Interstitial lung disease in a child heterozygous for the 1549C→GAA (121ins2) mutation of surfactant protein B
- *Dept of Paediatrics, Bronchopneumology Unit
- #Laboratory of Neonatal Biology
- ¶Dept of Medical and Surgical Neonatology
- +Dept of Pathology and Laboratory Medicine
- §Dept of Radiology, Bambino Gesù Children Hospital and Research Institute, Rome, Italy
- F.P. Rossi, Dept of Paediatrics, Bronchopneumology Unit, Bambino Gesù Children Hospital and Research Institute, Piazza Sant'Onofrio 4, 00165 Rome, Italy. E-mail: francescop.rossi{at}opbg.net
To the Editors:
The SFTPB gene encodes the hydrophobic pulmonary surfactant protein (SP)-B, which is essential for the build-up of the surfactant layer and lowering of surface tension in the airways. SP-B deficiency was the first reported genetic cause of lethal respiratory distress syndrome (RDS) in infants in 1993 [1].
The phenotype of infants with hereditary SP-B deficiency is of a typically full-term neonate with respiratory failure in the first 24–48 h of life; diagnosis can be delayed, as affected infants may show initially mild symptoms and not require ventilation or further medical support for some time. Chest radiography shows a bilateral, wide ground-glass pattern consistent with a diagnosis of hyaline membrane disease. Typical histological findings are the presence of periodic acid–Schiff-positive eosinophilic material in the alveoli, epithelial cell desquamation, enlarged alveolar macrophages with lamellar inclusions and accumulation of SP-A [2]. Since SP-B was found to be essential for the proteolytic processing of pro-SP-C, newborns with hereditary SP-B deficiency show aberrantly processed SP-C in the intra-alveolar lumen. Lung disease is rapidly progressive and fatal respiratory failure finally sets in within 3–6 months; lung transplantation is suggested as the only effective treatment. To our knowledge, heterozygous mutation has not previously been reported to cause clinical symptoms.
A 6-month-old male was admitted to the Bronchopneumology Unit (Bambino Gesù Children Hospital and Research Institute, Rome, Italy) in 2008; the patient was a term-born infant, admitted to another hospital at the age of 1 month for acute respiratory failure and pneumonia that required intubation with surfactant administration and mechanical ventilation. Clinical symptoms were consistent with a diagnosis of RDS. A lung computed tomography (CT) scan showed interstitial infiltration. Sweat test, CFTR mutations, lymphocyte subsets, α1-antitrypsin sampling, bronchoalveolar lavage (BAL) and sputum cultures were negative. The patient was discharged with continuous oral steroid treatment, inhaled salbutamol and ipratropium bromide.
On admission, the patient’s general condition was fairly good: weight and height below the third centile; wide crackled on chest auscultation; and arterial oxygen saturation 96% with oxygen (2 L·min−1).
Bronchoscopy did not demonstrate anomalies of tracheobronchial tree, and BAL cultures and viral search were negative; 2,000 cells·mL−1 BAL fluid were counted (differential cell count: 77% macrophages, 16% neutrophils, 6% lymphocytes and 1% eosinophils).
CT scan confirmed the previous findings (fig. 1).
The patient was treated with oral steroids and montelukast, inhaled salbutamol and fluticasone.
In February 2008, the patient underwent an open lung biopsy, which showed a desquamative interstitial pneumonia; electron microscopy revealed anomalies of type 2 pneumocytes, with intracytoplasmic surfactant bodies in numbers and distribution typical of SP anomaly related disease. Immunohistochemical staining for SP-B was negative, consistent with an SP-B deficit.
The study of anomalies for SP genes showed only a heterozygous mutation of SP-B (1549C→GAA; 121ins2), in blood and BAL fluid, while the analysis of the other known genes encoding SPs (including ABCA3 and the SP-C gene) was normal. The same mutation was reported in the patient’s father, who had no clinical manifestation of lung disease.
The actuarial clinical situation was stable; the patient needed continuous steroid treatment (low dose of prednisone) and had no need of oxygen supplementation.
SP-B deficiency causes fatal respiratory distress in newborn infants. In humans, it is inherited as an autosomal recessive gene that causes respiratory failure in the newborn and death in the first months of life.
Usually, genetic analysis in STPB deficit shows homozygosity for a frame-shift mutation in codon 121 (termed the 121ins2 mutation) and this mutation accounts for up to two-thirds of the mutant alleles identified in the SP-B locus, with an estimated allele frequency of one case per 1,000–3,000 individuals [3].
Tredano et al. [4] characterised SFTPB 1549C→GAA (1549C→GAA; 121ins2) and 457delC heterozygosity in an infant with severe unexplained respiratory distress and a complete absence of SP-B in BAL fluid. Previous studies on SFTPB-haploinsufficient murine lineages demonstrated decreased lung compliance and air trapping at birth. This finding could suggest that infants heterozygous for 121ins2 may have increased risk or severity of RDS. However, it was described that 121ins2 heterozygous healthy siblings and parents of 11 SP-B-deficient infants were completely asymptomatic; only one heterozygous asymptomatic nonsmoking sibling showed a decreased forced expiratory volume in 1 s on spirometry at adult age. These data suggest that these mutations would not cause symptoms in heterozygous individials [5].
To our knowledge, the patient of the present study is the first paediatric case of symptomatic interstitial lung disease (ILD) with an isolated heterozygous mutation of SP-B (1549C→GAA; 121ins2), as symptoms are usually present only in homozygous patients. Therefore, we speculate that heterozygous individuals may not be “healthy”, but that their clinical situation depends on the expression of the mutation, which provokes an abnormal amount of protein production or production of a functionally impaired protein, and/or that this clinical feature could depend on an associated but not yet identified mutation in others genes. For this reason, patients with severe respiratory infections should be investigated for SP deficiency, particularly if other more common diseases are excluded, because infections could reveal the hidden disease. Besides this, heterozygous siblings and parents of SP-B-deficient individuals should be carefully treated if respiratory symptoms are present.
Despite the fact that we do not know all the genes causing ILD in children and that we still miss certain mutations in the known genes, in our case, the identified heterozygous SFTPB mutation is linked to the absence of SP-B protein. Previous large cohort studies have found that subjects who are heterozygous for the mutation may be at increased risk of chronic obstructive pulmonary disease if they are smokers in adulthood, but to our knowledge, ILD has never previously been related to heterozygous SFTPB mutation in either adults or children.
The patient’s clinical situation was characterised by a normal pulmonary pressure and a transient need for oxygen supplementation; only low doses of oral prednisone were required. Presently, it is not possible to predict the patient’s clinical course, as no other similar cases have been reported. Lung transplantation currently represents the only treatment option for this disease, but it is hoped that new treatments will be developed that are based on a better understanding of the disease.
Footnotes
Statement of Interest
None declared.
- ©ERS 2011