SSY Chan, HC Yau, LM Wong

Abstract

Hypoparathyroidism, sensorineural deafness, and renal dysplasia (HDR) syndrome caused by mutation in the GATA3 gene is rare. This condition can be diagnostically challenging and delay in the diagnosis can have detrimental consequences of hypocalcaemic seizures or renal failure. This is a case series of 3 Chinese patients in Hong Kong with different mutations of the GATA3 gene. Our patients show great variability in presentation of hypoparathyroidism and renal abnormalities but all 3 have deafness as a consistent feature of this syndrome. Hypoparathyroidism can be managed by replenishing calcium and active vitamin D. None of our patients showed renal failure as to date. The mutations of our patients include c.708del, c1099C>T and c.815C>T. Earlier diagnosis emphasizes the need for genetic testing or for clinicians to look for other features of HDR syndrome to help with earlier intervention of complications.

Introduction

Hypoparathyroidism, sensorineural deafness, and renal dysplasia (HDR) syndrome, also known as Barakat syndrome; is a rare autosomal-dominant disease related to GATA3 gene mutations. It was first reported in 1977¹ and there have been over 100 mutations reported since then.²

GATA3 gene is located on chromosome 10p14-15 and expressed in the parathyroid glands, kidneys, inner ear, thymus, and the central nervous system. GATA3 belongs to a family of zinc finger transcription factors (ZF-TFs), constituted by two transactivating domains (TA1 and TA2) and two highly conserved zinc finger domains.³ Mutations can include total gene deletion, nonsense mutation, intragene deletion, intragene insertion and splice mutation (Figure 1).⁴ Majority are GATA3 truncation or deletion or Zinc finger 2 (C-terminal) deletion and these cause the loss of DNA binding ability. Zinc finger 1 (N-terminal) deletion reduces GATA3 DNA binding affinity. Another type of mutation is GATA3 protein conformational changes or loss of interaction with Friends of GATA proteins (FOG).⁵

Figure 1 Percentages of the different types of GATA3 germline mutations.4

The GATA3 gene is related to embryonic development in vertebrates and mutations results in haploinsufficiency which has a broad range of penetrance and clinical expression. Most literature reports hypoparathyroidism and sensorineural deafness occurring more frequently compared to renal dysplasia. Around 90% of patients have hypoparathyroidism and sensorineural deafness and 80% have renal dysplasia.³ A more detailed percentage breakdown of HDR phenotypes of those with GATA3 germline mutations is shown in Figure 2.⁴ Hypoparathyroidism can present with seizures, stiffness, spasms, cerebral infarctions, and recurrent kidney stones. Non-progressive hearing loss is usually bilateral sensorineural deafness. Kidney manifestations have a wide range of presentations, including renal hypoplasia or aplasia, vesico-ureteric reflux, nephrotic syndrome, cystic kidney, or chronic renal failure. Patients that present with diffuse proliferative glomerulonephritis or focal segmental glomerular sclerosis may eventually develop renal failure.⁶

Figure 2 Percentages of HDR syndromes phenotype frequencies.4

There have been no worldwide reports on the incidence of this condition as the numbers are too few. However, there are reports of population difference with more occurrence in Asians (52%); more specifically Chinese. The next population noted to have more frequent occurrence are Europeans (26%) and a much smaller number in Americans and Brazilians (4%). The mean age of presentation is 5.4 years old. Many patients report to have a delayed diagnosis.²

Objective

This case series reports 3 cases of HDR syndrome in Hong Kong with different clinical profiles.

Case 1
A 6-year-old girl presented with congenital unilateral kidney and bilateral hearing loss.

This female patient was born at maturity of 38 weeks via emergency caesarean section with a birth weight of 2.54 kilograms. Antenatal scans revealed a solitary kidney. The postnatal renal ultrasound on day 27 of life showed absent left kidney and a normal sized right kidney with multiple small milk of calcium cysts that were less than 5 millimeters in size. A single photon emission computed tomography scan was performed at 5 months of age and showed no ectopic kidney.

Apart from the congenital renal anomaly, the patient was also noted to have hearing impairment after birth. On day 1 of life, automated auditory brainstem response showed a failed result on both ears. At 2 months of age, bilateral hearing loss was confirmed with a failed auditory brainstem response showing a threshold of 70 dB of both ears. Hearing aids were initiated at 7 months of age. Computed tomography scan at 9 months of age showed an aplastic or severely stenotic round window niche in the right ear and unremarkable temporal bone anatomy on the left ear. Magnetic resonance imaging showed normal acoustic meatus on bilaterally.

