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Copyright 2008, 2012
NORD is very grateful to Amin J. Barakat, MD, FAAP, Clinical Professor of Pediatrics/Nephrology, Georgetown University Medical Center, for the preparation of this report.
Barakat syndrome is a rare genetic disorder with clinical diversity, characterized by 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), nerve deafness and kidney disease. Patients may present with hypocalcaemia, involuntary contraction of muscles (tetany), or afebrile convulsions at any age. Hearing loss is usually bilateral and may range from mild to profound impairment. Reported kidney abnormalities include nephrotic syndrome (kidney damage resulting in loss of large amounts of protein in the urine), chronic kidney disease, hematuria (blood in the urine), proteinuria (increased protein excretion in the urine), and various congenital kidney anomalies including cystic kidney, renal dysplasia (disorganized kidney tissue), hypoplasia (abnormally small Kidney), or aplasia (absence of kidney), and urologic abnormalities such as pevicalyceal deformity and vesicoureteral reflux.
Other abnormalities associated with the syndrome include female genital malformations (agenesis of vagina and uterus, ovarian cyst), ocular abnormalities (retinitis pigmentosa, nystagmus, pseudopapilledima, ptosis), psychomotor delay and growth failure.
Patients may present with symptoms associated with hypocalcaemia (low blood calcium) , such as muscle weakness, tetany, and convulsions as well as findings related to kidney disease such as proteinuria (increased excretion of protein in the urine), hematuria (blood in the urine), or nephrotic syndrome. Nerve deafness may be documented by a hearing test. The syndrome has also been associated with a heart defect and cleft palate and other atypical findings including retinitis pigmentosa (an eye condition producing blindness), psoriasis and severe growth failure.
Inheritance of Barakat syndrome is probably autosomal dominant. 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 disease may have variable expression in different family members from severe to mild to absent (reduced penetrance). Autosomal recessive or X-linked inheritance have been suspected in the original report, but Hasegawa et al suggested that inheritance in these patients might be autosomal dominant with reduced penetrance.
The defect in the majority of cases has mapped to chromosome10p (10p13, 10pter-p13, 10p13:5, 10p15.1-p14, 10p15.3-p15.1). Deletions of zinc-finger transcription factor (GATA3) gene or mutations in the GATA3 gene are essential in the embryonic development of the parathyroids, auditory system and kidneys, and appear to be the underlying cause of this syndrome. The occurrence of diverse renal abnormalities would not be inconsistent with a single gene mutation. Other unspecified genetic factors may play a role in the severity of the disease.
The prevalence is unknown, but the disease is considered to be rare. Affected individuals have been identified from various countries including the United States, Japan, Europe and the Middle East. Clinical awareness of this syndrome will probably increase the number of patients diagnosed. It affects males and females of any age equally.
The diagnosis is based on the clinical findings of hypoparathyroidism, nerve deafness and kidney disease. Suspected patients should benefit from the following tests: parathormone (PTH) levels, a hearing test, imaging studies of the kidneys, and a kidney biopsy in the presence of nephrotic syndrome, hematuria or proteinuria. The syndrome should be considered in infants who have been prenatally diagnosed with a chromosome 10p defect and those who have been diagnosed with well-defined phenotypes of urinary tract abnormalities. Siblings should be studied for deafness, parathyroid and renal disease. Molecular genetic testing for the GATA3 gene can be performed in specialized genetic labs.
Treatment consists of treating the low serum calcium associated with hypoparathyroidism as well as the deafness. The treatment of kidney disease depends on the abnormality. Some minor abnormalities not associated with other problems, such as cysts or small kidneys need no treatment, but require close observation. Certain kidney abnormalities might need medical or surgical treatment and prognosis depends on the nature and severity of the kidney disease. Patients with minor kidney disease should have a normal life expectancy.
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Moldovan D., et al. A new case of HDR syndrome with severe female genital tract malformation: comment on 'Novel mutation in the gene encoding the GATA3 transcription factor in a Spanish familial case of hypoparathyroidism, deafness, and renal dysplasia (HDR) syndrome with female genital tract malformations' by Hernandez et al. (Letter)Am. J. Med. Genet. 155A: 2329-2330, 2011. http://www.ncbi.nlm.nih.gov/pubmed/21834031
Muroya K, et al. GATA3 abnormalities and the phenotypic spectrum of HDR syndrome. J Med Genet 2001; 38: 374-80.
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 Gene 1999; 86: 427-9.
Hasegawa T, et al. HDR syndrome (hypoparathyroidism, sensorineural deafness, renal dysplasia) associated with del(10)(p13). Am J Med Genet 1997; 73: 416-8.
Bilous RW, et al. Brief report: Autosomal dominant familial hypoparathyroidism, sensorineural deafness, and renal dysplasia. New Eng J Med 1992; 327: 1069-74.
Barakat AY, et al. Familial nephrosis, nerve deafness, and hypoparathyroidism. J. Pediat 1977; 91: 61-4.
McKusick VA, ed. Online Mendelian Inheritance in Man (OMIM), Baltimore, MD. The Johns Hopkins University; Entry No. 146255 Last Updated 12/16/11 http://omim.org/entry/146255 Accessed on: 1/26/12.
Report last updated: 2012/01/31 00:00:00 GMT+0