Genetic Surfactant Protein Deficiencies

Monogenic disorders of pulmonary surfactant production and clearance — surfactant protein B deficiency (SFTPB), surfactant protein C disease (SFTPC), ABCA3 transporter deficiency, NKX2-1-related brain–thyroid–lung syndrome, hereditary pulmonary alveolar proteinosis due to CSF2RA and CSF2RB and syndromic surfactant dysfunction due to TMEM63B, described in 2026 — with expression ranging from fatal neonatal respiratory failure to childhood and adult interstitial lung disease.

Literature and regulatory information updated: 10 October 2026.

0. Initial Reference Table

Table 0.1 summarises each entity grouped in this article, and Table 0.2 the common elements of diagnosis, treatment and organisation of care. The transcripts stated are MANE Select (Matched Annotation from NCBI and EMBL-EBI) obtained through VariantValidator in October 2026 [1].

Table 0.1 — Entities, genes and identifiers

Table 0.2 — Shared elements

1. Introduction

1.1. Pulmonary surfactant and the concept of surfactant dysfunction disorders

Pulmonary surfactant is a mixture of phospholipids and proteins synthesised by type 2 pneumocytes, stored in lysosome-derived organelles, the lamellar bodies, and secreted into the alveolar air–liquid interface, where it lowers surface tension and prevents alveolar collapse at end-expiration. Surfactant protein B (SP-B) is essential to this function: it promotes alveolar stability, raises the collapse pressure of palmitic acid monolayers to approximately 70 mN/m and accelerates film spreading [4]. The ABCA3 transporter, anchored in the lamellar body limiting membrane, pumps phosphatidylcholine and phosphatidylglycerol into its lumen and is necessary for biogenesis of these organelles, where SP-B and SP-C are processed [14, 41]. The balance between production and consumption also depends on alveolar macrophages, which catabolise surfactant under stimulation by granulocyte-macrophage colony-stimulating factor (GM-CSF, granulocyte-macrophage colony-stimulating factor) [28, 42].

The term “surfactant metabolism dysfunction”, used by OMIM (Online Mendelian Inheritance in Man) for SMDP1 to SMDP5 entries, therefore combines two distinct mechanisms. Production deficiencies (SFTPB, SFTPC, ABCA3 and, indirectly, transcription factor NKX2-1) cause type 2 pneumocyte disease with associated interstitial abnormalities; GM-CSF receptor deficiencies (CSF2RA, CSF2RB) cause a clearance disorder with “pure” alveolar proteinosis and preserved alveolar walls [21, 23]. Current PAP classification places CSF2RA/CSF2RB forms among primary PAP, alongside autoimmune PAP, and reserves congenital PAP for surfactant production disorders because treatment and prognosis differ [23, 28].

1.2. Historical and molecular milestones

The first genetic surfactant disorder was described by Nogee and colleagues in 1993, identifying absent SP-B in newborns with fatal congenital alveolar proteinosis [43]. The following year, Hamvas and colleagues documented prenatal diagnosis through absent SP-B in amniotic fluid and showed that administration of SP-B-containing exogenous surfactant from birth did not normalise the patient's surfactant composition or function; the patient died at 54 days while awaiting transplantation [44]. In 2000, Cole and colleagues estimated the population frequency of the most common allele, 121ins2, in Missouri and New York cohorts [3].

In 2001, Nogee and colleagues associated an SFTPC variant with familial interstitial lung disease, establishing the group's first dominantly inherited gene [45]. In 2004, Shulenin and colleagues sequenced ABCA3 in 21 newborns with severe surfactant deficiency of unknown cause and found variants in 16 (76%), including homozygous siblings from five consanguineous families and highly abnormal lamellar bodies on electron microscopy [46].

NKX2-1-related disease has a dual history. Benign hereditary chorea was described as non-progressive familial chorea in a five-generation family by Haerer and colleagues in 1967 [17]. In 2002, Krude and colleagues associated NKX2-1 haploinsufficiency with the combination of choreoathetosis, congenital hypothyroidism and pulmonary abnormalities in five patients, and Breedveld and colleagues associated variants in the same gene, then called TITF-1, with benign hereditary chorea [47, 48]. Willemsen and colleagues coined “brain–thyroid–lung syndrome” in 2005 [49].

Hereditary PAP was established by Suzuki and colleagues in 2008 in two sisters with PAP, poor weight gain and elevated serum GM-CSF, carrying a maternal 1.6 Mb deletion in the pseudoautosomal region encompassing CSF2RA and a paternal p.Gly174Arg variant [50]. In 2011, Tanaka and colleagues described the first CSF2RB defect in a woman diagnosed at 36 years [25]. In 2014, pulmonary macrophage transplantation corrected disease in mice with β-chain deficiency, providing the basis for the first human hereditary PAP gene therapy trial [51, 52].

Clinically, the 2013 American Thoracic Society (ATS) guideline defined infant chILD syndrome and recommended targeted genetic testing of SFTPB, SFTPC, ABCA3 and NKX2-1 [31]. The 2015 European chILD-EU consortium protocols proposed staged investigation and harmonised corticosteroid, hydroxychloroquine and azithromycin regimens through Delphi [32]. The ATS update published in October 2026 replaced targeted testing with rapid exome or genome in infants with respiratory failure and recommended early transplant referral in monogenic diseases with a predictably poor prognosis [5]. In June 2026, TMEM63B was described as a cause of syndromic surfactant dysfunction [27].

1.3. Nomenclature, classifications and identifiers

OMIM numbers the entities as SMDP1 (SFTPB, 265120), SMDP2 (SFTPC, 610913), SMDP3 (ABCA3, 610921), SMDP4 (CSF2RA, 300770) and SMDP5 (CSF2RB, 614370), and NKX2-1-related disease appears as choreoathetosis and congenital hypothyroidism with or without pulmonary dysfunction (CAHTP, 610978) and benign hereditary chorea (118700) [4, 9, 17, 23, 41, 42]. The gene name NKX2-1 replaced TITF-1 and TTF-1 (thyroid transcription factor 1), which persist in pre-2010 literature and immunohistochemistry, and GeneReviews proposes “NKX2-1-related disorders” for the entire spectrum [17].

In Orphanet, SFTPC has two entries: ORPHA:440392 (Interstitial lung disease due to SP-C deficiency), with epidemiological data, and ORPHA:217566 (Chronic respiratory distress with surfactant metabolism deficiency), without an epidemiological record; both refer to autosomal dominant disease. ABCA3 deficiency corresponds to ORPHA:440402 (Interstitial lung disease due to ABCA3 deficiency); ORPHA:2032, associated with OMIM 610921 in some curated databases, denotes multifactorial idiopathic pulmonary fibrosis rather than ABCA3 deficiency. The three entities belong to Orphanet group 100049 (primary interstitial lung disease specific to childhood due to surfactant protein abnormalities) [6, 7, 11, 41].

The chILD Research Network (chILDRN) classification, adopted by the ATS in 2013 and retained in 2026, places “surfactant dysfunction mutations and related disorders” among diseases most prevalent in infancy, and associates each gene with a dominant histological pattern: PAP and a PAP variant for SFTPB, chronic pneumonitis of infancy (CPI, chronic pneumonitis of infancy) for SFTPC, a PAP variant with CPI, desquamative interstitial pneumonia (DIP) and non-specific interstitial pneumonia (NSIP) for ABCA3 [5, 31]. The chILD-EU registry proposed an aetiological classification across all ages in which surfactant metabolism disorders belong to native lung parenchymal diseases [10].

1.4. Definitions and scope of the article

chILD syndrome is defined in an infant with diffuse lung disease (DLD, diffuse lung disease), after common causes are excluded, by at least three of four criteria: respiratory symptoms, respiratory signs, hypoxaemia and diffuse imaging abnormalities; “chILD disease” denotes the syndrome with an identified specific aetiology [5, 31]. SP-B deficiency is disease due to biallelic loss-of-function SFTPB variants; SP-C-related disease, disease due to a heterozygous, typically missense, SFTPC variant; ABCA3 deficiency, disease due to biallelic ABCA3 variants; NKX2-1-related disease, disease due to a heterozygous pathogenic variant or deletion including or regulating NKX2-1; and hereditary PAP, PAP due to biallelic CSF2RA or CSF2RB variants, without anti-GM-CSF autoantibodies [5, 17, 22].

This article addresses childhood disease and adult forms of these genes insofar as they differ from familial pulmonary fibrosis. Adult familial pulmonary fibrosis, telomere genes and SFTPA1/SFTPA2, as well as non-syndromic congenital hypothyroidism, are part of the differential diagnosis, with only the thyroid component of NKX2-1-related disease addressed here.

2. Molecular Genetics and Pathophysiology

2.1. Overview: production, processing and clearance

The diseases in this article affect four points of the surfactant pathway: structural protein SP-B, essential to surface-active function; SP-C proprotein, whose incorrect processing injures the type 2 pneumocyte itself; lipid transporter ABCA3, without which lamellar bodies do not form; and transcription factor NKX2-1, which regulates expression of SFTPB, SFTPC and thyroid genes [4, 9, 41, 53]. Hereditary PAP results not from surfactant deficiency but from its accumulation, because of failed catabolism in alveolar macrophages without GM-CSF signalling [42]. Surfactant consists of about 90% lipids, mainly dipalmitoylphosphatidylcholine and phosphatidylglycerol, and 10% proteins, of which 2–3% are the specific proteins SP-A1, SP-A2, SP-B, SP-C and SP-D; the hydrophobic SP-B and SP-C give the film its surface-active properties and facilitate its adsorption and spreading, whereas the hydrophilic SP-A and SP-D, members of the collectin family, take part in local immunity, in opsonisation and phagocytosis of microorganisms and in the formation of tubular myelin, the intra-alveolar surfactant reservoir; the film is partly recycled by type 2 pneumocytes and degraded by alveolar macrophages and by mucociliary clearance [36]. Table 2.1 compares the mechanisms.

Table 2.1 — Molecular mechanisms by gene

2.2. SFTPB and SP-B deficiency

The SFTPB gene is located at 2p11.2 and encodes SP-B; the MANE Select transcript is NM_000542.5, whereas older clinical series used NM_198843 [1, 4, 55]. Disease results from biallelic loss-of-function variants. Study of an infant prospectively treated from birth showed endogenous surfactant without phosphatidylglycerol, minimum surface tension of 24 dynes/cm (normal <10), which did not decrease on adding SP-B in vitro, and pulmonary vascular permeability twice normal; SP-B was absent from type 2 pneumocytes at autopsy [44]. The study's conclusion — exogenous replacement does not correct disease because endogenous SP-B synthesis is necessary for normal surfactant processing — continues to explain commercial surfactant ineffectiveness [44, 56].

The most common variant is historical 121ins2, a substitution of one nucleotide by three causing a frameshift; in current nomenclature it corresponds to NM_000542.5:c.361delinsGAA, p.(Pro121GlufsTer95) [1, 57]. Complete loss-of-function genotypes predict severe disease; rare hypomorphic alleles with residual function and less severe or late-onset disease exist, including an adult ILD case due to a homozygous variant described in 2026 [5, 10, 58]. The gene encodes a preproSP-B that undergoes several proteolytic cleavages at the N- and C-terminal ends to yield the mature 79-amino-acid peptide (8 kDa); according to the 2021 French PNDS, 121ins2 is present in about two-thirds of cases, among more than 40 pathogenic variants described [36].

2.3. SFTPC and SP-C-related disease

SFTPC is located at 8p21.3; the MANE Select transcript is NM_001317778.2, and historical transcript NM_003018.4 gives the same notation for common clinical variants [1, 9]. Mature SP-C is a very hydrophobic peptide synthesised as a larger proprotein requiring processing and transport by the type 2 pneumocyte. Pathogenic variants are typically heterozygous missense variants causing proprotein misfolding and endoplasmic reticulum stress; injury results from abnormal protein rather than absent mature SP-C, explaining dominance despite one normal allele and the phenotypic continuum between neonatal alveolar filling and fibrosis after decades [8, 9]. The recurrent variant p.Ile73Thr (I73T), NM_001317778.2:c.218T>C, has another mechanism: wild-type SP-C concentrates in acidic lysosomal organelles, whereas SP-C I73T accumulates at the plasma membrane and in enlarged early endosomes, with loss of epithelial polarity in edited alveolar organoids [57, 59, 60]. ProSP-C undergoes palmitoylation and proteolytic cleavages to yield the mature 35-amino-acid peptide (4 kDa). Variants are classified into two groups according to the domain affected: those in the BRICHOS domain, a region with chaperone function required for targeting and insertion of proSP-C into the membrane and subsequently cleaved, and non-BRICHOS variants, such as I73T, with different functional consequences. According to the 2021 French PNDS, I73T accounts for about one-third of cases, among more than 50 variants described, and about half of the variants arise de novo [36].

ClinGen gene–disease validity curation classified SFTPC as definitively associated with dominantly inherited ILD in July 2024 [9]. De novo variants are frequent, requiring trio testing to identify them [5]. Some carriers of pathogenic variants remain asymptomatic, a feature retained in the conceptual figure of the 2013 and 2026 ATS guidelines [5, 31]. SFTPC expression is modulated by drugs: corticosteroids reduce SP-C messenger RNA and favour a less stable protein isoform, and hydroxychloroquine increased proSP-C misfolding and aberrant trafficking in I73T induced pluripotent stem cell (iPSC)-derived cells [10, 56].

2.4. ABCA3 and ABCA3 deficiency

ABCA3 spans approximately 80 kb at 16p13.3 and encodes a 1704-amino-acid protein with two transmembrane domains and two nucleotide-binding domains (NBDs), expressed in the lamellar body membrane; the MANE Select transcript is NM_001089.3 [1, 13, 14]. It belongs to the ABC transporter family, with homology to ABCA1, ABCA4 and the cystic fibrosis transmembrane conductance regulator (CFTR, ABCC7), providing the rationale for experimental CFTR modulator use [46, 61]. Deficiency causes failed lamellar body biogenesis, quantitative and qualitative surfactant deficiency and a characteristic ultrastructural signature: small, densely packed lamellar bodies with eccentric electron-dense inclusions [13, 41].

More than 300 pathogenic variants are described, mostly private [13, 14]. The 2021 French PNDS cited more than 200, classified as null, non-null with residual function and “other”, and gave for E292V a frequency of 0.4% in the general population of European ancestry; this value approximates the allele frequencies below 0.4% in population-based cohorts from Missouri and other countries, and does not match the proportion of European heterozygous carriers in gnomAD, of about 1.15% [14, 36, 62]. The most widely used functional classification separates “null” variants (nonsense, frameshift, splicing changes destroying the transcript, exon deletions with frameshift), without functional protein, from “other” or hypomorphic variants (missense, in-frame indels, partial splicing, distal nonsense), with residual function [13, 14, 63]. In cellular models, type 1 variants (e.g., L101P, historical notation = NP_001080.2:p.(Leu101Pro)) alter trafficking to LAMP3+ vesicles, and type 2 variants (E292V and E690K, = NP_001080.2:p.(Glu292Val) and p.(Glu690Lys)) phospholipid transport; lentiviral complementation with wild-type ABCA3 partially rescued lamellar body morphology and attenuated aberrant NF-κB signalling only in type 2 [54]. Missense variant hotspots lie in the first extracellular domain and second NBD, where the Walker A motif binds ATP, but variants outside the NBDs, such as NP_001080.2:p.(Gly202Arg) and p.(Pro246Leu), may also be severe [14]. In the Munich registry, variants in intracellular helix 2 and segment TMD2_P1 were associated with longer survival, and helix 2 variants with death before 1 year [63].

Variant p.(Glu292Val), NM_001089.3:c.875A>T, is most frequent in clinical series, lies in the second intracytoplasmic helix and reduces, without abolishing, ATP hydrolysis; it has approximately 1.15% heterozygous carriers in the European population and up to 20 homozygotes in gnomAD v4.1, and accounts for up to 35.7% of long-term survivors in adult series [14, 57]. p.(Ser1262Gly) is also described as hypomorphic, with 0.5% European carriers, but has conflicting ClinVar classifications [14, 57]. In 11% of patients in the Washington series, both variants were in cis, and complex alleles and uniparental isodisomy have been documented, making parental testing mandatory before irreversible decisions [13, 14, 61].

2.5. NKX2-1 and brain–thyroid–lung syndrome

NKX2-1 is located at 14q13.3 and encodes homeobox protein Nkx-2.1, essential for basal ganglia, lung and thyroid organogenesis; it activates thyroglobulin, thyroid peroxidase and thyroid-stimulating hormone (TSH) receptor promoters, and participates in globus pallidus and striatal cholinergic neuron development, lung branching, surfactant production and maintenance of thyroid architecture [17, 64]. The MANE Select transcript is NM_001079668.3 (three exons, where most variants are described); GeneReviews uses version .2 and short transcript NM_003317.3 is not MANE [1, 17]. The mechanism is haploinsufficiency. Functional studies of homeodomain variants, such as p.(Tyr214Cys), showed absent transactivation of SFTPB, SFTPC, TG and TPO, with absent pro-SP-C and SP-C in the biopsy of an infant with the most severe respiratory phenotype described [53].

