Alternative titles; symbols
ORPHA: 2440; DO: 0090021;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 7q21.3 | Split-hand/foot malformation 1 | 183600 | Autosomal dominant | 3 | DLX5 | 600028 |
A number sign (#) is used with this entry because some cases of split-hand/foot malformation-1 (SHFM1) represent a contiguous gene syndrome caused by deletion, duplication, or rearrangement of chromosome 7q21.3 involving the DSS1 (601285), DLX5 (600028), and DLX6 (600030) genes and possible regulatory elements in the region. Evidence exists that SHFM1 can also be caused by heterozygous mutation in the DLX5 gene.
Split-hand/foot malformation (SHFM) is a limb malformation involving 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 with SHFM1 have been found to have mental retardation, ectodermal and craniofacial findings, orofacial clefting (Elliott and Evans, 2006), and neurosensory hearing loss (Tackels-Horne et al., 2001).
Genetic Heterogeneity of Split-Hand/Foot Malformation
Additional SHFM loci include SHFM2 (313350) on chromosome Xq26; SHFM3 (246560), caused by duplication of chromosome 10q24; SHFM4 (605289), caused by mutation in the TP63 gene (603273) on chromosome 3q28; SHFM5 (606708) on chromosome 2q31; and SHFM6 (225300), caused by mutation in the WNT10B gene (601906) on chromosome 12q13.
Also see SHFM1D (220600) for a form of SHFM1 with deafness that may be caused by homozygous mutation in the DLX5 gene (600028).
Associations Pending Confirmation
For discussion of a possible association between split-hand/foot malformation and variation in the EPS15L1 gene, see 616826.0001.
The term ectrodactyly is derived from Greek ektroma (abortion) and daktylos (finger). It is a nonspecific term applied to a variety of malformations and is probably best reserved for transverse terminal aphalangia, adactylia, or acheiria. Cases defined in this way are usually sporadic. As a rule, one hand is involved and the feet are not affected. Congenital constriction rings ('amniotic bands') are sometimes associated. Many cases described as examples of autosomal dominant inheritance of ectrodactyly are in fact type B brachydactyly (113000) (Temtamy and McKusick, 1978). The anomaly here called split-hand deformity is also termed ectrodactyly.
Birch-Jensen (1949) recognized 2 anatomic types: typical 'lobster claw' and monodactyly. The anatomic classification has no genetic significance because either type may occur in the same family or on different limbs of the same person (Temtamy and McKusick, 1978). Absence of the central rays characterized the first anatomic type. The hand is divided into 2 parts by a cone-shaped cleft tapering proximally. The 2 parts of the hand can be apposed like a lobster claw. A comparable deformity of the feet may be present. In the second anatomic type, or monodactyly, the radial rays are absent with, as a rule, only the fifth digit remaining.
Vogel (1958) suggested that 2 varieties of split-hand deformity exist: (1) a type with constant involvement of the feet and regular autosomal dominant inheritance, and (2) a type with inconsistent involvement of the feet and irregular inheritance.
Viljoen and Beighton (1984) studied this anomaly in a remote African village. Lay reports of an 'ostrich-footed' tribe had appeared in the past.
Lewis (1912), subsequently Sir Thomas Lewis and a noted cardiologist, gave one of the earliest and clearest descriptions of a kindred with split-hand/split-foot.
Tackels-Horne et al. (2001) described 2 families with a form of SHFM in which deficiency of the central rays in the appendicular skeleton was associated with sensorineural hearing loss. In 1 family, variably expressed split-foot malformations were found in 6 of 11 presumed gene carriers, and mild to moderate sensorineural hearing loss in 4. Split-hand and cleft lip/palate in 1 individual and tibial deficiency in another suggested that these manifestations are uncommon components of the syndrome. There were no ectodermal abnormalities. In the other family, variable split-foot was observed in 3 of 4 gene carriers, and sensorineural deafness was present in 3. Split-hand was seen only in a gene carrier who also had split-foot and deafness. One gene carrier had only deafness.
