Genetic disorders of surfactant dysfunction

INTRODUCTION — Genetic surfactant dysfunction disorders are caused by DNA sequence variants in genes encoding proteins critical for the production and function of pulmonary surfactant. These rare disorders may produce familial or sporadic lung disease, with clinical presentations ranging from neonatal respiratory failure to childhood- or adult-onset interstitial lung disease. An overview of these disorders is presented in the table (table 1).

Interstitial lung diseases in children were initially categorized by their histologic appearance in a manner similar to that used for adult forms of interstitial lung disease (ILD). In children, the lung histopathology findings associated with desquamative interstitial pneumonitis (DIP) are now known to often result from genetic mechanisms that disrupt normal surfactant production and metabolism. By contrast, DIP in adults is considered to represent a distinct type of ILD, which is strongly associated with cigarette smoking and carries a relatively favorable prognosis [1]. These genetic disorders also result in histopathologic patterns other than DIP, including findings of pulmonary alveolar proteinosis and chronic pneumonitis of infancy. An understanding of the pathogenesis of these disorders permits a mechanistic classification as genetic surfactant dysfunction disorders instead of their previous classification based upon histologic appearance.

Issues related to genetic disorders of surfactant dysfunction will be reviewed here. The classification and description of other interstitial lung diseases in children are discussed separately. As these disorders involve more than just the pulmonary interstitium, they are more accurately referred to as diffuse lung diseases (DLD). (See "Classification of diffuse lung disease (interstitial lung disease) in infants and children".)

PATHOPHYSIOLOGY AND GENETICS — Pulmonary surfactant is a mixture of lipids and proteins that is produced by alveolar type II epithelial cells (AEC2) and secreted into the airspaces. Phospholipids are the major component of surfactant by weight, and are essential for lowering surface tension at the air-liquid interface, which prevents alveolar collapse at end-expiration.

Four proteins highly expressed in the lung and found in surfactant are designated surfactant proteins (SP) A, B, C, and D. Additional proteins including ABCA3 (member A3 of the ATP binding cassette family of proteins) and TTF-1 (thyroid transcription factor 1) are also important for the production of functional surfactant. The surfactant proteins are developmentally regulated, such that their expression increases in later gestation [1-4].

●SP-B and SP-C are low molecular weight, very hydrophobic proteins that interact with the lipid components and are important for the surface tension lowering properties of surfactant. SP-B is encoded by a single gene (SFTPB) on human chromosome 2. Proteolytic cleavage of a larger precursor protein (proSP-B) yields the 79 amino acid mature SP-B protein found in the airspaces. SP-C is among the most hydrophobic of all proteins in the human proteome, encoded by a single gene (SFTPC) on human chromosome 8. Proteolytic cleavage of a proprotein (proSP-C) yields the 35 amino acid mature SP-C.

●SP-A and SP-D are larger, structurally-related hydrophilic glycoproteins that have important roles in innate immunity of the lung.

●ABCA3 is a transmembrane protein found on the limiting membrane of lamellar bodies, the lysosomally-derived organelles in which surfactant is assembled and stored within the type II pneumocytes prior to secretion. It is encoded by a single gene (ABCA3) on human chromosome 16 and the 1704 amino-acid protein contains two transmembrane domains and two nucleotide-binding domains.

●TTF-1, encoded by the gene NKX2-1, is a member of the homeodomain family of transcription factors and binds to specific sequences in the genes encoding ABCA3, SP-B, and SP-C to regulate their expression [5,6]. NKX2-1 is a relatively small gene on human chromosome 14.

SFTPB sequence variants and SP-B deficiency — Most disease-causing sequence variants in SFTPB result in a complete lack of mature SP-B protein (MIM #265120). Lung disease is inherited in an autosomal recessive manner, requiring sequence variants on both alleles. Surfactant produced by infants with SP-B deficiency is abnormal in composition and does not function normally in lowering surface tension [7,8]. Surfactant from SP-B deficient infants is also lacking in mature SP-C due to incomplete processing of proSP-C, which further diminishes its effectiveness [9].

The most common SFTPB pathogenic sequence variant, c.397delCinsGAA (formerly called 121ins2), involves a net insertion of two base pairs that results in a frameshift and premature codon for the termination of translation, and unstable transcript. Many other sequence variants, including a deletion spanning two exons, have been reported [10-13]. A few sequence variants have been identified that result in production of reduced amounts of SP-B [14-16]. These variants causing "partial deficiency" are rare.

SP-B deficiency has a predicted disease incidence of <1 in 1,000,000 live births [17]. The most frequent c.379delCinsGAA variant has accounted for over one-half of the pathogenic SFTPB alleles identified to date [18,19]. It occurs primarily in individuals of northern European descent, probably due to a common ancestral origin. In samples from populations in the United States and Norway, the frequency of the SFTPB c.397delCinsGAA variant was approximately 0.1 percent; the variant was not found in samples from either Korea or South Africa [17].

