The lungs in Alström syndrome: a retrospective analysis

Summary

Background

Alström syndrome (AS) is a rare multisystemic disorder frequently associated with respiratory complications, which are a major cause of premature death. While fibrosis in multiple organs has been historically suggested as a hallmark of AS, including the lungs, definitive evidence in adult patients remains limited.

Methods

We conducted a retrospective study of adult patients diagnosed as AS seen in our National Multidisciplianry AS clinic from 2010 to 2024. Lung function test and high-resolution computed tomography (HRCT) of the thorax was performed in a subset of patients. Postmortem lung tissue analysis was available from four patients.

Findings

A total of 25/41 (61%) of the patients were unable to complete full lung function testing. Among those who did, 67% exhibited reduced lung volumes, with 47% showing decreased diffusing capacity of the lung for carbon monoxide but normal or elevated transfer coefficient for carbon monoxide, indicating extrapulmonary restrictive physiology. HRCT scans in 39 patients showed no evidence of diffuse interstitial lung fibrosis; however, breathing artefacts were common. Historical infantile cardiomyopathy was identified as a risk factor for adult pulmonary dysfunction. Post-mortem pathology reports were obtained from four patients and no diffuse fibrosis in the lung tissue was identified in any of the patients. Pulmonary hypertension and Acute Respiratory Distress Syndrome were identified as potential causes of respiratory morbidity and mortality, despite the absence of intrinsic interstitial lung disease.

Interpretation

This is the first large cohort study to depict the lung in adult patients with AS. This study provides no evidence for diffuse interstitial lung fibrosis in adult patients with AS, challenging prior assumptions. Pulmonary dysfunction appears mainly due to extrapulmonary restrictive physiology, with infantile cardiomyopathy as a possible risk factor. Pulmonary hypertension and acute respiratory distress syndrome, rather than intrinsic lung disease, likely underlie respiratory morbidity and mortality, highlighting the need for focused cardiopulmonary care. Although this study represents one of the largest single-centre cohorts of patients with AS reported to date, the overall sample size remains limited due to the ultra-rare nature of the disease and findings should be interpreted with caution.

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Research in context.

Evidence before this study

Alström syndrome (AS) is a rare multisystemic disorder frequently associated with respiratory complications, which are a major cause of premature death. However, there is a dearth of published literature about lung involvement in AS especially in adults. While fibrosis in multiple organs like liver, kidneys, testis, pancreas and lungs has been historically suggested as a hallmark of AS (Marshall et al., 2005), definitive evidence in adult patients remains limited.

Added value of this study adds

We conducted a retrospective study of adult patients regularly followed up in a large nationally commissioned highly specialised AS clinic. Apart from comprehensive multidisciplinary clinical evaluation, lung function testing in a subset of patients and high-resolution computed tomography (HRCT) of the thorax in most patients were performed. Postmortem lung tissue analysis was available from four patients.

Implications of all the available evidence

Our study highlights the difficulties with pulmonary function testing in AS patients and is the first study to find that diffuse lung fibrosis is not a major finding in AS as evidenced by high resolution CT Thorax in most patients. Our findings suggest that respiratory assessment in adults with Alström syndrome should focus on pulmonary function, cardiopulmonary complications, and pulmonary hypertension rather than assuming the presence of diffuse pulmonary fibrosis, thereby facilitating more appropriate surveillance and management. Although this study represents one of the largest single-centre cohorts of patients with AS reported to date, the overall sample size remains limited due to the ultra-rare nature of the disease and findings should be interpreted with caution.

Introduction

Alström syndrome (AS) is an ultra-rare autosomal recessive disease with multi organ involvement, described in literature for the first time by Carl-Henry Alström from Sweden in 1959.1, 2 It is estimated to have a prevalence of one per million of the population with over 1200 individuals known worldwide.2, 3 It is caused by mutations in the ALMS1 gene with pathogenic variants clustered in exons 8, 10 and 16.³ Over 200 pathogenic variants have been described to date with majority being nonsense or frameshift changes either in the form of insertions or deletions.3, 4

ALMS1 encodes a 461-kDa protein, which is located on the basal body of primary cilia, therefore linking it to ciliopathies.5, 6 Given the ubiquitous expression of ALMS1, multiple organ systems are affected with an array of clinical manifestations, typically beginning in infancy that continue to progress through adulthood leading to premature morbidity and mortality. This includes retinal degeneration, cardiomyopathies either as an infant or adult onset, recurrent chest infection with sometimes unexplained severe hypoxia, chronic kidney disease progressing to end stage renal failure7, 8 hearing loss, metabolic syndrome and its attendant complications including accelerated non-alcoholic fatty liver disease.

