Pseudohypoparathyroidism

Etiology

The first consensus on diagnosing and managing pseudohypoparathyroidism was published in 2018 after agreed-upon experts were invited from several countries worldwide.[1] Pseudohypoparathyroidism is subdivided into several categories. It first divides into PHP type 1 and PHP type 2. In general, PHP type 1 forms exhibit blunted cAMP and phosphate excretion in urine in response to PTH (cAMP being a downstream response to activation of G protein-coupled receptor for PTH). In PHP type 2, the cAMP response is normal but blunted phosphate excretion in response to PTH still occurs. Only a few cases of PHP type 2 have been documented, and its pathophysiology remains poorly understood.

PHP type 1 is further divided into several subtypes a,b, and c. PHP type 1b is isolated resistance to PTH in the kidney and normal PTH response in bone without phenotypic expression of Albright hereditary osteodystrophy (AHO). Novel defects are described in a recent study, and more information is being revealed as we have a better analysis of the genome in recent years.[2][3][4][5] Deletion of STX16 in the maternal gene has been shown to cause PTH resistance and progression to be autosomal dominant pseudohypoparathyroidism type 1b.[6] PHP 1a and 1c have PTH resistance, and both express a phenotype of AHO. AHO patients present with short stature, frequently below normal intelligence, obesity, round face, short neck, subcutaneous ossifications, brachydactyly, and shortened metatarsals. The shortened metacarpals often cause an absence of knuckles at the third, fourth and fifth or only some of those digits resulting in the classic "knuckle, knuckle, dimple, knuckle" sign.

PHP type 1a has reduced Gs alpha activity and presents with multi-hormone resistance. 

PHP type 1c, much like 1a, presents with multi-hormone resistance, but it is different from type 1a in that normal Gs alpha activity is present.[7]

Epidemiology

Pseudohypoparathyroidism and Albright hereditary osteodystrophy are very rare disorders. The estimated prevalence is between 0.3 and 1.1 cases per 100000 population, depending on geographic location.[1][8]

Pathophysiology

PHP type 1a results when there is a loss of function mutation in GNAS, PRKAR1A, PDE4D, or PDE3A.[9][10] The result is an aberrant response in many G protein-coupled receptors leading to multi-hormone resistance or unresponsiveness. Thus far, over 400 mutations within the GNAS coding region have been identified as causes of PHP 1a.[11] The mutations identified include frameshift, nonsense, missense, insertion, and deletions, as well as others. Of note, research has discovered a temperature-sensitive Gs alpha mutant (p.A366S) that can cause testotoxicosis and precocious puberty.[12]

In addition to PTH resistance, PHP type 1a infrequently exhibits blunted response to thyroid-stimulating hormone (TSH), luteinizing hormone (LH), follicle-stimulating hormone (FSH), and growth hormone-releasing hormone (GHRH) resulting in primary hypothyroidism, primary hypogonadism, and short stature, depending on the affected gene. 

The inheritance of GNAS mutation is fairly complex due to paternal genetic imprinting. Individuals who acquire the mutant GNAS allele from their father will only have the phenotypic expression of AHO (termed pseudopseudohypoparathyroidism) and do not have PTH resistance. Individuals who inherit the mutant allele from their mother express both AHO and multi-hormone resistance.

PHP type 1b results from abnormal methylation of GNAS regulatory elements. The abnormal methylation leads to subnormal production of Gs alpha protein expression and a blunted response to PTH.

History and Physical

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. 

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

The 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.[13]

In rare cases, the patient might present with seizures, and special imaging of the brain will be needed to rule out any cerebral pathology.[14]

In a recent case report, there was a finding of hypokalemia as the presenting sign of pseudohypoparathyroidism.[15]

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

Evaluation

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. A 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.[1] 

Monitoring of appropriate height and growth is important, and testing for growth hormone deficiency should take place even if the height is normal.[16] Screening and treatment for other endocrinopathies, such as hypogonadism, should be individualized.[17]

X-rays of the upper and lower extremities are recommended during the initial evaluation to screen for brachydactyly or other bone malformations.[18][19][20]

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 family inheritance patterns and provide insight into the possibility of affected offspring.

Treatment / Management

The overall goals in the treatment of PHP are to maintain normal calcium and 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 at 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 mid-normal range to avoid renal calculi and impaired kidney function. 

In patients with persistent 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 at 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 to 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 at the low end of normal.[21]

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.[7]

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

Differential Diagnosis

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 non-surgical. 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 condition 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 lead to increased parathyroid hormone release.

Prognosis

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.[8] 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.

Complications

• Chronic hypocalcemia and hyperphosphatemia can lead to parkinsonism which may or may not resolve with appropriate calcium and vitamin D supplementation.[22]
• Children with brachydactyly may suffer from difficulty with fine motor skills.
• There is an increased prevalence of carpal tunnel syndrome seen in AHO patients.[23]
• There are reports of higher than normal, as well as an earlier presentation of spinal stenosis, which can lead to lower extremity paraparesis.[24][25]
• Finally, there is a more than four-fold increased risk for sleep apnea reported in childhood.[26]