Journal of Perinatology (2006) 26,67–70 r 2006 Nature Publishing Group All rights reserved. 0743-8346/06 $30 www.nature.com/jp PERINATAL/NEONATAL CASE PRESENTATION Neonatal respiratory failure associated with mutation in the surfactant protein C gene

AS Soraisham, AJ Tierney and HJ Amin Division of Neonatology, Department of Pediatrics, Foothills Medical Centre, University of Calgary, Alberta, Canada

Case report We report on a term newborn with an unusual presentation and course of a A full term (39 weeks), male infant weighing 2940 g was born to a rare lung disease due to mutation in SFTPC gene. This particular SFTPC 36-year-old healthy gravida 3 para 1 mother by cesarean section mutation is novel, and the infant’s lung disease was unusually severe after failed vacuum extraction. Apgar scores were 9 and 9 at 1 and compared to what has been previously reported in association with SFTPC 5 min, respectively. mutations. The infant was well until day 3 of life. At that time, physical Journal of Perinatology (2006) 26, 67–70. doi:10.1038/sj.jp.7211417 examination revealed tachypnea and chest retractions; hence, the Keywords: neonate; respiratory distress; surfactant protein C infant was transferred to the special care nursery. A complete sepsis work up was done and antibiotics were commenced. The infant was started on 30% inspired oxygen via nasal prongs. A capillary blood gas revealed pH ¼ 7.32, PCO2 ¼ 53, PO2 ¼ 45; HCO3 ¼ 27 and Introduction BE ¼ 1. The chest radiograph revealed mildly hyperinflated lungs and mild perihilar interstitial markings (Figure 1). Pulmonary surfactant is a complex mixture of phospholipids and Echocardiogram showed an anatomically normal heart with no proteins that is synthesized by type II alveolar pneumocytes. structural malformation. On day 7, the infant developed progressive Surfactant lowers surface tension at the air–liquid interface, increase in work of breathing with increasing oxygen requirement; thereby maintaining alveolar expansion at end expiration. Of the continuous positive airway pressure was initiated. Chest radiograph four surfactant associated proteins (surfactant protein (SP)-A, showed increasing haziness of both lung fields with air SP-B, SP-C and SP-D), SP-B and SP-C interact with phospho- bronchograms (Figure 2). On day 10, the infant developed lipid components in a tightly coordinated itinerary of synthesis, progressive respiratory acidosis followed by intubation, mechanical secretion, film formation and recycling.1 Pulmonary SP-C is ventilation and transport to a neonatal intensive a highly hydrophobic peptide produced by type II alveolar cells care unit (NICU). through the processing of a high molecular weight precursor In the NICU, examination revealed the following: temperature (proSP-C) that enhances surface tension and facilitates the 37.41C pulse rate 160/min, respiratory rate 90/min and blood recycling of pulmonary surfactant in vitro. SFTPC gene is short, spanning only 3500 base pairs on the short arm of chromosome 8 pressure 72/42 mmHg. Systemic examination was unremarkable (8p23.1) near the gene coding for bone morphogenetic protein 1. except for respiratory distress. There was no clinical evidence of SP-C deficiency and mutations in the SFTPC have been associated pulmonary hypertension. He was initially ventilated on pressure with interstitial lung disease (ILD) in children and adults.2–5 settings of 20/4 cm H2O with a ventilatory rate of 60/min and 80% Hereditary SP-B deficiency, with over 20 different mutations of inspired oxygen. An arterial blood gas revealed hypoxia and SP-B, is a well established cause of severe respiratory failure in respiratory acidosis (pH ¼ 7.35; PaCO2 ¼ 60; PaO2 ¼ 41 and newborns.6 Mutation in SFTPC with resultant SP-C deficiency that HCO3 ¼ 32 with a/A ratio of 0.13 and oxygenation index (OI) presents as respiratory failure in the neonatal period is a rare of 14). entity. We report on a neonate who presented with progressive A complete sepsis work up was repeated. The white blood cell respiratory failure and was diagnosed to have mutation in SFTPC count was unremarkable. Chest radiograph revealed diffuse ground gene. glass appearance with air bronchogram (Figure 3). Nasopharyngeal and tracheal aspirates were sent for viral (antigen Correspondence: Dr AS Soraisham, Department of Pediatrics, Foothills Medical Centre, testing for Influenza A and B, Para influenza A and B, Respiratory University of Calgary, C-211, 1403, 29th Street, NW, Calgary, Alberta, Canada T2N2T9. E-mail: [email protected] syncytial virus, Herpes simplex and Adenovirus), chlamydia and Received 4 August 2005; revised 21 September 2005; accepted 22 September 2005 mycoplasma cultures that were subsequently reported as negative. Neonatal respiratory failure AS Soraisham et al 68