Given the multitude of organ involvement in the syndrome it is a life limiting condition leading to premature death with average life expectancy of around 35 years. The two main causes of death in AS are attributed to severe community acquired pneumonia or cardiovascular events. In addition, AS in adult is often characterised by severe hypoxia following a minor illness or any metabolic stressors. Despite all these, respiratory manifestations have not been well described apart from limited data mainly based on cross sectional study of children.⁹ To the best of our knowledge, there are no published longitudinal and systematic study of respiratory manifestations in adult AS. This series comprehensively evaluated the respiratory system in adult AS including clinical evaluation, lung function tests, and high-resolution computed tomography (HRCT) based on over 10 years of follow-up as well as postmortem studies of human lung tissues. The primary objective of this study was to systematically characterise respiratory involvement in adults with AS and to determine whether diffuse pulmonary fibrosis represents a major pathological feature of the disease.

Methods

Clinical, biochemical, and imaging assessment

All patients were followed up regularly in a nationally commissioned highly specialised clinic from 2010 to 2024 for AS in Queen Elisabeth Hospital in Birmingham, United Kingdom.¹⁰ At each clinic visit, patients underwent clinical and biochemical evaluation, and lung function test (including spirometry, lung volume testing and gas transfer test) where possible. Almost all patients had a one-off HRCT scan of the thorax. Clinical data including presence of asthma, kyphoscoliosis, cardiomyopathy, diabetes, hypertension, hepatic fibrosis, and past medical history about childhood asthma, childhood recurrent respiratory infections, infantile cardiomyopathy were collected from electronic patient records. Detailed clinical history of infancy and childhood (including the presence or absence of infant cardiomyopathy) was available for a subgroup of patients. The exact number of patients for whom these data were available, along with the group sizes for each lung function parameter, is reported in Table 1. All patients underwent genetic testing for ALMS1 pathogenic variants (Table S1) and had a confirmed diagnosis of AS based on genetic findings and/or major diagnostic criteria.⁵ Complete characterisation of both ALMS1 allelic variants was unavailable for 11 of the 46 patients (24%).

Table 1.

Baseline characteristics of patients with AS.

Characteristics (n = 46)	Value
Age (y, mean ± SD)	33.78 ± 8.97
Gender	29M/17F
Height (cm, mean ± SD)	159 ± 9
Weight (kg, mean ± SD)	82 ± 24
BMI (kg/m2, mean ± SD)	31.5 ± 7.0
Deceased, n (%)	11 (24)
History of childhood recurrent infections, n/N (%)	18/39 (46)
History of infantile cardiomyopathy, n/N (%)	15/38 (40)
History of asthma, in childhood, n/N (%)	9/37 (24)
Presence of cardiomyopathy, n/N (%)	19/44 (43)
Presence of asthma, n/N (%)	9/36 (25)
Kyphoscoliosis, n/N (%)	11/43 (26)
Diabetes, n/N (%)	37/43 (86)
Hypertension, n/N (%)	30/43 (70)
Lung function
FEV1pp, %, n/N (%)a	66 ± 15, 14/21 (67%)
FVCpp, %, n/N (%)a	65 ± 16, 16/21 (76%)
FEV1/FVC ratio, %, n/N (%)a	100 ± 14, 1/21 (5%)
TLCpp, %, n/N (%)a	73 ± 14, 13/18 (72%)
TLCOpp, %, n/N (%)a	69 ± 22, 7/15 (47%)
KCOpp,%, n/N (%)a	98 ± 30, 1/12 (8%)

FEV₁pp, forced expiratory volume in 1 s percent predicted; FVCpp, forced vital capacity percent predicted; TLCpp, total lung capacity percent predicted; TLCOpp, the transfer factor for carbon monoxide percent predicted; KCO, carbon monoxide transfer coefficient.

