Donnai-Barrow Syndrome

A number sign (#) is used with this entry because Donnai-Barrow syndrome is caused by homozygous or compound heterozygous mutation in the LRP2 gene (600073) on chromosome 2q31.

Description

The faciooculoacousticorenal (FOAR) syndrome was first described as comprising facial anomalies, ocular anomalies, sensorineural hearing loss, and proteinuria. Facial features include prominent brow, short nose, and hypertelorism, and ocular anomalies include myopia, iris hypoplasia, and/or retinal detachment (Regenbogen and Coscas, 1985). Donnai-Barrow syndrome (DBS) was first described as a distinct disorder characterized by diaphragmatic hernia, exomphalos, absent corpus callosum, myopia, and sensorineural deafness. The classic distinguishing features between the 2 disorders were presence of proteinuria and absence of diaphragmatic hernia and corpus callosum anomalies in FOAR (Donnai and Barrow, 1993). However, early reports noted that the 2 disorders shared many phenotypic features and may be identical (e.g., Devriendt et al., 1998). Although there is variability in the expression of some features (e.g., agenesis of the corpus callosum and proteinuria), the disorders are now considered to represent the same entity (Kantarci et al., 2007).

Clinical Features

Murdoch and Mengel (1971), Holmes and Schepens (1972), and Ozer (1974) independently reported a brother and sister with a syndrome of ocular and facial anomalies, telecanthus, perceptive deafness, epiphyseal dysplasia of the femoral heads, and proteinuria. Myopia and both telecanthus and true hypertelorism were present. Fraser (1976) described a single case with proteinuria.

Donnai and Barrow (1993) described 2 unrelated patients, a male and a female, with a syndrome of diaphragmatic hernia, exomphalos, hypertelorism, agenesis of the corpus callosum, severe sensorineural deafness, and severe myopia. One child had iris coloboma and retinal detachment. Monitoring of subsequent pregnancies in both families revealed a further affected fetus in each. In a note added in proof, Donnai and Barrow (1993) indicated that a third affected child, a female in a possibly related family, had been identified. The authors suggested autosomal recessive inheritance.

Gripp et al. (1997) described a male infant, the offspring of first-cousin parents from Saudi Arabia, who had wide anterior fontanel and metopic suture with frontal bossing, hypertelorism, downslanting palpebral fissures, bilateral iris coloboma, omphalocele, and bilateral absence of the diaphragm with herniation of internal organs causing pulmonary hypoplasia and death. Autopsy also showed intestinal malrotation. The findings were considered consistent with the syndrome described by Donnai and Barrow (1993).

Schowalter et al. (1997) reported an 11-year-old boy with FOAR syndrome. He had iris coloboma, iris hypoplasia, macular hypoplasia, cataract, high myopia, retinal detachment, moderate sensorineural hearing loss, and proteinuria without aminoaciduria. Facial features included prominent brow, flat nasal bridge, hypertelorism, and downslanting palpebral fissures. In contrast to the previously reported patients, he had normal intellect and was learning Braille.

Devriendt et al. (1998) reported a male infant with hypertelorism, severe myopia, sensorineural deafness, diaphragmatic hernia, and proteinuria. Other features included large anterior fontanel, depressed nasal bridge, downslanting palpebral fissures, and delayed development. The proteinuria was nonselective and did not include glucose or amino acids. Although the child did not have agenesis of the corpus callosum or exomphalos, the authors concluded that FOAR and Donnai-Barrow syndrome are the same entity. Devriendt et al. (1998) postulated that the brothers reported by Ohlsson (1963) may have had the same syndrome.

Avunduk et al. (2000) reported a male child, born of consanguineous parents, who had exomphalos, agenesis of the corpus callosum, right iris coloboma, high myopia, retinal anomalies, and sensorineural deafness. Facial features included prominent forehead, long nose, downslanting palpebral fissures, and hypertelorism. There was no evidence of diaphragmatic hernia or heart defects. The authors noted the striking similarities to the patients reported by Donnai and Barrow (1993). The report confirmed autosomal recessive inheritance.

Chassaing et al. (2003) reported Donnai-Barrow syndrome in 2 sets of sibs and in an unrelated child, with features including diaphragmatic hernia, exomphalos, absent corpus callosum, hypertelorism, myopia, and sensorineural deafness. Kantarci et al. (2007) reported follow-up of 1 affected girl reported by Chassaing et al. (2003). At age 6 years, she was legally blind with mild developmental delay, but was learning Braille. She had a nonacidotic proximal tubulopathy.

Kantarci et al. (2007) reported a large consanguineous family from the United Arab Emirates in which 5 sibs had Donnai-Barrow syndrome. The proband had characteristic cranial features and died of complications of congenital diaphragmatic hernia. Four surviving sibs had variable clinical features, including diaphragmatic eventration with pulmonary hypoplasia, omphalocele, sensorineural deafness, agenesis of the corpus callosum, hypertelorism, high myopia, large anterior fontanel, and developmental delay. One child also had retinal dystrophy, scoliosis, rib and vertebral anomalies, and short sternum. Imaging of 1 child showed numerous brain anomalies, including partially empty sella turcica, small pons, periventricular nodular heterotopia, small optic nerves and chiasm, ocular colobomas, and malformation of the left horizontal semicircular canal and vestibule. Urine samples from affected individuals showed proteinuria with spillage of retinol-binding proteins (see RBP1, 180260) and vitamin D-binding proteins (see DBP, 139200).

Inheritance

Donnai-Barrow syndrome usually shows an autosomal recessive mode of inheritance. Kantarci et al. (2008) reported a 9-year-old boy with classic features of the disorder due to a homozygous truncating mutation in the LRP2 gene resulting from paternal uniparental isodisomy for chromosome 2. The unaffected mother did not carry the mutation. The boy did not have expanded features, suggesting that paternal chromosome 2 is unlikely to carry imprinted genes affecting growth or development. Kantarci et al. (2008) noted the implications for genetic counseling in this family.

Mapping

By linkage analysis of several families with Donnai-Barrow syndrome, Kantarci et al. (2007) identified an 18-Mb candidate region on chromosome 2q23.3-q31.1 (maximum 2-point lod score of 4.31 and multipoint lod score of 6.24 between D2S1767 and D2S142).

Molecular Genetics

In 4 affected sibs with Donnai-Barrow syndrome from the United Arab Emirates, Kantarci et al. (2007) identified a homozygous mutation in the LRP2 gene (600073.0001). Kantarci et al. (2007) also identified pathogenic mutations in the LRP2 gene in affected individuals reported by Donnai and Barrow (1993) (600073.0004-600073.0006) and Chassaing et al. (2003) (see, e.g., 600073.0002-600073.0003).

Kantarci et al. (2007) identified mutations in the LRP2 gene (600073.0007; 600073.0008) in a Belgian child reported by Devriendt et al. (1998) as having faciooculoacousticorenal syndrome. The findings confirmed that FOAR and Donnai-Barrow syndrome are the same entity.