Pseudohypoparathyroidism (PHP) is a rare hereditary disorder characterized by the resistance or insensitivity of target organs to parathyroid hormone (PTH). The parathyroid glands are small glands located behind the thyroid in the neck and play a crucial role in regulating calcium and phosphorus levels in the bloodstream. PTH is essential for maintaining bone strength and proper muscle function by balancing calcium and phosphorus levels. Individuals with this syndrome typically present with hyperphosphatemia and hypocalcemia symptoms.

This condition is distinct from hypoparathyroidism, where the parathyroid glands are underactive and produce insufficient amounts of PTH.

Subtypes of Pseudohypoparathyroidism

There are five variants of Pseudohypoparathyroidism:

PHP type 1a (PHP-1a)
PHP type 1b (PHP-1b)
PHP type 1c (PHP-1c)
PHP type2(PHP-2)
Pseudopseudohypoparathyroidism (PPHP).

PHP type 1a is the most common subtype, representing 70% of cases.

PHP Type 1a

Autosomal dominant inheritance is the mode of inheritance for type 1a. That means that just one parent needs to give you the faulty gene for it to work. It is also known as Albright hereditary osteodystrophy. Moreover, symptoms of the disease include short stature, a round face, obesity, developmental delay, and small hand bones.¹ Whether you have the gene from your mother or father will affect the symptoms you experience.

PHP Type 1b

In type 1b, PTH resistance solely impacts the kidneys. Less research has been done on type 1b than type 1a. Although no other symptoms are similar to Albright hereditary osteodystrophy, the blood calcium level is low.²

PHP Type 1c

In Pseudohypoparathyroidism type 1c (PHP1c), the body resists PTH and other hormones. It appears as hypocalcemia, hyperphosphatemia, and increased PTH levels.

PHP Type 2

Furthermore, additional signs of the disease include low blood calcium levels and high blood phosphate levels. These individuals do not share the morphological traits of Type 1a people. Its genetic abnormality of origin is unknown. It differs from Type 1b regarding how the kidney responds to increased PTH levels.³

Pseudopseudohypoparathyroidism (PPHP)

The genetic disorder pseudopseudohypoparathyroidism (PPHP) results in small stature, a round face, and short hand bones. Joints and other soft tissues in the body stiffen due to PPHP. Consequently, the development of bones is also impacted. However, PPHP may harm bones, joints, and nerves, resulting in ongoing pain. Patients with PHPP only have Albright hereditary osteodystrophy and do not develop PTH or other hormone resistance.10% of PPHP sufferers also have a learning handicap. Genetic alterations in the GNAS gene cause PHPP, an autosomal dominantly inherited condition. Genetic imprinting typically dictates inheritance from the father. PPHP is genetically related to PHP-1a, a form of Pseudohypoparathyroidism.

Epidemiology

Pseudohypoparathyroidism is a very rare disorder. Depending on the area, the estimated prevalence ranges from 0.3 to 1.1 instances per 100,000 people.⁴ Moreover, the prevalence and incidence of Pseudohypoparathyroidism are more common in women than men.

Etiology of Pseudohypoparathyroidism

The Parathyroid hormone is created by the parathyroid glands. PTH is essential for bone density by controlling the blood’s calcium, phosphorus, and vitamin D amounts. If a patient has PHP, the body will manufacture the right amount of PTH. It is nevertheless “resistant” to their effects. This leads to low blood calcium and high blood phosphate levels. The inherited autosomal dominant condition pseudohypoparathyroidism is brought on by changes (variants) in the GNAS gene. GNAS mutations are present in about 76% of those with the disorder, and 38% had a parent who also had it. The explanation for the remaining cases is unknown.
Additionally, medical professionals refer to this condition as a dominant genetic illness, where a single defective gene copy can cause the disease. The affected person may have inherited the mutated or changed defective gene from one or both parents. During each pregnancy, there is a 50% risk that the affected parent will pass the faulty gene to the unborn child. The level of risk is the same for both men and women.