The variant spectrum includes single-nucleotide variants, gene deletions, contiguous 14q deletions (e.g., 14q12-q21.1 in a Colombian newborn with RDS, hypothyroidism and seizures), proximal deletions and an adjacent 3.5 Mb deletion not interrupting the gene [17, 65, 66]. Downstream structural variants without coding changes accounted for 27% of NKX2-1 diagnoses in a cohort of 26 chorea patients; in 8 families (13 affected individuals), downstream deletions caused chiefly neurological manifestations and complex rearrangements the complete triad [29].

Genotype–phenotype correlation is limited and intrafamilial variability occurs [17]. In the international registry of 68 individuals published in 2026, deletions were associated with better gross motor function, frameshift and nonsense variants with greater respiratory involvement, and homeodomain variants (exon 3) with decreasing chorea with age [18]. The 2021 French PNDS cites more than 50 variants, point variants or large deletions encompassing the whole gene or contiguous genes [36]. No other germline allelic phenotypes are known; somatic NKX2-1 variants occur in papillary thyroid carcinomas and sporadic lung adenocarcinomas [17].

2.6. CSF2RA and CSF2RB: hereditary PAP

The GM-CSF receptor is a heterodimer of a low-affinity α chain (CD116), encoded by CSF2RA in pseudoautosomal region 1 of chromosomes X and Y, and a common β chain (CD131), encoded by CSF2RB at 22q12.3 and shared with interleukin 3 and interleukin 5 receptors [21, 23, 42]. GM-CSF binding activates β-chain-associated JAK kinases and phosphorylates STAT5; without this signalling, alveolar macrophages do not mature or catabolise surfactant phospholipids and cholesterol [42]. As the ligand is not consumed, serum GM-CSF is elevated, a central diagnostic finding [21, 22].

The CSF2RA spectrum includes missense, nonsense, frameshift and splicing variants (e.g., c.1125+1G>A), exon duplications and deletions of several exons or the entire locus, including Xp22.3/Yp11.3 deletions [21, 22]. Variant p.Gly174Arg eliminates an N-glycosylation site in the cytokine-binding domain; signalling, markedly reduced at physiological concentrations, is partially restored at high GM-CSF concentrations, explaining slow progression in some patients [50]. Genetic damage extent does not predict severity: individuals homozygous for whole-gene deletion are not systematically more severely affected than missense variant carriers [21]. In CSF2RB, Tanaka's single-base deletion in exon 6 corresponds to c.631del, p.(Arg211Glufs*54), and variant c.631C>T, p.(Arg211*), NM_000395.3, was described in homozygosity in a Greek man [24, 25]. ClinVar records far more variants of uncertain significance (VUS) than pathogenic variants for CSF2RB (491 VUS versus 17 pathogenic in the September 2026 count), giving functional tests a role in interpretation [23].

2.7. TMEM63B and other recently identified genes

In 2026, Chan and colleagues, using chILD-EU registry and Undiagnosed Diseases Network data, described biallelic loss-of-function TMEM63B variants (two splice-donor splicing variants, two nonsense and one frameshift) in five individuals from four families, with family segregation and functional studies in three families; the Tmem63b-knockout mouse dies of neonatal respiratory failure due to deficient surfactant secretion [27]. The 2026 ATS guideline also includes RAB5B and LAMP3 among surfactant dysfunction genes and mentions recently identified aminoacyl-tRNA synthetase diseases (LARS, FARSA, FARSB) with early lung disease and multisystem involvement, detectable only by exome or genome when absent from panels [5].

2.8. Normalised variants

Table 2.2 presents variants with historical names frequent in the literature, normalised by ClinVar and VariantValidator on GRCh38. “121ins2” requires care: ClinVar also records NM_000542.5:c.361_362insAA, a variant distinct from classical 121ins2 [57].

Table 2.2 — Recurrent or historical variants

Other historical ABCA3 designations (IVS25-98C>T, F1203del) and CSF2RA variant p.Gly174Arg appear in the series with their original nomenclature and remain as published designations; c.3997_3998delAG corresponds to NM_001089.3:c.3997_3998del p.(Arg1333GlyfsTer24) [13, 50]. The 2021 French PNDS writes 121ins2 as p.(Asp121Glufs*95); ClinVar (record 13201, accessed in November 2026) and VariantValidator assign residue 121 to a proline, so the correct notation is p.(Pro121GlufsTer95) [1, 36, 57].

2.9. Modifiers, heterozygosity and allelic diseases

Heterozygosity for ABCA3 is not recessive disease but acts as a risk factor. Garmany and colleagues found E292V in 3.8% of newborns with RDS, ten times more than in the Missouri population cohort, without a second loss-of-function variant in carriers [62]. Wambach and colleagues, using pooled sequencing of newborns at ≥34 weeks, showed that a single ABCA3 variant was more frequent in newborns of European ancestry with RDS (14.3% vs 3.7%; p=0.002), without statistical significance in those of African ancestry (4.5% vs 1.5%; p=0.23), and estimated that these variants account for approximately 10.9% of the attributable risk of RDS at term and late preterm [12]. In 2026, in a North American series of 48 infants with a monoallelic variant and neonatal RDS, 8 (17%) were discharged on oxygen, and E292V was the most common variant in that group (6/8) [67]. GeneReviews on pulmonary fibrosis predisposition, by contrast, states that heterozygotes are asymptomatic and without disease risk; this divergence is resolved by distinguishing biallelic disease, absent in carriers, from a modest population-based neonatal risk documented in association studies [8, 12].

In adults, SFTPC accounts for 1–5% and ABCA3 less than 1% of familial pulmonary fibrosis, with phenotypes including combined fibrosis and emphysema and atypical upper-lobe involvement [8, 68–70]. These forms are part of the differential diagnosis, as are SFTPA1/SFTPA2-related diseases, associated with lung adenocarcinoma [8, 71, 72]. Overall, surfactant system genes are the second genetic cause of adult ILD, after the telomerase complex genes; the 2021 French PNDS includes SFTPA1 and SFTPA2 in its scope, with dominant inheritance, incomplete penetrance, predominantly adult phenotypes (fibrosing ILD and lung adenocarcinoma) and a fatal paediatric case due to a SFTPA1 variant [36].

3. Clinical Spectrum and Manifestations by System

3.1. Common presentation: chILD syndrome and neonatal respiratory failure

In infant diffuse lung disease, tachypnoea is the most prevalent sign (75–93% of patients); hypoxaemia, crackles and cough are common, some infants have wheeze or normal auscultation and poor weight gain is frequent [31]. Up to one third of children with chILD have normal auscultation, and desaturation may occur only during sleep, feeding or physical activity [10]. Genetic surfactant disorders manifest as neonatal respiratory failure or chILD syndrome; imaging shows diffuse ground-glass opacities with subsequent cystic lucencies, and histology combines type 2 pneumocyte hyperplasia, proteinaceous material, cholesterol clefts or macrophages in airspaces and fibrous septal expansion [5]. In the neonatal period, severe hypoxaemic respiratory failure with pulmonary hypertension (PH) may result from SP-B deficiency, ABCA3 deficiency, possibly SP-C deficiency, and alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) [31].

Circumstances of discovery vary with age [35, 36]. In term newborns, respiratory distress persists despite oxygen and ventilatory support, sometimes with PH, and transient improvement after intratracheal instillation of exogenous surfactant is common. In infants, symptoms develop progressively or persist after a common viral infection, such as bronchiolitis: dry cough, tachypnoea, difficulty and fatigue during feeds, retractions, cyanosis, sometimes wheeze and oxygen dependence, with faltering weight and then height gain because of feeding difficulty and increased energy expenditure; rarely, presentation is decompensated PH, fever or haemoptysis. In older children and adults, onset is insidious over weeks or months (dyspnoea during play and then on exertion, cough), sometimes revealed by acute decompensation during an infection or already in chronic respiratory failure with digital clubbing, cyanosis and poor weight gain; in adults it may be an incidental finding. Diagnosis may also result from family screening and, rarely, the molecular diagnosis of a child reveals the disease in a parent. Most diagnoses are made in the neonatal period or the first years, except in SFTPA1/SFTPA2-related diseases, which present mainly in adulthood; in the French network, mean age at diagnosis of childhood interstitial lung disease was 1.5 years. Chest deformity (subcostal groove, asymmetry, spinal deformity) may occur, secondary to chronic retractions or fibrotic distortion [35, 36].

3.2. SP-B deficiency

The classical phenotype is a term or late-preterm newborn with respiratory distress in the first hours, initially indistinguishable from hyaline membrane disease, without a sustained response to exogenous surfactant and progressing to respiratory failure; radiography shows a diffuse granular or ground-glass pattern that persists and progresses [4]. The pathological correlate is congenital alveolar proteinosis, with flocculent periodic acid–Schiff (PAS)-positive material derived from surfactant phospholipids and proteins [4, 43]. Without transplantation, biallelic loss of function leads to death or transplantation within the first months, between 3 and 6 months in most series [5, 56]. It is the rarest genetic surfactant deficiency [56]. Rare patients with partial deficiency had late presentation and prolonged survival, and an adult-onset ILD case due to a homozygous variant was published in 2026 [4, 58].

3.3. SP-C-related disease

SP-C-related disease has highly heterogeneous expression, with variable penetrance and intrafamilial variability: some carriers are asymptomatic, others present with tachypnoea, hypoxaemia, cough and poor weight gain in infancy, and others develop fibrosing ILD in childhood or adulthood [9, 56]. In infants, diffuse lung disease is associated with PAS-positive material in airspaces; biopsy typically shows CPI, with uniform alveolar epithelial hyperplasia, mild interstitial widening with lymphocytes, patchy accumulation of foamy macrophages and cholesterol clefts [9, 31]. In adults, disease may present at any age, often with usual interstitial pneumonia and progressive fibrosis without recognised childhood lung disease, and with atypical radiological patterns including combined fibrosis and emphysema and upper-lobe involvement [8, 34, 73].

Childhood evolution is variable. In follow-up of 17 children for a median of 3 years (0.9–19), progression occurred in 3 (17.6%) despite treatment, stability in 7 (41.1%) and improvement in 7 (41.1%), one apparently cured [34]. Five children with biopsy-diagnosed ILD and subsequently confirmed SFTPC variants, followed for a mean of 27.2 years, reached adulthood: three felt well and had normal lung function, and two women with residual restrictive disease had normal activity and healthy children [34]. In a French series of 22 infants with onset around 3 months, 16 stopped oxygen after a mean of 10.9±5.9 months and 4 remained on oxygen after 32±14.6 months [56]. Relapse and progression to refractory fibrosis may occur after years of relative stability [34]. In adults transplanted in France for surfactant gene-associated ILD, the 8 SFTPC variant carriers were diagnosed around 45 years and most had usual interstitial pneumonia in the explant [74].

3.4. ABCA3 deficiency

ABCA3 deficiency is the most frequent genetic cause of chILD and the leading cause of chILD at birth [14, 63]. Disease is limited to the lung. Three forms are distinguished: severe neonatal disease in a term or near-term newborn with hypoxaemic respiratory failure within hours to days, unexplained by prematurity, infection or meconium aspiration, potentially responding transiently to surfactant but without improvement after the first week; chronic chILD, from birth to early years, with cough, crackles, tachypnoea, poor weight gain, clubbing and slowly declining or stable lung function; and adolescent- or adult-onset pulmonary fibrosis [13, 41, 75]. Table 3.1 summarises the main cohorts; lung function is expressed by forced vital capacity (FVC) and forced expiratory volume in one second (FEV1).

Table 3.1 — Cohorts of patients with biallelic ABCA3 variants

The cohorts measure different things: Washington includes very severely affected patients referred for genetic investigation, Munich selects first-year survivors, and the French cohort includes only children with ILD diagnosed before 18 years; none estimates a genotype's lifetime risk [13, 14, 63]. Null/null genotypes are uniformly fatal in infancy without transplantation; in the remainder, evolution is variable and genotype explains only part of it. In the French series, genotype-specific survival at last observation (null/null 0/2, null/other 4/8, other/other 6/26) did not differ significantly, whereas neonatal onset (p=0.009), PH (p=0.037) and a Fan severity index of 5 (10/11 died in the neonatal period) were associated with poorer prognosis [14]. In two sibling pairs, the second child had a better course than the first, suggesting the influence of neonatal management, modifier genes or environment [14].

In first-year survivors, more than half required oxygen over the next 6 months, approximately 10% still used it after 16 years, and median survival was 9.7 years (95% confidence interval, 95% CI, 6.7–27.7) in those never requiring oxygen versus 3.0 years (1.5–5.0) in those persistently dependent (p=0.0126) [63]. Computed tomography (CT) evolves from diffuse ground-glass opacities in the first year to patchy ground-glass opacities, reticular opacities and parenchymal cysts, whose frequency rises from approximately 10% to approximately 60% after 2 years and may mark progression [14, 63]. Histology varies with age between PAP, DIP, NSIP and CPI [63, 75].

In adults, presentation is ILD with ground-glass opacities, reticulation and upper-predominant cysts; an E292V homozygote with onset at 25 years and transplantation at 47 has been described [8, 14]. Adult fibrosing forms include combined fibrosis and emphysema and a large Italian family with a new variant [69, 70].

3.5. NKX2-1-related disease

The spectrum ranges from isolated benign hereditary chorea to complete brain–thyroid–lung syndrome. In a review of 46 individuals, 50% had the triad, 30% only brain and thyroid involvement and 13% only chorea [17, 77]. In the international registry of 68 individuals (median age 16 years, 2–60), motor delay was the most common presentation (approximately 60%), chorea was present in more than 90%, neonatal RDS in one third and the triad in almost half; more than one third had psychiatric comorbidity, chiefly attention deficit hyperactivity disorder (ADHD) [18].

Neurological manifestations begin in the first year of life or, less often, late childhood. Chorea affects the face, tongue, neck, trunk and limbs, worsens with stress and disappears during sleep, progresses until the second decade and then stabilises or remits; hypotonia, motor delay and incoordination are common in infants and tend to improve [17]. In a series of 28 individuals from 13 families followed for a mean of 24.5 years, all had chorea and hypotonia, generally mild, improving until puberty or early adulthood [78]. Dysarthria, learning and attention difficulties, seizures and, rarely, psychosis have been described, and two siblings were initially diagnosed with ataxic-dyskinetic cerebral palsy [17]. Hypotonia and untreated hypothyroidism were associated with more severe chorea [18]. Neuroimaging is generally normal, and neuropathology in two cases showed reduced striatal and neocortical interneurons, consistent with a migration defect rather than neurodegeneration [17].

Pulmonary dysfunction is the second most frequent manifestation: up to 49% (61/124) in a meta-analysis of 29 reports [17, 78]. Neonatal RDS, with or without PH, is the most common form, and neonatal PH is described as a characteristic form of respiratory distress in this disease [17]. Neuroendocrine cell hyperplasia, ILD between 4 months and 7 years, recurrent pulmonary infections, asthma and fibrosis in older individuals complete the spectrum; histology may show desquamative interstitial pneumonia, foamy macrophages and PAP [17, 79]. Three infants died of respiratory failure in the immediate postnatal period, but respiratory function improves with time in most [17, 80–82]. In 2025, three French infants with lethal chILD were described [53]. At least two unrelated individuals and three family members with lung disease had no neurological symptoms [79]. Lung carcinoma risk begins in the early third decade [17, 83].

Thyroid dysgenesis causes primary congenital hypothyroidism or compensated hypothyroidism (low-normal T4 with elevated TSH): 40 of 46 individuals had overt or subclinical hypothyroidism, and imaging showed hypoplasia or hemiagenesis in 11/31 and agenesis in 3/31 [17, 77]. Iodide uptake may be reduced, with a positive perchlorate test, suggesting a dyshormonogenesis component [84]. Hypodontia, vesicoureteral reflux, hypogonadotrophic hypogonadism, growth hormone deficiency and septal heart defects have been described in isolated cases [17].

3.6. Hereditary PAP due to CSF2RA and CSF2RB

Hereditary PAP manifests as insidious progressive dyspnoea, hypoxaemia, exercise intolerance, poor weight gain in children and secondary infections; prolonged disease may progress to fibrosis [42]. In Suzuki's series of eight children, six had progressive dyspnoea at 4.8±1.6 years and two were asymptomatic at 5 and 8 years [22]. In the European series of nine children from the Kids Lung Register (Belgium, Germany, Turkey, Iran and Spain), median onset age was 3.5 years (0.2–19) and diagnostic age 5.3 years; chronic tachypnoea with dyspnoea occurred in 78%, poor weight gain in 78%, severe pulmonary infections before diagnosis in 67% and intubation for global respiratory failure in 33%. Earlier onset was associated with a more severe phenotype (p=0.0092), and there was discordance between sisters with the same variant and an asymptomatic homozygote [21]. The authors propose that a severe infection acts as a trigger disrupting surfactant homeostasis [21].

