ABSTRACT
PURPOSE: Hardikar syndrome (HS, MIM #301068) is a female-specific multiple congenital anomaly syndrome characterized by retinopathy, orofacial clefting, aortic coarctation, biliary dysgenesis, genitourinary malformations, and intestinal malrotation. We previously showed that heterozygous nonsense and frameshift variants in MED12 cause HS. The phenotypic spectrum of disease and the mechanism by which MED12 variants cause disease is unknown. We aim to expand the phenotypic and molecular landscape of HS and elucidate the mechanism by which MED12 variants cause disease. METHODS: We assembled and clinically and molecularly characterized a cohort of 11 previously-unreported individuals with HS. We additionally studied the effect of MED12 deficiency on ciliary biology and hedgehog and YAP signaling, pathways implicated in diseases with phenotypic overlap with HS. RESULTS: We report novel phenotypes associated with HS, including cardiomyopathy, arrhythmia, and vascular anomalies and expand the molecular landscape of HS to include splice site variants. We additionally demonstrate that MED12 deficiency causes decreased cell ciliation and impairs hedgehog and YAP signaling. CONCLUSION: Our data support updating HS standard-of-care to include regular cardiac imaging, arrhythmia screening, and vascular imaging. We further propose that dysregulation of ciliogenesis and YAP and hedgehog signaling contributes to the pathogenesis of HS.
ABSTRACT
BACKGROUND: Approximately 60% of older adults complain of dry mouth, which may be associated with polypharmacy, common in this population. Existing studies have reported treatment approaches to dry mouth but do not address long-term preventative measures that would more positively benefit the health and well-being of older adults. OBJECTIVE: We aimed to explore the consequences of dry mouth, associated with polypharmacy, on the physical and psychological health of older adults in order to establish the importance of preventing dry mouth. METHODS: This systematic review was conducted of studies reporting health conditions of dry mouth, in relation to polypharmacy in older adults (aged ≥ 65 years). MEDLINE, EMBASE, PsycINFO and CINAHL databases were searched using keywords such as 'polypharmacy', 'dry mouth', 'oral health' and 'quality of life' (PROSPERO: CRD42021288945). Joanna Briggs Institute critical appraisal tools were used to assess study quality. RESULTS: Of the 6852 citations screened, nine studies (cross-sectional, n = 8; longitudinal, n = 1) were included that comprised 37,459 participants (mean age range 68.5-85.0 years). Studies were published between 2005 and 2019. Because of the heterogeneity of reported study outcomes, a narrative synthesis was undertaken. The health conditions identified in this review were categorised as 'physical' or 'psychological'. The main physical health conditions reported in the studies related to dental health, such as tooth loss, and functional impairments, such as swallowing difficulties. An increase in the number of medicines taken, from 0 to 5, decreased the number of natural teeth remaining from 16 (standard deviation [SD] ± 9) to 12 (SD ± 8), respectively. Additionally, the number of dental complications increased from 1 (SD ± 2) to 2 (SD ± 2) as the number of medicines increased from 1 to ≥ 3. There was a paucity of studies (n = 2) that investigated psychological health conditions of dry mouth among older adults, with depression identified as a significant issue among older adults with dry mouth (where the reported prevalence was as high as 64%). An additional six psychological health conditions were identified: self-consciousness, feeling tense, difficulty relaxing, irritability, difficulty completing tasks and feeling less satisfied in life. CONCLUSIONS: High levels of physical health conditions of dry mouth are observed in older adults and, to a lesser extent, psychological health conditions. These conditions can negatively affect quality of life. There remains a need to prevent dry mouth and the adverse health conditions associated with it in older adults. The modifiable nature of polypharmacy could be targeted to minimise, and potentially prevent, dry mouth. The optimisation of medication regimes to effectively treat chronic conditions, but also limit the likelihood of dry mouth, is a practical approach. Dry mouth prevention should be a priority and polypharmacy can pave the way for prevention strategies, avoiding the need to treat dry mouth.