SFTPC sequence variants — Familial cases of SP-C dysfunction (MIM #610913) are generally inherited in an autosomal dominant pattern, although the onset and severity of lung disease are highly variable, even within the same family (see 'Clinical manifestations' below). Germline SFTPC sequence variants may also arise de novo and cause sporadic lung disease [20,21].

Population-based estimates of SP-C-related lung disease are not available. The most commonly identified SFTPC variant, p.Ile73Thr (or c.218 T>C), has been observed in approximately one-third to one-half of all reported cases of SP-C dysfunction [20-24]. This variant was not found in 4500 samples obtained from a neonatal screening program in the United States [17], nor is it listed in a large population database consistent with the rarity of the disease. The majority of other known SFTPC variants have been unique to a given kindred and located in the carboxy-terminal domain of proSP-C in a region homologous to other proteins involved in conformational disorders [25].

All known disease-causing SFTPC variants are predicted to result in the production of abnormal proSP-C protein, which is thought to fold incorrectly. How these variants produce disease is not well understood. Misfolded proSP-C may elicit the unfolded protein response, resulting in inflammation and AEC2 apoptosis via a toxic-gain-of-function mechanism [26,27]. Alternatively, because proSP-C self-associates in the secretory pathway, misfolded proSP-C that is targeted for degradation may also cause wild type proSP-C to be degraded in a dominant negative mechanism [26-28]. Finally, sequence variants may cause proSP-C to be misrouted in the cell, leading to accumulation in the endosomal pathway and interfering with autophagy [29,30].

ABCA3 sequence variants — DNA sequence variants in ABCA3 appear to be the most common cause of genetic surfactant dysfunction in humans [20,31-33]. The variants result in a loss of or reduced function of the ABCA3 protein, and are inherited in an autosomal recessive manner (MIM #610921). Absent or decreased protein expression, abnormal trafficking (Type 1 mutation), and diminished functional activity of ABCA3 protein (Type 2 mutation) have all been implicated [34-36]. The severe neonatal form of the disease is thought to result from a lack of functional surfactant, a hypothesis that is supported by data from both animal and human studies [37-40].

Lack of ABCA3 function has a variety of effects. Impaired phospholipid uptake was observed in cultured cells that expressed ABCA3 sequence variants identified in human infants [41]. Reduced amounts of mature SP-C and altered processing of proSP-B to SP-B have also been observed in humans with ABCA3 variants [34,42]. Mice engineered to be deficient in ABCA3 had abnormal lamellar body (LB) formation, aberrant SP-B processing, altered lung development late in gestation, and died shortly after birth [37-39].

Disease caused by ABCA3 sequence variants varies in its presentation and severity, depending in part on the genotype, as shown in a series of 185 individuals with various ABCA3 sequence variants [43]. The most severe phenotype (respiratory failure at birth, leading to death or lung transplantation by one year of age) was found in 100 percent of those with sequence variants predicted to preclude ABCA3 expression on both alleles (null/null), compared with 75 percent of those with genotypes of either null/other or other/other sequence variants. Similarly, in a case series of individuals with ABCA3 variants who survived beyond the first year of life, most (42 of 44 participants) had missense variants or small insertions or deletions on at least one allele that were predicted to have some residual ABCA3 transporter function [44]. However, discordant outcomes have been reported in siblings with the same ABCA3 genotype, suggesting that factors other than genotype contribute to disease severity [45,46].

Surfactant isolated from infants with severe ABCA3-related disease has decreased amounts of critical lipid components as well as impaired surface-tension lowering properties [40]. It is not known whether the milder disease seen in older children results from chronic surfactant deficiency or other mechanisms. In vitro studies of one sequence variant associated with interstitial lung disease in older children (p.Glu292Val) revealed less severely impaired ability to transport lipids compared with variants associated with more severe disease [47]. (See 'Clinical manifestations' below.)

Most sequence variants in ABCA3 are unique to a given kindred, with over 300 different variants reported in the literature to date [31,32,34,40,42,48-58]. The most common variant is p.Glu292Val (or p.E292V, c.875 A>T), which has been identified in multiple unrelated individuals with relatively mild disease but has accounted for less than 10 percent of identified pathogenic ABCA3 alleles [17,42,48]. In samples from populations in the United States and Norway, the frequency of the p.Glu292Val variant was approximately 0.4 percent; this variant was not found in samples from either Korea or South Africa [17]. The overall carrier frequency in the population for a deleterious ABCA3 sequence variant has been estimated to be between 1 in 33 to 1 in 70 individuals, predicting a disease incidence of between 1 in approximately 4400 to 1 in approximately 20,000 [59].

NKX2-1 sequence variants — NKX2-1 encodes TTF-1, which plays an important role in SP-B, SP-C, and ABCA3 expression. Reduced amounts of one or more of these proteins due to DNA sequence variants or gene deletions which inactivate one NKX2-1 allele (haploinsufficiency) is the presumed mechanism for surfactant dysfunction and lung disease [60-70].

