Delayed Presentation and Prolonged Survival of a Child with Surfactant Protein B Deficiency.

Surfactant protein B encoding gene mutations have been related to early onset fatal respiratory distress in full-term neonates. We report a school-aged male child homozygous for a surfactant protein B encoding gene missense mutation who presented after the neonatal period. His respiratory insufficiency responded to high dose intravenous methylprednisolone and hydroxychloroquine.

[Deficiency of surfactant protein: Case report]. / Déficit congénito de proteína de surfactante: caso clínico.

INTRODUCTION: Congenital surfactant deficiency is a condition infrequently diagnosed in newborns. A clinical case is presented of surfactant protein B deficiency. A review is performed on the study, treatment and differential diagnosis of surfactant protein deficiencies and infant chronic interstitial lung disease. CASE REPORT: The case is presented of a term newborn that developed respiratory distress, recurrent pulmonary opacification, and a transient response to the administration of surfactant. Immunohistochemical and genetic studies confirmed the diagnosis of surfactant protein B deficiency. CONCLUSIONS: Pulmonary congenital anomalies require a high index of suspicion. Surfactant protein B deficiency is clinically progressive and fatal in the majority of the cases, similar to that of ATP binding cassette subfamily A member 3 (ABCA3) deficiency. Protein C deficiency is insidious and may present with a radiological pulmonary interstitial pattern. Due to the similarity in the histological pattern, genetic studies help to achieve greater certainty in the prognosis and the possibility of providing adequate genetic counselling.

Rare combination of congenital heart disease and pulmonary alveolar proteinosis.

Here, we describe a case of total anomalous pulmonary venous return with coarctation of the aorta that was diagnosed as pulmonary alveolar proteinosis at autopsy in a male infant. Surgical repair was performed at 1 day of age, but the infant died on postoperative day 51 due to respiratory insufficiency without any evidence of pulmonary venous obstruction. He had been unexpectedly diagnosed with pulmonary alveolar proteinosis and pulmonary hypoplasia on autopsy. Congenital pulmonary alveolar proteinosis is a serious condition with a high mortality rate, which should be considered in the differential diagnosis in patients with a clinical picture of pulmonary venous obstruction, because most patients are unable to survive without proper treatment. In this report, we address specific issues that should be discussed in such cases based on our recent experience.

Hereditary interstitial lung diseases manifesting in early childhood in Japan.

BACKGROUND: Genetic variations associated with interstitial lung diseases (ILD) have not been extensively studied in Japanese infants. METHODS: Forty-three infants with unexplained lung dysfunction were studied. All 43, 22, and 17 infants underwent analyses of surfactant protein (SP)-C gene (SFTPC) and ATP-binding cassette A3 gene (ABCA3), SP-B gene (SFTPB), and SP-B western blotting, respectively. Two and four underwent assessment of granulocyte macrophage colony-stimulating factor-stimulating phosphorylation of signal transducer and activator of transcription-5 (pSTAT-5) and analyses of FOXF1 gene (FOXF1), respectively. RESULTS: ILD were diagnosed clinically in nine infants: four, three, and two had interstitial pneumonitis, hereditary pulmonary alveolar proteinosis (hPAP), and alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV), respectively. Genetic variations considered responsible were detected in six (67%) of the nine infants with ILD: three with hPAP (SFTPC p.Leu45Arg and p.Gln145fs, and ABCA3 p.Arg1583Trp/p.Val1495CysfsX21), two with interstitial pneumonitis (SFTPC p.Lys63Glu and p.Ser72Asn/p.Gly100Ala), and one with ACD/MPV (FOXF1 p.Leu300ArgfsX79). None showed SFTPB mutations or defects in pSTAT-5. The 17 bronchoalveolar lavage or tracheal aspirates contained enough SP-B protein. CONCLUSION: The SP-C abnormality was most prevalent, and SP-B deficiency was rare in Japanese infants with hereditary ILD.

Impaired surfactant protein B synthesis in infants with congenital diaphragmatic hernia.