Haberlandt et al. (2001) reported an 18-month-old boy, born of fourth-cousin Austrian parents, who had ectrodactyly of the right foot associated with conductive and profound sensorineural deafness and inner and middle ear malformations. Evaluation at 15 months of age due to failure to thrive revealed weight, length, and head circumference all below the 3rd centile; he also had arched eyebrows, a small triangular nose with depressed nasal bridge, hypertelorism, hypopigmented retina, large biparietal diameter, overfolded helices of ears with attached earlobes, micrognathia, submucous cleft palate, carious primary teeth and hypodontia, sparse light-colored hair, pale skin, cryptorchidism, and bilateral severe congenital vertical talus. In addition, psychomotor developmental delay was noted. CT and MRI scans revealed Mondini dysplasia of the inner ear, and cochlear implanting showed fixation of the ossicular chain.
Wieland et al. (2004) reported a 4-year-old boy with typical 'lobster claw' ectrodactyly of the left hand and both feet, with syndactyly of the third and fourth digits of the right hand, who also had dysplastic ears, retrognathia, and profound deafness with Mondini dysplasia of the inner ear on MRI. Psychomotor development was normal.
Wang et al. (2014) studied a Chinese mother and son with SHFM. The 31-year-old mother had typical deep median longitudinal clefts between the toes, with hands that appeared normal except for long thumbs. X-ray examination revealed triphalangeal thumbs as well as the absence of second metatarsals and second and third toes. Her 7-year-old son had 'lobster-claw-like' feet noted at birth, but no other visible abnormalities. There were no other affected family members.
Sowinska-Seidler et al. (2014) described affected individuals from 2 unrelated Polish families with isolated SHFM. In the first family, the only affected individual was a 28-month-old boy who was born with typical bilateral hand ectrodactyly involving aplasia of the middle finger. His feet were unaffected, and he had normal psychomotor development with no other congenital anomalies. In the second family, the proband was a 35-year-old man who had quadrupedal SHFM, with severe bilateral hypoplasia of the third fingers as well as fusion, contractures, and hypoplasia of the fourth and fifth fingers. He had bilateral split-foot malformation due to aplasia of the central digital ray, including the corresponding metatarsal. His 4-year-old son had a relatively mild unilateral defect of the left foot, consisting of a broad hallux, hypoplastic second toe, syndactyly of the third and fourth toes, and clinodactyly of the fifth toe. The proband's 5.5-year-old nephew had bilateral asymmetric split-foot malformation, with a broad hallux and absent central toes on the left, and shortening of the second and third toes on the right. His hands were normal. All affected individuals had normal intellectual development, and their SHFM phenotypes were not associated with hearing impairment or other congenital anomalies.
Birch-Jensen (1949) estimated the frequency of split-hand/foot at birth to be about 1 in 90,000 in Denmark.
About 70 pedigrees were reported prior to 1965 (Temtamy and McKusick, 1978). Regular autosomal dominant inheritance through 3 or more generations was demonstrated by about 27 of the 70 pedigrees. Skipping of a generation was noted by at least 4 authors. Two or more affected sibs with both parents normal were noted by several authors, e.g., MacKenzie and Penrose (1951) and Neugebauer (1962). Gonadal (or germinal) mosaicism was suggested by Auerbach (1956) as a possible explanation. De Smet et al. (2001) presented further evidence for germinal mosaicism in cleft hand/cleft foot syndrome. Two affected half sisters with the same normal father and different mothers presented with the typical syndrome.
In those pedigrees with variable involvement of the feet, the genetics is less clear. A disturbed segregation ratio was found in the family first reported by McMullan and Pearson (1913) and brought up to date by Stevenson and Jennings (1960). A marked preponderance of affected sons of affected fathers suggested germinal selection to the latter workers.
Ford (1963) raised the question of chromosomal aberration but could demonstrate none by the available methods. Anomalous segregation has also been observed with aniridia (106210) and with Alport syndrome (104200).
Ray (1970) described 2 cases among the children of first-cousin, unaffected parents.
The family described by Emery (1977) indicates how wide the gaps of failure of penetrance may be in a family and raises the question of minor hand anomalies as a partial expression.
Bujdoso and Lenz (1980) stated that monodactyly occurs with 3 distinct genetic forms of ectrodactyly, each an autosomal dominant. In the first type only the first and fifth or only the fifth toes are present on both feet. The trait is fully expressed in all affected children of patients, with no skipping of generations. On the other hand, both parents of several affected children may be normal, suggesting single strand mutation. The second type, the EEC syndrome (129900), which combines ectrodactyly with ectodermal defects and cleft lip-palate, has monodactyly less frequently and has more variable limb malformations. In the third type of ectrodactyly, extreme intrafamilial variability is the rule.