No epidemiologic estimates are currently available for NKX2-1 haploinsufficiency. Nearly all NKX2-1 pathogenic variants described to date have been unique to a given kindred, precluding screening for a predominant sequence variant to estimate the frequency of this disorder [68]. The majority of reported variants have occurred de novo [66,67], but autosomal dominant inheritance has been observed [65,71].

In addition to neonatal lung disease, sequence variants in NKX2-1 can present with interstitial lung disease, and/or neurologic abnormalities or hypothyroidism. The neurologic manifestations may include hypotonia, developmental delay, chorea, or seizures. In a case series of 21 patients with pathogenic NKX2-1 sequence variants, 76 percent presented with neonatal lung disease, and 19 percent presented with interstitial lung disease [71]. More than one-half of the patients had or ultimately developed the triad of pulmonary, neurologic, and thyroid disease (sometimes known as brain-lung-thyroid syndrome, MIM #610978). (See "Clinical features and detection of congenital hypothyroidism", section on 'Thyroid dysgenesis'.)

HISTOPATHOLOGY — Several different patterns may be seen on histopathologic examination of lung tissue from patients with surfactant dysfunction. The findings on routine histopathology may be suggestive for one of these disorders, but do not distinguish among the different genetic causes [72]. Common characteristic features include interstitial widening, foamy alveolar macrophages in the airspaces, hyperplasia of the type 2 alveolar epithelial cells (AEC2), and variable amounts of granular, proteinaceous material in the distal airspaces, known as pulmonary alveolar proteinosis (PAP) [10,20,31,73-75]. The proteinosis may be very subtle or absent. Other findings may include nonspecific changes of lung injury due to mechanical ventilation and hyperoxia. Review by a pathologist with special expertise in childhood interstitial lung disease (ILD) and the findings associated with genetic surfactant dysfunction may be helpful.

Chronic pneumonitis of infancy (CPI) was the most common pattern seen in children under two years old with symptomatic lung disease due to SFTPC sequence variants in a multicenter review of lung biopsy samples [72]. The predominant patterns observed in patients with ABCA3 sequence variants were PAP, desquamative interstitial pneumonitis (DIP), and nonspecific interstitial pneumonia (NSIP). A PAP picture was seen mainly in younger children with symptomatic disease due to ABCA3 variants [72,76], while DIP was more commonly seen in older children with ILD due to ABCA3 variants [42,48]. Usual interstitial pneumonia (UIP), the most common frequent histologic pattern seen in adults with ILD, has been reported in 15-year-old with ABCA3 variants [56]. Specialized immunohistochemical studies may provide additional useful information, but are currently available only in research laboratories [10,34,42,77]. The differential diagnosis and treatment of infants and children with PAP is discussed in a separate topic review. (See "Pulmonary alveolar proteinosis in children".)

Electron microscopy may be used to help distinguish among the genetic causes of surfactant dysfunction. In individuals with ACBA3 and SFTPB sequence variants, electron microscopic examination of AEC2s demonstrates abnormal structure of the lamellar bodies (LBs), which are the organelles in which surfactant is stored [31,34,49]. In children with ABCA3-related disease, LBs appear small and dense, with eccentrically-placed inclusions. Composite LBs formed by fusion of two or more LBs may also be seen, while some LBs appear normal [48]. By contrast, LBs in children with SFTPB sequence variants appear disorganized and poorly lamellated, with vesicular inclusions [49]. Abnormal LBs also have been described in patients with SFTPC variants, although this is not a consistent feature [78]. Lung biopsy specimens should be properly handled at the time of initial processing in order to allow for electron microscopy studies and maximize diagnostic yield [79].

Lung pathology findings from patients with NKX2-1 haploinsufficiency have been infrequently reported, and included deficient alveolarization, septal fibrosis, and lung cysts, with numerous LBs visualized by light microscopy [6,67,69]. Decreased staining for ABCA3 and SP-A protein was also noted in a single patient [6].

CLINICAL MANIFESTATIONS — Sequence variants in SFTPB cause pulmonary disease due to production of insufficient amounts and/or functionally abnormal surfactant, resulting in restrictive pathophysiology, with lungs that are poorly compliant and prone to atelectasis and low lung volumes. The early clinical picture may be similar to that of respiratory distress syndrome (RDS) of the newborn, which is caused by insufficient surfactant production in preterm neonates due to pulmonary immaturity (see "Respiratory distress syndrome (RDS) in the newborn: Clinical features and diagnosis"). Premature infants with RDS generally improve in response to treatment with exogenous surfactant and also improve as they mature and become able to produce their own surfactant. By contrast, infants with genetic surfactant dysfunction remain symptomatic because they are unable to produce normal surfactant and their AEC2 function remains abnormal. The clinical presentation of surfactant dysfunction may also resemble persistent pulmonary hypertension of the newborn (PPHN) (see "Persistent pulmonary hypertension of the newborn (PPHN): Clinical features and diagnosis"), and the distinction becomes apparent if the infant does not respond to standard therapies for PPHN [52]. The majority of patients with SFTPB sequence variants progress to fatal respiratory failure within days of birth to three to six months [10], although rare children with milder lung disease associated with sequence variants that result in partial SP-B deficiency have been reported [14,15].

