Pseudopseudohypoparathyroidism (PPHP) is an inherited disorder, named for its similarity to pseudohypoparathyroidism in presentation. It is more properly Albright hereditary osteodystrophy, although without resistance of parathyroid hormone (PTH), as frequently seen in that affliction. The term is used to describe a condition where the individual has the phenotypic appearance of pseudohypoparathyroidism type 1a, but has (unexpected for the phenotype) normal labs, including

calcium Calcium is a chemical element; it has symbol Ca and atomic number 20. As an alkaline earth metal, calcium is a reactive metal that forms a dark oxide-nitride layer when exposed to air. Its physical and chemical properties are most similar to it ...

and PTH. It can be considered a variant of Albright hereditary osteodystrophy (pseudohypoparathyroidism type 1A), as they present with the same constellation of signs and symptoms, including short stature, brachydactyly, subcutaneous calcification, and

obesity Obesity is a medical condition, considered by multiple organizations to be a disease, in which excess Adipose tissue, body fat has accumulated to such an extent that it can potentially have negative effects on health. People are classifi ...

Presentation

Pseudopseudohypoparathyroidism can be best understood by comparing it to other conditions: Hormone resistance is not present in pseudopseudohypoparathyroidism.

Short stature Short stature refers to a height of a human which is below typical. Whether a person is considered short depends on the context. Because of the lack of preciseness, there is often disagreement about the degree of shortness that should be called ...

may be present.

Obesity Obesity is a medical condition, considered by multiple organizations to be a disease, in which excess Adipose tissue, body fat has accumulated to such an extent that it can potentially have negative effects on health. People are classifi ...

is less common in pseudopseudohypoparathyroidism than in pseudohypoparathyroidism. Osteoma cutis may be present.

Genetics

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, but pseudopseudohypoparathyroidism has normal calcium homeostasis because of the normal maternal allele in the

kidney In humans, the kidneys are two reddish-brown bean-shaped blood-filtering organ (anatomy), organs that are a multilobar, multipapillary form of mammalian kidneys, usually without signs of external lobulation. They are located on the left and rig ...

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 Spermatogenesis is the process by which haploid spermatozoa develop from germ cells in the seminiferous tubules of the testicle. This process starts with the Mitosis, mitotic division of the stem cells located close to the basement membrane of ...

, imprinting of the GNAS1 gene inactivates both copies of his genes: one will be functional, and the other will be defective. Tissues in the body will re-activate different copies of the GNAS1 gene selectively; the kidneys will selectively activate the (functional) maternal copy while keeping the (defective) paternally-derived gene imprinted and inactive, even in normal individuals. Since the maternally-derived GNAS1 gene is functional, renal handling of calcium and phosphate is normal, and homeostasis is maintained in pseudopseudohypoparathyroidism. However, the rest of the tissues will instead selectively display the defective gene, resulting in

haploinsufficiency Haploinsufficiency in genetics describes a model of dominant gene action in diploid organisms, in which a single copy of the wild-type allele at a locus in heterozygous combination with a variant allele is insufficient to produce the wild-type ...

of the GNAS1 product in most tissues, and giving the phenotype of pseudohypoparathyroidism type 1a. As a result, there is also a normal response of urinary cAMP to PTH, and normal serum PTH.

Diagnosis

The diagnosis is based on the presence of the Albright hereditary osteodystrophy pseudotype but without the PTH resistance. Blood tests including calcium, phosphate, and PTH will exclude other forms of pseudohypoparathyroidism. X-rays may reveal a short fourth metacarpal.

Genetic testing Genetic testing, also known as DNA testing, is used to identify changes in DNA sequence or chromosome structure. Genetic testing can also include measuring the results of genetic changes, such as RNA analysis as an output of gene expression, or ...

can confirm the diagnosis by showing GNAS gene mutation.

Treatment

Treatments focuses on symptoms, with

genetic counseling Genetic counseling is the process of investigating individuals and families affected by or at risk of genetic disorders to help them understand and adapt to the medical, psychological and familial implications of genetic contributions to disease. ...

recommended.

History

It was characterized in 1952 by Fuller Albright as "pseudo-pseudohypoparathyroidism" (with hyphen).

References

External links

{{Deficiencies of intracellular signaling peptides and proteins Cell surface receptor deficiencies Rare diseases English words