Split-Hand/foot Malformation With Long Bone Deficiency 1

This form of split-hand/foot malformation with long bone deficiency (SHFLD1) maps to chromosome 1q42.2-q43.

See also SHFLD2 (610685), which maps to chromosome 6q14.1, and SHFLD3 (612576), which maps to chromosome 17p13.3-p13.1. Split-hand/foot malformation with fibular hypoplasia/aplasia has also been reported, see 113310.

Clinical Features

Roberts (1967) described a family in which persons in 4 generations had one cleft hand with a missing middle finger and flexed ring finger; one person also had grossly deformed legs with missing tibias requiring amputation and a sib had only the severe leg deformity. Another member had absent forearms with the leg deformity. Majewski et al. (1985) stated that this disorder was first described by Otto in 1850 in a fetus and that the first familial instance was published by White and Baker (1888).

Majewski et al. (1985) reported 6 families and concluded that the disorder is autosomal dominant with markedly reduced penetrance. In addition to bilateral aplasia of the tibias and split-hand/split-foot deformity (the full-blown syndrome), malformations may include distal hypoplasia or bifurcation of the femurs, hypo- or aplasia of the ulnas, and minor anomalies such as aplasia of the patellas, hypoplastic big toes, and cup-shaped ears. They stated that the mildest visible manifestation may be hypoplastic big toes, whereas the severest is tetramonodactyly or transverse hemimelia.

Sener et al. (1989) described a 19-year-old man with bilateral involvement of the hands and legs. His parents were first cousins. A great-great-grandfather through both his mother and his father was said to have had grossly deformed legs with unilateral split-hand. Der Kaloustian and Mnaymneh (1973) described this syndrome in the offspring of parents related as first cousins once removed. Another member of the family related as a first cousin to the proband's mother and as a first cousin once removed to the proband's father was identically affected.

Naveed et al. (2006) described an 8-generation consanguineous Arab family with multiple severe limb anomalies resembling ectrodactyly with aplasia of the long bones. Eighteen of 23 affected individuals had tibial aplasia, mostly unilateral and on the right side. Expression of the phenotype was variable and included ectrodactyly, syndactyly, camptodactyly, short femur, and clubfoot, with or without bilateral or unilateral tibial aplasia. The mode of inheritance appeared to be autosomal dominant with reduced penetrance.

Inheritance

Hoyme et al. (1987) described 4 families in which multiple members were affected with ectrodactyly and/or tibial hypoplasia/aplasia; multiple obligate carriers in each family were unaffected. The authors concluded that ectrodactyly associated with long bone deficiency is an autosomal dominant trait with widely variable expression or nonpenetrance.

Both Sener et al. (1989) and Der Kaloustian and Mnaymneh (1973) favored autosomal dominant inheritance with reduced penetrance, despite the consanguinity in these families.

Zlotogora (1994) analyzed published pedigrees with nonsyndromal ectrodactyly and other limb defects (usually tibial aplasia or hypoplasia) in at least one family member. In this group of families, penetrance was only 0.66. Sometimes obligatory carriers of the gene were unaffected for several generations. To explain this phenomenon, Zlotogora (1994) proposed the influence of another gene and raised the possibility of trinucleotide repeat expansion.

Majewski et al. (1996) examined the question of the existence of a recessive form of ectrodactyly and absence (hypoplasia) of the tibia. They presented a kindred of brother, sister, and cousin with ectrodactyly and hypoplasia of the tibia. The parents of the cousin were consanguineous; the parents of the sibs originated from the same small Algerian village. They also reported a boy with tibial defect and split hands and feet with consanguineous parents. Although the observations suggested an autosomal recessive form of ectrodactyly, review of these and previously reported cases did not demonstrate any clinical differences between the seemingly recessive and the dominant types. Statistical analysis of 17 families with affected sibs and normal parents showed a 1:3.1 ratio of affected to unaffected by the proband method. Despite consanguinity among 9 sets of parents, this ratio and data from approximately 30 additional reported families generally favor autosomal dominant inheritance with reduced penetrance.

Witters et al. (2001) presented further evidence for autosomal recessive inheritance. A consanguineous Turkish couple gave birth to 3 children with malformations. The first, a boy, died neonatally of pulmonary hypertension with congenital alveolar capillary dysplasia (265380) and also had tibial agenesis and ectrodactyly. The second child, a girl, died after birth with the same abnormality of the lungs without skeletal malformations. After the birth of 3 unaffected children, echographic examination at 15 weeks of gestation in the sixth pregnancy documented agenesis of the tibias and symmetric ectrodactyly of the hands and feet. Autopsy did not show additional malformations, and lung development was normal for gestational age. This observation also confirmed the autosomal recessive inheritance pattern of congenital alveolar capillary dysplasia.

Naveed et al. (2007) presented evidence for 2 susceptibility loci in the same family, and hypothesized that SHFLD could fit the model of digenic inheritance.

Mapping

One form of ectrodactyly (absence of the middle rays, i.e., the central digits of the hands and/or feet) results from mutation at a locus (SHFM1; 183600) in 7q21.2-q22.1. Marinoni et al. (1994) described a large family in which ectrodactyly was associated with long bone deficiency in the form of aplasia of bones of the lower leg or forearm in an autosomal dominant pattern. Linkage to markers in the 7q21-q22 region was excluded.

Naveed et al. (2006) analyzed 18 microsatellite markers from chromosomes 7p13, 7q36, 8q24.1 and 10q24 in an 8-generation consanguineous Arab family with ectrodactyly and aplasia of the long bones, but found no significant evidence of linkage under both autosomal dominant and recessive models.

Naveed et al. (2007) conducted a genomewide linkage analysis using a 10K SNP array in a large consanguineous family from the United Arab Emirates, previously reported by Naveed et al. (2006), and identified 2 novel SHFLD susceptibility loci, one at 1q42.2-q43 (SHFLD1) and another at 6q14.1 (SHFLD2; 610685). These results were supported by multipoint parametric linkage analysis. Maximum multipoint lod scores of 3.20 and 3.78 were detected for the 2 locations on 1q and 6q, respectively, with the use of an autosomal dominant mode of inheritance with reduced penetrance. Haplotype analysis with informative crossovers enabled mapping of SHFLD1 to a region between single-nucleotide polymorphisms rs1124110 and rs535043 on 1q42.2-q43. Naveed et al. (2007) hypothesized that SHFLD could fit the model of digenic inheritance.

Cytogenetics

Babbs et al. (2007) reported a patient with SHFLD manifested as oligodactyly of the hands with multiple absent phalanges and complete absence of the first ray of the right hand. A single toe was present on each foot, and there was bilateral shortening of the tibiae associated with bilateral patellar dislocation and a bowed fibula on 1 leg. Metaphyses of the femur showed distal flaring. Molecular analysis revealed a de novo translocation t(2;18)(q14.2;p11.2). Characterization of the breakpoints revealed that neither disrupted any known gene. Analysis of several candidate genes within the 2q region showed no abnormalities in 44 additional patients with SHFM, SHFLD, or long bone deficiency. The chromosome 2q14.2 breakpoint coincides with the homologous region of the mouse to which the 'dominant hemimelia' (Dh) limb formation has been mapped (see 131290). Babbs et al. (2007) postulated that the 2q14.2 region may represent a novel locus for SHFLD and that the translocation disrupted a putative long-acting cis regulatory element.