Pseudohypoparathyroidism (PHP) is a rare genetic disorder where the body is unable to respond properly to parathyroid hormone (PTH). The four parathyroid glands in the neck produce PTH to regulate calcium and phosphorus levels in the blood. In people with PHP, the body produces sufficient amounts of PTH, but tissues like the bones and kidneys are resistant to its effects, leading to a mineral imbalance. The condition differs from true hypoparathyroidism, where the body fails to produce enough PTH.
The Underlying Genetic Causes
Pseudohypoparathyroidism is caused by mutations in the GNAS gene, which provides instructions for a protein essential for many hormones to function. These genetic defects lead to end-organ resistance to PTH and other hormones. The mutations can be inherited or occur spontaneously.
The disorder’s manifestation is influenced by genomic imprinting, where genes are expressed differently depending on which parent they are inherited from. In tissues like the kidneys, only the maternal copy of the GNAS gene is active. This imprinting is why the parent who passes on the mutation determines the specific subtype and symptoms.
When the faulty GNAS gene is inherited from the mother, it results in PHP Type 1a (PHP-Ia), the most common form. This type involves both hormone resistance and a collection of physical traits. This is because the kidneys require a functioning maternal GNAS allele to respond to PTH. If the same mutation is inherited from the father, it results in a related condition with the physical traits but without the hormone resistance.
Other forms of the disorder exist. PHP Type 1b (PHP-Ib) also involves PTH resistance but lacks the associated physical features. It is caused by methylation defects, which are epigenetic changes affecting how the GNAS gene is expressed without altering the DNA sequence itself. PHP Type 2 is biochemically similar to Type 1 with PTH resistance, but its specific genetic cause is not fully understood and it also lacks the characteristic physical signs.
Associated Signs and Symptoms
The signs of pseudohypoparathyroidism fall into two categories: biochemical consequences of hormone resistance and a set of physical characteristics. The resistance to parathyroid hormone (PTH) leads to low blood calcium (hypocalcemia) and high phosphate (hyperphosphatemia). This mineral imbalance causes a variety of symptoms.
Low calcium can cause neuromuscular irritability, manifesting as numbness or tingling around the mouth, hands, or feet. More severe effects include muscle cramps, painful spasms (tetany), and seizures. The mineral imbalance can also lead to dental problems, such as delayed tooth eruption and weakened enamel.
Many people with PHP Type 1a display physical features known as Albright’s Hereditary Osteodystrophy (AHO). These traits include short stature, a round face, and obesity starting in early childhood. A distinctive sign is brachydactyly, the shortening of bones like the fourth and fifth metacarpals in the hands, which can create a dimpled appearance over the knuckles.
Additional AHO features include a short neck and small, bony nodules under the skin (subcutaneous ossifications). These physical traits are specific to certain types of PHP. Individuals with PHP Type 1b and Type 2 experience hormonal resistance but do not have the AHO phenotype.
The Diagnostic Process
Diagnosing pseudohypoparathyroidism involves clinical evaluation, lab tests, and genetic analysis. A physician will perform a physical examination, looking for signs of Albright’s Hereditary Osteodystrophy (AHO) like short stature or brachydactyly. A detailed family history is also reviewed to identify inheritance patterns.
Blood testing is a primary diagnostic tool. Lab analysis reveals low blood calcium (hypocalcemia) and high blood phosphate (hyperphosphatemia). Blood tests will also show that the level of parathyroid hormone (PTH) is normal or, more often, significantly elevated. This combination of findings points toward hormone resistance rather than a deficiency in hormone production.
Urine tests are used to measure excreted calcium and phosphorus. Normally, PTH prompts the kidneys to conserve calcium and excrete phosphate. The absence of this response in urine helps confirm resistance.
Genetic testing is often performed to finalize the diagnosis and determine the subtype. This analysis of the GNAS gene for mutations or epigenetic alterations can confirm PHP. It also distinguishes between types like 1a and 1b, which is important for understanding potential symptoms and for genetic counseling.
Management and Treatment Strategies
There is no cure for the genetic defect in pseudohypoparathyroidism, but its symptoms are managed with lifelong treatment. The goal is to normalize blood calcium and phosphate levels to prevent symptoms like muscle spasms and seizures. This is achieved through supplementation.
Patients are treated with high-dose calcium supplements and an active form of vitamin D, such as calcitriol. Calcitriol helps the intestines absorb calcium, a process normally stimulated by PTH. Providing this active vitamin D bypasses the need for PTH in calcium absorption, helping to raise blood calcium levels toward the normal range.
Regular monitoring is a key part of management. Patients undergo frequent blood tests to measure calcium and phosphate levels, allowing for supplement dose adjustments. The goal is to keep these minerals in a target range while avoiding complications like excess calcium in the urine (hypercalciuria), which can cause kidney stones.
Since the GNAS gene affects other hormone signals, patients may be screened for other endocrine issues. Resistance to thyroid-stimulating hormone (TSH) can cause hypothyroidism, while other hormone resistances can affect growth and development. If identified, these are managed with appropriate hormone replacement therapies.