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Vnitrni Lekarstvi 2023Barakat syndrome, also known as HDR syndrome, is a clinically heterogenous, autosomal dominant rare genetic disease, which frequency is unknown. It is primarily caused...
Barakat syndrome, also known as HDR syndrome, is a clinically heterogenous, autosomal dominant rare genetic disease, which frequency is unknown. It is primarily caused by deletion of chromosome 10p14 or mutation of GATA3 gene, located on chromosome 10. Although this syndrome is phenotypically defined by its triad of HDR: hypoparathyroidism (H), deafness (D), renal disease (R), the literature identifies cases with different components, consisting of HD, DR, HR (1). The syndrome was first described by Amin J. Barakat et al. in 1977 in siblings with hypocalcemia and proteinuria (2). So far, about 180 cases have been reported in the worldwide medical literature (3). In this report we present our own case report of patient with Barakat syndrome with hypoparathyrodism, unilateral deafness and renal impairment.
Topics: Humans; Nephrosis; Hearing Loss, Sensorineural; Hypoparathyroidism; Syndrome
PubMed: 37468331
DOI: 10.36290/vnl.2023.036 -
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 -
Auris, Nasus, Larynx Apr 2024Hypoparathyroidism, deafness, and renal dysplasia (HDR) syndrome is an autosomal dominant disorder. Because HDR syndrome is caused by haploinsufficiency in GATA3, it...
Hypoparathyroidism, deafness, and renal dysplasia (HDR) syndrome is an autosomal dominant disorder. Because HDR syndrome is caused by haploinsufficiency in GATA3, it exhibits variation in the onset and progression of hearing loss. In previous reports, the automated auditory brainstem response (AABR) was considered insufficient to detect sensorineural hearing loss caused by HDR syndrome. We report a case of HDR syndrome whose congenital hearing loss was detected by newborn hearing screening (NHS) using AABR. In this case, HDR syndrome was suspected due to hearing loss, hypocalcemia, and her family history. Genetic testing confirmed the diagnosis of HDR syndrome at 5 months of age. Because the phenotype of hearing loss due to HDR syndrome is variable and includes progressive hearing loss, these cases may not be detected by the HNS. However, most of the previous reports were published before the NHS became common and given the frequency of hearing loss complications in HDR syndrome. We consider that there is a reasonable number of HDR syndrome cases with abnormalities on the NHS. We believe that the NHS may also be useful for early detection of hearing loss due to HDR syndrome.
Topics: Humans; Infant, Newborn; Female; Hearing Loss, Sensorineural; Hearing Loss; Hypoparathyroidism; Hearing; Neonatal Screening; Kidney Tubules, Proximal; Nephrosis; Urogenital Abnormalities
PubMed: 37640596
DOI: 10.1016/j.anl.2023.08.007 -
Journal of Endocrinological... Feb 2024Hypoparathyroidism, deafness, and renal dysplasia (HDR) syndrome, also known as Barakat syndrome, is a rare autosomal dominant disease characterized by the triad of...
PURPOSE
Hypoparathyroidism, deafness, and renal dysplasia (HDR) syndrome, also known as Barakat syndrome, is a rare autosomal dominant disease characterized by the triad of hypoparathyroidism, deafness, and renal abnormalities. The disorder is caused by the haploinsufficiency of the zinc finger transcription factor GATA3 and exhibits a great clinical variability with an age-dependent penetrance of each feature. We report two unrelated kindreds whose probands were referred to our outpatient clinic for further evaluation of hypoparathyroidism.
METHODS
The proband of family 1, a 17-year-old boy, was referred for severe hypocalcemia (5.9 mg/dL) incidentally detected at routine blood tests. Abdomen ultrasound showed bilateral renal cysts. The audiometric evaluation revealed the presence of bilateral moderate hearing loss although the patient could communicate without any problem. Conversely, the proband of family 2, a 19-year-old man, had severe symptomatic hypocalcemia complicated by epileptic seizure at the age of 14 years; his past medical history was remarkable for right nephrectomy at the age of 4 months due to multicystic renal disease and bilateral hearing loss diagnosed at the age of 18 years.
