Genetic and phenotypic spectrum in the NONO-associated syndromic disorder

The non-POU domain-containing octamer-binding (NONO) protein is involved in multiple steps of gene regulation such as RNA metabolism and DNA repair. Hemizygous pathogenic variants in the NONO gene were confirmed to cause a rare X-linked syndromic disorder. Through our in-house diagnostics and subsequent matchmaking, we identified six unrelated male individuals with pathogenic or likely pathogenic NONO variants. For a detailed comparison, we reviewed all published characterizations of the NONO-associated disorder. The combined cohort consists of 16 live-born males showing developmental delay, corpus callosum anomalies, non-compaction cardiomyopathy and relative macrocephaly as leading symptoms. Seven prenatal literature cases were characterized by cardiac malformations. In this study, we extend the phenotypic spectrum through two more cases with epilepsy as well as two more cases with hematologic anomalies. By RNA expression analysis and structural modeling of a new in-frame splice deletion, we reinforce loss-of-function as the pathomechanism for the NONO-associated syndromic disorder.     

Acute effects of lithium augmentation on the kidney in geriatric compared with non-geriatric patients with treatment-resistant depression

Introduction

Lithium augmentation (LA) of antidepressants is a first-line therapy option for treatment-resistant depression (TRD). Nevertheless, it is rarely used in geriatric patients mostly because of the fear of kidney toxicity. The purpose of this study is to investigate estimated glomerular filtration rate (eGFR) changes and number of acute kidney injuries (AKI) using LA in geriatric compared with non-geriatric patients.

Methods

In a prospective multicenter cohort study, eGFR changes were measured in 201 patients with unipolar depression (n_{age≥65years} = 29; n_age<65years = 172) at baseline and over 2–6 weeks of LA. We used linear mixed models to investigate changes in eGFR upon LA and assessed the number of AKIs, according to the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines.

Results

Both age groups showed a significant eGFR decline over the course of treatment with lower eGFR in geriatric patients. The lithium serum level (interpretable as “effect of LA”) had a significant effect on eGFR decline. Both effects (age group and lithium serum level) on eGFR decline did not influence each other, meaning the effect of LA on eGFR decline did not differ between age groups. Two AKIs were observed in the geriatric age group when serum lithium levels exceeded the therapeutic range of >0.8 mmol/L.

Conclusion

This is the first study investigating eGFR change and AKI upon LA for TRD in geriatric compared with non-geriatric patients. Our data suggest that LA, as an effective treatment option in geriatric patients, should be closely monitored to avoid AKIs.     

Neutrophilic dermatoses – Pathomechanistic concepts and therapeutic developments

Neutrophilic dermatoses are a group of clinically heterogeneous diseases characterized by infiltration of neutrophils in the affected tissue. Skin symptoms comprise a spectrum of wheals, papules, plaques, pustules, nodules and ulcerations often in combination with systemic symptoms. Although the pathogenesis of these diseases has not yet been elucidated in depth, broad pathophysiological and clinical overlaps exist with autoinflammatory syndromes. Additionally, recent years have shown the relevance of the signaling pathways of TNF-α, IL-1, IL-12/23 and IL-17 in neutrophilic dermatoses. In this review, we present four selected neutrophilic dermatoses, namely pyoderma gangraenosum, Sweet syndrome, generalized pustular psoriasis and Schnitzler syndrome, discuss pathophysiological aspects and specifically address novel therapeutic options derived from the most recent pathophysiological findings.     

MPO-ANCA-positive granulomatosis with polyangiitis and concurrent IgG4-related disease with periaortitis and tubulointerstitial nephritis: A case report of a new overlap syndrome?

Immunoglobulin G4-related disease (IgG4-RD) is a fibroinflammatory condition that was first recognized as a unique disease entity in the early 2000s. Its diagnosis is based on specific pathologic, serologic, and clinical features, and the exclusion of several differential diagnoses, such antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). However, emerging evidence suggests that these 2 conditions may overlap in some cases. Here, we report a new case of overlapping IgG4-RD and AAV. The patient was diagnosed with IgG4-RD owing to the presence of periaortitis and IgG4 positive tubulointerstitial nephritis. Myeloperoxidase (MPO)-ANCA positivity, chronic paranasal sinusitis, and glomerulonephritis with granuloma led to a concurrent diagnosis of MPO-ANCA-positive granulomatosis with polyangiitis. Our case supports the hypothesis that diagnoses of IgG4-RD and AAV are not mutually exclusive but can overlap. It can be assumed that an overlap with IgG4-RD typically affects the granulomatous form of AAV, suggesting a common pathophysiological pathway for these 2 conditions.     

Maternal stress during pregnancy and gestational duration: A cohort study from the Danish National Birth Cohort

Background

Preterm birth is one of the most important contributors to neonatal mortality and morbidity. Experiencing stress during pregnancy may increase the risk of adverse birth outcomes, including preterm birth. This association has been observed in previous studies, but differences in measures used limit comparability.

Objective

The objective of the study was to investigate the association between two measures of maternal stress during pregnancy, life stress and emotional distress, and gestation duration.

Methods

Women recruited in the Danish National Birth Cohort from 1996 to 2002, who provided information on their stress level during pregnancy and expecting a singleton baby, were included in the study. We assessed the associations between the level of life stress and emotional distress in quartiles, both collected at 31 weeks of pregnancy on average, and the rate of giving birth using Cox regression within intervals of the gestational period.

Results

A total of 80,991 pregnancies were included. Women reporting moderate or high levels of life stress vs no stress had a higher rate of giving birth earlier within all intervals of gestational age (e.g. high level: 27–33 weeks: hazard ratio (HR) 1.38, 95% confidence interval (CI) 1.04, 1.84; 34–36 weeks: 1.10, 95% CI 0.97, 1.25; 37–38 weeks: 1.21, 95% CI 1.15, 1.28). These associations between life stress and preterm birth were mainly driven by pregnancy worries. For emotional distress, a high level of distress was associated with shorter length of gestation in the preterm (27–33 weeks: 1.38, 95% CI 1.02, 1.86; 34–36 weeks: 1.05, 95% CI 0.91, 1.19) and early term (1.11, 95% CI 1.04, 1.17) intervals.

Conclusions

Emotional distress and life stress were shown to be associated with gestational age at birth, with pregnancy-related stress being the single stressor driving the association. This suggests that reverse causality may, at least in parts, explain the earlier findings of stress as a risk factor for preterm birth.