Brachydactyly in 14 Genetically Characterized Pseudohypoparathyroidism Type Ia Patients

Abstract

Brachydactyly, classically described as shortening of III, IV, and V metacarpals and I distal phalanx, is the typical and most specific sign of Albright's hereditary osteodystrophy, a peculiar phenotype reported in subjects with pseudohypoparathyroidism type Ia (PHP-Ia) caused by mutations in the GNAS gene, which encodes for the alpha-subunit of the stimulatory G protein (Gsalpha). It has been reported in 70% of PHP subjects from routine radiological examinations, but there are no specific data for hand alterations in genetically characterized PHP-Ia subjects. We evaluated the metacarpophalangeal pattern profile in 14 GNAS-mutated PHP-Ia subjects and determined the prevalence and patterns of left hand bone shortening. To search for genotype/phenotype correlations, we compared metacarpophalangeal pattern profiles in subjects with identical mutations. Shortening below -2 SD score (SDS) was present in at least one bone in each subject, with a prevalence of 100%; however, great variability existed between subjects and between hand bone segments. Between subjects, shortening ranged from -2 to -10.4 SDS and involved 1-19 hand bones (5.3-100%). Between segments, III-IV metacarpals were the most compromised (-10.4 and -10.0 SDS, respectively); V metacarpals and I-IV distal phalanges were the most frequently shortened (85.7%). Overall, bone length median values revealed shortening below -2 SDS in all metacarpals and all distal phalanges, i.e. brachymetacarpia and brachytelephalangy, that cluster together. These segments were shortened in 64.3-85.7% of patients, significantly differing from proximal and middle phalanges, which were shortened in 21.4-50%. Even if these hand alterations were a constant and typical finding in our PHP-Ia population, cluster analysis in subjects with the same genotypes did not generally show a genotype/phenotype correlation. Variability between subjects may be the result of complex interactions between GNAS defects and other genetic or epigenetic factors. In conclusion, hand shortening analysis in 14 genetically characterized patients showed typical brachymetacarpia and brachytelephalangy. Further studies in PHP-Ia subjects without GNAS mutations and in other brachydactyly syndromes will determine whether the pattern described is also specific.

Pseudohypoparathyroidism Type 1A-Subclinical Hypothyroidism and Rapid Weight Gain as Early Clinical Signs: A Clinical Review of 10 Cases

“…When present, this sign was apparent in only 60% of our patients, all of whom were aged 5 years and above (mean 7.6 yrs at diagnosis), as also reported earlier by Fernandez-Rebollo et al (9). The fact that we did not calculate the metacarpophalangeal pattern profile in all our patients, as suggested by Poznanski et al (23), could have led to an underestimation of the true prevalence of this typical sign of PHP (23,24). …”

Genetic and epigenetic alterations in the GNAS locus and clinical consequences in Pseudohypoparathyroidism: Italian common healthcare pathways adoption

“…BR is one of the most typical sign of PHP-Ia; its prevalence lower than 100% among subjects with genetic mutations may be explained by their young age (below to the indicated cut-off age of 5 years [39]), and also by the fact that the MPP hasn’t been performed in all subjects, thus potentially underdiagnosing the milder bone alterations. The new prevalence data of 50% among epimutated patients, raises the question if even a slight reduction in Gsα activity might produce specific alterations in hand bone growth: comparative studies are needed to define if it involves the same pattern as in mutated patients.…”

Pseudohypoparathyrodism vs. tricho-rhino-phalangeal syndrome: patient reclassification

“…Regarding radiological findings, although they are not highly specific for PHP/PPHP [apart from shortening of the IV and V metacarpals and of the distal phalanx of the thumb (18,19)], patients with TRPS present cone-shaped epiphyses at the phalanges, outcarving and deformation of the cones, which are more easily appreciated after epiphysis fusion (20,21). These features have not been observed in patients with PHP/PPHP (19,22).…”