Loss-of-function variants in AP3D1 have been linked to Hermansky–Pudlak syndrome (HPS) 10, a severe multisystem disorder characterized by oculocutaneous albinism, immunodeficiency, neurodevelopmental delay, hearing loss (HL), and neurological abnormalities, fatal in early childhood. Here, we report a consanguineous family who presented with presumably isolated autosomal recessive (AR) HL. Whole-exome sequencing was performed on all core family members, and selected patients were screened using array-based copy-number analysis and karyotyping. Candidate variants were validated by Sanger sequencing and assessed in silico. A homozygous, likely pathogenic p.V711I missense variant in AP3D1 segregated with the HL. The family was characterized by thorough medical and laboratory examination. The HL was consistent across patients and accompanied by neurological manifestations in two brothers. The sole female patient was diagnosed with premature ovarian failure. Further findings, including mild neutropenia and reduced NK-cell cytotoxicity in some as well as brain alterations in all homozygous patients, were reminiscent of HPS10, though milder and lacking the characteristic albinism. Previously unrecognized, milder, isolated HL was identified in all heterozygous carriers. A protein model indicates that the variant interferes with protein–protein interactions. These results suggest that a missense variant alters inner-ear-specific functions leading to HL with mild HPS10-like symptoms of variable penetrance. Milder HL in heterozygous carriers may point towards semi-dominant inheritance of this trait. Since all previously reported HPS10 cases were pediatric, it is unknown whether the observed primary ovarian insufficiency recapitulates the subfertility in Ap3d1-deficient mice.
BackgroundClimate change has been associated with a higher frequency of extreme weather events, resulting in an overall increase in morbidity and mortality. Acute otitis media (AOM) is one of the most common otolaryngological infections and accounts for 1.5% of emergency department visits. This study aimed to identify associations between extreme weather events and the immediate and delayed risks for AOM-related emergency department visits (EV).MethodsA total of 1,465 AOM-related EVs were identified in the Vienna General Hospital between 2015 and 2018. A distributed lag non-linear model was applied to evaluate the relationship between extreme weather conditions and the total number of AOM-related EVs per day. The relative risk (RR) and cumulative RR (cRR) of single-day events and extended weather events over three days were analyzed over a lag period of 14 days.ResultsAOM-related EVs showed a pronounced seasonality, with the highest occurrence during winter. Single-day weather events affected AOM-related EVs only at high relative humidity. Prolonged extreme weather conditions over three days, however, significantly increased the cRR for AOM-related EVs to 3.15 [1.26–7.88; p = 0.014] and 2.14 [1.14–4.04; p = 0.018] at mean temperatures of −4°C (1st-percentile - p1) and 0°C (p5) on the same day. Relative humidity of 37% (p1) decreased RR to 0.94 [0.88–0.99; p = 0.032] on day 7, while extremely high humidity of 89% (p99) led to an increased cRR of 1.43 [1.03–2.00; p = 0.034] on day 7. Heavy prolonged precipitation of 24mm (p95) reduced cRR beginning day 4 up until day 14 to 0.52 [0.31–0.86; p = 0.012]. Prolonged low atmospheric pressure events of 985hPa (p5) reduced the RR to 0.95 [0.91–1.00; p = 0.03], whereas extremely high atmospheric pressure events of 1013hPa (p99) increased the RR to 1.11 [1.03–1.20; p = 0.008]. Extremely low wind speeds significantly diminished the RR of AOM-related EVs.ConclusionsWhile single-day extreme weather events had little impact on the occurrence of AOM-related EVs, extended periods of extreme temperatures, relative humidity, precipitation, wind speeds and atmospheric pressure significantly impacted the RR for AOM-related EVs. These findings could help improve healthcare resource allocation in similar climates and aid in educating patients about the role of environmental factors in AOM.
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