Donnai-Barrow syndrome is a rare autosomal recessive disorder marked by the presence of diaphragmatic hernia, exomphalus, absent corpus callosum, hypertelorism, myopia, and sensorineural deafness. In addition to congenital diaphragmatic hernia and agenesis of the corpus callosum, Donnai-Barrow syndrome is characterized by facial dysmorphism, including a severe hypertelorism with downslanting palpebral fissures, a short bulbous nose, and posteriorly rotated ears. Some patients also have iris coloboma, retinal detachment, and intestinal malrotation. Intellectual impairment is variable. In rare cases, proteinuria is present. This condition is not life-threatening, but the functional prognosis depends on the degree of visual and hearing handicap.
Only two features distinguish Donnai-Barrow syndrome from the faciooculoacousticorenal (FOAR) syndrome: the absence of proteinuria and presence of diaphragmatic hernia and agenesis of the corpus callosum in Donnai-Barrow syndrome. Thus, the two disorders are now considered to represent the same condition.
Mutations in the LRP2 gene are known to cause Donnai-Barrow syndrome. LRP2 gene codes for megalin protein. It is a multi-ligand receptor that regulates levels of diverse circulating compounds.
Kantarci et al. (2007) described two female siblings with DBS and born to healthy first cousin parents. The younger sister has left-sided diaphragmatic hernia, severe hypertelorism, anomalies of corpus callosum, large anterior fontanel, and hearing loss. While the elder sister has severe hypertelorism, high myopia, severe hearing loss, and mild developmental delay. At molecular level, both patients were found to be homozygous for a frameshift mutation in the LRP2 gene (c.9358_9359delAG, p.S3120Wfs26).
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.
Kantarci et al. (2007) described a consanguineous large inbred Emirati family of Yemeni origin who had five children (three females and two males) with DBS. Both parents were entirely healthy. The proband, a female, had characteristic craniofacial features, but died of complications secondary to congenital diaphragmatic hernia (CDH). Of the four surviving children with DBS, one has right-sided diaphragmatic eventration and left pulmonary hypoplasia, while two have documented agenesis of the corpus callosum. Chromosome analyses on the four survivors, and 1 Mb array-based comparative genome hybridization on two survivors, were normal. Brain imaging for one affected child demonstrated numerous abnormalities including hypogenesis of the corpus callosum, partially empty sella turcica, small pons, extensive periventricular nodular heterotopia, small optic nerves and chiasm, small ocular colobomas, and malformation of the left horizontal semicircular canal and vestibule. Cortical surface reconstruction of the same patient was abnormal compared to an age-matched control. At molecular level, all patients were found to be homozygous for a missense mutation in the LRP2 gene (c.7564T>C, p.Y2522H).
[See: United Arab Emirates > Kantarci et al., 2007].