Donnai-Barrow syndrome (ORPHA:2143)
A multiple congenital malformation syndrome characterized by typical facial dysmorphism, myopia and other ocular findings, hearing loss, agenesis of the corpus callosum, low-molecular-weight proteinuria, and variable intellectual disability. Congenital diaphragmatic hernia (CDH) and/or omphalocele are common.
Epidemiology
The prevalence and incidence of Donnai-Barrow syndrome (DBS) 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.
Clinical description
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 40% of patients have CDH and/or omphalocele. Developmental delay and variable intellectual deficit are frequent. High myopia (> 6 diopters), a distinctive optic nerve head dysgenesis, and an increased risk of retinal detachment may lead to progressive loss of vision. Iris coloboma, Focal segmental glomerulosclerosis and proximal tubule dysfunction (rarely progressing to renal insufficiency) are reported occasionally.
Etiology
DBS is an autosomal recessive disorder caused by loss of function variants 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.
Diagnostic methods
Diagnosis is suggested by a combination of clinical and neuroimaging features along with a typical pattern of low-molecular-weight proteinuria, increased urinary levels of retinol-binding protein (RBP) and RBP/creatinine ratio. The diagnosis is confirmed by molecular genetic testing.
Differential diagnosis
DBS has a characteristic constellation of clinical features limiting differential diagnoses. However, some overlapping signs are found in tetrasomy 12p, Fryns, Chudley-McCullough, Acrocallosal, and Craniofrontonasal syndromes. The renal phenotype partly resembles Dent disease and Lowe syndrome. The ocular phenotype may be suggestive of Stickler syndrome.
Antenatal diagnosis
Detection of hypertelorism, agenesis of the corpus callosum, and either CDH or omphalocele by prenatal imaging should raise suspicion of DBS. Prenatal diagnosis for at-risk pregnancies is possible and requires prior identification of the disease-causing mutation in the family.
Genetic counseling
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. The sole exception reported to date is a patient with DBS due to uniparental disomy (UPD).
Management and treatment
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 for vision, hearing and intellectual disabilities should be provided as is needed for affected children.
Prognosis
Affected individuals can achieve useful vision and hearing with correction. Overall health status in patients is generally good in childhood and adolescence. End-stage kidney failure is a rare and life-threatening complication. Pre- or peri-natal presentation with diaphragmatic and abdominal wall defects requires surgical intervention and is associated with elevated morbidity and mortality.

                            Last update: 
                            June 2019


                            - Expert reviewer(s): 
                            Dr Mauro LONGONI  - Dr Barbara POBER