Pseudohypoparathyroidism typically gets discovered during early childhood. There may or may not be an obvious family history of the disease depending on which parent the child inherited the disease from as genetic imprinting can hide its expression. The presence of the AHO phenotype should prompt physicians to complete biochemical workup.

Patients experiencing symptoms of hypocalcemia may complain of paresthesias, peri-oral numbness, and muscle cramping or spasms. 

Physical exam for PHP type 1b would likely only find symptomatic hypocalcemia. Hypocalcemia can present with positive Chvostek sign and Trousseau sign.

Chovostek sign is positive when tapping on the facial nerve leads to the contraction of facial muscles on the same side due to the nerve's hyperexcitable state. A positive Trousseau sign is when inflation of a sphygmomanometer to higher than systolic blood pressure and maintaining that pressure for 3 minutes leads to transient ischemia and carpal pedal spasm due to hypocalcemia. 

PHP type 1a and 1c may have signs of hypocalcemia but will also exhibit the AHO phenotype.

Serum calcium, phosphorus, and parathyroid hormone levels should be checked together as well as 25OH Vitamin D levels. 

The presence of hypocalcemia, hyperphosphatemia, normal 25 hydroxyvitamin D and elevated parathyroid hormone levels suggest pseudohypoparathyroidism. Synthetic PTH challenge test can be performed (Ellsworth-Howard test) but is not necessary for diagnosis. 

An electrocardiogram is likely appropriate if significant hypocalcemia is present to assess for prolonged QT interval and risk for arrhythmia.

PHP1 patients should have biochemical testing completed annually, including PTH, calcium, phosphate, TSH, and urine calcium.[2]

Monitoring of appropriate height and growth is important, and testing for growth hormone deficiency should take place even if the height is normal.[7]

Screening and treatment for other endocrinopathies such as hypogonadism should be individualized.

X-rays of upper and lower extremities to screen for brachydactyly are recommended during the initial evaluation.

In patients with PHP with AHO, genetic testing is essential. Genetic testing and counseling provide information regarding likely disease manifestations and future complications. Additionally, genetic testing can help determine inheritance patterns within families and provide insight into the possibility of affected offspring.

The overall goals in the treatment of PHP are to maintain normal calcium, normal phosphorus, avoid hypercalciuria, and lower PTH levels to normal if possible. It is typically not possible to achieve all electrolyte and hormone level goals; however, getting them as close as possible is recommended. 

Calcium and phosphorus goals are usually attainable with the administration of calcitriol (active vitamin D metabolite) with or without calcium supplementation. Dosing is adjusted so that calcium remains in the low end of the normal range. In addition to checking serum calcium, 24-hour urine calcium levels should be maintained in the low to the mid-normal range to avoid renal calculi and impaired kidney function. 

In patients with continued hypocalcemia, treatment with calcium supplementation is a requirement. 

In the acute setting, the recommendation is for intravenous calcium Patients who are symptomatic (spasms, seizure, etc.), those with prolonged QT interval on electrocardiogram or if corrected calcium is less than 7.5mg/dL and the patient is considered to be high risk should receive IV calcium infusion. Initially, 1 to 2 g of calcium gluconate administration should be over a 10 to 20-minute interval followed by a slow infusion of calcium. The slow infusion can be achieved by diluting 1000 mg elemental calcium into 1 L of 5% dextrose or normal saline and running at a rate of around 1 cc/kg/hr. Oral calcium and vitamin D supplementation should start as soon as possible. Oral calcium carbonate 2-8g elemental calcium/day and oral calcitriol 0.25 to 1.0 mcg twice a day are usually sufficient doses and allow calcium infusion to stop within a few hours. 

These patients will require permanent active vitamin D supplementation with or without calcium. Calcitriol 0.25-1.0 mcg/day should be used (not other forms of vitamin D due to decreased 1 alpha-hydroxylase activity which converts vitamin D to an active form). Calcium carbonate or calcium citrate should be given 2 to 8 g elemental calcium daily in divided doses to keep calcium low end of normal.

