Alternative titles; symbols
SNOMEDCT: 237659007; ORPHA: 79445; DO: 4183;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 20q13.32 | Pseudopseudohypoparathyroidism | 612463 | Autosomal dominant | 3 | GNAS | 139320 |
A number sign (#) is used with this entry because pseudopseudohypoparathyroidism (PPHP) is caused by a mutation resulting in loss of function of the Gs-alpha isoform of the GNAS gene (139320) on the paternal allele. This results in expression of the Gs-alpha protein only from the maternal allele.
See also pseudohypoparathyroidism type Ia (PHP1A; 103580), which is caused by a mutation resulting in loss of function of the Gs-alpha isoform of the GNAS gene on the maternal allele and resultant expression of the Gs-alpha protein only from the paternal allele.
Patients with pseudopseudohypoparathyroidism do not show resistance to parathyroid hormone (PTH; 168450) or other hormones, as is the case with PHP1A (103580), but do manifest the 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 (Kinard et al., 1979; Fitch, 1982; Mantovani and Spada, 2006).
PPHP occurs only after paternal inheritance of the molecular defect, whereas PHP1A occurs only after maternal inheritance of the molecular defect (see Inheritance and Pathogenesis below). This is an example of imprinting, with differential gene expression depending on the parent of origin of the allele (Davies and Hughes, 1993; Wilson et al., 1994).
For a general phenotypic description, classification, and a discussion of molecular genetics of pseudohypoparathyroidism, see PHP1A (103580).
Albright et al. (1952) described a 29-year-old woman with physical features similar to those reported by Albright et al. (1942) as Albright hereditary osteodystrophy, but there were no serum calcium abnormalities suggestive of PTH resistance. Albright et al. (1952) termed this disorder 'pseudopseudohypoparathyroidism' (PPHP) to distinguish it from the disorder reported by Albright et al. (1942) as 'pseudohypoparathyroidism.'
Weinberg and Stone (1971) described a family in which a brother and sister had PHP1A (103580) and the son and daughter of the brother had PPHP. All had clinical features of AHO, which were more prominent in the patients with PHP1A. The patients were of normal intelligence but showed ectopic calcification and ossification, rounded facies, 'absent 4th knuckles,' and short feet and hands with particularly short fourth metacarpals.
Warner et al. (1998) reported a 24-year-old man with PPHP. Developmental delay, brachycephaly, and decreased muscle tone were noted by age 10 months. Throughout childhood he was small for his age and stocky in appearance. By 6 years, he developed learning disabilities as well as impulsive and aggressive behavior. Brachydactyly involved the distal phalanx of the thumb and the fourth metacarpals bilaterally. He also had intracranial calcifications in the globus pallidus. There was no evidence of resistance to parathyroid hormone or thyrotropin. Genetic analysis identified a de novo heterozygous mutation in the GNAS gene (139320.0016).
Fischer et al. (1998) reported a large kindred in which 2 mothers with PPHP had 6 offspring with PHP Ia. The PPHP patients had decreased erythrocyte Gs activity, but normal urinary cAMP responses to PTH, normal TSH levels and responses to TRH, and normal serum levels of calcium and PTH.
Chase et al. (1969) found that persons with PPHP showed abnormally high basal urinary excretion of cyclic AMP (cAMP) and a normal increase in urinary cAMP after PTH infusion. This finding was in contrast to persons with PHP1A (103580), who had blunted urinary cAMP excretion after PTH infusion.
Chase et al. (1969) reported a family in which 2 patients with PHP (103580) were the progeny of a mother with PPHP. Another family had 3 brothers with PHP; the mother had PPHP.
Weinberg and Stone (1971) described a family in which a brother and sister had PHP1 and the son and daughter of the brother had PPHP. All had clinical features of AHO, which were more prominent in the patients with PHP1. The patients were of normal intelligence but showed ectopic calcification and ossification, rounded facies, 'absent 4th knuckles,' and short feet and hands with particularly short fourth metacarpals.
In a review of the literature, Fitch (1982) favored autosomal dominant inheritance with sex modification.
Fitch (1982) and Kinard et al. (1979) also reported kindreds in which some individuals had AHO without hormone resistance (PPHP), while others had hormone resistance as well (PHP1A), suggesting that PHP and PPHP are genetically related.
Williams et al. (1977) described 4 females and 1 male in a family pedigree who showed wide clinical variability encompassing both PHP and PPHP. Farfel et al. (1981) reported a woman with PPHP whose daughter had classic PHP type Ia. The mother had AHO, no history of hypocalcemia or other endocrine abnormalities, and reduced N-protein activity.
Wilson et al. (1994) used an intragenic GNAS1 FokI polymorphism to determine the parental origin of the gene mutations in sporadic and familial AHO. A mutation identified in a sporadic case of PPHP was found to be paternally derived.
