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Carhart notch example. Pure-tone audiogram from the right ear of a 25-year-old man with GACI showing a conductive hearing loss with narrowing of the air-bone gap at 2000 Hz characteristic of a Carhart notch. This patient's tympanogram is normal (Type A) and acoustic stapedial reflexes are absent
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Background and importance
Hearing loss (HL) has been sporadically described, but not well characterized, in Generalized Arterial Calcification of Infancy (GACI), a rare disease in which pathological calcification typically presents in infancy.
Objectives
This study aims to describe the clinical audiologic and otologic features and potential etiolo...
Contexts in source publication
Context 1
... chain dysfunction (OCD) was defined as: normal hearing and normal tympanogram with elevated or absent acoustic reflexes, or normal tympanogram with air-bone gaps of > 10 dB, or presence of a Carhart-notch (e.g., Fig. 1). The Carhart-notch is a characteristic artifactual worsening in bone conduction threshold and narrowing of the air-bone gap, typically Conclusions and relevance: Hearing loss is common in GACI; it is most often conductive, and mild to moderate in severity. The etiology of HL is likely multifactorial, involving dysfunction of the ...
Context 2
... 15 patients with pure-tone threshold data, 10 had sufficient data for OCD categorization; of these, 80% (n = 8) were categorized as having an audiometric pattern consistent with OCD in one or both ears (Table 2). An example of this pattern finding is shown in Fig. ...
Context 3
... of osteocyte characteristics showed a significantly decreased number of osteocyte lacunae per bone area (N.Ot.Lc/B.Ar, 626.8 ± 132.1 vs.1163.0 ± 144.6 / mm2, p = 0.004; Fig. 3D) and decreased mean osteocyte lacunar area (Lc.Ar, 12.63 ± 0.98 vs.15.95 ± 0.73 µm 2 , p = 0.004; Fig. 3E) in ENPP1 asj/asj mice compared to WT mice. In the incus and stapes, the Lc.Ar was similarly lower in ENPP1 asj/asj mice than in WT (Additional file 1: Figures S1E & S2E), but the N.Ot.Lc/B.Ar and BMDD Page 8 of 10 Theng et al. Orphanet Journal of Rare Diseases (2022) 17:273 parameters showed no significant differences between groups. ...
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Background and Importance
Hearing loss (HL) has been sporadically described, but not well characterized, in Generalized Arterial Calcification of Infancy (GACI), a rare disease in which pathological calcification typically presents in infancy.
Objectives
This study aims to describe the clinical audiologic and otologic features and potential etiolog...
Citations
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The enzyme ectonucleotide pyrophosphatase/phosphodiesterase-1 ( ENPP1) codes for a type 2 transmembrane glycoprotein that hydrolyzes extracellular ATP to generate pyrophosphate (PP i ) and adenosine monophosphate, thereby contributing to downstream purinergic signaling pathways. The clinical phenotypes induced by ENPP1 deficiency are seemingly contradictory and include early-onset osteoporosis in middle-aged adults and life-threatening vascular calcifications in the large arteries of infants with generalized arterial calcification of infancy. The progressive overmineralization of soft tissue and concurrent undermineralization of skeleton also occurs in the general medical population, where it is referred to as paradoxical mineralization to highlight the confusing pathophysiology. This review summarizes the clinical presentation and pathophysiology of paradoxical mineralization unveiled by ENPP1 deficiency and the bench-to-bedside development of a novel ENPP1 biologics designed to treat mineralization disorders in the rare disease and general medical population.
Expected final online publication date for the Annual Review of Pathology: Mechanisms of Disease, Volume 19 is January 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
Loss‐of‐function variants in the ectonucleotide pyrophosphatase/phosphodiesterase family member 1 (ENPP1) cause ENPP1 Deficiency, a rare disorder characterized by pathological calcification, neointimal proliferation and impaired bone mineralization. The consequence of ENPP1 Deficiency is a broad range of age dependent symptoms and morbidities including cardiovascular complications and 50% mortality in infants, autosomal recessive hypophosphatemic rickets type 2 (ARHR2) in children, and joint pain, osteomalacia and enthesopathies in adults. Recent research continues to add to growing clinical presentation profile as well as expanding the role of ENPP1 itself. Here we review the current knowledge on the spectrum of clinical and genetic findings of ENPP1 Deficiency reported in patients diagnosed with GACI or ARHR2 phenotypes using a comprehensive database of known ENPP1 variants with associated clinical data. A total of 108 genotypes were identified from 154 patients. Of the 109 ENPP1 variants reviewed, 72.5% were demonstrably disease‐causing, a 3‐fold increase in pathogenic/likely pathogenic variants over other databases. There is substantial heterogeneity in disease severity, even among patients with the same variant. The approach to creating a continuously curated database of ENPP1 variants accessible to clinicians is necessary to increase the diagnostic yield of clinical genetic testing and accelerate diagnosis of ENPP1 Deficiency. This article is protected by copyright. All rights reserved.
