Introduction

Barakat syndrome, also known as Hypoparathyroidism-Deafness-Renal Dysplasia (HDR) syndrome, is a rare genetic disorder that affects multiple organ systems in the body. This complex condition, characterised by a triad of hypoparathyroidism, sensorineural deafness, and renal anomalies, presents unique challenges for both patients and healthcare providers. Understanding the genetic basis of Barakat syndrome is crucial for improving diagnosis, treatment, and management strategies for affected individuals.1,2

This article aims to provide a comprehensive overview of Barakat syndrome, exploring its genetic underpinnings, clinical manifestations, diagnostic approaches, and current treatment options. By delving into the molecular mechanisms and inheritance patterns associated with this disorder, we aim to shed light on its complexities and highlight the importance of genetic research in advancing our understanding of rare diseases.3

What is Barakat syndrome?

Barakat syndrome is a rare genetic disorder first described by Dr. Barakat and his colleagues in 1977. It is classified as a developmental disorder affecting multiple organ systems, primarily the parathyroid glands, auditory system, and kidneys.4

The syndrome is characterised by three main features:

Hypoparathyroidism: results in low levels of parathyroid hormone (PTH), leading to decreased calcium levels in the blood and increased phosphate levels. Symptoms may include muscle cramps, tingling sensations, seizures, and developmental delays 1,5

Sensorineural deafness: affected individuals often experience varying degrees of hearing loss, which can range from mild to profound and may be present at birth or develop later in life 2

Renal anomalies: kidney abnormalities can vary widely, from minor structural defects to more severe issues such as renal dysplasia or aplasia. These anomalies may lead to impaired kidney function or renal failure in some cases 3,6

In addition to these primary features, patients with Barakat syndrome may experience other symptoms:1,4

Growth delays

Cognitive impairments

Skeletal abnormalities

Cardiovascular issues

Dysmorphic facial features

The severity and combination of symptoms can vary significantly among affected individuals, even within the same family, highlighting the complex nature of this genetic disorder.2,5

Genetic background

The discovery of Barakat syndrome marked the beginning of a journey to understand its genetic basis. It was not until 1997 that researchers identified mutations in the GATA3 gene as the underlying cause of the disorder. This breakthrough provided crucial insights into the molecular mechanisms driving the development of Barakat syndrome. 3,6

The GATA3 gene plays a vital role in embryonic development and the function of various tissues throughout life. It belongs to a family of transcription factors that regulate gene expression during development and in adult tissues. GATA3 is particularly important for the development and function of the parathyroid glands, inner ear, and kidneys – the three main organ systems affected in Barakat syndrome.1,2,4

Mutations in the GATA3 gene disrupt its normal function, leading to the characteristic features of Barakat syndrome. These mutations can affect the gene's ability to bind to DNA, interact with other proteins, or regulate target genes, ultimately impacting the development and function of multiple organ systems.5

Barakat syndrome follows an autosomal dominant inheritance pattern, meaning that a single copy of the mutated GATA3 gene is sufficient to cause the disorder. This inheritance pattern has important implications for family planning and genetic counselling. In many cases, an affected individual has an affected parent, but the condition can also arise from a new mutation in the GATA3 gene (de novo mutation). 1,3,4,6

Understanding the genetic basis of Barakat syndrome is crucial for accurate diagnosis, appropriate genetic counselling, and potential targeted therapies in the future. 2,5

Molecular mechanisms

The pathophysiology of Barakat syndrome is closely linked to the role of GATA3 in embryonic development and tissue-specific functions.3

GATA3 mutations can affect gene function in several ways:

DNA binding: many mutations occur in the zinc finger domains of GATA3, which are crucial for its ability to bind to specific DNA sequences. Impaired DNA binding can prevent GATA3 from regulating its target genes effectively 1,6

Protein stability: some mutations may lead to the production of an unstable GATA3 protein that is quickly degraded, resulting in reduced levels of functional GATA3 in cells 2,4

