NORD gratefully acknowledges Amin J. Barakat, MD, FAAP, Professor of Clinical Pediatrics, Georgetown University Medical Center, Washington, DC for the preparation of this report.
First described by Barakat, et al in 1977, the 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, pseudopapilledema), basal ganglia calcifications, psoriasis, growth failure, and cognitive disability.
Patients may present with symptoms associated with low blood calcium (hypocalcemia) such as muscle weakness, tetany, and convulsions, or findings related to kidney disease 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.
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. The defect in the majority of patients is caused by deletions 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).
The exact prevalence is unknown, but the disease is considered to be very rare. So far, about 180 patients have been reported from various countries including the United States, Japan, India, China, Europe and the Middle East. There is equal prevalence across ethnic groups, genders and ages of diagnosis. Clinical awareness of this syndrome will probably increase the number of patients diagnosed.
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”. In view of 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 a 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 of patients with this syndrome should be comprehensive and should include genetic counseling. 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 normal life expectancy.
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Barakat AJ, et al. Barakat syndrome revisited. Am J Med Genet A. 2018 Apr 16. doi: 10.1002/ajmg.a.38693. [Epub ahead of print]. https://www.ncbi.nlm.nih.gov/pubmed/29663634
Belge H, et al. Clinical and mutational spectrum of hypoparathyroidism, deafness and renal dysplasia syndrome. Nephrology Dialysis Transplantation 2017; 32: 830–7. https://www.ncbi.nlm.nih.gov/pubmed/27387476
Ali A, et al. Functional characterization of GATA3 mutations causing the hypoparathyroidism-deafness-renal (HDR) dysplasia syndrome: Insight into mechanisms of DNA binding by the GATA3 transcription factor. Human Molecular Genetics 2007; 16: 265–75.
Barakat AY, et al. Familial nephrosis, nerve deafness, and hypoparathyroidism. J. Pediat 1977; 91: 61-4.
Bilous RW, et al. Brief report: Autosomal dominant familial hypoparathyroidism, sensorineural deafness, and renal dysplasia. New Eng J Med 1992; 327: 1069-74.
Hasegawa T, et al. HDR syndrome (hypoparathyroidism, sensorineural deafness, renal dysplasia) associated with del(10)(p13). Am J Med Genet 1997; 73: 416-8.
Fujimoto S, et al. Recurrent cerebral infarctions and del (10) (p14p15.1) de novo in HDR (hypoparathyroidism, sensorineural deafness, renal dysplasia) syndrome. Am J Med Genet 1999; 86: 427-9.
Muroya K, et al. GATA3 abnormalities and the phenotypic spectrum of HDR syndrome. J Med Genet 2001; 38: 374-80.
Online Mendelian Inheritance in Man (OMIM), Baltimore, MD. Authored and edited at the McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, under the direction of Dr. Ada Hamosh. Entry No. 146255.
Last Updated 08/09/16.http://omim.org/entry/146255 Accessed June 1, 2018.
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