Zlotogora (1994) analyzed reported pedigrees with nonsyndromal SHSF (without other limb defects) and showed dominant transmission of the defect with almost complete penetrance (99/103).
Jarvik et al. (1994) studied new pedigrees and reviewed them in conjunction with so-called historical pedigrees which included most of those summarized by Stevenson and Jennings (1960). Jarvik et al. (1994) concluded that the new pedigrees with defined ascertainment confirmed the existence of nonmendelian transmission characterized by the overtransmission of SHSF from affected fathers to sons. Crow (1991) pointed out that segregation distortion, defined as departure from normal mendelian ratios, does not require that a meiotic process be known to underlie the departure. Thus, the deviation from mendelian expectations seen for SHSF may be termed segregation distortion. Jarvik et al. (1994) claimed that segregation distortion had not been documented for any other human developmental disorder. The segregation distortion, as well as the reduced penetrance and variable expression in this disorder, awaits molecular elucidation.
Del Porto et al. (1983) described a boy with microcephaly, ectrodactyly of feet, and facial dysmorphism (beak-like nose, low-set ears) who had del(7)(q11-q22). At least 9 other cases of ectrodactyly with interstitial deletions of 7q have been reported (Tajara et al., 1989; Morey and Higgins, 1990; Roberts et al., 1991; Marinoni et al., 1995; McElveen et al., 1995). The minimal overlapping segment in all these cases was 7q21.2-q21.3. Sharland et al. (1991) reported the case of a boy with tetramelic ectrodactyly who had an exceedingly complex chromosomal rearrangement resulting from 5 breaks in chromosomes 5, 7, and 9: 5q11.2, 5q34, 7q21.2, 7q31.3, and 9q22.1. There was no apparent deletion. Both parents had normal chromosomes. Because of reports of ectrodactyly with chromosomal aberrations involving 7q21, Sharland et al. (1991) proposed that the break at 7q21.2 had disrupted a gene responsible for complete hand ray development. Except for minor facial peculiarities, the boy appeared to be normal in all respects including growth and development. Genuardi et al. (1993) found an apparently balanced translocation, t(2;7)(q21.1;q22.1), in a female patient with bilateral split-hand and right split-foot. SHFD segregated as an autosomal dominant with low penetrance in her family. The translocation was present in 6 of 13 additional relatives investigated, one of whom also had split-hand on the right. Cobben et al. (1995) described a case of typical tetramelic split hand-foot malformation in association with a pericentric inversion of chromosome 7: 46,XY,inv(7)(p22q21.3). The limbs and chromosomes of the parents were normal. Ignatius et al. (1996) reported an adult male with tetramelic ectrodactyly and a complex 6-break chromosomal rearrangement, including a break at 7q21.3. Taken together with data from previously reported cases, the 'critical region' for ectrodactyly appears to be 7q21.1-q22.1. A review of reported SHFD cases with chromosome 7 abnormalities suggested preferential involvement of the feet and of the right side. Surprisingly, 4 out of 8 apparently balanced rearrangements leading to ectrodactyly had 3 (Koiffmann et al., 1993; Naritomi et al., 1993), 5 (Sharland et al., 1991), or 6 (Ignatius et al., 1996) breakpoints.
Marinoni et al. (1995) found deletion of 7q21.2-q22.1 in a patient with split-foot and developmental retardation. Molecular analysis using PCR showed deletion of 3 microsatellite markers, D7S527, D7S479, and D7S554, in the patient's paternal chromosome.
By karyotype analysis of an 18-month-old boy with ectrodactyly of the right foot and profound sensorineural deafness, Haberlandt et al. (2001) identified a de novo interstitial deletion of chromosome 7q21.1-q21.3. Haplotype analysis defined an 8.9- to 17-cM deletion that occurred on the paternal allele and encompassed the critical interval on 7q21.3 previously associated with either SHFM1 or EEC (see EEC1, 129900) syndrome. Haberlandt et al. (2001) suggested that a specific pattern of facial anomalies characterizes patients with aberrations of chromosome 7q21-q22, noting that at least 6 previously published reports described facial dysmorphism similar to that of this patient (see, e.g., Tajara et al., 1989, Sharland et al., 1991, and Marinoni et al., 1995).
