Donnai–Barrow syndrome

Overview

Donnai–Barrow syndrome (DBS), also known as Facio-oculo-acoustico-renal (FOAR) syndrome, is a rare autosomal recessive genetic disorder characterized by a combination of congenital anomalies affecting the face, eyes, ears, and kidneys, along with developmental delays. It was first described in the early 1990s by Donnai and Barrow. The syndrome is caused by mutations in the LRP2 gene, which plays a crucial role in cellular signaling and nutrient transport, particularly in the kidney and nervous system.

Causes

Donnai–Barrow syndrome is caused by mutations in the LRP2 gene located on chromosome 2q31.1. This gene encodes a protein called megalin, which is involved in endocytosis—a process by which cells absorb molecules. Megalin is especially active in the kidneys, brain, and other epithelial tissues. When LRP2 is mutated, the resulting deficiency in megalin function leads to the multisystem abnormalities seen in this syndrome. The disorder follows an autosomal recessive inheritance pattern, meaning both copies of the gene must be altered for the condition to manifest.

Symptoms

The clinical presentation of Donnai–Barrow syndrome is variable, but common features include:

• Facial anomalies: Widely spaced eyes (hypertelorism), a broad nasal bridge, prominent forehead, and cleft lip and/or palate.

• Ocular abnormalities: Severe myopia (nearsightedness), retinal detachment, and other visual impairments.

• Hearing loss: Bilateral sensorineural deafness is common.

• Proteinuria: Loss of proteins in urine due to impaired kidney tubular function.

• Developmental delay: Mild to moderate intellectual disability and delayed milestones.

• Corpus callosum agenesis: Partial or complete absence of the corpus callosum, affecting interhemispheric brain communication.

• Diaphragmatic hernia: Present in some cases, causing breathing and gastrointestinal issues.

Diagnosis

Diagnosis of Donnai–Barrow syndrome involves a combination of clinical assessment, imaging, and genetic testing. Diagnostic steps include:

• Clinical evaluation: Based on recognizable craniofacial features, hearing and vision tests, and developmental assessment.

• MRI of the brain: May reveal absence or hypoplasia of the corpus callosum.

• Urine analysis: Detects proteinuria indicating renal involvement.

• Ophthalmologic and audiologic testing: To assess the degree of vision and hearing impairment.

• Genetic testing: Confirmatory testing through sequencing of the LRP2 gene to identify causative mutations.

Treatment

There is no cure for Donnai–Barrow syndrome. Treatment focuses on managing the individual symptoms and improving quality of life through a multidisciplinary approach. Management strategies include:

• Hearing aids or cochlear implants: To manage sensorineural hearing loss.

• Corrective eye procedures: Including surgery or corrective lenses for vision abnormalities.

• Speech and developmental therapy: To support language and cognitive development.

• Renal monitoring: Regular follow-ups with a nephrologist to manage proteinuria and preserve kidney function.

• Surgical repair: For cleft palate or diaphragmatic hernia when present.

• Educational support: Individualized learning plans tailored to cognitive abilities.

Prognosis

The prognosis for individuals with Donnai–Barrow syndrome varies depending on the severity of symptoms and the availability of supportive care. With early intervention and appropriate therapies, many individuals can achieve developmental progress and lead relatively functional lives. However, lifelong medical monitoring is necessary, particularly for hearing, vision, kidney health, and neurodevelopmental issues. The condition is not typically life-threatening but can significantly impact quality of life if not managed properly.