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Pseudopseudohypoparathyroidism (pseudoPHP) is an inherited disorder, named for its similarity to pseudohypoparathyroidism in presentation. The term pseudopseudohypoparathyroidism is used to describe a condition where the individual has the phenotypic appearance of pseudohypoparathyroidism type 1a, but is biochemically normal.

It is sometimes considered a variant of Albright hereditary osteodystrophy.^[1]

It was characterized in 1952 by Fuller Albright as "pseudo-pseudohypoparathyroidism" (with hyphen).^[2]^[3]

Presentation

Pseudopseudohypoparathyroidism can be best understood by comparing it to other conditions:

Condition		Appearance	PTH levels	Calcitriol	Calcium	Phosphates	Imprinting
Hypoparathyroidism		Normal	Low	Low	Low	High	Not applicable
Pseudohypoparathyroidism	Type 1A	Skeletal defects	High	Low	Low	High	Gene defect from mother (GNAS1)
	Type 1B	Normal	High	Low	Low	High	Gene defect from mother (GNAS1 and STX16)
	Type 2	Normal	High	Low	Low	High	?
Pseudopseudohypoparathyroidism		Skeletal defects	Normal	Normal	Normal^[4]	Normal	Gene defect from father

Hormone resistance is not present in pseudopseudohypoparathyroidism.^[5] Short stature may be present.^[6] Obesity is less common in pseudopseudohypoparathyroidism than in pseudohypoparathyroidism.^[7] Osteoma cutis may be present.^[8]

Pathophysiology

The GNAS1 gene involved in both pseudohypoparathyroidism type 1a and pseudopseudohypoparathyroidism is greatly affected by imprinting. When a father who has pseudohypoparathyroidism undergoes spermatogenesis, imprinting of the GNAS1 gene inactivates both copies of his genes, including the defective one. The seemingly contradictory presentation of symptoms can be explained by the fact that most tissues in the body (e.g., bone) reactivate the GNAS1 copy, whereas the kidneys do not. Thus, the result is haploinsufficiency of the GNAS1 product in most tissues, giving the phenotype of pseudohypoparathyroidism type 1a. In the kidneys, however, the paternally-derived gene remains imprinted and inactive, even in normal individuals, leaving only the non-imprinted maternally-derived gene. As a result, as long as the maternally-derived GNAS1 gene is functional, renal handling of calcium and phosphate is normal, and homeostasis is maintained.

Inheritance

A male with pseudohypoparathyroidism has a 50% chance of passing on the defective GNAS gene to his children, although in an imprinted, inactive form. Any of his children receiving this gene will have pseudopseudohypoparathyroidism. Any of his daughters that have pseudopseudohypoparathyroidism may in turn pass along pseudohypoparathyroidism 1A to her children as the imprinting pattern on the inherited paternal gene will be changed to the maternal pattern in the mother's ovum during meiosis. The gene will be reactivated in any children who inherit it.

Pseudopseudohypoparathyroidism and pseudohypoparathyroidism both involve the same GNAS gene,^[9] but pseudopseudohypoparathyroidism has normal calcium homeostasis because of the normal maternal allele in the kidney.^[10]

References

^ Solomon SS, Kerlan RM, King LE, Jones GM, Hashimoto K (January 1975). "Pseudopseudohypoparathyroidism with fibrous dysplasia". Arch Dermatol. 111 (1): 90–3. doi:10.1001/archderm.111.1.90. PMID 1119829.
^ Philip R. Beales; I. Sadaf Farooqi; Stephen O'Rahilly (12 September 2008). The genetics of obesity syndromes. Oxford University Press US. pp. 91–. ISBN 978-0-19-530016-1. Retrieved 30 October 2010.
^ ALBRIGHT F, FORBES AP, HENNEMAN PH (1952). "Pseudo-pseudohypoparathyroidism". Trans. Assoc. Am. Physicians. 65: 337–50. PMID 13005676.
^ Shahid Hussain; Sharif Aaron Latif; Adrian Hall (1 July 2010). Rapid Review of Radiology. Manson Publishing. pp. 262–. ISBN 978-1-84076-120-7. Retrieved 30 October 2010.
^ Mouallem M, Shaharabany M, Weintrob N, et al. (February 2008). "Cognitive impairment is prevalent in pseudohypoparathyroidism type Ia, but not in pseudopseudohypoparathyroidism: possible cerebral imprinting of Gsalpha". Clin. Endocrinol. (Oxf). 68 (2): 233–9. doi:10.1111/j.1365-2265.2007.03025.x. PMID 17803690.
^ Riggs JE (July 1997). "Military service and pseudopseudohypoparathyroidism: recognizing red flags for rare medical conditions". Mil Med. 162 (7): 510–2. PMID 9232985.
^ Long DN, McGuire S, Levine MA, Weinstein LS, Germain-Lee EL (March 2007). "Body mass index differences in pseudohypoparathyroidism type 1a versus pseudopseudohypoparathyroidism may implicate paternal imprinting of Galpha(s) in the development of human obesity". J. Clin. Endocrinol. Metab. 92 (3): 1073–9. doi:10.1210/jc.2006-1497. PMID 17164301.
^ Jeong KH, Lew BL, Sim WY (May 2009). "Osteoma cutis as the presenting feature of albright hereditary osteodystrophy associated with pseudopseudohypoparathyroidism". Ann Dermatol. 21 (2): 154–8. doi:10.5021/ad.2009.21.2.154. PMC 2861203. PMID 20523775.
^ Lebrun M, Richard N, Abeguilé G, et al. (June 2010). "Progressive osseous heteroplasia: a model for the imprinting effects of GNAS inactivating mutations in humans". J. Clin. Endocrinol. Metab. 95 (6): 3028–38. doi:10.1210/jc.2009-1451. PMID 20427508.
^ David Terris; Christine G. Gourin (15 November 2008). Thyroid and Parathyroid Diseases: Medical and Surgical Management. Thieme. pp. 193–. ISBN 978-1-58890-518-5. Retrieved 30 October 2010.

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UpToDate Contents

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1. 幼児および小児における低カルシウム血症の病因 etiology of hypocalcemia in infants and children

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[The mouth of patients with hypo- and pseudohypoparathyroidism].

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