Surfactant dysfunction due to sequence variants in ABCA3 has a more variable phenotype, depending in part on the genotype (see 'ABCA3 sequence variants' above). The initial presentation may be identical to that of SP-B deficient infants, with a severe RDS-picture in a full-term neonate. Many affected infants have progressive disease that leads to early death, while other infants may stabilize or improve, and some individuals present later in infancy or childhood. The ABCA3 genotype is a prognostic indicator; biallelic null alleles carry a very poor prognosis (see 'ABCA3 sequence variants' above). In infants under two years of age, tachypnea, hypoxemia, gastroesophageal reflux, and failure to thrive are frequent features, while wheezes and crackles are uncommon [72]. In patients who present later in childhood, cough, tachypnea, dyspnea and exercise intolerance are the most common symptoms reported. On physical examination, children older than two years of age with ABCA3 sequence variants commonly have retractions, crackles, digital clubbing, and low body weight (table 2) [42,48]. In a case series of 44 individuals with ABCA3 disease who survived beyond infancy, more than 80 percent were alive without lung transplantation at six years of age but had progressive, often severe, lung disease [44]. Environmental exposures, such as cigarette smoking, may play a role in triggering or exacerbating symptoms in individuals with sequence variants in ABCA3 [48,56].

SP-C-related lung disease has an even more variable age of onset. In two case series of children presenting with lung disease due to SFTPC sequence variants, the median age of presentation was three months [24]. The most common clinical features noted at presentation in children were cough, tachypnea, and hypoxemia, while crackles and digital clubbing were seen less commonly [22,24,80]. Another case series described five patients who presented during infancy or childhood and experienced a waxing and waning course, with minor functional impairment in adulthood [81]. Each patient in this series appeared to improve when treated with hydroxychloroquine (see 'Pharmacologic therapies' below). Patients with disease-causing SFTPC sequence variants may remain asymptomatic well into adult life, although radiographic changes may be seen in older patients even before clinical symptoms develop [82].

Haploinsufficiency for NKX2-1 may cause neurologic symptoms (chorea, ataxia, hypotonia), hypothyroidism, and lung disease. The presence of all three has been termed "Brain-Thyroid-Lung" syndrome, but individuals reported with this disorder have expressed various combinations of these features (MIM #610978) [66,68,69]. Affected individuals may present with respiratory distress during the neonatal period and progress to respiratory failure early in life [6,63,66,67]. Other patients develop a more chronic phenotype characterized by recurrent pulmonary infections [61,62,65,68].

DIAGNOSIS

Radiographic studies — Neonatal respiratory failure due to disorders of surfactant metabolism is associated with diffuse alveolar and/or interstitial infiltrates seen in all lung fields on chest radiographs, including ground-glass densities.

High-resolution computed tomography (HRCT) provides more specific information than chest radiography to support the diagnosis of interstitial lung disease, often revealing ground-glass opacities of the alveolar spaces and thickening of the interlobular and intralobular septa. HRCT is not generally helpful in distinguishing the cause of surfactant dysfunction, but findings may be associated with its severity. (See "Approach to the infant and child with diffuse lung disease (interstitial lung disease)".)

The HRCT pattern in some children with SFTPC sequence has been noted to change over time. In one study of five affected children from a single family with long-term follow-up, ground glass opacities predominated early in the clinical course, and the dissipation of ground glass opacities and appearance of cysts correlated with clinical improvement [22]. Another study showed a similar progression in HRCT patterns [83], with a study showing a progression to a more fibrotic pattern [84]. In patients with ABCA3-related disease, HRCT scans commonly revealed ground-glass opacities, septal thickening, parenchymal cysts, and pectus excavatum [48,85].

Genetic testing — Analysis of the genes involved in surfactant dysfunction disorders is now available in diagnostic laboratories in the United States, Europe, and Australia. Such testing is recommended because it is noninvasive and a positive molecular diagnosis may obviate the need for lung biopsy [86]. Next-generation sequencing (NGS) panels that allow simultaneous analysis of multiple genes have largely supplanted targeted gene testing as they are more cost-effective and can be designed to also detect copy number variants (large deletions or duplications involving multiple exons or the entire locus.) A list of clinical laboratories that perform these genetic tests is available through the Genetic Testing Registry website. The interpretation of genetic studies may not be straightforward, particularly if variants are identified that alter the coding sequence but whose clinical significance is unknown; these are termed variants of uncertain significance, or VUS. A number of laboratories offer panels that test multiple genes, which can be more cost-effective as well as sensitive to small duplications or deletions. However, testing of additional genes may also uncover VUS in genes likely unrelated to the child's presentation, further complicating interpretation. Inconclusive findings on genetic testing may warrant tissue examination.

