Childhood Cystic Fibrosis in the Era of Highly Effective Modulator Therapy: A Critical Narrative Review of Diagnosis, Multisystem Disease and Evolving Management

Congenital hepatic fibrosis and related ciliopathies across the life course: current management, disease burden, and unmet needs in the era of genomic diagnosis and translational therapeutics

Congenital hepatic fibrosis (CHF) is a rare autosomal recessive hepatobiliary developmental disorder characterised by extensive fibrosis of the portal tracts and ductal plate malformation, representing a significant cause of portal hypertension in children and adolescents. Despite its low incidence, the disease exhibits considerable clinical heterogeneity, ranging from asymptomatic presentations to severe complications of portal hypertension, thereby posing substantial diagnostic and management challenges. The long-term disease burden is profound, adversely affecting both quality of life and prognosis. Currently, clinical management focuses primarily on the surveillance and treatment of portal hypertensive complications, with a conspicuous absence of targeted therapies addressing the underlying disease processes. Furthermore, notable deficiencies persist in multidisciplinary coordination, individualised therapeutic strategies, and long-term follow-up frameworks. This review aims to comprehensively examine the pathophysiology, genetics, clinical manifestations, diagnostic approaches, complication management strategies, and therapeutic interventions pertaining to this condition. It systematically evaluates the associated disease burden and critically appraises the limitations of current diagnostic and treatment paradigms, as well as the unmet needs in clinical practice. Ultimately, this review seeks to provide critical insights and a theoretical framework to inform future research directions, optimise therapeutic regimens, and facilitate the development of integrated care models. Unlike previous reviews focusing mainly on pathology or case-based clinical presentation, this review emphasizes life-course management, patient burden, and translational gaps in the era of genomic diagnosis.

Year in Review: Cystic Fibrosis Modulator Therapy-Efficacy, Access, and Evolution.

A summary of recent literature pertaining to CFTR modulators is provided to enhance the knowledge of the growing body of evidence guiding the next era of CF care, in which disease modification at the molecular level is increasingly achievable.

Late-Diagnosed Cystic Fibrosis in an Octogenarian With an Atypical Phenotype of Pancreatic Sufficiency and Preserved Pulmonary Function

Cystic fibrosis (CF) was historically described as a severe childhood disease associated with pancreatic destruction, malnutrition, recurrent respiratory infection, and early mortality. Advances in sweat chloride testing, cystic fibrosis transmembrane conductance regulator (CFTR) gene discovery, newborn screening, multidisciplinary care, and CFTR modulator therapy have transformed the natural history of the disease. However, CF remains clinically heterogeneous, and patients with residual CFTR function may present later in life with chronic bronchiectasis, sinus disease, atypical respiratory infections, or nonspecific gastrointestinal symptoms. Diagnosis in advanced age is uncommon and may be delayed when pancreatic function is preserved and sweat chloride values are intermediate. An 87-year-old woman with late-diagnosed cystic fibrosis was followed longitudinally for chronic sinopulmonary disease. She had a history of recurrent sinus infections and was evaluated at a tertiary institution, where CF was diagnosed at approximately age 62. Her family history was notable for a maternal aunt who died from an unspecified respiratory illness. Diagnostic evaluation demonstrated an intermediate sweat chloride value of 41 mmol/L and CFTR testing showing one copy of F508del, M470V polymorphism, and a rare C76W variant. Her phenotype included chronic bronchiectasis, chronic sinusitis with nasal polyps, two prior sinus surgeries, and prior Mycobacterium avium complex infection treated in 1995. She had pancreatic sufficiency, with normal fecal elastase and no clinical response to pancreatic enzyme replacement therapy. Pulmonary function testing showed preserved lung function with stage I obstruction, including FEV1 1.33 L, 89% predicted; FVC 1.95 L, 85% predicted; and FEV1/FVC ratio of 68%, stable compared with the prior year. Her course was also notable for osteoporosis with prior vertebral compression fractures, which limited tolerance of vest-based airway clearance. Management included airway clearance with an oscillatory positive expiratory pressure device, individualized bronchodilator therapy due to tachycardia with albuterol, surveillance respiratory cultures, nutritional and weight monitoring, otolaryngology follow-up for chronic sinusitis and nasal polyps, osteoporosis management, and treatment with vanzacaftor/tezacaftor/deutivacaftor, to which she reported symptomatic improvement. This case highlights an uncommon late-diagnosed CF phenotype in an octogenarian with pancreatic sufficiency, intermediate sweat chloride, chronic sinopulmonary disease, preserved lung function, and new isolation of Pseudomonas aeruginosa. The case emphasizes that preserved pancreatic function and advanced age do not exclude CF and that adult patients with chronic bronchiectasis, sinus disease, and atypical respiratory infections should be evaluated for CFTR dysfunction when clinically appropriate.

Journal of Cystic Fibrosis

Familial pulmonary fibrosis: a UK consensus framework for the investigation and management of patients and their relatives.