Protein-protein interactions: GATA3 interacts with various other proteins to regulate gene expression. Mutations can disrupt these interactions, altering the gene regulatory networks controlled by GATA3 5

The impact of GATA3 mutations on different organ systems in Barakat syndrome can be explained as follows:

Calcium metabolism: GATA3 is crucial for the development and function of parathyroid glands. Mutations can lead to impaired parathyroid gland development or function, resulting in hypoparathyroidism and disrupted calcium homeostasis 1,3

Ear development: GATA3 plays a critical role in the development of the inner ear, particularly the cochlea. Mutations can disrupt the formation and function of hair cells and other structures essential for hearing, leading to sensorineural deafness 2,6

Kidney function: GATA3 is involved in kidney development and the maintenance of certain kidney cell types. Mutations can result in various renal anomalies, ranging from structural defects to impaired kidney function 4,5

Genotype-phenotype correlations in Barakat syndrome are complex, with considerable variability in symptoms even among individuals with the same mutation. This variability suggests that other genetic or environmental factors may influence the expression of the disorder. 1,3

Some studies have reported that certain types of mutations (those affecting DNA binding) may be associated with more severe phenotypes, but more research is needed to establish clear correlations.6

Diagnostic approaches

Diagnosing Barakat syndrome requires a combination of clinical evaluation and genetic testing. The clinical diagnosis is based on the presence of at least two of the three main features. However, the variable expressivity of the disorder means that not all affected individuals will present with all three features. 1,4,5

Genetic testing plays a crucial role in confirming the diagnosis and identifying the specific GATA3 mutation. 2,6

Several types of genetic tests may be used:

Sequence analysis: this method can detect small changes in the GATA3 gene, such as point mutations or small insertions/deletions.3

Deletion/duplication analysis: this technique can identify larger genomic changes, such as deletions or duplications of the entire GATA3 gene or parts of it 1,4

Next-generation sequencing panels: these tests can analyse multiple genes associated with hypoparathyroidism or deafness, including GATA3, in a single test 2,5

Interpreting genetic test results requires expertise, as not all genetic changes in GATA3 are pathogenic. Genetic counsellors and medical geneticists play a crucial role in explaining the significance of test results and their implications for patients and families. 3,6

Current and emerging treatments

While there is currently no cure for Barakat syndrome, treatment focuses on managing the individual symptoms and complications associated with the disorder.1,4

Hypoparathyroidism management

Calcium and vitamin D supplementation to maintain normal calcium levels

Regular monitoring of blood calcium, phosphate, and PTH levels

In severe cases, recombinant PTH therapy may be considered 2,5

Hearing loss treatment

Hearing aids for mild to moderate hearing loss

Cochlear implants for severe to profound hearing loss

Speech and language therapy to support communication skills 3,6

Renal anomalies treatment

Regular monitoring of kidney function and structure

Management of specific renal issues (e.g., urinary tract infections, hypertension)

In cases of severe kidney dysfunction, dialysis or kidney transplantation may be necessary 1,4

Advances in genetic therapies offer hope for future treatments targeting the underlying cause of Barakat syndrome. 2,5

Potential approaches include:

Gene therapy: introducing functional copies of the GATA3 gene into affected tissues

Gene editing: using technologies like CRISPR-Cas9 to correct GATA3 mutations

RNA-based therapies: modulating gene expression or correcting splicing defects caused by GATA3 mutations 3,6

While these approaches are still in the early stages of research, they hold promise for more targeted and effective treatments in the future. Ongoing clinical trials and research efforts continue to explore new therapeutic strategies for Barakat syndrome and related disorders. 1,4

Genetic counselling and family planning

Genetic counselling plays a crucial role in the management of Barakat syndrome, providing individuals and families with information about the genetic basis of the disorder, inheritance patterns, and reproductive options. Key aspects of genetic counselling for Barakat syndrome include:

Explaining the 50% risk of passing the GATA3 mutation to offspring in each pregnancy