A limitation of NGS panels is that the time for results to be available (turnaround time) is variable and may be several weeks or longer, which may be unacceptably long for a critically ill newborn or older child in an intensive care unit. Studies have demonstrated the feasibility and cost-effectiveness of programs employing whole-exome sequencing (WES) or whole-genome sequencing (WGS) for rapid diagnosis of unknown disorders in critically ill children. While rapid WES and WGS are more expensive than targeted NGS panels, the potential for shorter turnaround time may make them more cost-effective [87,88].

Identification of the causative gene can provide important information regarding prognosis. While SFTPB sequence variants are associated with nearly 100 percent mortality without lung transplantation, ABCA3 and SFTPC sequence variants may be associated with less severe disease and prolonged survival. Additionally, identification of pathogenic or likely pathogenic sequence variants also allows families to be informed about risk of recurrence with future pregnancies and allow for prenatal diagnosis. Testing of the proband's parents can provide important information. It can inform whether sequence variants identified in the proband are on opposite alleles (in trans) versus on the same allele (in cis), or possibly arose de novo, as these findings have different implications for diagnosis and reproductive decision-making [89].

The predictive value of genetic testing is limited, probably because of the effects of environmental, genetic, and epigenetic modifiers. These factors are suggested by observations of substantial phenotypic variability among individuals with the same SFTPC sequence variants within a given family [21,22,90]. As an example, ABCA3 may act as a disease-modifying gene in patients with SFTPC variants: Infants with a known disease-causing SFTPC sequence variant who were also heterozygous for the ABCA3 p.Glu292Val variant had earlier onset of and more severe symptoms than other family members who had only the SFTPC sequence variant [50].

Genetic testing is also limited because it is unable to detect some disease-causing sequence variants, as suggested by the following examples:

●Patients have been reported with a phenotype consistent with ABCA3 deficiency and typical lung histopathology findings, but only one identifiable ABCA3 sequence variant [31,32,42].

●Other cases have been described with no identifiable sequence variants but ultrastructural findings consistent with ABCA3 deficiency and family studies consistent with linkage to the ABCA3 gene [77]. These observations indicate that current genetic testing approaches are not able to detect all functionally significant ABCA3 sequence variants.

●Chromosomal deletions resulting in NKX2-1 haploinsufficiency have been reported. Such deletions will not necessarily be detected by PCR-based sequencing approaches and require specific methods for their detection. Assays specifically designed to detect small deletions, comparative genomic hybridization assays, or other methods sensitive to gene dosage should be obtained in children suspected of an NKX2-1 gene abnormality, although they may be included in NGS panels. Deletions in SFTPB, SFTPC, and ABCA3 have also been recognized as causes of lung disease and may need to be sought specifically depending upon the degree of clinical suspicion [91].

Lung biopsy — Genetic testing may obviate the need for lung biopsy if a definitive result is obtained in a timely fashion. However, lung biopsy may be indicated for diagnosis when disease is rapidly progressive and there is insufficient time needed to await the results from genetic testing, or if results of genetic testing are ambiguous or negative. Some clinicians still consider biopsy to be the "gold standard" for diagnosis of interstitial lung disease (ILD). Lung tissue may be obtained by open thoracotomy or via thoracoscopic approach. Transbronchial biopsy may be considered but may not provide sufficient material for diagnosis and may not be feasible in small infants [92]. Tissue obtained should be handled and processed according to the guidelines [79]. Biopsy tissue should also be fixed in glutaraldehyde and prepared for electron microscopy studies as needed. (See 'Histopathology' above.)

Laboratory testing — Biomarkers that are clinically useful for establishing the diagnosis or prognosis of genetic disorders of surfactant dysfunction in children have not been established. Measurement of serum concentrations of KL-6, a protein produced by pulmonary epithelial cells, may be useful in distinguishing disorders of surfactant metabolism from neuroendocrine cell hyperplasia of infancy (NEHI), which is a different and less severe form of childhood ILD [76]. However, serum KL-6 levels are not generally available for clinical use at this time. Serum levels of surfactant proteins A and D have been shown to be elevated in children with ILD, and levels appear to correlate with disease severity [93]. However, these findings are based on a small number of patients with a variety of different ILD disorders, none of whom had known surfactant dysfunction. Further research on biomarkers in surfactant dysfunction disorders is needed.

Analysis of bronchoalveolar lavage (BAL) fluid for the various protein components of surfactants and their precursors has been reported in many research studies but is not available for clinical testing [22,24]. Some patients with SFTPC sequence variants have increased neutrophil counts on BAL, but this has not been observed universally [22,24]. BAL fluid from a limited number of patients with NKX2-1 haploinsufficiency was found to have decreased amounts of SP-B, SP-C and surfactant phospholipids [6,69].