Disease is limited to the lung, without a consistent haematological or eosinophilic phenotype [23]. Imaging and histology are indistinguishable from autoimmune PAP [22]. CSF2RB-related PAP is rarer and may begin in adulthood: the index case was diagnosed at 36 years and the same alteration was associated with PAP recurrence in the graft and fibrosis after bilateral lung transplantation [24–26]. Female predominance in the series (7/8 and 7/9) does not correspond to X-linked inheritance [21, 22].

3.7. Syndromic TMEM63B-related dysfunction

The five individuals described had early respiratory distress, chronic hypoxaemia and diffuse parenchymal abnormalities; one died in childhood, two received bilateral lung transplants and two remained on oxygen. Histology showed alveolar simplification, type 2 pneumocyte hyperplasia and interstitial fibrosis. All had developmental delay, chiefly language delay, and one had white matter abnormalities and another mild cerebral atrophy, without epilepsy [27].

3.8. Survivors in adulthood

In a European study of 34 centres, 244 chILD survivors had a median age of 25 years, median FVC of 70% predicted and diffusing capacity for carbon monoxide (DLCO) of 48%; 32% used long-term oxygen, 60% still took corticosteroids and surfactant-related disorders accounted for 21% of diagnoses. After transition, diagnosis was respecified in 9.8% and treatment in 16% [85]. Health-related quality of life, measured in the chILD-EU registry in 424 patients, was lower after recent hospital admission and with poor weight gain, and correlated weakly with lung function [86].

4. Clinical Recognition and Warning Signs

4.1. Newborn

Suspicion should arise in a term or late-preterm newborn with respiratory distress unexplained by prematurity, infection or meconium aspiration, with absent or merely transient (hours) response to exogenous surfactant, increasing oxygen or ventilation requirements, or disproportionate PH [4, 41, 56]. Family history of neonatal respiratory failure, unexplained neonatal death, childhood or adult ILD, and consanguinity increase recessive disease probability (SFTPB, ABCA3); absence of consanguinity or family history does not exclude diagnosis because of de novo variants, compound heterozygosity and minimally symptomatic relatives [10, 31, 33]. Respiratory distress with congenital hypothyroidism and hypotonia points towards NKX2-1, and refractory PH with cardiac, gastrointestinal or genitourinary malformations towards FOXF1-related ACDMPV [31].

TSH-based newborn congenital hypothyroidism screening detects the thyroid component of NKX2-1-related disease, which is primary; a positive result in a newborn with respiratory distress should prompt questions about family history of neonatal respiratory distress and movement disorders [17, 84]. Where hypothyroidism screening is not routine, newborns with familial risk should be screened [17]. No newborn screening exists for surfactant deficiencies [4].

4.2. Infant and child

In infants, suspicion rests on chILD syndrome criteria: resting tachypnoea, retractions, crackles, clubbing, poor weight gain, hypoxaemia (including desaturation only during sleep, feeding or exertion) and diffuse imaging abnormalities, after exclusion of cystic fibrosis, immunodeficiency, congenital heart disease, bronchopulmonary dysplasia, infection, primary ciliary dyskinesia and recurrent aspiration [5, 10, 31]. Diffuse lung disease with poor weight gain and alveolar proteinosis suggests GM-CSF receptor deficiency, and hepatomegaly or elevated liver enzymes with PAP suggests MARS1 [31, 33]. In older children, non-progressive chorea with hypotonia, ataxia and motor delay, particularly with hypothyroidism or lung disease, suggests NKX2-1; chorea initially classified as dyskinetic cerebral palsy should be reassessed [17].

The French PNDS detail the history and examination oriented towards these diseases [35, 36]. The history records the origin of both parents (no known ethnic predominance), consanguinity (especially for SFTPB and ABCA3), extended family history of ILD, pulmonary fibrosis and lung adenocarcinoma, with a pedigree, personal and family history of neonatal respiratory distress and of transient response to exogenous surfactant, involvement of other organs (hypothyroidism, hypotonia, chorea), arthralgia and other signs of systemic disease, exposure to tobacco smoke and pneumotoxic drugs, and also cough, exertional or resting dyspnoea, feeding difficulty, limitation of activities, cyanosis, growth curve, vomiting, oral feeding disorders and gastro-oesophageal reflux. Examination includes weight, height, head circumference and temperature, resting respiratory rate, retractions, digital clubbing, cyanosis, chest or spinal deformity, crackles and spot or prolonged overnight oximetry according to severity, and looks for signs of malnutrition, PH, and neurological, thyroid or joint signs [36].

4.3. Adolescent and adult

Pulmonary fibrosis beginning before 30 years, or with a wide range of onset ages among affected family members, suggests SFTPC or ABCA3; PAP without anti-GM-CSF autoantibodies, or unclassifiable PAP, warrants genetic testing of CSF2RA/CSF2RB at any age [8, 24]. Family history of lung adenocarcinoma directs towards SFTPA1/SFTPA2 [10].

4.4. Signs of urgency

Urgent signs are increasing oxygen or ventilatory support requirements, use of inhaled nitric oxide or extracorporeal membrane oxygenation (ECMO), progressive PH and impending respiratory failure in known chILD; in these situations, the 2026 ATS guideline recommends rapid genetic testing and suggests early referral for transplant assessment [5]. In children with hereditary PAP, intubation for global respiratory failure occurred in one third of the European series [21].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. chILD syndrome criteria

The 2013 ATS definition, retained in 2026, applies to infants under 2 years and does not include pulmonary function tests because these are not always available (Table 5.1). It is a sensitive definition whose specificity has not been determined or studied prospectively [5, 31].

Table 5.1 — chILD syndrome (≥3 of 4 criteria, after common causes are excluded)

Source: [5, 31].

All patients with diffuse lung disease should be assessed for immunodeficiency, which does not exclude a chILD diagnosis; gastro-oesophageal reflux with aspiration coexists in 26–49% of children diagnosed with chILD, without proven causality [31].

The 2017 French PNDS uses the same rule of three out of four clinical or radiological criteria, after other chronic lung diseases have been excluded [35]. The 2021 PNDS defines surfactant disease by the presence of ILD and molecular confirmation, and accepts that, in rare cases, the disease is strongly suggested by CT or biopsy without the molecular change being identified by the available techniques: a negative molecular study does not exclude the diagnosis. It recommends discussion of cases at a multidisciplinary team meeting (MDT), with national ILD MDTs organised by the RespiFIL network and genetics MDTs for familial ILD, and organises the approach in three stages: diagnosis of ILD, search for the genetic cause and assessment of its impact [36].

5.2. Algorithms: ATS 2013, European protocols and ATS 2026

The 2013 ATS recommended phenotype-directed tests: SFTPB, SFTPC and ABCA3 in newborns with severe, rapidly progressive disease or a family history (strong); NKX2-1 with congenital hypothyroidism and hypotonia (strong); FOXF1 in refractory PH (weak); SFTPC and ABCA3 in undiagnosed infants beyond the neonatal period (strong); and CSF2RA/CSF2RB with serum GM-CSF in infants with alveolar proteinosis and negative SFTPC/ABCA3 results (weak) [31]. The rationale was that approximately 25% of infants with severe refractory diffuse lung disease had an SFTPB, SFTPC or ABCA3 variant, and that beyond the neonatal period, SFTPC accounted for up to 17% and ABCA3 for 5–22% of cases, in selection-biased series [31]. The 2015 chILD-EU protocols and the 2023 ERS Clinical Research Collaboration review propose a two-stage investigation — general paediatrician (clinical and family history, blood tests, radiography, echocardiography) and specialist centre (high-resolution CT, bronchoalveolar lavage, specific tests, function tests, genetics and possibly biopsy, in a multidisciplinary meeting) — and place genetics before lavage and biopsy [32, 33]. The French pathway follows the same logic: the initial assessment is carried out in a reference or competence centre of the RespiRare network, during a short admission, day-hospital visit or outpatient appointment, and includes radiography and HRCT, oximetry and, if necessary, blood gases, function tests when age allows, thyroid, nutritional and pre-treatment laboratory assessment, BAL, pH monitoring if reflux is suspected, echocardiography, genetic study at a genetics clinic and, in selected cases, biopsy [35, 36].

The 2026 ATS update changed the order and method (Table 5.2). It recommends rapid broad genetic testing — preliminary result within 7 days of sampling, by exome or genome rather than a single gene or panel — in infants with chILD syndrome and respiratory failure in whom potentially fatal diseases (SFTPB, ABCA3, FOXF1) are considered; the panel raised strength from conditional to strong, with very low certainty of evidence [5]. It also suggests genetic testing before an invasive intervention, chest CT in diagnostic assessment and biopsy when other tests have not identified disease and there is no improvement, and recommends biopsy when urgent and genetics is not feasible, timely or conclusive [5]. Guideline Figure 3 proposes broad untargeted genetic testing when cystic fibrosis, primary ciliary dyskinesia or PH are also in the differential [5].

Table 5.2 — Diagnostic and referral recommendations: ATS 2013 and ATS 2026

Source: [5, 31, 33].

5.3. Genetic testing: methods, yield and limitations

In the 2026 ATS systematic review (9 registry studies with 26 to 790 children), only 55% (10–70%) of children under 2 years with chILD syndrome had undergone genetic testing; a monogenic diagnosis was obtained in 26% (17–41%), approximately 70% remained undiagnosed, approximately 8% had VUS, and one study reported 28% false negatives (2 of 7 patients with non-diagnostic genetics and suggestive histology) [5]. When genetic surfactant dysfunction was suspected, yield was 21% (6–36%), with SFTPC (5–83%), ABCA3 (11–48%) and SFTPB (0–24%) the most frequent genes and substantial variation by phenotype and ancestry [5]. In a study cited by the guideline, trio exome sequencing in 36 children identified 5 pathogenic variants, only one of which would have been detected by a 75-gene chILD panel [5]. The European review estimates a genetic cause in approximately 20% of chILD, and up to 20–30% in some series, and recommends genetic analysis in all children with unexplained chronic ILD [33]. The 2021 French PNDS extends the recommendation to all paediatric and young adult patients with chronic ILD, sporadic or familial, without another cause, with prior information on the implications for the patient and relatives and written informed consent; it provides for next-generation sequencing of the six genes SFTPA1, SFTPA2, SFTPB, SFTPC, ABCA3 and NKX2-1 in the index case, Sanger testing for the variants in relatives and study of both parents to establish segregation and inherited or de novo status; any positive result is followed by a genetic counselling appointment, which is presymptomatic when the gene carries a risk of fibrosis or lung adenocarcinoma in adulthood [36]. This targeted panel diverges from the later 2026 ATS recommendation of rapid exome or genome sequencing in infants with respiratory failure; the two documents agree on the need for parental study and counselling [5, 36].

Table 5.3 — Sequencing approaches (2026 ATS guideline supplement)

Source: [5].

Test limitations have concrete consequences in this group. Exome sequencing may miss non-coding regions, such as upstream FOXF1 deletions and downstream NKX2-1 regulatory structural variants; in a chorea cohort, exome with CNV analysis captured 92% of diagnoses only when the downstream region was assessed as a target [5, 29]. Deletions are frequent in FOXF1, NKX2-1 and CSF2RA, so testing should include CNV detection; in NKX2-1-related disease, GeneReviews advises sequencing, then targeted deletion and duplication analysis and, if both are negative, chromosomal microarray (CMA) [5, 17, 42]. Exon sequencing does not detect deep intronic variants, promoter variants or large ABCA3 deletions [13]. Trio testing identifies de novo variants (frequent in FOXF1, NKX2-1 and SFTPC) and allows phasing of variants in trans in recessive diseases; in ABCA3, 11% of patients in one series had both variants in cis [5, 13]. In silico classification of a variant as hypomorphic may not reflect its actual function [63]. A negative result does not exclude disease, and exome or genome reanalysis after an interval is recommended, although optimal timing is undefined [5, 33].

In NKX2-1-related disease, Table 5.4 shows the proportion of probands and families with a variant detectable by each method according to HGMD data; this is the proportion of known variants detectable by each technique rather than clinical test sensitivity [17].

Table 5.4 — NKX2-1-related disease: variants detectable by method

Source: [17].

The report should state the gene, versioned transcript (e.g., NM_001089.3 for ABCA3), variant in HGVS (Human Genome Variation Society) nomenclature, zygosity, variant phase when known and classification according to American College of Medical Genetics and Genomics and Association for Molecular Pathology (ACMG/AMP) criteria; for ABCA3 variants, predicted functional class (null or hypomorphic) should be stated [14, 87]. A VUS neither establishes nor excludes diagnosis; family segregation, histology and, in PAP, functional tests help reclassification [17, 23]. Interpretation and communication should involve a clinical geneticist or genetic counsellor, and the 2026 ATS guideline lists undesirable effects of broad testing: anxiety associated with VUS and negative results, disclosure of consanguinity or non-paternity, incidental findings, privacy and insurance issues and scarcity of experts [5].

5.4. Imaging

High-resolution CT (HRCT) is first-line imaging, performed at a paediatric centre using the lowest adequate dose, with controlled ventilation or free breathing provided the protocol is reproducible; contrast is justified only with PH or suspected pulmonary vein stenosis [5, 33]. In hereditary surfactant disorders, infants have dense diffuse ground-glass opacities and older children ground-glass opacities with peripheral cysts, traction bronchiectasis and reticulation; crazy paving suggests alveolar proteinosis [33]. Figure 2 of the 2026 ATS guideline illustrates ground-glass opacities with cystic lucencies in a 4-month-old infant with ABCA3 deficiency, and diffuse ground-glass opacities in a 4-month-old infant with SFTPC-related disease and another aged 2 months with NKX2-1 [5]. Patterns are not diagnostic and are confounded by acute illness and prolonged ventilation [5]. The guideline supplement's radiological algorithm groups findings into architectural distortion, hyperinflation, air trapping or cysts; ground-glass opacities; and interlobular septal thickening, and proposes genetic testing or biopsy if suspicion persists with normal CT [5].

The French PNDS add details of technique and interpretation [35, 36]. Frontal radiography, without other views, is the first-line examination: it shows diffuse ground-glass opacities and, in more advanced stages, reticulation, and may be normal, especially in asymptomatic carriers. HRCT is performed in most cases without sedation, after a feed in infants or with simple restraint before 4–5 years, during quiet breathing before 5–6 years and in inspiratory breath-hold thereafter; in adults, with millimetric slices, forced inspiration and sometimes in the prone position. Intravenous contrast is not systematic and is used to look for pulmonary artery dilatation suggestive of PH or, in adults during an exacerbation, thromboembolism. In infants, diffuse ground-glass opacities predominate, sometimes confluent and with density close to consolidation, with interlobular septal thickening, intralobular reticulation and sometimes cysts; in older children and adults, ground glass tends to decrease and signs of fibrosis appear (reticulation, honeycombing, traction bronchiectasis and bronchiolectasis, subpleural cysts). Lung ultrasound defines an interstitial syndrome by the presence of at least three B-lines per intercostal space, separated or confluent, with irregularity or thickening of the pleural line and reduced sliding; it has good sensitivity but low specificity in adult studies and does not replace CT, its role in follow-up being under evaluation. Magnetic resonance imaging with ultrashort echo time sequences gives images close to those of CT, but is not used in routine practice [36].

5.5. Bronchoalveolar lavage, biopsy and electron microscopy

Bronchoalveolar lavage (BAL) serves chiefly to exclude infection, found in approximately half of immunocompromised and one third of immunocompetent infants with diffuse infiltrates [31]. Milky BAL with granular PAS-positive material and hypocellularity indicates alveolar proteinosis and should prompt investigation for surfactant dysfunction, GM-CSF pathway defects and lysinuric protein intolerance [31]. BAL pro-SP-C measurement and surfactant protein Western blot are not routine [31, 33].

In the 2021 French PNDS, BAL fluid may be milky, with PAS-positive lipoproteinaceous aggregates reflecting some degree of proteinosis, especially in SP-B deficiency; it may show neutrophilic alveolitis, signs of alveolar haemorrhage on Perls staining or lipid-laden macrophages on Oil Red O staining, suggestive of reflux or microaspiration, or be normal; it allows a search for concomitant infection and, in adults, tumour cells, given the increased risk of bronchial cancer. Electron microscopy and surfactant protein expression studies in BAL fluid are performed only in research [36]. The 2017 PNDS describes standardised processing (volume and appearance, cell count, cytocentrifugation, May-Grünwald-Giemsa, Papanicolaou, Perls and PAS stains, and Ziehl and Grocott when indicated, with storage of supernatant and cell pellet) and reference values in children (Table 5.5) [35].