Abnormality was defined as a value below the lower limit of normal (LLN) based on GLI-derived reference values. For FEV1, FVC, TLC, TLCO, and KCO, values with a standardised residual (SR) < −1.645 were classified as abnormal. For the FEV1/FVC ratio, abnormality was defined as <70%.

^an/N (%), number of patients who have abnormal result of lung function.

Lung tissue obtained was fixed in 10% neutral-buffered formalin, routinely processed, and embedded in paraffin. Sections were prepared and stained with haematoxylin and eosin for general histological assessment and Elastic Van Gieson stain for evaluation of elastic fibres and vascular architecture. Histological examination was performed by an experienced pathologist using standard light microscopy.

Ethics

Study approval including post-mortem study approval from the National Research Ethics Committee was sought (REC Reference 22/WM/0035 & RGT/1/010332749) and all patients or their next of kin were informed and consented to participate in the study.

Role of funding source

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Statistical analysis

Quantitative data are presented as mean ± standard deviation (SD), and categorical data as frequency (%). Comparisons of continuous variables were performed using the independent-samples t-test or non-parametric tests, as appropriate according to data distribution. Categorical variables were compared using the chi-square test or Fisher's exact test, as appropriate. Given the small sample sizes in some subgroups, pulmonary function parameters between patients with and without a history of infantile cardiomyopathy were compared using the Mann–Whitney U test. Fisher's exact test was used to compare the proportions of abnormal pulmonary function parameters between patients with and without a history of infant cardiomyopathy. Statistical analyses were performed using SPSS version 25.0 (IBM Corp., Armonk, NY, USA) and GraphPad Prism version 9 (GraphPad Software, San Diego, CA, USA). All tests were two-sided, and P < 0.05 was considered statistically significant.

Results

Clinical characteristics of patients with AS

A total of 46 adult AS patients aged 18–69 years old with confirmed AS were recruited to this study. There were 29 males and 17 females and 11 of them have unfortunately deceased. 37/43 (86%) patients had diabetes and 30/43 (70%) patients were diagnosed to have hypertension. 9/37 (24%) of the patients had a history of childhood asthma. 18/39 (46%) patients had recurrent childhood respiratory infections. About a quarter of these patients had some degree of kyphoscoliosis (26%). 19/44 (43%) patients had cardiomyopathy and 15/38 (40%) had history of infantile cardiomyopathy.

Lung function

Totally, 41/46 (89%) patients underwent lung function test. However, 46% (19/41) of the patients could not complete any of the lung function test including spirometry, lung volume test, and gas transfer test. 21/41 (51%) could do Spirometry, 18/41 (44%) could do Lung Volumes and 15/41 (37%) could do Transfer factor (Fig. 1).

Fig. 1.

The distribution of patient's capability to complete the lung function test.

For those who could complete the test, the average level of the forced expiratory volume in 1 s percent predicted (FEV₁pp) was 66 ± 15 and about 67% (14/21) of the patients had an abnormal spirometry result. This was generally mild restrictive defect. 72% (13/18) of the patients had an abnormal level of total lung capacity percent predicted (TLCpp) with average value 73 ± 14. And for the gas transfer test, the average levels of the transfer factor for carbon monoxide percent predicted (TLCOpp) and carbon monoxide transfer coefficient (KCO) were 69 ± 22 and 98 ± 30 respectively implying extra pulmonary restriction. 47% (7/15) of them had normal diffusing capacity TLCOpp.

The lung function tests were more difficult to perform in those patients with apraxia. However, this was not formally assessed.

Then, we analysed the risk factors that could influence the lung function test results. There was no difference when comparing the lung function in patients with or without history of childhood recurrent infection, asthma, kyphoscoliosis or other factors listed in Table 1. Interestingly, results showed that patients with a history of infantile cardiomyopathy showed a significantly decrease level of FEV₁pp, , forced vital capacity percent predicted (FVCpp), TLCpp, and TLCOpp while no difference was found between patients with or without current presence of cardiomyopathy and lung function was found (Fig. 2). And the proportion of abnormal pulmonary function tests did not differ significantly between groups (Table S2).