Symptoms of Pseudohypoparathyroidism

The signs and symptoms of Pseudohypoparathyroidism might change greatly from child to child. Patients with PHP type 1a present with a characteristic phenotype, collectively called Albright hereditary osteodystrophy (AHO).
Obesity is a common feature of AHO, although brachydactyly is the most reliable sign in the diagnosis of this condition (see the image below). Brachydactyly can manifest in a symmetrical or asymmetrical fashion and may affect one or both hands and feet. The condition primarily results from the shortening of the metacarpals, leading to the reduced length of certain digits, particularly the fourth and fifth ones. During a physical examination, the shortening of metacarpals can be observed as dimpling over the knuckles when making a fist. Additionally, the shortening of the distal phalanx of the thumb is noticeable through an increased width-to-length ratio of the nail, often referred to as murderer’s thumb or potter’s thumb.

Observing metacarpal shortening in Pseudohypoparathyroidism Type 1a.

Children with PTH resistance may exhibit the following symptoms:

Tingling or numbness in the hands, feet, or mouth area
Face, hand, arm, and foot spasms that are uncontrollable and excruciating
Spasms of muscles that make it difficult to breathe or speak
Muscle pain
Seizures
Reduced blood pressure
Unstable emotions, anxiety, or sadness
Dental issues such as thin tooth enamel or teeth that are developing slowly
Brittle, coarse hair
Toenails and fingernails that are readily broken.

Life Expectancy of Pseudohypoparathyroidism

Pseudohypoparathyroidism often has no effect on a person’s life expectancy. With the aid of adequate medical care, the majority of people with Pseudohypoparathyroidism can lead generally normal lives. This treatment typically requires calcium and vitamin D supplements to maintain healthy calcium levels. However, the specific life expectancy can vary based on the individual’s general health, any issues, and the effectiveness of their treatment strategy.⁵

Pseudohypoparathyroidism Vs. Hypoparathyroidism

Hypoparathyroidism occurs when the glands produce too little PTH. The blood calcium level falls, and the phosphorus level rises.⁶ This deficiency directly disrupts the regulation of calcium and phosphorus in the body, causing symptoms such as muscle cramps, seizures, and fatigue.
In contrast, pseudohypoparathyroidism is a genetic disorder in which the body produces normal or even elevated levels of PTH, but the target tissues fail to respond effectively to the hormone. This resistance to PTH results in similar biochemical abnormalities as hypoparathyroidism—low calcium and high phosphorus levels—despite adequate hormone production. Pseudohypoparathyroidism is often associated with additional physical features, such as Albright hereditary osteodystrophy, which includes characteristics like short stature, brachydactyly, and obesity.
While both conditions disrupt calcium and phosphorus homeostasis, their underlying mechanisms are distinct: one is due to a deficiency in hormone production, and the other is due to resistance to the hormone’s effects.

Diagnosis of Pseudohypoparathyroidism

Laboratory studies:

Laboratories use serum calcium assays, including measuring serum total calcium and ionized calcium, to diagnose Pseudohypoparathyroidism (PHP) and confirm a hypocalcemic state. To differentiate PHP from other causes of hypocalcemia, the intact parathyroid hormone (PTH) level is measured using sensitive assays, such as immunoradiometric assays (IRMA). In PHP, despite low calcium levels, serum PTH concentrations are elevated, reflecting the body’s compensatory response to hypocalcemia. This elevated PTH level in the presence of hypocalcemia suggests either secondary hyperparathyroidism or a form of PHP, where the underlying issue is resistance to PTH action rather than its deficiency.

Imaging studies:

The three imaging procedures that are most frequently requested are X-rays, CT scans, and MRI tests. X-ray imaging of the hand may display a distinct pattern, showing severe shortening of the bones, particularly in the distal phalanx of the thumb and the third through fifth metacarpals. Small soft tissue opacities (calcifications/ossifications) may also be visible on radiographs. Computed tomography (CT) scanning can reveal calcification in the basal ganglia.

