Barakat syndrome, also known as HDR syndrome is a clinically variable (heterogeneous), rare genetic disorder characterized by three characteristics: hypoparathyroidism (H) (decreased function of the parathyroid glands which are small endocrine glands in the neck whose main function is to maintain the body calcium level), sensorineural deafness (D), and renal disease (R). Patients may present at any age with deafness, hypocalcemia, intermittent muscular spasms, caused by malfunction of the parathyroid glands and a consequent deficiency of calcium (tetany), and afebrile seizures. “H” occurs in 93% of patients. “D” occurs in 96% of patients and is usually in both ears (bilateral), ranging from moderate to profound impairment. “R” occurs in 72% of patients and includes congenital anomalies of the kidney and urinary tract (cystic, dysplastic, hypoplastic or aplastic kidneys, pelvicalyceal deformity, vesicoureteral reflux), chronic kidney disease, nephrotic syndrome (kidney disorder resulting in loss of large amounts of protein in the urine), hematuria (blood in the urine), proteinuria (increased protein excretion in the urine) and others. Several additional features have been described; among others, congenital heart disease, facial and ocular abnormalities (retinitis pigmentosa, nystagmus, pseudo papilledema), basal ganglia calcifications, psoriasis, growth failure, and cognitive disability.
Barakat syndrome is an autosomal dominant rare genetic disease caused by the haploinsufficiency of the GATA binding protein 3 (GATA3) gene. It is also known as HDR syndrome and is characterized by varying degrees of hypoparathyroidism, sensorineural deafness, and renal disease. Hearing loss is usually bilateral and may range from mild to profound impairment. The renal disease includes nephrotic syndrome, cystic kidney, renal dysplasia, hypoplasia or aplasia, pelvicalyceal deformity, vesicoureteral reflux, chronic renal failure, hematuria, proteinuria, and renal scarring.
Symptoms
Patients may present with symptoms associated with low blood calcium (hypocalcemia) such as muscle weakness, tetany, and convulsions, or findings related to kidney diseases such as proteinuria, hematuria, and nephrotic syndrome. Deafness may be a presenting symptom or may be found on a routine hearing test. Since prenatal ultrasound is now a routine, congenital anomalies of the kidney and urinary tract may be the presenting finding.
It is a genetic developmental disorder with clinical diversity characterized by hypoparathyroidism, sensorineural deafness, and renal disease. Affected people usually present with hypocalcemia, tetany, or afebrile convulsions at any age. Hearing loss is usually bilateral and may range from mild to profound impairment. The renal disease includes nephrotic syndrome, cystic kidney, renal dysplasia, hypoplasia or aplasia, pelvicalyceal deformity, vesicoureteral reflux, chronic kidney disease, hematuria, proteinuria, and renal scarring. Other reported features include intellectual disability, polycystic ovaries, particular distinct facial characteristics, ischaemic stroke, and retinitis pigmentosa.[rx]
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).
Causes
This syndrome is primarily caused by haploinsufficiency of the dual zinc finger transcription factor, GATA3 (glutamyl amidotransferase subunit A), or mutations in the GATA3 gene, which is contained on the short arm of chromosome 10[rx, rx].
Barakat syndrome is inherited in an autosomal dominant pattern. Dominant genetic disorders occur when only a single copy of the abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy. The risk is the same for males and females. Deletions cause the defect in most patients in chromosome 10p14 or mutations in the GATA3 gene. The GATA3 gene belongs to a family of dual zinc-finger transcription factors involved in vertebrate embryonic development of the parathyroid glands, auditory system, kidney as well as the thymus and central nervous system. Different mutations in the GATA3 gene can result in different clinical presentations of the condition (phenotypic heterogeneity).
Diagnosis
The diagnosis of this syndrome is based on the clinical findings of “H”, “D” and “R”. The following studies should be performed: parathormone (PTH) levels, a hearing test, imaging studies of the kidneys, and possibly a kidney biopsy in the presence of nephrotic syndrome, hematuria or proteinuria. Molecular genetic testing for mutations in the GATA3 gene may be performed in specialized genetic labs. The syndrome should be considered in infants who have been prenatally diagnosed with a chromosome 10p defect or congenital anomalies of the kidney and urinary tract. Siblings and family members should be studied for “D”, “H” and “R” and possibly GATA3 gene testing.
The “HDR” triad was found in around 65% of reported cases, while the others seem to have various combinations of “H”, “D”, and “R”. Given these findings, Barakat et al (2018) suggested that the diagnosis of the syndrome is confirmed in patients who have the “HDR” triad or those who have two of the three findings and positive family history. Patients with isolated deafness or renal disease and those who do not fit the above criteria need to have a GATA3 gene mutation to confirm the diagnosis. GATA3 mutations have not been reported in association with isolated hypoparathyroidism.
Treatment
Treatment of patients with this syndrome should be comprehensive and should include genetic counseling. Management consists of treating the clinical abnormalities at the time of presentation and includes genetic counseling, correcting calcium, treating hearing problems, monitoring kidney function, and close monitoring of cysts of the kidney.
Management is essentially symptomatic and depends on the clinical findings and severity of the disease. Hypocalcemia is usually the most common problem requiring treatment. Deafness should be diagnosed and treated early with hearing amplification, and if needed cochlear implantation. The treatment of kidney disease depends on the abnormality. Some minor abnormalities such as cysts or small kidneys need no treatment but require close observation. Certain kidney abnormalities might need medical or surgical treatment. Chronic kidney disease should be diagnosed early and treated to delay or prevent end-stage renal disease. Renal transplantation has been performed successfully in these patients. Prognosis depends on the nature and severity of the kidney disease. Patients with minor kidney problems have a normal life expectancy.
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