Table 5.5 — BAL reference values in children without parenchymal disease (mean ± standard deviation)

Source: [35], which brings together four paediatric series compiled by the ERS task force on BAL in children. ND, not determined.

Surgical lung biopsy by VATS or minithoracotomy has diagnostic utility of 81–100% under 2 years and changes management in 57–63% of these patients (corticosteroid dose or transition to palliative care); risks include mortality of <1–3%, pneumothorax in approximately 15%, bleeding and more intensive care days, and transbronchial biopsy or cryobiopsy are generally inappropriate in infants [5, 10, 33]. The sample should be divided for formalin histology, culture, freezing (including somatic genetics) and glutaraldehyde for electron microscopy, with haematoxylin–eosin, PAS, Perls, Grocott, reticulin and Masson stains and immunohistochemistry for TTF-1 and surfactant proteins [31, 33]. Electron microscopy shows small dense lamellar bodies with eccentric inclusions in ABCA3 deficiency, characteristic in all adequate samples in the Houston series, but neither establishes genotype nor reliably distinguishes other surfactant disorders [41, 75]. In SP-B deficiency, absent SP-B immunostaining in type 2 pneumocytes and improperly processed proSP-C strongly support the diagnosis, which is confirmed by biallelic variants [4]. The same variant may yield different histological patterns between individuals and over time [10]. The French PNDS place biopsy as a second-line option, discussed case by case, by surgical route or by transbronchial cryobiopsy according to the centre and age, and reserve CT-guided percutaneous biopsy for nodular lesions suspected of infection or cancer in adults without a diagnosis after endoscopy; the option of cryobiopsy diverges from the ATS and ERS position, which considers transbronchial biopsy and cryobiopsy generally inappropriate in infants [5, 33, 36]. The pathology annex of the 2021 PNDS illustrates the patterns by gene: eosinophilic lipoproteinaceous material filling the alveoli (alveolar proteinosis) in SP-B deficiency; interstitial thickening, alveolar collapse with macrophages and little lipoproteinaceous material in SFTPC-related disease; rigid, thickened septa with marked type 2 pneumocyte hyperplasia in ABCA3 deficiency; and abnormal alveolar development in NKX2-1-related disease [36].

5.6. Diagnosis of hereditary PAP

The first step is measurement of anti-GM-CSF antibodies, a biomarker of autoimmune PAP; antibody-negative PAP with elevated serum GM-CSF is highly suggestive of hereditary PAP. This identified the original five children among 187 patients referred for autoantibody testing [22, 42]. Peripheral blood functional tests measure GM-CSF-stimulated STAT5 phosphorylation (pSTAT5) in monocytes and granulocytes, reduced or abolished in 6 of 6 European-series patients, and CD116 and CD131 surface expression by flow cytometry; in CSF2RA deficiency, the β chain is present and α absent (6/8) or abnormal (2/8), and in CSF2RB deficiency the pattern reverses [21–23]. Granulocytes allow testing with less blood in infants [21]. Functional tests do not distinguish the two genes without chain phenotyping, and molecular diagnosis should include deletion analysis, a frequent mechanism in CSF2RA [42]. PAS-positive milky BAL, HRCT crazy paving (present in all 7 assessed European-series patients), DLCO and the alveolar–arterial oxygen gradient complete the assessment; serum lactate dehydrogenase (LDH) is elevated in most PAP, without specificity [21, 42]. Biopsy shows alveolar proteinosis with granular PAS-positive material, foamy macrophages and preserved alveolar walls [21]. The 2017 French PNDS includes MARS1, CSF2RA and CSF2RB in the genetic study when alveolar proteinosis is suspected in children [35].

5.7. Thyroid and neurological assessment in NKX2-1-related disease

Hypothyroidism in NKX2-1-related disease is primary (elevated TSH, low or low-normal free thyroxine); ultrasound, scintigraphy, thyroglobulin, urinary iodine and maternal TSH-receptor-blocking antibodies are requested according to suspicion [17]. In congenital hypothyroidism assessment, neonatal respiratory distress and familial movement disorders suggest NKX2-1, cleft palate FOXE1 and renal abnormalities PAX8 [84]. After diagnosis, GeneReviews recommends neurological assessment and brain magnetic resonance imaging, pulmonary assessment with function tests, TSH, T4 and T3 measurement with thyroid palpation, developmental assessment at 12 months and neuropsychiatric assessment [17].

5.8. Prenatal and preimplantation diagnosis

SP-B deficiency was diagnosed prenatally in 1994 through absent SP-B in amniotic fluid at 37, 38 and 40 weeks [44]. Today, prenatal diagnosis and preimplantation genetic testing (PGT) are based on identified familial variants and require prior confirmation of phase in trans in recessive disorders; early genetic diagnosis also enables counselling about transplantation or palliative care [5, 13, 17]. In France, each request is discussed beforehand, case by case, in a multidisciplinary prenatal diagnosis centre (CPDPN); sampling is by chorionic villus sampling between 11 and 13 weeks of gestation or by amniocentesis from 15 weeks [35, 36].

5.9. Functional and comorbidity assessment

The French PNDS include functional assessment in the evaluation of severity, to be carried out as early as possible after diagnosis if the child's condition allows [35, 36]. The typical pattern is restrictive, with reduced total lung capacity and vital capacity; DLCO is measured by rebreathing or breath-hold according to age, and lung compliance requires an oesophageal catheter. In infants, volume measurements are possible only during sleep, with premedication; between 3 and 6 years they require active cooperation (nose clip and mouthpiece); after 6–8 years they approach those of adults, functional residual capacity being the most widely used measure. A search for an obstructive component (resistance, volumes and forced expiratory flows) completes the study, because the association is not exceptional. Gas exchange is impaired only in severe forms, but an exercise test may reveal hypoxaemia in mild forms; the 6-minute walk test is feasible from 4 years. Arterial or arterialised capillary blood gases and overnight recording of gas exchange complete the assessment according to severity [36].

Laboratory tests assess nutritional impact, guide aetiology (thyroid function) and help exclude differential diagnoses (full blood count, liver and renal function, immune and metabolic assessment); the 2017 PNDS lists, for childhood interstitial lung disease in general, an extended panel (infectious and hypersensitivity serology, immunoglobulins and subclasses, autoantibodies, angiotensin-converting enzyme, amino acids and organic acids if a metabolic disorder is suspected) [35, 36]. Gastro-oesophageal reflux is very common in children with surfactant disease, and in adults with ILD its prevalence exceeds 60%. pH monitoring is not systematic and is indicated in four situations: confirmation of reflux in case of doubt before prolonging an antisecretory drug (off treatment), confirmation of cure before stopping treatment (at least 3 days after withdrawal), verification of treatment efficacy before intensifying it or discussing anti-reflux surgery (on treatment) and, possibly, before a gastrostomy; manometry and pH-impedance monitoring are discussed with gastroenterology, and these indications are not consensual in adults [35, 36]. Echocardiography is performed early and systematically and repeated annually, supplemented by right heart catheterisation if abnormal; it looks for PH, an important prognostic factor that may justify specific treatment, left heart obstruction (differential diagnosis with pulmonary oedema) and cardiac involvement by a systemic disease [35, 36].

6. Differential Diagnosis

The differential is organised by setting: term newborn with respiratory failure, infant with chILD syndrome, alveolar proteinosis at any age and, in NKX2-1-related disease, chorea and congenital hypothyroidism. Table 6.1 summarises the main hereditary entities.

Table 6.1 — Hereditary differential

6.1. Term newborn with respiratory failure

The acquired differential includes hyaline membrane disease, meconium aspiration, persistent PH, pneumothorax, transient tachypnoea, polycythaemia and non-pulmonary causes, and congenital diaphragmatic hernia [17]. Among disorders of severe neonatal chILD syndrome, the 2013 ATS lists acinar dysplasia, pulmonary hypoplasia with alveolar simplification, ACDMPV, pulmonary interstitial glycogenosis (PIG), SP-B and ABCA3 deficiencies, NKX2-1-related disease, pulmonary haemorrhagic syndromes and pulmonary lymphangiectasia [31]. ACDMPV is the most important differential because it shares severity and PH; in the 2026 ATS review, FOXF1 variants or deletions were found in 60% (33–70%) of newborns with clinical suspicion (persistent severe respiratory failure ≥7 days or severe refractory PH at term) [5].

6.2. Infant with chILD syndrome

Infancy-specific diseases of undefined aetiology — neuroendocrine cell hyperplasia of infancy (NEHI) and PIG — have a favourable prognosis; a non-diagnostic genetic result is reassuring in these cases, but NEHI may be associated with NKX2-1, FOXP1 or SRRM2 [5]. Serum marker KL-6 is elevated in paediatric ILD but not NEHI and remains investigational [10]. Immune-mediated diseases (COPA, STING1, OAS1, CCR2) have an interferon signature or autoimmunity and targeted treatments, justifying exome or genome sequencing [5, 10]. Mimics include hypertensive vasculopathy, veno-occlusive disease, lymphatic diseases and congestion due to cardiac dysfunction [31]. The 2017 French PNDS specifies the key tests for exclusion: sweat test (cystic fibrosis), ear, nose and throat assessment with nasal endoscopy and nasal nitric oxide (primary ciliary dyskinesia), echocardiography and possibly catheterisation (congenital heart disease and primary PH), and testing for bacterial (Mycoplasma, Chlamydia, Ureaplasma), viral (Epstein-Barr virus, cytomegalovirus, adenovirus) and fungal (Pneumocystis jirovecii) infections. In the same document, the most frequent causes of ILD in immunocompetent children are surfactant disorders, alveolar proteinoses, idiopathic pulmonary haemosiderosis, sarcoidosis and respiratory involvement in connective tissue diseases and vasculitides, and the BAL profile guides diagnosis: neutrophilia (fibrosis, infection, aspiration), CD4 lymphocytosis (sarcoidosis) or CD8 lymphocytosis (hypersensitivity pneumonitis, exposures, histiocytosis, vasculitides), eosinophilia, foamy macrophages (Niemann-Pick, Gaucher), siderophages above 30% of macrophages or a Golde score above 50 (alveolar haemorrhage), milky appearance with positive PAS (proteinosis) and CD1a- and langerin-positive cells (histiocytosis) [35].

6.3. Alveolar proteinosis

Autoimmune PAP accounts for more than 90% of primary PAP and 91.5% of 249 confirmed PAP cases in the 2004–2018 North American diagnostic programme, versus 3% hereditary PAP, 4% secondary PAP and 1.5% congenital PAP due to surfactant disorders [19]. Imaging and histology are indistinguishable; the discriminating test is serum anti-GM-CSF antibody, and antibody-negative PAP requires serum GM-CSF, functional tests and genetics [22, 24]. In children, histological PAP results chiefly from surfactant production disorders with associated interstitial abnormalities, whereas GM-CSF receptor disorders cause PAP without interstitial involvement [21]. Secondary PAP occurs in LPI, where lung disease is a major complication and frequently causes death, with recurrence after heart–lung transplantation; in haematological neoplasms, toxic dust inhalation and immunosuppression; and in MARS1, OAS1 and GATA2 disorders [10, 21, 89, 90]. The genetic annex of the 2017 French PNDS assigns recessive inheritance to GATA2-related PAP; GATA2 deficiency is autosomal dominant, as indicated in Table 6.1 [10, 35].

6.4. Differential of NKX2-1-related disease

Childhood-onset chorea is distinguished from physiological infant chorea and acquired choreas (drugs, toxins, metabolic and endocrine causes, Sydenham and other post-infectious choreas, vascular and immunological causes and kernicterus) [17]. The hereditary differential includes ADCY5, sharing the Orphanet benign hereditary chorea entry, PRRT2, SGCE-related myoclonus-dystonia, Huntington disease and phenocopies (HTT, JPH3, TBP, PRNP, ATN1), Wilson disease, neurodegeneration with brain iron accumulation, chorea-acanthocytosis (VPS13A) and McLeod syndrome (XK); some patients labelled as benign hereditary chorea actually had myoclonus-dystonia or Huntington disease [16, 17]. In congenital hypothyroidism, differentials are dysgenesis and dyshormonogenesis genes and thyroxine-binding globulin deficiency; neonatal PH with hypothyroidism and hypotonia points towards NKX2-1 [17, 84].

6.5. Adolescent and adult

In adults with fibrosing ILD, the differential includes acquired causes (fibrogenic exposures, connective tissue diseases, drugs, sarcoidosis) and other genetic causes of pulmonary fibrosis (telomere genes and SFTPA1/SFTPA2); telomere length above the 10th centile directs towards panels including SFTPC, SFTPA1 and SFTPA2 [8]. Telomere gene variants were also found in two children with undefined chILD [10].

7. Treatments and Risk Management Strategies

7.1. General principles and level of evidence

No authorised treatment corrects any genetic surfactant deficiency or hereditary PAP. Until 2013, there were no controlled chILD syndrome trials, and management relied on series, reports, experience and indirect evidence [31]. The 2026 systematic review included 100 chILD therapy publications, only 5 randomised trials, 89% from high-income countries and 75% of reports concerning children under 2 years [56]. The 2026 ATS guideline did not address pharmacological treatment because it was not included in PICO questions (population, intervention, comparator, outcome) [5]. Care should be longitudinal, interdisciplinary and provided at experienced centres, involving paediatric respiratory medicine, neonatology, intensive care, radiology, pathology, surgery, genetics and genetic counselling, nutrition, physiotherapy and social work [5, 31]. Families should be included in registries, the main source of knowledge about natural history [34, 38].

The French PNDS set the goals of improving quality of life, improving or stabilising respiratory function and exercise tolerance, maintaining satisfactory PaO2 or SpO2, preventing and treating exacerbations, PH and heart failure, maintaining nutritional status and treating oral feeding disorders, providing therapeutic education and psychological and social support and combating aggravating environmental factors, such as passive smoking [36]. The team is coordinated by a reference or competence centre of the RespiFIL network, in liaison with the paediatric department near the patient's home and with the attending physician, and includes paediatric and adult pulmonology, gastroenterology, cardiology, intensive care, radiology, genetics, pathology, respiratory physiology, paediatric endocrinology and neurology in NKX2-1-related disease, physiotherapy, dietetics, psychology, coordinating nursing, speech and language therapy, psychomotor therapy, genetic counselling, social services, educational support, adapted physical activity and home care providers [36].

7.2. Supportive care

Oximetry guides daytime, nocturnal, exertional and mealtime oxygen prescription, and invasive or non-invasive ventilation is used in severe disease [31]. The 2025 ERS review gives a long-term oxygen therapy criterion of mean saturation 92% with more than 5% of time below 90%, with a broader indication in PH [10]. The French PNDS apply the 2012 paediatric criteria of the French GRAPP group, which differ by age: under 2 years, long-term oxygen therapy if mean SpO2 is below 93% (sleep or wakefulness), if more than 5% of sleep time is spent with SpO2 below 90% or if PH is present; over 2 years, if mean SpO2 is below 90%, if more than 10% of sleep is spent below 90% or if PH is present; targets are mean SpO2 above 94% with PH and above 92% without PH [36]. The ERS threshold of 92% lies between the two French thresholds, and the criterion of 5% of time below 90% coincides only in infants [10, 36]. Hypoxaemia is assessed by prolonged oximetry during sleep, wakefulness and meals, and capnia by at least spot measurement, ideally overnight (oximetry or transcutaneous measurement of SpO2 and pCO2); long-term non-invasive ventilation is discussed in chronic hypercapnia (pCO2 above 45 mmHg outside exacerbations, according to the 2017 PNDS), and prolonged invasive ventilation is exceptional. In chronic hypoxaemia, complications are sought: PH, right ventricular hypertrophy and right heart failure, polycythaemia and growth faltering [35, 36]. Up to 80% of patients with respiratory failure need energy intake of approximately 120% of age recommendations; feeding difficulties, reflux and vomiting frequently necessitate nasogastric tube or gastrostomy feeding, used in 89% of ABCA3-deficient children in the French cohort [10, 14]. The 2021 PNDS agrees on an intake of about 120% and provides for calcium, vitamin D and potassium supplements during corticosteroid therapy, a nasogastric tube if enteral nutrition is short-term and gastrostomy in other cases, regular dietetic follow-up and specific treatment of oral feeding disorders by teams including speech and language therapy; the 2017 PNDS reserves prolonged parenteral nutrition for association with severe chronic digestive disease [35, 36]. Reflux should be sought systematically and treated early and maximally, because of the risk of acid microaspiration: thickening of milk in infants, proton pump inhibitors if necessary and, rarely, anti-reflux surgery. In PH, oxygen is the main treatment, pharmacological treatment (bosentan, sildenafil) is decided with paediatric cardiology and right heart catheterisation defines the haemodynamic parameters [36]. Vaccination includes the routine schedule, pneumococcal vaccine and annual influenza vaccine; live vaccines should be avoided during pulses or prolonged oral corticosteroid therapy, or given at least 2 weeks beforehand, and varicella vaccine should be considered before immunosuppression [10, 31]. The 2021 French PNDS is more restrictive and more detailed (Table 7.6): live attenuated vaccines are contraindicated during corticosteroid pulses and until 3 months after their discontinuation, and with corticosteroid doses above 2 mg/kg/day or 10 mg/day of prednisone equivalent; the other vaccines are given at a distance from pulses, about 15 days; annual influenza vaccine is indicated for the child or, under 6 months, for the parents; RSV immunoprophylaxis is discussed in severe ILD in children under 2 years at the start of the epidemic season; varicella vaccine is given before pulses if there is no immunity; hepatitis B vaccine is recommended, human papillomavirus vaccine is discussed in adolescents, especially if transplantation is planned, and SARS-CoV-2 vaccine is offered when age allows; on corticosteroids the vaccine response may be lower, and serology guides revaccination [36]. The divergence from the North American and ERS sources lies in timing: these accept live vaccines at least 2 weeks before immunosuppression, and the PNDS adds an interval of 3 months after pulses [10, 31, 36]. Respiratory syncytial virus (RSV) immunoprophylaxis is generally considered in severely affected infants because of increased hospitalisation risk, but benefit has not been studied in chILD [31, 56]. Pneumocystis jirovecii prophylaxis applies to immunocompromised patients, tobacco smoke exposure should be avoided, and adapted physical activity, physiotherapy and psychosocial and family support form part of the plan [10, 31]. The PNDS add that, as a rule, group childcare (nursery) is contraindicated in infants because of viral exposure, that regular physical activity is recommended according to age and abilities, with an adapted physical activity teacher, physiotherapist or monitored exercise reconditioning programmes in specialised centres, and that therapeutic education, psychological support for the patient and family and social assessment should be systematically offered [35, 36].

