Combined pulmonary fibrosis and emphysema syndrome associated with ABCA3 mutations

To the Editor:

Herein, we present the first report of combined pulmonary fibrosis and emphysema (CPFE) in an adult patient who was compound heterozygous for mutations of the ATP-binding cassette subfamily A member 3 gene (ABCA3, MIM 601615).

A 41-year-old nonsmoking male presented with dyspnoea on mild exertion. The patient’s medical history indicated neonatal respiratory distress, gastro-oesophageal reflux and pneumonia 8 years previously that resolved with antibiotics. His physical examination revealed a mild pectus excavatum, finger clubbing and bilateral basal crackles. High-resolution computed tomography (HRCT) of the chest showed voluminous emphysema in the upper zones of the lungs associated with honeycomb fibrosis and ground-glass opacity in lower lobes, predominating in left lung (fig. 1). The bronchoalveolar lavage differential cell count was 67% macrophages, 22% neutrophils and 8% lymphocytes. Pulmonary function tests showed: total lung capacity of 75%, vital capacity (VC) of 50%, residual volume of 134%; forced expiratory volume in 1 s (FEV₁) of 49%, diffusing capacity of the lung for carbon monoxide of 38% predicted, FEV₁/VC of 74%, and arterial oxygen tension at room air was 96 mmHg. During a 6-min walk test the peripheral oxygen saturation decreased from 96% at rest to 90% after 630 m (80% of predicted value). A lung biopsy was not performed. Doppler echocardiography showed normal heart cavities, with estimated systolic pulmonary arterial pressure of 37 mmHg. Serum α₁-antitrypsin levels, autoimmune markers (including anti-nuclear antibody and rheumatoid factor), and immunoglobulin pattern were normal.

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Figure 1–

High-resolution computed tomography of the chest showing a, b) left upper lobe predominant emphysema associated with a, c) ground-glass opacities and c) asymmetric honeycomb pattern in the lower zones.

This clinical presentation of CPFE in a young patient prompted us to screen mutations in genes causing surfactant dysfunction. After informed consent was obtained, sequencing analysis of the surfactant protein C gene (SFTPC, MIM 178620) revealed no mutation. Sequence analysis of the ABCA3 gene identified two mutations: 1) c.3081_3092delinsCG resulting in a serine to valine change at codon 1028 with the creation of a stop codon 103 amino acids downstream (p.Ser1028Valfs*103); and 2) the common mutation c.875A>T changing a glutamic acid to a valine at codon 292 (p.Glu292Val). None of these mutations were found in either the public polymorphism database or our controls. 2 years after presentation, chest HRCT as well as lung function worsened and azithromycin (250 mg every other day) was initiated.

Pulmonary surfactant, a complex mixture of lipids and specific proteins located at the air–liquid interface, lowers alveolar surface tension thereby preventing alveolar collapse at the end of expiration. It is synthesised by alveolar type II cells, stored in lamellar bodies, and secreted by exocytosis. ABCA3 is expressed in the lamellar bodies of alveolar type II cells and is crucial to pulmonary surfactant storage and homeostasis. Several studies indicated a role of genes involved in surfactant metabolism in the development of diffuse lung diseases [1].

CPFE is a syndrome characterised by the coexistence of emphysema and pulmonary fibrosis in the same patient [2]. It typically occurs in male smokers and is associated with dyspnoea, upper lobe emphysema, lower lobe fibrosis and abnormalities of gas exchange. In the absence of the SFTPC mutation, previously associated with CPFE [3], we decided to analyse other genes involved in surfactant metabolism, such as ABCA3. Recessive loss-of-function mutations in ABCA3 present as lethal surfactant deficiency in the newborn, whereas other recessive mutations in ABCA3 can result in interstitial lung disease in older children [4]. Previous studies showed that homozygous or compound heterozygous ABCA3 mutations led to abnormal processing and/or trafficking of the ABCA3 protein [5], alterations in ABCA3 protein functions such as ATPase activity [6], or impaired lipid transport [7]. As previously described, our patient had a less severe phenotype than is usually associated with ABCA3 mutations [4]. These variations in the clinical and radiological features may be related to the nature of the mutation. Our patient was found to be compound heterozygous for ABCA3 mutations. The first is the common mutation p.Glu292Val, which is found in heterozygous form with a frequency of <1% [8] and has been previously reported to be associated with mild lung disease. The second has not yet been described but is expected to be a disease-causing mutation as it introduces a premature termination codon, likely to be associated with markedly reduced mRNA levels due to nonsense-mediated degradation. Such a “null” allele precludes any functional ABCA3 from being made resulting in abnormal lamellar bodies, but should be less deleterious in combination with the mild mutation p.Glu292Val. Interactions with variants in other genes and/or with external factors such as viral or bacterial infections, as observed in our case, may also influence the observed phenotype [9].

The phenotype of our patient is very similar to that observed in the case reported by Cottin et al. [3] carrying SFTPC mutations. Our patient is a nonsmoker and the emphysematous lesions were voluminous and localised, mostly in the upper lobes, whereas asymmetric fibrosis lesions were predominant in the lower lobes.

There is no specific treatment for CPFE syndrome. Supported immunosuppressive therapy was not indicated in this case without evidence of active inflammation. Improvement of severe interstitial lung disease in a young patient with ABCA3 deficiency has been reported after treatment with azithromycin, an azalide macrolide antibiotic characterised by a nitrogen in the macrolide ring [10]. Although, there is no evidence of efficacy of azithromycin in CPFE, the worsening of our patient’s respiratory status together with the safety of this drug incited us to initiate this treatment in our patient.

To our knowledge, this is the first report of a phenotype of CPFE syndrome in an adult patient carrying mutations of the ABCA3 gene. Although further studies are needed to confirm the role of surfactant metabolism in CPFE, this result suggests that this syndrome may have an underlying genetic predisposition.

• Received August 19, 2013.
• Accepted September 21, 2013.

• ©ERS 2014