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Endocrinology, Diabetes & Metabolism... Oct 2023Barakat syndrome, also called HDR syndrome, is a rare genetic disorder encompassing hypoparathyroidism (H), sensorineural deafness (D) and renal disease (R). A...
SUMMARY
Barakat syndrome, also called HDR syndrome, is a rare genetic disorder encompassing hypoparathyroidism (H), sensorineural deafness (D) and renal disease (R). A 64-year-old woman was referred to our endocrinology clinic for a switch in treatment (from dihydrotachysterol to calcitriol). She had progressive sensorineural deafness since the age of 18 and idiopathic hypoparathyroidism diagnosed at age of 36. Her medical history included osteoporosis with hip/spine fractures, nephrolithiasis and a family history of hearing loss, osteoporosis and kidney disease. The patient's clinical presentation indicated Barakat syndrome. Genetic analysis found a GATA3:c.916C>T nonsense variant. Further tests such as audiometry, labs and renal imaging supported the diagnosis. Due to rarity and manifold symptoms, diagnosis can be challenging. Optional GATA3 testing was suggested in 2018, except in cases of isolated sensorineural deafness or renal disease with pertinent family history. In isolated 'H' cases without 'D' and 'R', GATA3 studies are not required, as no haploinsufficiency cases were reported. Given the rise in genetic disorders, physicians should consistently consider rare genetic disorders in patients with suggestive symptoms, even decades after onset. Although diagnosis might not always impact management directly, it aids patients in accepting their condition and has broader family implications.
LEARNING POINTS
There is currently an important increase in genetic and clinical characterization of new orphan diseases and their causative agents. Unbiased re-evaluation for possible genetic disorders is necessary at every consultation. It is essential to recognize the differential diagnosis of idiopathic hypoparathyroidism. The patient's clinical presentation and family history can be important to establish the correct diagnosis. Physicians should not hesitate to search a patient's signs and symptoms online.
PubMed: 38116790
DOI: 10.1530/EDM-23-0018 -
BMC Endocrine Disorders Oct 2019Barakat syndrome is an autosomal dominant rare genetic disease caused by haploinsufficiency of the GATA binding protein 3 (GATA3) gene. It is also known as HDR syndrome,...
BACKGROUND
Barakat syndrome is an autosomal dominant rare genetic disease caused by 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. This is the first report of a heterozygous GATA3 whole gene deletion causing HDR syndrome in a Sri Lankan family.
CASE PRESENTATION
A 13-year-old boy with an acute febrile illness, hypocalcaemia and bilateral carpopedal spasm was referred for evaluation. A past medical history of treatment for persistent hypocalcaemic symptoms since the age of 7 months was obtained. Biochemical investigations showed persistent low serum corrected calcium levels with hyperphosphataemia, hypomagnesaemia, low parathyroid hormone levels, hypercalciuria, and low total 25-hydroxy vitamin D levels. His renal functions and renal sonography were normal. Audiometry showed bilateral moderate to severe sensorineural hearing loss. On screening, his mother was also found to have asymptomatic hypocalcaemia, hypomagnesaemia, hyperphosphataemia, hypercalciuria and low total 25-hydroxy vitamin D levels. She had impaired renal functions and chronic parenchymal changes in the renal scan. Audiometry showed bilateral profound sensorineural hearing loss. Genetic analysis using multiplex-ligation dependent probe amplification showed a reduced gene dosage for GATA3 that is consistent with a heterozygous whole gene deletion in both the child and mother.
CONCLUSIONS
This report demonstrates the wide intra-familial phenotypic variability observed in HDR syndrome and adds further to the existing scientific literature on the genotype-phenotype correlation of this syndrome. It highlights the need for HDR syndrome to be considered in the differential diagnosis of persistent hypocalcaemia with sensorineural deafness and/or renal involvement, and for appropriate genetic evaluation to be done to confirm the diagnosis.
Topics: Adult; Aged; Biomarkers; Blood Glucose; Case-Control Studies; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Female; Follow-Up Studies; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Male; Middle Aged; Prognosis; Prospective Studies
PubMed: 31660939
DOI: 10.1186/s12902-019-0438-4 -
Molecular Genetics & Genomic Medicine May 2020Barakat syndrome is an autosomal dominant disorder characterized by the triad of hypoparathyroidism, sensorineural deafness, and renal anomalies and is caused by...
