Cenani-Lenz Syndactyly Syndrome

A number sign (#) is used with this entry because Cenani-Lenz syndactyly syndrome (CLSS) is caused by homozygous or compound heterozygous mutation in the LRP4 gene (604270) on chromosome 11p11.

Clinical Features

Cenani and Lenz (1967) described 2 brothers with a form of syndactyly resembling that of Apert syndrome (101200). However, additional features were severe shortening of the ulna and radius with fusion, fusion of the metacarpals and 'disorganization' of phalangeal development. The feet were less severely affected. They identified similar cases reported by Liebenam (1938), Borsky (1958), and Yelton (1962).

Yelton (1962) observed concordantly affected like-sex twins. Lenz and Cenani later reported another pair of affected sibs; their parents were consanguineous.

Drohm et al. (1976) reported an affected 7-year-old girl. Pfeiffer and Meisel-Stosiek (1982) reported affected brothers; one of them had 2 daughters, each by a different woman.

Elcioglu et al. (1997) described this disorder in a 4.5-year-old boy from a consanguineous Turkish family. The digital anomalies consisted partly of synostosis and partly of malformations of the phalanges. Although there was no radioulnar synostosis or abnormality of the bones of the feet, the findings were considered comparable to those described in the Cenani-Lenz type syndactyly. Dermatoglyphic features were described and correlated with the bony malformations.

Seven et al. (2000) reported a 16-month-old girl who had small spoon-like hands with complete syndactyly of all fingers, nail fusion, absent thumbs, syndactyly of the second through fifth toes on the right and of the second and third on the left, and scoliosis of the thoracic vertebral column. Radiography revealed bilateral radioulnar synostosis, with only 2 carpals on the right hand and 3 on the left, and complete disorganization of metacarpals and phalanges, with metacarpals represented by 4 bony masses on the right and 3 on the left. The right foot had synostosis between the fourth and fifth metatarsals and between the third and fourth proximal phalanges, and the left foot had only 4 metatarsal bones, and the fourth metatarsal was broad and short. There was scoliosis of the thoracic spine, and hemivertebrae at T10, T11, and T12, as well as rib abnormalities including a fork-like fifth rib, a thickened eighth rib, and wide separation between the sixth and seventh ribs. On CT scan, diastometamyelia was noted at T12. The patient also had mixed hearing loss. Dermatoglyphic examination revealed bilateral absence of axial triradius t and transverse alignment of the ridges of the proximal palm.

Bacchelli et al. (2001) described Cenani-Lenz syndactyly in the offspring of first-cousin Asian parents. In addition to striking and characteristic limb changes, ultrasound showed bilateral renal hypoplasia. The limb abnormalities in Cenani-Lenz syndactyly closely resemble those found in a recessive mouse mutant, 'limb deformity' (ld). Renal hypoplasia or agenesis is an associated feature of the mouse mutant, which is known to be due to mutations in the formin gene (FMN1; 136535). A downstream target of formin is gremlin (GREM1; 603054), which encodes a secreted BMP (bone morphogenetic protein) antagonist whose expression is lost in ld mice. Formin maps to 15q13-q14; gremlin lies in the same chromosomal region. Since the parents were first cousins, the child was likely to be homozygous by descent for a mutation in the gene underlying Cenani-Lenz syndactyly. Therefore, Bacchelli et al. (2001) carried out haplotype analysis of the patient and her parents using 9 polymorphic markers from a 12-cM interval on 15q13-q14 that contains both the formin and the gremlin genes. The patient proved to be heterozygous for all 9 markers, thereby excluding a recessively-acting inherited-by-descent mutation in either of these 2 genes as the cause of limb and renal abnormalities.

Temtamy et al. (2003) reported 2 probands with typical features of Cenani-Lenz syndactyly who also had similar mild facial dysmorphism: a high broad, prominent forehead, hypertelorism, a depressed nasal bridge, downslanting palpebral fissures, a short nose, a short prominent philtrum, and malar hypoplasia. Both sets of parents were consanguineous. In 1 family, the proband had a similarly affected brother and father; however, the father's parents were also consanguineous, suggesting quasidominant inheritance. In the other family, there was a similarly affected sib who also had genital anomalies and cleft palate.

Percin and Percin (2003) reported a 29-year-old woman who had Cenani-Lenz syndactyly associated with duplication of the distal phalanges of the first and second toes of the right foot and proximal phalangeal duplication of the first toe of the left foot. In addition, the patient had right congenital cataract and a history of systemic lupus erythematosus. The patient's mother had hypoplastic middle and distal phalanges of the second through fifth toes of both feet; and a 15-year-old niece, who was born of consanguineous parents, had 4 fingers on each hand with synostosis of all the phalanges of the third and fourth fingers, and partial soft tissue syndactyly of the right second and third toes.

Jarbhou et al. (2008) described a girl with Cenani-Lenz syndactyly who had facial dysmorphism consisting of prominent forehead, deep-set eyes, low-set ears, retrognathia, high-arched narrow palate, short-beaked nose, and high nasal bridge. Abdominal ultrasound showed that the right kidney was hypoplastic and ectopic. Additional, previously unreported, features in this patient included congenital hypothyroidism, laryngomalacia, and congenital dislocation of the hips. Jarbhou et al. (2008) proposed that Cenani-Lenz syndactyly be reclassified as a syndromic form of syndactyly.

Li et al. (2010) examined affected individuals from 14 families with Cenani-Lenz syndactyly syndrome (CLSS), 6 of which had been previously reported (Elcioglu et al., 1997; Seven et al., 2000; Bacchelli et al., 2001; Temtamy et al., 2003; Percin and Percin, 2003; and Jarbhou et al., 2008). There was mild facial dysmorphism in the majority of CLS cases, with prominent forehead, hypertelorism, downslanting palpebral fissures, and micrognathia. Typical limb malformations included total to partial syndactyly of hands and feet, as well as distal bone malformations affecting the radius and ulna in addition to the metacarpal and phalangeal bones. Li et al. (2010) noted that kidney anomalies, including renal agenesis and hypoplasia, were present in more than 50% of families.

Mapping

Li et al. (2010) performed homozygosity mapping in 6 consanguineous families with Cenani-Lenz syndactyly syndrome, including the families previously reported by Elcioglu et al. (1997), Seven et al. (2000), Bacchelli et al. (2001), Temtamy et al. (2003), and Percin and Percin (2003), and obtained a combined parametric lod score of 7.46 at a 19.7-Mb region between SNPs rs1346671 and rs490192 on chromosome 11p11.2-q13.1. Li et al. (2010) considered the LRP4 gene to be a highly relevant positional and functional candidate gene.

Molecular Genetics

In 14 unrelated consanguineous families with Cenani-Lenz syndactyly syndrome, Li et al. (2010) sequenced the candidate gene LRP4 and identified homozygous and compound heterozygous missense and splice site mutations (see, e.g., 604270.0001-604270.0008) that segregated with disease in 12 of the families, including the families previously reported by Elcioglu et al. (1997), Seven et al. (2000), Bacchelli et al. (2001), Temtamy et al. (2003), Percin and Percin (2003), and Jarbhou et al. (2008). The fact that LRP4 mutations were not found in 2 CLSS families suggested further locus heterogeneity.

For discussion of a possible role of variation in the APC gene in Cenani-Lenz syndrome, see 611731.0052.