Pseudohypoparathyroidism

What pseudohypoparathyroidism is

PTH is made by four small parathyroid glands in the neck. It raises blood calcium by releasing calcium from bone, holding on to calcium in the kidney, making the kidney excrete phosphate, and activating vitamin D. PTH works by binding to a receptor that signals through a protein called Gsα, encoded by the GNAS gene.

In PHP, a fault in this signaling chain, usually in GNAS, means the kidney (and sometimes other tissues) cannot respond to PTH. The result looks like hypoparathyroidism: low calcium and high phosphate. But PTH levels are high, because the glands keep trying. That is the "pseudo" in the name.

The same Gsα protein carries signals for other hormones, including thyroid-stimulating hormone (TSH), growth hormone-releasing hormone and the reproductive hormones. This is why some types involve several hormone problems.

Types of pseudohypoparathyroidism

Because GNAS is "imprinted", the same mutation causes PHP 1a when passed from the mother and PPHP when passed from the father. Experts now group these conditions as inactivating PTH/PTHrP signaling disorders (iPPSD).

Symptoms

Low calcium symptoms

Hypocalcemia often develops gradually in childhood and may not be obvious at birth.

• Tingling or numbness around the mouth and in the fingers and toes.
• Muscle cramps and stiffness.
• Hand and foot spasms (tetany).
• Seizures.
• Fatigue, irritability, anxiety or low mood.
• Heart rhythm changes (a long QT interval).
• Long-term: cataracts, dental enamel defects, and calcium deposits in the brain (basal ganglia calcification).

Albright hereditary osteodystrophy (types 1a and 1c, and PPHP)

• Short adult height.
• A round face and short neck.
• Short fingers and toes, especially the 4th and 5th: when you make a fist, knuckles are replaced by dimples.
• Hard bone-like lumps under the skin (subcutaneous ossifications).
• Early-onset obesity in PHP 1a.
• Learning difficulties in some.

Other hormone problems

• Hypothyroidism from TSH resistance, sometimes found on newborn screening.
• Growth hormone deficiency, contributing to short stature.
• Delayed or incomplete puberty and fertility problems.

How pseudohypoparathyroidism is diagnosed

1. Blood tests: low calcium, high phosphate, high PTH, normal magnesium and normal kidney function. Vitamin D (25-hydroxyvitamin D) is checked to exclude deficiency, which can look similar.
2. Thyroid function and other hormone tests.
3. Hand X-rays: short 4th and 5th metacarpals.
4. Genetic and methylation testing of GNAS: confirms the type and guides family counseling.
5. Eye exam, dental checks and sometimes a brain CT for calcification.

Treatment

There is no cure, but treatment is effective.

• Active vitamin D (calcitriol) and calcium supplements raise calcium and lower phosphate. Unlike hypoparathyroidism, PHP usually allows calcium to be kept in the normal range with less risk of kidney stones, because the part of the kidney that holds on to calcium still responds to PTH. Doses are adjusted by your endocrinologist.
• Normal vitamin D levels maintained with standard vitamin D.
• Monitoring: blood calcium, phosphate, PTH and urine calcium regularly, more often in growing children.
• Thyroid hormone for hypothyroidism.
• Growth hormone for children with documented deficiency.
• Sex hormones for delayed puberty.
• Weight management from early childhood in PHP 1a.
• Surgery for troublesome subcutaneous ossifications, although they can recur.
• Educational support for learning difficulties.

Acute severe hypocalcemia with seizures or tetany is treated in hospital with IV calcium.

Outlook

With treatment, most people with PHP lead full lives. Long-term care focuses on keeping calcium stable, managing weight and other hormone problems, and supporting growth and learning in children. Genetic counseling helps families understand the chance of passing it on, which depends on which parent carries the change.

Frequently asked questions

What is the difference between hypoparathyroidism and pseudohypoparathyroidism?

In hypoparathyroidism, the glands do not make enough PTH, so PTH is low. In pseudohypoparathyroidism, the glands make plenty of PTH, but the body does not respond to it, so PTH is high. Both cause low calcium and high phosphate.

What are the lab findings in pseudohypoparathyroidism?

Typical results are low blood calcium, high phosphate and high PTH, with normal magnesium and normal kidney function. Vitamin D should be normal or replaced. TSH may be mildly raised from thyroid hormone resistance. Genetic testing of GNAS confirms the diagnosis.

What is Albright hereditary osteodystrophy?

It is a set of physical features caused by GNAS mutations: short stature, a round face, short 4th and 5th fingers and toes, hard calcium lumps under the skin and, in PHP 1a, obesity. It occurs in PHP 1a, PHP 1c and pseudopseudohypoparathyroidism.

Is pseudohypoparathyroidism inherited?

Yes. It is inherited in an autosomal dominant way, but which condition appears depends on which parent passes on the GNAS change. From the mother, it typically causes PHP 1a with hormone resistance; from the father, it causes pseudopseudohypoparathyroidism without hormone resistance.

How is pseudohypoparathyroidism treated?

It is treated with active vitamin D (calcitriol) and calcium to keep blood calcium normal and lower phosphate, with regular blood and urine monitoring. Thyroid hormone, growth hormone or sex hormones are added if needed. Treatment is lifelong and managed by an endocrinologist.