Pulmonary function testing — While reports of pulmonary function testing (PFT) in patients with disorders of surfactant dysfunction are limited, the predominant pattern is restrictive, with reduced forced vital capacities and forced expiratory volumes in one second (FEV₁). The results tend to correlate with the severity of the lung disease.

In a small case series of older children with lung disease due to ABCA3 deficiency, PFTs demonstrated restrictive lung disease, with reduced forced vital capacities and FEV₁ [48]. Infant PFTs may be useful in the diagnosis and management of infants with SP-C dysfunction [94]. In older patients with disease due to STFPC sequence variants, PFT findings ranged from relatively normal to restrictive defects with or without decreased D_LCO [22]. Infants with SFTPB sequence variants typically have been too ill to undergo infant pulmonary function testing, although a restrictive pattern may be seen on ventilator flow-volume tracings. A restrictive pattern was observed in two of five patients with lung disease due to NKX2-1 sequence variants [70].

TREATMENT — Because surfactant dysfunction disorders are rare, blinded, controlled evaluation of therapies has not been feasible. All data described below are anecdotal and have not been subjected to systematic evaluation. The significant phenotypic variability makes interpreting such data even more difficult. Collaborative clinical trials are needed to explore and evaluate treatment modalities for patients with surfactant dysfunction disorders.

Supportive therapy — Supportive therapy is the mainstay of treatment for individuals with a surfactant dysfunction disorder. Long-term nutritional support may be necessary because patients expend excess calories due to increased work of breathing [20,22]. High-frequency oscillatory ventilation and neuromuscular blockade may help stabilize SP-B deficient infants while awaiting diagnosis or lung transplantation [95].

Lung transplantation — Lung transplantation is the only definitive treatment option for patients with severe disease due to SP-B deficiency. Infants who have undergone lung transplantation for SP-B deficiency have had long-term outcomes comparable to infants transplanted for other indications, although the numbers of infants transplanted are too small to provide a good estimate of success [96,97]. The mortality and morbidity associated with lung transplantation in infants is considerable, with a five-year survival rate of approximately 50 percent. Although some of the patients undergoing lung transplantation for this disorder developed antibodies to SP-B, the presence of antibodies was not associated with poorer outcomes. Since there are few pediatric lung transplant centers in the United States, early referral to a center with expertise in infant lung transplantation is recommended.

Patients with severe pulmonary disease due to NKX2-1, SFTPC, and ABCA3 sequence variants have also undergone successful lung transplantation [33,76,78,98,99]. The variable course of SP-C deficiency complicates the decision for pursuing transplantation, as even severely ill infants in respiratory failure may stabilize and improve [100].

Therapies with unproven or marginal benefit

Pharmacologic therapies — Because neonates with genetic surfactant dysfunction often present with clinical and radiographic findings of respiratory distress syndrome (RDS), they are often treated with exogenous surfactant. Such treatment may have resulted in transient improvement in lung function. However, the benefit usually is not sustained and it is also not a viable long-term treatment option, particularly for older children with these disorders. Moreover, surfactant replacement therapy does not correct the intracellular defects present in these disorders.

The use of systemic corticosteroids, hydroxychloroquine, azithromycin, and other immunosuppressives has been described in patients with SP-C dysfunction [22-24,101]. In several reports with a small number of subjects, hydroxychloroquine appeared to be beneficial in patients with SP-C dysfunction [81,102]. The highly variable nature of disease due to SFTPC sequence variants makes interpretation of these small, unblinded therapeutic trials difficult. Moreover, in an in vitro study, hydroxychloroquine was observed to aggravate cellular perturbations due to a known pathogenic SFTPC variant in cells derived from a subject with the variant [103].

The ABCA3 gene promoter contains sterol-response elements, and glucocorticoids have been show to increase ABCA3 expression in vitro [5,104,105]. Therapy with corticosteroids (in most cases with concomitant hydroxychloroquine) has been used in patients with ABCA3 sequence variants, but whether the treatment had any clinical effect is unclear [48,106]. Both hydroxychloroquine and azithromycin have been reported to benefit children with ABCA3 deficiency in case reports [107,108].

Because some ABCA3 sequence variants result in abnormal trafficking of the gene product, experimental therapies which improve trafficking of misfolded proteins, or which augment the function of protein with reduced or partial activity, may be useful options to explore in the future for some patients. A systematic review examined data supporting drug treatment approaches in cell systems, animal models, and human subjects [109]. Agents aimed at facilitating protein folding, trafficking, and function such as those that have been used to treat cystic fibrosis show promise for ABCA3 deficiency in in vitro studies but have yet to be studied in human subjects and are likely to be sequence variant-dependent [110]. While preliminary in vitro studies of agents to facilitate ABCA3 expression, trafficking, and function are promising, these agents are generally not available and have not been studied in vivo. As an example, a 2021 study identified cyclosporine A as a potent corrector for some ABCA3 sequence variants in cell culture models [111]. Carefully designed studies to fully evaluate the risks and benefits of potential correctors will be necessary before they are used clinically, even for those that are repurposed from other indications. Gene replacement strategies may be helpful in the future for these disorders, based on preliminary work using animal models [112].