In view of congenital solitary kidney and bilateral moderate to severe hearing loss, genetic test by gene panel sequencing was performed at 3 years old and a heterozygous pathogenic variant c.708del in exon 3 of the GATA3 gene (NM_001002295.1) was detected.

The patient has normal neurodevelopment although she requires hearing aids. Her clinical condition is stable, and no medical treatment is required. Besides the single right kidney, serial renal ultrasound at 8 months, 4 years, and 6 years old were unremarkable and her renal function tests have been all normal. There has been regular monitoring of the serum calcium, phosphate and parathyroid hormone levels which have been normal up to the age of 6 years old.

Case 2
A 7-year-old boy first presented with asymptomatic hypocalcaemia during his neonatal period and was found to have hearing loss at 3 years old.

This male patient was born at 37 weeks via caesarean section. There was incidental finding of hypocalcaemia with serum calcium of 1.98 mmol/L [2.13-2.75 mmol/L] during routine blood taking at a few weeks of age. Serum phosphate was 2.92 mmol/L [1.55-2.71 mmol/L] and alkaline phosphatase was 346 IU/L [134-518 IU/L]. Further investigations showed hypoparathyroidism with parathyroid hormone (PTH) of <0.5 pmol/L [1.6-7.2 pmol/L] and mild vitamin D deficiency with 25-Hydroxyvitamin D of 38 nmol/L [50-220 nmol/L]. Urinary calcium to creatinine ratio was normal. Serum calcium and phosphate levels of both parents were within normal ranges.

The patient was treated with oral calcium supplement and alfacalcidol (1α-hydroxyvitamin D3) for hypoparathyroidism, and the serum calcium level normalised. Urinary calcium to creatinine ratio was normal during medical treatment and there were no features of nephrocalcinosis on renal ultrasound. Furthermore, there were no abnormal facial features suggestive of CATCH22 microdeletion syndrome and there was no cleft lip or palate. Imaging including echocardiogram and chest X-ray were normal.

However, developmental assessment at 3 years old found that his left ear had hearing loss of 65 dB and right ear had hearing loss of 75 dB. He received speech therapy training and hearing aids were initiated at 5 years of age.

Genetic testing by gene panel sequencing was performed at 5 years old based on hypoparathyroidism with bilateral hearing loss. The molecular analysis showed a pathogenic variant c1099C>T (p.Arg367*) on the GATA3 gene (NM_001002295.2).

The patient was diagnosed to have HDR syndrome due to GATA3 gene mutation. Regular monitoring of his renal function tests were normal and yearly renal ultrasounds up to the age of 7 years old have shown no abnormalities. The serum calcium levels have remained within normal range whilst on oral calcium supplement and alfacalcidol.

Case 3
A 19-year-old male first presented with neonatal seizures due to hypocalcaemia and hypoparathyroidism and was found to have hearing impairment during the neonatal period.

This male patient was born at 38 weeks via spontaneous vaginal delivery with a birth weight of 3.27 kilograms. On day 6 of life, he developed neonatal seizures that were generalised tonic-clonic seizures. Biochemical investigations revealed hypocalcaemia with serum calcium of 1.53 mmol/L [1.96-2.7 mmol/L], and hypoparathyroidism with "inappropriate normal" parathyroid hormone (PTH) level of 22.6 pg/mL [15-65 pg/mL]. Serum phosphate was 2.74 mmol/L [1.45-2.16 mmol/L] and alkaline phosphatase was 543 IU/L [130-350 IU/L]. Urine calcium to creatinine ratio was normal (0.16 mmol/mmol). This patient's mother had normal serum calcium and parathyroid hormone level.

The patient was treated with calcium supplement and calcitriol (1,25-dihydroxycholecalciferol) for his hypoparathyroidism. Hypocalcaemia resolved with medications and there was no recurrence of seizures. No significant side effects were noted during medical treatment, and monitoring of the urinary calcium to creatinine ratio was normal without hypercalciuria. Renal ultrasounds showed no sonographic evidence of nephrocalcinosis or other renal abnormalities.

In addition to hypoparathyroidism, the patient was also found to have hearing impairment during the neonatal period. He failed his newborn hearing screening test bilaterally and brainstem auditory evoked response suggested bilateral mild grade hearing loss. The brainstem auditory evoked response was repeated at 1 year of age which showed bone conduction hearing loss at 30 dB and air conduction hearing loss at 50 dB bilaterally. Hearing aids were initiated at 2 years of age.

