Pseudohypoparathyroidism is a term applied to a heterogeneous group of disorders whose common feature is end-organ resistance to parathyroid hormone (PTH; 168450). In addition to PTH resistance, PHP Ia is characterized by resistance to other hormones, including thyroid-stimulating ... Pseudohypoparathyroidism is a term applied to a heterogeneous group of disorders whose common feature is end-organ resistance to parathyroid hormone (PTH; 168450). In addition to PTH resistance, PHP Ia is characterized by resistance to other hormones, including thyroid-stimulating hormone (TSH; see TSHB, 188540) and gonadotropins. PHP Ia is associated with a constellation of clinical features referred to as Albright hereditary osteodystrophy (AHO), which includes short stature, obesity, round facies, subcutaneous ossifications, brachydactyly, and other skeletal anomalies. Some patients have mental retardation (Mantovani and Spada, 2006). In contrast, pseudopseudohypoparathyroidism (PPHP; 612463) is characterized by the physical findings of AHO but without hormone resistance (Kinard et al., 1979; Fitch, 1982; Mantovani and Spada, 2006). PHP1A occurs only after maternal inheritance of the molecular defect, whereas PPHP occurs only after paternal inheritance of the molecular defect (Davies and Hughes, 1993; Wilson et al., 1994). This is an example of imprinting, with differential gene expression depending on the parent of origin of the allele. See INHERITANCE and PATHOGENESIS sections.
Albright et al. (1942) described 3 patients with short stature, round face, short neck, obesity, subcutaneous calcifications, and shortened metacarpals associated with hypocalcemia and hyperphosphatemia. Although the phenotype resembled parathyroid hormone deficiency, renal function was normal and apparently ... Albright et al. (1942) described 3 patients with short stature, round face, short neck, obesity, subcutaneous calcifications, and shortened metacarpals associated with hypocalcemia and hyperphosphatemia. Although the phenotype resembled parathyroid hormone deficiency, renal function was normal and apparently unresponsive to administration of bovine parathyroid extract. The authors hypothesized that the clinical findings were due to resistance to PTH rather than to PTH deficiency, and termed the disorder 'pseudohypoparathyroidism' (PHP). The specific pattern of observable physical features described by Albright et al. (1942) constitutes 'Albright hereditary osteodystrophy.' Mann et al. (1962) observed parathyroid hyperplasia in patients with PHP, suggesting increased serum PTH, not deficiency of PTH. Chase and Aurbach (1968) found that PTH circulated in abnormally high concentration in pseudohypoparathyroidism, and that secretion of the hormone responded normally to physiologic control by calcium. In patients with PHP, Chase et al. (1969) found that urinary cAMP did not increase in response to PTH administration, a finding that was in contrast to controls. The authors suggested that the basic defect in PHP may be a deficient amount or function of PTH-sensitive adenyl cyclase in kidney and bone. Farfel et al. (1980) found that 5 patients with PHP I and AHO had abnormally low urinary cAMP excretion in response to PTH infusion. There was also a 40 to 50% reduced activity of the G protein, which the authors termed 'N,' that couples the membrane hormone receptor to adenylate cyclase. Farfel et al. (1981) reported 10 patients with PHP type Ia. Typical features included short stature, brachydactyly, hypocalcemia, elevated serum PTH, and decreased urinary excretion of cAMP following exogenous PTH infusion. Erythrocyte Gs activity was decreased by approximately 50% in 15 patients with PHP type I, but was normal in 19 of their clinically normal first-degree relatives. Inheritance patterns were not consistent with a single mode of transmission. Bourne et al. (1981) reported 5 patients with PHP type I patients who showed a 40% reduction in red cell N protein activity. Downs et al. (1983) reported a 16-year-old girl with PHP Ia who had resistance to PTH, thyrotropin, and gonadotropins. She had multiple subcutaneous calcifications, uniformly short metacarpals, hypocalcemia, hyperphosphatemia, elevated serum PTH, no response in urinary cAMP to PTH infusion, elevated plasma thyrotropin, low serum thyroxine, no thyroid enlargement, oligomenorrhea, low serum estrogen, high LH and FSH, and normal response to endogenous ACTH during a standard metyrapone test and after insulin-induced hypoglycemia. Red cell membrane Gs activity was 57% of control; renal membranes showed only 30% of control. Weisman et al. (1985) observed congenital hypothyroidism as the presenting manifestation of PHP. Levine et al. (1985) reported a brother and sister with infantile hypothyroidism whose mother had PHP type Ia. Both children were normocalcemic. Resistance to thyroid-stimulating hormone was reflected in the reduced level of Gs in red cell membranes. Hewitt and Chambers (1988) reported a patient with PHP type I in whom subcutaneous calcification developed at the age of 3 months. 