Fig. 2.

Comparison of lung function between patients with and without a history of infant cardiomyopathy. Pulmonary function parameters are expressed as percentage of predicted values and presented as mean ± standard deviation (SD). Sample sizes for patients with vs. without a history of infantile cardiomyopathy were: FEV1, n = 5 vs. 15; FVC, n = 5 vs. 15; FEV1/FVC ratio, n = 5 vs. 15; TLC, n = 4 vs. 14; TLCO, n = 3 vs. 12; and KCO, n = 3 vs. 11, respectively. The numbers above the bars represent exact nominal P values derived from the Mann–Whitney U test.

Longitudinal pulmonary function data from patients with repeated assessments are presented in Figure S1. No consistent pattern of progressive decline was observed across the cohort, although individual variability was evident.

Imaging

HRCT scans were available for 39 patients (16 Females and 23 Males) (Tables S3 and S4, and Fig. 3). Most of them had normal results. Breathing artefact was the most common finding, reported in 53.84% of these patients. Additionally, three patients (7.69%) had reports of minimal scarring. Two patients (5.13%) were identified to have ground glass opacities, and one of them was localised and the other one showed diffuse changes due to heart failure. Interestingly, diffuse interstitial fibrosis was not found in any of the patients. One patient had reports of fibrotic bands, but they were minimal and only localised to the periphery of the left lung.

Fig. 3.

Imaging finding of the HRCT scan.

21 of the 39 (53.84%) patients had some degree of breathing artefacts but no diffuse fibrosis. However even in the 10/39 patients who had no breathing artefacts at all there was no evidence of any diffuse interstitial fibrosis.

We then looked for risk factors that could influence the results of HRCT scan. Unfortunately, no risk factor was identified.

Cardiac catheterisation

Six patients (13%) underwent right and left heart catheterisation due to clinical and echocardiographic evidence of pulmonary hypertension. They had elevated mean pulmonary artery pressures and mean pulmonary capillary wedge pressures. Mean pulmonary artery pressures was 46 mm Hg (normal 9–18 mmHg), mean pulmonary capillary wedge pressure 23 mm Hg (normal 6–12 mm Hg), Left ventricular End Diastolic Pressure 21 mm Hg (normal 5–12 mm Hg), Right atrial pressure 9 mm Hg (normal 2–6 mm Hg). The pulmonary artery saturations were 68.5% (normal 70–80%). Cardiac output 3.1 L/min (normal 4–8 L/min), Cardiac Index 1.7 L/min/m² (normal 2.5–4.2 L/min/m²), aortic saturations 98% and aortic systolic pressure 107 mm Hg. Only one patient had severe valvular heart disease (Mitral regurgitation).

Histology of patients’ lungs

During follow-up, eleven patients died. A descriptive survival curve of the adult cohort is provided in Figure S2. We obtained post-mortem pathology reports from four patients including one female and three males who unfortunately passed away (Table 2). The age of death was 33, 40, 39, and 58 respectively. Two patients died of pneumonia. One died of cardiomyopathy and subsequent complications of heart lung transplant. One patient died of pulmonary thromboembolism. It should be noted that no diffuse fibrosis in the lung tissue was identified in any of the patients (Fig. 4).

Table 2.

The post-mortem result of patients with AS.

Patient number	Age of death	Gender	Macroscopy	Microscopy	Cause of death
39	33	Female	Both lungs congested. No cavitation, no fibrosis, no honeycombing, no clots.	Many haemosiderin laden macrophages and patchy bone formation. Mild patchy interstitial and interalveolar fibrosis.	AS Cardiomyopathy
16	40	Male	Bilateral, panlobar mottled pneumonic consolidation, no cavitation, no appreciable fibrosis, no honeycomb change.	NA	Bilateral pneumonia.
23	39	Male	There was moderate suppurative/erosive tracheo-bronchitis, panlobar pneumonic consolidationno cavitation, no appreciable fibrosis, no honeycomb change.	NA	Adult respiratory distress syndrome. Community acquired pneumonia.
41	58	Male	Thrombus in pulmonary trunk, Left main pulmonary artery Segmental atelectasis in both lungs, No consolidation, no fibrosis, no honeycomb change.	NA	Pulmonary Thromboembolism

NA, Not Assessed (Microscopy was not performed for this patients).

