Pseudohypoparathyroidism (PHP) is a heterogeneous group of rare endocrine disorders characterized by normal renal function and resistance to the action of parathyroid hormone (PTH), manifesting with hypocalcemia, hyperphosphatemia, and increased serum concentration of PTH. There are 5 variants of pseudohypoparathyroidism: PHP type 1a (PHP-1a), PHP type 1b (PHP-1b), PHP type 1c (PHP-1c), PHP type 2 (PHP-2), and pseudopseudohypoparathyroidism (PPHP). PHP type 1a is the most common subtype and represents 70% of cases.
In 1942, Fuller Albright first introduced the term pseudohypoparathyroidism to describe patients who presented with PTH-resistant hypocalcemia and hyperphosphatemia along with an unusual constellation of developmental and skeletal defects, collectively termed Albright hereditary osteodystrophy (AHO). These features included short stature, rounded face, shortened fourth metacarpals and other bones of the hands and feet, obesity, dental hypoplasia, and soft-tissue calcifications/ossifications. In addition, administration of PTH failed to produce the expected phosphaturia or to stimulate renal production of cyclic adenosine monophosphate (cAMP). However, the AHO phenotype is not a feature of PHP-1b or PHP-2.
The molecular defects in the gene (GNAS1) encoding the α subunit of the stimulatory G protein (Gsα) contribute to at least 4 different forms of the disease: PHP-1a, PHP-1b, PHP-1c, and PPHP.
While PHP-2 is associated with renal resistance to PTH action, the genetic abnormalities causing PHP-2 remain to be identified.
Diagnosis of PHP is defined by the coexistence of hypocalcemia and hyperphosphatemia with elevated PTH levels in the presence of normal vitamin D values and normal renal function and the absence of hypercalciuria. Pseudohypoparathyroidism can be diagnosed by blood or urine tests to measure the levels of calcium, phosphorous, and parathyroid hormone. Genetic testing for a mutation in the GNAS1 gene can confirm diagnosis and identify subtype.
The goals of pharmacotherapy are to correct calcium deficiency, prevent complications, and reduce morbidity. Intravenous calcium is the initial treatment for all patients with severe symptomatic hypocalcemia. Administration of oral calcium and 1alpha-hydroxylated vitamin D metabolites, such as calcitriol, remains the mainstay of treatment and should be initiated in every patient with a diagnosis of PHP. Maintaining serum total and ionized calcium levels within the reference range discourages hypercalciuria and suppresses PTH levels to normal. Patients with intracranial calcifications may experience seizures related to chronic neuropathic changes, and they may need antiepileptic medications.
(See the image below.)
Patient with pseudohypoparathyroidism showing shortened fourth metacarpals.