevant in ways its title and abstract do not spell out - so read them before deciding:
PMC:PMC11805609 (1 mention) - Fun in the sun: ribosomes defend against UV irradiation.Weighed against this report's own most characteristic terms: web, established, sfmmp, hearing, foot, zak, affected, family, molecular, normal, variant, allele, phenotype, dbkj8jkwy7ge7ebdykffduzx, loss, map3k20, limb, sfmmp-specific, disease, variable.
All extracted references resolved successfully. Resolving is not the same as being relevant, though - see the references listed above as possibly off topic.
Checked with linkml-term-validator 0.4.5, through the ols: adapter.
| Outcome | Count |
|---|---|
| Terms checked | 33 |
| Resolved | 25 |
| Unresolved (possible confabulation) | 0 |
| Obsolete | 0 |
| Unverifiable | 8 |
Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: ORPHA, Gene, OMIM, Taxon, MGI.
25 of 33 terms resolved to a current term; the rest could not be looked up either way.