Years published: 2008, 2012, 2015, 2018, 2023
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 the triad of hypoparathyroidism (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 and renal disease.
Hypoparathyroidism occurs in about 93% of patients. Deafness is the most consistent feature of the syndrome occurring in about 96% of patients. It usually affects both ears and is characterized by early onset and moderate to severe sensorineural hearing loss. Renal disease occurs in about 72% of patients and includes congenital anomalies of the kidney and urinary tract (cystic, dysplastic, hypoplastic or aplastic kidneys, pelvicalyceal deformity, vesicoureteral reflux), blood in the urine (hematuria), increased protein excretion in the urine (proteinuria), nephrotic syndrome (kidney disorder resulting in loss of large amounts of protein in the urine), chronic kidney disease 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. The likelihood of occurrence of each component increases with age, and by age 50 all patients will probably have all three components of the syndrome.
Since newborn hearing screening and prenatal ultrasonography are now performed routinely, deafness and congenital anomalies of the kidney and urinary tract have become the more common modes of presentation. Patients may also present with symptoms associated with low blood calcium (hypocalcemia) caused by malfunction of the parathyroid glands such as muscle weakness, tetany and convulsions, or signs of kidney disease such as proteinuria, hematuria and chronic kidney disease. Deafness may be a presenting symptom or may be found on a routine hearing test at any age.
Barakat syndrome is inherited in an autosomal dominant pattern. Dominant genetic disorders occur when only a single copy of a non-working gene is necessary to cause a particular disease. The non-working gene can be inherited from either parent or can be the result of a changed (mutated) gene in the affected individual. The risk of passing the non-working gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.
In most patients, there is a deletion in chromosome 10p14 or heterogenous changes (mutations or pathogenic variants) 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. So far, 93 GATA3 pathogenic variants have been reported in the literature. Different variants in the GATA3 gene can result in different clinical presentations of the condition.
The exact prevalence is unknown, but the disease is considered to be rare. So far, about 200 patients have been reported in the literature worldwide. Clinical awareness of this syndrome will certainly increase the number of patients diagnosed and reported. There is equal prevalence across ethnic groups, genders and ages of diagnosis (from newborns to age 60 years).
The diagnosis of this syndrome is based on the clinical findings of hypoparathyroidism, deafness and renal disease. The following studies should be performed: parathormone (PTH) and calcium levels, hearing test, urinalysis, 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 abnormality or congenital anomalies of the kidney and urinary tract. Siblings and family members should be studied for hypoparathyroidism, deafness and renal disease and offered GATA3 gene testing.
The “HDR” triad has been found in around 65% of reported cases, while the others seem to have various combinations of hypoparathyroidism, deafness and renal disease. 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 study to confirm the diagnosis. Pathogenic variants in the GATA3 gene have not been reported in association with isolated hypoparathyroidism.
Management of patients with this syndrome should be comprehensive and include genetic counseling. Treatment is essentially symptomatic and depends on the clinical findings and severity of the disease. Hypocalcemia is usually the most common problem requiring immediate attention. Treatment of hearing loss in children should be instituted as early as possible with hearing amplification, and if needed cochlear implantation to help their speech, language and social skills so they can reach their full potential. 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 and urinary tract abnormalities might need medical or surgical treatment. Since prognosis depends on the nature and severity of the kidney disease, renal function should be carefully monitored. Chronic kidney disease should be diagnosed early and treated promptly to prevent or delay end-stage renal disease (ESRD). Renal transplantation has been performed successfully in patients with ESRD. Patients with minor kidney problems have normal life expectancy.
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Lemos MC, et al. Hypoparathyroidism, deafness and renal dysplasia syndrome: 20 years after the identification of the first GATA3 mutations. Hum Mutat. 2020; 41: 1341-50. https://doi.org/10.1002/humu.24052
Barakat AJ, et al. Barakat syndrome revisited. Am J Med Genet A. 2018; 176: 1341-8. https://doi.org/10.1002/ajmg.a.38693
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. https://doi.org/10.1093/hmg/ddl454
Muroya K, et al. GATA3 abnormalities and the phenotypic spectrum of HDR syndrome. J Med Genet. 2001; 38: 374-80. https://doi.org/10.1136/jmg.38.6.374
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. https://doi.org/10.1002/(SICI)1096-8628(19991029)86:5%3C427::AID-AJMG6%3E3.0.CO;2-I
Hasegawa T, et al. HDR syndrome (hypoparathyroidism, sensorineural deafness, renal dysplasia) associated with del(10)(p13). Am J Med Genet 1997; 73: 416-8. https://doi.org/10.1002/(sici)1096-8628(19971231)73:4%3C416::aid-ajmg9%3E3.0.co;2-l
Bilous RW, et al. Brief report: Autosomal dominant familial hypoparathyroidism, sensorineural deafness, and renal dysplasia. New Eng J Med. 1992; 327: 1069-74. https://doi.org/10.1056/nejm199210083271506
Barakat AY, et al. Familial nephrosis, nerve deafness, and hypoparathyroidism. J. Pediat. 1977; 91: 61-4.
Hypoparathyroidism, sensorineural deafness, and renal dysplasia Online Mendelian Inheritance in Man (OMIM). Entry No. 146255. Last Updated 11/10/2022. http://omim.org/entry/146255 Accessed May 11, 2023.
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