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Commentary.

As a rare disorder, the diagnosis of pseudohypoparathyroidism (PHP) [2] is challenging. This case illustrates, however, that an understanding of parathyroid action and of the genetic mechanisms underlying PHP can effectively guide its diagnosis.

The spectrum of severe hypocalcemia, hyperparathyroidism, and hyperphosphatemia raises suspicion for PHP. An increased parathyroid hormone (PTH) concentration distinguishes PHP from hypoparathyroidism. Severe vitamin D deficiency and renal dysfunction can resemble PHP, but measurement of glomerular filtration rate and 25-OH vitamin D should aid this distinction. If the diagnosis remains uncertain, one can measure urinary cAMP response to injected PTH, which is impaired in PHP.

PHP arises from a deficiency of the [alpha] subunit of stimulatory G protein ([G.sub.s][alpha]), particularly in cells where it mediates PTH/PTH-related peptide receptor (PPR) signaling. Encoded in the GNAS gene locus, Gsa production in PPR-producing renal proximal tubule cells is dependent on the maternal allele, owing to silencing of the paternal allele via mechanisms not yet fully understood. Paternal allele silencing is also found in the pituitary, gonads, and thyroid. Maternal allele mutations lead to parathyroid resistance seen in pseudohypoparathyroidism-1a via [G.sub.s][alpha] deficiency in renal proximal tubule. Albright hereditary osteodystrophy arises from [G.sub.s][alpha] deficiency in the other tissues mentioned.

Biochemical evidence of parathyroid hormone resistance without Albright hereditary osteodystrophy, seen with this patient, suggests pseudohypoparathyroidism1b. In PHP1b, methylation defects silence the maternal allele in PPR-producing renal proximal tubule cells. As other tissues are unaffected, Albright hereditary osteodystrophy is generally not seen.

Management of PHP remains challenging. Even with normocalcemia, patients suffer a wide range of debilities, especially in PHP1a. Furthermore, there remain long-term risks of tissue calcifications, particularly of the basal ganglia. Maintaining calcium in low-normal range (8-8.5 mg/dL) could theoretically lower this risk, but this is uncertain. Ongoing research of [G.sub.s][alpha] molecular biology will hopefully direct future strategies toward treating these complex disorders.

Author Contributions: The author confirmed they have contributed to the intellectual content of this paper and have met the following 3 requirements: (a) significant contributions to the conception and design, acquisition of data, or analysis and interpretation of data; (b) drafting or revising the article for intellectual content; and (c) final approval of the published article.

Authors' Disclosures or Potential Conflicts of Interest: The author declared no potential conflicts of interest.

References

(1.) Montavani G. Pseudohypoparathyroidism: diagnosis and treatment. J Clin Endocrinol Metab 2011;96:3020-30.

(2.) Turan S, Bastepe M. GNAS spectrum of disorders. Curr Osteoporos Rep 2015;13: 146-58.

Partha S. Sinha [1] *

[1] Beth Israel Deaconess Medical Center, Boston, MA.

* Address correspondence to the author at: Gryzmish 6th Floor, 330 Brookline Ave., Boston, MA 02215. Fax 617-667-7060; e-mail psinha@bidmc.harvard.edu.

Received October 28,2017; accepted November 6,2017.

DOI: 10.1373/clinchem.2017.282467

[2] Nonstandard abbreviations: PHP, pseudohypoparathyroidism; PTH, parathryroid hormone; PPR, PTH/PTH-related peptide receptor.
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Title Annotation:Clinical Case Study
Publication:Clinical Chemistry
Date:Mar 1, 2018
Words:480
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