Wieland et al. (2004) performed haplotype analysis in a 4-year-old boy with ectrodactyly and deafness and his unaffected, nonconsanguineous parents, and identified a microdeletion at chromosome 7q21.3-q22.1 on the paternal allele. Southern blot analysis localized the deletion breakpoints to between the DNCI1 gene (603772) and marker D7S821 proximally and between the DLX5 gene (600028) and marker D7S618 distally, narrowing the deletion to a 0.9- to 1.8-Mb interval encompassing the DLX5, DLX6 (600030), and DSS1 (601285) genes.
Bernardini et al. (2008) reported a 5-year-old girl with ectrodactyly of the right hand and feet, deafness, craniofacial dysmorphism, cleft palate, tetralogy of Fallot, and psychomotor delay. Karyotype analysis detected a de novo reciprocal interstitial translocation t(7;8)(q21q22;q23q24). FISH and array CGH analysis showed a paracentric inversion of 7q, which interrupted the CUTL1 gene (116896), and a microdeletion of 7q21.13, which included the FZD1 gene (603408). The findings confirmed the locus on 7q identified by Tackels-Horne et al. (2001). Bernardini et al. (2008) suggested that the involvement of band 8q may have contributed to the dysmorphic facial features and heart defect.
Saitsu et al. (2009) studied a 9-year-old Japanese girl with a complex chromosomal rearrangement involving 7q21.3, who had bilateral split-foot malformation as well as micrognathia, full lower lip, strabismus, and bilateral stenosis of the ear canals with a mixed conductive and sensorineural type of hearing loss. Her hands were normal clinically and radiographically. Developmental milestones were delayed, and self-injuries, hyperactivity, and sleep problems were observed from 3 years of age. G-banded karyotype was 46,XX,t(7;15)(q21;q15),t(9;14)(q21;q11.2)dn. Because the patient had SHFM and hearing loss, the authors focused on the breakpoint at 7q21, which did not disrupt any genes and mapped to 38 kb telomeric to the DSS1 gene and 258 kb and 272 kb centromeric to the DLX6 and DLX5 genes, respectively. Microarray analysis followed by cloning revealed a 0.8-Mb deletion located 750 kb telomeric to the translocation breakpoint on 7q21, encompassing part of the potential candidate gene LMTK2 (610989); however, analysis of LMTK2 in 29 Japanese SHFM patients revealed no mutations.
Velinov et al. (2012) described a female patient with a duplication of 719 kb at 7q21.3 (chr7:96,303,736-97,022,335; NCBI36). Clinical evaluation at 2 months showed unilateral syndactyly of fingers 3 and 4 on her right hand. Her right food showed overgrowth and lateral deviation of her great toe with split-foot malformation and absent fifth toe. The left hand and foot were normal, and the patient had no hearing loss. The duplicated region harbored only the DLX5 and DLX6 gene and was confirmed to be a de novo occurrence in the patient.
Rattanasopha et al. (2014) studied a large 4-generation Thai family with SHFM mapping to the SHFM1 locus on chromosome 7q21. The 8 affected individuals manifested a broad spectrum of clinical manifestations, ranging from unilateral cutaneous syndactyly between 2 digits to bilateral split hands and feet. In addition, the proband's father exhibited central polydactyly of his right hand; the authors noted that polydactyly had not been previously reported in SHFM1. Microarray analysis revealed a heterozygous 103-kb deletion (chr7:95,694,099_95,797,866delinsTCATC), encompassing exons 14 to 17 of the DYNC1I1 gene and exons 13 to 18 of the SLC25A13 gene (603859), that was present in all 8 affected members as well as 2 unaffected members of the family (penetrance of 80%). Analysis of the proband's cultured osteoblasts demonstrated complete absence of DLX5 and DLX6 RNA and proteins, rather than the expected 50% decrease. Allelic expression studies in cultured osteoblasts of an unaffected individual showed that DSS1, DLX6, and DLX5 expressed only paternal alleles, indicating that these genes were maternally imprinted in osteoblasts. Rattanasopha et al. (2014) concluded that SHFM1 in this family was caused by heterozygous paternal deletion of enhancers of the osteoblast-specific maternally imprinted DLX6 and DLX5 genes, resulting in absence of their proteins.
To map the SHFD1 locus, Scherer et al. (1994) constructed somatic cell hybrid lines from cytogenetically abnormal individuals with split-hand/foot deformity. Molecular analysis resulted in the localization of 93 DNA markers to 1 of 10 intervals surrounding the SHFD1 locus. The translocation breakpoints in 4 SHFD patients were encompassed by the smallest region of overlap among the SHFD-associated deletions. The order of DNA markers in the critical region was defined as PON (168820)--D7S812--SHFD1--D7S811--ASNS (108370). One DNA marker, D7S811, detected altered restriction enzyme fragments in 3 patients with translocations when examined by pulsed field gel electrophoresis (PFGE).
