Overview of Barakat syndrome

Barakat syndrome is a rare genetic disorder displaying autosomal dominant inheritance.¹ Barakat syndrome is also known as HDR syndrome owing to its three salient features:

• Hypoparathyroidism
• Sensorineural deafness
• Kidney (Renal) abnormalities

Endocrine problems in Barakat syndrome are related to hypoparathyroidism, an underactivity of the parathyroid gland, which produces parathormone, the hormone crucial to maintaining healthy calcium levels in the body.

Diagnosing Barakat syndrome is challenging as it displays variable penetrance. This means that not all patients carrying the abnormal gene will develop all of the clinical features. Whilst most patients display hypoparathyroidism and deafness, only about 65% develop abnormalities of the kidneys.²

The genetic defect in Barakat syndrome is a group of mutations in the GATA3 gene. Several different mutations have been identified. During the development of the human embryo, the GATA3 gene is involved in the formation of structures that go on to become the inner ear, the thymus and the kidneys, thus mutations in the GATA3 gene lead to abnormalities in these organs.² 

Endocrine manifestations of Barakat syndrome

When discussing the endocrine issues in Barakat syndrome, we are talking about hypoparathyroidism, or underactivity of the parathyroid glands. The parathyroid glands lie within the neck and are about the shape and size of a pea. Usually there are four but this can vary. The parathyroid gland’s main function is to regulate the levels of calcium in the body.³

Sensors in the cell membranes of the parathyroid gland can detect the presence of calcium in the bloodstream. When levels of calcium are high, these sensors send messages to the parathyroid cells to reduce the secretion of parathormone, the hormone that regulates calcium levels. Conversely, when calcium levels are low, they send fewer messages, which results in increased secretion of parathormone. In hypoparathyroidism there is decreased production and secretion of parathormone.³

Low levels of parathormone lead to a decrease in blood calcium levels, this is known as hypocalcaemia. Parathormone acts at different sites in the body to regulate calcium levels. In the kidneys, parathormone increases the absorption of calcium from the urine back into the bloodstream. The kidney’s role is also to manufacture the active form of vitamin D, 1,25 hydroxyvitamin D. This form of vitamin D is required to promote the absorption of calcium from the intestine. In bone both 1,25 hydroxy vitamin D and parathormone have a direct action on the breakdown of bone by cells called osteoclasts. Most of the body’s excess calcium is stored in the bones. Breakdown of bone releases calcium and phosphate into the bloodstream. Therefore, low levels of parathormone lead to low levels of blood calcium, or hypocalcemia.³

Diagnostic evaluation

The diagnosis of hypoparathyroidism is based on taking a clinical history and performing a clinical examination to detect the symptoms and signs of hypocalcemia. The symptoms and signs of hypocalcemia are:⁴     

• Muscle pain (myalgia)
• Muscle spasm
• twitching
• new-onset seizures (fits)
• numbness around the mouth
• pins and needles in the hands and feet
• Laryngospasm (spasm of the throat)
• Tetany, where there is widespread rigidity and spasm of the muscles in the body⁴
• Trosseau’s sign may be present
• Chovstek’s sign may be present

There may also be generalized symptoms and signs or signs of complications of hypocalcemia affecting the kidneys, heart and central nervous system, such as:⁴

• Generalised: coarse hair with patchy alopecia, flaky skin, brittle nails
• Symptoms of kidney stones or a past history of kidney stones, particularly recurrent in  nature
• A two-fold increased risk in vertebral fractures, despite increased bone density
• Symptoms of cardiac abnormalities caused by low calcium levels –congestive heart failure, cardiomyopathy – shortness of breath, leg swelling, arrhythmias (disorders of the heart rhythm and palpitations)
• Neuropsychiatric symptoms of hypocalcemia: memory loss, depression, anxiety, bipolar disorder
• Cataracts may be present

In Barakat syndrome, a family history of sensorineural deafness and hypoparathyroidism with or without kidney disease may be present.²

Laboratory tests

The next stage of diagnosis is laboratory testing. Measurement of blood levels of calcium and phosphate along with parathormone (measured by a test called radioimmunoassay) can confirm the diagnosis of hypoparathyroidism.⁴

Low levels of calcium, along with high levels of phosphate, confirm the diagnosis of hypocalcemia. If parathormone levels are low, a diagnosis of hypoparathyroidism can be made, although a normal parathormone level in the presence of low calcium does not rule out hypoparathyroidism as in the presence of low calcium, parathormone level should be high. Serum magnesium and vitamin D levels should also be checked in hypocalcemia as low levels of vitamin D or magnesium can lead to hypocalcemia. Additionally, urine calcium level can be checked and will be high in hypoparathyroidism. Blood tests of renal function should also be performed, as hypoparathyroidism leads to calcium deposits in the kidney and kidney stones, which can affect the overall kidney function.⁴