Discussing the variable expressivity of the disorder and the unpredictability of symptom severity

Exploring family planning options and reproductive technologies

For couples at risk of having a child with Barakat syndrome, several options are available:

Prenatal genetic testing: chorionic villus sampling or amniocentesis can detect GATA3 mutations during pregnancy

Preimplantation genetic testing (PGT): this involves in vitro fertilisation (IVF) with genetic testing of embryos before implantation, allowing selection of unaffected embryos

Gamete donation: using eggs or sperm from an unaffected donor can prevent transmission of the GATA3 mutation

Adoption: this option allows couples to have a family without the risk of passing on the genetic mutation

Genetic counsellors work closely with families to provide support, information, and guidance throughout the decision-making process, ensuring that individuals can make informed choices about family planning.

Summary

Barakat syndrome is a rare genetic disorder that impacts various organ systems. It features hypoparathyroidism, sensorineural deafness, and kidney problems. Understanding its genetic causes is essential for improving diagnosis and treatment for those affected. Key characteristics include hypoparathyroidism, which leads to low calcium and high phosphate levels, resulting in symptoms such as muscle cramps and seizures, sensorineural deafness, which may occur at birth or develop later, and various kidney abnormalities, potentially leading to renal failure. Other possible symptoms include growth delays, cognitive challenges, and facial differences. The genetic basis of Barakat syndrome was linked to mutations in the GATA3 gene, which is crucial for organ development. These mutations disrupt normal gene functions, causing the syndrome's features and following an autosomal dominant inheritance pattern. Diagnosis involves clinical evaluations and genetic testing, focusing on the presence of at least two main features. Genetic tests like sequence analysis and deletion/duplication analysis identify specific GATA3 mutations, which help confirm diagnosis. Currently, there is no cure. Treatments include managing symptoms such as calcium supplementation for hypoparathyroidism, hearing aids, and regular kidney monitoring. Future therapies may involve gene therapies and editing to address GATA3 mutations. Genetic counselling is vital, informing families about inheritance risks and discussing reproductive options like prenatal testing and adoption, enabling informed family planning decisions.

References

Spennato U, Siegwart J, Hartmann B, Fischer EJ, Bracco C, Capraro J, et al. Barakat syndrome diagnosed decades after initial presentation. Endocrinology, Diabetes & Metabolism Case Reports. 2023;2023(4). https://doi.org/10.1530/edm-23-0018.

Zaikova NM, Morozov SL, Ryabova SE, Dlin VV. Barakat syndrome: clinical polymorphism of the disease. Rossiyskiy Vestnik Perinatologii i Pediatrii (Russian Bulletin of Perinatology and Pediatrics). 2023;68(2): 86–92. https://doi.org/10.21508/1027-4065-2023-68-2-86-92.

Joseph ADD, Sirisena ND, Kumanan T, Sujanitha V, Strelow V, Yamamoto R, et al. Hypoparathyroidism, Sensorineural deafness and renal disease (Barakat syndrome) caused by a reduced gene dosage in GATA3: a case report and review of literature. BMC Endocrine Disorders. 2019;19(1). https://doi.org/10.1186/s12902-019-0438-4.

Yu S, Chen W, Lu W, Chen C, Ni Y, Duan B, et al. Novel heterozygous GATA3 and SLC34A3 variants in a 6‐year‐old boy with Barakat syndrome and hypercalciuria. Molecular Genetics & Genomic Medicine. 2020;8(5). https://doi.org/10.1002/mgg3.1222.

Vidavalur R, Devapatla S. A Unique Genomic Variant of HDR Syndrome in Newborn. Indian Pediatrics. 2018;55(8): 705–706. https://doi.org/10.1007/s13312-018-1364-7.

Alkaissi HR, Banerji MA. Primary Hypoparathyroidism Presenting as Idiopathic Intracranial Hypertension in a Patient With Barakat Syndrome. Cureus. 2022; https://doi.org/10.7759/cureus.24521.