Pseudohypoparathyroidism

Basics

  • Pseudohypoparathyroidism (PHP) is similar to hypoparathyroidism in its presentation, but, rather than resulting from the body’s lack of parathyroid hormone (PTH) production, the signs are due to the lack of the body’s response or resistance to PTH; hence, the term “pseudo.”
  • PHP was first described in 1942 by Fuller Albright.
  • PHP is a group of heterogeneous disorders defined by targeted organ (kidney and bone) resistance to the action of PTH.
  • PHP is characterized by hypocalcemia, hyperphosphatemia, and elevated PTH levels.
  • Synonym(s): Albright hereditary osteodystrophy (AHO)

Epidemiology

Prevalence

  • PHP is very rare.
  • To date, no information regarding its worldwide prevalence is available.
  • A 1998 epidemiologic survey from Japan revealed a period prevalence of 3.4 cases per 1 million and a study published in 2014 from Italy showed a prevalence of PHP (Ia, Ib, PPHP) of 1 per 150,000.
  • No ethnic or racial difference has been identified.
  • It has a female predominance: Female to male ratio is 2:1.

Etiology and Pathophysiology

Genetics

  • Heterozygous mutations in the GNAS1 gene, which encodes Gsa (G protein activator of adenylyl cyclase), contribute to PHP type Ia and PHP type Ib.
  • GNAS1 defects are not detected in PHP Ic and PHP type II.
  • An autosomal dominant pattern of inheritance is seen in PHP type Ia and Ib.
  • Genomic imprinting leads to different disease manifestation.
  • Resistance to other hormones with receptors coupled via Gsa is also seen such as TSH, gonadotropin, growth hormone-releasing hormone, and calcitonin.

Commonly Associated Conditions

PHP may be associated with other hormonal resistance leading to:

  • Hypogonadism (gonadotropin resistance)
  • Hypothyroidism (TSH resistance)
  • Short stature (GHRH resistance)
  • Neuropsychiatric disorders sometimes
  • Subtypes of PHP (1):
    • PHPIa: AHO features present (see “Physical Exam”), hormone resistance (PTH, TSH, gonadotropins, GHRH), GNAS1 defect: maternally derived inactivating mutations
    • PHPIb: AHO features absent, hormone resistance (PTH, TSH), GNAS1 defect: imprinting dysregulation
    • PHPIc: AHO features present, hormone resistance (PTH, TSH, gonadotropins), not associated with GNAS1 defect
    • PHP II: AHO features absent, hormone resistance (PTH), not associated with GNAS1 defect

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