Adult lung study finds no diffuse fibrosis in Alström syndrome

Adults with Alström syndrome, an ultra-rare genetic disorder that affects many organs and typically shortens life to around 35 years, have long been assumed to carry widespread scarring in their lungs. A retrospective analysis of 46 adults followed for more than a decade at a nationally commissioned specialist clinic in Birmingham, United Kingdom, now challenges that assumption. Across high-resolution computed tomography (HRCT) scans of the thorax in 39 patients and post-mortem lung tissue from four deceased patients, the researchers found no evidence of diffuse interstitial pulmonary fibrosis in a single case, a result that directly contradicts the long-standing view that fibrosis in the lungs, liver, kidneys, pancreas and testes is a hallmark of the disease.

Alström syndrome was first described by Carl-Henry Alström in Sweden in 1959. It is caused by mutations in the ALMS1 gene, which encodes a 461-kilodalton protein located on the basal body of primary cilia, placing the condition among the ciliopathies. More than 200 pathogenic variants have been described, most of them nonsense or frameshift changes clustered in exons 8, 10 and 16.

Because ALMS1 is expressed almost everywhere in the body, the syndrome produces retinal degeneration, cardiomyopathy, hearing loss, chronic kidney disease, metabolic syndrome and accelerated fatty liver disease, alongside recurrent chest infections and episodes of severe, sometimes unexplained hypoxia. Respiratory illness, particularly severe community-acquired pneumonia and cardiovascular events, is among the leading causes of premature death. Despite this burden, lung involvement in adults had never been systematically studied.

The limited existing data came mainly from a cross-sectional study of children, which reported recurrent otitis media in 92 percent, bronchitis or pneumonia in 61 percent, sinusitis in 50 percent and chronic cough in 42 percent of 38 children. The new study, based on patients regularly reviewed at Queen Elizabeth Hospital in Birmingham between 2010 and 2024, set out to characterise respiratory involvement in adults and to determine whether diffuse pulmonary fibrosis is truly a major pathological feature of the disease. The cohort comprised 46 adults aged 18 to 69 with genetically confirmed Alström syndrome, 29 males and 17 females, of whom 11 had died during follow-up.

The clinical picture reflected the multisystem nature of the condition: 86 percent had diabetes, 70 percent hypertension, 43 percent cardiomyopathy, 40 percent a history of infantile cardiomyopathy, 46 percent recurrent childhood respiratory infections, 24 percent childhood asthma and 26 percent some degree of kyphoscoliosis. All patients underwent genetic testing for ALMS1 pathogenic variants, although complete characterisation of both allelic variants was unavailable for 11 of the 46 patients. Lung function testing proved unexpectedly difficult.

Although 41 of the 46 patients, or 89 percent, attempted pulmonary function tests, nearly half of them, 19 of 41, could not complete any of the tests, including spirometry, lung volume measurement and gas transfer assessment. Only 21 patients completed spirometry, 18 completed lung volume testing and 15 completed transfer factor measurement. The researchers attribute this striking failure rate partly to apraxia, particularly ideomotor apraxia, which has been described in Alström syndrome, and partly to the dual sensory loss of vision and hearing that makes it hard for patients to coordinate their breathing with the demands of the testing equipment.

The same difficulties likely explain why breathing artefact was the most common finding on HRCT scans, reported in just over half of the scanned patients. Among those who could complete the tests, the results pointed away from intrinsic lung disease. The mean forced expiratory volume in one second, expressed as a percentage of the predicted value, was 66 plus or minus 15, and 67 percent of those tested had an abnormal spirometry result, generally a mild restrictive defect.

Total lung capacity was abnormal in 72 percent of those measured, averaging 73 percent predicted. That combination indicates extrapulmonary restriction, in which factors outside the lung tissue, rather than scarring within it, limit lung expansion. The imaging and post-mortem findings reinforced this interpretation.

Of the 39 patients with HRCT scans, most had normal results apart from breathing artefact; three had minimal scarring, two had ground glass opacities, one localised and the other diffuse and attributable to heart failure, and one had minimal fibrotic bands confined to the periphery of the left lung. Diffuse interstitial fibrosis was found in none of the patients, including the 10 whose scans were free of breathing artefact altogether. Post-mortem lung tissue was available from four patients who died at ages 33, 40, 39 and 58, of pneumonia in two cases, of cardiomyopathy and heart-lung transplant complications in one, and of pulmonary thromboembolism in one.

Histological examination, including haematoxylin and eosin and Elastic Van Gieson staining, identified no diffuse fibrosis, honeycombing or remodelling in any of these lungs, including the explanted native lung from the transplant patient. One intriguing risk factor emerged from the lung function data. Patients with a history of infantile cardiomyopathy showed significantly lower forced expiratory volume in one second, forced vital capacity, total lung capacity and transfer factor as adults, although the proportions of abnormal results did not differ significantly between groups, and no difference was seen according to current cardiomyopathy status, childhood infections, asthma or kyphoscoliosis.

The subgroup comparisons rested on very small numbers, for example three to five patients with a history of infantile cardiomyopathy for each parameter, so the authors urge caution. Longitudinal data from repeated assessments in individual patients showed no consistent pattern of progressive decline across the cohort, although individual variability was evident. The cardiac catheterisation findings in six patients who underwent right and left heart catheterisation for clinical and echocardiographic evidence of pulmonary hypertension add an important dimension.

These patients had a mean pulmonary artery pressure of 46 mm Hg against a normal range of 9 to 18, a mean pulmonary capillary wedge pressure of 23 mm Hg against a normal of 6 to 12, a left ventricular end diastolic pressure of 21 mm Hg, a reduced cardiac output of 3.1 litres per minute and a cardiac index of 1.7 litres per minute per square metre. Only one patient had severe valvular heart disease, mitral regurgitation. The pattern of high pulmonary artery pressures with reduced cardiac output alongside a markedly raised wedge pressure suggests that left heart disease from restrictive cardiomyopathy is the main driver of pulmonary hypertension in this subset of adults with Alström syndrome, rather than primary lung pathology.

The authors propose that the severe hypoxia seen during minor illnesses and metabolic stress in these patients arises not from fibrotic lungs but from a combination of increased oxygen demand during infection and a diminished pulmonary vascular reserve, possibly reflecting vascular dysfunction or microthrombosis, which limits the ability to raise pulmonary blood flow and gas transfer. This mechanism may also explain why two patients aged 39 and 40 developed acute respiratory distress syndrome during pneumonia, a condition usually seen in the elderly or immunocompromised. The study's limitations are substantial: the ultra-rarity of the disease restricted the sample size, not all patients could complete all assessments, and subgroup analyses had limited statistical power.

Respiratory assessment in adults with Alström syndrome should focus on pulmonary function, cardiopulmonary complications and pulmonary hypertension rather than assuming diffuse pulmonary fibrosis, allowing surveillance and management to be directed at the complications that actually threaten these patients' lives.

Subject of Research: Respiratory involvement and the absence of diffuse lung fibrosis in adults with Alström syndrome

Article Title: The lungs in Alström syndrome: a retrospective analysis

Article References: Madathil, S. C., Zhang, Q., & Geberhiwot, T. (2026). The lungs in Alström syndrome: a retrospective analysis. eClinicalMedicine, 101, Article 104292. https://doi.org/10.1016/j.eclinm.2026.104292

Image Credits: AI Generated

DOI: 10.1016/j.eclinm.2026.104292

Keywords: Alström syndrome, ALMS1, pulmonary fibrosis, lung function testing, high-resolution CT, pulmonary hypertension, cardiomyopathy, ciliopathy, retrospective study, hypoxia, rare disease, lungs