H Ni, A Htet
berakat syndrome, hdr syndrome, hypoparathyroidism, renal disease, sensorineural deafness
H Ni, A Htet. Hypoparathyroidism, Deafness and Renal Disease: Berakat Syndrome. The Internet Journal of Internal Medicine. 2012 Volume 9 Number 2.
Berakat Syndrome is a combination of hypoparathyroidism, sensorineural deafness, and renal disease which is inherited as autosomal dominant. It is an extremely rare congenital disorder, also known as “HDR syndrome”. The exact prevalence of this disorder is not known but is very rare, with only about a dozen cases reported in the literature.We report a case of 28 year-old single lady from Myanmar who presented generalized oedema due to nephrotic-nephritic syndrome. Further history revealed bilateral hearing loss since birth. On examination, she was short, obese with round face and short 4th and 5th metacarpals. Tuning fork tests as well as audiogram confirmed sensorineural deafness of both side, more prominent on left. Her laboratory data were consistent with hypoparathyroidism. She was diagnosed to have HDR or Berakat syndrome based on her clinical and laboratory data. In conclusion, we need to be aware of rare inherited conditions in a patient with abnormal physical and laboratory findings even though their initial presentation was simple with nephrotic- nephritis.
Berakat syndrome or HDR syndrome is characterized by hypoparathyroidism, sensorineural deafness and renal dysplasia. It was first described by Barakat et al in 1977 . It is a rare congenital disorder, inherited as autosomal dominant. Gene-mapping studies and mutation analysis revealed GATA 3 haplo insufficiency due to various mutations in human HDR syndrome .
In this report, we demonstrate a case of HDR syndrome presented with nephrotic syndrome associated with progressive nerve deafness since birth and hypoparathyroidism.
A 28 year-old single lady from Myanmar was admitted with facial puffiness and bilateral leg swelling of 10 days’ duration associated with breathlessness and orthopnoea for 4 days.
Further history revealed progressive hearing loss since birth but there was no developmental delay. She had no siblings and both her parents passed away since her childhood. Because of hearing loss, she could only study until primary grade six. She had no menstrual problems.
On examination, she was obese with short stature and round face. The weight was 56 kg and the height was 1.48 m. She was in respiratory distress with periorbital puffiness and pitting pedal oedema. There was no cataract or dental hypoplasia. Normal breast development and secondary sexual characteristics were noted. There were short 4 th and 5 th metacarpals bilaterally. (Figure 1)
Blood pressure on admission was 170/130 mmHg and pulse rate was 84/ minute. There was clinical evidence of bilateral pleural effusion but no ascites and organomegaly on abdominal examination.
Motor, sensory and higher cortical function were intact. There was reduced hearing on both sides upon whispering, especially the left side. Rinne’s test
Her laboratory results showed hypocalcemia, hyper phosphataemia with hypoparathyroidism. (Table 1)
The ECG revealed no QT prolongation. No calcification was seen on skull X-ray. X ray of both hands confirmed short 4 th and 5 th metacarpal bones. (Figure 2)
Renal involvement was evidenced by 3+ albuminuria, hypoalbuminaemia, hypercholesterolaemia with nephrotic range 24 hour proteinuria. The ultrasonographic examination revealed bilateral pleural effusion with no abnormalities in abdomen. Chest X ray showed bilateral pleural effusion with pulmonary congestion. (Figure 3)
The renogram indicated delayed tubular and excretory phases on both kidneys. Ultrasound guided renal biopsy result was compatible with acute glomerulonephritis. The karyotyping was normal but genetic mutation analysis was unavailable. Since her parents passed away and she was the only child, family tracing was not applicable in this patient.
She was treated for pulmonary oedema and fluid overload, as well as hyperkalemia, hypertension and hypercholesterolaemia. Her condition improved, blood pressure returned to normal and was discharged with calcium and vitamin D supplementation.
HDR syndrome is a genetically inherited disorder with variable clinical presentations. It was first reported in 1977 by Berakat et al, in two brothers who died at the age of five and eight years due to steroid resistant nephrosis and progressive renal failure. They were also reported to have hypocalcemia and sensorineural deafness. At post mortem, the parathyroid gland was found to be absent in one brother and hypoplastic in the other .
The genetic basis of HDR syndrome was known when Bilous et al reported a family, two brothers and two daughters of one affected brother, with hypoparathyroidism, nerve deafness and renal dysplasia in 1992. All of these four affected family members with full HDR syndrome revealed submicroscopic deletion of chromosome 10p 15 on DNA analysis . Further deletion mapping studies and mutation analysis demonstrated the haplo-insufficiency of GATA 3 gene located on the terminal area of 10p chromosome due to various mutations was responsible for human HDR syndrome [2, 4-7].
GATA 3 is a dual zinc finger transcription factor whose expression plays a role in the development of parathyroid glands, inner ear, kidneys, thymus as well as central nervous system .
GATA 3 transcription is detected in neural tube, Wolffian duct, foregut, otic vesicles, parathyroid, thymus, second and third branchial arches and mesonephros during the 4th week of gestation in human embryos. Normal kidney development requires metanephric differentiation which results from interaction between metanephric blastema and ureteric bud from Wolffian duct. During this process which usually occurs at 7 th week of gestation, GATA 3 is essential at the interface of these two structures. This explains the occurrence of renal abnormalities in HDR syndrome as a result of GATA 3 mutation .
Various renal manifestations of Berakat Syndrome has been reported, including renal dysplasia, hypoplasia or aplasia, cystic kidney, vesicoureteric reflux, pelvicocalyceal deformity, nephrotic syndrome, chronic renal failure, haematuria, proteinuria, renal scarring, nephrocalcinosis and distal renal tubular acidosis. [10-12]. In this report, our patient presented generalized oedema, nephrotic range proteinuria hypoalbuminaemia and hypercholesterolaemia consistent with nephrotic syndrome. No renal dysplasia was detected on imaging studies.
Hearing loss in HDR syndrome is usually bilateral, ranging from mild to profound impairment, more severe at the higher end of the frequency of the spectrum and is usually progressive. In contrast to renal presentations, nerve deafness in HDR syndrome does not vary significantly among the patients with this syndrome . The presented case had progressive sensorineural deafness since birth, predominantly affecting the left ear.
Hypoparathyroidism usually manifests with tetany, convulsions, tingling and numbness with positive Chvostek and Trousseau signs. Prolonged QT interval on ECG and intracaranial calcification is common due to hypocalcemia. Short 4 th and 5 th metacarpals are conventionally seen in pseudo-hypoparathyroidism and pseudopseudo- hypoparathyroidism. However, there were reported cases of abnormal phalanges in hypoparathryoidism [13,14]. The presence of short 4 th and 5 th metacarpals in our case may lead to the possibility of pseudohypoparathyroidism, but her biochemical profile showed decreased parathyroid hormone level, confirming hypoparathyroidism. Furthermore, the presented case had round face, short stature and obese but she had no mental retardation.
In the present case, no abnormality was detected on karyotyping. However, genetic study to indentify the exact mutation was not applicable. To the best of our knowledge this case is the first case of Berakat syndrome reported from Myanmar. Based on the findings of the present case, it is highly recommended that in the patients presented with nephrotic-neprhitic syndrome associated with skeletal abnormalities and deafness, performing audiometry, calcium, phosphate, parathyroid hormone determination and renal imaging studies can probably reveal this extremely rare genetic disorder of Berakat syndrome.