A Novel De Novo GATA Binding Protein 3 Mutation in a Turkish Boy with Hypoparathyroidism, Deafness, and Renal Dysplasia Syndrome.

Hypoparathyroidism, deafness, and renal dysplasia (HDR; OMIM 146255) syndrome is a rare disease, inherited dominantly and found to be related with GATA3 (GATA binding protein 3) gene mutations. A 13-year and 8-month-old boy who presented with hypocalcemia was diagnosed with hypoparathyroidism. He also had dysmorphic facial features, renal anomaly (pelvic kidney), and mild sensorineural hearing loss. His cranial computed tomography revealed multiple calcifications in bilateral centrum semiovale, corona radiata, and basal ganglions suggesting a persistent hypoparathyroidism. Thus, the presence of triad of HDR syndrome was considered, and genetic analysis using a next-generation sequencer identified a novel de novo missense mutation in exon 4 p.R276Q (c.827G>A) of GATA3 gene. This is the second patient who was reported to have a mutation in GATA3 gene from Turkey. In conclusion, although HDR syndrome is a rare condition, it should be kept in mind in patients with hypoparathyroidism. Classical triad can easily be identified if patients diagnosed with hypoparathyroidism are also evaluated with a urinary tract ultrasound and an audiometer.

WHAT IS ALREADY KNOWN ON THIS TOPIC?

Hypoparathyroidism, deafness, and renal dysplasia is a rare syndrome, generally inherited dominantly and characterized with classic triad of hypoparathyroidism, deafness, and renal dysplasia. It is usually related to GATA3 (GATA binding protein 3) gene mutations.

WHAT THIS STUDY ADDS?

A novel heterozygous missense mutation p.R276Q(c.827G>A) in exon 4 of GATA3 gene was identified by DNA sequencing. The lack of this mutation in family members suggests that this is a de novo mutation, however, presence of renal anomaly in the mother suggested plausible mosaic somatic mutation in her ovaries and kidneys.

INTRODUCTION

Hypoparathyroidism, deafness, and renal dysplasia (HDR; OMIM 146255) syndrome is a rare disease which is first defined by Barakat et al (1) in 1977. It is characterized by hypoparathyroidism, sensorineural deafness, and renal dysplasia, inherited dominantly, and is found to be related with GATA3 (GATA binding protein 3) gene mutations. This gene is located on 10p15 and is essential in the embryonic development of the parathyroid glands, auditory system, and kidneys (2). DiGeorge syndrome (DGS) is also characterized by hypoparathyroidism. The locus related with DGS 2 is along with GATA3, and deletions of distal 10 p region lead to phenotypic findings of DGS in addition to HDR syndrome (3).

A patient clinically diagnosed with HDR syndrome having a novel mutation on the GATA3 gene is presented in this case report.

CASE REPORT

A 13-year and 8-month-old boy was admitted because of spasm of the hands for approximately two weeks. Hypocalcemia was detected, and the patient was referred to pediatric endocrinology clinic. He was a full-term infant born from non-consanguineous parents with a birth weight of 2,400 gr. Neuromotor development was delayed and school performance was poor. He did not have a history of chronic disease, medication, or surgery. Family history did not reveal mental retardation, hypocalcemia, renal disease, and deafness.

He appeared well and conscious in physical examination. The heart rate was 94/min, the blood pressure was 120/75 mmHg, and Chvostek sign was present. His height was 165.9 cm (50-75 p), weight was 57.5 kg (50-75 p). He had facial dysmorphism characterized by hypertelorism (Figure 1), low-set ears, and highly-arched palate. Thyroid gland was non-palpable, and pubertal stage was Tanner stage 5. Cataract was not detected in ophthalmologic examination. Laboratory findings were as follows: serum calcium (Ca) was 6.7 mg/dL, phosphorus (P): 9.5 mg/dL, parathyroid hormone (PTH): 20 pg/mL, 25 hydroxy-vitamin D (25OHD): 27 ng/mL, magnesium: 1.8 mg/dL, Ca/creatinin ratio in spot urine: 0.05. Serum albumin, glucose, electrolytes, renal functions, and complete blood count were normal. Early morning cortisol was 14.7 mcg/dL, thyroid functions were normal, and thyroid antibodies were negative.

Figure 1

Dysmorphic facial features of our case with marked hypertelorism

The patient was diagnosed to have hypoparathyroidism. Oral calcitriol and Ca replacement treatment was commenced. Renal ultrasonography (USG) revealed that the right kidney was 96x57 mm in normal localization, while the left kidney was ectopic and significantly smaller than the right one. Decreased renal function in the ectopic kidney was detected by dimercaptosuccinic acid (DMSA) scan. Multiple calcifications in bilateral centrum semiovale, corona radiate, and basal ganglions were shown by cranial computed tomography (CT) (Figure 2), echocardiography was normal, and audiometer revealed bilateral mild sensorineural hearing loss. Intelligence quotient (IQ) score was reported as 57 in Weschler Intelligence Scale For Children test, suggesting mild mental retardation.

