Otopalatodigital Syndrome, Type I

A number sign (#) is used with this entry because otopalatodigital syndrome type I (OPD1) is caused by gain-of-function mutations in the gene encoding filamin A (FLNA; 300017) on chromosome Xq28.

Description

Otopalatodigital syndrome-1 is 1 of 4 otopalatodigital syndromes caused by mutations in the FLNA gene. The disorders, which include frontometaphyseal dysplasia (FMD1; 305620), otopalatodigital syndrome-2 (OPD2; 304120), and Melnick-Needles syndrome (MNS; 309350), constitute a phenotypic spectrum. At the mild end of the spectrum, males with OPD1 have cleft palate and mild skeletal anomalies with conductive deafness caused by ossicular anomalies. FMD is characterized by a generalized skeletal dysplasia, deafness and urogenital defects. Males with OPD2 have disabling skeletal anomalies in addition to variable malformations in the hindbrain, heart, intestines, and kidneys that frequently lead to perinatal death. The most severe phenotype, MNS, is characterized by a skeletal dysplasia in the heterozygote. Affected males exhibit severe malformations similar to those observed in individuals with OPD2, resulting in prenatal lethality or death in the first few months of life (review by Robertson, 2005). Verloes et al. (2000) suggested that these disorders constitute a single entity, which they termed 'frontootopalatodigital osteodysplasia.'

Clinical Features

Dudding et al. (1967) described 3 male sibs with conduction deafness, cleft palate, characteristic facies, and a generalized bone dysplasia. A broad nasal root gives the patient a pugilistic appearance. Wide-spacing of the toes creates a resemblance to the foot of a tree frog. X-linkage and autosomal inheritance could not be distinguished. Roentgenologic features were reviewed in the same patients by Langer (1967). (The male patient reported by Taybi (1962) may have had this condition.) Conductive hearing loss, somewhat broad thumbs and great toes, short fingernails, fifth finger clinodactyly, dislocation of the head of the radius, pectus excavatum, and mild dwarfism were also features. A secondary ossification center at the base of the second metacarpal and metatarsal is characteristic.

Turner (1970) observed affected half brothers who had different fathers, thus supporting X-linked inheritance. Weinstein and Cohen (1966) suggested that an X-linked form of cleft palate exists. Affected males and carrier females showed hypertelorism and median frontal prominence. Four males in 3 sibships connected through 5 presumably heterozygous females were affected. Gorlin (1967) suggested that the condition in this family was the OPD syndrome. The x-ray changes in the hands and feet were consistent (Gorlin, 1971). Gall et al. (1972) and Poznanski et al. (1974) demonstrated heterozygote changes in radiographs of the hands and feet.

Pazzaglia and Beluffi (1986) described a family with affected persons in 4 generations. Severe scoliosis was present in 1 patient, a feature that apparently had not previously been reported in the OPD syndrome. Also in this family, there was no deafness or cleft palate. On the other hand, many of the skeletal findings were thought to be characteristic. The pedigree was consistent with X-linked inheritance with variable and intermediate expression in the female.

Rosenbaum et al. (1986) described a family with affected mother, son, and daughter; in only the male was the expression complete. The mother was related to her husband as a first cousin. Another couple, both of whom were related to this man and his wife as first cousins, had 3 children thought to have Larsen syndrome (245600), manifest by congenital dislocation of the hips and knees associated with flattened facies.

Le Marec et al. (1988) described a family with affected persons in 5 generations. They suggested that the disorder called OPD II (304120) by Fitch et al. (1983) might be allelic.

Kozlowski (1993) pointed out that long second metacarpal and fifth metatarsal are typical in OPD I. Extracarpal bones occur as in Larsen syndrome, particularly typical changes at the elbow and especially a deepened fossa at the proximal ulna. Kozlowski (1993) emphasized that OPD I, a relatively common bone dysplasia, can have very subtle clinical and radiologic expression that may go unnoticed until the disorder is recognized in a more severely affected member of the family. OPD II, on the other hand, is a severe disorder. Gorlin (1993) indicated that mental retardation is not a feature of OPD I.

Verloes et al. (2000) reported a mild case of OPD2, a severe case of OPD2 with anomalies of the central nervous system and some manifestations of frontometaphyseal dysplasia, a lethal case of OPD2 with similarities to Melnick-Needles syndrome, and 3 unrelated boys born to mothers with MNS (1 with a severe form, 1 with a lethal form, and an aborted fetus). They reviewed the features in these disorders and in OPD1 and suggested that these disorders constitute a single entity, which they called 'fronto-otopalatodigital osteodysplasia.' Verloes et al. (2000) also discussed the relationship to similar syndromes, such as Yunis-Varon syndrome (216340), type III atelosteogenesis (108721), and boomerang dysplasia (112310).

Morava et al. (2003) described 2 families in which both males and females showed the facial and skeletal characteristics of FMD in association with severe progressive scoliosis. Some also had hearing loss and urogenital anomalies, leading Morava et al. (2003) to suggest that these were examples of frontootopalatodigital osteodysplasia as described by Verloes et al. (2000).

Mapping

In studies of a 3-generation family with OPD1, Hoo et al. (1991) and Hoar et al. (1992) found a suggestion of linkage to DNA markers on the distal long arm of the X chromosome. Studies of another family by Biancalana et al. (1991) excluded linkage to the Xq26 region and provided further support for mapping of the OPD1 gene to Xq28. A combined lod score of 3.19 was reported.

Robertson et al. (2001) found linkage of the more severe, frequently lethal phenotype, termed OPD2, to the same region of distal Xq28 to which the OPD1 locus had been mapped. This provided support for allelism between OPD1 and OPD2. Furthermore, it was possible to reduce the size of the disease interval to 1.8 to 2.1 Mb. They demonstrated that female carriers of OPD2 exhibited skewed inactivation that segregated with the high-risk haplotype and may be inversely related to the severity with which they manifest features of the disorder.

Molecular Genetics

Robertson et al. (2003) demonstrated that OPD1 is caused by gain-of-function mutations in the gene encoding filamin A (FLNA; 300017). They also demonstrated FLNA mutations in OPD2.

In a 26-year-old Mexican female with OPD1, Hidalgo-Bravo et al. (2005) identified a heterozygous missense mutation in the FLNA gene (300017.0020). The patient had prominent features of OPD1, including cleft palate; an extremely skewed pattern of X inactivation toward the maternal allele was noted.

Robertson et al. (2006) identified a mutation in the FLNA gene (300017.0009) in 2 brothers with OPD1. The mutation was not identified in leukocytes of the mother, suggesting germline mosaicism. The authors emphasized the importance of the finding for genetic counseling.

In 6 females with cranial hyperostosis and various skeletal abnormalities from a 4-generation pedigree, Stefanova et al. (2005) identified heterozygosity for a deletion in the FLNA gene (300017.0016). The phenotype of affected females resembled FMD with some overlap to OPD1 and OPD2, but no signs specific for MNS. However, males had severe extraskeletal malformations and died early, thus constituting an overlap with OPD2 and MNS. Stefanova et al. (2005) concluded that the disorder in this family is best described as an intermediate OPD-spectrum phenotype that bridges the FMD and OPD2 phenotypes.

Zenker et al. (2006) described a de novo mutation in the FLNA gene (300017.0022) in a girl with manifestations of FMD and OPD1.