Scherer et al. (1994) constructed a physical map consisting of overlapping YAC clones for the 7q21.3-q22.1 region to which the SHFM1 gene had been mapped. Somatic cell hybrid and fluorescence in situ hybridization analyses defined split-hand/foot-associated chromosomal rearrangements in 12 patients. A critical interval of 1.5 Mb was established by analyses of 5 patients with deletions. Translocation or inversion breakpoints found in 6 patients were mapped within 700 kb of each other in the critical region. Scherer et al. (1994) noted that 8 of the patients analyzed had syndromic ectrodactyly (SE). They reviewed the clinical and genetic features of 9 types of syndromic ectrodactyly: EEC syndrome (129900), LADD syndrome (149730), ADULT syndrome (103285), EEC syndrome without cleft lip/palate (129810), Fontaine syndrome (183700), acral-renal-mandibular syndrome (200980), ECP syndrome (129830), ectrodactyly and hearing loss (220600), and Karsch-Neugebauer syndrome (183800). They also demonstrated that DLX5 (600028), a member of the distal-less homeobox gene family, and another DLX gene (DLX6; 600030) are located in the SHFM1 critical interval and thus are candidate genes.
In 2 affected families with SHFM and deafness, Tackels-Horne et al. (2001) found that the disorder was linked to markers on chromosome 7q21, the region of the SHFM1 locus, with a combined maximum lod score of 4.37 at theta = 0.0 for D7S527, at 80% penetrance.
Wieland et al. (2004) described a 4-year-old boy with SHFM1 and Mondini dysplasia who was found to have a 0.9- to 11.8-Mb deletion on 7q21.3. The boy had ectrodactyly of the left hand and both feet and syndactyly of the third and fourth digits of the right hand. He had dysplastic ears, retrognathia, and profound deafness with Mondini dysplasia. Haplotype analysis of the SHFM1 critical region showed loss of the paternal markers D7S821, D7S491, and D7S624. Quantitative Southern blot analysis showed loss of one copy each of the DLX5 and DLX6 genes.
Roberts and Tabin (1994) reviewed the events of early limb development, which are similar for all tetrapods in that they define patterning in both the proximal/distal, i.e., humerus to digits, and the anterior/posterior, i.e., first to fifth digits, orientations. Most of the now classic embryologic experiments that defined limb patterning were performed in the chick. Roberts and Tabin (1994) listed 7 candidate genes for human limb-development defects.
Duijf et al. (2003) reviewed the molecular genetics of split-hand/foot malformation in man and mouse.
In a 31-year-old Chinese woman with SHFM, Wang et al. (2014) performed whole-exome sequencing followed by screening of 17 candidate genes in the 6 known SHFM loci and identified heterozygosity for a missense mutation in the DLX5 gene (Q186H; 600028.0002); no coding variants were detected in any other SHFM-associated genes. Direct DNA sequencing confirmed the mutation in the proband; the mutation was not found in 3 unaffected relatives, including her parents, or in 200 ethnically matched controls. Noting that homozygosity for a nearby missense mutation in the DLX5 gene (Q178P; 600028.0001) had been identified by Shamseldin et al. (2012) in a consanguineous Yemeni family segregating recessive SHFM with hearing impairment (SHFM1D; 220600), Wang et al. (2014) hypothesized that affected members of the Chinese family might harbor another mutation in the regulatory element.
In the probands from 2 unrelated Polish families with isolated SHFM, Sowinska-Seidler et al. (2014) sequenced the TP63 (603273), WNT10B (601906), and DLX5 genes and identified heterozygosity for the same nonsense mutation in the DLX5 gene in both probands (E39X; 600028.0003); no mutations were detected in TP63 or WNT10B. In the first family, the proband inherited the mutation from his clinically unaffected mother. In the second family, the mutation was also identified in the proband's affected son and an affected nephew, as well as in the nephew's apparently unaffected father (brother of the proband) and sister; the mutation was not detected in 2 additional unaffected family members. Because family members refused consent to an x-ray evaluation, a mild presentation of SHFM could not be excluded in the clinically unaffected carriers of the nonsense mutation, which was not found in 190 ethnically matched controls or in 6,500 controls in the Exome Variant Server database. Screening of the DLX6 gene (600030) in both probands revealed no pathogenic variants, and analysis of limb-specific enhancer elements in exons 15 and 17 of DYNC1I1 (603772) excluded regulatory point mutations or deletions that might affect DLX5 expression. In addition, common SHFM-associated copy number variants (CNVs) were excluded by array CGH. Quantitative real-time PCR determined the copy number of all 3 exons of the DLX5 gene, suggesting that a second mutation in DLX5 was highly unlikely.