Exogenous surfactant gives transient oxygenation improvement for hours in SP-B and ABCA3 deficiency, with diminishing response; in Kröner's cohort it was used in 31 patients, without effect in 15 and with transient effect in 12, and in the French cohort it improved half of 15 treated newborns very transiently [14, 56]. ECMO serves only as a bridge, as in Hamvas's infant, who died at 54 days awaiting transplantation despite surfactant, corticosteroids and ECMO [4, 44].

Table 7.6 — Pneumococcal vaccination in surfactant disease according to the 2021 PNDS (historical schedule, superseded by the HAS in 2023 and 2026)

Source: [36]. The schedule uses the vaccines available in France in 2021; the 2017 PNDS merely recommended the 23-valent polysaccharide vaccine after the conjugate vaccine from 5 years of age [35]. This schedule has been superseded and should not be applied: in July 2023 the HAS replaced the 13-valent conjugate + 23-valent polysaccharide sequence for at-risk adults with a single dose of high-valency conjugate vaccine and, in the revision validated in July 2026, recommends in at-risk children, from 15 months to 18 years, a single dose of PCV20 (Prevenar 20®), at least 8 weeks after the last pneumococcal vaccine dose, abandoning PCV13, PCV15 and PPSV23 (Pneumovax®) in them, and prefers PCV21 (Capvaxive®) from 18 to 64 years in those at risk, without addressing revaccination [93].

7.3. Systemic corticosteroids

Corticosteroids are the most commonly used empirical treatment in surfactant disorders despite never having been evaluated in a controlled chILD trial; a phase 2 trial was started in France, and a NEHI trial is registered [10]. Their action is non-specific, and in SP-C-related disease they reduce SP-C expression and favour a less stable isoform [56]. The 2015 European protocols, obtained by Delphi with more than 100 clinicians, propose initial intravenous methylprednisolone pulses of 10 mg/kg or 500 mg/m², potentially increasing to 30 mg/kg in severe cases, or oral prednisolone 2 mg/kg as an alternative in non-ventilated patients, and oral prednisolone 1 mg/kg between pulses in ventilated patients; expected response time is 7 days in ventilated patients and 28 days in the remainder, and duration is undefined [32, 56]. These doses come from the protocol description in a 2026 systematic review because the full protocol text was inaccessible [56]. The 2004 ERS task force described oral prednisolone 1–2 mg/kg/day or pulses of 10–30 mg/kg/day for 3 days, monthly for 3–6 months [56]. In the French ABCA3 deficiency cohort, 27 of 28 children received corticosteroids, typically monthly pulses of 300 mg/m²/day for 3 days with initial oral prednisolone [14].

The French PNDS, which consider corticosteroid therapy the main treatment of these diseases, give a regimen with maximum doses (Table 7.7) [35, 36]. Intravenous methylprednisolone pulses, used in the initial phase and while significant hypoxaemia or signs of respiratory failure persist, are given at 300–500 mg/m²/day or 10 mg/kg/day (maximum 500 mg) for 3 consecutive days, repeated every 3–4 weeks in a day hospital or as inpatients, with monitoring of heart rate, blood pressure, SpO2, temperature and blood glucose. Oral prednisolone usually starts at 2 mg/kg/day (maximum 60 mg), in severe forms in the interval between pulses, is maintained for several weeks to 2–3 months and is tapered slowly over months, seeking the minimum effective dose; complete withdrawal may be considered if the respiratory situation normalises or stabilises, with prevention of adrenal insufficiency. In adulthood, the efficacy and dosage of corticosteroids in these diseases are unknown [36]. Measures associated with pulses or prolonged corticosteroid therapy are prophylaxis with co-trimoxazole (sulfamethoxazole + trimethoprim) 20–30 mg/kg/day 3 days a week, a dose expressed without indicating the reference component, which may be stopped if only pulses are given and lymphocytes exceed 1000/mm³ or CD4 counts exceed 500/mm³; calcium (500 mg to 1 g/day), vitamin D and possibly potassium chloride (600 to 1800 mg/day) supplements; bone densitometry from 8–10 years; ophthalmological surveillance (nuclear and posterior subcapsular cataracts, exophthalmos, ocular hypertension); and restriction of salt and carbohydrates. Adverse effects to be prevented include arterial hypertension, hyperglycaemia, mood changes, weight gain with cushingoid appearance, growth retardation, hypertrichosis, glaucoma, bone demineralisation, hypokalaemia, adrenal insufficiency and depressed cellular immunity [36].

The French and European regimens diverge on three points. The PNDS caps the pulse at 500 mg and does not provide for the increase to 30 mg/kg accepted by the chILD-EU protocols in severe cases nor the 10–30 mg/kg/day of the 2004 ERS task force; it gives the alternative of 300–500 mg/m²/day, whereas the European protocols cite 500 mg/m²; and it maintains oral prednisolone at 2 mg/kg/day between pulses in severe forms, whereas the European protocols use 1 mg/kg between pulses in ventilated patients [32, 36, 56]. The 2017 PNDS accepts other immunosuppressants (azathioprine, methotrexate, mycophenolate mofetil, cyclophosphamide) in corticosteroid resistance or for corticosteroid sparing, decided case by case, without consensus on the choice and with rare use, depending on the aetiology and mechanism of the ILD [35].

Table 7.7 — Doses in the French PNDS compared with other sources

Source: [30–32, 36, 56, 94, 95].

Predominant practice is to use intravenous pulses in acute disease and deterioration and oral treatment for chronic therapy, because pulses have at least equal efficacy and fewer adverse effects (hypertension, diabetes, bone demineralisation) [56]. Chronic corticosteroid therapy requires bone mineral density, growth and ophthalmological monitoring [31]. Prolonged high-dose requirements should bring forward transplant discussion [56]. Documented effects in series are sparse: in Kröner's cohort, among 34 ABCA3-deficient patients treated with corticosteroids, 22 had no effect, 8 a moderate effect and 2 a good effect [56].

7.4. Hydroxychloroquine

Hydroxychloroquine has been used for decades as a steroid-sparing drug on an anecdotal basis and is administered to approximately half of children with chILD [30, 56]. The proposed mechanism includes inhibition of cytokines (IL-1, IL-6, TNFα, IFNγ) and autophagic degradation and possible interference with aberrant SFTPC and ABCA3 proteins degraded through the lysosomal pathway [30]. In vitro studies show variant-dependent responses in ABCA3 deficiency and a possible harmful effect for SP-C I73T [10]. In a Munich series of 39 ABCA3-deficient patients, 19 improved or remained stable and 20 deteriorated during hydroxychloroquine, and the variant's in vitro effect correlated with in vivo response [56].

The only randomised trial, conducted by the chILD-EU consortium at 6 German university hospitals, was negative. In a START arm, 26 children received hydroxychloroquine or placebo for 4 weeks; in a STOP arm, 9 children already treated for ≥3 months were randomised to continue or stop for 12 weeks. Study dosing was 10 mg/kg/day in the first week then 6.5 mg/kg/day orally in the evening, using individually prepared weight-adjusted formulations. There were no responders by the protocol definition in any randomised group (0/13 placebo and 0/7 hydroxychloroquine in START; 0/3 with hydroxychloroquine and 0/5 with placebo in STOP), and combined analysis showed decreasing quality of life and body mass index centile with hydroxychloroquine. The 35 patients included 7 with ABCA3 deficiency, 6 with SP-C-related disease and 2 with NKX2-1. Adherence was 91%, adverse effects (chiefly gastrointestinal and respiratory infections) did not differ from placebo, and the small, short trial does not exclude a type II error [30]. The authors conclude that, if prescribed, efficacy should be assessed repeatedly and quantitatively, duration limited and the patient followed in a registry [30].

The 2015 European protocols specified 6.5–10 mg/kg/day, as second line at 10 mg/kg/day reducible to 6.5 mg/kg/day in children under 6 years to minimise adverse effects; 54% of Delphi clinicians accepted first-line use in mild stable chILD [32, 56]. Outside these recommendations, reports use 6–10 mg/kg/day [56]. In adults with surfactant gene-associated ILD, French trial NCT07443436 uses 400 mg/day [95]. The paediatric sources define no maximum dose; for comparison, the Plaquenil® label indicates 200–400 mg/day as a chronic dose in adults with rheumatic disease and states that daily doses above 5 mg/kg of actual body weight increase the incidence of retinopathy, a value below the doses of 6.5–10 mg/kg/day used in chILD [94]. Use is always off-label: the US Plaquenil® label establishes paediatric efficacy only in malaria and states that film-coated tablets cannot be administered to children under 31 kg because they cannot be split or crushed [94]. Serious adverse effects include cardiomyopathy, QT prolongation and ventricular arrhythmias, irreversible cumulative-dose-dependent retinal toxicity, severe skin reactions and haematological and renal toxicity; the label recommends baseline and on-treatment retinal examination, and the 2013 ATS guideline periodic full blood counts and ophthalmological assessment [31, 94]. In the chILD-EU trial, monitoring included full blood count, transaminases, creatinine, electrolytes, creatine kinase, blood glucose, drug blood level, electrocardiogram, echocardiogram and ophthalmological examinations [30].

The 2021 French PNDS places hydroxychloroquine, with azithromycin, as second line, in combination with corticosteroids to spare them or, for some teams, as monotherapy in stable and moderate forms, at 10 mg/kg/day (6.5 mg/kg/day under 6 years) as a single daily oral dose, without an absolute maximum dose; it was drafted before publication of the negative chILD-EU trial, which it then cited as ongoing [30, 36]. Monitoring includes full blood count and liver function at 15 and 30 days and then every 6 months, and a baseline ophthalmological assessment before initiation or within the first 6 months, with fundoscopy, optical coherence tomography and, from 6 years, possibly multifocal electroretinography; follow-up is adapted to the initial result, the patient's background, the dose and the duration. The listed risk factors for maculopathy are cumulative dose above 1000 g, exposure longer than 5 years, daily dose above 6.5 mg/kg, advanced age, renal or hepatic impairment, pre-existing retinal disease and obesity or thinness; the PNDS acknowledges that adult recommendations are difficult to extrapolate to children [36]. The 2017 PNDS provided for ophthalmological examination every 6 months (fundoscopy, electroretinography and colour vision), an interval that the examinations annex of the 2021 PNDS retains for hydroxychloroquine and for prolonged corticosteroid therapy (fundoscopy, visual acuity, intraocular pressure, colour vision and possibly electroretinography), whereas the 2021 text individualises the interval [35, 36]. The dose of 10 mg/kg/day exceeds the threshold of 6.5 mg/kg/day that the PNDS itself considers a retinal risk factor and the label's 5 mg/kg/day [36, 94]. The 6.5 mg/kg/day threshold is the former threshold based on ideal body weight; the 2016 American Academy of Ophthalmology recommendation, which reviewed the risk data, sets the maximum daily dose at ≤5 mg/kg of actual body weight and requires baseline fundoscopy and annual screening with automated visual fields and spectral-domain OCT from 5 years of use in patients without major risk factors (renal impairment, tamoxifen, high dose), with multifocal electroretinography and autofluorescence as confirmatory tests [96]. The 2025 revision maintains the maximum of 5.0 mg/kg/day of actual body weight, below 400 mg/day in severe obesity, but now recommends a baseline examination soon after initiation (fundoscopy, OCT and autofluorescence), with OCT and wide-field autofluorescence as primary tests and visual fields and multifocal electroretinography as confirmatory; screening is annual and may be deferred during the first 5 years in the absence of significant risk factors (renal disease, tamoxifen, older age at initiation) [97].

7.5. Azithromycin

Azithromycin is widely used in surfactant disorders for its immunomodulatory and local antimicrobial effect, and an antifibrotic effect has been proposed on the basis of idiopathic pulmonary fibrosis data; there is no trial in chILD, and its widespread use with low-quality evidence and a risk of selecting resistance has been criticised [10, 56]. The 2015 European protocols specified 10 mg/kg on 3 days a week, with a response expected within 3 months, without preference over hydroxychloroquine; 51% of clinicians accepted monotherapy in mild stable chILD [32, 56]. The 2021 French PNDS uses 10 to 20 mg/kg/day (maximum 250 to 500 mg) on only 3 days a week, because of the long half-life, as second line after or in addition to corticosteroids, or as monotherapy in moderate or slowly progressive forms; adverse effects are mainly gastrointestinal (abdominal pain, faster transit), and prolonged use requires a prior electrocardiogram with QT interval measurement and contraindicates combination with QT-prolonging drugs. The upper limit of 20 mg/kg/day diverges from the 10 mg/kg of the chILD-EU protocols [32, 36]. In adults, reports and trial NCT07443436 use 250 mg 3 times a week [61, 95]. A French patient with homozygous p.(Asp253His) ABCA3 deficiency had marked improvement and stability into adulthood on azithromycin 250 mg 3 times a week from 6 years of age [61].

7.6. Antifibrotics

Usual interstitial pneumonia patterns have been described in children with SFTPC- and ABCA3-related disease, and fibrotic NSIP accounts for 2.1% of biopsies before 2 years and 6.7% between 2 and 18 years [56]. InPedILD (NCT04093024, 1199.337) randomised 2:1 39 children aged 6 to 17 years with clinically significant fibrosing ILD to nintedanib or placebo for 24 weeks; surfactant protein deficiency was the most frequent diagnosis (26.9% in the nintedanib arm, 38.5% in placebo). Primary outcomes were exposure, similar to adults, and adverse effects (84.6% in both arms); FVC change at 24 weeks was +0.31% predicted versus −0.89% (difference 1.21; 95% CI −3.40 to 5.81), without statistical significance [10, 98]. Bayesian analysis with adult data estimated a 95.5% probability of superiority [56].

The European Medicines Agency (EMA) authorised nintedanib in children aged 6 to 17 years with clinically significant progressive fibrosing ILD, with weight-based dosing (Table 7.4), initiation only after assessment by an experienced multidisciplinary team, dental examination at least every 6 months until complete dentition, annual bone imaging while epiphyses remain open and growth surveillance; it is not recommended below 6 years or 13.5 kg [98]. The Food and Drug Administration (FDA) retains the adult-only indication and states that efficacy was not demonstrated in the paediatric study, citing juvenile animal growth plate and dental toxicity [99]. As most ABCA3-deficient children are under 6 years, most are ineligible [14]. Pirfenidone has only case reports, was well tolerated and showed no clear benefit [56]. In adults with SFTPC- or ABCA3-related disease, antifibrotics are used by extrapolation from idiopathic and progressive pulmonary fibrosis trials [8]. The 2021 French PNDS, which predates the European paediatric extension, considered antifibrotics unvalidated in children, cited an ongoing nintedanib tolerability study and accepted discussion of an antifibrotic in adults with progressive fibrosis associated with surfactant variants, since they may meet the inclusion criteria of progressive fibrosis trials [36].