'Hard lumps' were located on the chest wall and groin. Izraeli et al. (1992) described a family in which 5 members of 3 successive generations had the clinical features of AHO associated with progressive osseus heteroplasia (POH; 166350), which is caused by activating mutations of GNAS1 inherited on the paternal allele. Zung et al. (1996) pictured subcutaneous nodules of the left heel in a 7-year-old girl with AHO features. The mother, aged 38 years, had multiple subcutaneous masses of the limbs and bilateral shortening of the fourth metacarpals. A mammogram showed calcified breast nodules which were also palpable. Aldred et al. (2000) reported a sister and brother with PHP Ia, including hypocalcemia, resistance to PTH, and elevated thyroid-stimulating hormone. Both sibs also had neonatal diarrhea and pancreatic insufficiency that corrected spontaneously after several months. Mantovani et al. (2003) investigated the presence of pituitary resistance to hypothalamic hormones acting via G-coupled receptors in patients with PHP Ia. Six of 9 patients showed an impaired growth hormone (GH; 139250) responsiveness to GHRH (139190) plus arginine, consistent with a complete GH deficiency; partial and normal responses were found in 2 and 1 patient, respectively. Accordingly, IGF1 (147440) levels were below and in the low-normal range in 7 and 2 patients, respectively. The authors concluded that in addition to PTH and TSH resistance, patients with PHP Ia display variable degrees of GHRH resistance, consistent with Gs-alpha imprinting in the human pituitary. The findings were consistent with abnormalities of secretion of thyroid hormone (de Wijn and Steendijk, 1982) and gonadotropins (Shapiro et al., 1980) that had been described in patients with PHP. Brachydactyly, classically described as shortening of III, IV, and V metacarpals and I distal phalanx, is the typical and most specific feature of AHO. This phenotype has been reported in 70% of PHP subjects from routine radiologic examinations. De Sanctis et al. (2004) evaluated the metacarpophalangeal pattern profile in 14 genetically characterized patients with PHP Ia and determined the prevalence and patterns of left hand bone shortening. Shortening below -2 SD score was present in at least 1 bone in each subject, with a prevalence of 100%; however, great variability existed between subjects and between hand bone segments. Brachymetacarpia and brachytelephalangy characterized the hands of the subjects. - Clinical Variability De Nanclares et al. (2007) reported 4 unrelated patients who were thought to have PHP1A because of PTH and TSH resistance and mild features of Albright hereditary osteodystrophy. Two patients showed decreased G-alpha activity in erythrocytes. However, genetic analysis did not reveal germline point mutations in the GNAS gene in any of the patients; instead, all were found to have GNAS methylation defects, which are usually associated with PHP1B. Furthermore, 1 of the patients with normal G-alpha activity was found to have a 3.0-kb STX16 deletion (603666.0001), which is usually associated with PHP1B. The findings suggested that there may be an overlap between the molecular and clinical features of PHP1A and PHP1B, and that methylation defects may manifest as mild PHP1A.
Levine et al. (1988) studied 8 kindreds with 1 or more members affected with AHO or PHP and decreased activity of the Gs protein. RNA blot analysis showed about 50% reduced GNAS1 mRNA levels in fibroblasts of affected ... Levine et al. (1988) studied 8 kindreds with 1 or more members affected with AHO or PHP and decreased activity of the Gs protein. RNA blot analysis showed about 50% reduced GNAS1 mRNA levels in fibroblasts of affected members from 6 of the pedigrees, but normal levels in affected members of the other 2 pedigrees. No abnormalities of restriction fragments or gene dosage were identified using a cDNA hybridization probe, leading the authors to conclude that major rearrangements or deletions of GNAS1 were not a common cause for the disorder. In a proband and his mother with PHP Ia, Patten et al. (1989, 1990) identified a heterozygous mutation in the GNAS gene (139320.0001). In a mother with PPHP (612463) and her 4 daughters with PHP Ia (Kinard et al., 1979), Gejman et al. (1990) and Weinstein et al. (1990) identified a heterozygous mutation in the GNAS gene (139320.0002). A son of 1 of the affected daughters also had PHP Ia and carried the mutation. A second heterozygous mutation (139320.0003) was identified in a second family in which the mother had PPHP and her daughter had PHP Ia. In an Italian patient with PHP Ia and features of AHO, Mantovani et al. (2000) detected a heterozygous 1-bp deletion (139320.0025) in the GNAS gene. This mutation was also found in the patient's mother, who had PPHP. In a brother and sister with PHP type Ia, who also had neonatal diarrhea and pancreatic insufficiency, Aldred et al. (2000) identified heterozygosity for a 12-bp insertion in the GNAS1 gene (139320.0035). The mutation was not found in 2 unaffected sibs and was also not detected in the lymphocyte DNA of either of the clinically unaffected parents. Haplotype analysis confirmed germline mosaicism and indicated that the mutation was maternal in origin. Makita et al. (2007) performed biochemical and intact cell studies of the 12-bp insertion (AVDT) and suggested that the PHP-Ia phenotype results from instability of the Gs-alpha-AVDT mutant and that the accompanying neonatal diarrhea may result from its enhanced constitutive activity in the intestine. Aldred et al. (2002) reported 2 patients with Albright hereditary osteodystrophy and deletions of chromosome 20q, including complete deletion of the GNAS1 gene. One boy had a paternally inherited deletion of chromosome 20q13.13-q13.32 and a normal biochemical evaluation consistent with PPHP. The other patient had a maternally derived deletion of chromosome 20q13.31-q13.33 and PHP type Ia.