Pseudopseudohypoparathyroidism (PPHP) is an inherited disorder, named for its similarity to

pseudohypoparathyroidism Pseudohypoparathyroidism is a condition associated primarily with resistance to the parathyroid hormone. Those with the condition have a low serum calcium and high phosphate, but the parathyroid hormone level (PTH) is appropriately high (due to th ...

in presentation. It is more properly Albright hereditary osteodystrophy although without resistance of

parathyroid hormone Parathyroid hormone (PTH), also called parathormone or parathyrin, is a peptide hormone secreted by the parathyroid glands that regulates the serum calcium concentration through its effects on bone, kidney, and intestine. PTH influences bone ...

as frequently seen in that affliction. The term Pseudopseudohypoparathyroidism 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 with the 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 ...

and PTH. It can be considered a variant of Albright hereditary osteodystrophy, or Pseudohypoparathyroidism type 1A, as they present with the same constellation of signs and symptoms, including short stature,

brachydactyly Brachydactyly (Greek βραχύς = "short" plus δάκτυλος = "finger"), is a medical term which literally means "short finger". The shortness is relative to the length of other long bones and other parts of the body. Brachydactyly is an i ...

, subcutaneous calcification, and

obesity Obesity is a medical condition, sometimes considered a disease, in which excess body fat has accumulated to such an extent that it may negatively affect health. People are classified as obese when their body mass index (BMI)—a person's ...

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, sometimes considered a disease, in which excess body fat has accumulated to such an extent that it may negatively affect health. People are classified as obese when their body mass index (BMI)—a person's ...

is less common in Pseudopseudohypoparathyroidism than in Pseudohypoparathyroidism.

Osteoma cutis Osteoma cutis is a cutaneous condition characterized by the presence of bone within the skin in the absence of a preexisting or associated lesion. See also * Calcinosis cutis * Skin lesion * List of cutaneous conditions Many skin conditio ...

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 The kidneys are two reddish-brown bean-shaped organs found in vertebrates. They are located on the left and right in the retroperitoneal space, and in adult humans are about in length. They receive blood from the paired renal arteries; blo ...

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 testis. This process starts with the mitotic division of the stem cells located close to the basement membrane of the tubu ...

, 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 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 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; t ...

recommended.

History

It was characterized in 1952 by

Fuller Albright Fuller Albright (January 12, 1900 – December 8, 1969) was an American endocrinologist who made numerous contributions to his field, especially to the area of calcium metabolism. Albright made great strides and contributions to the understanding ...

as "pseudo-pseudohypoparathyroidism" (with hyphen).

References

External links

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