Seizure, deafness and renal agenesis: A rare case of barakat syndrome.

Etiologic diagnosis of seizure requires proper consideration of apparently unrelated clinical features of the patient. Here, we report the case of a patient of status epilepticus with moderate-to-severe bilateral sensorineural deafness. Investigations showed extensive intracranial calcification, hypoparathyroidism and unilateral renal agenesis. The features were consistent with Barakat syndrome, a rare developmental disorder associated with mutations in the GATA3 gene. To the best of our knowledge, this is the first reported case of Barakat syndrome from India.

Introduction

Seizures are one of the commonest causes of emergency admissions worldwide. Anti-seizure treatment and a search for the precipitating cause should go on simultaneously in such patients. An etiologic diagnosis of seizure and rational therapy requires cohesive analysis of all the clinical facets of the patient, even though some of them may appear unrelated. The present case aptly demonstrates this fact.

Barakat syndrome, also known as hypoparathyroidism, deafness, and renal dysplasia (HDR) syndrome, is a rare developmental disorder. The syndrome was first noted in siblings with hypocalcemia and proteinuria, that subsequently progressed to steroid-resistant nephrotic syndrome.[1] Fluorescence in situ hybridization and microsatellite analysis have shown that HDR syndrome is associated with deletions in chromosome 10p.[2] Molecular analysis has shown that majority of HDR patients have mutations in the GATA3 gene, which encodes a transcription factor related to the development of the parathyroid glands, kidneys, inner ear, and central nervous system.

Several mutations of the GATA3 gene lead to the HDR phenotype.[3] Therefore, HDR patients exhibit a spectrum of phenotypes. The severity of sensorineural deafness varies and is symmetrical in majority of HDR patients. The term “renal dysplasia” represents various abnormalities such as agenesis, hypoplasia, pelvicalyceal deformity, and renal scarring. Most patients present with symptoms related to hypocalcemia; however, some patients have normal calcium levels or show asymptomatic hypocalcemia.[2]

The familial forms of hypoparathyroidism can follow an autosomal dominant, autosomal recessive, or X-linked recessive pattern. Hypoparathyroidism can present as an isolated disorder or may be associated with other congenital abnormalities such as DiGeorge Syndrome. Here, we report the case of a patient who presented with seizure, extensive intracranial calcification, and hypocalcemia, and who was subsequently diagnosed with HDR syndrome.

Case Report

A 40-year-old man with status epilepticus, residing in Kolkata, was admitted to our hospital. Two years before his admission, he had experienced the first episode of generalized seizure, for which he had been receiving sodium valproate. He had been experiencing recurrent episodes of generalized tonic clonic seizures for 2 days before his admission despite the continuation of sodium valproate in regular doses. He had a history of progressive hearing loss for the last 2 years and perioral paresthesia for the last 2 months. He did not have a family history of similar illness, head trauma in the past, or fever. Neuroimaging or electroencephalography (EEG) was not performed previously. His vital parameters were within the normal range, except that he had tachycardia. Neurological examination showed depression of deep tendon reflexes in both upper and lower extremities. He exhibited no neurological signs, except for Chvostek's and Trousseau's signs.

Non-contrast computed tomography (CT) of the brain showed extensive intracranial calcification involving the basal ganglia, cerebellum, and cerebral cortex on both the right and left sides [Figure 1]. Electrocardiography during the immediate postictal phase showed a prolonged QT interval. The results of routine blood examination were as follows: hemoglobin, 14.7 gm/ dL; (14-16 gm/dL) erythrocyte sedimentation rate, 20 mm during the first hour; <5 mm 1st hour random blood glucose, 142 mg/dL; albumin, 4.5 g/ dL; (3.5-5.5 gm/ dL) urea, 26.0 mg/dL (normal range, 10–20 mg/dL); creatinine, 2.2 mg/ dL (normal range, 0.6–1.2 mg/dL, estimated glomerular filtration rate - eGFR ~32 ml/min)); sodium, 146 mmol/dL (normal range, 137–145 mg/dL); potassium, 3.6 mmol/ dL (normal range, 3.5–5.5 mg/dL); calcium, 3.8 mg/ dL (normal range, 8.8–10.6 mg/ dL); phosphorus, 9.78 mg/dL (normal range, 2.7–4.5 mg/dL); and magnesium, 0.7 meq/L (normal range, 1.3–2.5 meq/L). Hormonal assay showed that the level of 1,25-dihydroxyvitamin D3 was 10.9 pg/mL (normal range, 19.6–54.3 pg/mL); electrochemiluminescence immunoassay (ECLIA) showed that the serum intact parathyroid hormone (PTH) level was 1.44 pg/mL (normal range, 15–65 pg/mL). The patient did not have any history of neck surgery or radiation exposure that could have led to hypoparathyroidism.

Figure 1

Non contrast computed tomography scan of brain showing bilateral basal ganglia calcification

Pure tone audiometry (PTA) showed bilateral moderate-to-severe hearing loss that was more severe at the higher end of the frequency spectrum [Figure 2a and b]. Ultrasonography showed the absence of renal shadow on the left kidney and an increased cortical echogenicity of 8.4 cm in the right kidney [Figure 3]. Because of the simultaneous occurrence of hypoparathyroidism, deafness, and renal agenesis, the patient was diagnosed with HDR syndrome. However, chromosomal analysis with trypsin G-banding yielded normal results.

Figure 2

(a) Pure tone audiogram showing bilateral severe sensorineural deafness, predominantly in higher frequencies. (b) Legend for the audiogram

Figure 3

Ultrasonography of abdomen showing an empty left renal fossa (indicated by the arrow)

The patient was administered intravenous phenytoin, levetiracetam, and calcium gluconate. After the seizures were controlled, he was administered oral phenytoin, levetiracetam, calcium carbonate, and alfacalcidol. He was discharged on the 10th day and is being followed up.

Discussion

HDR syndrome can occur at any age, and patients with this syndrome usually show symptoms related to hypocalcemia. However, HDR patients do not usually present with status epilepticus, as observed in our case.[4] Moreover, basal ganglia calcification is not usually observed on the brain CT scans of HDR patients; however, this calcification was observed in the case of our patient.

In the HDR syndrome, renal involvement varies, and only a minority of patients whose cases are described in the literature showed renal agenesis. However, most patients show progression to chronic renal failure and require renal replacement therapy.[2] Our patient showed unilateral left renal agenesis, and his other kidney showed normal functioning. Deafness is a consistent feature of HDR syndrome. HDR patients have been reported to experience bilateral sensorineural deafness, which is more severe at higher frequencies.[5] Our patient also showed similar features on PTA.

In conclusion, HDR syndrome provides an opportunity to study the role of GATA3 transcription factor in embryonic development and the consequences of haploinsufficiency of the GATA3 gene.