ABSTRACT

Objectives

Hypoparathyroidism, sensorineural deafness and renal disease (HDR) syndrome, also known as Barakat syndrome, is an autosomal dominant transmission hereditary disease with a wide range of penetrance and expressivity. Haploinsufficiency of the GATA3 two finger zinc transcription factor is believed to be its cause. This is the first time this orphan disease is reported in Latin America, so the publishing of this report is expected to raise awareness on these types of syndrome, that are usually underdiagnosed in our region, which in turn causes an increase in the years lost to disability (YLDs) rates, as well as higher costs to be assumed by public health systems.

Methods

A 36-year-old Colombian woman diagnosed with parathyroid gland agenesis was referred from the Endocrinology Service to the Outpatient Service. According to her medical record, in the past she had developed hypocalcaemia, left renal agenesis, hypoparathyroidism, bicornate uterus and sensorineural hearing loss. Through a genetic analysis a pathological mutation on the short arm of the GATA 3 gen (c.404dupC, p Ala136 GlyfsTER 167) was confirmed, which led to a HDR syndrome diagnosis.

Discussion

This case proves that there is a possibility that mutations described in other continents may be developed by individuals from our region. Regardless of ethnicity, Barakat syndrome should be considered as a possible diagnosis in patients presenting the typical triad that has been described for this condition, since there could be underdiagnosis of this disease in Latin-America due to the lack of knowledge on this condition in said region, and that genetic counseling in these patients is of great importance for the implications of the syndrome in future generations.

Key Words:
Hypoparathyroidism; deafness; gata3 transcription factor; uterine cervical disease; zinc fingers (source: MeSH, NML)

RESUMEN

Objetivos

El síndrome de hipoparatiroidismo, sordera neurosensorial y displasia renal (HDR) también llamado síndrome de Barakat, es una enfermedad hereditaria de transmisión autosómica dominante con amplia penetrancia y expresividad genética. El síndrome es causado por la haploinsuficiencia del factor de transcripción de dedos de Zinc GATA3. Esta es la primera vez que esta enfermedad huérfana es reportada en latinoamerica, y buscamos generar consciencia de la presencia de estas enfermedades, las cuales usualmente son infradiagnósticadas en nuestro medio y llevan a un aumento de años perdidos por discapacidad y costos para el sistema de salud pública.

Métodos

Una mujer colombiana de 36 años ingresó a consulta externa de genética referida por el servicio de endocrinología por una agenesia de paratiroides. La paciente tenía antecedentes de hipocalcemia, agenesia renal izquierda, hipoparatiroidismo, sordera neurosensorial y útero bicorneo. Se realizó un análisis genético que confirmo una mutación patológica en el brazo corto del gen GATA3 (c.404dupC, p Ala136 GlyfsTER 167) diagnóstica del síndrome de Barakat.

Discusión

Este caso demuestra la posibilidad de existencia de mutaciones descritas en otros continentes en nuestra población. Sin importar la etnia, el síndrome de Barakat debe ser estudiado en pacientes que presenten la triada típica, ya que podría existir un infra diagnóstico de la enfermedad secundario al desconocimiento de la misma en Latinoamérica y teniendo en cuenta la importancia que tiene la consejería genética en estos pacientes por las implicaciones de la enfermedad en futuras generaciones.

Palabras Clave:
Hipoparatiroidismo; sordera; factor de transcripción GATA3; enfermedades del cuello del útero; dedos de zinc (fuente: DeCS, BIREME)

Hypoparathyroidism, sensorineural deafness and renal disease (HDR) syndrome, also known as Barakat syndrome, is a hereditary autosomal dominant disease first described in 1977 by Barakat et al., when reporting the case of two male siblings with nephrotic syndrome, nerve deafness and hypoparathyroidism ¹1. Barakat A, D'Albora J, Martin M, Jose P. Familial nephrosis, nerve deafness, and hypoparathyroidism. J Pediatr [Internet]. 1977 [cited 2017 Jul 11]; Available from: Available from: https://goo.gl/e5jAdc .
https://goo.gl/e5jAdc... . In 1997, Hasewaga et al. ²2. Hasegawa T, Hasegawa Y, Aso T, Koto S, Nagai T, Tsuchiya Y, et al. HDR syndrome (hypoparathyroidism, sensorineural deafness, renal dysplasia) associated with del(10)(p13). Am J Med Genet [Internet]. 1997 Dec 31 [cited 2017 Jul 11];73(4):416-8. Available from: Available from: https://goo.gl/dJxoBF .
https://goo.gl/dJxoBF... named it HDR syndrome, when they reported the case of a girl with the same clinical features and deletion of locus10p13 ²2. Hasegawa T, Hasegawa Y, Aso T, Koto S, Nagai T, Tsuchiya Y, et al. HDR syndrome (hypoparathyroidism, sensorineural deafness, renal dysplasia) associated with del(10)(p13). Am J Med Genet [Internet]. 1997 Dec 31 [cited 2017 Jul 11];73(4):416-8. Available from: Available from: https://goo.gl/dJxoBF .
https://goo.gl/dJxoBF... .