BACKGROUND
Barakat syndrome is an autosomal dominant disorder characterized by the triad of hypoparathyroidism, sensorineural deafness, and renal anomalies and is caused by mutations in GATA3 gene. SLC34A3 is the cause gene of hypophosphatemic rickets with hypercalciuria, and heterozygous carriers may have milder clinical symptoms. The aim of this study was to identify the underlying genetic cause of a patient who initially presented with renal failure, hypercalciuria, kidney stone, and bilateral sensorineural deafness.
METHODS
A 6-year-old boy with complex clinical presentations was investigated. Comprehensive medical evaluations were performed including auditory function tests, endocrine function tests, metabolic studies, and imaging examinations. Molecular diagnoses were analyzed by trio whole-exome sequencing.
RESULTS
One novel de novo deleterious variant (c. 324del) of the GATA3 gene was identified in the patient. The patient can be diagnosed with Barakat syndrome. In addition, one novel variant (c. 589A>G) of the SLC34A3 gene was detected, which was inherited from the father. This heterozygous variant can explain the hypercalciuria and kidney stone that occurred in both the patient and his father.
CONCLUSION
This study provides a special case which is phenotype-driven dual diagnoses, and the two novel variants can parsimoniously explain the complex clinical presentations of this patient.
Topics: Adult; Child; GATA3 Transcription Factor; Hearing Loss, Sensorineural; Heterozygote; Humans; Hypercalciuria; Hypoparathyroidism; Male; Mutation; Nephrosis; Pedigree; Sodium-Phosphate Cotransporter Proteins, Type IIc
PubMed: 32155322
DOI: 10.1002/mgg3.1222 -
Nefrologia : Publicacion Oficial de La... 2016
Topics: Deafness; Hearing Loss, Sensorineural; Humans; Hypoparathyroidism; Kidney Diseases; Nephrosis; Syndrome
PubMed: 26651600
DOI: 10.1016/j.nefro.2015.04.003 -
JCEM Case Reports Jan 2023HDR syndrome is a rare genetic disorder caused by mutations in the gene and characterized by hypoparathyroidism, sensorineural deafness, and renal disease. Here, we...
HDR syndrome is a rare genetic disorder caused by mutations in the gene and characterized by hypoparathyroidism, sensorineural deafness, and renal disease. Here, we report case of a 9-month-old male with history of hydronephrosis and sensorineural deafness who presented with febrile seizures. He was found to have hypocalcemia and inappropriately normal parathyroid hormone. His neurologic and infectious workup were negative. Genetic testing revealed a nonsense mutation in the gene, consistent with HDR syndrome. Hypocalcemia was responsive to calcium carbonate and calcitriol treatment. This case highlights hypocalcemia caused by hypoparathyroidism as a potential etiology of seizures. When hypoparathyroidism is detected with either hearing loss or renal disease, HDR syndrome should be considered, and other features of the syndrome should be investigated.
PubMed: 37908274
DOI: 10.1210/jcemcr/luac025 -
Indian Journal of Nephrology 2020
PubMed: 32269443
DOI: 10.4103/ijn.IJN_132_19 -
Cureus Apr 2022Unlike hyperparathyroidism, hypoparathyroidism is rarely encountered in clinical practice. Usually, it results from surgical resection, an autoimmune phenomenon, or an...
Unlike hyperparathyroidism, hypoparathyroidism is rarely encountered in clinical practice. Usually, it results from surgical resection, an autoimmune phenomenon, or an infiltrative process. Under certain circumstances, one may encounter a genetic etiology of hypoparathyroidism, often combined with myriad other syndromic manifestations. We report a case of a young female with congenital deafness and subacute visual loss. Hypocalcemia and primary hypoparathyroidism were subsequently discovered, and the cause of the vision loss was diagnosed as idiopathic intracranial hypertension, likely secondary to severe primary hypoparathyroidism. The patient was also found to have small bilateral kidneys, with tubular loss of magnesium and calcium, yet with a normal glomerular filtration rate. The constellation of congenital deafness, hypoparathyroidism, and renal dysfunction suggests Barakat syndrome, one of the less common causes of syndromic primary hypoparathyroidism.
PubMed: 35651450
DOI: 10.7759/cureus.24521 -
Scientific Reports Nov 2021Transcription factors (TFs) play important roles in many biochemical processes. Many human genetic disorders have been associated with mutations in the genes encoding...
