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The Genetics of Split-Hand/Foot Malformation (SHFM) - A Pakistani Perspective.

Byline: Sher Alam Khan, Muhammad Humayun, Anwar Kamal, Mehran-Ud-Din, Hamid Nawaz, Waheed Ullah, Noor Muhammad and Saadullah Khan


Split-hand/foot malformation (SHFM) is a multifaceted, congenital malformation of rare limb developments including deep median clefts of hands and feet, and aplasia and/or hypoplasia of the phalanges. Highly diverse in its presentation, SHFM can range from mild abnormalities of a single limb to severe defect of all four limbs and can occur as isolated (non-syndromic) or part of a complex syndrome. To date six forms of isolated SHFM harboring autosomal dominant, autosomal recessive and X-linked inheritance has been reported globally. In Pakistan, only autosomal recessive and X-linked families have been reported. The review aims to systematically read and analyze various types of isolated SHFM prevalent in Pakistani population.

Key words: SHFM, Autosomal dominant, recessive, X-linked.


Development of the vertebrate limbs is completed in three phases i.e. initiation of limb bud, early patterning of the limb and late limb morphogenesis. Embryonic limb bud starts limb bud initiation, while different signaling molecules and transcription factors expresses both spatially and temporally for proper patterning of limbs. At the limb initiation stage, limb buds are formed from the lateral plate mesoderm while apical ectoderm ridge (AER) is formed by early limb mesoderm growth1. In the early patterning phase, AER directs proximal/distal limb growth. Patterning of the limb along the anterior-posterior (A/P) axis is performed by zone of polarizing activity (ZPA); while dorsal-ventral polarity is maintained by non-AER limb ectoderm signaling2,3. In late limb morphogenesis phase, skeletal elements, muscles, tendons, blood vessels are formed and mature to make the limb a functional organ4,5.

Split-hand/foot malformation (SHFM) is a multifaceted, congenital malformation of rare limb developments including deep median clefts of hands and feet, and aplasia and/or hypoplasia of the phalanges. Greater variations among phenotypes of SHFM have been observed not only in families originating from different ethnic groups, but also among affected members within the same ethnic groups and also within the same family. Few cases have been reported where within the same individual one extremity was found more affected than the other. SHFM conditions are found both in isolated (non-syndromic) as well as part of a complex syndrome6.

To date six different forms of isolated (non-syndromic) SHFM described in humans. Mode of inheritance of four forms (SHFM-1, SHFM-3, SHFM-4, SHFM-5) is autosomal dominant, SHFM-6 is autosomal recessive while SHFM-2 has X-linked inheritance pattern. Of the 6 SHFM types, to date only three (SHFM1, SHFM4, SHFM6) have been solved at the gene level6. All the SHFM types are discussed below.

Split Hand/Foot Malformation Type 1 (SHFM-1)

Affected individuals of split hand/foot malformation type 1 show absence of central digital rays, deep median clefts, and syndactyly of the digits. It was mapped on the long arm of chromosome at region 2 (7q21-q22) after chromosomal rearrangements7. A microdeletion of region has refined the critical interval to 0.9 Mb, having DSS1, DLX5, and DLX6 as candidate genes8.

Deletions or rearrangements in the genome of two homeobox genes DLX5 and DLX6 are reported to be linked with SHFM-I. The double knockout of Dlx5 and Dlx6 (Dlx5/6 D-KO) in the mouse leads to ectrodactyly in the hind limbs with defective development of the middle portion of AER9.

Recently the actual disease gene dilemma in SHFM-1 was solved by Shamseldinet al10 who studied an autosomal recessive SHFM consanguineous Yemeni family at molecular level and reported a homozygous missense mutation in the gene DLX5. Affected members show complex SHFM phenotype including tibial deficiency, palms dorsalization with cylindrical fingernails, craniofacial dysmorphism,and hearing impairments. To date only a single homozygous missense mutation (c.A533C; p.Gln178Pro) has been reported in the gene DLX5 causing SHFM-110.

Split Hand/Foot Malformation Type 2 (SHFM2)

SHFM-2 is transmitted as X-chromosomal trait and the locus was identified in a seven generations consanguineous Pakistani family characterized by all four limbs involvement with monodactylor bidactyly of both hands and lobster-claw deformities of both feet 11. Later another worker12 linked the family to chromosome Xq26. Finally the family was fine mapped to a 5.1-Mb region interval containing approximately 70 genes on Xq26.313. At least 19 candidate genes have been sequenced in the fine mapped region, however no sequence variant have been identified. To date only a single family of Pakistani origin has been reported as having X-linked inheritance fashion.

Split Hand/Foot Malformation Type 3 (SHFM-3)

Affected individuals of SHFM-3 show phenotype of phalangeal, metacarpals and metatarsalsaplasia and/or hypoplasia. Mode of inheritance of SHFM-3 is autosomal dominant. Several families have been reported showing linkages to a large interval on the large arm of chromosome 10 (10q) 14-16. Researchers have reported that complex rearrangement on chromosome 10q24-q25 around the Dactylyn locus is possibly associated with gene inactivation17, however no demonstration yet is reported that dactylyn is the disease gene for SHFM-3. Notably, this locus in humans was known to be similar to the locus in mice causing the Dactylaplasia (Dac) phenotype, which comprises of absence of the central digits with clefts or monodactyly and thus closely resembles human SHFM. Several genes in limb development are known to be involved in the duplicated segments at the SHFM-3 locus and the nearby region. However till to date in humans, the precise mechanism by which the duplications cause SHFM and other associated phenotypes is unknown.

To date no such type of Pakistani family has been reported showing linkage to SHFM-3.

