Hypoparathyroidism, Sensorineural Deafness, And Renal Disease

A number sign (#) is used with this entry because the phenotype of hypoparathyroidism, sensorineural deafness, and renal disease (HDR), also known as Barakat syndrome, is caused by haploinsufficiency of the GATA3 gene (131320) on chromosome 10p14.

Clinical Features

Barakat et al. (1977) reported steroid-resistant nephrosis with progressive renal failure and death at ages 5 and 8 years in 2 brothers who also had nerve deafness and hypoparathyroidism. At autopsy, the parathyroid glands were absent in 1 child and hypoplastic in the other. Barakat et al. (1977) also described male twins from another family with similar findings and death at age 3 years. At autopsy, their parathyroid glands were fibrotic and glomerular basement membranes were thickened. The same syndrome may have been present in the families reported by Yumita et al. (1986) and Shaw et al. (1991).

Bilous et al. (1992) described 2 brothers and 2 daughters of 1 of the brothers with hypoparathyroidism, sensorineural deafness, and renal dysplasia. The deafness consisted of a bilateral, symmetric, sensorineural deficit affecting all frequencies but slightly more marked at the higher end of the frequency range. A similarity of the deficit in the adults and children studied suggested that it was not progressive, and the patients did not believe that their hearing loss had changed with age. Intravenous urography showed changes consistent with the presence of bilateral renal dysplasia; they had small, irregular kidneys and abnormally compressed collection systems. Four other members of the most recent generation were either partially affected or possibly affected. Possibly similar reported families were reviewed. Autosomal dominant hypoparathyroidism (146200) and X-linked hypoparathyroidism (307700) have been described. Hypoparathyroidism also occurs in the autosomal dominant DiGeorge syndrome (188400) and occurs in association with candidosis and ectodermal dysplasia in the autosomal recessive syndrome of autoimmune polyendocrinopathy (240300).

Phenotypically, the disorder with presumed autosomal recessive inheritance described by Barakat et al. (1977) is very similar to the disorder described by Bilous et al. (1992). Barakat (1997) rightly suggested that the mode of inheritance may not be a fundamental difference; the disorder in the 2 families may be due to different mutations in the same gene. Hasegawa et al. (1997) and Hasegawa (1998) suggested that the inheritance in the family of Barakat et al. (1977) might be autosomal dominant with reduced penetrance since the paternal grandmother and her 3 sibs had hearing loss.

Watanabe et al. (1998) ascertained a 3-generation family through a male infant admitted to hospital for seizures that began at 10 days of age. Despite serum and urinary biochemical findings typical of hypoparathyroidism, there were no clinical features of CATCH22 and the karyotype was normal without microdeletion of 22q11.2 by an in situ hybridization method. Five family members were found to have hypoparathyroidism with sensorineural deafness. Normal DNA sequence was found for the PTH gene (168450) and for the calcium-sensing receptor (CASR; 601199). This family was distinguished by the lack of renal dysplasia. Renal tubular function and renal imaging were normal.

Ferraris et al. (2009) studied a 14-year-old boy who had symptomatic hypoparathyroidism, bilateral sensorineural deafness, unilateral renal dysplasia, bilateral palpebral ptosis, and horizontal nystagmus. Funduscopy revealed symmetric pseudopapilledema, and brain CT scan showed basal ganglia calcifications.

Moldovan et al. (2011) reported a 29-year-old Portuguese woman with severe hypoparathyroidism, bilateral mild neurosensory deafness that was diagnosed in childhood, and agenesis of the vagina and uterus. She had normal renal and abdominal ultrasound and normal renal function. Pelvic ultrasound showed absence of the uterus and vagina, normal uterine adnexae, and a left ovarian cyst. The authors stated that this was the third case of female genital tract malformation associated with HDR, including the mother and daughter reported by Hernandez et al. (2007).

Cytogenetics

Hasegawa et al. (1997) found this syndrome, which they referred to as HDR syndrome (for hypoparathyroidism, deafness, and renal dysplasia), in a Japanese girl with a de novo deletion of 10p13. The experience led them to suggest that the gene responsible for HDR syndrome is located in the 10pter-p13 region. Hasegawa et al. (1997) found reports of 14 patients with deletion of 10p13: 5 had hypoparathyroidism or hypocalcemia, 6 had urinary tract abnormalities (such as renal dysplasia, agenesis of unilateral kidney, or vesicoureteral reflux), and 2 had deafness. Partial DiGeorge syndrome (188400) was diagnosed in 4 of 5 patients with hypoparathyroidism. None of the patients had all components of the triad of HDR syndrome, however.

Van Esch et al. (1999) described 2 patients with a partial DiGeorge syndrome (facial dysmorphism, hypoparathyroidism, renal agenesis, mental retardation) and a rearrangement of chromosome 10p.

Fujimoto et al. (1999) reported a Japanese boy with HDR syndrome and recurrent cerebral infarctions in the basal ganglia. Chromosome analysis demonstrated a de novo deletion of 10p15.1-p14, suggesting that the putative gene responsible for HDR syndrome is located at 10p15.1-p14.