Background: There is a growing recognition that genetic predisposition contributes to the development of fibrotic interstitial lung disease. Adult onset monogenic disease is most commonly due to dysfunctional telomere maintenance, with a small proportion caused by surfactant biology disorders. These conditions can be associated with additional intrapulmonary and extrapulmonary features which themselves may require surveillance or treatment, making it important to make a genetic diagnosis. The recent introduction in England of a genetic testing panel accessible to respiratory physicians means that genetic information for these individuals is increasingly available but there is currently little standardisation of the subsequent management of patients and their relatives, which can be complex.Aims: This consensus considers the causes and clinical features of familial pulmonary fibrosis and provides a suggested framework for genetic investigation and clinical management of both patients and their relatives.Narrative: We suggest an initial workup that may help identify those with monogenic disease, with focus on key points in the history and examination that may identify features of a telomere or surfactant biology disorder. We highlight that clinical and radiological presentations are diverse and discuss the importance of making a genetic diagnosis to inform multidisciplinary management and facilitate screening of close family members. We also discuss the many outstanding uncertainties and challenges, including the investigation and management of non-monogenic familial pulmonary fibrosis and the management of asymptomatic family members who have inherited a potentially disease-causing genetic variant.Conclusions: We suggest a pathway for the workup and management of patients with familial pulmonary fibrosis, aiming to standardise clinical care for patients and their relatives and provide a framework for the development of a national database to facilitate disease phenotyping and clinical research to improve the evidence base for clinical practice.

Comment on “Translating Emerging Data for Fetal Treatment of Cystic Fibrosis”

Cystic fibrosis (CF) is a multisystem genetic disease caused by pathogenic variants in the cystic fibrosis transmembrane receptor ( CFTR ) gene, leading to abnormal function in the lungs, pancreas, intestines, and other organs. CFTR modulators (CFTRm), small molecule therapies for CF, have significantly improved disease prognosis. As a result, more patients with CF can conceive, and pregnancy has become more common. While data surrounding CFTRm use during pregnancy are limited, the significant risk of untreated CF on maternal and pregnancy outcomes means that many patients opt to continue CFTRm during gestation. In addition, CF begins to manifest before birth, with potential in-utero complications like pancreatic injury and meconium ileus. This review article summarizes pregnancy safety data, animal studies, and emerging case reports with prenatal CFTRm therapy for fetuses affected by CF. Available data are generally reassuring for patients with CF who continue CFTRm during pregnancy. Continuation has been associated with preserved maternal lung function, while discontinuation has been linked in some cases to clinical decline that resolves when therapy is restarted. These medications can cross the placenta, with fetal levels equal to or higher than maternal levels, and are present at low levels in breastmilk. Some safety concerns remain, including rare hepatotoxicity, and complications seen in animal models include development of cataracts and drug accumulation in the fetal brain. However, in a CF ferret model, in utero ivacaftor prevented intestinal disease, preserved exocrine pancreatic function, and preserved the vas deferens in male offspring. This supports the possibility that treatment before birth could protect against some fetal CF manifestations. Human data on CFTRm during pregnancy remain limited but suggest possible fetal benefits. Twenty published cases describe prenatal CFTRm use in unaffected pregnant carriers whose fetuses were diagnosed with CF. Most received standard adult dosing of elexacaftor/tezacaftor/ivacaftor (Trikafta or triple therapy) after invasive prenatal diagnosis. Among 15 fetuses with meconium ileus who were treated through maternal CFTRm during pregnancy, ultrasound findings resolved before delivery in 10 cases. Findings were less likely to resolve when treatment began later or when complications such as volvulus, meconium peritonitis, or meconium pseudocyst were already present. Among published cases, the mean gestational age at diagnosis of meconium ileus was 23.8 weeks, while treatment began at a mean of 30.4 weeks, reflecting delays in diagnosis and access to therapy. Several reports also described preserved or borderline pancreatic function and lower-than-expected sweat chloride levels. Because prenatal treatment can reduce biochemical signs of pancreatic injury, newborn screening may be falsely negative, so infants with known prenatal CF diagnoses still need postnatal diagnostic evaluation. Prenatal CFTRm therapy is promising but remains investigational. Standardized guidelines for treatment have not been created, and care should include multidisciplinary counseling, genetic confirmation of fetal CF, maternal liver function monitoring, fetal ultrasound surveillance, and postnatal follow-up. Significant unanswered questions include the optimal timing of treatment, minimum effective dose, neurodevelopmental safety, and whether treatment should continue after birth to avoid withdrawal effects. Access is also a major ethical issue because therapy is expensive and insurance delays can push treatment later into gestation. Overall, the review suggests that prenatal CFTRm may prevent or improve fetal manifestations of CF, particularly meconium ileus, but prospective studies are needed before this approach can become routine care. (Summarized from Zaretsky MV, Blumenfeld YJ, Szentpetery SS, et al Translating emerging data for fetal treatment of cystic fibrosis. Prenat Diagn. 2026;46:417-423. doi:10.1002/pd.70098)