7.7. Targeted therapies under investigation in ABCA3 deficiency

The homology between ABCA3 and CFTR led to testing of CFTR modulators: in vitro, ivacaftor and genistein partially restored the activity of certain ABCA3 variants [61]. In a French compassionate-use series, three adults (30, 22 and 48 years) received elexacaftor/tezacaftor/ivacaftor at the dose recommended for cystic fibrosis for 6 months: the first patient went from dyspnoea 46/100 to 0/100, with gains of 240 mL in FVC, 8% in DLCO and 40 m in the 6-minute walk test at 3 months and reduced ground glass; the other two had smaller functional gains and imaging improvement, without adverse effects. A child homozygous for NP_001080.2:p.(Thr1173Arg) treated with lumacaftor/ivacaftor at 4 years had parent-reported improvement in cough, discontinuation because of adenovirus infection and death at 6 years without a compatible donor [61]. Short follow-up, early discontinuation, the number of patients and the absence of in vitro testing of the variants preclude conclusions; the authors call for prospective studies [61].

Ciclosporin A was identified by high-throughput screening as a corrector of some ABCA3 variants whose maturation normalises in vitro [10, 56]. In 2026, the first report of ciclosporin dose, monitoring and safety in an infant with ABCA3 dysfunction was published; its doses could not be extracted from the sources consulted [100].

7.8. Lung transplantation

Bilateral lung transplantation is the only definitive therapy in SP-B deficiency, ABCA3 deficiency with null/null genotype and other severe progressive forms [4, 5]. The 2026 ATS guideline recommends early referral for transplant assessment, defined as less than 1 month after genetic confirmation, in monogenic diseases with predictably poor prognosis (strong recommendation, very low certainty), and suggests it in chILD syndrome with mechanical ventilation, ECMO or progressive PH, or chILD disease with progressive respiratory symptoms or impending respiratory failure (conditional) [5]. Referral means communication with the centre and does not imply transfer; approximately half of families at the St. Louis centre decided not to proceed after counselling [5, 55]. The guideline supplement describes the practical sequence: centre contact, communication between teams, additional testing before transfer, caregiver education, administrative authorisations, transport team capacity assessment and family accommodation [5]. The 2021 French PNDS asks that, from the onset of chronic respiratory failure, follow-up identify candidates early, with a collegial decision according to age, therapeutic plan, potential for progression and comorbidities, and considers the risk of recurrence of the genetic disease in the graft theoretically nil, because these proteins are expressed only in the lung, with the exception of NKX2-1-related disease [36]. This reasoning does not apply to hereditary PAP, in which proteinosis recurs in the graft through repopulation with recipient macrophages [24, 26].

Urgency results from waiting-list mortality: in a study of 207 transplant recipients (190 under 18 years), age below 2 years was the only factor associated with shorter time between listing and waiting-list death, with a median of 36 days (4–259) in infants up to 2 years; ECMO and mechanical ventilation at transplantation were associated with greater in-hospital mortality, and graft failure predictors included preoperative Burkholderia cepacia colonisation (relative risk 29.3; 2.84–303.2), postoperative fungal infection (3.81; 1.39–10.4) and ventilation days (1.02; 1.01–1.04) [5]. Younger infants have less rejection and bronchiolitis obliterans syndrome, but airway complications in approximately 20% [5]. Table 7.1 summarises outcomes and Table 7.2 contraindications.

Table 7.1 — Lung transplantation in genetic surfactant disorders

Table 7.2 — Contraindications to lung transplantation in infants and young children (ATS 2026)

Source: [5]. ECMO and prolonged ventilation are assessed case by case according to patient and centre.

There are fewer than ten paediatric lung transplant centres in the United States, with long travel and inequitable access; the guideline suggests institutional referral pathways and telemedicine [5]. In multisystem diseases (NKX2-1, FOXF1, TBX4, FLNA), extrapulmonary involvement affects candidacy [5]. In adults with surfactant disease, lung cancer screening before and after transplantation is advised and bilateral transplantation preferred [74]. In an alternative described for SFTPC-related disease with persistent respiratory failure, tracheostomy with chronic ventilation and anti-inflammatory treatment allowed decannulation and complete weaning within 2 to 6 years in some patients [55].

7.9. Treatment of hereditary PAP

Whole-lung lavage is standard care for PAP syndrome and the cornerstone of hereditary PAP treatment. All symptomatic patients in the eight-child CSF2RA deficiency series responded well, and in the nine-child European series all seven undergoing the procedure had a favourable course, including severe cases; lavage numbers ranged from 3 to 56 (median 19.3, or 0.7 to 6.8 per follow-up year), and two patients underwent periodic lavage every 4 to 8 weeks for years. After more than ten years of monthly or two-monthly lavage, one patient went more than one year without needing it, with normal clinical findings and imaging [21, 22]. The procedure requires general anaesthesia and an experienced centre, is repeated at a median interval of approximately 15 months in PAP syndrome overall and does not correct myeloid dysfunction [42, 103]. In mild cases, disease is often self-limiting [21]. Remaining treatment is supportive: oxygen, prompt infection treatment, vaccination, smoking avoidance and functional monitoring [23]. The 2017 French PNDS describes the paediatric technique: general anaesthesia in the operating theatre, child in the lateral decubitus position on the side to be lavaged, one lung per session through a flexible bronchoscope adapted to the calibre of the endotracheal tube, with 10 mL/kg of normal saline at 37 °C, lavage of the contralateral lung in a second procedure a few days later and repetition at a rate dictated by progress; the same document mentions subcutaneous or inhaled GM-CSF and rituximab, used in adults with autoimmune PAP, without evaluation in children [35].

Inhaled GM-CSF has no mechanistic rationale when the receptor is defective and should not be used in hereditary PAP. The 2025 ERS review states that inhaled GM-CSF was tried unsuccessfully in this form, and the only trial targeting partial receptor dysfunction (NCT01511068, inhaled sargramostim 250 µg weekly for 12 weeks, Cincinnati) included only 2 patients and was described as terminated for insufficient recruitment, without demonstrated efficacy [10, 104]. The adult CSF2RB-related PAP report concludes that no functional data support inhaled GM-CSF in this disease and therefore does not recommend it [24]. No GM-CSF product is indicated for PAP: the Leukine® (sargramostim) label covers haematological indications rather than the inhaled route, making that use off-label [23, 105].

Lung transplantation has been attempted in severe respiratory failure, with this disease's major caveat: PAP recurred in the graft because donor alveolar macrophages are replaced by recipient monocyte-derived macrophages retaining the defect. In a patient with a CSF2RB variant, PAP recurred 9 months after bilateral living-donor transplantation, progressing to fibrosis in both grafts and death 5 years later; in another adult patient, autopsy showed recurrent PAP and fibrosis in the graft [24, 26]. In the Greek man with p.(Arg211*), PAP had not recurred one year after transplantation [24]. Allogeneic haematopoietic stem cell transplantation has been attempted in isolated cases: a child with biallelic CSF2RA loss improved after matched unrelated-donor transplantation despite severe graft-versus-host disease, with stable function at 40 months; another patient with complete CD116 deficiency, lavage from 3 years and fibrosis received bilateral lung transplantation followed by allogeneic marrow transplantation at 18 years; and one death from marrow transplant complications is described. Infection, graft-versus-host disease and toxicity limit the approach [21, 24, 42]. Atorvastatin was anecdotally useful [10].

7.10. Treatment of NKX2-1-related disease

There are no published clinical practice guidelines for NKX2-1-related disorders; treatment is supportive and multidisciplinary [17]. Levothyroxine replacement should start in the neonatal period under an endocrinologist to prevent developmental consequences of untreated hypothyroidism; levothyroxine is indicated in congenital hypothyroidism at all ages, including newborns [17, 64]. Nevertheless, neurological prognosis is not determined by early hypothyroidism treatment because it depends on NKX2-1's role in brain development [47]. Respiratory management includes neonatal support as needed, early aggressive treatment of asthma and respiratory infections, RSV immunoprophylaxis in infancy and ILD follow-up by a respiratory physician [17]. Early developmental intervention and physiotherapy target motor and gait difficulties, and neuropsychiatric manifestations, chiefly ADHD, receive standard treatment [17].

For chorea, GeneReviews considers vesicular monoamine transporter type 2 (VMAT2) inhibitors — tetrabenazine, deutetrabenazine or valbenazine — first-line treatment, starting low and gradually increasing, and states an initial dose of 0.5 mg/kg/day in children and 37.5 mg/day in adults, divided into 2 to 3 doses, without specifying which of the three drugs this applies to and without a maximum dose defined in the source [17]. For comparison, the US tetrabenazine label for adult Huntington chorea starts at 12.5 mg/day, titrates weekly by 12.5 mg, and sets a maximum of 100 mg/day (maximum single dose 37.5 mg) in CYP2D6 extensive or intermediate metabolisers and of 50 mg/day (maximum single dose 25 mg) in poor metabolisers or with CYP2D6 inhibitors [106]. This is a real source limitation: none of the three drugs is indicated for benign hereditary chorea or has established paediatric safety and efficacy, so use is off-label (Table 7.3). Levodopa is second line for chorea and improves it in some children, but first line when gait is impaired, with marked improvement and fewer falls in two reports; GeneReviews gives no dose [17]. Dopamine receptor blockers, including olanzapine, are not recommended first line because of tardive dyskinesia risk, potentially worsening chorea long term [17]. Pulmonary carcinoma receives standard oncological treatment [17]. The French PNDS provide, in NKX2-1-related disease, care directed by paediatric endocrinology and neurology and measurement of T4 and TSH at intervals set by the endocrinologist [36].

Table 7.3 — Regulatory status of drugs used in these diseases

Table 7.4 — Nintedanib: EU-authorised paediatric dose (6 to 17 years, twice daily, approximately 12 hours apart)

Source: [98]. Dose is reduced in Child–Pugh A hepatic impairment and for adverse-effect management; treatment is interrupted if weight falls below 13.5 kg, is not recommended below 6 years and is contraindicated in Child–Pugh B or C.

7.11. Clinical trials and their interpretation

Table 7.5 brings together relevant randomised trials. None tested a therapy in a population consisting exclusively of genetic surfactant deficiency patients.

Table 7.5 — Randomised trials

These results require three cautions. First, they are not comparable: populations (children with chILD, adults with autoimmune PAP), outcomes (composite clinical response, alveolar–arterial gradient, DLCO, FVC) and durations differ, and no valid indirect comparison exists. Second, inhaled GM-CSF trials were conducted in autoimmune PAP, where the receptor is functional and autoantibodies are the problem; the meta-analysis of 4 phase 3 trials with 402 adults showed a mean difference of +5.09 percentage points in DLCO (95% CI 2.05–8.13; I²=0%) and −4.25 mmHg in alveolar–arterial gradient, without improved lung volumes or exercise capacity, and continuous and intermittent regimens were similar [115]. Extrapolating these results to hereditary PAP would be a mechanistic error because the receptor is absent or non-functional [24, 42]. Third, the negative hydroxychloroquine trial is the best available evidence for one of the most widely used therapies, and the initial hypothesis (70% response with hydroxychloroquine versus 35% with placebo) was based on a review of 85 patients treated between 1984 and 2013, with 41% response and probable publication bias [30].

7.12. Research and developments in the last twelve months

The evidence level of each development is explicitly stated; none of these approaches is available outside trials or compassionate use.

Human studies ongoing or published in the last twelve months include the first human hereditary PAP gene therapy trial (NCT05761899, phase 1/2, recruiting in Cincinnati since June 2023): autologous macrophages derived from marrow CD34+ cells, transduced with a CSF2RA lentiviral vector, instilled bronchoscopically on three occasions 2 months apart, with a maximum target dose of 778 million corrected macrophages per 70 kg, an estimated 3 patients over 18 years, primary safety outcome and estimated primary completion September 2026, without published results [52]; French trial NCT07443436 (phase 2, updated September 2026, not yet recruiting, estimated start November 2026), randomising 30 adults with surfactant gene variant ILD to 12 months of azithromycin 250 mg three times weekly, prednisone 10 mg/day and hydroxychloroquine 400 mg/day, all off-label, versus usual care, with 1-year FVC decline as primary outcome [95]; the open-label paediatric nintedanib extension (NCT05285982), recruiting [10]; the French CFTR modulator series in ABCA3 deficiency (3 adults and 1 child, compassionate use) [61]; description of TMEM63B as a new gene (5 individuals from 4 families, human study published June 2026) [27]; respiratory outcomes in 48 infants with a monoallelic ABCA3 variant [67]; the international registry of 68 individuals with NKX2-1-related disease [18]; description of downstream NKX2-1 regulatory structural variants in 8 families [29]; the three French infants with lethal NKX2-1-related chILD with functional characterisation [53]; the adult ILD case due to a homozygous SFTPB variant [58]; and the exploratory IMPALA-2 exercise distance and duration analysis, published September 2026 [116].

Regulatorily, inhaled molgramostim is not authorised in any jurisdiction. Available information comes from company press releases rather than regulatory databases: FDA acceptance of the biologics licence application for priority review in February 2026, EMA validation of the European application in March 2026 with a decision expected in the first quarter of 2027, submission to the British agency in March 2026 and, in April 2026, a three-month FDA decision deadline extension to 22 November 2026 because company responses were classified as a major amendment, without, according to the company, safety, efficacy or manufacturing concerns being raised. The product has fast-track, breakthrough therapy and orphan drug designations at the FDA and EMA for autoimmune PAP and uses a specific nebuliser. The intended indication is adult autoimmune PAP [107–109].

Preclinical work indicates possible directions. In SP-B deficiency, optimised lung-tropic adeno-associated vectors restored surfactant homeostasis and markedly prolonged survival of deficient mice [10, 56]. In SFTPC-related disease, intra-amniotic CRISPR-Cas9 editing inactivated the mutant allele in a mouse model, improving morphology and postnatal survival; engraftment of wild-type type 2 pneumocytes into Sftpc−/− mice attenuated injury for 2 months; proSP-C maturation and edited alveolar organoid studies clarified aberrant I73T isoform trafficking; and a 2026 editorial comment discussed a dual mutant allele silencing and gene replacement strategy, whose original article was not located [56, 59, 60, 117, 118]. In ABCA3 deficiency, lentiviral complementation partially rescued type 2 variant function in cell lines, and repair in iPSC-derived pneumocytes rescued lamellar bodies [54]. In hereditary PAP, pulmonary macrophage transplantation corrected disease, systemic manifestations and biomarkers in Csf2rb−/− mice with one administration, with macrophage persistence beyond one year, and haematopoietic stem cell gene therapy was effective in a mouse model; iPSC-derived pulmonary macrophages gave encouraging results [10, 51]. Mesenchymal stromal cells, tested in human bronchopulmonary dysplasia, were well tolerated but with disappointing results [10]. No human gene therapy trial for SFTPB, SFTPC or ABCA3 was found in consulted registries, which does not prove none exists [56].

7.13. Agents to avoid, pregnancy and perioperative context

Tobacco smoke exposure, which worsens pulmonary dysfunction and increases lung cancer risk in NKX2-1-related disease, should be avoided, as should fibrogenic exposures (metal fumes and dusts, wood dust, stone and sand particles, farming and livestock exposures, bird feathers and droppings, aerosolised moulds) and pneumotoxic drugs (chemotherapy agents, antiarrhythmics, nitrofurantoin) in fibrosing disease [8, 17]. In NKX2-1-related chorea, dopamine receptor blockers are not recommended first line [17]. Live vaccines should be avoided during immunosuppression [10].

There is no known increased pregnancy risk in NKX2-1-related disease, but antichoreic drug safety should be reviewed before conception or early in pregnancy [17]. Two women with SFTPC-related disease and residual restriction had healthy children [34]. Perioperatively, whole-lung lavage requires general anaesthesia at an experienced centre, and infant CT entails anaesthetic and transport risks in critically ill patients [5, 42]. After recent respiratory infection, waiting 6 to 8 weeks before follow-up imaging is advisable [5].

7.14. Transition to adult care

Survivors are frequently followed at adult ILD centres with significant lung function loss and non-matching disease classifications [10]. The 2024 ERS statement argues that active transition should be ensured for all chILD patients, even asymptomatic or in remission, but concludes that published evidence on transition systems in this field is insufficient and makes no evidence-based recommendations; it proposes a transition report including age at first symptoms and diagnosis, precise diagnosis and estimated prognosis, perinatal history, comorbidities, other organ involvement, vaccines, imaging (particularly HRCT), date and details of genetic testing, medication adverse effects and transfer of the patient to an adult registry [34]. Generic transition programmes begin between 11 and 14 years and end between 16 and 23 years in better-studied chronic diseases [34]. Among 244 European survivors, 7% never transitioned, and transition led to respecification of diagnosis in 9.8% and treatment in 16% [85]. In France, the RespiRare paediatric reference centre works with the reference centre for rare adult lung diseases, OrphaLung, within the RespiFIL network, and transition, a critical stage especially for treatment adherence, relies on adolescent units, transition spaces and joint clinics of paediatric and adult teams [35, 36].