In view of hypoparathyroidism and bilateral sensorineural hearing loss, genetic test by target gene sequencing was performed and showed pathogenic variant c.815C>T p.(Thr272Ile) on the GATA3 gene (NM_001002295.2).

The diagnosis of HDR syndrome due to GATA3 gene mutation was substantiated for this patient. No renal abnormalities have been found up to the age of 19 years old. Renal ultrasounds and renal function tests monitored regularly have been normal. The patient is asymptomatic and normocalcaemic whilst on oral calcium supplement and calcitriol.

Literature Review

HDR syndrome is described as a triad syndrome but only about half exhibit all 3 phenotypes. Deafness is usually noted during childhood, but hypoparathyroidism and renal dysplasia can remain undetected for some time. Overtime, the components of the syndrome surface with age and patients older than 50 years almost all have at least one feature of the triad as shown in Figure 3.⁴ The mean age for the diagnosis of hypoparathyroidism, sensorineural deafness and renal dysplasia was 15 years, 8 years, and 14 years, respectively. Regarding the genotype-phenotype correlation, it is noted that patients with more severe mutations had symptoms presenting at a younger age but overall, the reports show difficulty with direct correlation between mutation type and the severity.⁴

Figure 3 The cumulative frequency of HDR features in age ranges.4

The GATA3 gene mutation can usually be identified when there are two or three of HDR triad features.⁷ Some even suggest that it is justified for genetic testing for patient with isolated sensorineural deafness as it is usually the first sign of the HDR syndrome but is just a small percentage as shown in Figure 2.⁴ A study was performed in 50 patients with hearing loss that had genetic testing with a gene panel of almost 200 genes and found that 1 patient had GATA3 gene mutation.⁸ This is portraying that screening patient with isolated deafness may reveal undetected HDR syndrome patients and help with earlier diagnosis and anticipation. It was thought that detecting hearing loss in newborn screening was rare, but as more places have this routine screening it may be that there will be more earlier detection of hearing loss.

For patients with isolated hypoparathyroidism or isolated renal dysplasia, there have been occasionally reports of detecting GATA3 gene mutations. A study of 173 paediatric-onset patients that had isolated hypoparathyroidism had a 15 gene panel testing detected 4 patients with GATA3 gene mutations.⁹ Another study with 202 patients with congenital abnormalities of the kidneys found 1 patient with GATA3 gene mutation¹⁰ and another study of 650 patients found 2 patients.¹¹ The widespread use of prenatal ultrasonography can also help with detecting large structural renal abnormalities. All in all, this means that in those patients with isolated hypoparathyroidism or renal dysplasia with other HDR features excluded, those patients may not benefit from genetic testing for GATA3 gene mutation.

Treatment of HDR syndrome depends on the clinical problem. For hypoparathyroidism; hypocalcaemia and hyperphosphataemia are due to low or inappropriately normal PTH.¹² Treatment is aimed to replenish levels of calcium in which acute situations can be given intravenously with calcium gluconate. In non-acute situations, replacement can be given with oral calcium and active vitamin D. Monitoring is important as overtreatment can cause hypercalciuria and nephrocalcinosis in which care must be taken in those HDR patients with renal abnormalities.¹³ In patients with chronic hypoparathyroidism that have inadequate control with standard therapy, recombinant PTH replacement therapy can be considered, but this has yet to be reported in literature.¹² The earlier detection of deafness and correction is important for language and social development of a child. These children can be managed with hearing aids or cochlear implants.¹⁴ Renal problems need to be detected early as this majorly affects the prognosis of HDR syndrome. Monitoring and early intervention in the treatment of renal disease may prevent or slow the progression to renal failure.¹⁵

Discussion

To the best of our knowledge, our 3 cases of HDR syndrome are the first to be reported in Hong Kong. All 3 of our patients are of Chinese ethnicity. These cases of HDR syndrome have both similar and different features. The degree of hypoparathyroidism shows the marked difference. Case 1 has so far not shown any signs of hypoparathyroidism, Case 2 had asymptomatic hypoparathyroidism and Case 3 was symptomatic within the first few weeks of life. Case 1 had a unilateral kidney and Case 2 and Case 3 had normal kidneys. The common feature was that all 3 cases had bilateral hearing loss.