Split Hand/Foot Malformation Type 4 (SHFM-4)

SHFM-4 exhibit variable phenotype of split hands and feet malformation with missing phalanges, metacarpals and metatarsals along with or without syndactyly and webbing. SHFM-4 has also autosomal dominant inheritance pattern. Mutation in the gene p63, coding for a transcription factor homologous p53 and p73 having been reported to cause SHFM-418-20. Ianakiev et al.18 reported two missense mutations (c.724AG; c.982TC) in the gene p63 in two African families.

The gene TP63 (tumor protein p63, MIM 603273) lies on chromosome 3q27, encodes a homolog of the tumor suppressor. p63, a homologue of the cell-cycle regulator TP53 and plays a critically important role in regulation of the formation and differentiation of apical ectoderm ridge (AER).

Split Hand/Foot Malformation Type 5 (SHFM5)

Affected members show severe limb malformation in all four limbs. Individuals of SHFM-5 have stylopod, zeugopod and autopod in their limbs. Mode of inheritance is autosomal dominant. It was mapped on chromosome 2 with a genetic address of 2q31 21. The linked region includes closely related genes DLX1 and DLX2 with no pathogenic sequence variants yet reported 22. The double knockout of Dlx5 and Dlx6 (Dlx5/6 D-KO) in the mice causes ectrodactyly in the hind limbs with defective development of the middle portion of the apical ectoderm ridge (AER)23,24. Due to haplo insufficiency of the 5 HOXD, EVX2, or DLX1 and DLX2 genes, SHFM-5 and other digit defects may be caused25.

Split Hand/Foot Malformation Type 6 (SHFM-6)

Affected members have great phenotypic variability with some individuals having only complete and incomplete cutaneous, pre-axial and postaxial syndactyly and pre-axial and postaxial polydactyly. Several others individuals have fusion, hypoplasia and aplasia of fingers and toes, duplication of fingers, dysplastic hands, classical cleft hands and classical cleft foot 26-29. SHFM-6 has autosomal recessive inheritance. Ugur and Tolun 26 reported a multi generation consanguineous Turkish family having autosomal recessive inheritance with reduced penetrance showing typical SHFM phenotypes. By using several microsatellite markers, genotyping data and haplotype analysis established linkage in the family to SHFM-6 locus on chromosome 12 with a genetic address of 12q11-q13.

WNT10B gene was selected and sequenced as best candidate gene in the linked region and reported the first mutation (p.Arg332Trp) in the gene. Mutation p.Arg332Trp was detected in the homozygous state in all SHFM individuals as well as in an unaffected individual of the same family. The authors proposed a model suggesting either the contribution of a second locus or the presence of a suppressor mutation in the non-penetrant individual. A sporadic case was reported having homozygous 4-bp duplication (c.458_461dupAGCA) mutation in a Swiss woman27. A missense homozygous mutation p.Thr329Arg was identified in a multigenerational large consanguineous Pakistani family28. Recently Aziz et al. 29 reported three Pakistani families from Khyber Pakhtunkhwa province harboring 4-bp deletion mutation (c.1165_1168delAAGT) in a family and 7-bp duplication mutation (c.300_306dupAGGGCGG) in two other families.

To date five mutations including three from Pakistani population have been reported all over the world causing SHFM6 phenotypes.

The gene WNT10B consists of five exons, encodes aprotein of 389 amino acid sand spanning 6.42 Kbp of genomic DNA on chromosome 12q13.12. The WNT10B is a member of WNT genes of which 19 members are known in mammals. The WNT proteins act as ligands for cell surface receptors complexes composed of frizzled (FZ) and low-density lipoprotein receptor-related protein 5/6 family members. Downstream of these complexes, WNT signaling is involved in translocation of AY-catenin to the nucleus and binds to several transcription factors. As a result several genes are transcribed and involved in proliferation and osteoblastogenesis30. Wnt10b expresses in several stem cell compartments including bone marrow, postnatal growth plate and osteoblastic precursors31,32. Stevens et a33 have studied the role of Wnt10b in null mice and concluded that both alleles of the gene are required for maintenance of adult bone density and loss of Wnt10b results in reduction of the numbers of bone marrow-derived mesenchymal progenitors.

Social customs in Pakistan, including large family size as well as inbreeding, both within isolated villages and among relatives, create a high genetic burden for the population. Consequently, large pedigrees with unique inherited disorders, including SHFM, are more common in Pakistan than in many other countries. Large families allow the inheritance pattern to be unequivocally determined, allow each phenotype and its variability to be well described, and allow the natural history of each disorder to be documented.

The SHFM phenotypes have more variations among affected individuals of the families grading from complete and incomplete cutaneous, pre-axial and postaxial syndactyly and pre-axial and postaxial polydactyly to classical cleft hands and classical cleft foot.

In several cases, obligate carriers of autosomal dominant SHFM showed

no phenotypic abnormalities (reduced penetrance). The phenomenon of variable expressivity was also observed in the families with autosomal recessive SHFM described too26,27 29. However in Pakistani families reported by Khan et al 28 along with other variable phenotypes reported earlier, additional phenotypes like absence of fingers and thumbs were also reported.

High rate of consanguineous marriages among various ethnic groups in Pakistan is mainly responsible for causing genetic disorders. Characterizing the clinical spectrum resulting from mutations in the genes causing SHFM deformities will improve diagnosis and can direct clinical care of the family members. Localization of the disease gene and mutational data will be helpful in identifying carriers of recessive and X-linked disorders in individual family members and with a population. Data about genetic disorders should be accumulated which will provide more detailed information about disease pathogenesis, carrier screening, genetic counseling and DNA based diagnosis.


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Publication:Pakistan Journal of Medical Research
Article Type:Report
Date:Jun 30, 2015
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