A gene mutation has been identified on GATA3 gene, located on 10p15 loci; more than 50 GATA3 mutations have been associated with HDR syndrome, and haploin-sufficiency has been considered as the underlying mechanism ³3. Lindstrand A, Malmgren H, Verri A, Benetti E, Eriksson M, Nordgren A, et al. Molecular and clinical characterization of patients with overlapping 10p deletions. Am J Med Genet A [Internet]. 2010 May [cited 2017 Jul 4];152A(5):1233-43. Available from: Available from: https://goo.gl/iRfmuk .
https://goo.gl/iRfmuk...

4. Nesbit MA, Bowl MR, Harding B, Ali A, Ayala A, Crowe C, et al. Characterization of GATA3 Mutations in the Hypoparathyroidism, Deafness, and Renal Dysplasia (HDR) Syndrome. J Biol Chem [Internet]. 2004 May 21 [cited 2017 Jul 11];279(21):22624-34. Available from: Available from: https://goo.gl/bam8W4 .
https://goo.gl/bam8W4...

5. Ali A, Christie PT, Grigorieva I V, Harding B, Esch H Van, Ahmed SF, et al. Functional characterization of GATA3 mutations causing the hypo-parathyroidism-deafness-renal (HDR) dysplasia syndrome: insight into mechanisms of DNA binding by the GATA3 transcription factor. Hum Mol Genet [Internet]. 2007 [cited 2017 Jul 13];16(3):265-75. Available from: Available from: https://goo.gl/F6PKwN
https://goo.gl/F6PKwN... ^-66. Barakat AJ. Hypoparathyroidism, sensorineural deafness, and renal disease. 2006 [cited 2017 Jul 17]; Available from: Available from: https://goo.gl/wwTG83 .
https://goo.gl/wwTG83... . The syndrome has a wide range of penetrance and expressivity, which makes its diagnosis a challenge for medical health providers and in many cases, unfortunately, the condition is not diagnosed ⁷7. Belge H, Dahan K, Cambier J-F, Benoit V, Morelle J, Bloch J, et al. Clinical and mutational spectrum of hypoparathyroidism, deafness and renal dysplasia syndrome. Nephrol Dial Transplant [Internet]. 2016 Jul 6 [cited 2017 Jul 17]; 109(5):gfw271. Available from: Available from: https://goo.gl/DcCiMf .
https://goo.gl/DcCiMf... .

Clinical features include hypoparathyroidism at any age (probably the most specific symptom), and calcium levels variations, from normal to very low levels, which may lead to tetany and seizures. Undetectable or very low serum PTH levels is one of the main features of HDR syndrome ⁶6. Barakat AJ. Hypoparathyroidism, sensorineural deafness, and renal disease. 2006 [cited 2017 Jul 17]; Available from: Available from: https://goo.gl/wwTG83 .
https://goo.gl/wwTG83... ^,77. Belge H, Dahan K, Cambier J-F, Benoit V, Morelle J, Bloch J, et al. Clinical and mutational spectrum of hypoparathyroidism, deafness and renal dysplasia syndrome. Nephrol Dial Transplant [Internet]. 2016 Jul 6 [cited 2017 Jul 17]; 109(5):gfw271. Available from: Available from: https://goo.gl/DcCiMf .
https://goo.gl/DcCiMf... , and an early sensorineural deafness onset (usually bilateral) is a common characteristic and the most penetrant⁶6. Barakat AJ. Hypoparathyroidism, sensorineural deafness, and renal disease. 2006 [cited 2017 Jul 17]; Available from: Available from: https://goo.gl/wwTG83 .
https://goo.gl/wwTG83... ^,77. Belge H, Dahan K, Cambier J-F, Benoit V, Morelle J, Bloch J, et al. Clinical and mutational spectrum of hypoparathyroidism, deafness and renal dysplasia syndrome. Nephrol Dial Transplant [Internet]. 2016 Jul 6 [cited 2017 Jul 17]; 109(5):gfw271. Available from: Available from: https://goo.gl/DcCiMf .
https://goo.gl/DcCiMf... . Renal abnormalities can be unilateral or bilateral and may vary from minor to severe ⁶6. Barakat AJ. Hypoparathyroidism, sensorineural deafness, and renal disease. 2006 [cited 2017 Jul 17]; Available from: Available from: https://goo.gl/wwTG83 .
https://goo.gl/wwTG83...

