Duane-Radial Ray Syndrome

A number sign (#) is used with this entry because Duane-radial ray syndrome (DRRS) is caused by heterozygous mutation in the SALL4 gene (607343) on chromosome 20q13.

The IVIC syndrome (147750) is an allelic disorder with a similar phenotype.

Description

Duane-radial ray syndrome, also known as Okihiro syndrome, is an autosomal dominant disorder characterized by upper limb anomalies, ocular anomalies, and, in some cases, renal anomalies. The combination of the 3 findings was earlier referred to as 'acro-renal-ocular syndrome.' The ocular anomalies usually include Duane anomaly (see 126800), but this finding may be absent in some patients (Kohlhase et al., 2003). Similarly, renal anomalies are not always seen and may not have been investigated, particularly in cases reported before routine renal imaging (Aalfs et al., 1996). Other less common features include sensorineural deafness and gastrointestinal anomalies, such as imperforate anus.

The Holt-Oram syndrome (142900), caused by mutation in the TBX5 gene (601620) on chromosome 12q24, shows similar anomalies of the upper limb, but can be differentiated from Duane-radial ray syndrome by the absence of ocular and renal anomalies and the presence of severe congenital heart defects (Kohlhase, 2003).

Clinical Features

Ferrell et al. (1966) reported a family in which a father and 3 of his 5 children had radial defects in an autosomal dominant pattern of inheritance. The father and 1 child also had Duane anomaly, 1 child had atrial septal defect without Duane anomaly, and the third had radial defects only. Radial malformations in this family ranged from hypoplasia of the thenar musculature to absence of the thumb and first metacarpal. Ferrell et al. (1966) suggested that the family had both the Duane anomaly and a heart-hand syndrome (likely Holt-Oram syndrome).

Okihiro et al. (1977) reported a family who showed Duane anomaly and hypoplasia of the thenar eminence in 5 persons in 3 generations. One of the 5 had Hirschsprung disease and another was congenitally deaf. A sixth person, without Duane anomaly, had more extensive malformation of the upper limbs and unilateral deafness.

Temtamy et al. (1975) and Temtamy and McKusick (1978) described father and son with some combination of Duane anomaly, radial defects, and kidney anomalies. The father had Duane anomaly, bilateral thenar and thumb hypoplasia with syndactyly of the index finger and unilateral club hand deformity, and malrotation of both kidneys with partial horseshoe anomaly. The son had apparently normal eyes, bilateral club hand with absent thumbs, and absent right kidney with malrotation of the left kidney. Other features included malformed pinnas, pectoral and upper limb hypoplasia, facial nerve weakness, and congenital deafness.

Halal et al. (1984) reported a French-Canadian family in which 7 persons in 3 generations had various combinations of acral, renal, and ocular defects. The acral anomalies varied from mild hypoplasia of the distal part of the thumb with limitation of motion at the interphalangeal joint to severe thumb hypoplasia and preaxial polydactyly. Renal anomalies varied from mild malrotation to crossed renal ectopia without fusion; other urinary tract anomalies were vesicoureteral reflux and bladder diverticula. Ocular features included 'complete' coloboma, coloboma of the optic nerve, ptosis, and Duane anomaly. The disorder showed autosomal dominant inheritance with high penetrance but variable expressivity. Dermatoglyphic abnormalities were described. Halal et al. (1984) noted the considerable phenotypic overlap in their family with the disorder reported by Temtamy and McKusick (1978), but also noted that it differed from the latter family by the absence of pectoral and upper limb involvement.

Hayes et al. (1985) gave the designation Okihiro syndrome to the combination of Duane anomaly, radial ray abnormalities, and deafness. They reported a family in which the proband had fusion of C2 and C3, in addition to Duane anomaly, bilateral hypoplasia of the thenar eminence with inability to flex the interphalangeal joint of the thumb, and severe bilateral sensorineural hearing loss. A sister had hemifacial microsomia, cervical abnormalities, and hypoplasia of the thenar eminence. Four other relatives had thenar hypoplasia; a fifth had preaxial polydactyly. Duane anomaly was present in 2 distant relatives.

MacDermot and Winter (1987) reported a family in which a mother and 2 of her 3 children, a son and a daughter, had bilateral radial defects and absent thumbs transmitted in an autosomal dominant pattern. In addition, Duane anomaly was present in both offspring, one of whom also had anal stenosis.

Pierquin et al. (1991) described another case of acrorenoocular syndrome.

Aalfs et al. (1996) reported an affected family from the Dutch Antilles. The proband had hypoplasia of the right thumb and absence of the left thumb, hypoplastic left forearm, microphthalmia, microcornea, coloboma of iris and choroid, cataract, and left-crossed renal ectopia with fusion. His mother had hypoplastic left thumb and cataract (possibly due to diabetes mellitus). The sister of the proband demonstrated absence of both thumbs, radii and ulnae, and bilateral chorioretinal scars between optic disc and fovea. Urologic investigations could not be done in the proband's mother and sister. The clinical picture in this family was consistent with the acrorenoocular syndrome.