Transcription factors (TFs) play important roles in many biochemical processes. Many human genetic disorders have been associated with mutations in the genes encoding these transcription factors, and so those mutations became targets for medications and drug design. In parallel, since many transcription factors act either as tumor suppressors or oncogenes, their mutations are mostly associated with cancer. In this perspective, we studied the GATA3 transcription factor when bound to DNA in a crystal structure and assessed the effect of different mutations encountered in patients with different diseases and phenotypes. We generated all missense mutants of GATA3 protein and DNA within the adjacent and the opposite GATA3:DNA complex models. We mutated every amino acid and studied the new binding of the complex after each mutation. Similarly, we did for every DNA base. We applied Poisson-Boltzmann electrostatic calculations feeding into free energy calculations. After analyzing our data, we identified amino acids and DNA bases keys for binding. Furthermore, we validated those findings against experimental genetic data. Our results are the first to propose in silico modeling for GATA:DNA bound complexes that could be used to score effects of missense mutations in other classes of transcription factors involved in common and genetic diseases.
Topics: Binding Sites; Breast Neoplasms; DNA; Female; GATA3 Transcription Factor; Hearing Loss, Sensorineural; Humans; Hypoparathyroidism; Mutation; Nephrosis
PubMed: 34815386
DOI: 10.1038/s41598-021-01832-z -
BMC Medical Genetics Oct 2017Hypoparathyroidism, sensorineural hearing loss, and renal disease (HDR) syndrome, also known as Barakat syndrome, is a rare genetic disorder with high phenotypic...
BACKGROUND
Hypoparathyroidism, sensorineural hearing loss, and renal disease (HDR) syndrome, also known as Barakat syndrome, is a rare genetic disorder with high phenotypic heterogeneity caused by haploinsufficiency of the GATA3 gene on chromosome 10p14-p15. For these reasons, the diagnosis of HDR syndrome is challenging and requires a high index of suspicion as well as genetic analysis.
CASE PRESENTATION
A 14-month-old boy, with sensorineural hearing loss in both ears, showed typical radiological features of X-linked stapes gusher on preoperative temporal bone computed tomography (CT) for cochlear implantations. Then after his discharge from hospital, he suffered a hypocalcemic seizure and we discovered a renal cyst during investigation of hypocalcemia. He was finally diagnosed with HDR syndrome by clinical findings, which were confirmed by molecular genetic testing. Direct sequencing of the GATA3 gene showed a heterozygous 2-bp deletion (c.1201_1202delAT), which is predicted to cause a frameshift of the reading frame (p.Met401Valfs*106).
CONCLUSIONS
To our knowledge, this is the first case of HDR syndrome with a novel de novo variant mimicking a congenital X-linked stapes gusher syndrome. Novel mutations and the diversity of clinical manifestations expand the genotypic and phenotypic spectrum of HDR syndrome. Diagnosis of HDR syndrome is still challenging, but clinicians should consider it in their differential diagnosis for children with a wide range of clinical manifestations including hypocalcemia induced seizures and deafness. We hope that this case will contribute to further understanding and studies of HDR-associated GATA3 mutations.
Topics: Chromosomes, Human, Pair 10; Cochlear Implantation; Diagnosis, Differential; Frameshift Mutation; GATA3 Transcription Factor; Gene Expression; Genetic Diseases, X-Linked; Haploinsufficiency; Hearing Loss, Conductive; Hearing Loss, Sensorineural; Heterozygote; Humans; Hypoparathyroidism; Infant; Male; Nephrosis; Tomography, X-Ray Computed
PubMed: 29073906
DOI: 10.1186/s12881-017-0484-6 -
Indian Pediatrics Aug 2018HDR syndrome (also known as Barakat syndrome) is a rare genetic disorder due to deletions/mutations on specific regions of zinc-finger transcription factor (GATA3) gene.
BACKGROUND
HDR syndrome (also known as Barakat syndrome) is a rare genetic disorder due to deletions/mutations on specific regions of zinc-finger transcription factor (GATA3) gene.
CASE CHARACTERISTICS
A male preterm infant presented with multiple dysmorphic features characterized by small for gestational age, hypognathia and facial abnormalities.
OBSERVATION
Investigations revealed hypocalcemia and low parathyroid hormone levels and bilateral sensorineural deafness.
OUTCOME
Chromosomal microarray analysis revealed a combination of deletion on chromosome 10p (10p15.3p14) with loss of GATA3 gene and duplication of chromosome 20p (20p13p12.3) as a result of unbalanced 10:20 translocation.
MESSAGE
Detecting this syndrome at neonatal age is very important because it allows early intervention to minimize future clinical problems.
Topics: Base Sequence; Chromosomes, Human, Pair 10; Chromosomes, Human, Pair 20; GATA3 Transcription Factor; Genetic Markers; Hearing Loss, Sensorineural; Humans; Hypoparathyroidism; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Male; Nephrosis; Sequence Deletion; Trisomy
PubMed: 30218523
DOI: No ID Found