7. Belge H, Dahan K, Cambier J-F, Benoit V, Morelle J, Bloch J, et al. Clinical and mutational spectrum of hypoparathyroidism, deafness and renal dysplasia syndrome. Nephrol Dial Transplant [Internet]. 2016 Jul 6 [cited 2017 Jul 17]; 109(5):gfw271. Available from: Available from: https://goo.gl/DcCiMf .
https://goo.gl/DcCiMf... ^-88. Chenouard A, Isidor B, Allain-Launay E, Moreau A, Le Bideau M, Roussey G. Renal phenotypic variability in HDR syndrome: glomerular nephropathy as a novel finding. Eur J Pediatr [Internet]. 2013 Jan 5 [cited 2017 Jul 4];172(1):107-10. Available from: Available from: https://goo.gl/WiAQwc .
https://goo.gl/WiAQwc... . Genitourinary malformations have also been reported a few times, and have been associated with GATA3 haploinsufficiency ⁹9. Hernández AM, Villamar M, Roselló L, Moreno-Pelayo MA, Moreno F, Del Castillo I. Novel mutation in the gene encoding the GATA3 transcription factor in a Spanish familial case of hypoparathyroidism, deafness, and renal dysplasia (HDR) syndrome with female genital tract malformations. Am J Med Genet A [Internet]. 2007 Apr 1 [cited 2017 Jul 4];143A(7):757-62. Available from: Available from: https://goo.gl/d4a9ds .
https://goo.gl/d4a9ds...

10. Moldovan O, Carvalho R, Jorge Z, Medeira A. A new case of HDR syndrome with severe female genital tract malformation: Comment on "Novel Mutation in the Gene Encoding the GATA3 Transcription Factor in a Spanish Familial Case of Hypoparathyroidism, Deafness, and Renal Dysplasia (HDR) Syndrome With Fe. Am J Med Genet Part A [Internet]. 2011 Sep 1 [cited 2017 Oct 24];155(9):2329-30. Available from: Available from: https://goo.gl/yBHo9X .
https://goo.gl/yBHo9X... ^-1111. Nakamura A, Fujiwara F, Hasegawa Y, Ishizu K, Mabe A, Nakagawa H, Molecular analysis of the GATA3 gene in five Japanese patients with HDR syndrome. Endocr J [Internet]. 2011 [cited 2017 Jul 4];58(2):123-30. Available from: Available from: https://goo.gl/2maiBu .
https://goo.gl/2maiBu... .