Figure 3 X-ray of chest (on day 10) showing diffuse pulmonary Figure 1 X-ray of chest (on day 3 of age) showing mild lung atelectasis with air bronchograms and loss of cardiac silhouette. hyperinflation and perihilar streaking.

laboratory (CLIA certified) at Johns Hopkins Hospital (http:// www.hopkinsmedicine.org/dnadiagnostic). Assisted ventilatory support was continued. He required high ventilatory pressures and FiO2. He was treated with repeated doses of surfactant every 24–26 h. Dexamethasone treatment was intermittently attempted with apparent pulmonary improvement as assessed by ability to reduce the frequency of surfactant administration. Computerized tomography (CT) studies of the chest showed diffuse atelectasis, bronchial inflation and accentuation of interlobular septa. There were no focal parenchymal or mass lesions. On day 25 of life, he developed temperature instability, feeding intolerance, tachycardia and increasing oxygen requirement. Laboratory studies showed leukocytosis with a left shift; C-reactive protein of 28 mg/l (normal: 0–8 mg/l) and bacteremia with coagulase negative staphylococcus. He was treated with vancomycin for 7 days. During this episode, he required more Figure 2 X-ray of chest (on day 7) showing diffuse haziness of both frequent surfactant therapy every 18–24 h. He also developed lung fields and air bronchograms. hepatosplenomegaly and conjugated hyperbilirubinemia. Abdominal ultrasonography showed hepatosplenomegaly, but no structural or focal lesions on abdominal He was treated with antibiotics; acyclovir and bovine lipid ultrasonography. extract surfactant. After the surfactant administration, the inspired Initial results of the surfactant protein studies showed the oxygen was reduced to 60% with improvement in the blood gas presence of surfactant protein B in the tracheal aspirate. However, (pH ¼ 7.39; PaCO2 ¼ 52; PaO2 ¼ 99; HCO3 ¼ 31 and a/A ¼ 0.37 his clinical course, response to surfactant and radiological findings with OI ¼ 5). Tracheal aspirate sample for surfactant protein indicated functional surfactant protein deficiency. Subsequently, analysis was collected 24 h after the first dose of surfactant. Based DNA sequencing showed a single base deletion (Nt 392 del T) in on the clinical response to surfactant and radiographic findings, he exon 4 of SFTPC gene. was suspected to have surfactant protein deficiency. After informed On day of life 44, he developed unremitting hypoxemia that was and written parental consent, tracheal aspirate and blood for unresponsive to surfactant therapy. The ventilator management molecular typing for surfactant protein were sent to DNA Diagnostic was withdrawn with death ensuing thereafter.

