Clinical, radiological and histopathological features of patients with familial pulmonary fibrosis.

BACKGROUND: In familial pulmonary fibrosis (FPF) at least two biological relatives are affected. Patients with FPF have diverse clinical features. RESEARCH QUESTION: We aimed to characterize demographic and clinical features, re-evaluate high-resolution computed tomography (HRCT) scans and histopathology of surgical lung biopsies, assess survival and investigate the suitability of risk prediction models for FPF patients. STUDY DESIGN: A retrospective cohort study. METHODS: FPF data (n = 68) were collected from the medical records of Oulu University Hospital (OUH) and Oulaskangas District Hospital between 1 Jan 2000 and 11 Jan 2023. The inclusion criterion was pulmonary fibrosis (PF) (ICD 10-code J84.X) and at least one self-reported relative with PF. Clinical information was gathered from hospital medical records. HRCT scans and histology were re-evaluated. RESULTS: Thirty-seven (54.4%) of the patients were men, and 31 (45.6%) were women. The mean ages of the women and men were 68.6 and 61.7 years, respectively (p = 0.003). Thirty-seven (54.4%) patients were nonsmokers. The most common radiological patterns were usual interstitial pneumonia (UIP) (51/75.0%), unclassifiable (8/11.8%) and nonspecific interstitial pneumonia (NSIP) (3/4.4%). Pleuroparenchymal fibroelastosis (PPFE) was observed as a single or combined pattern in 13.2% of the patients. According to the 2022 guidelines for idiopathic pulmonary fibrosis (IPF), the patients were categorized as UIP (31/45.6%), probable UIP (20/29.4%), indeterminate for UIP (7/10.3%) or alternative diagnosis (10/14.7%). The histopathological patterns were UIP (7/41.2%), probable UIP (1/5.9%), indeterminate for UIP (8/47.2%) and alternative diagnosis (1/5.9%). Rare genetic variants were found in 9 patients; these included telomerase reverse transcriptase (TERT, n = 6), telomerase RNA component (TERC, n = 2) and regulator of telomere elongation helicase 1 (RTEL1, n = 1). Half of the patients died (n = 29) or underwent lung transplantation (n = 5), with a median survival of 39.9 months. The risk prediction models composite physiology index (CPI), hazard ratio (HR) 1.07 (95.0% CI 1.04-1.10), and gender-age-physiology index (GAP) stage I predicted survival statistically significantly (p<0.001) compared to combined stages II and III. CONCLUSIONS: This study confirmed the results of earlier studies showing that FPF patients' radiological and histopathological patterns are diverse. Moreover, radiological and histological features revealed unusual patterns and their combinations.

Brain MRI findings in paediatric genetic disorders associated with white matter abnormalities.

AIM: To describe the specific brain magnetic resonance imaging (MRI) patterns of the paediatric genetic disorders associated with white matter abnormalities in Northern Finland. METHOD: In this retrospective population-based longitudinal study, brain MRI scans accumulated from 1990 to 2019 at Oulu University Hospital, Finland, were assessed. Inclusion criteria were defined as leukodystrophies or genetic diseases with significant white matter abnormalities that did not meet the criteria for leukodystrophy, at least one brain MRI, and age under 18 years at diagnosis. RESULTS: A total of 83 patients (48 males, 35 females) were found with 52 different diseases. The median age at the time of the brain MRI was 22 months (interquartile range [IQR] = 46 months). In 72 (87%) of the children, brain MRIs revealed abnormal findings, including cerebral white matter abnormalities (n = 49, 59%), brainstem signal abnormalities (n = 28, 34%), thinning of the corpus callosum (n = 30, 36%), delayed myelination (n = 11, 13%), and permanent hypomyelination (n = 9, 11%). INTERPRETATION: Symmetrical and bilateral white matter signal patterns of the brain MRI should raise suspicion of genetic disorders when the clinical symptoms are compatible. This study illustrates brain imaging patterns of childhood-onset genetic disorders in a population in Northern Finland and improves the diagnostic accuracy of rare genetic disorders.

Evidence for the additivity of rare and common variant burden throughout the spectrum of intellectual disability.

Intellectual disability (ID) is a common disorder, yet there is a wide spectrum of impairment from mild to profoundly affected individuals. Mild ID is seen as the low extreme of the general distribution of intelligence, while severe ID is often seen as a monogenic disorder caused by rare, pathogenic, highly penetrant variants. To investigate the genetic factors influencing mild and severe ID, we evaluated rare and common variation in the Northern Finland Intellectual Disability cohort (n = 1096 ID patients), a cohort with a high percentage of mild ID (n = 550) and from a population bottleneck enriched in rare, damaging variation. Despite this enrichment, we found only a small percentage of ID was due to recessive Finnish-enriched variants (0.5%). A larger proportion was linked to dominant variation, with a significant burden of rare, damaging variation in both mild and severe ID. This rare variant burden was enriched in more severe ID (p = 2.4e-4), patients without a relative with ID (p = 4.76e-4), and in those with features associated with monogenic disorders. We also found a significant burden of common variants associated with decreased cognitive function, with no difference between mild and more severe ID. When we included common and rare variants in a joint model, the rare and common variants had additive effects in both mild and severe ID. A multimodel inference approach also found that common and rare variants together best explained ID status (ΔAIC = 16.8, ΔBIC = 10.2). Overall, we report evidence for the additivity of rare and common variant burden throughout the spectrum of intellectual disability.