PTH levels require monitoring during treatment with the goal of reduction into the normal range or as close as possible. Lowering PTH attempts to minimize skeletal resorption and later development of osteoporosis.[1]

Treatment with parathyroid hormone or parathyroid hormone analogs is not recommended.

Pseudohypoparathyroidism presents with hypocalcemia, hyperphosphatemia, elevated PTH levels, normal 25 hydroxyvitamin D, and normal kidney function. Additionally, many patients express the phenotype of Albright hereditary osteodystrophy, but not always. Although no other diseases present identically, many conditions share similar characteristics providing the following differential diagnoses.

• True hypoparathyroidism
  • It presents with hypocalcemia and hyperphosphatemia, but the PTH levels are low. True hypoparathyroidism typically classifies as either surgical or nonsurgical. The most frequent cause of hypoparathyroidism is surgical, post parathyroidectomy for treatment of hyperparathyroidism or accidental removal of parathyroid glands during other neck surgeries such as thyroidectomy. Non-surgical hypoparathyroidism can result from a variety of inherited and acquired disorders. Examples include hemochromatosis or other infiltrative diseases and mutations in the PTH gene, CaSR gene and autoimmune polyendocrine syndrome type 1 (APS1) which presents with the triad of hypoparathyroidism, primary adrenal insufficiency, and mucocutaneous candidiasis.
• Vitamin D deficiency
  • This presents with hypocalcemia and elevated PTH levels (secondary hyperparathyroidism) but obviously low 25 OH vitamin D levels.
• Worsening chronic kidney disease (CKD)
  • Patients with impaired glomerular filtration rate (GFR) present with similar findings. 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. The impaired conversion to active vitamin D leads to its low levels in patients with CKD. In addition to low active vitamin D levels, higher than normal phosphate frequently accumulates in the blood due to declining GFR. The low active vitamin D levels and high phosphate levels both lead to increased release of parathyroid hormone.

The prognosis of PHP is variable. In mild forms of the disease when treated appropriately with calcium and vitamin D, a normal life expectancy is not unreasonable.[3] For others with a more severe expression of the AHO phenotype, the presence of obesity, sleep apnea, and mental retardation can cause significant morbidity and mortality.

Chronic hypocalcemia and hyperphosphatemia can lead to parkinsonism which may or may not resolve with appropriate calcium and vitamin D supplementation.[8]

Children with brachydactyly may suffer from difficulty with fine motor skills.

There is an increased prevalence of carpal tunnel syndrome seen in AHO patients.[9]

There are reports of higher than normal, as well as an earlier presentation of spinal stenosis, which can lead to lower extremity paraparesis.[10][11]

Finally, there is a more than four-fold increased risk for sleep apnea reported in childhood.[12]

Unfortunately, PHP is an inherited disorder, and once an individual has developed the condition; there is no cure. Genetic testing and counseling are recommendations for individuals who have PHP, especially if they plan to have children so that there can be full identification of their risk of passing on the disease. Patients with PHP should have yearly screening exams, even if they are feeling well.

Patients with pseudohypoparathyroidism should follow with an endocrinologist. Regular testing of serum calcium levels are necessary as well as screening for other hormone resistance. Each patient's care requires individualization to their specific expression of hormone resistance.

Diagnosing, treating, and managing pseudohypoparathyroidism requires an interprofessional healthcare team approach. The patient's family doctor will enlist the services of an endocrinologist, as stated above. A specialist in genetics is also a necessary consult. The involvement of other healthcare team members will vary based on individual patient presentation. If IV interventions are required, the nurse will be administering those and monitoring the effectiveness of treatment, reporting their findings to the treating clinician. The pharmacist will prepare the IV, and in cases of oral therapy can counsel the patient on dosing and administration. As treatment progresses, the team must be able to adapt based on patient response and coordinate with the next steps as described above in the Treatment section. With open communication and collaborative effort, the interprofessional team can help drive outcomes to the best possible result for the patient. [Level V]