Shortened Fingers and Toes: GNAS Abnormalities are Not the Only Cause

Abstract

The PTH/PTHrP receptor (PTHR1) mediates the actions of parathyroid hormone (PTH) and PTH-related peptide (PTHrP) by coupling this G protein-coupled receptor (GPCR) to the alpha-subunit of the heterotrimeric stimulatory G protein (Gsα) and thereby to the formation of cAMP. In growth plates, PTHrP-dependent activation of the cAMP/PKA second messenger pathway prevents the premature differentiation of chondrocytes into hypertrophic cells resulting in delayed growth plate closure. Heterozygous mutations in GNAS, the gene encoding Gsα, lead to a reduction in cAMP levels in growth plate chondrocytes that is sufficient to cause shortening of metacarpals and/or -tarsals, i. e. typical skeletal aspects of Albright’s Hereditary Osteodystrophy (AHO). However, heterozygous mutations in other genes, including those encoding PTHrP, PRKAR1A, PDE4D, and PDE3A, can lead to similar or even more pronounced acceleration of skeletal maturation that is particularly obvious in hands and feet, and reduces final adult height. Genetic mutations other than those resulting in Gsα haploinsufficiency thus reduce intracellular cAMP levels in growth plate chondrocytes to a similar extent and thereby accelerate skeletal maturation.

A novel mutation in PTHLH in a family with a variable phenotype with brachydactyly, short stature, oligodontia and developmental delay

“…The amino-acid substitution at codon 9 could have effect on the signal peptide cleavage site, resulting in PTHLH loss of function ( Wang et al, 2015 ). This can lead to increased chondrocyte apoptosis and premature closure of growth plates resulting in BDE, advanced bone age and short stature like in our patients ( Reyes et al, 2020 ; Reyes et al, 2019 ). PTHR1 activates the Gsα-cAMP-PKA-PDE4D signaling pathway and mutations in other genes encoding for proteins in this pathway, namely GNAS (leading to PHP or PPHP), PRKAR1A and PDE4D (leading to acrodysostosis type 1 and 2 respectively), can also lead to BDE and short stature ( Reyes et al, 2019 ; Thomas-Teinturier et al, 2016 ).…”