Currently, HDR syndrome prevalence is unknown, for less than 120 cases have been reported since Barakat et al. described the first report ¹1. Barakat A, D'Albora J, Martin M, Jose P. Familial nephrosis, nerve deafness, and hypoparathyroidism. J Pediatr [Internet]. 1977 [cited 2017 Jul 11]; Available from: Available from: https://goo.gl/e5jAdc .
https://goo.gl/e5jAdc... ^,22. Hasegawa T, Hasegawa Y, Aso T, Koto S, Nagai T, Tsuchiya Y, et al. HDR syndrome (hypoparathyroidism, sensorineural deafness, renal dysplasia) associated with del(10)(p13). Am J Med Genet [Internet]. 1997 Dec 31 [cited 2017 Jul 11];73(4):416-8. Available from: Available from: https://goo.gl/dJxoBF .
https://goo.gl/dJxoBF... ^,66. Barakat AJ. Hypoparathyroidism, sensorineural deafness, and renal disease. 2006 [cited 2017 Jul 17]; Available from: Available from: https://goo.gl/wwTG83 .
https://goo.gl/wwTG83... ^,77. Belge H, Dahan K, Cambier J-F, Benoit V, Morelle J, Bloch J, et al. Clinical and mutational spectrum of hypoparathyroidism, deafness and renal dysplasia syndrome. Nephrol Dial Transplant [Internet]. 2016 Jul 6 [cited 2017 Jul 17]; 109(5):gfw271. Available from: Available from: https://goo.gl/DcCiMf .
https://goo.gl/DcCiMf... ^,1212. Adachi M, Tachibana K, Asakura Y, Tsuchiya T. A novel mutation in the GATA3 gene in a family with HDR syndrome (Hypoparathyroidism, sensorineural Deafness and Renal anomaly syndrome). J Pediatr Endocrinol Metab [Internet]. 2006 Jan [cited 2017 Jul 4];19(1):87-92. https://goo.gl/ZLZDem.
https://goo.gl/ZLZDem... . Taking this into account, this would be the first case to be reported in Latin America, and as authors we believe publishing this report will help to raise awareness on the occurrence and existence of rare diseases in our regional context.

Case presentation

A 36-year-old Colombian female with a diagnosis of parathyroid gland agenesis and hypocalcaemia was referred from the Endocrinology Service to the Outpatient Medical Genetics Service. The patient was asymptomatic and according to her medical history, she had left renal agenesis and bicornuate uterus, conditions that were found out incidentally after an ultrasound was made. Also, she had been diagnosed with hypoparathyroidism and sensorineural hearing loss, which was assumed to be secondary to a measles infection in her childhood. In addition, her sister had been diagnosed with hypocalcaemia, osteoporosis and hearing loss, and her mother, hypocalcaemia and osteoporosis (Figure 1). The patient had been taking 3600 mg per day of calcium carbonate and 0.5 mcg per day of calcitriol (1, 25-dihydroxyvitamin D3).

After the physical examination was made, the following characteristics were observed: short stature, short neck, micrognathia, proptosis, posteriorly rotated ears, fourth toe clinodactyly and presence of bilateral hearing aids (Figure 2). Her vital signs were normal, she was 1.49 mts and weighed64.5 kg (BMI: 32.91). Her relatives had similar facies and phenotype, a fact that drew the attention of the authors of this article.

The first diagnostic impression was that the patient had HDR syndrome, since laboratory tests reported a low PTH level and a slightly low serum calcium level, somehow serum calcium level was normal in further studies. Based on evoked potentials, a neurosensory bilateral involvement with a peripheral lesion was confirmed, while left renal agenesis, right simple renal cysts, and bicornuate uterus were confirmed through and abdominal ultrasonography. In addition, an MRI scan was performed, in which complete septate uterus was observed. Ovaries were normal. The karyotype was normal (46 XX), and through a bidirectional ng sequencing of GATA 3 gene, performed in an AB13130 automatic sequencer, a pathological mutation was found: c.404dupC (p. Ala136 GlyfsTER 167) (Figure 1).

DISCUSSION

A GATA3 gene mutation was found in the patient (Figure 1), the mutated gene showed a cytosine duplication at position 404, which caused a glycine to be replaced by an alanine at position 136 of the protein, resulting in a frame shift producing a terminal codon that ended the protein prematurely. This mutation disrupts TA2 (transactivating-2) domain and two zinc fingers (ZnF1 and ZnF1), which causes the same effect described by Adachi et al. in their report of a Japanese girl and her father ¹²12. Adachi M, Tachibana K, Asakura Y, Tsuchiya T. A novel mutation in the GATA3 gene in a family with HDR syndrome (Hypoparathyroidism, sensorineural Deafness and Renal anomaly syndrome). J Pediatr Endocrinol Metab [Internet]. 2006 Jan [cited 2017 Jul 4];19(1):87-92. https://goo.gl/ZLZDem.
https://goo.gl/ZLZDem... .