Becker et al. (2002) reported 2 families with an overlapping phenotype of Okihiro syndrome and acrorenoocular syndrome. In 1 family, the proband had severe radial ray defects and Duane anomaly, whereas her mother had radial ray defects, a small left kidney, and sensorineural hearing loss. In the other family, the proband had abnormal thumbs, Duane anomaly, mild hearing loss, and renal anomalies, including pelvicalyceal dilatation and vesicoureteric reflux. Her father had radial ray defects, Duane anomaly, and optic disc hypoplasia. Mutation analysis of the PAX2 gene (167409) showed no mutations. Becker et al. (2002) suggested that Okihiro syndrome and the acrorenoocular syndrome are the same entity.

Kohlhase et al. (2003) observed hypertelorism and epicanthic folds in 2 of their patients and reported previously undescribed slit-like openings of the external auditory meatus. They suggested that this feature may help discriminate Okihiro syndrome from Holt-Oram syndrome if no Duane anomaly is present. They also described characteristic flat feet and large sandal gaps in both affected members of 1 family. As indicated by patients reported by Kohlhase et al. (2003), the diagnosis of this disorder is often missed because the associated Duane anomaly is overlooked in combination with striking limb anomalies, which suggest Holt-Oram syndrome.

Molecular Genetics

Based on the phenotypic overlap between some patients with Okihiro syndrome and those with Townes-Brocks syndrome (107480), Kohlhase et al. (2002) postulated that Okihiro syndrome might result from mutations in a member of the human SALL gene family (see, e.g., SALL1; 602218). In affected members of 5 families with the Okihiro syndrome, Kohlhase et al. (2002) identified 5 different mutations in the SALL4 gene (see, e.g., 607343.0001-607343.0003).

In affected members of the family with Duane-radial ray syndrome originally reported by Okihiro et al. (1977), Al-Baradie et al. (2002) identified a nonsense mutation in the SALL4 gene (R865X; 605343.0005). They also identified 2 additional SALL4 mutations (607343.0004; 607343.0006) in 2 other affected families. The authors suggested that SALL4 plays a critical role in abducens motoneuron development.

There is phenotypic overlap between Okihiro syndrome and Holt-Oram syndrome. Patients with presumed HOS were found by Brassington et al. (2003) to have mutations in the SALL4 gene. In one of these patients, after a mutation in SALL4 was found, the primary care physician reexamined the patient and noted the presence of ophthalmoplegia, making the diagnosis of Okihiro syndrome (Bamshad, 2003). Bamshad (2003) also stated that he had not considered kidney defects typical of HOS and 1 of the 2 SALL4 cases had a pelvic kidney. Kohlhase (2003) did not consider severe congenital heart defects such as those observed in HOS to be part of the Duane-radial ray syndrome.

Kohlhase et al. (2003) found a mutation in the SALL4 gene (607343.0005) in family 1 reported by Becker et al. (2002). The patient had Duane anomaly in addition to the limb and renal changes, indicating that the appropriate diagnosis was Okihiro syndrome. In affected members of family 2 reported by Becker et al. (2002) as having acrorenoocular syndrome, Borozdin et al. (2004) identified a heterozygous deletion of at least 135 kb, including the entire SALL4 gene (607343.0010).

In an Italian child with a mild form of Duane-radial ray syndrome originally reported by Parentin and Perissutti (2003), Miertus et al. (2006) identified a heterozygous missense mutation in the SALL4 gene (H888R; 607343.0012). The mutation was present in the affected father and maternal grandmother, but not in the unaffected mother or twin sister of the proband. The proband had mild features of Duane-radial ray syndrome as well as cranial midline defects, including facial dysmorphism, pituitary hypoplasia, and a single central incisor.

Nomenclature

Temtamy (1986) preferred the designation DR syndrome because she and her colleagues (Temtamy et al., 1975; Temtamy and McKusick, 1978) described and named the disorder earlier than Okihiro et al. (1977) and because D is a mnemonic for Duane and deafness and R for radial and renal.

The designation Duane-radial ray syndrome may be preferable to the Okihiro eponymic designation because it indicates that the disorder represents a combination of Duane anomaly and radial ray abnormalities. Use of the hyphen indicates that Duane anomaly and radial ray abnormalities are separate manifestations of the syndrome, not that this is a second syndrome described by Duane.

History

Duane anomaly with associated deformity of the upper extremities was reported by Crisp (1918), Mennerich (1923), and Gifford (1926).