Characterization of hearing-impairment in Generalized Arterial Calcification of Infancy (GACI)

Abstract

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 etiology of hearing impairment in GACI and gain pathophysiological insight from a murine model of GACI.

Design: Cross-sectional cohort study of individuals with GACI. Murine ossicle micromorphology of the ENPP1^asj/asj mutant compared to wild-type.

Setting: Clinical research hospital; basic science laboratory.

Participants: Nineteen individuals with GACI who met clinical, biochemical, and genetic criteria for diagnosis.

Main outcomes and measures: Clinical, biochemical, and radiologic features associated with hearing status.

Results: Pure-tone thresholds could be established in 15 (n = 30 ears) of the 19 patients who underwent audiological assessments. The prevalence of HL was 50% (15/30) of ears, with conductive HL in 80% and sensorineural HL in 20%. In terms of patients with HL (n = 8), seven patients had bilateral HL and one patient had unilateral HL. Degree of HL was mild to moderate for 87% of the 15 ears with hearing loss. Of those patients with sufficient pure-tone and middle ear function data, 80% (8/10) had audiometric configurations suggestive of ossicular chain dysfunction (OCD). Recurrent episodes of otitis media (ROM) requiring pressure-equalizing tube placement were common. In patients who underwent cranial CT, 54.5% (6/11) had auricular calcification. Quantitative backscattered electron imaging (qBEI) of murine ossicles supports an OCD component of auditory dysfunction in GACI, suggesting loss of ossicular osteocytes without initiation of bone remodeling.

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 ossicular chain and/or recurrent otitis media. Clinically, this study highlights the importance of early audiologic and otologic evaluation in persons with GACI. Novel findings of high rates of OCD and ROM may inform management, and in cases of unclear HL etiology, dedicated temporal bone imaging should be considered.

Trial registration: ClinicalTrials.gov NCT00369421 NCT00024804.

Fig. 1

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

Fig. 2

Temporal bone CT images of GACI patients. Abnormal findings (A–D) in the 25-year-old GACI patient, including an axial view of (A) an abnormal malleus and incus in the left ear (white arrow), a coronal view of a (B) left-sided high-riding jugular bulb with diverticulum (blue arrow), and axial views of (C) right and (D) left calcified stapes footplate (encircled). Abnormal findings (E–F) in the 35-year-old GACI patient were bilateral auricular calcifications (white arrows) and bilateral enlarged vestibular aqueduct (arrowheads)

Fig. 3

Micromorphology of murine mallei from Enpp1^asj/asj mutant mice. A Mallei evaluated by qBEI showed no differences in B mean calcium content (or Ca_Mean; p = 0.877) but showed statistically significant decreases in C mineralization heterogeneity (or Ca_Width; p = 0.038), D number of osteocyte lacunae per bone area (N.Ot.Lc/B.Ar) (p = 0.004), and E mean osteocyte lacunae area (p = 0.004). For the incus and stapes ossicles, please refer to Additional file 1: Figures S1 and S2