The term pseudohypoparathyroidism (PHP) refers to a heterogeneous group of rare disorders of mineral metabolism with resistance to parathyroid hormone (PTH) and frequently to other hormones activating cAMP-dependent responses downstream of various G protein-coupled receptors (1). It presents with the features of functional hypoparathyroidism, i.e. hypocalcemia and hyperphosphatemia, but PTH levels are typically elevated indicating the end-organ resistance to PTH. In addition, fractional excretion of urinary calcium is low, phosphaturic reponse to PTH is lacking, and skeletal responsiveness to PTH is conserved, as pointed out by normal or elevated bone turnover markers.
PHP type 1: characterized by decreased or absent nephrogenous cAMP response to PTH, caused by mutations within the GNAS locus (at 20q13), genomically imprinted, encoding the α subunit of Gs (Gαs)and several splice variants.
- type 1a: (OMIM#103580, mostly familial), caused by mutations within exons 1-13 of the GNAS gene, leading to a generalized reduction in Gαs expression (Gα shaploinsufficiency).
- type 1b: (OMIM#603233, mostly sporadic), caused by an epigenetic defect resulting in selective PTH resistance in organs where GNAS locus is imprinted (i.e. switching the maternal GNAS allele to a paternal pattern of methylation). In familial forms, deletions within the GNAS locus (STX16, NESP55) have been demonstrated.
- type 1c: (OMIM#612462) cause not known.
PHP type 2: decreased phosphaturic with conserved nephrogenous cAMP response to PTH; cause not known.
Signs and symptoms of PHP are related to hypocalcemia (from parestesias in the mild forms to muscle cramps, seizures, and laryngospasms in the most severe forms). In long-standing undiagnosed PHP, patients may be asymptomatic. PTH infusion test helps in the differential diagnosis between hypoparathyroidism (HP) and PHP, and to distinguish among the different forms of PHP, detecting the absent phosphaturic response (due to renal resistance to PTH) and assessing the nephrogenous cAMP response.
type 1a: characterized by renal resistance to PTH and frequently to other hormones (e.g. TSH, GHRH, gonadotropins). Signs of Albright hereditary osteodistrophy (AO) characterized by short stature, brachidactily, mild mental retardation, subcutanous ossification, and obesity. Subjects with paternally inherited Gαs mutations display only AO (pseudo-PHP) without renal PTH resistance (since the wild-type maternal allele is expressed in the kidney). In these patients, disabling progressive osseous heteroplasia (POH), which is characterized by heterotopic ossification in the skin, subcutanous tissue, muscles, tendons, and ligaments, may sometimes occur.
type 1b: characterized by renal resistance to PTH, rarely associated with mild TSH resistance. Skeletal responsiveness is usually maintained, and some patients may display bone lesions similar to those occurring in hyperparathyroidism.
type 1c: features of PHP type 1, but without apparent Gαs defects.
type 2: features of PHP type 1b, likely due to severe forms of vitamin D deficiency.
Hypocalcemia related to PHP is often mild to moderate, rarely severe and requiring acute intravenous administration of calcium gluconate (see hypoparathyroidism). Even when serum calcium is very low, patients are often mildly symptomatic, given the gradual onset of the disease.
Chronic management of hypocalcemia requires the administration of oral calcium and calcitriol, in order to maintain serum calcium within the normal range, to reduce/normalize PTH levels. Unlike hypoparathyroidism, patients with PHP do not usually experience hypercalciuria given the conserved reabsorption of calcium by PTH in the renal distal tubule. Nonetheless, it is advisable to monitor for urinary calcium excretion along with serum calcium, phosphate, and PTH in the follow up. In PTH1b, normalizing PTH levels in order to prevent and/or limit skeletal consequences and prevent tertiary hyperparathyroidism is of particular importance. Tertiary hyperparathyroidism, rarely developing into long-standing PHP, is generally sustained by parathyroid hyperplasia and can require surgery if a severe bone disease is also present.
In the case of resistance to other hormones (e.g. TSH, GHRH, gonadotropins) treatment with levo-thyroxine, GH, and oral contraceptives (in females) or testosterone (males) can be required.
There are no specific treatments for the neurocognitive and physical manifestations of AHO. The heterotopic ossifications in AHO and POH do not require surgery unless impairing movement and/or greatly deforming.
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