Lichtner et al. (2000) reported clinical and molecular deletion analysis of a patient described by Hasegawa et al. (1997) and a new case, both with the HDR phenotype: hypoparathyroidism, deafness, and renal dysplasia. They were found to have partial monosomy for 10p due to terminal deletions with breakpoints between D10S585 and D10S1720. By comparison with data previously published on patients with DiGeorge/velocardiofacial syndrome associated with 10p monosomy (see 601362), Lichtner et al. (2000) concluded that HDR is a contiguous gene syndrome. Hemizygosity for a proximal region can cause cardiac defects and T cell deficiency; hemizygosity for a more distal region can cause hypoparathyroidism, sensorineural deafness, and renal dysplasia.

Bernardini et al. (2009) reported a 14-month-old girl with the HDR triad associated with psychomotor delay, facial dysmorphism, bilateral cleft lip/palate, tetralogy of Fallot, and tapering fingers and malpositioned toes with cutaneous syndactyly of toes 2 and 3. Array comparative genomic hybridization (CGH) analysis identified a 6.5-Mb deletion of chromosome 10p15.3-p15.1, as well as a 1.9-Mb duplication of chromosome 10p15.1-p14. Both imbalances were de novo. The duplicated sequence included the GATA3 gene and 1.5 Mb upstream and 0.3 Mb downstream of GATA3; real-time PCR confirmed a 2-fold increase in GATA3 copy number compared to controls, and direct DNA sequencing did not show any alteration in GATA3 sequence. Bernardini et al. (2009) suggested that both GATA3 deletion and duplication could lead to a similar phenotype.

Molecular Genetics

Van Esch et al. (2000) performed deletion-mapping studies in 2 HDR patients (see 131320.0001 and 131320.0002) and defined a critical 200-kb region that contains the GATA3 gene (131320). This gene belongs to a family of zinc finger transcription factors that are involved in vertebrate embryonic development. Search for GATA3 mutations in 3 other HDR probands identified 1 nonsense mutation (131320.0005) and 2 intragenic deletions (131320.0003, 131320.0004) that predicted a loss of function, as confirmed by absence of DNA binding by the mutant GATA3 protein. These results demonstrated that GATA3 is essential in the embryonic development of the parathyroids, auditory system, and kidneys, and showed that GATA3 haploinsufficiency causes human HDR syndrome.

Muroya et al. (2001) reported analysis of the GATA3 gene in 9 Japanese families with HDR syndrome. Sequence analysis showed heterozygous novel mutations in 3 families, including missense (131320.0006), insertion (131320.0007), and nonsense (131320.0008) mutations. Deletions of GATA3 were found in 4 families; the chromosome with the deletion was of paternal origin in 3 of these. No mutations were identified in 2 families. The phenotype was variably expressed between and within families. One individual had repeated cerebral infarction which the authors suggested might be related to GATA3 haploinsufficiency since GATA3 is expressed in the central nervous system. Of the 2 families in which no GATA3 abnormalities were detected, typical features of HDR were present in one, but atypical features, including retinitis pigmentosa (268000) and severe growth failure in addition to the HDR triad, were found in the other.

Hernandez et al. (2007) reported a mother and daughter with HDR and female genital tract malformations in whom they identified a deletion in the GATA3 gene (131320.0009). The mother had a nonfunctional right kidney and a septate uterus, whereas her daughter had right renal agenesis and uterus didelphys with septate vagina. An unaffected sister and maternal aunt, who did not carry the mutation, had no uterine anomalies.

In a 14-year-old boy with neurologic symptoms in addition to the HDR syndrome triad of hypoparathyroidism, sensorineural deafness, and renal dysplasia, who did not have any microdeletion in the 22q11.2 or 10p14 regions by FISH analysis, Ferraris et al. (2009) identified heterozygosity for a de novo 2-bp deletion (131320.0013) in exon 2 of the GATA3 gene, predicted to cause premature termination of the protein. Ferraris et al. (2009) concluded that haploinsufficiency of GATA3 may be responsible for a complex neurologic picture in addition to the known triad of HDR syndrome. Ferraris et al. (2009) stated that 46 HDR cases had been reported, 44 of which had undergone molecular analysis, with another 31 cases known in probands' parents or relatives; they tabulated the clinical and molecular findings of reported patients to date.

Sun et al. (2009) reported a Han Chinese brother and sister with hypoparathyroidism and sensorineural hearing impairment, in whom they identified heterozygosity for a GATA3 nonsense mutation (R367X; 131320.0008), previously identified in a Japanese man with HDR syndrome (Muroya et al., 2001). The Chinese sibs did not have any apparent renal disease. The mutation was not found in either of their unaffected parents; Sun et al. (2009) concluded that 1 of the parents likely had germinal mosaicism of the mutant GATA3 gene.

In a 29-year-old Portuguese woman who had severe hypoparathyroidism, bilateral mild neurosensory deafness, and agenesis of the vagina and uterus but no kidney abnormalities, Moldovan et al. (2011) analyzed the GATA3 gene and identified a heterozygous missense mutation (C342Y; 131320.0014). The authors noted that this case, along with the mother and daughter studied by Hernandez et al. (2007) who also had HDR and female genital tract malformations, seemed to confirm the role of GATA3 in regulating developmental mechanisms of the uterus and vagina.