Donnai-Barrow syndrome (DBS) is a rare, often severe, multiple congenital malformation syndrome with typical facial dysmorphism, ocular findings, hearing loss, agenesis of the corpus callosum, and variable intellectual disability. Congenital diaphragmatic hernia (CDH) and/or omphalocele are common (see these terms).
Prevalence and incidence are difficult to estimate. Fewer than 50 individuals from about 20 families have been reported. DBS affects all ethnicities; it is more commonly diagnosed in the offspring of consanguineous unions. Males and females are affected equally.
Almost all patients have the following features: agenesis/hypogenesis of the corpus callosum, enlarged anterior fontanelle, marked sensorineural hearing loss and hypertelorism. Characteristic facial features include: down-slanting palpebral fissures, short nose with flat nasal bridge, tall broad forehead, widow's peak in the anterior hairline, and sometimes prominent globes. About 50% of patients have CDH and/or omphalocele. Developmental delay and variable intellectual deficit are frequent. High myopia (> 6 diopters) may lead to retinal detachment/dystrophy and progressive loss of vision. Iris coloboma, cardiovascular abnormalities and renal insufficiency are reported occasionally.
DBS is caused exclusively by mutations in the LRP2 low-density lipoprotein receptor-related protein 2 gene (2q31.1) encoding the protein megalin, expressed on multiple absorptive epithelia, notably in the brain, kidney, and eye. Megalin plays an important role in endocytosis of numerous ligands and in various signaling pathways.
Diagnosis is suggested by a combination of clinical and neuroimaging features along with a typical pattern of low-molecular-weight proteinuria, and it is confirmed by genetic testing.
DBS has a characteristic constellation of clinical features limiting differential diagnoses. However, some overlapping signs are found in tetrasomy 12p, Fryns, Chudley-McCullough, Acrocallosal, Lowe, and craniofrontonasal syndromes, and Dent disease (see these terms).
Detection of hypertelorism and either CDH or omphalocele by prenatal imaging should raise suspicion of DBS. Prenatal diagnosis for at-risk pregnancies is available and requires prior identification of the disease-causing mutation in the family.
DBS is an autosomal recessive disorder. Genetic counseling should be provided to parents of affected children and to their relatives. Parents of an affected child are obligate carriers for the disease-causing allele, except for a single reported case of uniparental disomy (UPD).
Regular screening of vision, hearing, and renal function should be established. Corrective lenses, preventive treatment for retinal detachment, and hearing aids and/or cochlear implants may be required. CDH and/or omphalocele, when present, necessitate surgical intervention. Specific adapted education should be provided for affected children.
Pre- or peri-natal presentation of DBS is associated with high morbidity and mortality. Long-term survivors can achieve useful vision and hearing with correction. Overall health status in patients is generally good in childhood and adolescence.
Last update: November 2013
- Dr Mauro LONGONI
- Dr Barbara POBER