In a literature review including 48 SHFM1 patients, 40 SHFM3 patients, 45 SHFM4 patients, and 20 SHFM5 patients, Elliott et al. (2005) found that preaxial involvement of the upper extremities was a significant locus discriminator, most commonly seen in patients with SHFM3 (60% of patients). Preaxial involvement occurred in approximately 40% of SHFM5, 4% of SHFM4, and 2% of SHFM1 patients. In further analysis of the previously studied SHFM patients, Elliott and Evans (2006) identified phenotypic patterns involving mental retardation, ectodermal and craniofacial findings, and orofacial clefting associated with the mapped genetic SHFM loci.
Johnson et al. (1995) suggested that a potential model for SHFM may be the mouse dactylaplasia mutation (Dac), which is also characterized by missing central digits and other distal limb malformations. They mapped the Dac gene to the distal end of mouse chromosome 19 by backcross segregation analysis. Homozygotes were shown to be viable and fertile, but had a more severe limb malformation (only a single remaining digit) than heterozygotes. They found, furthermore, that expression of the abnormal limb phenotypes of Dac/Dac+ and Dac/Dac mice depends on homozygosity for a recessive allele of another unlinked gene, symbolized mdac, that is polymorphic among inbred mouse strains. They mapped mdac to the middle of mouse chromosome 13 by segregation analysis of both recombinant inbred strains and backcross progeny. Judging from conserved synteny, the human equivalent of Dac would most likely be found in the 10q23-q25 region, and the most likely map location for the human equivalent of mdac is either 5q or 9q. Johnson et al. (1995) suggested that the anomalous inheritance patterns of SHFM which sometimes appears to be recessive and often skips generations and displays disturbed segregation ratios might be the consequence of a polymorphic epistatic gene such as mdac.
Crackower et al. (1998) showed that in heterozygous Dac embryos, the apical ectodermal ridge (AER), a critical signaling center that directs the outgrowth and patterning of the developing limb, is morphologically normal at E10.5, but, by E11.5, its central segment degenerates, leaving the anterior and posterior segments intact. This suggested that localized failure of ridge maintenance activity is the fundamental developmental defect in Dac and, by inference, in SHFM.
Merlo et al. (2002) inactivated the Dlx5 (600028) and Dlx6 (600030) genes in mice. No expression of either gene was detected, but expression of the Dss1 gene (601285) was unaffected. The Dlx5/Dlx6-null mice exhibited bilateral ectrodactyly of the posterior limbs and severe craniofacial abnormalities characterized by apparent homeotic transformation of the entire mandibular arch. Merlo et al. (2002) stated that the hindlimb defect was strongly reminiscent of SHFM1. They noted that the specific craniofacial lesion in the mutant mice has never been observed in patients, but that an etiologic association has been established between SHFM1 and syndromic ectrodactylies in which cleft lib and/or palate, hearing loss, and genitourinary anomalies are often present.
A malformation is a primary structural abnormality, whereas a deformity is a secondary structural abnormality, e.g., clubfoot that develops in association with spina bifida. Since the anomaly discussed in this entry is a malformation and not a deformity, Palmer et al. (1994) proposed that it should be referred to as split-hand/split-foot malformation and that the gene should be symbolized SHSF1. According to this system, the second autosomal dominant (SHFM3; 246560) and phenotypically indistinguishable form of the disorder would be designated SHSF2, and the X-linked form (SHFM2; 313350) would be designated SHSF3. The nomenclature committee determined in 1994 that split-hand/foot malformation should be symbolized SHFM.
Wildervanck (1963) observed the association of split-hand/foot malformation with sensorineural hearing loss in 2 sons of unrelated parents. Birch-Jensen (1949) mentioned a sporadic case of the association, and Fraser (1976) reported a brother and sister with this combination.
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