Data from literature also suggested that not all patients will have all 3 features of HDR syndrome. The reported percentage that has all 3 is about 50-70%. Our 3 cases coincide with other reports internationally and all have hearing impairment as the prevailing feature. The next most predominant feature is hypoparathyroidism and 2 out of 3 cases in this report had this feature. Regarding the hypoparathyroidism, 34% are reported to have seizures and a slightly higher percentage of 37% of patients are reported to have asymptomatic hypoparathyroidism. Compatible with our findings, renal abnormalities were the lowest occurrence in our cases and in those reported internationally (74%).² The cases in this study did not have brain imaging to look for calcifications in the basal ganglia as other reports have stated.5 Also, our patients did not report any behavioural or emotional problems.

For Case 1 with pathogenic variant c.708del in exon 3, the frame shift of amino acids causing a premature stop codon on 265 has been previously reported.^7,16 The other 2 patients reported with the same variant were of African American ethnicity and diagnosed in adult ages of 45 and 49 years. Both patients had hypoparathyroidism, but it is not reported whether this was symptomatic or asymptomatic. Bilateral sensorineural hearing loss from the age of 2 years was reported in both patients. Only one patient had renal cysts and both patients had bilateral kidneys. There were no reports of unilateral kidneys.¹⁶

The c.1099C>T mutation in exon 6 of Case 2 is nonsense in character and has been reported more with all cases presenting in young childhood (range 11 months - 5 years).¹⁷ There is a wide range of ethnicity in the reports including Brazilian,¹⁷ Turkish,¹⁸ Northern European,¹⁹ Japanese²⁰ and Chinese.²¹ There have been 10 cases reported worldwide with this mutation.² About 70% of cases had hypoparathyroidism and no mention of whether these were symptomatic or asymptomatic. Not all patients had sensorineural deafness, only 86% of cases. Renal abnormalities were reported in 70% of patients, these include unilateral kidney, nephrocalcinosis, proteinuria and haematuria.^9,17,19,20

Regarding the mutation of Case 3, two other reports of the c.815C>T mutation located on exon 4 and characterised by missense have been known. This mutation causes a reduction in DNA binding without affecting the stability of the binding, there is a loss of interaction of FOG2 ZnF1 and ZnF6. The transactional availability is reduced, and consistent with DNA binding reduction. The other 2 patients reported with the same mutation are of European ethnicity and both had hypoparathyroidism presenting during the neonatal period with seizures alike Case 3 in this report. The two reports found that both patients had bilateral hearing loss and abnormal position of the kidney.^22,23 Our Case 3 is slightly different to others reported in that those with missense mutations supposedly have noticeably greater number of asymptomatic hypoparathyroidism. Case 3 was the only symptomatic presentation in our case series.

Specifically related to the ethnicity of our patients, there are 15 other GATA3 genotypes reported in literature for Chinese as shown in Table 1. Case 2 in this report with genotype c.1099C>T has been reported previously in 2009 in 2 other Chinese patients.²¹ Even with the same genotype the hypoparathyroidism presented at different ages and was not present in all patients. The similar features of Case 2 with the previous case reports are that all the patients with genotype c.1099C>T have hearing impairment and normal kidneys. The genotypes of Case 1 and Case 3 have not previously been reported in Chinese.

All reported HDR syndrome in Chinese patients have hearing impairment. About half of the Chinese patients have problems with the kidneys. The most severe renal condition reported in the Chinese population was a boy presenting at 5 years old with renal failure requiring haemodialysis.³¹ The genetic diagnosis c.324delC mutation in GATA3 gene was found shortly after his presentation which emphasizes the importance of an earlier genetic diagnosis. There have been no other reports in the literature for the genotype c.324delC therefore we do not know if this mutation will likely cause severe renal failure given the clinical phenotype of GATA3 gene mutation can be so variable.

Conclusion

This is the first report of HDR syndrome in the paediatric and adult population in Hong Kong. We found that this condition has shown variable penetrance phenotype in which other parts of the world have also reported. We have compared the clinical presentation of Chinese patients with this condition and have found that even with the same gene mutation, the clinical presentation can be very different. HDR syndrome is still considered to be very rare and this rarity with the variability in phenotypic expression can sometimes make the diagnosis difficult or even delayed. Early onset hearing loss is a consistent feature and may warrant an earlier genetic investigation. Hypoparathyroidism and renal abnormalities may not always be present and if isolated, should alert clinicians to look for other features of HDR syndrome. When patients are diagnosed earlier this can help with the prevention of complications from hypocalcaemia, earlier intervention for hearing loss and hope for earlier diagnosis of any renal disease with means to stop the progression of disease. The ultimate goal is to try and improve the prognosis of these patients so that they can have a better quality of life.

Declaration of Interest

The authors declare that they have no conflicts of interest.

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