Donnai Barrow Syndrome

Donnai Barrow Syndrome

Donnai Barrow Syndrome is a rare congenital disease

This condition is characterized by eye problems, facial deformities, intellectual disabilities, hearing loss, deformities in the brain and low-molecular-weight proteinuria.

Synonyms

• DBS/FOAR syndrome
• Diaphragmatic hernia-exomphalos-hypertelorism syndrome
• Diaphragmatic hernia-hypertelorism-myopia-deafness syndrome
• Diaphragmatic hernia-hypertelorism-myopia-hearing loss syndrome
• FOAR syndrome
• Facio-oculo-acoustico-renal syndrome
• Holmes-Schepens syndrome
• Syndrome of ocular and facial anomalies, telecanthus and deafness
• Syndrome of ocular and facial anomalies, telecanthus and hearing loss

How common is Donnai Barrow Syndrome?

• less than 1 in 1000000

Inheritance pattern

Autosomal recessive 

What is the Age of onset?

Neonatal

Antenatal

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.

What are the Symptoms of Donnai Barrow Syndrome

Most Common Symptoms

• Aplasia/Hypoplasia of the corpus callosum 
• Depressed nasal bridge
• Downslanted palpebral fissures 
• Global developmental delay
• Hypertelorism 
• Intellectual disability 
• Myopia 
• Posteriorly rotated ears 
• Proteinuria 
• Sensorineural hearing impairment
• Short nose 
• Wide anterior fontanel 
• Widow’s peak

Common Symptoms

• Broad forehead 
• Congenital diaphragmatic hernia 
• Macrocephaly
• Omphalocele 
• Progressive visual loss 
• Proptosis 
• Retinal detachment 
• Umbilical hernia 

Occasional Symptoms

• Abnormality of the uterus 
• Bicornuate uterus 
• Intestinal malrotation 
• Iris coloboma 
• Retinal dystrophy 
• Seizures 
• Ventricular septal defect

Clinical Signs

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 and Life Expectancy

Prognosis is good with favourable overall health status in childhood and adolescence.

With correction, vision and hearing can be restored.

Diaphragmatic abnormalities and abdominal wall defects are common in Pre- or peri-natal life which requires surgical intervention. Usually there are high chances of mortality with these defects are associated with elevated morbidity and .

There is a possibility of a rare complication that is End stage kidney failure

Sources

Donnai-Barrow syndrome