Pseudohypoparathyroidism types Ia, Ib, Ic and II; Albright hereditary osteodystrophy of (AHO); Pseudopseudohiporatiroidismo (Pseudohypoparathyroidism -PHP- types Ia, Ib, Ic and II, Albright hereditary osteodystrophy -AHO; Pseudopseudohypoparathyroidism -PPHP-) - Gen GNAS.
The Pseudohypoparathyroidism (PHP) includes a heterogeneous characterized by resistance to the action of parathyroid hormone (PTH) group diseases. The Pseudohypoparathyroidism has been classified into several types (Ia, Ib, Ic and II) depending on factors such as the associated clinical manifestations, biochemical parameters and the underlying molecular mechanism hormone resistance.
The type Ia (PHP-Ia), Pseudohypoparathyroidism is the most common type of different types of pseudohipoparatiroidismos. This type occurs in the first year of life, but it becomes evident, in general, only after 4 years of age. In addition to resistance to PTH, type Ia (PHP-Ia) Pseudohypoparathyroidism is characterized by resistance to other hormones, including thyroid stimulating hormone (TSH) and any hormone that use signaling protein Gs and adenylyl cyclase to generate cAMP as a second cellular messenger. As a result, the PHP-Ia is characterized by symptoms hipoparatiroideos and high concentrations of PTH. Also, individuals with PHP-Ia, exhibit a phenotype characteristic is known as Albright Hereditary osteodystrophy (AHO). The clinical features of AHO include short stature, obesity, round face, subcutaneous calcifications, brachydactyly, and other skeletal abnormalities. In addition, it is estimated that between 50% and 75% of patients with PHP-Ia mental retardation have a mild to moderate.
PHP-Ia has similar type PHP-Ic clinical features, however, both phenotypes differ in the PHP-Ia presents a partial deficiency function Gsa protein in the membrane of different cell types, while this is not it happens in individuals with type PHP-Ic, which maintain the function. Individuals with PHP-Ib show resistance to PTH isolated and slight resistance to thyroid stimulating hormone (TSH) with normal activity Gsa, and have no phenotype Albright. Furthermore, reference to Pseudoseudohipoparatiroidismo (PPHP) is made when, in families with Pseudohypoparathyroidism, patients manifest only Albright phenotype, but without hormone resistance.
The type Ia (PHP-Ia), Pseudohypoparathyroidism is due to mutations in the GNAS gene, located on the long arm of chromosome 20 (20q13.3). This gene encodes the α subunit of Gs protein signaling. G proteins are transducers that mediate binding of extracellular receptor ligands to intracellular messenger systems. Thus, the activity of adenylate cyclase catalyzes the conversion of ATP to cAMP, is under control of Gs stimulation and inhibition of Gi. Adenylate cyclase enzyme, is involved in the production control of several hormones that help regulate the activity of the endocrine glands such as the thyroid, pituitary, ovaries, testes and adrenals. It is believed that the enzyme also plays a key role in osteogenesis. Thus, the enzyme helps the body to prevent the production of ectopic bone.
They have been described at least 150 mutations in the GNAS gene. The mutations described so far have been: missense mutations (67), and cutting mutations -splicing- junction (17), regulatory mutations (1), small deletions (29), small insertions (21), insertions / deletions small ( 1), larger deletions (9), larger inserts / duplications (2) and complex rearrangements (3). Mutations in the gene result GNAS loss function Gsa isoform of the protein encoded by the gene GNAS. This leads to the expression of protein Gsa only from the paternal allele. Mutations in the maternal allele lead to loss of expression of Gsa protein in distal tubule and therefore the loss of the action of parathyroid hormone (PTH) in the kidney, whereas mutations of paternal allele have little effect on the action of PTH. Therefore, paternal transmission of GNAS gene mutation will lead to a phenotype Pseudoseudohipoparatiroidismo (PPHP), while the maternal transmission originates dismorfogénicas alterations associated with resistance to various hormones (PTH and THS, etc.). The AHO (Albright Hereditary osteodystrophy) phenotype when the mutation occurs in Gsa inherited from either parent.
This disease is inherited as an autosomal dominant, which means that a copy of the altered gene in each cell is sufficient for the disease to be expressed. In most cases, an affected person has a parent with the disease.
Tests in IVAMI: in IVAMI perform detection of mutations associated with Pseudohypoparathyroidism type Ia (PHP-Ia), by complete PCR amplification of exons GNAS gene, and subsequent sequencing.
Samples recommended: EDTA blood collected for separation of blood leukocytes, or impregnated sample card with dried blood (IVAMI may mail the card to deposit the blood sample).