8. Reproductive Options and Family Counselling

8.1. Recurrence risks by inheritance pattern

In SP-B and ABCA3 deficiencies and CSF2RB-related hereditary PAP, inheritance is autosomal recessive: parents are presumed obligate heterozygotes, siblings have a 25% probability of being affected, 50% of being carriers and 25% of being non-carriers, an affected person's children are obligate carriers and aunts and uncles have a 50% carrier probability [8]. When only one parent is a carrier, possible explanations are a de novo variant in the proband, parental mosaicism or uniparental isodisomy, described in an ABCA3-deficient patient whose two alleles were on the same chromosome [8, 61]. CSF2RA-related PAP follows a pseudoautosomal recessive pattern because the gene lies in pseudoautosomal region 1 of chromosomes X and Y: it requires two altered copies and is not transmitted as a classical X-linked disease, so offspring risks are those of a recessive disorder [42]. Consanguinity was documented in 8 of 9 families in the European CSF2RA deficiency series (first cousins) and 33% of families in the French ABCA3 deficiency cohort [14, 21].

SFTPC- and NKX2-1-related diseases are autosomal dominant, with a 50% risk for each descendant of an affected individual. In NKX2-1-related disease, most probands have an affected parent, but the proportion of de novo cases is unknown; in an isolated case parents should be tested, and absence of the variant in both parents' leucocyte DNA, with confirmed paternity, points to a de novo variant or parental germline mosaicism, with residual sibling risk estimated at approximately 1%. An apparently negative family history may result from mild manifestations, early death or late onset in a parent, and clinically unaffected but untested parents have a low but increased risk from reduced penetrance and mosaicism [17]. In dominant surfactant genes, reduced penetrance and intrafamilial variability make onset age, severity and progression unpredictable, which should be included in counselling [8, 31].

The 2021 French PNDS considers genetic counselling indispensable in all these diseases and classifies SFTPA1, SFTPA2, SFTPC and NKX2-1 as dominant, with transmission from a parent in familial forms but frequently de novo, and SFTPB and ABCA3 as recessive; the recurrence risk is 25% per pregnancy in recessive disorders and 50% in dominant disorders when a parent is a carrier, and low, but not nil, for de novo variants, because of possible germline mosaicism; expressivity is variable for all genes and penetrance incomplete for SFTPA1, SFTPA2, NKX2-1 and SFTPC [36]. The PNDS attributes about half of SFTPC and NKX2-1 cases to de novo variants, whereas GeneReviews considers the proportion unknown in NKX2-1-related disease; the difference does not change the recommendation to test the parents of an isolated case [17, 36].

8.2. Cascade testing and carriers

Carrier detection requires prior knowledge of familial variants [8]. In recessive disorders, confirmation of variant phase in the proband using parental DNA is necessary for correct counselling: 11% of ABCA3-deficient patients in one series had both variants in cis, and the French cohort confirmed compound heterozygosity with parental DNA in 16 of 21 cases, finding two complex alleles [13, 14]. The 2026 ATS guideline recommends that cascade testing of relatives be accompanied by genetic counselling, and notes that testing coverage in asymptomatic individuals is limited, that US legislation protects health insurance but not life and disability insurance, and that testing may reveal non-paternity, consanguinity and incidental findings [5]. In France, since Decree No. 2013-527 of 20 June 2013, informing relatives is a legal obligation when a serious genetic alteration is diagnosed for which preventive or care measures exist: for minors, the parents or legal representatives transmit the information, with the relatives to be informed and the nature of the risk defined at the genetics clinic; if the carrier does not wish to inform them personally, they may ask the physician to do so, and relatives are invited to a consultation without disclosure of the carrier's name, the variant or the risks. The obligation concerns mainly recessive forms with consanguinity and inherited dominant forms; for de novo variants there is no particular risk to the parents' siblings [35, 36].

Carriers of one ABCA3 variant need a precise message: they do not have the recessive disease or risk developing it, but population studies associate heterozygosity with increased RDS risk in term and late-preterm newborns, accounting for approximately 10.9% of attributable risk, and recent follow-up showed that 17% of 48 infants with a monoallelic variant and RDS were discharged on oxygen [12, 67]. GeneReviews on pulmonary fibrosis predisposition states that heterozygotes are asymptomatic without disease risk; the divergence concerns scope rather than facts, and counselling should distinguish absence of Mendelian disease from a small neonatal risk modifier [8, 12]. In SFTPC-related disease, some pathogenic variant carriers are asymptomatic, and genetic counselling should be offered particularly when asymptomatic relatives may carry a dominant variant, especially if disease is associated with adult ILD [5, 31]. In relatives at risk of NKX2-1-related disease, clarifying genetic status before or soon after birth identifies newborns at risk of hypothyroidism and lung disease and prevents developmental consequences of untreated hypothyroidism [17].

8.3. Prenatal diagnosis, preimplantation testing and neonatal decisions

Prenatal diagnosis and PGT are possible after identification of familial variants [5, 8, 17]. In SP-B deficiency, prenatal diagnosis was achieved through absent SP-B in amniotic fluid in 1994, before the molecular era [44]. In dominant disorders, PGT is technically possible but onset age, severity and progression cannot be predicted, a limitation that should be explicit [8]. DNA storage is recommended when there is no confirmed molecular diagnosis [8].

Rapid neonatal genetic diagnosis has immediate reproductive and clinical decision consequences: it enables counselling about transplantation or palliative care in genotypes with predictably poor prognosis, information about 25% sibling recurrence risk and prenatal diagnosis or PGT in a subsequent pregnancy [4, 5]. In ABCA3 null/null genotypes, discussion of transplantation or compassionate care should be prompt; in other genotypes, decisions are individualised [13]. In diseases precluding transplantation or when the family declines it, palliative care, social support and bereavement care form part of the plan, and counselling should include recurrence risk [4, 5].

8.4. Counselling minors and practical aspects

Predictive testing of an asymptomatic minor requires prior identification of the familial variant [17]. In NKX2-1-related disease, testing at-risk relatives is justified by concrete preventive interventions — neonatal levothyroxine replacement, pulmonary and thyroid surveillance — distinguishing it from predictive testing in diseases without available measures [17]. In surfactant disorders with variable onset, the decision depends on the existence of useful surveillance and should be discussed at a genetics clinic [5]. Counselling should address disease nature, inheritance pattern, implications for relatives, access to registries and patient associations and community support, including home nursing and social work [17, 31]. The French PNDS recommend that the diagnosis be disclosed in a protected setting, with time, preferably with both parents or a trusted person and with physicians and other professionals (nursing, psychology), and that it include explanation of the results, the disease, the mode of transmission to siblings and other relatives, current severity, treatment and its adverse effects, the need for multidisciplinary follow-up and the possibility of taking part in research; the RespiFIL network distributes a booklet supporting disclosure, which can be given to relatives, and families receive the contact details of patient associations [35, 36].

9. Special Considerations: Population Diversity and Epidemiology

9.1. What each number measures

This group's epidemiology relies on referral registries, insurance databases and literature counts rather than population studies; no entity has a measured true incidence. Orphanet case or family counts reflect indexed literature rather than prevalence [2]. Prevalences classified as <1/1 000,000 are classes rather than point estimates [11, 20]. Proportions of patients with variants in a gene depend strongly on the population studied: when genetic surfactant dysfunction is suspected, diagnostic yield was 21% (6–36%) in the 2026 ATS review, with SFTPC ranging from 5% to 83% and ABCA3 from 11% to 48% across studies [5].

9.2. Prevalence and incidence of chILD and surfactant disorders

The 2026 ATS guideline estimates chILD or paediatric diffuse lung disease prevalence between 0.15 and 4.6 cases per 100,000 children, depending on definition and ascertainment [5]. Recent French and Spanish studies indicate higher values: incidence 4.4 to 8.2 per million per year and prevalence 44 to 46.4 per million. The French cohort of 790 children (2000–2022) yielded incidence 4.4 per million per year and prevalence 44 per million; the Spanish cohort of 381 children (2018–2019), 8.18 and 46.53 per million; the German cohort of 56 children (2005–2006), 1.32 per million per year; and the Australian and New Zealand cohort of 115 children (2003–2013), prevalence 1.5 per million. Other cohorts with more than 50 children come from Denmark (884, 1995–2005), Europe through the chILD-EU registry (575, 2013–2016), China (133, 2013–2018), Turkey (416, 2021–2023) and the United States (93, 256, 683 and 306 in different periods) [10]. The difference between older and recent estimates results chiefly from registry ascertainment and genetic testing rather than changing true disease frequency. The 2021 French PNDS, based on a national survey from the United Kingdom and Ireland, gives a chILD prevalence below 1 per 100,000 children and mortality of about 15%, and the 2017 PNDS a mean age at diagnosis of 1.5 years in the French network; these values predate the recent cohorts and measure different populations [35, 36].

Genetic surfactant disorders explain some of these cases. ABCA3 deficiency accounts for 1.8 to 4.4% of chILD in recent studies and is the leading chILD cause at birth [14]. The 2021 French PNDS, by contrast, considers SFTPC variants probably the most frequent cause of surfactant disease in children; none of the sources presents a population-based comparison that resolves the divergence [14, 36, 63]. Among the genetic causes identified in approximately 20% of chILD, most involve surfactant metabolism genes, and approximately 40% of children with chILD syndrome remain without a specific diagnosis [5, 33]. In France, 543 of 706 RespiRare patients (76.9%) had been tested [14].

For SP-B deficiency, the only population-based estimate is allele frequency of 121ins2: 1 per 1000 in a linked Missouri birth and death database (n=1,052,544; 95% CI 0.03–5.6 per 1000) and 0.15 per 1000 in a New York cohort (n=6599; 95% CI 0.08–0.25 per 1000), statistically non-different values corresponding to approximately 1 allele per 1000 to 3000 individuals and not explaining most term newborns with fatal RDS [3]. Orphanet gives birth prevalence below 1 per 1,000,000, with a mean value of 0.067 per 100,000 [2]. The series of 33 SP-B-deficient infants at one centre over 12 years is a referral count [4, 101].

For PAP, the best North American estimate comes from an insurance database with approximately 15 million patients: 6.87±0.33 per million, a minimum estimate, similar between sexes and increasing with age; in the same work, 249 confirmed PAP cases in a reference diagnostic programme between 2004 and 2018 comprised 91.5% autoimmune, 4% secondary, 3% hereditary due to GM-CSF receptor variants and 1.5% congenital due to surfactant disorders [19]. PAP is more prevalent in smokers and affects all ages, ethnicities and regions [23]. Only a few dozen CSF2RA cases and fewer CSF2RB cases are described: by 2014 there were 13 published CSF2RA and 2 CSF2RB cases [21].

For NKX2-1-related disease, more than 120 individuals are described, prevalence is unknown, Orphanet classifies brain–thyroid–lung syndrome as below 1 per 1,000,000 with 100 indexed cases or families and assigns benign hereditary chorea (also including ADCY5) a point prevalence of 0.02 per 100,000; these values provide an order of magnitude rather than precise rates [15–17].

9.3. Geography, ancestry and founder populations

ABCA3 variants are private in approximately 80% of cases, but examples of founder effects and consanguinity exist. Homozygous p.(Tyr1515Ter) was found in 19 Middle Eastern infants, all with severe neonatal RDS and death before 3 months, and homozygous IVS25-98C>T in 4 Hispanic newborns, also with fatal infantile courses [13]. p.(Glu292Val) has approximately 1.15% European carriers and up to 20 homozygotes in gnomAD v4.1, and p.(Ser1262Gly) approximately 0.5% European carriers [14]. In controls, 1.5 to 3.7% of individuals of African and European ancestry carry ABCA3 missense variants [13]. These numbers imply that some classical variants are hypomorphic with reduced penetrance, an interpretation that should appear in laboratory reports [14].

Population frequencies of the three most studied historical variants — SFTPB 121ins2, ABCA3 E292V and SFTPC I73T — are below 0.4% in Missouri, Norwegian, South Korean and South African cohorts; E292V was found in 3.8% of newborns with RDS in a case–control study of 420 individuals, ten times more than in the Missouri cohort (p<0.001), and lies on a single haplotype derived from recombination of two common haplotypes [62]. Monoallelic ABCA3 variant overrepresentation in RDS was significant in newborns of European ancestry (14.3% versus 3.7%; p=0.002), but not African ancestry (4.5% versus 1.5%; p=0.23), potentially reflecting allele frequency differences or inadequate statistical power; in the population-based Missouri cohort (n=1066), 3.6% of newborns of European ancestry and 1.5% of those of African ancestry carried a single rare ABCA3 variant, rare individually but frequent collectively [12]. The 2026 ATS review notes that SFTPC and ABCA3 are rarely reported in Chinese and Japanese registries, potentially because of allele frequencies, testing practices or both [5]. In the European CSF2RA series, patients came from Belgium, Germany (three of Turkish ancestry), Turkey, Iran and Spain (one of Moroccan ancestry), with first-cousin parents in 8 of 9 families [21].

Lysinuric protein intolerance, the main metabolic cause of secondary PAP, has a Finnish founder population, where a cohort of 39 patients had proteinuria in 74% and haematuria in 38%; of 14 patients reviewed in one study, 10 had respiratory abnormalities [90].

9.4. Data from Portugal and Brazil

The sources consulted contain two Portuguese findings. The first is the Portuguese family with benign hereditary chorea described by Costa and colleagues in 2005: mother and son with chorea from childhood, myoclonus, falls and dysarthria, with a novel nonsense TITF1 (NKX2-1) variant, c.745C>T, p.Gln249* in the article's nomenclature (= NM_001079668.3:c.745C>T p.(Gln249Ter)); maternal magnetic resonance imaging showed hyperintense pallida and cerebral and cerebellar cortical atrophy, and the son's cerebellar hyperintense foci [119]. The second is a Portuguese ABCA3 deficiency case included in Serra and colleagues' review of 2004–2025 cases: a term newborn girl with NP_001080.2:p.(Leu798Pro) and p.(Arg1612Pro) variants, RDS in the first hours, four surfactant doses, methylprednisolone and hydroxychloroquine, who died at 101 days after withdrawal of intensive care; the finding is cited indirectly through that review [87]. No Brazilian data were found in the sources consulted; the search was not country-directed, and absence from these sources does not demonstrate absence of published data.

9.5. Special populations

Prematurity confounds diagnosis: surfactant disorders typically present in term or late-preterm newborns (94% term in the French ABCA3 cohort), and bronchopulmonary dysplasia is an exclusion criterion for chILD syndrome [14, 31]. ABCA3 heterozygosity is particularly relevant in late-preterm and term newborns with RDS [12]. In immunocompromised patients, diffuse lung disease requires exclusion of opportunistic infection, and immunodeficiency does not exclude chILD [31]. In multisystem diseases (NKX2-1, FLNA, TBX4), extrapulmonary involvement influences transplant candidacy [5]. Geography affects access: fewer than ten paediatric lung transplant centres exist in the United States, with long travel, and 89% of chILD therapy publications come from high-income countries, chiefly the United States and France [5, 56].

9.6. Reference networks, registries and patient associations

The relevant European reference network is ERN-LUNG, with 79 providers in 25 countries, organised into ten core networks and functional committees for trials, ethics, registries and biobanks, patient-reported outcomes and quality, and with a virtual ILD academy [37]. The Munich-led chILD-EU registry and biobank has recruited since December 2013, estimates one thousand patients and has primary completion planned for December 2028; it includes all children with suspected or confirmed ILD, mimics and rare localised parenchymal diseases [38]. The chILD-EU registry also provides central peer diagnostic review, which did not confirm the centre's diagnosis in 13% of cases, with 64% interobserver agreement [33]. Other registries are chILDRN (United States, since 2004), RespiRare (France, since 2008), chILD-Spain, ARNOLD and chILDRANZ (Australia and New Zealand), chILD-TR (Turkey) and RaDiCo-ILD (France) [10, 39]. In France, the RespiFIL network coordinates rare respiratory diseases [40]. The RespiRare paediatric reference centre is multisite, coordinated by Trousseau Hospital (Paris), with constituent sites in Créteil and at Necker-Enfants malades Hospital and, in the 2017 list, 28 competence centres in metropolitan France and on Réunion Island; the reference centre for rare adult lung diseases, OrphaLung, also multisite, provides adult follow-up, and the RespiFIL network organises national ILD MDTs [35, 36]. The French associations listed by the PNDS are the Association française des pneumopathies interstitielles de l'enfant (AFPIE), the association Respirer c'est Grandir, the association Ensemble pour Pedro, dedicated to brain–thyroid–lung syndrome, the Alliance maladies rares and the Maladies rares info services helpline. The planned social support includes the application for exemption from patient co-payment (ticket modérateur) for paramedical care, assessment by the maison départementale des personnes handicapées (MDPH) for child or adult disability allowances, support from a school life assistant and the parental presence allowance [35, 36].

