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2q37 Deletions in Patients With an Albright Hereditary Osteodystrophy Phenotype and PTH Resistance
Francesca Marta Elli1, Luisa de Sanctis2, Bruno Madeo3
1Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy.
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.
Insights
Brachydactyly-mental retardation syndrome (BDMR) deletions were identified in 5.3% of pseudohypoparathyroidism (PHP) patients, highlighting a rare misdiagnosis. Some patients with 2q37 deletions showed PHP1A features without typical BDMR signs.
Area of Science:
- Endocrinology
- Genetics
- Rare Diseases
Background:
- Pseudohypoparathyroidism (PHP) is a rare endocrine disorder caused by GNAS gene defects affecting parathyroid hormone (PTH) action.
- PHP subtypes include PHP1A (hormone resistance, Albright hereditary osteodystrophy - AHO) and pseudopseudohypoparathyroidism (PPHP - AHO without PTH resistance).
- Some PHP/PPHP patients lack molecular diagnosis and are reclassified as brachydactyly-mental retardation syndrome (BDMR) or AHO-like syndrome.
Purpose of the Study:
- To investigate the prevalence of 2q37 deletions, associated with BDMR, in PHP and PPHP patients lacking molecular diagnosis.
- To improve differential diagnosis between PHP subtypes and BDMR.
- To identify clinical features aiding in avoiding misdiagnosis of BDMR in PHP patients.
Main Methods:
- Analysis of 24 PHP1A and 51 PPHP patients without molecular diagnosis for 2q37 deletions.
- Molecular investigations to identify deletions.
- Clinical assessment of affected patients for Albright hereditary osteodystrophy (AHO) features and PTH resistance.
Main Results:
- Four unrelated patients (5.3% of the cohort) were found to have 2q37 deletions.
- Affected patients presented characteristic AHO features; three showed mild PTH resistance, and none developed ectopic ossifications.
- Three deletion-bearing patients exhibited a PHP1A phenotype without specific BDMR findings, indicating potential diagnostic overlap.
Conclusions:
- The study confirms that BDMR is rarely misdiagnosed as PHP, with 2q37 deletions found in a small subset of PHP patients.
- Clinical presentation can be variable, with some 2q37 deletion cases mimicking PHP1A without typical BDMR characteristics.
- Further research with larger cohorts is necessary to clarify the relationship between these conditions and enable early patient identification.
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