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Donnai-Barrow Syndrome

Last updated Sept. 5, 2018

Approved by: Maulik P. Purohit MD, MPH

Donnai-Barrow Syndrome (DBS) is a multi-system genetic disorder. The syndrome is caused by mutation(s) in the LRP2 gene, which is located on chromosome 2.

What are the other Names for this Condition? (Also known as/Symptoms)

  • DBS/FOAR Syndrome
  • Diaphragmatic Hernia-Exomphalos-Corpus Callosum Agenesis
  • Facio-Oculo-Acoustico-Renal Syndrome (FOAR Syndrome)

What is Donnai-Barrow Syndrome? (Definition/Background Information)

  • Donnai-Barrow Syndrome (DBS) is a multi-system genetic disorder. The syndrome is caused by mutation(s) in the LRP2 gene, which is located on chromosome 2
    • Under normal circumstances, the gene codes for a functional protein called megalin, which is a membrane protein involved in the development and function of various organs, as well as stress response, immune response and vitamins A and D absorption
    • In Donnai-Barrow Syndrome, the mutated LRP2 gene leads to a non-functional megalin protein, which does not allow crucial cellular signaling processes to take place. This probably results in the symptoms observed in the disorder
  • It has been reported that children born to parents who are close relatives (such as first cousins) and those with a family history of the disorder are at increased risk of developing Donnai-Barrow Syndrome
  • The disorder is inherited in an autosomal recessive pattern. In this type of inheritance, an individual must have two defective copies of the causative gene in each of his/her cell for the disorder to manifest itself
  • The signs and symptoms of Donnai-Barrow Syndrome include structural abnormalities in the brain, characteristic facial features (prominet forehead, protruding eyes, and broad nasal bridge), seizures, intellectual disability, hearing loss, and defects in diaphragm, among many others. Miscarriage at the prenatal stage is a potential complication. After birth, progressive vision and hearing loss are possible
  • Treatment of Donnai-Barrow Syndrome for various symptoms depends on their severity. Typically, structural deformities, such as a hole in the diaphragm, are corrected through surgery. Corrective lenses and cochlear implants for impaired vision and hearing respectively, medication for seizures and special education may be required for normal development of the affected individual
  • When the symptoms are severe and are apparent before birth, the prognosis of Donnai-Barrow Syndrome is guarded. If the child can tolerate corrective surgeries during early infancy, he/she is reported to have reasonably good health in childhood and adolescence with careful monitoring of the condition

Who gets Donnai-Barrow Syndrome? (Age and Sex Distribution)

  • Donnai-Barrow Syndrome is an extremely rare genetic disorder that is known to occur worldwide. The disorder can affect individuals belonging to all races and ethnicities
  • The disorder is more common in children born to closely-related parents (such as first or second cousins)
  • Both male and female genders are equally susceptible to Donnai-Barrow Syndrome
  • The exact prevalence of the disorder is not known; less than 50 cases have been reported so far. Some reports indicate that worldwide around 20 families may be affected

What are the Risk Factors for Donnai-Barrow Syndrome? (Predisposing Factors)

  • Since Donnai-Barrow Syndrome is a genetic disorder, a positive family history of the disorder is a major risk factor
  • Additionally, children born to parents who are close- or blood- relatives (e.g. first cousins) are considered to be more prone to DBS

It is important to note that having a risk factor does not mean that one will get the condition. A risk factor increases ones chances of getting a condition compared to an individual without the risk factors. Some risk factors are more important than others.

Also, not having a risk factor does not mean that an individual will not get the condition. It is always important to discuss the effect of risk factors with your healthcare provider.

What are the Causes of Donnai-Barrow Syndrome? (Etiology)

  • Donnai-Barrow Syndrome is caused by mutations in the LRP2 gene (low-density lipoprotein receptor-related protein 2 gene) located on chromosome 2 (2q31.1). DBS is inherited in an autosomal recessive manner
  • Under normal circumstances, the LRP2 gene codes for a protein called megalin (a receptor), which resides on the cell membrane
    • Megalin binds to many ligands (proteins that fit into the groove of the receptor) and initiates cellular events relating to immune response, stress response, fat transport in blood, and absorption of vitamins A and D
    • Megalin ligand signaling is also crucial to the proper development and function of the brain and spinal cord, ears, eyes, lungs, the intestines, kidneys, and the reproductive organs
  • A mutation in LRP2 gene leads to a non-functional megalin protein. The specific ligands of megalin protein are unable to bind, and thus rendered incapable of bringing about desired cellular responses, growth and development. This possibly leads to the various symptoms of the disorder
  • One affected individual was reported to have inherited both defective copies of LRP2 gene from the father. This phenomenon is known as uniparental disomy, where an individual receives both the affected chromosomes from one parent, or part of the chromosome from one parent and no copies from the other. Uniparental disomy can occur during gamete formation (egg or sperm) or during early fetal development

Autosomal recessive: Autosomal recessive conditions are traits or disorders that occur when two copies of an abnormal gene have been inherited on a non-sex chromosome. If both parents have an autosomal recessive condition, there is a 100% likelihood of passing on the mutated genes to their children. If, however, only one mutant copy of the gene is inherited, the individual will be a carrier of the condition, but will not be present with any symptoms. Children, born to two carriers, have a 25% chance of being homozygous dominant (unaffected), a 50% chance of being heterozygous (carrier), and a 25% chance of being homozygous recessive (affected). 

