Growth Hormone Deficiency in Pseudohypoparathyroidism Type 1a: Another Manifestation of Multihormone Resistance

Abstract

Albright hereditary osteodystrophy (AHO) is a genetic disorder caused by heterozygous inactivating mutations in GNAS1, the gene encoding the alpha-chain of G(s), and is associated with short stature, obesity, brachydactyly, and sc ossifications. AHO patients with GNAS1 mutations on maternally inherited alleles also manifest resistance to multiple hormones (e.g. PTH, TSH, LH, FSH), a variant termed pseudohypoparathyroidism (PHP) type 1a, due to paternal imprinting of G alpha(s) transcripts in specific tissues. Recent evidence has shown that G alpha(s) transcripts are also imprinted in the pituitary somatotrophs that secrete GH. Because this imprinting could influence GHRH-dependent stimulation of somatotrophs, we hypothesized that maternally inherited GNAS1 mutations would impair GH secretion. We studied GH status in 13 subjects with PHP type 1a. GH responses to arginine/L-dopa and arginine/GHRH were deficient in nine subjects, all of whom were obese and had low serum concentrations of IGF-I. By contrast, none of the four GH-sufficient subjects were obese, and all had normal IGF-I levels. Our data indicate that GH deficiency is common (69%) in PHP type 1a and may contribute to the obesity and short stature typical of AHO. We propose that GH status be evaluated in all patients with PHP type 1a.

From pseudohypoparathyroidism to inactivating PTH/PTHrP signalling disorder (iPPSD), a novel classification proposed by the EuroPHP network

“…Resistance to growth hormonereleasing hormone (GHRH), leading to growth hormone deficiency, is the most frequent additional resistance found in PHP1A, affecting as many as 60% of patients (97,98,99). Calcitonin resistance has been described without clinical features in patients affected with PHP1A (27).…”

Diagnosis and management of pseudohypoparathyroidism and related disorders: first international consensus statement

“…In brief, PHP1A is caused by inactivating variants on the maternal allele of the GNAS gene within exons 1-13 (referring sequences NG_016194.1/NM_001077488.1 and LRG_1051), including both point mutations and rare gene rearrangements 16,23,27,41,45,86,88,97,112,122,[143][144][145][146][147][148] ( Supplementary Fig. 1b).…”

“…The height deficit in patients with PHP develops over time. Small cohorts of patients with PHP1A have shown declining growth velocity a few years after birth, a lack of a pubertal growth spurt and premature cessation of statural growth 86,97,107,217 . This finding is also supported by observations from the authors' dayto-day practice (L.d.S., H.J., A.L., P.K., G.M., G.A.M.-M., O.M., A.R.…”

Pseudohypoparathyroidism in Children

“…Pohlenz et al(Pohlenz, 2003) have reported a missense mutation, which results in the amino-acid substitution (Lys338Asn) in codon 338 of exon 12 of the GNAS gene associated with congenital hypothyroidism in AHO, though they did not state the precise mechanism by which this mutation leads to hypothyroidism. A Q35X mutation in exon 1 has been associated with growth-hormone deficiency (Germain-Lee, 2003), whereas a de novo, missense mutation, W281R in exon 11, has been linked to progressive osseous heteroplasia, a rare, autosomal-dominant condition that presents in childhood as dermal ossification that progresses to involve deep skeletal muscles (Chan, 2004). Germain-Lee et al(Germain-Lee, 2003) identified a patient with a Q29X mutation, and Nwosu et al (Nwosu, 2009) reported the association of Q29X mutation with a phenotype that includes Albright hereditary osteodystrophy, morbid obesity, acanthosis nigricans, insulin resistance, growth-hormone deficiency, hypothyroidism, and subcutaneous calcification.…”

“…Germain-Lee et al (Germain-Lee, 2003) reported a patient with acanthosis nigricans in a cohort of 13 patients with PHP 1a who had normal hemoglobin A1c and fasting insulin levels. Nwosu et al (Nwosu, 2009) described a child with PHP 1a with acanthosis nigricans and insulin resistance (Figure 2).…”