Imaging and other diagnostic studies

ECG - an electrocardiogram (heart tracing) may show specific abnormalities associated with a low calcium level. Additionally, an ECG can show disorders of the heart rhythm, which may be associated with hypocalcemia.⁴

CT imaging may show features of calcium deposits, particularly in the brain around an area called the basal ganglia and thickening of the skull vault, but diagnosis is based on laboratory testing rather than imaging findings.⁵

Imaging of the kidneys with ultrasound and CT scanning may show kidney stones (nephrolithiasis) and calcium deposits in the kidneys.⁴

Acute management of hypocalcemia

Low calcium levels can present as a medical emergency, particularly if the degree of hypocalcemia is severe. The symptoms and signs of emergency or acute hypocalcaemia are:

Marked neurological symptoms – muscle cramps, tetany, paraesthesia (pins and needles) or seizures, positive Trosseau’s and Chovstek’s signs. Noisy breathing caused by spasm of the larynx (voice box) and main airway (stridor) or a blood calcium level below 7.5mg/dl.⁶

Immediate interventions involve rapidly correcting the low calcium level by giving intravenous calcium. This is given as calcium gluconate via intravenous injection over 10 minutes. ECG monitoring should be performed during treatment. If the patient continues to have symptoms, or the calcium level is not corrected a calcium drip may be administered until it is practical to start treatment with oral calcium and vitamin D.⁶

Long-term management strategies

The long-term management of hypocalcemia due to hypoparathyroidism is by replacement of calcium with oral calcium supplements and vitamin D analogues such as Calcitriol. Treatment is lifelong. A typical regime would be calcium carbonate 500mg-3g per day and 0.5mcg-1 mcg of Calcitriol per day.⁷

The dose given depends on the patient’s response but it is generally advised to aim for a calcium level on the low side of normal. This is because there is an increased risk of nephrolithiasis (kidney stones) and calcium deposits forming within the kidneys in patients treated with calcium supplements.

If magnesium levels are found to be low, supplementation with oral magnesium is also advised. Blood calcium and phosphate levels should be monitored regularly throughout treatment. Measuring urine calcium can also be helpful in reducing the risk of kidney stones. Another strategy is to prescribe a thiazide diuretic in addition to calcium supplements, which reduces the excretion of calcium by the kidneys.⁷

Hormone replacement therapy

In 2015, the FDA approved a recombinant human Parathormone, Pth 1-84, for use in hypoparathyroidism. It had the advantage of being taken once per day by injection and reduced the need for calcium supplements and their associated problems,⁸ however it was recalled due to a manufacturing defect and is currently not available.⁹ Palopegteriparatide (also known as TransCon PTH and sold under the brand name Yorvipath) is a modified parathormone molecule administered by once-daily injection, approved by the European Medicines Agency in 2023,¹⁰ however it has been denied approval by the FDA, owing to manufacturing concerns. Talks are ongoing between the manufacturers and the FDA. In the UK the MHRA (Medicines Health and Regulatory Authority) approved Yorvipath in April 2024.

Dietary and lifestyle management

Dietary sources of calcium are predominantly from dairy produce (milk, yogurt, cheeses) in addition to soya products such as tofu. Broccoli, Kale, Spinach and other leafy green vegetables are also rich in calcium.¹¹ Also important is to minimize foods high in phosphates, such as cooked pork, chicken, turkey and seafood and liver. Regular exercise is important for bone health and exposure to sunlight helps promote vitamin D synthesis in the skin.

Pediatric considerations

In children with Barakat syndrome, monitoring growth and development is important. Barakat syndrome is one of many genetic syndromes associated with hypothyroidism in children.¹² Genetic testing for abnormalities of the GATA3 gene may be helpful in both coming to terms with the diagnosis and to establish family carriage of Barakat syndrome. In Barakat syndrome, prognosis is usually dependent on the severity of any kidney abnormalities however education and support for all aspects of the disease including endocrine considerations are important. Protocols for oral supplementation with Calcium and vitamin D analogues are available for children.¹² 

Summary

Barakat syndrome is a rare cause of hypoparathyroidism. Hypoparathyroidism presents with low levels of calcium in the bloodstream requiring lifelong corrective therapy with calcium and vitamin D. The use of recombinant human parathormone offered an alternative to traditional calcium and vitamin D supplementation but is no longer commercially available. A new modified parathormone treatment has however just been approved for use in Europe and the UK.