Whole lung lavage — Whole lung lavage has been used to treat older children and adults with pulmonary alveolar proteinosis (PAP), which has many different causes (see "Pulmonary alveolar proteinosis in children", section on 'Whole lung lavage'). Because genetic disorders of surfactant dysfunction sometimes results in alveolar proteinosis, whole lung lavage has been considered for these disorders. One report described apparent beneficial effects from serial whole lung lavages in combination with hydroxychloroquine and azathioprine to treat a young child with lung disease due to the SFTPC p.Ile73Thr sequence variant [20]. Administration of bovine surfactant via alveolar lavage also was used during an acute illness in one patient with lung disease due to ABCA3 sequence variant, with apparent benefit [55]. However, because whole lung lavage will not correct the underlying genetic defect, it is unlikely to provide sustained benefit in children with genetic surfactant dysfunction disorders.

OUTCOMES — Lung disease resulting from SP-B deficiency almost uniformly results in death within three to six months without lung transplantation [10,113]. A few patients with partial SP-B deficiency, milder lung disease, and prolonged survival have been reported [14-16].

As noted above, the severity of disease caused by ACBA3 or SFTPC sequence variants is variable, and the prognosis varies accordingly. In a small series of children with ABCA3 sequence variants, severe lung disease at a young age was associated with a poor outcome (all three subjects evaluated prior to one year of age died) [48]. In another series, patients with ABCA3 sequence variants generally presented earlier and had a worse prognosis than those with SFTPC variants [72]. Later-onset ILD due to SFTPC and ABCA3 sequence variants has exhibited more variability in outcomes as compared with ILD presenting during infancy [21,42,114]. The ABCA3 genotype may be helpful in predicting outcome; infants with pathogenic sequence variants on both alleles that are predicted to preclude ABCA3 expression are likely to die before age one year [43]. In contrast, no correlation has been observed between SFTPC genotype and outcome [83].

The majority of patients with NKX2-1 haploinsufficiency and pulmonary involvement experienced neonatal respiratory distress, which was fatal in some instances [68], but with long-term survival in other cases [62,65,66,68]. This apparent tendency for neonatal onset of this disorder may represent ascertainment bias. However, a large proportion of patients with NKX2-1 sequence variants have not had any pulmonary disease reported, although patients with this disorder may not be consistently evaluated for pulmonary disease [68]. Whether some patients with NKX2-1 sequence variants develop milder pulmonary disease later in life, or whether they may remain truly asymptomatic, perhaps related to genotype, requires further study.

SURFACTANT-RELATED GENES AS DISEASE MODIFIERS — Variants in surfactant genes may act as modifiers of lung disease in both newborns and adults. While ABCA3 deficiency is a recessive disorder with sequence variants on both alleles (biallelic) necessary to cause disease, having a single ABCA3 sequence variant (monoallelic) increased the risk for RDS in late preterm and near-term infants [59,115]. Similarly, having a single ABCA3 sequence variant may also increase risk for interstitial lung disease (ILD) in children [116]. In an adult Danish cohort, carriers for the SFTPB c.397delCinsGAA (121ins2) variant who were smokers were found to have decreased lung function and a twofold increased risk for the development of chronic obstructive pulmonary disease (COPD) [117]. In a separate study, an SFTPC variant, p.Ala53Thr, was associated with a twofold increased risk of asthma [118]. However, neither this variant nor another one identified (Y106X) were associated with an increased risk of COPD or ILD.

RELATED DISORDERS — Additional genetic causes of lung disease involving alterations in surfactant metabolism or catabolism have been described. No data are currently available on the prevalence of these disorders.

Pulmonary alveolar proteinosis (PAP) refers to the accumulation of lipoproteinaceous material within the alveoli, which has several genetic and acquired causes. It can be caused by pathogenic sequence variants in the genes encoding the components of the receptor for granulocyte-macrophage colony-stimulating factor (GM-CSF) [119-123]. Because alveolar macrophages are involved in the uptake and recycling of surfactant components, loss-of-function sequence variants in the GM-CSF receptor (CSF2RA, CSF2RB) are thought to lead to PAP by preventing the clearing of surfactant materials and resulting in their accumulation in the alveolar air spaces. This form of PAP can thus be considered a genetic disorder of surfactant catabolism. Additional genetic causes of PAP in children have been identified, including sequence variants in the genes SLC7A7 (resulting in the disorder lysinuric protein intolerance), MARS (encoding methionyl-tRNA synthetase), and GATA2 (a transcription factor). More recently, gain-of-function sequence variants in the gene OAS1, which encodes a protein important in innate immunity, have been shown to result in PAP in young infants [124,125]. Because these genes are expressed in tissues other than the lung, infants with by these disorders manifest symptoms related to other organ systems [126]. PAP in adults is usually caused by an autoimmune process due to neutralizing autoantibodies directed against GM-CSF. This mechanism of PAP is rare in children [127]. (See "Pulmonary alveolar proteinosis in children".)