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Partial autopsy was performed. The lung histology showed predispose a person to recurrent atelectasis, lung injury and diffuse interstitial thickening with proliferation of mesenchymal inflammation.2 fibroblastic cells and chronic inflammatory infiltrates of Unlike surfactant protein B deficiency, the age at presentation of lymphocytes, plasma cells and scattered eosinophils. A surfactant protein C mutation is variable and ranges from the superimposed widespread acute bronchopneumonia affected all neonatal period to adulthood.11 The clinical presentation varies lobes of both lungs. Hyperplasia of type II alveolar cells was from mild tachypnea, respiratory distress and failure to thrive to present. No misalignment of pulmonary vessels was evident. progressive respiratory failure. The course of the infant in this case All family members of this infant including the siblings are report was more severe than previous case reports with SFTPC healthy without respiratory symptoms. mutations. The novel SFTPC gene mutation in this infant very likely led to a frameshift. Frameshift mutations often result in the unstable mRNA transcripts. This probably led to early disruption of Discussion SP-C metabolism and surfactant dysfunction with associated In this report, we describe a term infant with progressive fatal widespread lung injury and inflammation.12 respiratory failure during the first 2 months of life that was At present, there is no definite treatment for respiratory failure associated with mutation (Nt 392 del T) in exon 4 of SFTPC gene. associated with mutation of SFTPC. Although, lung transplantation This deletion causes a shift in the open reading frame resulting in may be an option in progressive respiratory failure,12 there are no a premature stop codon approximately 54 amino-acids clear guidelines for SFTPC mutation since the time of presentation downstream, and 13 codons upstream of the normal stop codon. and severity of illness are variable. Lung transplantation was This SFTPC mutation has not been reported previously. In our successful in children with SFTPC gene mutation as noted in one patient, this mutation was associated with early onset severe case report.4 Few cases of surfactant protein C deficiency treated respiratory insufficiency and on autopsy was appeared as a with hydroxychloroquine have been reported.1,13 nonspecific interstitial pneumonia. We report this case to highlight the high index of suspicion for Nogee et al.3 published the first report of an association between SFTPC mutation in a neonate presenting with an unusual course mutation in SFTPC and a disease in a full-term female infant, who of severe respiratory failure. This infant was found to have a novel presented with respiratory distress at 6 weeks of age. Hamvas et al.4 SFTPC gene mutation. reported another infant with progressive and severe ILD associated with mutation in SFTPC gene. This infant was healthy until 3 months of age and subsequently developed growth failure and ILD Acknowledgments resulting in lung transplantation by 14 months of age. Brasch We acknowledge Dr Lawrence Nogee, who guided and assisted us with the 7 et al. reported a 13-month-old child with severe respiratory surfactant protein analysis. insufficiency associated with de novo missense mutation of SFTPC. The mutations in the SFTPC gene have been associated with familial and sporadic ILD in children and adults.2–5 The clinical References and histological expressions of these mutations have been variable 1 Whitsett JA, Weaver TE. Hydrophobic surfactant proteins in lung function with children exhibiting chronic pneumonitis of infancy or and disease. N Engl J Med 2002; 347: 2141–2148. nonspecific ILD and adults exhibiting usual interstitial 2 Amin RS, Wert SE, Baughman RP, Tomashefski Jr JF, Nogee LM, Brody AS pneumonitis, desquamative interstitial pneumonitis or idiopathic et al. Surfactant protein deficiency in familial interstitial lung disease. pulmonary fibrosis. J Pediatr 2001; 139: 85–92. The exact mechanisms of lung disease associated with SFTPC 3 Nogee LM, Dunbar AE, Wert SE, Askin F, Hamvas A, Whitsett JA. A mutation gene mutation are not completely known. The absence of mature in the surfactant protein C gene associated with familial interstial lung SP-C in the large aggregate surfactant and juxtanuclear disease. N Engl J Med 2001; 344: 573–579. accumulation of pro-SP-C are consistent with a dominant-negative 4 Hamvas A, Nogee LM, White FV, Schuler P, Hackett BP, Huddleston CB et al. effect of presumably misfolded peptide that prevents normal pro- Progressive lung disease and surfactant dysfunction with a deletion in SP-C trafficking into the multivesicular and lamellar bodies.8 It surfactant protein C gene. Am J Respir Cell Mol Biol 2004; 30: 771–776. has been speculated that the aggregation of misfolded pro-SP-C 5 Thomas AQ, Lane K, Philips III J, Prince M, Markin C, Speer M et al. Heterozygosity for a surfactant protein C gene mutation associated with may interfere with the unfolded protein response and result in toxic usual interstitial pneumonitis and cellular non-specific interstitial gain of function similar to that seen in mice that overexpress SP-C pneumonitis in one kindred. Am J Respir Crit Care Med 2002; 165: or in patients with Alzheimer’s disease, alpha 1 antitrypsin 1322–1328. 9,10 deficiency and cystic fibrosis. Surfactant dysfunction may be 6 Nogee LM, Wert SE, Proffit SA, Hull WM, Whitsett JA. Allelic heterogeneity in another factor that probably contributed to the infant’s hereditary surfactant protein B (SP-B) deficiency. Am J Respir Crit Care development of respiratory failure. Deficiency of SP-C could Med 2000; 161: 973–981.

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7 Brasch F, Griese M, Tredano M, Johnen G, Ochs M, Rieger C et al. 10 Perlmutter DH. The cellular response to aggregated proteins associated with Interstitial lung disease in a baby with a de novo mutation in the SFTPC human disease. J Clin Invest 2002; 110: 1219–1220. gene. Eur Respir J 2004; 24: 30–39. 11 Cameron HS, Somaschini M, Carrera P, Hamvas A, Whitsett JA, Wert SE et al. 8 Kabore AF, Wang WJ, Russo SJ, Beers MF. Biosynthesis of surfactant protein A common mutation in the surfactant protein C gene associated with lung C: characterization of aggresome formation by EGFP chimeras containing disease. J Pediatr 2005; 146: 370–375. propeptide mutants lacking conserved cysteine residues. J Cell Sci 2001; 114: 12 Moreno A, Maestre J, Balcells J, Marhuenda C, Cobos N, Roman A et al. Lung 293–302. transplantation in young infants with interstitial pneumonia. Transplant 9 Conkright JJ, Na CL, Weaver TE. Over expression of surfactant protein-C Proc 2003; 35: 1951–1953. mature peptide causes neonatal lethality in transgenic mice. Am J Respir 13 Rosen DM, Waltz DA. Hydroxychloroquine and surfactant protein C Cell Mol Biol 2002; 26: 85–90. deficiency. N Engl J Med 2005; 352: 207–208.

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