Fig. 4.

Explanted native lung from AS patient who underwent heart lung transplant for AS cardiomyopathy. Showing no fibrosis or scarring, no remodelling, no mucostasis, and no inflammation. A. Haematoxylin and Eosin stain X 1. B. Elastic Van Gieson stain X 1. C. Haematoxylin and Eosin stain X 4. D. Elastic Van Gieson stain X 1.5.

Discussion

A common cause of morbidity and premature death in AS is due to respiratory illness. This is the first large cohort study to depict the lung in adult patients with AS. It shows that 61% (25/41) of the patients have trouble completing the lung function tests and for those who could, 67% (14/21) shows reduced lung volumes based on spirometry and lung volume testing results. TLCO was also reduced in 47% (7/15) of the patients. However, the diffusing capacity for KCO was normal or raised in all these patients suggesting the restrictive pattern that is likely due to extrapulmonary factors. Concurrently, HRCT scan showed that breathing artefact was reported in half of the patients. Interestingly, no patient had established interstitial fibrosis on HRCT.

Fibrosis in multiple organs in AS have been described and often has been considered as a significant feature of AS.5, 11 In 2005, Marshall et,al. described fibrosis in liver, kidney, testes, pancreas, and lungs based on pathologic specimens in five AS patients.¹¹ Even an anti-fibrosis drug, PBI-4050 has been on a clinical trial for the treatment of AS patients.¹² However, recent large cohort studies only showed evidence of fibrosis in liver caused by metabolic syndrome¹³ and heart.¹⁴

Our series does not show any evidence of diffuse fibrosis in lungs. Based on our study, HRCT scan from 39 patients indicated no signs of diffuse pulmonary fibrosis (Fig. 3). In addition, the postmortem result of lung from four patients also do not show any significant lung fibrosis.

Kim et,al. found no apparent fibrosis in kidney of the fat aussie (foz) mouse strain of AS on chow diet but significantly greater fibrosis on western diet (20% fat, 0.2% Cholesterol and 34% sucrose by weight).¹⁵ However, they did not analyse other organs. To the best of our knowledge, no evidence from other animal model of AS support the existence of fibrosis in lung.

We found that many AS patients have difficulty completing the lung function test. Apraxia, especially ideomotor apraxia has been described in AS.¹⁶ This may partly explain why such a large number of AS patients could not complete a lung function test. This also partly explains the inability of some AS patients to take a deep breath during a clinical examination or hold their breath during investigations contributing to the breathing artefacts on HRCT scans of the thorax The dual sensory loss, both eye sight and hearing could also be a significant factor influencing their ability to coordinate their breathing with demands of the lung function test.

We interestingly found that history of infant cardiomyopathy is a risk factor for poor lung function in adult life of AS. Infant cardiomyopathy is a critical and well-recognised feature of AS and it is controversial whether it is transient or have a more prolonged effect on the health.1, 17 It is also possible that all cases of infantile cardiomyopathy in Alstrom Syndrome are not picked up as milder cases may be misdiagnosed as asthma or other respiratory problems in infancy. It is not clear why current cardiomyopathy did not seem to influence the lung function, probably because of the limited number of patients.

In children or adolescents, reported respiratory tract complication include recurrent otitis media (92%, 35/38), bronchitis or pneumonia (61%, 23/38), sinusitis (50%,19/38), nasal congestion or rhinorrhoea (47%, 18/38), chronic cough (42%, 16/38), and chronic or recurrent wheezing (37%, 14/38).⁹

However, in adults with AS, upper respiratory symptoms were not a frequent issue. However, they have difficulty in completing lung function tests and had breathing artefacts on HRCT scans, and many patients had a predominantly extrapulmonary restriction on lung function. Pulmonary disease is a common cause of mortality in AS, mostly Acute Respiratory Distress Syndrome (ARDS) often in the setting of pneumonia.

