The Barakat syndrome, also known as HDR syndrome, is a clinically variable (heterogeneous) rare genetic condition first identified by Barakat et al. in 1977. This clinical entity has a wide range of genotypic and phenotypic variants and is genetically diverse.

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The GATA binding protein 3 (GATA3) gene haploinsufficiency causes Barakat syndrome, an autosomal dominant uncommon genetic disorder. It is marked by three main characteristics including, hypoparathyroidism (H), sensorineural deafness (D), and renal disease (R). Specific symptoms and severity, on the other hand, can differ.

About 65% of patients with Barakat syndrome have all three characteristics, whereas the rest have different combinations. In 93% of patients, hypoparathyroidism is present, while renal dysfunction is present in 72%.

Deafness affects 96% of patients, and it frequently affects both ears (bilateral deafness), ranging from mild to severe impairment. One or more of these features, along with additional characteristics, are present in some people with Barakat syndrome.

Causes and symptoms

Barakat syndrome is passed down through the generations in an autosomal dominant form. The faulty gene can be inherited from either parent or caused by a new mutation (gene alteration) in the affected person. Each pregnancy has a 50% chance of transferring the defective gene from the affected parent to the offspring. Males and females are equally at risk.

Symptoms of hypocalcemia and renal diseases may be present. Deafness can be discovered during a routine hearing exam. Hypoparathyroidism causes low calcium levels in the blood (hypocalcemia), which can induce muscle discomfort, spasms, seizures, and, in rare cases, cardiomyopathy.

The most common symptom of Barakat syndrome is hearing loss. It is usually bilateral and can range in severity from mild to severe. The sort of renal illness that a person has can differ from one person to the other. Some people with Barakat syndrome are born with structural (underdeveloped or improperly formed) kidney or urinary tract problems, while others may have functional abnormalities (such as nephrotic syndrome, hematuria, renal tubular acidosis, or chronic kidney disease).

Various additional features have been reported in some people with Barakat syndrome, such as distinctive facial features, retinitis pigmentosa, polycystic ovaries, intellectual disability, ischemic stroke, growth failure, congenital heart disease, and other birth defects.

Genetics of barakat syndrome

The deficiency is caused by deletions on chromosome 10p14 or mutations in the GATA3 gene in the majority of the patients. The GATA3 gene is a dual zinc-finger transcription factor involved in the development of the parathyroid glands, auditory system, kidney, thymus, and central nervous system in vertebrates during embryonic development. Different mutations in the GATA3 gene can cause various clinical manifestations of the disease (phenotypic heterogeneity).

Exons 2–6 encode a 444-amino-acid transcription factor with two transactivating domains (TA1, TA2) and two zinc finger domains (ZF1, ZF2). The GATA3 gene spans 20 kb of genomic DNA and encodes a 444-amino-acid transcription factor with two transactivating domains (TA1, TA2) and two zinc finger domains (ZF1, ZF2). GATA3 is one of the six transcription factors in the GATA family.

They play a role in the development of the parathyroid glands, auditory system, kidneys, thymus, and central nervous system in vertebrates. Several human abnormalities have been linked to the GATA family of zinc-finger transcription factors, according to research.

Epidemiology

The disease’s actual prevalence is unclear. However, it is thought to be extremely rare. Approximately 180 patients have been recorded from the United States, Japan, India, China, Europe, and the Middle East to date. There is an equal prevalence of diagnosis across ethnic groups, genders, and ages. The number of people diagnosed will very certainly increase as clinical awareness of this illness grows.

Diagnosis and treatment

The clinical findings of “H,” “D,” and “R” are used to diagnose this syndrome. In the presence of nephrotic syndrome, hematuria, or proteinuria, tests like hearing tests, imagining examinations (kidneys), and kidney biopsy are performed. In specialized genetic labs, mutations in the GATA3 gene can be tested via molecular genetic testing.

The syndrome should be evaluated in newborns who have been prenatally identified with a chromosome 10p defect or congenital kidney and urinary tract malformations. Siblings and family members should be tested for the “D,” “H,” and “R” genes, as well as the GATA3 gene.

Patients with this syndrome receive comprehensive care, which includes genetic counseling. The treatment is symptomatic and is determined by the clinical findings and severity of the condition. The most common condition requiring therapy is hypocalcemia. Hearing aids and, if necessary, cochlear implants should be used to correct deafness as soon as possible. The treatment for kidney disease is determined by the nature of the disorder.

Some minor anomalies, such as cysts or tiny kidneys, might not require treatment but must be closely monitored. Medical or surgical therapy may be required for certain kidney disorders. To delay or avoid end-stage renal disease, chronic kidney disease should be recognized early and treated. These patients have had their kidneys transplanted successfully.

The nature and severity of the kidney disease determine the prognosis. The life expectancy of patients with modest kidney issues is normal.

There is a need for HDR syndrome to be explored in the differential diagnosis of recurrent hypocalcemia with sensorineural deafness and/or renal dysfunction, and genetic testing should be performed to confirm the diagnosis.

References:

• Joseph, A., Sirisena, N. D., Kumanan, T., Sujanitha, V., Strelow, V., Yamamoto, R., Wieczorek, S., & Dissanayake, V. (2019). Hypoparathyroidism, Sensorineural deafness and renal disease (Barakat syndrome) caused by a reduced gene dosage in GATA3: a case report and review of literature. BMC endocrine disorders, 19(1), 111. https://doi.org/10.1186/s12902-019-0438-4
• Barakat Syndrome. [online] NIH – National Center for Advancing Translational Sciences (Genetic and Rare Diseases Information Center. Available at: https://rarediseases.info.nih.gov/diseases/2911/barakat-syndrome
• Barakat Syndrome. [online] National Organization for Rare Disorders. Available at: https://rarediseases.org/rare-diseases/barakat-syndrome/

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