Nonclassic features of pseudohypoparathyroidism type 1A

Abstract

Purpose of review: To provide readers with a review of contemporary literature describing the evolving understanding of the pseudohypoparathyroidism type 1A (PHP1A) phenotype.

Recent findings: The classic features of PHP1A include multihormone resistance and the Albright Hereditary Osteodystrophy phenotype (round facies, short stature, subcutaneous ossifications, brachydactyly, and early-onset obesity. Obesity may be because of a decrease in resting energy expenditure because most patients do not report significant hyperphagia. Patients with PHP1A have an increased risk of type 2 diabetes. In addition to brachydactyly and short stature, orthopedic complications can include spinal stenosis and carpal tunnel syndrome. Hearing loss, both sensorineural and conductive, has been reported in PHP1A. In addition, ear-nose-throat findings include decreased olfaction and frequent otitis media requiring tympanostomy tubes. Sleep apnea was shown to be 4.4-fold more common in children with PHP1A compared with other obese children; furthermore, asthma-like symptoms have been reported. These new findings are likely multifactorial and further research is needed to better understand these nonclassic features of PHP1A.

Summary: Along with the Albright Hereditary Osteodystrophy phenotype and hormone resistance, patients with PHP1A may have additional skeletal, metabolic, ear-nose-throat, and pulmonary complications. Understanding these nonclassic features will help improve clinical care of patients with PHP1A.

Figures

Figure 1

The GNAS gene complex on chromosome 20. PHP1A is caused by mutations involving exons 1–13 of GNAS, the gene encoding the alpha-subunit of the stimulatory G protein (Gsα) and multiple splice variants. Additional sense and antisense transcripts are derived from the GNAS locus and the alternate first exons A/B, XLαs and Nesp55. In some tissues, Gsα transcripts are preferentially expressed from the maternal allele, due to tissue-specific paternal imprinting. Mutations in the gene GNAS give rise to the disease pseudohypoparathyroidism type 1A (PHP1A) when inherited on the maternal allele or the less severe disease pseudopseudohypoparathyroidism (PPHP) when inherited on the paternal allele. Loss of the normal methylation pattern results in pseudohypoparathyroidism type 1B (PHP1B).

Figure 2

Left hand film of a female child with pseudohypoparathyroidism type 1a (PHP1A). The red circle highlights brachydactyly, the shortening of the 3rd–5th metacarpals.