Figure 2

Multiple calcifications in bilateral centrum semiovale, corona radiata and basal ganglions were shown by cranial computed tomography

Clinical and laboratory findings were supporting the diagnosis of HDR syndrome. Family members were also evaluated in terms of hypocalcemia, hearing loss, and renal dysgenesis. His mother had horse-shoe kidney, but others did not have any of the suspected findings.

The karyotype of this patient was 46, XY. Genetic analysis using a next-generation sequencer identified a missense mutation in exon 4 p.R276Q (c.827G>A) of GATA3 gene (Figure 3). This mutation was confirmed by Sanger direct sequencing. The mutation was not detected in his parents, brother, or sister.

Figure 3

A heterozygous novel missense mutation (R276Q) (c.824G>A) was identified in exon 4 of GATA3 gene

DISCUSSION

Since HDR syndrome (Barakat syndrome) is a very rare disorder, its prevalence is not known exactly. A limited number of patients were reported in the literature (4).

Nearly 90% of patients with HDR syndrome have hypoparathyroidism and hearing loss, while 80% have renal dysplasia. Occurrence of findings is variable in reported cases. Some of the patients present with neuromuscular irritability and convulsions (5), while some of them are asymptomatic for many years despite severe hypocalcemia (6). This patient had symptomatic hypocalcemia for two weeks, however, the presence of cerebral calcifications on CT suggested a longer time of disease duration in our case. Although the etiopathogenesis of intracranial calcifications is not well-defined, calcifications are thought to be due to hyperphosphatemia rather than hypoparathyroidism itself. Interestingly, ectopic calcifications due to hyperphosphatemia are located on the vascular structure if it is caused by renal failure, while they are located in brain tissue if caused by hypoparathyroidism (7). Intracranial calcifications associated with HDR have been previously reported in the literature (6,8).

Renal disorders, which are the most heterogeneous component of this syndrome, include either functional or structural abnormalities. Renal hypoplasia, dysplasia, cystic kidneys, vesicoureteric reflux, nephritic syndrome, pelvicalyceal abnormality, hematuria, proteinuria, proximal and distal renal tubular acidosis with nephrocalcinosis were reported in association with HDR. Our patient had a pelvic kidney which has been previously reported in one patient (9).

Mental disabilities in the HDR syndrome are not common. Neuropsychiatric symptoms are thought to be related with calcifications of basal ganglia. The neurologic examination of our patient was completely normal despite the intracranial calcifications. Gaynor et al (9) similarly reported one case with HDR having motor and mental retardation.

No typical facial appearance has been described for this syndrome. Hypertelorism was the most prominent dysmorphic finding in our patient. There are few HDR cases with hypertelorism which were reported in the literature. These cases were found to have deletion in the chromosome 10 (3,10,26). Despite having only a single nucleotide change, our patient interestingly have dysmorphic appearance similar to these cases. This condition does not support a genotype-phenotype correlation in HDR syndrome. The phenotypical features of the cases with HDR syndrome reported in the literature are summarized in Table 1.

Table 1

The phenotypical features which were detected in the cases with hypoparathyroidism, deafness, and renal dysplasia syndrome

A heterozygous missense mutation p.R276Q (c.827G>A) in exon 4 of GATA3 gene was identified by DNA sequencing. This mutation resided within the first zinc finger domain. This mutation has not been identified in patients with HDR syndrome, however, Nesbit et al (20) previously performed in vitro analysis of artificially generated p.R276Q mutant and found that this mutant could not stabilize DNA binding. The lack of this mutation in family members of the present case suggests that this is a de novo mutation, although HDR syndrome cases are generally reported to be inherited dominantly (3). The GATA3 mutation was absent in the proband’s mother with horse-shoe kidney. Our results indicate that the kidney malformation in the mother is unrelated to the GATA3 mutation. However, we cannot exclude the possibility that the mother has a mosaic somatic GATA3 mutation in the kidney and ovary, but not in peripheral lymphocytes. Although somatic mosaicism of GATA3 mutations has not been reported so far, such phenomenon was reported in several congenital diseases such as osteogenesis imperfecta type 2 (27). There are also some examples of somatic mosaic mutations in PIK3CA and FMR1 genes that were only detected in relevant tissues but not in the blood (28,29). Unfortunately, we could not perform the GATA3 gene mutation analysis in the peripheral tissues of the parents.

This is the second case with HDR syndrome and GATA3 mutation that was reported from Turkey. The first patient was a 4-month-old infant who had a previously known mutation (p.R367X) in GATA3 gene (5).

In conclusion, although HDR syndrome is a rare condition, it should be in patients with hypoparathyroidism. Classical triad can easily be identified if patients diagnosed with hypoparathyroidism are also evaluated with a urinary tract USG and an audiometer.