SHFM
MCID: SPL061
MIFTS: 42

Split Hand-Foot Malformation (SHFM)

Categories: Bone diseases, Ear diseases, Fetal diseases, Genetic diseases, Mental diseases, Neuronal diseases, Rare diseases

Aliases & Classifications for Split Hand-Foot Malformation

MalaCards integrated aliases for Split Hand-Foot Malformation:

Name: Split Hand-Foot Malformation 12 15
Split-Hand/foot Malformation 36 6 39 70
Ectrodactyly 20 44 70
Split Hand Foot Malformation 20 6
Split Hand Foot Deformity 1 70
Split Hand Foot Deformity 70
Lobster-Claw Deformity 12
Split-Hand Deformity 12
Shfm 20

Classifications:



External Ids:

Disease Ontology 12 DOID:0090020
KEGG 36 H00471
ICD9CM 34 755.58
MeSH 44 C574275
SNOMED-CT 67 81208006
ICD10 32 Q71.6
UMLS 70 C0265554 C2699510 C2931018 more

Summaries for Split Hand-Foot Malformation

GARD : 20 Split hand foot malformation (SHFM) is a type of birth defect that consists of missing digits (fingers and/or toes), a deep cleft down the center of the hand or foot, and fusion of remaining digits. The severity of this condition varies widely among affected individuals. SHFM is sometimes called ectrodactyly; however, this is a nonspecific term used to describe missing digits. SHFM may occur by itself (isolated) or it may be part of a syndrome with abnormalities in other parts of the body. At least six different forms of isolated SHFM have been described. Each type is associated with a different underlying genetic cause. SHFM1 has been linked to chromosome 7, and SHFM2 is linked to the X chromosome. SHFM3 is caused by a duplication of chromosome 10 at position 10q24. Changes ( mutations ) in the TP63 gene cause SHFM4. SHFM5 is linked to chromosome 2, and SHFM6 is caused by mutations in the WNT10B gene. SHFM may be inherited in an autosomal dominant, autosomal recessive, or X-linked manner.

MalaCards based summary : Split Hand-Foot Malformation, also known as split-hand/foot malformation, is related to split-hand/foot malformation with long bone deficiency 1 and split-hand/foot malformation 1 with sensorineural hearing loss, autosomal recessive. An important gene associated with Split Hand-Foot Malformation is SHFM2 (Split Hand/Foot Malformation (Ectrodactyly) Type 2), and among its related pathways/superpathways are Neural Crest Differentiation and Signaling pathways regulating pluripotency of stem cells. Affiliated tissues include bone marrow, bone and eye, and related phenotypes are digestive/alimentary and craniofacial

Disease Ontology : 12 A bone development disease characterized by malformation of the central rays of the autopod and presenting with syndactyly, median clefts of the hands and feet, and aplasia and/or hypoplasia of the phalanges, metacarpals, and metatarsals. Some patients also have mental retardation, ectodermal and craniofacial findings, and orofacial clefting.

KEGG : 36 Split hand/foot malformation (SHFM) is a congenital limb malformation characterized by median clefts of hands and foot. Disrupted formation of the apical ectodermal ridge during development results in central ray deficiency in SHFM patients.

Related Diseases for Split Hand-Foot Malformation

Diseases in the Split Hand-Foot Malformation family:

Split-Hand/foot Malformation 1 Split-Hand/foot Malformation 6
Split-Hand/foot Malformation 3 Split-Hand/foot Malformation 2
Split-Hand/foot Malformation 4 Split-Hand/foot Malformation 5

Diseases related to Split Hand-Foot Malformation via text searches within MalaCards or GeneCards Suite gene sharing:

(show top 50) (show all 271)
# Related Disease Score Top Affiliating Genes
1 split-hand/foot malformation with long bone deficiency 1 33.1 SHFLD2 SHFL1
2 split-hand/foot malformation 1 with sensorineural hearing loss, autosomal recessive 32.8 WNT10B TP63 SEM1 FBXW4 DLX6 DLX5
3 split-hand/foot malformation 4 32.7 WNT10B TP63 SEM1 FBXW4 DLX6 DLX5
4 split-hand/foot malformation 6 32.7 WNT10B TP63 SEM1 FBXW4 DLX6 DLX5
5 split-hand/foot malformation 5 32.6 TP63 SHFM5 SEM1 FBXW4 DLX6 DLX5
6 split-hand/foot malformation 3 32.5 SHFM3 SEM1 FBXW4 DLX6 DLX5 BTRC
7 split-hand/foot malformation 2 32.4 WNT10B TP63 SHFM2 SEM1 FBXW4 DLX6
8 split-hand/foot malformation 1 32.3 TP63 SEM1 PLAA FGFR2 DLX5
9 ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome 3 32.1 WNT10B TP63 DLX6 DLX5 BHLHA9
10 isolated split hand-split foot malformation 32.0 WNT10B TP63 SEM1 DLX6 DLX5 BTRC
11 ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome 1 31.9 TP63 FGFR2 FGFR1
12 hemimelia 30.7 GLI2 BHLHA9
13 rapp-hodgkin syndrome 30.4 TP63 DLX6 DLX5
14 synostosis 29.9 FGFR2 FGFR1 BHLHA9
15 lobar holoprosencephaly 29.7 GLI2 FGFR1
16 cleft palate, isolated 29.4 TP63 GLI2 FGFR2 FGFR1 DLX6 DLX5
17 tooth agenesis 29.4 WNT10B TP63 FGFR2 FGFR1 DLX5
18 apert syndrome 29.2 HAND2 FGFR2 FGFR1
19 chromosome 2q35 duplication syndrome 29.1 WNT10B TP63 SEM1 HAND2 GLI2 FGFR2
20 orofacial cleft 28.9 TP63 HAND2 GLI2 FGFR2 FGFR1 DLX6
21 chromosome 17p13.3, telomeric, duplication syndrome 12.0
22 ulnar hypoplasia with lobster-claw deformity of feet 11.7
23 split hand/foot malformation x-linked 11.7
24 split-hand/foot malformation with long bone deficiency 2 11.6
25 tibial aplasia-ectrodactyly syndrome 11.6
26 ectodermal dysplasia, ectrodactyly, and macular dystrophy syndrome 11.6
27 cleft palate, cardiac defect, genital anomalies, and ectrodactyly 11.4
28 brachydactyly-ectrodactyly with fibular aplasia or hypoplasia 11.4
29 intellectual disability-spasticity-ectrodactyly syndrome 11.3
30 femur bifid with monodactylous ectrodactyly 11.3
31 acrofacial dysostosis 1, nager type 11.3
32 fibular aplasia, tibial campomelia, and oligosyndactyly syndrome 11.3
33 microphthalmia, syndromic 8 11.3
34 split hand split foot malformation autosomal recessive 11.3
35 triphalangeal thumbs with brachyectrodactyly 11.2
36 split-foot deformity with mandibulofacial dysostosis 11.2
37 ectrodactyly and ectodermal dysplasia without cleft lip/palate 11.2
38 ectrodactyly-polydactyly 11.2
39 ectrodactyly cardiopathy dysmorphism 11.1
40 anonychia-onychodystrophy with brachydactyly type b and ectrodactyly 11.1
41 phocomelia ectrodactyly deafness sinus arrhythmia 11.1
42 anonychia-ectrodactyly 11.1
43 focal dermal hypoplasia 11.1
44 phocomelia-ectrodactyly, ear malformation, deafness, and sinus arrhythmia 11.1
45 ectrodactyly-cleft palate syndrome 11.0
46 limb defects, distal transverse, with mental retardation and spasticity 11.0
47 kasznica carlson coppedge syndrome 11.0
48 split-hand with congenital nystagmus, fundal changes, and cataracts 11.0
49 ectrodactyly of lower limbs, congenital heart defect, and micrognathia 10.9
50 jones hersh yusk syndrome 10.9

Graphical network of the top 20 diseases related to Split Hand-Foot Malformation:



Diseases related to Split Hand-Foot Malformation

Symptoms & Phenotypes for Split Hand-Foot Malformation

MGI Mouse Phenotypes related to Split Hand-Foot Malformation:

46
# Description MGI Source Accession Score Top Affiliating Genes
1 digestive/alimentary MP:0005381 10.02 BTRC DLX5 DLX6 FGFR1 FGFR2 GLI2
2 craniofacial MP:0005382 9.95 DLX5 DLX6 FGFR1 FGFR2 GLI2 HAND2
3 limbs/digits/tail MP:0005371 9.91 BHLHA9 DLX5 DLX6 FBXW4 FGFR1 FGFR2
4 hearing/vestibular/ear MP:0005377 9.8 DLX5 DLX6 FGFR1 FGFR2 GLI2 HAND2
5 muscle MP:0005369 9.76 DLX5 FGFR1 FGFR2 GLI2 HAND2 PLAA
6 no phenotypic analysis MP:0003012 9.5 FBXW4 FGFR1 FGFR2 GLI2 HAND2 TP63
7 skeleton MP:0005390 9.32 DLX5 DLX6 FBXW4 FGFR1 FGFR2 GLI2

Drugs & Therapeutics for Split Hand-Foot Malformation

Interventional clinical trials:


# Name Status NCT ID Phase Drugs
1 Randomized Controlled Trial to Compare the Effects of Single Versus Repeated Intracoronary Application of Autologous Bone Marrow-derived Mononuclear Cells on Total and SHFM-predicted Mortality in Patients With Chronic Post-infarction Heart Failure Active, not recruiting NCT01693042 Phase 2, Phase 3

Search NIH Clinical Center for Split Hand-Foot Malformation

Cochrane evidence based reviews: ectrodactyly

Genetic Tests for Split Hand-Foot Malformation

Anatomical Context for Split Hand-Foot Malformation

MalaCards organs/tissues related to Split Hand-Foot Malformation:

40
Bone Marrow, Bone, Eye, Breast

Publications for Split Hand-Foot Malformation

Articles related to Split Hand-Foot Malformation:

(show top 50) (show all 145)
# Title Authors PMID Year
1
Whole genome sequencing reveals translocation breakpoints disrupting TP63 gene underlying split hand/foot malformation in a Chinese family. 61
33471964 2021
2
Split hand/foot malformation associated with 20p12.1 deletion: A case report. 61
31698100 2020
3
Rare missense variant p.Ala505Ser in the ZAK protein observed in a patient with split-hand/foot malformation from a non-consanguineous pedigree. 61
32266845 2020
4
[Clinical feature and pathogenic analysis of a fetus with split hand-foot malformation]. 61
32219838 2020
5
[Genetic analysis of a pedigree affected with congenital split-hand/foot malformation]. 61
32219839 2020
6
A classification system for split-hand/ foot malformation (SHFM): A proposal based on 3 pedigrees with WNT10B mutations. 61
31421290 2020
7
[Surgical Treatment of Congenital Cleft Foot - Case Study and Literature Review]. 61
32131973 2020
8
Novel missense alteration in LRP4 gene underlies Cenani-Lenz syndactyly syndrome in a consanguineous family. 61
31750994 2020
9
Nonsyndromic Split-Hand/Foot Malformation: Recent Classification. 61
32021595 2020
10
A Novel Missense Variant of TP63 Heterozygously Present in Split-Hand/Foot Malformation. 61
33294441 2020
11
Comprehensive clinical and molecular studies in split-hand/foot malformation: identification of two plausible candidate genes (LRP6 and UBA2). 61
31332306 2019
12
A novel mutation (c.1010G>T; p.R337L) in TP63 as a cause of split-hand/foot malformation with hypodontia. 61
31420900 2019
13
[Congenital ectrodactyly caused by chromosome 10q24.31 duplication and its pathogenetic analysis]. 61
31447422 2019
14
The role of ultrasound and genetic counsel in prenatal diagnosis of split hand/foot malformation with long bone deficiency. 61
31307755 2019
15
WNT10B variants in split hand/foot malformation: Report of three novel families and review of the literature. 61
31050392 2019
16
Split hand/foot malformation with long bone deficiency associated with BHLHA9 gene duplication: a case report and review of literature. 61
31200655 2019
17
Split Hand Foot Malformation Syndrome: A Novel Heterozygous FGFR1 Mutation Detected by Next Generation Sequencing. 61
31929729 2019
18
Genetic regulatory pathways of split-hand/foot malformation. 61
30101460 2019
19
Insights into the pathogenesis and treatment of split/hand foot malformation (cleft hand/foot). 61
30380990 2019
20
17p13.3 genomic rearrangement in a Chinese family with split-hand/foot malformation with long bone deficiency: report of a complicated duplication with marked variation in phenotype. 61
29970136 2018
21
Prenatal limb defects: Epidemiologic characteristics and an epidemiologic analysis of risk factors. 61
30024522 2018
22
Split hand-foot malformation and a novel WNT10B mutation. 61
29427788 2018
23
Deletion of a Long-Range Dlx5 Enhancer Disrupts Inner Ear Development in Mice. 61
29301908 2018
24
Split hand/foot malformation: a potential clue to underlying FGFR1 mutation in patients with isolated congenital hypogonadotropic hypogonadism. 61
29146774 2018
25
Importance of complete phenotyping in prenatal whole exome sequencing. 61
29392406 2018
26
Bhlha9 regulates apical ectodermal ridge formation during limb development. 61
28324176 2018
27
Homozygous sequence variants in the WNT10B gene underlie split hand/foot malformation. 61
29384555 2018
28
Bilateral split hand foot malformation in siblings: Case series. 61
29499514 2018
29
A differential expression network method identifies ankylosing spondylitis-related genes. 61
29970661 2018
30
Microduplications of 10q24 Detected in Two Chinese Patients with Split-hand/foot Malformation Type 3. 61
29263051 2017
31
Copy-number variants and candidate gene mutations in isolated split hand/foot malformation. 61
28539665 2017
32
Molecular Genetic Characterization of a Chinese Family with Severe Split Hand/Foot Malformation. 61
28422522 2017
33
A New Split Hand/Foot Malformation with Long Bone Deficiency Familial Case. 61
28496997 2017
34
FGFR1 Analyses in Four Patients with Hypogonadotropic Hypogonadism with Split-Hand/Foot Malformation: Implications for the Promoter Region. 61
28087897 2017
35
A Novel Heterozygous Intragenic Sequence Variant in DLX6 Probably Underlies First Case of Autosomal Dominant Split-Hand/Foot Malformation Type 1. 61
28611547 2017
36
Novel heterozygous frameshift mutation in distal-less homeobox 5 underlies isolated split hand/foot malformation type 1. 61
27085093 2016
37
Split hand/foot malformation genetics supports the chromosome 7 copy segregation mechanism for human limb development. 61
27821526 2016
38
Ectrodactyly and Lethal Pulmonary Acinar Dysplasia Associated with Homozygous FGFR2 Mutations Identified by Exome Sequencing. 61
27323706 2016
39
Recurrence of split hand/foot malformation, cleft lip/palate, and severe urogenital abnormalities due to germline mosaicism for TP63 mutation. 61
27351625 2016
40
Prenatal Diagnosis of Ectrodactyly in the First Trimester by Three-Dimensional Ultrasonography. 61
26989570 2016
41
Hartsfield Syndrome 61
26937548 2016
42
Phenotypic subregions within the split-hand/foot malformation 1 locus. 61
26839112 2016
43
Split Hand / Foot Malformation Syndrome with Cerebral Degeneration. 61
27730782 2016
44
Split Hand/Foot Malformation Associated with 7q21.3 Microdeletion: A Case Report. 61
27022330 2016
45
Selective chromatid segregation mechanism proposed for the human split hand/foot malformation development by chromosome 2 translocations: A perspective. 61
26477560 2015
46
Identification of Critical Region Responsible for Split Hand/Foot Malformation Type 3 (SHFM3) Phenotype through Systematic Review of Literature and Mapping of Breakpoints Using Microarray Data. 61
27600068 2015
47
FGF8, c-Abl and p300 participate in a pathway that controls stability and function of the ΔNp63α protein. 61
25911675 2015
48
Array comparative genomic hybridization characterization of multiple interstitial deletions involving 7p22.1, 7q11.23, 7q21.3-q22.1, 19p13.3-p12, and 19q13.11-q13.43 in a fetus associated with split hand-foot malformation. Role of EPS15L1 in pathogenesis. 61
26384072 2015
49
Congenital hypogonadotropic hypogonadism with split hand/foot malformation: a clinical entity with a high frequency of FGFR1 mutations. 61
25394172 2015
50
A novel c.1037C > G (p.Ala346Gly) mutation in TP63 as cause of the ectrodactyly-ectodermal dysplasia and cleft lip/palate (EEC) syndrome. 61
25983622 2015