Pulmonary hypoplasia and hypertension account for significant morbidity and mortality in neonates with congenital diaphragmatic hernia (CDH). Whether CDH is associated with surfactant dysfunction remains controversial. Therefore, we measured disaturated phosphatidylcholine (DSPC) and surfactant protein (SP)-B concentration in tracheal aspirates and their synthesis rate in infants with CDH compared to infants without lung disease. (2)H2O as a precursor of DSPC and 1-(13)C-leucine as a precursor of SP-B were administered to 13 infants with CDH and eight controls matched for gestational age. DSPC and SP-B were isolated from tracheal aspirates, and their fractional synthesis rate was derived from (2)H and (13)C enrichment curves obtained by mass spectrometry. DSPC and SP-B amounts in tracheal aspirates were also measured. In infants with CDH, SP-B fractional synthesis rate and amount were 62±27% and 57±22% lower, respectively, than the value found in infants without lung disease (p<0.01 and p<0.05, respectively). There were no significant group differences in DSPC fractional synthesis rate and amount. Infants with CDH have a lower rate of synthesis of SP-B and less SP-B in tracheal aspirates. In these infants, partial SP-B deficiency could contribute to the severity of respiratory failure and its correction might represent a therapeutic goal.

De novo complex X chromosome rearrangement unmasking maternally inherited CSF2RA deletion in a girl with pulmonary alveolar proteinosis.

We report on a 3-year-old girl with a de novo complex X chromosome rearrangement associated with congenital pulmonary alveolar proteinosis (PAP) and short stature. Array comparative genome hybridization and FISH analyses contributed to characterize the complex rearrangement consisting of a 7.37 Mb terminal deletion of Xp22.33p22.2, a 17.3 Mb interstitial inverted duplication of Xp22.2p21.3, and a 10.14 Mb duplication of Xq27.3q28. PCR analysis of microsatellite markers supported a paternal origin of the X chromosome rearrangement. A pre-meiotic two-step mechanism may explain the occurrence of this complex X rearrangement: an inverted duplication deletion event on Xp, and duplication of the Xq27.3qter region through a telomere capture event stabilizing the broken chromosome Xp end. The girl has also inherited from her healthy mother an X chromosome with a colony stimulating factor 2 receptor, alpha (CSF2RA) gene deletion. Consistent with the recessive mode of inheritance, the de novo paternal Xp22.33p22.2 deletion combined to the maternally inherited CSF2RA gene deletion led to homozygous deletion of CSF2RA and PAP diagnosis in the girl. The Xp deletion encompasses the pseudoautosomal region 1 (PAR1) which contains genes that escape X inactivation. Short stature homeobox (SHOX) haploinsufficiency explains growth retardation. Absence of other symptoms in relation to the X deletion/amplification is most probably due to skewed X inactivation. Finally, inherited deletions may unmask rare pathogenic genomic rearrangement and contribute to clinical phenotypes by a recessive mode of gene action.

ABO-incompatible lung transplantation in an infant.

Waitlist mortality continues to be a limiting factor for all solid-organ transplant programs. Strategies that could improve this situation should be considered. We report the first ABO-incompatible lung transplantation in an infant. The recipient infant was ABO blood group A1 and the donor group B. The recipient was diagnosed with surfactant protein B deficiency, which is a fatal condition and lung transplantation is the only definitive therapy. At 32 days of age, a bilateral lung transplantation from a donation after cardiac death (DCD) donor was performed. Intraoperative plasma exchange was the only preparatory procedure performed. No further interventions were required as the recipient isohemagglutinins were negative before transplant and have remained negative to date. At 6 months posttransplant, the recipient is at home, thriving, with normal development. This outcome suggests that ABO-incompatible lung transplantation is feasible in infants, providing another option to offer life-saving lung transplantation in this age range.

Long-term follow-up and treatment of congenital alveolar proteinosis.

BACKGROUND: Clinical presentation, diagnosis, management and outcome of molecularly defined congenital pulmonary alveolar proteinosis (PAP) due to mutations in the GM-CSF receptor are not well known. CASE PRESENTATION: A 2 1/2 years old girl was diagnosed as having alveolar proteinosis. Whole lung lavages were performed with a new catheter balloon technique, feasible in small sized airways. Because of some interstitial inflammation in the lung biopsy and to further improve the condition, empirical therapy with systemic steroids and azathioprin, and inhaled and subcutaneous GMCSF, were used. Based on clinical measures, total protein and lipid recovered by whole lung lavages, all these treatments were without benefit. Conversely, severe respiratory viral infections and an invasive aspergillosis with aspergilloma formation occurred. Recently the novel homozygous stop mutation p.Ser25X of the GMCSF receptor alpha chain was identified in the patient. This mutation leads to a lack of functional GMCSF receptor and a reduced response to GMCSF stimulation of CD11b expression of mononuclear cells of the patient. Subsequently a very intense treatment with monthly lavages was initiated, resulting for the first time in complete resolution of partial respiratory insufficiency and a significant improvement of the overall somato-psychosocial condition of the child. CONCLUSIONS: The long term management from early childhood into young adolescence of severe alveolar proteinosis due to GMCSF receptor deficiency requires a dedicated specialized team to perform technically demanding whole lung lavages and cope with complications.

