What Is Familial Isolated Hypoparathyroidism?

Hypothyroidism is a condition characterized by the underproduction of parathyroid hormone (PTH) by the four small glands located near the thyroid gland in the neck. PTH plays a vital role in regulating calcium and phosphate levels in the bloodstream by facilitating the transfer of calcium from both the bone and diet into the bloodstream.

Familial Isolated Hypoparathyroidism (FIH) represents a unique subtype of hypoparathyroidism, distinguished by its specific genetic, clinical, and management characteristics. It also underscores the critical importance of providing support to individuals affected by this condition.¹

FIH  differs from other types of hypothyroidism due to its ‘familial’ and ‘isolated’ nature; it’s ‘familial’ because it can be passed down from parent to child and ‘isolated’ as it mainly affects the parathyroid gland. This genetic aspect makes understanding FIH crucial for affected individuals and their families.²

Causes of familial isolated hypothyroidism 

The primary causes of this condition arise exclusively from mutations in specific genes that play a pivotal role in regulating calcium balance, such as the Calcium-sensing receptor (CASR) and Glial Cells Missing-2 (GCM2). The inheritance pattern for this condition can vary, encompassing both autosomal dominant and autosomal recessive modes or X-linked recessive patterns. "Autosomal" pertains to genes not located on the sex chromosomes in the reproductive system, and X-linked means the mutation is found on an X chromosome, which is a sex chromosome; this is why females are more likely than males to obtain this condition as they have two X chromosomes.³

To better comprehend the concepts of dominance and recessiveness, let's draw an analogy using one gene that determines eye colour, Gene B. Each of these genes has distinct versions known as alleles. Gene B has "B" and "b" alleles.

Dominant: "B" dictates brown eyes. Having one "B" allele (B,b) or two (BB) results in brown eyes.

Recessive: "b" signifies blue eyes. Both alleles must be "b" (bb) to have blue eyes.

Additionally, surgical damage to the parathyroid glands during thyroid surgery is a common cause of hypoparathyroidism.

Moreover, most cases of hypoparathyroidism are most commonly due to inadvertent damage to the parathyroid glands during thyroid surgery.⁴

Signs and symptoms of FIH

The disruption of calcium balance arising from underactive parathyroid glands causes weakness and rapid fatigue of any muscles under voluntary control, known as neuromuscular irritability, and this is displayed by various symptoms, including numbness, tingling, spasms of hands and feet, and seizures. These symptoms commonly occur during early childhood however, they can occur anytime from birth to adulthood. Usually, the first symptoms that are shown are seizures, which are like sudden fits or episodes where a person's body moves uncontrollably. This is especially true for babies and children.

As children grow up with this condition, it can impact their teeth. The outer layer of their teeth, called enamel, might not develop properly, making their teeth weak and prone to problems like cavities. This can lead to difficulties with eating and taking care of their teeth.

Another challenging aspect of this condition is something called laryngospasm. This is when the muscles around the throat suddenly tighten up, making it hard to breathe. Think of it like a sudden "choking" sensation. This can be really frightening and dangerous, as it can block the normal flow of air into the lungs.

That's not all; over time, people with this condition might also experience calcium deposits forming in their brains or kidneys. These deposits are like hard, unwanted rocks inside these important organs. They can interfere with how the brain and kidneys work, causing more health problems. Moreover, Hypoglycemia (low blood sugar), occurs in individuals with hypoparathyroidism due to the low level of PTH causing fatigueness.

So, catching this condition early is important. With the right treatment, we can help children and adults manage these challenges and avoid the more serious issues that might come along with it.⁵

Diagnostic approaches

To diagnose FIH, doctors perform a standard blood test to check levels of calcium, phosphate, PTH, and magnesium in the body. In FIH, calcium levels are consistently low, while phosphate levels stay mostly normal or may even be high. PTH levels are also typically low in FIH. Additionally, examining minerals in the urine, especially in people with a specific genetic issue called an activating CaSR mutation, is important. This urine test helps confirm the diagnosis and can reveal elevated magnesium and calcium levels, which are typical in this condition.⁶

It's also crucial to distinguish FIH from acquired forms of hypoparathyroidism, which can happen after surgery due to autoimmune problems or other medical issues. These different types of hypoparathyroidism have different causes and need tailored treatments. Furthermore, some genetic disorders can mimic FIH symptoms, mainly involving low calcium levels. So, conducting genetic testing is necessary not only to confirm hypoparathyroidism but also to identify it within affected families.⁷