Pathogenic sequence variants in SFTPA1 and SFTPA2, the two genes encoding mature SP-A, have been reported in association with adult-onset pulmonary fibrosis and lung carcinoma [128-130]. SFTPA1 or SFTPA2 sequence variants have very rarely been identified as a cause of childhood-onset lung disease. Similarly, common SFTPD variants have been associated with chronic obstructive pulmonary disease and asthma [131]. However, in a study of 73 children with idiopathic interstitial lung disease, no SFTPD disease-causing sequence variants were identified [89].

In 2022, a pathogenic sequence variant in RAB5B was identified by trio exome sequencing in an infant with clinical, radiographic, and lung histopathology findings of surfactant dysfunction but had no sequence variants identified in any surfactant-related genes [132]. The child also had developmental delay, hypotonia, and dysmorphic features and died from respiratory failure at age two years. RAB5B encodes a GTPase important in vesicular fusion, and decreased SP-B and SP-C expression was found in the child's lung tissue. In vitro studies also supported a role for RAB5B in the regulated surfactant secretory pathway that influenced the phenotype. While it is not yet known whether variants in this gene will be found in other patients with surfactant dysfunction and an as-yet-unidentified genetic cause, this study illustrates the potential for exome sequencing to identify new genetic causes of lung disease.

SUMMARY AND RECOMMENDATIONS

●Pathophysiology and genetics – Genetic surfactant dysfunction disorders are caused by pathogenic or likely pathogenic DNA sequence variants in genes responsible for the production and function of pulmonary surfactant. These disorders are rare and may produce familial or sporadic lung disease, with clinical presentations ranging from neonatal respiratory failure to childhood- and adult-onset interstitial lung disease. An overview of these disorders is presented in the table (table 1).

•Most disease-causing sequence variants in SFTPB result in a complete lack of mature surfactant B protein. Affected individuals present with respiratory distress during the neonatal period and progress to fatal respiratory failure within three to six months. The early clinical picture may resemble respiratory distress syndrome (RDS) or persistent pulmonary hypertension of the newborn (PPHN). (See 'SFTPB sequence variants and SP-B deficiency' above and 'Clinical manifestations' above.)

•Disease-causing variants in SFTPC result in the production of an abnormal form of the precursor for mature surfactant protein C. The related lung disease has a highly variable age of onset and clinical course, even within the same family. Affected individuals may present during early infancy or remain asymptomatic well into adult life. The most common clinical features noted at presentation in children were cough, tachypnea, and hypoxemia. (See 'SFTPC sequence variants' above and 'Clinical manifestations' above.)

•Surfactant dysfunction due to sequence variants in ABCA3 has a variable phenotype. Many affected infants may present during the neonatal period with severe progressive disease that leads to early death, while other infants may stabilize or improve. Some individuals may also present later in infancy or childhood with cough, tachypnea, hypoxemia, gastroesophageal reflux, and failure to thrive. (See 'ABCA3 sequence variants' above and 'Clinical manifestations' above.)

●Clinical presentation – The diagnosis of a genetic disorder of surfactant dysfunction is suspected in an infant presenting with unexplained respiratory distress, neonates with symptoms suggesting respiratory distress syndrome but no history of prematurity, or an older infant or child with pulmonary function testing (PFT) suggesting restrictive lung disease.

●Evaluation and diagnosis

•The diagnosis of genetic surfactant dysfunction is supported by findings of ground-glass opacifications of the alveolar spaces and thickening of the interstitium on high-resolution computed tomography (HRCT). It is confirmed by genetic testing, either with panels targeted to genes known to be associated with lung disease or through diagnostic studies involving whole-exome or -genome sequencing. (See 'Radiographic studies' above and 'Genetic testing' above.)

•Lung biopsy may be indicated for diagnosis when disease is rapidly progressive and there is insufficient time needed to await the results from genetic testing, or if results of genetic testing are ambiguous or negative. (See 'Lung biopsy' above.)

●Management

•Supportive therapy is the mainstay of treatment for individuals with a surfactant dysfunction disorder. It may include nutrition support and, in some cases, ventilatory support for selected patients who are candidates for lung transplantation.

•Lung transplantation is the only definitive treatment option for most infants with SP-B deficiency and for individuals with severe forms of SFTPC and ABCA3-related surfactant dysfunction. (See 'Lung transplantation' above.)

•Exogenous surfactant may provide transient improvement in lung function for select patients with genetic surfactant dysfunction, but it is not a viable long-term treatment option. Therapy with corticosteroids (in most cases, with concomitant hydroxychloroquine) has been used in patients with ABCA3 and SFTPC sequence variants, but whether these treatments truly provide clinical benefit is unclear. (See 'Pharmacologic therapies' above.)