ECG:

It can show prolongation of QT interval due to hypocalcemia.

BMD testing:

Patients with PHP, particularly type 1b, may be at risk of parathyroid-related bone disease due to dysregulated calcium and phosphate metabolism. Therefore, bone mineral density (BMD) should be evaluated using tools like the DEXA scan in this patient population.

Genetic testing:

Genetic testing, specifically analysis of the GNAS1 gene, plays a crucial role in confirming the diagnosis and identifying variants of PHP. For PHP-1b, testing for GNAS methylation abnormalities is essential, as loss of methylation at the A/B region of the maternally inherited allele is consistently observed in all cases. Some laboratories focus only on this region due to its reliability in detecting the condition. Additional tests can identify minor deletions in STX16, abnormalities in GNAS, or paternal uniparental isodisomies of chromosome 20q. These tests can also uncover GNAS deletions that may cause PHP-1a.⁷

Differential diagnosis of Pseudohypoparathyroidism

Vitamin D deficiency:

Hypocalcemia and high PTH levels (secondary hyperparathyroidism) are the symptoms of this illness, yet vitamin D levels are conspicuously low.

Worsening chronic kidney disease (CKD):

Similar findings are observed in patients with reduced glomerular filtration rate (GFR). The kidney is the primary site for 1-alpha-hydroxylation of 25 OH vitamin D, which produces the active form of the hormone 1,25(OH)2 vitamin D. Poor conversion to active vitamin D leads to low levels of vitamin D in CKD patients. In addition to having low amounts of active vitamin D, people with diminishing GFR frequently have blood phosphate levels that are greater than normal. However, increased parathyroid hormone release is brought on by low levels of active vitamin D and excessive levels of phosphate.⁸

Treatment of Pseudohypoparathyroidism

Healthcare professionals may employ various therapy approaches depending on the subtype, patient age, general health, and comorbidities. Likewise, enhancing the patient’s quality of life, managing symptoms, and avoiding negative effects are the main objectives of treatment. Typical treatments for Pseudohypoparathyroidism include the following:

Calcium and Vitamin D Supplementation:

Patients with Pseudohypoparathyroidism typically need calcium and vitamin D supplements to maintain normal blood calcium levels. These nutrients help prevent the clenching, trembling, and stiffness symptoms of hypocalcemia.⁹

Phosphate-Binding Medications:

To treat hyperphosphatemia caused by Pseudohypoparathyroidism, doctors may prescribe phosphate-binding medications. Therefore, these medications slow phosphorus absorption from the diet, aiding in the treatment of elevated blood phosphate levels.

Dietary Management:

The calcium and phosphorus levels are managed by altering the diet. However, it might also suggest eating a lot of calcium.

Genetic Counseling:

Because Pseudohypoparathyroidism is genetic in origin, genetic counseling may be beneficial for both individuals and families to understand the inheritance pattern and any potential risks for future generations.

Complications of Pseudohypoparathyroidism

Parkinsonism can result from it, which may or may not get better with the right calcium and vitamin D supplements.
Children may struggle with their fine motor abilities.
Patients frequently experience carpal tunnel syndrome.
There have been instances of higher-than-average spinal stenosis levels as well as an earlier presentation, which can result in lower extremity paraparesis.
Children face a sleep apnea risk of more than four times higher, as reported.

In conclusion, Pseudohypoparathyroidism, a rare hereditary condition, affects the body’s reaction to parathyroid hormone. It causes a calcium and phosphorus imbalance, which leads to symptoms similar to hypoparathyroidism. Moreover, genetic abnormalities alter hormone signaling pathways in target tissues, causing the disease. To control calcium and phosphorus levels, active Vitamin D and supplements are necessary. Pseudohypoparathyroidism comes in various forms, with Type 1a being the most common and associated with particular physical traits. Therefore, advances in genetic studies offer hope for more effective diagnostic and therapeutic approaches for this complex condition.

Refrences

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Pseudohypoparathyroidism: Decoding the Rare Disorder

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