Bilateral partial lung lavage in an infant with pulmonary alveolar proteinosis.

Pulmonary alveolar proteinosis (PAP) is a rare disease in infancy, resulting from abnormalities of surfactant production or decreased catabolism of surfactant. The only effective treatment of the congenital form of PAP is bronchoalveolar lavage. A 4-month-old boy with severe PAP received bilateral partial lung lavage on two occasions resulting in clinical improvement. We performed partial lung lavage using a 3.1 mm flexible fibreoptic bronchoscope introduced through a 4.0 mm tracheal tube under general anaesthesia. The infant did not require extra-corporeal oxygenation during the procedure or postoperative ventilation. This method may offer a feasible option for performing lavage in a resource constrained environment.

A lung tropic AAV vector improves survival in a mouse model of surfactant B deficiency.

Surfactant protein B (SP-B) deficiency is an autosomal recessive disorder that impairs surfactant homeostasis and manifests as lethal respiratory distress. A compelling argument exists for gene therapy to treat this disease, as de novo protein synthesis of SP-B in alveolar type 2 epithelial cells is required for proper surfactant production. Here we report a rationally designed adeno-associated virus (AAV) 6 capsid that demonstrates efficiency in lung epithelial cell transduction based on imaging and flow cytometry analysis. Intratracheal administration of this vector delivering murine or human proSFTPB cDNA into SP-B deficient mice restores surfactant homeostasis, prevents lung injury, and improves lung physiology. Untreated SP-B deficient mice develop fatal respiratory distress within two days. Gene therapy results in an improvement in median survival to greater than 200 days. This vector also transduces human lung tissue, demonstrating its potential for clinical translation against this lethal disease.

[Congenital pulmonary alveolar proteinosis related to a surfactant protein B deficiency: report of two cases]. / Protéinose alvéolaire pulmonaire congénitale en rapport avec un déficit en protéine B du surfactant : à propos de deux observations.

Congenital pulmonary alveolar proteinosis is an uncommon affection, distinct from adult's alveolar proteinosis by its clinical, pathological, etiological and evolutive characteristics. We report two cases of congenital alveolar proteinosis related to a surfactant protein B deficiency. Clinical presentations were similar: the two children were full-term newborns and had swiftly developed respiratory distress. Chest radiography demonstrated bilateral alveolar syndrome. Echocardiography was normal. There was no sign of infection. The two children died respectively at three weeks and two months of life. Lung biopsy showed lesions of alveolar proteinosis in the two cases. Both children were homozygotes for the 121ins2 mutation of the SFTPB gene. Diagnosis of surfactant protein B deficiency must be suspected in congenital alveolar proteinosis. It can be confirmed by the absence of detection of the surfactant B protein by immunohistochemistry on fixed and paraffin-embedded lung tissue or by western blot on bronchoalveolar fluid and by the absence of mRNA by RT-PCR. We report the value of molecular diagnosis for genetic counseling and the possibility of early prenatal diagnosis by trophoblast biopsy.

Methionyl-tRNA synthetase novel mutation causes pulmonary alveolar proteinosis.

The  methionyl-tRNA  synthetase  (MARS)  mutation is  a  very  rare  cause  of  congenital  pulmonary  alveolar proteinosis.We report a 6-month-old boy born with symmetrical intrauterine growth retardation presented with unexplained persistent tachypnea and hypoxemia associated with severe failure to thrive, anemia, hypoalbuminemia and hepatomegaly. Detailed pulmonary investigations including computed tomography chest scan, bronchoscopy and bronchoalveolar lavage revealed pulmonary alveolar proteinosis. Whole exome sequencing identified a homozygous novel variant in the MARS gene, c.854T>C p.(Ile285Thr).

Reversal of Surfactant Protein B Deficiency in Patient Specific Human Induced Pluripotent Stem Cell Derived Lung Organoids by Gene Therapy.

