Details of Disease

General Information of Disease (ID: DIS8PKGD)

• Disease Name: Split hand-foot malformation
• Synonyms: isolated split hand-split foot malformation; split hand-split foot malformation; split hand foot malformation; split-hand deformity; split-hand/foot malformation; SHFM; Split Hand/Split Foot Malformation; FEWER digits; lobster-claw deformity; ectrodactyly
• Definition: Split hand-split foot malformation (SHFM) refers to a spectrum of genetically and clinically heterogenous terminal limb defect characterized by hypoplasia/ absence of central rays of the hands and feet (that can occur in one to all four digits), median clefts of the hands and/ or feet, aplasia and syndactyly, with a wide range of severity ranging from malformed central finger/ toe to a lobster claw-like appearance of the hands and feet. SHFM can be an isolated malformation or can be a feature in various syndromes (ADULT syndrome, EEC syndrome). SHFM usually follows an autosomal dominant pattern of inheritance with incomplete penetrance, but autosomal recessive and rarely X-linked inheritance have also been reported.
• Disease Hierarchy:
  DISYKSRF: Genetic disease
  DISHPNVX: Dysplasia
  DIS8PKGD: Split hand-foot malformation
• Disease Identifiers:
  MONDO ID: MONDO_0016576
  MESH ID: C574275
  UMLS CUI: C0265554
  MedGen ID: 78566
  HPO ID: HP:0100257
  SNOMED CT ID: 81208006

Molecular Interaction Atlas (MIA) of This Disease

This Disease Is Related to 15 DOT Molecule(s)

Gene Name	DOT ID	Evidence Level	Mode of Inheritance	REF
WNT10B	OTH0Z1XV	Supportive	Autosomal dominant	[1]
CKAP4	OTDUC9ME	Limited	Genetic Variation	[2]
SEM1	OTASLBM1	Limited	Genetic Variation	[4]
SNX3	OTXL5W8F	Disputed	Genetic Variation	[5]
DLX5	OTEEFBEU	Supportive	Autosomal dominant	[6]
DLX6	OT0FIJHY	Supportive	Autosomal dominant	[7]
EPS15L1	OTTFPZY2	Supportive	Autosomal dominant	[8]
TP63	OT0WOOKQ	Supportive	Autosomal dominant	[9]
BTRC	OT2EZDGR	moderate	Genetic Variation	[10]
BHLHA9	OT80XOJB	Strong	Biomarker	[11]
INHBB	OT2QLD11	Strong	Genetic Variation	[12]
INSIG2	OTX4VY51	Strong	Genetic Variation	[12]
MID1	OTWN1PGU	Strong	Biomarker	[13]
QTRT1	OTC33MCV	Strong	Genetic Variation	[14]
RANGAP1	OTZGD3LJ	Strong	Genetic Variation	[15]

This Disease Is Related to 2 DTT Molecule(s)

Gene Name	DTT ID	Evidence Level	Mode of Inheritance	REF
RPE65	TTBOH16	Limited	Genetic Variation	[2]
CDH3	TTARMD9	moderate	Biomarker	[3]

References

• [1] Homozygous WNT10b mutation and complex inheritance in Split-Hand/Foot Malformation. Hum Mol Genet. 2008 Sep 1;17(17):2644-53. doi: 10.1093/hmg/ddn164. Epub 2008 May 30.
• [2] Mutant p63 Affects Epidermal Cell Identity through Rewiring the Enhancer Landscape.Cell Rep. 2018 Dec 18;25(12):3490-3503.e4. doi: 10.1016/j.celrep.2018.11.039.
• [3] Distinct CDH3 mutations cause ectodermal dysplasia, ectrodactyly, macular dystrophy (EEM syndrome). J Med Genet. 2005 Apr;42(4):292-8. doi: 10.1136/jmg.2004.027821.
• [4] A 0.7Mb de novo duplication at 7q21.3 including the genes DLX5 and DLX6 in a patient with split-hand/split-foot malformation.Am J Med Genet A. 2012 Dec;158A(12):3201-6. doi: 10.1002/ajmg.a.35644. Epub 2012 Nov 20.
• [5] Sorting nexin 3 (SNX3) is disrupted in a patient with a translocation t(6;13)(q21;q12) and microcephaly, microphthalmia, ectrodactyly, prognathism (MMEP) phenotype. J Med Genet. 2002 Dec;39(12):893-9. doi: 10.1136/jmg.39.12.893.
• [6] Exome sequencing reveals a heterozygous DLX5 mutation in a Chinese family with autosomal-dominant split-hand/foot malformation. Eur J Hum Genet. 2014 Sep;22(9):1105-10. doi: 10.1038/ejhg.2014.7. Epub 2014 Feb 5.
• [7] A Novel Heterozygous Intragenic Sequence Variant in DLX6 Probably Underlies First Case of Autosomal Dominant Split-Hand/Foot Malformation Type 1. Mol Syndromol. 2017 Mar;8(2):79-84. doi: 10.1159/000453350. Epub 2016 Dec 20.
• [8] First direct evidence of involvement of a homozygous loss-of-function variant in the EPS15L1 gene underlying split-hand/split-foot malformation. Clin Genet. 2018 Mar;93(3):699-702. doi: 10.1111/cge.13152. Epub 2018 Jan 25.
• [9] Split-hand/split-foot malformation is caused by mutations in the p63 gene on 3q27. Am J Hum Genet. 2000 Jul;67(1):59-66. doi: 10.1086/302972. Epub 2000 Jun 5.
• [10] Clinical, genetic, and molecular aspects of split-hand/foot malformation: an update.Am J Med Genet A. 2013 Nov;161A(11):2860-72. doi: 10.1002/ajmg.a.36239. Epub 2013 Sep 24.
• [11] Gene dosage of the transcription factor Fingerin (bHLHA9) affects digit development and links syndactyly to ectrodactyly.Hum Mol Genet. 2014 Oct 15;23(20):5394-401. doi: 10.1093/hmg/ddu257. Epub 2014 May 22.
• [12] Characterization of two ectrodactyly-associated translocation breakpoints separated by 2.5 Mb on chromosome 2q14.1-q14.2.Eur J Hum Genet. 2009 Aug;17(8):1024-33. doi: 10.1038/ejhg.2009.2. Epub 2009 Feb 18.
• [13] Genes causing clefting syndromes as candidates for non-syndromic cleft lip with or without cleft palate: a family-based association study.Eur J Oral Sci. 2008 Dec;116(6):507-11. doi: 10.1111/j.1600-0722.2008.00574.x.
• [14] TP63 mutation and clefting modifier genes in an EEC syndrome family.Clin Genet. 2004 Sep;66(3):217-22. doi: 10.1111/j.1399-0004.2004.00287.x.
• [15] Heterozygous DLX5 nonsense mutation associated with isolated split-hand/foot malformation with reduced penetrance and variable expressivity in two unrelated families.Birth Defects Res A Clin Mol Teratol. 2014 Oct;100(10):764-71. doi: 10.1002/bdra.23298. Epub 2014 Sep 5.