GNAS is a heavily imprinted locus, with different expression of its isoforms in different tissues dependent on the parental origin of the gene. Individuals with PHP1A (103580) and PPHP show about a 50% decrease in Gs expression in erythrocytes, which normally express both parental alleles. Renal tubule cells are unique in that they only express the maternal allele of Gs; the paternal allele is not expressed. Thus, renal cells of PPHP patients have normal Gs expression when a defect in the GNAS gene is inherited from the father because maternal expression remains normal. These patients have normal cAMP response to PTH infusion and lack features of hormone resistance. The features of AHO are believed to result from defective signaling in other cells due to Gs haploinsufficiency (Bastepe and Juppner, 2005; Mantovani and Spada, 2006).
In a mother with PPHP and her 4 daughters with PHP Ia (103580) (Kinard et al., 1979), 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.
In affected members of a large kindred in which 2 mothers had PPHP and their 6 offspring had PHP Ia, Fischer et al. (1998) identified a heterozygous mutation in the GNAS gene (139320.0015).
Albright, F., Burnett, C. H., Smith, P. H., Parson, W. Pseudo-hypoparathyroidism--an example of 'Seabright-Bantam syndrome': report of three cases. Endocrinology 30: 922-932, 1942.
Albright, F., Forbes, A. P., Henneman, P. H. Pseudo-pseudohypoparathyroidism. Trans. Assoc. Am. Phys. 65: 337-350, 1952. [PubMed: 13005676]
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Chase, L. R., Melson, G. L., Aurbach, G. D. Pseudohypoparathyroidism: defective excretion of 3(prime)-5(prime)-AMP in response to parathyroid hormone. J. Clin. Invest. 48: 1832-1844, 1969. [PubMed: 4309802] [Full Text: https://doi.org/10.1172/JCI106149]
Davies, S. J., Hughes, H. E. Imprinting in Albright's hereditary osteodystrophy. J. Med. Genet. 30: 101-103, 1993. [PubMed: 8383205] [Full Text: https://doi.org/10.1136/jmg.30.2.101]
Farfel, Z., Brothers, V. M., Brickman, A. S., Conte, F., Neer, R., Bourne, H. R. Pseudohypoparathyroidism: inheritance of deficient receptor-cyclase coupling activity. Proc. Nat. Acad. Sci. 78: 3098-3102, 1981. [PubMed: 6265935] [Full Text: https://doi.org/10.1073/pnas.78.5.3098]
Fischer, J. A., Egert, F., Werder, E., Born, W. An inherited mutation associated with functional deficiency of the alpha-subunit of the guanine nucleotide-binding protein Gs in pseudo- and pseudopseudohypoparathyroidism. J. Clin. Endocr. Metab. 83: 935-938, 1998. [PubMed: 9506752] [Full Text: https://doi.org/10.1210/jcem.83.3.4656]
Fitch, N. Albright's hereditary osteodystrophy: a review. Am. J. Med. Genet. 11: 11-29, 1982. [PubMed: 6278930] [Full Text: https://doi.org/10.1002/ajmg.1320110104]
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Warner, D. R., Weng, G., Yu, S., Matalon, R., Weinstein, L. S. A novel mutation in the switch 3 region of Gs-alpha in a patient with Albright hereditary osteodystrophy impairs GDP binding and receptor activation. J. Biol. Chem. 273: 23976-23983, 1998. [PubMed: 9727013] [Full Text: https://doi.org/10.1074/jbc.273.37.23976]
Weinberg, A. G., Stone, R. T. Autosomal dominant inheritance in Albright's hereditary osteodystrophy. J. Pediat. 79: 996-999, 1971. [PubMed: 5125407] [Full Text: https://doi.org/10.1016/s0022-3476(71)80196-8]
Weinstein, L. S., Gejman, P. V., Friedman, E., Kadowaki, T., Collins, R. M., Gershon, E. S., Spiegel, A. M. Mutations of the Gs alpha-subunit gene in Albright hereditary osteodystrophy detected by denaturing gradient gel electrophoresis. Proc. Nat. Acad. Sci. 87: 8287-8290, 1990. [PubMed: 2122458] [Full Text: https://doi.org/10.1073/pnas.87.21.8287]
Williams, A. J., Wilkinson, J. L., Taylor, W. H. Pseudohypoparathyroidism: variable manifestations within a family. Arch. Dis. Child. 52: 798-800, 1977. [PubMed: 931429] [Full Text: https://doi.org/10.1136/adc.52.10.798]
Wilson, L. C., Oude Luttikhuis, M. E. M., Clayton, P. T., Fraser, W. D., Trembath, R. C. Parental origin of Gs-alpha gene mutations in Albright's hereditary osteodystrophy. J. Med. Genet. 31: 835-839, 1994. [PubMed: 7853365] [Full Text: https://doi.org/10.1136/jmg.31.11.835]