Management and treatment

The main goal for the treatment of FIH is to bring calcium levels back to normal and alleviate symptoms, which includes avoiding high levels of calcium excretion in the urine; achieving this balance involves the regulation of calcium and PTH. Vitamin D and calcium supplements are the standard Food and Drug Administration (FDA) approved therapy for all types of hypoparathyroidism, especially for patients with FIH. The most common active forms of vitamin D used for patients with hypoparathyroidism are vitamin D3 and calcitriol, and two other synthetic forms of vitamin D usually used are cholecalciferol and dihydrotachysterol. These synthetic forms have a longer period of action; many individuals receive a combination of short and longer-acting vitamin D.⁸

In some situations, doctors may consider using recombinant PTH therapy to manage FIH. This treatment has been looked at as an experimental hormone replacement therapy for chronic hypoparathyroidism for several years. Research has found some positive results, like a decrease in urinary calcium levels. Interestingly, Teriparatide, a form of recombinant parathyroid hormone known as Forteo, originally used for severe osteoporosis treatment, has shown promise for treating hypoparathyroidism. People have reported feeling better when they receive Teriparatide, which they usually get as a daily injection under the skin. Additionally, adjusting the diet to a high calcium and phosphate one may help.⁹

Regular monitoring of calcium, phosphate, and PTH levels is essential to ensure treatment efficacy and adjust dosages as needed. Long-term care includes addressing potential complications such as kidney stones and bone health.

Patient and family support

Patient and Family Support plays a crucial role in the care of patients suffering from FISH as well as any painful disorder. Genetic counselling is a beneficial resource for coping with an emotionally and physically challenging disorder by providing individuals and families with information about the condition's inheritance pattern and involvement in future family planning. Apart from the medical aspect, addressing the emotional and social harm like anxiety, depression, and social consequences of having the typically rare disorder. Support groups and educational resources offer an opportunity to be part of a community and platform that shares similar experiences and offers a network of individuals who understand the challenges of living with FIH. This can, in turn embrace the emotional and psychological depth of living with FIH.⁵

Real-life cases

In 2005, Baumber and colleagues conducted a study involving a closely related Pakistani family spanning five generations. Within this familial group, they observed four individuals who displayed early-onset isolated hypoparathyroidism. Among these four cases, three individuals began exhibiting symptoms during infancy, including seizures. Upon further examination, it was determined that these individuals had low calcium levels and reduced PTH (parathyroid hormone) levels. Consequently, they were promptly initiated on treatment involving vitamin D and calcium supplements.

Remarkably, the fourth individual in this family received unique attention. Thanks to their family's medical history, they underwent screening for hypocalcemia shortly after birth. This early screening enabled a swift diagnosis and timely initiation of treatment.

Baumber et al. (2005) identified homozygosity for a missense mutation in the GCM2 gene (R47L; 603716.0002) in affected members of this consanguineous Pakistani family with familial isolated hypoparathyroidism.¹⁰

Research and future directions

As our understanding of genetic disorders continues to advance, we have made significant progress in unravelling the complexities of Familial Isolated Hypoparathyroidism (FIH). This rare condition is driven by specific genetic mutations that directly impact the parathyroid glands, which play a critical role in regulating calcium and phosphate levels within our bodies. Although FIH remains relatively uncommon, ongoing research is steadily illuminating the intricate genetic factors that underlie this condition. Looking forward, the field of FIH research holds promising prospects, including the potential discovery of further genetic intricacies and the refinement of treatment modalities. As our scientific comprehension deepens, we can anticipate the development of more tailored and effective interventions for individuals affected by FIH, ultimately leading to an improved quality of life.²

Summary

To summarise, Familial Isolated Hypoparathyroidism (FIH) is a rare genetic illness with serious consequences for affected individuals and their families. This illness, caused by certain genetic abnormalities affecting the parathyroid glands, affects our bodies' delicate calcium and phosphate balance. Nonetheless, continuing research is gradually revealing the complicated genetic variables at work in FIH. This increased understanding holds the prospect of more precise and successful treatments, providing hope for those suffering from FIH. Aside from medicinal therapies, emotional and social support, such as genetic counselling and support groups, are critical in assisting individuals in navigating the physical and emotional hurdles presented by FIH. While FIH poses unique challenges, the future appears to be brighter with the potential for enhanced management and improved prospects for those struggling with this condition.