Chromosome 2q35 Duplication Syndrome

A number sign (#) is used with this entry because syndactyly type I and Philadelphia-type craniosynostosis are caused by different-sized duplications on chromosome 2q35.

Clinical Features

Lueken (1938) reported syndactyly I in 18 males and 29 females of 5 generations illustrating the various degrees of expressivity of the same gene. The author stated that there were no other symptoms of degeneration or malformation in any members of the family. See MOLECULAR GENETICS.

Hsu (1965) described bilateral syndactyly in 6 generations of a Chinese family. Of the 31 descendants of one syndactylous woman, 22 were affected. Skin and bony fusion of the distal phalanges of the third, fourth and fifth fingers were present. At least one person also showed union of the third, fourth, and fifth toes.

Montagu (1953) described a 4-generation family of German origin in which 10 individuals had syndactyly of ring and middle fingers of one hand. No description or radiographs of the feet were given. Whereas Montagu (1953) suggested that the inheritance in this family was X-linked dominant, Temtamy and McKusick (1978) included this family with the discussion of autosomal dominant type I syndactyly.

In a collaborative Latin-American study, Castilla et al. (1980) reported an incidence of syndactyly (without other associated limb anomalies, Poland complex, or amniotic bands) in 174 of 599,109 consecutive newborn infants (3 per 10,000). In 133, syndactyly was the only diagnosed anomaly. The most common type was isolated syndactyly of toes 2 and 3 (70 cases); it affected more males than females and had a higher than expected frequency in infants of white non-Latin-European ancestry. The second most frequent form was isolated syndactyly of fingers 3 and 4 (18 cases), and the third was isolated syndactyly of toes 4 and 5 (13 cases). All 3 types fall into the category of type I syndactyly, or zygodactyly.

Craniosynostosis, Philadelphia Type

Robin et al. (1996) described a form of acrocephalosyndactyly that they referred to as craniosynostosis, Philadelphia type. They reported on a 5-generation kindred segregating sagittal craniosynostosis and syndactyly of the fingers and toes in an autosomal dominant manner. It was clearly distinct from other craniofacial syndromes with involvement of the limbs. The hands were involved in a mitten-like syndactyly resembling those of Apert syndrome (101200). However, the absence of significant bony syndactyly and other bony anomalies distinguished the hands and feet in this family from those seen in Apert syndrome. See MOLECULAR GENETICS.

Classification of Syndactyly

From the medical literature and from their own experience, Temtamy and McKusick (1978) concluded that there are at least 5 phenotypically different types of syndactyly involving the hands, with or without foot involvement. All are inherited as autosomal dominant traits and within any pedigree there is uniformity of type of syndactyly, allowing for the variation characteristic for dominant traits. These genetic types of syndactyly have to be differentiated from syndactyly associated with congenital amniotic bands for which there is little or no evidence of a genetic basis. In this common type of syndactyly, sometimes called zygodactyly, there is usually complete or partial webbing between the third and fourth fingers, which is occasionally associated with fusion of the distal phalanges of these fingers. Other fingers are sometimes also involved, but the third and fourth fingers are the most commonly affected. In the feet there is usually complete or partial webbing between the second and third toes. Sometimes only the hands are affected and sometimes only the feet.

The Temtamy and McKusick (1978) classification of isolated, nonsyndromic polydactyly and syndactyly was based on a logical anatomic approach. As pointed out by Winter and Tickle (1993), considerable advances in the molecular embryology of the developing limb bud may adumbrate a molecular classification. These advances include the proposal that retinoic acid and/or related retinoids are the morphogens responsible for the morphogenetic gradient giving rise to anterior-posterior pattern formation of the limb bud, the suggestion that the HOX4 complex and other homeotic genes are involved in patterning, and a greater understanding of other mechanisms such as programmed cell death (apoptosis) in the shaping of the final hand and foot.

Malik et al. (2005) proposed a protocol for simplifying clinical typing of syndactylies.