Surfactant protein B (SFTPB) deficiency is a fatal disease affecting newborn infants. Surfactant is produced by alveolar type II cells which can be differentiated in vitro from patient specific induced pluripotent stem cell (iPSC)-derived lung organoids. Here we show the differentiation of patient specific iPSCs derived from a patient with SFTPB deficiency into lung organoids with mesenchymal and epithelial cell populations from both the proximal and distal portions of the human lung. We alter the deficiency by infecting the SFTPB deficient iPSCs with a lentivirus carrying the wild type SFTPB gene. After differentiating the mutant and corrected cells into lung organoids, we show expression of SFTPB mRNA during endodermal and organoid differentiation but the protein product only after organoid differentiation. We also show the presence of normal lamellar bodies and the secretion of surfactant into the cell culture medium in the organoids of lentiviral infected cells. These findings suggest that a lethal lung disease can be targeted and corrected in a human lung organoid model in vitro.

Congenital Pulmonary Alveolar Proteinosis: From Birth to Ten-years of Age.

Pulmonary alveolar proteinosis is a rare lung disease in which lipoproteinaceous material accumulates within the alveoli, interfering with gas exchange. The disease is classified into congenital, secondary, and acquired. The congenital form includes inborn errors of surfactant metabolism, lysinuric protein intolerance and mutations in the components of granulocyte-macrophage colony-stimulating factor receptor. The main symptoms are non-specific. The radiologic appearance of pulmonary alveolar proteinosis is bilateral, symmetric and perihilar airspace consolidation. Bronchoalveolar lavage is crucial for diagnosis of the disease. There is only one ten-year-old patient with diagnosed congenital form in Croatia. What makes him different from other children in the world is that since the ninth month of his life he has been mechanically ventilated. Diagnosis of postnatal alveolar proteinosis should be considered in every infant with respiratory distress with diffuse alveolar and interstitial infiltrate.

A newly identified novel variant in the CSF2RA gene in a child with pulmonary alveolar proteinosis: a case report.

BACKGROUND: The congenital form of pulmonary alveolar proteinosis due to colony stimulating factor 2 receptor alpha gene mutations is a rare disease with only a few cases reported worldwide. In this study we report a new case of pulmonary alveolar proteinosis with a novel variant in colony stimulating factor 2 receptor alpha gene. CASE PRESENTATION: A 5-year-old Saudi boy presented with a history of progressive dyspnea over 6 months; he was diagnosed as having pulmonary alveolar proteinosis. A molecular study revealed a novel variation in colony stimulating factor 2 receptor alpha gene. His clinical condition showed significant improvement after whole lung lavage. CONCLUSIONS: This case has the typical presentation of congenital pulmonary alveolar proteinosis due to colony stimulating factor 2 receptor alpha defect with a novel variant in this gene likely to be pathogenic.

Featured Article: Electroporation-mediated gene delivery of surfactant protein B (SP-B) restores expression and improves survival in mouse model of SP-B deficiency.

Surfactant Protein B Deficiency is a rare but lethal monogenetic, congenital lung disease of the neonate that is unresponsive to any treatment except lung transplantation. Based on the potential that gene therapy offers to treat such intractable diseases, our objective was to test whether an electroporation-based gene delivery approach could restore surfactant protein B expression and improve survival in a compound knockout mouse model of surfactant protein B deficiency. Surfactant protein B expression can be shut off in these mice upon withdrawl of doxycycline, resulting in decreased levels of surfactant protein B within four days and death due to lung dysfunction within four to seven days. Control or one of several different human surfactant protein B-expressing plasmids was delivered to the lung by aspiration and electroporation at the time of doxycycline removal or four days later. Plasmids expressing human surfactant protein B from either the UbC or CMV promoter expressed surfactant protein B in these transgenic mice at times when endogenous surfactant protein B expression was silenced. Mean survival was increased 2- to 5-fold following treatment with the UbC or CMV promoter-driven plasmids, respectively. Histology of all surfactant protein B treated groups exhibited fewer neutrophils and less alveolar wall thickening compared to the control groups, and electron microscopy revealed that gene transfer of surfactant protein B resulted in lamellar bodies that were similar in the presence of electron-dense, concentric material to those in surfactant protein B-expressing mice. Taken together, our results show that electroporation-mediated gene delivery of surfactant protein B-expressing plasmids improves survival, lung function, and lung histology in a mouse model of surfactant protein B deficiency and suggest that this may be a useful approach for the treatment of this otherwise deadly disease. Impact statement Surfactant protein B (SP-B) deficiency is a rare but lethal genetic disease of neonates that results in severe respiratory distress with no available treatments other than lung transplantation. The present study describes a novel treatment for this disease by transferring the SP-B gene to the lungs using electric fields in a mouse model. The procedure is safe and results in enough expression of exogenous SP-B to improve lung histology, lamellar body structure, and survival. If extended to humans, this approach could be used to bridge the time between diagnosis and lung transplantation and could greatly increase the likelihood of affected neonates surviving to transplantation and beyond.

