• Pseudohypoparathyroidism Ia (PHP1A, OMIM phenotype number #103580)
  • Pseudohypoparathyroidism Ib (PHP1B, OMIM phenotype number #603233)
  • Pseudohypoparathyroidism Ic (PHP1C, OMIM phenotype number #612462)
  • Pseudohypoparathyroidism II (PHP2, OMIM phenotype number #203330)
  • Pseudopseudohypoparathyroidism (PPHP, OMIM phenotype number #240300)

The term pseudohypoparathyroidism encompasses several rare related metabolic disorders characterized by features of functional hypoparathyroidism (hypocalcemia, hyperphosphatemia) but with high serum PTH levels.
Pseudohypoparathyroidism Ia (PHP1A, OMIM phenotype number #103580) is caused by maternally inherited mutations in G protein subunit alpha (Gs alpha, OMIM gene number #139320, on chromosome 20q13.32), a protein essential for transmembrane hormone receptor signaling and differentially expressed in different tissues because of genetic imprinting. Genetic imprinting is an epigenetic phenomenon by which some genes are expressed in a parent-of-origin specific manner. In the kidney and other endocrine glands the maternal copy of the gene is expressed, so that when mutations in Gs alpha are inherited from the mother will determine the features of PhP1A. PHP1A can be sporadic or inherited as a autosomal dominant trait. Along with hypoparathyroidism, which is not generally present at birth but manifest later usually in the first decade, characterized by hypocalcemia and hyperphosphatemia, with inappropriately high PTH levels, other somatic developmental abnormalities are characteristics of the disease, resulting in the so called Albright ereditary osteodistrophy (AHO). Individuals with AHO with central obesity, short stature, rounded face with short and low-set nasal bridge, short neck, brachydactyly with shortening of one or more metacarpals or metatarsals, and various degrees of mental retardation. Sometimes, ectopic ossification of subcutaneous tissues can be present. As a distinctive feature, PTH stimulus fails to increase urinary PTH, demonstrating renal resistance to the action of PTH due to altered maternally inherited Gs alpha in the kidney. In affected individual, resistance to multiple peptide hormones acting via Gs alpha signaling through G-protein coupled receptors, such as TSH, ACTH, gonadotropins, growth hormone releasing hormone (GHRH). When the Gs alpha mutation is paternally inherited, since the paternal allele is inactivated in the kidney, AHO is present without hypoparathyroidism, configuring pseudopseudohypoparathyroidism (PPHP, OMIM phenotype number #240300). Subjects with PPHP often carry ectopic bone in the dermis or subcutaneous fat. Progressive osseous heteroplasia (POH, OMIM phenotype number #166350), consists of a dermal ossification beginning in infancy, followed by increasing and extensive bone formation in deep muscle and fascia. It is caused by paternally inherited GS alpha mutations.
Usually, cases of PHP1A and PPHP coexist in the same family, depending on whether the mutation is inherited from the mother or the father, respectively. Pseudohypoparathyroidism type Ic (PHP1c, OMIM phenotype number #612462) is clinically indistinguishable for PHP1A, but with preserved Gs alpha activity in blood cells in vitro. Some of these patients harbor a mutation in Gs alpha which impairs the interaction with the hormone receptor but it does not affect cAMP production.
Pseudohypoparathyroidism Ib (PHP1B, OMIM phenotype number #603233) is a disorder due to epigenetic alterations (i.e. altered methylation) in Gs alpha locus (GNAS) leading to altered imprinting of the gene and lack of the expression of maternal allele in renal tissue. In some cases isolated renal resistance to PTH without the features of Albright hereditary osteodystrophy characterizes the disease. Most cases are sporadic, while few cases are familial. In familial cases STX16 mutations affecting GNAS imprinting have been demonstrated. Few patients present various degrees of bone involvement from mild bone loss and osteoporosis, to severe forms of osteitis fibrosa cystica characterized by markedly elevated bone resorption leading to cyst-like brown tumors throughout the skeleton, because of the detrimental effects of markedly elevated PTH on bone.

Genes

In PHP1A, PHP1C and PPHP inactivating mutations of Gs alpha (OMIM gene number #139320, on chromosome 20q13.32); in PHP1B altered methylation of GNAs locus, in some cases gene deletions

Phenotype

Increased neuromuscular irritability (spasms, tetany, seizures) ocular (cataracts), cardiovascular (prolongation QT interval), soft tissue calcifications; features of AHO in PHP1A, PHP1C and PPHP. Osteitis fibrosa cystica in some cases of PHP1B.

Main biochemical alterations:

  • PHP1A low Ca, high Pi, high PTH levels in the absence of vitamin D deficiency, low/normal 1-25(OH)2D3, associated with low Ur cAMP in response to PTH infusion and multiple hormone resistance (e.g. blunted GH response to provocative tests, high LH and FSH with low estradiol and testosterone levels, high TSH levels without thyroid autoantibodies and normal thyroid scan)
  • PHP1B low Ca, high Pi, high PTH levels in the absence of vitamin D deficiency, low/normal 1-25(OH)2D3, associated with low Ur cAMP in response to PTH infusion; multiple hormone resistance syndromes may be present.

Other resources

References:

  1. Levine M.A. Molecular and Clinical Aspects of Pseudohypoparathyroidism. In: The Parathyroids: Basic and Clinical Concepts, Third Edition, Academic Press, 2015.
  2. Lemos MC, Thakker RV. GNAS mutations in Pseudohypoparathyroidism type 1a and related disorders. Hum Mutat. 2015 Jan;36(1):11-9.
  3. Turan S, Bastepe M. GNAS Spectrum of Disorders. Curr Osteoporos Rep. 2015 Jun;13(3):146-58.
  4. Levine MA. An update on the clinical and molecular characteristics of pseudohypoparathyroidism. Curr Opin Endocrinol Diabetes Obes. 2012 Dec;19(6):443-51.
  5. Mantovani G. Clinical review: Pseudohypoparathyroidism: diagnosis and treatment. J Clin Endocrinol Metab. 2011 Oct;96(10):3020-30.
  6. www.omim.org