What are the Signs and Symptoms of Donnai-Barrow Syndrome?

The signs and symptoms of Donnai-Barrow Syndrome depend upon the body part affected and may include:

  • Brain-related signs and symptoms:
    • Tissue connecting the two halves (corpus callosum) is underdeveloped or absent
    • Other structural abnormalities, such as enlarged anterior fontanelle (the soft part at the top of head in a newborn)
    • Intellectual disability
  • Abnormal facial features that include:
    • Down-slanted eyes
    • Protruding eyes
    • Flat nasal bridge
    • Short nose
    • Prominent forehead
    • Ears rotated backwards
  • Congenital diaphragmatic hernia: A defect or hole in the muscle that separates the chest and the abdomen. This can result in the crowding of heart and lungs during development, when the gut organs move in to the chest cavity
  • Omphalocele, or an opening in the abdominal wall that allows the organs to protrude through the navel
  • Delay in achieving developmental milestones
  • Congenital heart defects
  • Kidney dysfunction: Proteinuria or presence of protein (of low-molecular weight) in urine
  • Severe short-sightedness that may lead to retinal detatchment
  • Iris coloboma, or a hole in the iris
  • Sensorineural hearing loss
  • Seizures

How is Donnai-Barrow Syndrome Diagnosed?

A diagnosis of Donnai-Barrow Syndrome may be made through the following tests and procedures after birth of the child:

  • A complete physical examination and an assessment of the presenting signs and symptoms
  • An evaluation of family medical history
  • Urine analysis
  • Blood tests:
    • To determine the levels of vitamins A and D in blood
    • To check for abnormalities in kidney function (through determining serum creatinine and blood urea nitrogen concentrations)
  • Neuroimaging studies of the brain
  • Imaging studies of the abdomen
  • Vision tests to check for short-sightedness and abnormalities in eye structure
  • Hearing (audiometric) tests
  • Electroencephalography (EEG), if seizures are reported
  • Prenatal genetic molecular testing of fetal cells may be conducted: If the condition is suspected, a prenatal diagnosis can be undertaken (prior to birth of the child)

Many clinical conditions may have similar signs and symptoms. Your healthcare provider may perform additional tests to rule out other clinical conditions to arrive at a definitive diagnosis.

What are the possible Complications of Donnai-Barrow Syndrome?

Some potential complications of Donnai-Barrow Syndrome include:

  • Congenital abnormalities in the fetus, which may result in a miscarriage
  • Progressive loss of vision
  • Progressive hearing loss and deafness

How is Donnai-Barrow Syndrome Treated?

The treatment options for Donnai-Barrow Syndrome depend on the type and severity of symptoms and it may include the following:

  • Vision: Corrective lenses and surgery for structural abnormalities; procedures to prevent retinal detachment (such as peripheral laser photocoagulation)
  • Hearing: Use of hearing aids and cochlear implants
  • Surgical repair  of congenital diaphragmatic hernia and omphalocele
  • Anti-epileptic medications may be administered for seizures
  • Special education to accommodate intellectual disability and hearing and vision impairment (when present)
  • Vocational training to help an individual become independent and have a better quality of life

Regular check-ups and follow-ups are necessary to monitor disorder progression in the affected individuals.

How can Donnai-Barrow Syndrome be Prevented?

  • Currently, there are no specific methods or guidelines to prevent Donnai-Barrow Syndrome, since it is a genetic condition
  • Genetic testing of the expecting parents (and related family members) and prenatal diagnosis (molecular testing of the fetus during pregnancy) may help in understanding the risks better during pregnancy
  • If there is a family history of the condition, then genetic counseling will help assess risks, before planning for a child
  • Active research is currently being performed to explore the possibilities for treatment and prevention of inherited and acquired genetic disorders such as Donnai-Barrow Syndrome
  • Regular medical screening at periodic intervals with tests and physical examinations are highly recommended

What is the Prognosis of Donnai-Barrow Syndrome? (Outcomes/Resolutions)

The prognosis of Donnai-Barrow Syndrome is determined by the type and severity of the signs and symptoms.

  • If the disorder is apparent during fetal development or just before/after birth, the prognosis is guarded
  • If the child survives early symptom manifestation and responds positively to corrective treatments for the symptoms, then the overall health into one’s childhood and adolescence is reported to be good
  • With corrective measures and surgeries to repair vision and hearing impairment, long-term survivors are reported to retain useful vision and hearing

Additional and Relevant Useful Information for Donnai-Barrow Syndrome:

According to the US National Center for Biotechnology Information (NCBI), the following terms should no longer be used while referring to Donnai-Barrow Syndrome:

  • Syndrome of Ocular and Facial Anomalies, Telecanthus, and Deafness
  • Holmes-Schepens Syndrome
  • Diaphragmatic Hernia-Exomphalos-Hypertelorism Syndrome
  • Diaphragmatic Hernia-Hypertelorism-Myopia-Deafness Syndrome

What are some Useful Resources for Additional Information?

References and Information Sources used for the Article:

Helpful Peer-Reviewed Medical Articles:

Reviewed and Approved by a member of the DoveMed Editorial Board
First uploaded: Jan. 4, 2017
Last updated: Sept. 5, 2018