Interstitial lung disease in newborns.

The term 'interstitial lung disease' (ILD) refers to a group of disorders involving both the airspaces and tissue compartments of the lung, and these disorders are more accurately termed diffuse lung diseases. Although rare, they are associated with significant morbidity and mortality, with the prognosis depending upon the specific diagnosis. The major categories of ILD in children that present in the neonatal period include developmental disorders, growth disorders, surfactant dysfunction disorders, and specific conditions of unknown etiology unique to infancy. Whereas lung histopathology has been the gold standard for the diagnosis of ILD, as many of the disorders have a genetic basis, non-invasive diagnosis is feasible, and characteristic clinical and imaging features may allow for specific diagnosis in some circumstances. The underlying mechanisms, clinical, imaging, and lung pathology features and outcomes of ILD presenting in newborns are reviewed with an emphasis on genetic mechanisms and diagnosis.

Function and Safety of Lentivirus-Mediated Gene Transfer for CSF2RA-Deficiency.

Hereditary pulmonary alveolar proteinosis (hPAP) is a rare disorder of pulmonary surfactant accumulation and hypoxemic respiratory failure caused by mutations in CSF2RA (encoding the granulocyte/macrophage colony-stimulating factor [GM-CSF] receptor α-chain [CD116]), which results in reduced GM-CSF-dependent pulmonary surfactant clearance by alveolar macrophages. While no pharmacologic therapy currently exists for hPAP, it was recently demonstrated that endotracheal instillation of wild-type or gene-corrected mononuclear phagocytes (pulmonary macrophage transplantation [PMT]) results in a significant and durable therapeutic efficacy in a validated murine model of hPAP. To facilitate the translation of PMT therapy to human hPAP patients, a self-inactivating (SIN) lentiviral vector was generated expressing a codon-optimized human CSF2RA-cDNA driven from an EF1α short promoter (Lv.EFS.CSF2RAcoop), and a series of nonclinical efficacy and safety studies were performed in cultured macrophage cell lines and primary human cells. Studies in cytokine-dependent Ba/F3 cells demonstrated efficient transduction, vector-derived CD116 expression proportional to vector copy number, and GM-CSF-dependent cell survival and proliferation. Using a novel cell line constructed to express a normal GM-CSF receptor ß subunit and a dysfunctional α subunit (due to a function-altering CSF2RAG196R mutation) that reflects the macrophage disease phenotype of hPAP patients, it was demonstrated that Lv.EFS.CSF2RAcoop transduction restored GM-CSF receptor function. Further, Lv.EFS.CSF2RAcoop transduction of healthy primary CD34+ cells did not adversely affect cell proliferation or affect the cell differentiation program. Results demonstrate Lv.EFS.CSF2RAcoop reconstituted GM-CSF receptor α expression, restoring GM-CSF signaling in hPAP macrophages, and had no adverse effects in the intended target cells, thus supporting testing of PMT therapy of hPAP in humans.

Surfactant protein B: From biochemistry to its potential role as diagnostic and prognostic marker in heart failure.

Growing interest raised on circulating biomarkers of structural alveolar-capillary unit damage and very recent data support surfactant protein type B (SP-B) as the most promising candidate in this setting. With respect to other proteins proposed as possible markers of lung damage, SP-B has some unique qualities: it is critical for the assembly of pulmonary surfactant, making its lack incompatible with life; it has no other known site of synthesis except alveolar epithelial cells different from other surfactant proteins; and, it undergoes a proteolytic processing in a pulmonary-cell-specific manner. In the recent years circulating SP-B isoforms, mature or immature, have been demonstrated to be detectable in the circulation depending on the magnitude of the damage of alveolar capillary membrane. In the present review, we summarize the recent knowledge on SP-B regulation, function and we discuss its potential role as reliable biological marker of alveolar capillary membrane (dys)function in the context of heart failure.