Variations for Split Hand-Foot Malformation

ClinVar genetic disease variations for Split Hand-Foot Malformation:

6 (show all 18)
# Gene Name Type Significance ClinVarId dbSNP ID Position
1 overlap with 7 genes Duplication Pathogenic 590885 GRCh37: 10:102887490-103524625
GRCh38:
2 FGFR2 NM_000141.5(FGFR2):c.764G>A (p.Arg255Gln) SNV Likely pathogenic 869459 GRCh37: 10:123279668-123279668
GRCh38: 10:121520154-121520154
3 PLAA NM_001031689.3(PLAA):c.1487-1G>A SNV Likely pathogenic 598964 rs1426488816 GRCh37: 9:26913946-26913946
GRCh38: 9:26913948-26913948
4 UBA2 NM_005499.3(UBA2):c.364C>G (p.Arg122Gly) SNV Uncertain significance 978773 GRCh37: 19:34925778-34925778
GRCh38: 19:34434873-34434873
5 FBXW4 NM_022039.4(FBXW4):c.504_506GGC[3] (p.Ala170dup) Microsatellite Uncertain significance 298539 rs768227529 GRCh37: 10:103454353-103454354
GRCh38: 10:101694596-101694597
6 TP63 NM_003722.5(TP63):c.*1947dup Duplication Uncertain significance 344418 rs140654135 GRCh37: 3:189614229-189614230
GRCh38: 3:189896440-189896441
7 TP63 NM_003722.5(TP63):c.*2555dup Duplication Uncertain significance 344435 rs772929136 GRCh37: 3:189614841-189614842
GRCh38: 3:189897052-189897053
8 FBXW4 NM_022039.4(FBXW4):c.*311_*314dup Duplication Uncertain significance 298524 rs562226127 GRCh37: 10:103370733-103370734
GRCh38: 10:101610976-101610977
9 FBXW4 NM_022039.4(FBXW4):c.374T>C (p.Val125Ala) SNV Uncertain significance 298545 rs886046646 GRCh37: 10:103454489-103454489
GRCh38: 10:101694732-101694732
10 TP63 NM_003722.5(TP63):c.*1130_*1133del Deletion Uncertain significance 344407 rs886058229 GRCh37: 3:189613419-189613422
GRCh38: 3:189895630-189895633
11 TP63 NM_003722.5(TP63):c.*235_*238del Deletion Uncertain significance 344394 rs886058225 GRCh37: 3:189612523-189612526
GRCh38: 3:189894734-189894737
12 TP63 NM_003722.5(TP63):c.*519C>T SNV Uncertain significance 344400 rs886058228 GRCh37: 3:189612810-189612810
GRCh38: 3:189895021-189895021
13 FBXW4 NM_022039.4(FBXW4):c.485_487AGG[6] (p.Glu168del) Microsatellite Likely benign 298540 rs560966094 GRCh37: 10:103454358-103454360
GRCh38: 10:101694601-101694603
14 TP63 NM_003722.5(TP63):c.*2719_*2720del Deletion Likely benign 344438 rs574327104 GRCh37: 3:189615007-189615008
GRCh38: 3:189897218-189897219
15 TP63 NM_003722.5(TP63):c.*2636del Deletion Likely benign 344437 rs5855278 GRCh37: 3:189614927-189614927
GRCh38: 3:189897138-189897138
16 TP63 NM_003722.5(TP63):c.*2544del Deletion Benign 344434 rs201395656 GRCh37: 3:189614829-189614829
GRCh38: 3:189897040-189897040
17 TP63 NM_003722.4(TP63):c.*2789A>G SNV Benign 369418 rs11708746 GRCh37: 3:189615080-189615080
GRCh38: 3:189897291-189897291
18 TP63 NM_003722.5(TP63):c.*1844dup Duplication Benign 344416 rs146332971 GRCh37: 3:189614134-189614135
GRCh38: 3:189896345-189896346

Expression for Split Hand-Foot Malformation

Search GEO for disease gene expression data for Split Hand-Foot Malformation.