Unlike previous suggestions our study has not shown significant pulmonary interstitial fibrosis. However cardiorespiratory complications remain the main cause of death in AS. Chronic inflammation associated with recurrent infection or vascular congestion may contribute to diminished vascular reserve in the lung as a result of the combination of vascular pathology and/or microthrombosis. During infection the demand for oxygen increases. Vascular dysfunction may probably happen at a low threshold in AS patients with sepsis or other stress. Hence a combination of increased oxygen demand and decreased ability to enhance pulmonary blood flow and gas transfer probably contributes to the hypoxia observed during infection and perioperative periods in AS patients.

Pulmonary hypertension is being increasingly recognised in adults with AS. One of our patients had very severe pulmonary hypertension and left heart disease and underwent heart lung transplant. The pulmonary hypertension may be related to historic or current cardiomyopathy, obesity, obstructive sleep apnoea, extra thoracic restriction as noted in our lung function tests or as yet not fully understood pulmonary vascular dysfunction in AS. Only one patient had severe valvular heart disease (Mitral regurgitation). This picture of high pulmonary artery pressures with reduced cardiac output and cardiac index in presence of a significantly raised pulmonary capillary wedge pressure (which reflects left atrial pressure) and raised left ventricular end diastolic pressure is likely to reflect left heart disease from restrictive cardiomyopathy as the main cause of pulmonary hypertension in a subset of adult Alstrom syndrome patients. The cardiac findings in our cohort of patients have been published recently.¹⁸

Pneumonia progressing to ARDS is generally more common in the elderly or immunocompromised. ARDS causes reduced lung compliance, reduced functional residual capacity and impairment of ventilation perfusion ratio. The factors above mentioned for pulmonary hypertension may also be responsible for some young adults with AS developing ARDS as happened in two of our patients aged 39 and 40.

Several limitations should be considered when interpreting our findings. First, although this study represents one of the largest single-center cohorts of patients with AS reported to date, the overall sample size remains limited due to the ultra-rare nature of the disease. Moreover, not all patients were able to complete all pulmonary function assessments, resulting in smaller and varying sample sizes across spirometry, lung volume, and gas transfer measurements. Sample sizes were further reduced in subgroup analyses, particularly in comparisons according to a history of infantile cardiomyopathy. Consequently, the statistical power to detect less common clinical manifestations and subgroup differences was limited. Future multicentre and international collaborative studies with larger cohorts and standardised pulmonary function assessments are needed to validate and extend these findings.

Clinically, these findings suggest that respiratory assessment in adults with Alström syndrome should focus on pulmonary function, cardiopulmonary complications, and pulmonary hypertension rather than assuming the presence of diffuse pulmonary fibrosis, thereby facilitating more appropriate surveillance and management.

Conclusion

Respiratory complications remain an important cause of morbidity and mortality in AS. Contrary to current belief, we did not find significant pulmonary fibrosis in our cohort of adult patients with AS in spite of comprehensive assessments including clinical examination, Lung Function testing, HRCT scans of the Thorax and in the post mortem specimens studied.

Contributors

Qianwen Zhang and Shyam C. Madathil conceived the study.

Qianwen Zhang and Shyam C Madathil accessed and verified the underlying data.

Qianwen Zhang analysed the data and wrote the first draft. Tarekegn Geberhiwot, Qianwen Zhang and Shyam C. Madathil wrote parts of the manuscript, read and provided comments on the manuscript, had full access to all the data in the study, and had final responsibility for the decision to submit for publication.

Data sharing statement

Individual participant data pooled for the current study cannot be shared with third parties due to clauses in data sharing agreements for each individual cohort study.

Declaration of interests

Qianwen Zhang and Shyam C. Madathil have been provided free conference registration and accommodation by the Alstrom Syndrome International patient society for their recent meeting in May 2026. This has no bearing on the contents of the manuscript.

Tarekegn Geberhiwot has no competing interests to declare.