The GATA3 gene expression can be detected from the beginning of the 4^th gestational week in humans¹³13. Van Esch H, Devriendt K. Transcription factor GATA3 and the human HDR syndrome. Cell Mol Life Sci [Internet]. 2001 Aug [cited 2017 Oct 5];58(9):1296-300. Available from: Available from: https://goo.gl/YfufpD .
https://goo.gl/YfufpD... . GATA3 transcripts are mainly observed in parathyroid glands, inner ear and kidneys, which correlates with the phenotype of patients with HDR syndrome, nevertheless the GATA3 expression can also be detected in multiple tissues and organs like the developing central nervous system (CNS), the liver, the foregut and the eyes, but these organs seem to be less prone to the haploinsufficiency of GATA3 since they are not generally affected in patients with this syndrome ¹³13. Van Esch H, Devriendt K. Transcription factor GATA3 and the human HDR syndrome. Cell Mol Life Sci [Internet]. 2001 Aug [cited 2017 Oct 5];58(9):1296-300. Available from: Available from: https://goo.gl/YfufpD .
https://goo.gl/YfufpD... .

On the other hand, some reports describing patients with HDR syndrome and who additionally developed genitourinary tract abnormalities (as it happened in the case reported here) suggest that the underlying mechanism that causes the syndrome is the same triggering in the development of genitourinary abnormalities, since GATA3 seems to be involved in uterine development⁹9. Hernández AM, Villamar M, Roselló L, Moreno-Pelayo MA, Moreno F, Del Castillo I. Novel mutation in the gene encoding the GATA3 transcription factor in a Spanish familial case of hypoparathyroidism, deafness, and renal dysplasia (HDR) syndrome with female genital tract malformations. Am J Med Genet A [Internet]. 2007 Apr 1 [cited 2017 Jul 4];143A(7):757-62. Available from: Available from: https://goo.gl/d4a9ds .
https://goo.gl/d4a9ds... ^,1010. Moldovan O, Carvalho R, Jorge Z, Medeira A. A new case of HDR syndrome with severe female genital tract malformation: Comment on "Novel Mutation in the Gene Encoding the GATA3 Transcription Factor in a Spanish Familial Case of Hypoparathyroidism, Deafness, and Renal Dysplasia (HDR) Syndrome With Fe. Am J Med Genet Part A [Internet]. 2011 Sep 1 [cited 2017 Oct 24];155(9):2329-30. Available from: Available from: https://goo.gl/yBHo9X .
https://goo.gl/yBHo9X... ^,1414. Nakamura A, Fujiwara F, Hasegawa Y, Ishizu K, Mabe A, Nakagawa H, et al. Molecular analysis of the GATA3 gene in five Japanese patients with HDR syndrome. Endocr J [Internet]. 2011 [cited 2017 Oct 24];58(2):123-30. Available from: Available from: https://goo.gl/SZ51ZA .
https://goo.gl/SZ51ZA... .

Orphan diseases (OD) such as HDR syndrome have an estimated frequency that ranges from 37.3 and 52.8 per 1000 people in Colombia ¹⁵15. Bernal Villegas, Jaime; Suárez Obando F. La carga de la enfermedad genética en Colombia, 1996-2025. Univ Médica. 2008;49(1):12-28.. The prevalence of this genetic disease is increasing and it has been concluded that it is underdiagnosed, which leads to inaccurate reports of the syndrome in the country's databases and, therefore, a huge impact in terms of public health caused by the amount of years lost to disability (YLDS) in these patients ¹⁵15. Bernal Villegas, Jaime; Suárez Obando F. La carga de la enfermedad genética en Colombia, 1996-2025. Univ Médica. 2008;49(1):12-28.^,1616. Malambo-Garcia DI et al. Frecuencia de enfermedades huérfanas en Cartagena de Indias, Colombia. Rev Salud Pública (Bogotá). 2016;18(6):858-70..

Unawareness on this disease may lead to underdiagnosis in Latin-American countries. The diversity found in the Colombian population makes it necessary to suspect genetic diseases traditionally reported in other countries in patients presenting typical symptoms. HDR syndrome must be suspected regardless of ethnicity, and thus the patient must be referred to a human genetics specialist as soon as possible to provide an early diagnosis and counseling on the condition•

Acknowledgments:

To Carlos Castro MD, Research Division, Fundación Universitaria de Ciencias de la Salud; Jeisson Rojas, Design Department, Fundación Universitaria de Ciencias de la Salud; Yuly Barón, Design Department, Fundación Universitaria de Ciencias de la Salud, and Daniel León, Design Department, Fundación Universitaria de Ciencias de la Salud.

REFERENCES

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