RESULTS
Based on clinical, biochemical, and radiologic data, HDR syndrome was suspected and genetic analysis of the GATA3 gene revealed the presence of two pathogenetic variants in exon 3, c.404dupC and c.431dupG, in the proband of family 1 and 2, respectively.
CONCLUSION
HDR syndrome is a rare cause of hypoparathyroidism and must be excluded in all patients with apparently idiopathic hypoparathyroidism. A correct diagnosis is of great importance for early detection of other HDR-related features and genetic counseling.
Topics: Male; Humans; Adolescent; Infant; Young Adult; Adult; Hypocalcemia; Hypoparathyroidism; Deafness; Italy; Hearing Loss, Sensorineural; Nephrosis
PubMed: 37561279
DOI: 10.1007/s40618-023-02171-8 -
Molecular Genetics and Metabolism... Mar 2024Hypoparathyroidism, sensorineural deafness, and renal dysplasia (HDR) syndrome (Barakat syndrome) is a rare autosomal dominant disorder caused by mutations in the gene...
BACKGROUND
Hypoparathyroidism, sensorineural deafness, and renal dysplasia (HDR) syndrome (Barakat syndrome) is a rare autosomal dominant disorder caused by mutations in the gene encoding on chromosome 10p14.
METHOD
Informed consent was obtained from a 38-year-old female patient. 5 mL of venous blood was collected and sent for whole-exome sequencing. constructs of both wild-type and mutant were transfected into HEK-293 T cells. Three-dimensional modeling, luciferase-reporter gene test, western blotting and cellular immunofluorescence were used to evaluate the effect of the mutation.
RESULTS
A novel frameshift mutation c. 677dup(p.Pro227AlafsTer77), named P227Afs, was found in . Three-dimensional modeling revealed that the mutation caused the loss of the dual zinc finger structures 1 and 2 (ZNF1 and ZNF2) of the synthesized protein. Expression of wild-type GATA3 produced a six-fold increase in luciferase activity when compared with pcDNA3.1 vector only ( < 0.001), whereas the P227Afs mutant showed no increase. The mutation significantly reduced the transcriptional activity of . Immunofluorescence and western blotting analyses demonstrated that the mutation changed the nuclear location of GATA3 and caused difficulty in nuclearization.
CONCLUSION
A novel heterozygous frameshift mutation in was identified and showed to result in difficult nuclearization, and a dominant-negative effect on the wild-type.
PubMed: 38469092
DOI: 10.1016/j.ymgmr.2024.101063 -
Frontiers in Endocrinology 2023The HDR syndrome is a rare autosomal dominant disorder characterised by Hypoparathyroidism, Deafness, and Renal dysplasia, and is caused by inactivating heterozygous...
The HDR syndrome is a rare autosomal dominant disorder characterised by Hypoparathyroidism, Deafness, and Renal dysplasia, and is caused by inactivating heterozygous germline mutations in the gene. We report an 11-year-old girl with HDR syndrome caused by a heterozygous mutation located at the splice acceptor site of exon 5 of the gene (NM_001002295.2: c.925-1G>T). Functional studies using a minigene assay showed that this splice site mutation abolished the normal splicing of the pre-mRNA and led to the use of a cryptic splice acceptor site, resulting in the loss of the first seven nucleotides (TCTGCAG) of exon 5 in the mRNA. These findings increase the understanding of the mechanisms by which splicing mutations can cause HDR syndrome.
Topics: Female; Humans; Child; RNA Splice Sites; Hypoparathyroidism; Mutation; Deafness; GATA3 Transcription Factor
PubMed: 37600721
DOI: 10.3389/fendo.2023.1207425