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Hypoparathyroidism-sensorineural deafness-renal disease syndrome
Hypoparathyroidism-sensorineural deafness-renal disease syndrome is a rare, clinically heterogeneous genetic disorder characterized by the triad of hypoparathyroidism (H), sensorineural deafness (D) and renal disease (R).
ORPHA:2237Classification level: Disorder
The exact prevalence is unknown, but the syndrome is considered to be very rare. So far, about 180 individuals from different racial and ethnic groups have been reported in the worldwide medical literature. Patients of both sexes have been described.
HDR syndrome may present at any age with deafness, hypocalcemia, tetany and afebrile convulsions. Since prenatal ultrasonography is now a routine, congenital kidney and urinary tract anomalies could be the first presenting finding. ''H'' occurs in 93% of patients. ''D'' occurs in 96% of patients and is usually 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, hematuria, proteinuria and others. Several additional features, such as congenital heart disease, facial and ocular abnormalities (retinitis pigmentosa, nystagmus, pseudopapilledema), basal ganglia calcifications, psoriasis, growth failure, and cognitive disability, among others, have also been described.
HDR syndrome is primarily caused by mutations in GATA3, located on chromosome 10p (10p14). However, since GATA3 defects have not been detected in all reported patients, the presence of other gene defects being associated is possible. GATA3 belongs to a family of dual zinc-finger transcription factors involved in vertebrate embryonic development of the parathyroid glands, auditory system, and kidneys, as well as the thymus and central nervous system. Variability of expression and incomplete penetrance of GATA3 mutations results in the phenotypic heterogeneity observed.
Diagnosis is based on the clinical findings and may be assisted by measurement of parathormone levels, an audiogram or auditory brain stem response study, renal imaging studies, and, if indicated, a renal biopsy. Although the syndrome is phenotypically defined by the ''HDR'' triad, only 65% of reported patients present it, while the others have various combinations of ''H'', ''D'', and ''R''. Diagnosis is confirmed in patients who have the ''HDR'' triad or, alternatively, have two out of three features plus a positive family history. Patients with isolated deafness or renal disease and those who do not fit the above criteria need positive GATA3 testing to confirm the diagnosis. GATA3 mutations have not been associated with isolated hypoparathyroidism.
Differential diagnoses include familial idiopathic hypoparathyroidism, progressive sensorineural deafness without renal disease, autosomal recessive hypoparathyroidism with renal insufficiency and developmental delay, and deletion 22q11 syndrome. HDR syndrome should be considered in infants prenatally diagnosed with chromosome 10p defect or congenital anomalies of the kidney and urinary tract.
Inheritance is autosomal dominant. Family members of affected patients should be studied, investigating for ''H'', ''D'', and ''R''. GATA3 testing should be considered.
Management and treatment
Treatment of patients with HDR syndrome should be comprehensive and should include genetic counseling. Management is essentially symptomatic and depends on the specific clinical findings and severity of the disease. Hypocalcemia is usually the most common problem requiring treatment. Deafness should be treated early with hearing amplification, and, if needed, cochlear implantation. Treatment of kidney disease depends on the particular abnormality and ranges from close observation, such as for cysts, to medical or surgical treatment, including renal transplantation. Chronic kidney disease should be diagnosed and treated early to prevent or delay end-stage renal disease.
Prognosis depends on the nature and severity of the kidney disease. Patients with minor kidney problems have normal life expectancy.