At a Glance

Pseudohypoparathyroidism is a heterogeneous group of rare disorders whose hallmark is insensitivity to parathyroid hormone (PTH). These disorders may present with defects isolated to the parathyroid gland (type Ib or II) or as a syndrome with a constellation of developmental and skeletal defects (type Ia). The most well-known of these is Albright hereditary osteodystrophy (type Ia pseudohypoparathyroidism), an autosomal dominant disorder that classically presents with short stature, rounded face, shortened fourth metacarpals, and soft-tissue calcifications. All types of pseudohypoparathyroidism are rare. Many cases of pseudohypoparathyroidism are due to mutations in the gene for Gs-alpha (GNAS1). The classic biochemical features of pseudohypoparathyroidism include hypocalcemia, hyperphosphatemia, and increased serum PTH, all of which are ultimately related to resistance to the biochemical actions of PTH.

What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?

The initial biochemical work-up consists of serum calcium, PTH, albumin, thyroid function tests (e.g., thyroid stimulating hormone (TSH), free thyroxine), and measures of kidney function (e.g., blood urea nitrogen, creatinine). If Albright hereditary osteodystrophy is suspected, a wider endocrine work-up to include tests of gonadal function and growth hormone would be appropriate. The common biochemical pattern in pseudohypoparathyroidism is hypocalcemia, hyperphosphatemia, and increased serum PTH. Follow-up tests include skeletal and renal responsive to administration of PTH, usually by an endocrinologist experienced in parathyroid disorders. Patients with pseudohypoparathyroidism will fail to show expected biochemical responses to PTH administration (e.g., increased urinary phosphate).

Are There Any Factors That Might Affect the Lab Results? In particular, does your patient take any medications – OTC drugs or Herbals – that might affect the lab results?

Low serum albumin can complicate interpretation of serum calcium. In patients with hypoalbuminemia, corrected calcium should be calculated or, alternatively, an ionized calcium measured.

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What Lab Results Are Absolutely Confirmatory?

Analysis of mutations in the GNAS1 gene is available, although not widely used. Otherwise, the diagnosis is made through a combination of history, physical, and laboratory findings.

Additional Factors of Clinical Importance

The hereditary nature of type Ia pseudohypoparathyroidism means that genetic counseling should be offered to affected patients and their relatives.

Errors in Test Selection and Interpretation

Pseudohypoparathyroidism is a rare disorder and may not be initially considered by clinicians.

The developmental abnormalities of Albright hereditary osteodystrophy may be confused with other developmental disorders, such as Down syndrome or Turner syndrome, with failure to order laboratory tests aimed at assessing parathyroid function.

Some of the biochemical features of pseudohypoparathyroidism (e.g., hypocalcemia, elevated serum PTH) can be seen in renal disease or vitamin D deficiency, which are both much more common than pseudohypoparathyroidism.

Proper diagnosis really rests on challenging patients with administration of PTH. This may require referral to endocrinologist with experience in diagnosing and managing parathyroid disorders.