Abstract
Pseudohypoparathyroidism (PHP) is a rare endocrine disorder derived from the defective activation of the cAMP pathway by the parathyroid hormone secondary to GNAS molecular defects. PHP subtypes are defined by the presence/absence of specific clinical/biochemical features. PHP1A is characterized by resistance to multiple hormones with features of Albright hereditary osteodystrophy (AHO), while pseudopseudohypoparathyroidism (PPHP) is characterized by AHO in the absence of PTH resistance. Small subsets of PHP and PPHP patients without known molecular defects have been re-diagnosed as being affected by the brachydactyly-mental retardation syndrome (BDMR), also known as the AHO-like syndrome. This study aimed to analyse 24 PHP1A and 51 PPHP patients without a molecular diagnosis for the presence of BDMR-associated 2q37 deletions to improve the differential diagnosis and to identify features that might help to avoid a misdiagnosis. Molecular investigations identified 4 deletions in 4 unrelated patients. The affected patients showed a combination of the most pathognomonic AHO features. Of note, 3 of the patients also displayed mild PTH resistance, and none of the patients developed ectopic ossifications. Our work confirmed the rarity of the misdiagnosis of BDMR in PHP patients through the identification of 4 patients bearing a 2q37 deletion in a cohort of 73 PHP patients (5.3%). Three patients with the deletion presented a PHP1A phenotype in the absence of any BDMR-specific findings. Further studies on larger case series are needed to elucidate the overlap between these clinical entities and to allow the early identification of patients.
Highlights
Pseudohypoparathyroidism (PHP) is a rare endocrine disorder derived from the defective activation of the cAMP transduction pathway by the parathyroid hormone (PTH) secondary to molecular defects affecting the alpha subunit of the stimulatory G protein (Gsα), which is encoded by the GNAS gene [1]
We were not able to identify the precise location of the breakpoints, the analysis of variable number tandem repeats (VNTRs) in the 2q37 region allowed the approximate delineation of the extension of deletions because heterozygous markers represented a biallelic condition
The smallest region of overlap (SRO) containing the gene or genes potentially involved in the clinical presentation, that is the region ranging from nucleotides 239′ 306′ 199 to 242’855′ 711, where all four found deletions overlapped, removed ∼3.5 Mbp hosting 38 genes (Figure 1 and Supplementary Table 2)
Summary
Pseudohypoparathyroidism (PHP) is a rare endocrine disorder derived from the defective activation of the cAMP transduction pathway by the parathyroid hormone (PTH) secondary to molecular defects affecting the alpha subunit of the stimulatory G protein (Gsα), which is encoded by the GNAS gene [1]. PHP type 1B/PHP1B-MIM#603233, PHP type 1C/PHP1C – MIM#612462, PHP type 2/PHP2 – MIM#203330 and progressive osseous heteroplasia POH – MIM#166350) have been defined by the presence/absence of specific clinical/biochemical features and by the presence/absence of underlying genetic, further divided into maternal or paternal, or epigenetic molecular GNAS defects [2,3,4]. PPHP is defined as AHO in the absence of PTH resistance and is associated with paternal GNAS genetic alterations [5]. Research studies on these diseases allowed the identification of both clinical and molecular overlap among subtypes and with closely related disorders deriving from alterations of elements involved in the cAMP transduction pathway other than the Gsα, making the classification obsolete [4, 6]. One of the additional strengths of the new classification is the provision of a category, iPPSDx, for those patients lacking a known genetic/epigenetic molecular determinant [8]
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