Malik et al. (2005) proposed to group type I syndactyly into 4 subtypes, which are all autosomal dominantly inherited. Subtype 1, zygodactyly (cutaneous webbing of second and third toe without hand involvement), is the mildest and most common form. The phenotype varies from unilateral minor expression of webbing to bilateral complete webbing of second and third toe including a fusion of nails. Bony involvement is never observed. See 609815. Subtype 2 is characterized by bilateral cutaneous and/or bony webbing of third and fourth fingers and of second and third toes. The phenotype maps to chromosome 2q34-q36 and is designated SD1 (for syndactyly 1). The hallmark of subtype 3 is bilateral cutaneous and bony webbing of the third and fourth fingers, while subtype 4 shows bilateral cutaneous webbing of fourth and fifth toes. Both subtypes 3 and 4 are rare entities.

Inheritance

Schofield (1921) presented a pedigree that suggested holandric inheritance to Castle (1922). Stern (1957) was unable, however, to obtain further evidence of same and suggested that inheritance is autosomal dominant. Straus (1926) supported the latter mode of inheritance.

Mapping

In a large, 8-generation German family segregating syndactyly type I, originally described by Lueken (1938), Bosse et al. (2000) found evidence of linkage of the disorder, which the authors designated SD1, to chromosome 2q34-q36 (maximum lod score of 12.40 for marker D2S301).

Ghadami et al. (2001) confirmed linkage of syndactyly type I to the 2q34-q36 region in an Iranian family in which 33 members in 6 generations were affected. Linkage analysis of 15 affected and 16 unaffected persons in this family gave a maximum lod score of 6.92 for marker D2S2179.

By genomewide linkage analysis of a large family with the Philadelphia type of craniosynostosis reported by Robin et al. (1996), Jain et al. (2008) found evidence suggestive of linkage to a region on chromosome 2q35-q36.3 (parametric lod score of 2.40; multipoint nonparametric lod score of 8.50) that overlapped with that observed for syndactyly type I, which shows phenotypic similarity. In this family, the locus for Philadelphia craniosynostosis spanned from D2S2361 to D2S2297. Assuming that the 2 disorders could be caused by the same gene, a narrowing of the interval using both phenotypes yielded a 5.1-Mb minimum common region from D2S2319 to D2S344.

Heterogeneity

Malik et al. (2005) presented clinical and molecular data on a large Pakistani family with zygodactyly that was mapped to a new locus on 3p21.31 by genomewide linkage analysis. Malik et al. (2005) defined zygodactyly as a subtype of syndactyly I in which there is not hand involvement. See ZD1 (609815). In an unrelated German family, Malik et al. (2005) found that zygodactyly was linked to neither 2q34-q36 nor 3p21.31.

Molecular Genetics

In a large German family with 77 affected members segregating autosomal dominant syndactyly over 8 generations, originally reported by Lueken (1938), Klopocki et al. (2011) performed array CGH and identified a 59-kb microduplication at the IHH (600726) locus on chromosome 2q35, involving the entire IHH gene plus 49 kb upstream of the IHH start site. In addition, 2 families with craniosynostosis and syndactyly, 1 of which was the 5-generation kindred reported by Robin et al. (1996), were also found to have microduplications, both upstream of the IHH gene. The 3 duplications, which all cosegregated with disease in the respective families, overlapped in a 9.1-kb region located 40 kb 5-prime of the IHH gene, within a large intron of the neighboring NHEJ1 gene (611290) that contains a highly conserved noncoding element (CNE). The smallest region of overlap between the 2 families with craniosynostosis and syndactyly extended 14.6 kb and encompassed 3 CNEs. Klopocki et al. (2011) noted that the limb phenotypes were very similar in all 3 families, and that the patients did not show any phenotypic overlap with known IHH-associated phenotypes. Studies in transgenic mouse embryos demonstrated that the involved CNEs drive reporter gene expression in a pattern highly similar to wildtype Ihh expression, suggesting that the critical duplicated region within the NHEJ1 gene serves as a long-range enhancer of IHH, specifically regulating IHH expression during endochondral bone formation. Klopocki et al. (2011) postulated that the observed duplications lead to misexpression and/or overexpression of IHH, thereby affecting the complex regulatory signaling network during digit and skull development.

History

The term zygodactyly for cutaneous webbing of toes 2 and 3 without hand involvement originated with Weidenreich (1924). Authors who wrote on the inheritance of zygodactyly in the past include Lionel Penrose (1946).