Cleft Lip/palate-Ectodermal Dysplasia Syndrome

A number sign (#) is used with this entry because of evidence that cleft lip/palate-ectodermal dysplasia syndrome (CLPED1) is caused by homozygous mutation in the PVRL1 gene (NECTIN1; 600644) on chromosome 11q23. Mutation in the PVRL1 gene has also been found in a form of orofacial cleft (OFC7).

Zlotogora et al. (1987) reported 2 sibs with a syndrome including cleft lip and palate, sparse scalp hair, malformed protruding ears, and partial syndactyly of the fingers and toes. An older sib also had mental retardation and pili torti. The parents were consanguineous. In 2 Turkish sibs, products of a second-cousin marriage, Ogur and Yuksel (1988) found the combination of tetramelic syndactyly, ectodermal dysplasia, cleft lip and palate, renal anomalies, and mental retardation. In 3 Brazilian brothers and a half brother, all born of first-cousin matings in a Brazilian kindred, Rodini and Richieri-Costa (1990) described a syndrome which they proposed to call the Zlotogora-Ogur syndrome on the basis of the reports by Zlotogora et al. (1987) and Ogur and Yuksel (1988). The features were ectodermal dysplasia, bilateral cleft lip/palate, mental retardation, and syndactyly of fingers 2 and 3.

In the Caribbean island of Margarita off the coast of northeastern Venezuela (Nueva Esparta State), Bustos et al. (1991) identified a form of ectodermal dysplasia in 15 females and 12 males in 7 families, each with considerable consanguinity. It was considered likely that the 7 families were related to each other. The patients had scanty eyebrows and eyelashes, sparse, short and dry scalp hair, and striking changes in the teeth, which showed hypodontia mainly of the upper lateral incisors and changes in size and shape. Cleft lip/palate (in 7), syndactyly of fingers and toes (in 13), and onychodysplasia were often also observed. Males and females were affected to an equal degree, although in general severity was variable. Notably, sweating was normal in all.

Zlotogora (1994) gave a review of the syndrome of syndactyly, ectodermal dysplasia, and cleft lip/palate in which he proposed that the disorder called Zlotogora-Ogur syndrome (Zlotogora and Ogur, 1988) is the same as that reported by Bustos et al. (1991) and referred to here as the Margarita form of ectodermal dysplasia. Mental retardation was present in those families described as having Zlotogora-Ogur syndrome but absent in the Margarita families. Zlotogora (1994) noted that mental development may differ from family to family. Zlotogora (1994) and Rodini and Richieri-Costa (1990) considered this to be a separate disorder from that described by Rosselli and Gulienetti (1961) (see 225000) and from other clefting-ectodermal dysplasia syndromes with limb involvement.

Suzuki et al. (1998) pointed out that Columbus discovered Isla de Margarita, a group of 3 islands in the south-central Caribbean, in 1498 and that one of the earliest Spanish colonies in the New World was established there. They also commented that the philtrum is strikingly broad and flat in many Margarita Island ectodermal dysplasia (ED) obligate heterozygotes, who would be expected to number perhaps 1 in 22 among the indigenous population of the island. The incidence of nonsyndromic cleft lip/cleft palate is quite high on Margarita Island, approximately 5.4 per 1,000. Although this high incidence might result from environmental factors, such as lack of dietary folate, it is also possible that heterozygosity for ED4 constitutes a significant genetic risk factor for nonsyndromic cleft lip/cleft palate on the island.

Suzuki et al. (1998) described linkage disequilibrium mapping of the gene for ED4, using an affected-only DNA-pooling strategy. Haplotype analysis of 4 complex Margarita Island ED4 families localized the ED4 gene to an approximately 1- to 2-Mb interval on 11q23 spanned by just 2 YACS. Suzuki et al. (1998) pointed out that 'rough fur' (ruf) in the mouse is located in the region of chromosome 9 with conserved synteny to 11q24. The ruf locus gives rise to autosomal recessive rough fur and hyperkeratosis, features reminiscent of Margarita Island ED.

In patients with the Margarita type of ectodermal dysplasia, Suzuki et al. (2000) identified a homozygous nonsense mutation in the PVRL1 (600644.0001). The authors suggested that the high frequency of the disorder on Margarita Island may have resulted from resistance of heterozygotes to infection by alpha-herpesviruses. In 2 families from Israel and Brazil described as having Zlotogora-Ogur syndrome, Suzuki et al. (2000) also found homozygous mutations in the PVRL1 gene (600644.0002-600644.0003).

Sozen et al. (2001) demonstrated a highly significant association between heterozygosity for the W185X mutation in the PVRL1 gene (600644.0001) and sporadic, nonsyndromic cleft lip with or without cleft palate in northern Venezuela.