Pathways for Split Hand-Foot Malformation

Pathways related to Split Hand-Foot Malformation according to GeneCards Suite gene sharing:

# Super pathways Score Top Affiliating Genes
1 11.14 FGFR2 FGFR1 DLX5
2 11.08 WNT10B FGFR2 FGFR1 DLX5

GO Terms for Split Hand-Foot Malformation

Biological processes related to Split Hand-Foot Malformation according to GeneCards Suite gene sharing:

(show all 22)
# Name GO ID Score Top Affiliating Genes
1 positive regulation of canonical Wnt signaling pathway GO:0090263 9.8 WNT10B SEM1 FGFR2 DLX5
2 SCF-dependent proteasomal ubiquitin-dependent protein catabolic process GO:0031146 9.76 SEM1 FBXW4 BTRC
3 cellular response to organic cyclic compound GO:0071407 9.74 WNT10B GLI2 BTRC
4 roof of mouth development GO:0060021 9.73 HAND2 DLX6 DLX5
5 positive regulation of epithelial cell proliferation GO:0050679 9.72 FGFR2 DLX6 DLX5
6 inner ear morphogenesis GO:0042472 9.71 FGFR2 DLX6 DLX5
7 odontogenesis of dentin-containing tooth GO:0042475 9.7 TP63 HAND2 GLI2
8 embryonic digit morphogenesis GO:0042733 9.69 HAND2 GLI2 FBXW4
9 skeletal system development GO:0001501 9.65 TP63 GLI2 FGFR1 DLX6 DLX5
10 developmental process GO:0032502 9.63 TP63 HAND2 BHLHA9
11 epithelial cell differentiation GO:0030855 9.62 TP63 FGFR2 DLX6 DLX5
12 positive regulation of mesenchymal cell proliferation GO:0002053 9.61 FGFR2 FBXW4
13 hair follicle morphogenesis GO:0031069 9.61 TP63 GLI2 FGFR2
14 embryo development GO:0009790 9.6 DLX6 DLX5
15 sympathetic nervous system development GO:0048485 9.59 TP63 HAND2
16 positive regulation of phospholipase activity GO:0010518 9.58 FGFR2 FGFR1
17 head development GO:0060322 9.54 GLI2 DLX6 DLX5
18 prostatic bud formation GO:0060513 9.48 TP63 GLI2
19 embryonic limb morphogenesis GO:0030326 9.46 TP63 FBXW4 DLX6 DLX5
20 squamous basal epithelial stem cell differentiation involved in prostate gland acinus development GO:0060529 9.4 TP63 FGFR2
21 multicellular organism development GO:0007275 9.36 WNT10B TP63 PLAA HAND2 GLI2 FGFR2
22 anatomical structure formation involved in morphogenesis GO:0048646 9.26 TP63 GLI2 DLX6 DLX5

Molecular functions related to Split Hand-Foot Malformation according to GeneCards Suite gene sharing:

# Name GO ID Score Top Affiliating Genes
1 transcription regulatory region sequence-specific DNA binding GO:0000976 9.26 TP63 HAND2 GLI2 DLX5
2 fibroblast growth factor-activated receptor activity GO:0005007 8.62 FGFR2 FGFR1

Sources for Split Hand-Foot Malformation

3 CDC
7 CNVD
9 Cosmic
10 dbSNP
11 DGIdb
17 EFO
18 ExPASy
19 FMA
20 GARD
28 GO
29 GTR
30 HMDB
31 HPO
32 ICD10
33 ICD10 via Orphanet
34 ICD9CM
35 IUPHAR
36 KEGG
37 LifeMap
39 LOVD
41 MedGen
44 MeSH
45 MESH via Orphanet
46 MGI
49 NCI
50 NCIt
51 NDF-RT
53 NINDS
54 Novoseek
56 OMIM via Orphanet
57 OMIM® (Updated 05-Apr-2021)
61 PubMed
63 QIAGEN
68 SNOMED-CT via HPO
69 Tocris
70 UMLS
71 UMLS via Orphanet
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