Relevant patient associations include the chILD Foundation in the United States, chILD UK (which funded the Munich cohort), the European Lung Foundation chILD group and the PAP Foundation; the Pulmonary Fibrosis Foundation is the reference for adult pulmonary fibrosis [8, 63, 120–122]. The chILD Foundation address cited by the 2013 ATS guideline no longer responded and was replaced by the current address [31, 120]. For NKX2-1-related disease, GeneReviews indicates MedlinePlus and the US state-specific newborn screening resource [17].

10. Illustrative Clinical Case

10.1. Neonatal-onset ABCA3 deficiency

Serra and colleagues described, in 2025, a Sicilian girl born at 35 weeks and 5 days by vaginal delivery after a pregnancy complicated by chorioamnionitis, the first child of healthy non-consanguineous parents, with a mother smoking 4 to 5 cigarettes daily. Apgar scores were 7 at one minute and 9 at five minutes, weight 2270 g, length 46 cm and head circumference 33 cm. She had respiratory distress and oxygen dependence from birth, was intubated and received exogenous surfactant with slight improvement, was extubated to non-invasive ventilation and transferred around two weeks to a university unit in Palermo, with increasing oxygen requirements up to 100%. Three additional surfactant doses given by a less invasive technique provided partial brief benefit. She had two severe episodes of sepsis, due to Serratia marcescens and Klebsiella pneumoniae, compensated hypercapnia normalising after the first month, LDH 738 IU/L, generalised central hypotonia, germinal matrix cystic lesions, atrial septal defect and mild to moderate PH, treated with furosemide, spironolactone, hydrochlorothiazide and sildenafil [87].

The next-generation sequencing panel for congenital lung diseases, performed as a trio on GRCh37, identified compound heterozygosity in ABCA3: maternally inherited NM_001089.3:c.464G>A p.(Arg155Gln), absent from gnomAD, previously described in patients and classified as likely pathogenic (ACMG class 4), and paternally inherited NM_001089.3:c.2921G>A p.(Gly974Glu), absent from gnomAD and undescribed, classified as a VUS (class 3). The first lies in the first extracellular domain and the second in the second extracellular domain near known variants. The paternal variant was absent in the half-sisters. Parents declined lung biopsy and additional measurements, so the diagnosis rests partly on an allele of uncertain significance, a limitation acknowledged by the authors [87].

At 2 months, the team started the 2015 European protocol: intravenous corticosteroid 10 mg/kg/day, progressively reduced to 2.5 mg/kg/day over one week, followed by oral methylprednisolone 1 mg/kg/day, on alternate days in the last three days, for a total 14-day course; oral azithromycin 10 mg/kg on alternate days for 11 weeks; and hydroxychloroquine 10 mg/kg/day from 3 months. She received parenteral nutrition in the first quarter and percutaneous endoscopic gastrostomy at 3 months because of desaturation during feeds and aspiration risk, with physiotherapy, speech and language therapy and psychological family support; she was discharged around 5 months on high-flow oxygen (mean inspired oxygen fraction 45%) and home support. At 9 months chronological age (8 months and 13 days corrected), she was in good general condition on a high-flow nasal cannula with 40% oxygen, weighed 6350 g (2nd centile, standard deviation score −1.98), measured 69 cm (45th centile) and had a head circumference of 44.5 cm (76th centile), with axial hypotonia, mild to moderate PH with tricuspid regurgitation and supratentorial triventricular dilatation. Radiography showed bilateral reticular thickening [87].

Article figure 1, consulted on its page, shows (a) radiography with diffuse decreased transparency and a reticulomicronodular pattern and (b) CT with diffusely increased ground-glass density, inter- and intralobular septal thickening and multiple bilateral subcentimetre air cavities (https://pmc.ncbi.nlm.nih.gov/articles/PMC12155473/figure/jcm-14-03704-f001/) [87].

Management in this report does not represent routine practice. The pharmacological protocol followed corresponds to the 2015 European consensus, whose efficacy has not been demonstrated in a trial, and hydroxychloroquine was negative in the only randomised trial; in an equivalent situation the 2026 ATS guideline would recommend rapid exome or genome with a preliminary result in seven days rather than a panel, and transplant assessment referral within the first month after genetic confirmation for a genotype with predictably poor prognosis [5, 30]. Parental refusal of biopsy and complementary studies when one allele is a VUS illustrates the difficulty of confidently establishing a recessive diagnosis and the role of parental testing and periodic reanalysis [5, 87].

10.2. CSF2RB-related hereditary PAP diagnosed in adulthood

The course of a Greek male smoker (90 pack-years) described by Papiris and colleagues shows the opposite end of the spectrum. In 1996, asymptomatic at 21 years, a radiograph revealed ILD. In 2003 and 2004, at 29 years, VATS biopsy showed alveolar proteinosis with chronic lymphocytic inflammation, interstitial cholesterol cleft granulomas, cystically dilated subpleural alveolar spaces and collagenous fibrosis; he was treated with cyclophosphamide then azathioprine with corticosteroids for 24 months and disengaged from follow-up. In 2012, at 37 years, he worsened; anti-GM-CSF antibodies were not measured and bronchoscopic lobar lavage improved him. The 2013 CT showed extensive patchy ground-glass opacities and nodular consolidations with subpleural sparing and some cysts, without typical crazy paving. In August 2022, at 47 years, he presented with hypoxaemic respiratory failure, CT showing reduced ground-glass opacities replaced by numerous clustered cysts, and was referred late for transplantation. Telomere gene testing was negative and genetics identified homozygous CSF2RB (NM_000395.3) c.631C>T, p.(Arg211*), absent from gnomAD, with CADD 36 and a premature stop codon in exon 6 of 14, classified as likely pathogenic (PVS1, PM2). The explant showed alveolar proteinosis and usual interstitial pneumonia with sharply demarcated areas, and he was alive one year after transplantation without PAP recurrence [24].

Article figure 1, consulted on its page, combines histology from the 2004 biopsy, CTs from 2013 and 2022 and the explant with alveolar proteinosis and usual interstitial pneumonia (https://pmc.ncbi.nlm.nih.gov/articles/PMC10726220/figure/F1/) [24].

The case illustrates three practice points. First, hereditary PAP may manifest in adulthood and be mistaken for unclassifiable ILD for decades, leading the authors to conclude that genetic testing should be performed in all patients with anti-GM-CSF-antibody-negative or unclassifiable PAP [24]. Second, immunosuppression used in 2004 does not correspond to current practice, based on whole-lung lavage [21, 24]. Third, PAP graft recurrence described in other CSF2RB variant patients requires informing patients before transplantation, even when, as here, it has not occurred within the first year [24, 26].

11. Prognosis and Long-Term Follow-up

11.1. Prognosis by entity

Prognosis ranges from near-certain lethality in the first months to prolonged stability and depends chiefly on gene and genotype. The 2026 ATS guideline identifies as monogenic diseases generally fatal in infancy without transplantation SP-B deficiency (biallelic pathogenic SFTPB variants), ABCA3 deficiency with null/null genotype and FOXF1-related ACDMPV; it notes that complete loss-of-function genotypes predict severe disease, rare hypomorphic alleles cause less severe SP-B deficiency and these alleles are more frequent in ABCA3, hence recommending geneticist consultation for interpretation [5].

In SP-B deficiency, biallelic loss of function leads to death or transplantation within the first months, usually between 3 and 6 months [5, 56]. In ABCA3 deficiency, all 45 null/null infants in one series died (43) or underwent transplantation (2) by 1 year, versus 62% of null/other and other/other genotypes (p<0.001), and only 16% (22/139) of those presenting at birth were alive without transplantation at 1 year; of 25 patients with post-neonatal onset before 1 year, 72% were alive without transplantation [5, 13]. Among first-year survivors in the Munich registry, 82% were alive without transplantation at median age 6.3 years, with survival 67.6% in hypomorphic/hypomorphic genotypes and 15.4% in null/null, and functional decline of 1.1% predicted per year in FVC and 1.7% in FEV1 [63]. In the French cohort, 5-year overall survival was 25%, median 0.33 years, 61% died in the first year and only 4 reached young adulthood; neonatal onset, PH and a Fan index of 5 were poor prognostic factors [14]. Patients surviving beyond 2 years all had at least one allele with a missense variant outside nucleotide-binding domains, E292V or a distal frameshift [14].

In SFTPC-related disease, the course is unpredictable: progression in 17.6%, stability in 41.1% and improvement in 41.1% of 17 children followed for a median of 3 years, and survival into adulthood with normal lung function in some patients followed for 27 years; relapse and progression to refractory fibrosis may occur after years of stability [34]. In NKX2-1-related disease, life expectancy is described as normal, chorea improves until puberty and stabilises or remits, compensated hypothyroidism is generally well controlled and long-term pulmonary and thyroid prognoses are poorly known, with rare progression but risks of early-childhood respiratory failure, recurrent infections and lifelong asthma; neonatal RDS predicts later respiratory symptoms [17, 18, 78]. In hereditary PAP, the course was favourable in all whole-lung-lavage-treated patients in the two main series, and mild cases are often self-limiting, but prolonged disease may progress to fibrosis and respiratory failure [21, 22, 24].

For context, overall paediatric diffuse lung disease prognosis is intermediate: 5-year survival 64% in a series aged 1 month to 18 years, falling to 38% with PH at presentation; 6% mortality with improvement in 74% in a European task force requiring at least 3 months of symptoms and thus excluding rapidly progressive neonatal cases; and 30% mortality with continuing morbidity in 50% in the North American network of biopsy-diagnosed children under 2 years [31]. chILD has overall mortality of approximately 15% according to the European consortium [30]. These estimates measure different populations and are not comparable.

11.2. Surveillance

There is no consensus on chILD monitoring frequency; specific exacerbation criteria and minimal important differences for vital signs and quality of life were defined in a large European cohort [10]. Table 11.1 brings together surveillance based on the sources consulted.

Table 11.1 — Surveillance

In NKX2-1-related disease, annual neurological, pulmonary and thyroid surveillance applies even to carriers without manifestations in the respective system because of variable expression [17].

The French PNDS set a minimum follow-up schedule denser than the other sources: at least four visits a year, annual radiography, periodic function tests and blood gases, annual echocardiography and drug tolerance tests, with more frequent repetition in case of deterioration or if the result guides therapy [36]. They diverge from the 2026 ATS on follow-up CT, which they reserve for unexplained deterioration for radiation protection reasons, and the 2021 PNDS itself has different intervals in the text and in the annex for function tests (six-monthly and annual) and for the exercise test (every 1–2 years and annual) [5, 36].

11.3. Treatment monitoring and indicators of progression

Chronic corticosteroid therapy requires bone densitometry, growth surveillance and ophthalmological assessment; hydroxychloroquine requires periodic full blood counts and ophthalmological assessment, with baseline retinal examination according to the label, and in the European trial also included transaminases, creatinine, electrolytes, creatine kinase, blood glucose, drug blood level, electrocardiogram and echocardiogram [30, 31, 94]. Paediatric nintedanib in the EU requires dental examination at least every 6 months until complete dentition, annual bone imaging while epiphyses remain open and growth monitoring [98]. In ABCA3-deficient patients followed long term, appearance of parenchymal CT cysts (from approximately 10% before 2 years to approximately 60% afterwards) may mark progression, and fibrosis signs increase with age [63]. In surfactant disorders, five studies with 38 patients and repeat CTs between 3 months and 18 years showed, in most, progressive architectural distortion with worsening septal thickening, fibrosis, bronchiectasis and honeycombing; in one study, reduced ground-glass opacities with emerging cysts was associated with clinical improvement, and in another reduced ground-glass opacities did not correlate with clinical status or oxygen requirements [5].

After transplantation, surveillance follows centre protocols, with attention to bronchiolitis obliterans (56–60% in children in the St. Louis series), infection, post-transplant lymphoproliferative disease, hypertension, reduced linear growth and, in infants, motor and speech delay and hearing loss [55]. In transplanted hereditary PAP, recurrence of graft proteinosis should be sought [24, 26]. The French PNDS add laboratory monitoring of corticosteroid and hydroxychloroquine tolerance (full blood count, liver and renal function), densitometry to assess the effect of corticosteroids and deconditioning on bone growth and specific ophthalmological surveillance (Table 11.1) [35, 36].

12. Summary and Final Considerations

Genetic surfactant protein deficiencies bring together diseases affecting surfactant production by type 2 pneumocytes — SFTPB, SFTPC, ABCA3 and transcription factor NKX2-1 — and diseases affecting its clearance by alveolar macrophages — CSF2RA and CSF2RB — joined in 2026 by syndromic TMEM63B dysfunction. The distinction is clinically relevant: in the former, definitive therapy is lung transplantation, and in the latter the cornerstone is whole-lung lavage, with the caveat that proteinosis may recur in the graft because recipient macrophages repopulate transplanted lungs.

Recognition rests on two settings. In a term or late-preterm newborn with respiratory distress unexplained by prematurity, infection or aspiration, without a sustained exogenous surfactant response and progressing to respiratory failure, SP-B deficiency, ABCA3 deficiency and FOXF1-related ACDMPV should be considered; associated congenital hypothyroidism and hypotonia points towards NKX2-1. In infants or children with chILD syndrome — at least three of four criteria after common causes are excluded — the main genes to consider are SFTPC and ABCA3, and alveolar proteinosis with negative anti-GM-CSF antibodies and elevated serum GM-CSF directs towards GM-CSF receptor deficiency.

The most relevant recent practice change is methodological. In 2013, phenotype-directed gene-by-gene testing and biopsy when other tests failed were recommended; the October 2026 ATS guideline recommends, in infants with respiratory failure and suspected potentially fatal disease, rapid exome or genome with a preliminary result in seven days, suggests genetics before any invasive procedure and recommends transplant assessment referral within the first month after genetic confirmation in diseases with predictably poor prognosis. The approach should include copy-number variation detection and preferably trio testing, identifying de novo variants, frequent in SFTPC and NKX2-1, and confirming phase in recessive disorders — a practical issue in ABCA3, where some patients have both variants on the same allele. A negative genetic result does not exclude disease, approximately 8% of tests yield variants of uncertain significance and periodic reanalysis is recommended.

Prognosis depends on genotype but extends beyond it. Complete biallelic loss of SFTPB function and ABCA3 null/null genotype are uniformly fatal in early infancy without transplantation. In other ABCA3 genotypes, European and French cohorts show very different survival depending on whether they select first-year survivors or all diagnosed cases, and neonatal onset, pulmonary hypertension and initial severity weigh more than variant class. SFTPC-related disease is the most unpredictable, with asymptomatic carriers, apparent childhood remission and relapse with fibrosis decades later. NKX2-1-related disease has a life expectancy described as normal, chorea tending to improve in adolescence, hypothyroidism well controlled with neonatal levothyroxine and lung carcinoma risk justifying surveillance from adolescence. Hereditary PAP responds well to whole-lung lavage, but this repeated therapy does not correct myeloid dysfunction.

For pharmacological treatment, candour is part of clinical information. No medicine is authorised for any of these diseases. Corticosteroids, hydroxychloroquine and azithromycin are widely used off-label, with doses from a Delphi-based 2015 European consensus, and the only existing randomised trial, the chILD-EU hydroxychloroquine trial, was negative, at doses of 10 mg/kg/day in the first week and 6.5 mg/kg/day thereafter. The 2017 and 2021 French PNDS give regimens with maximum doses — methylprednisolone pulses up to 500 mg, oral prednisolone up to 60 mg/day, azithromycin up to 20 mg/kg/day on 3 days a week — and detailed vaccination and surveillance rules, which diverge on specific points from the European protocols. Nintedanib has an EU-authorised paediatric dose for progressive fibrosing interstitial lung disease from 6 to 17 years, with dental and bone surveillance, whereas the US agency states paediatric efficacy has not been demonstrated; most ABCA3-deficient children are too young for that indication. Inhaled GM-CSF has consistent randomised evidence only in autoimmune PAP and no rationale in hereditary PAP, where the receptor is absent or non-functional; inhaled molgramostim is not authorised in any jurisdiction, and information on its regulatory pathway comes from company press releases. CFTR modulators in ABCA3 deficiency and pulmonary transplantation of genetically corrected macrophages in CSF2RA-related PAP are the most advanced targeted approaches, the former in compassionate use in a series of three adults and one child, the latter in a first human trial of three patients without published results.

Four practical priorities follow: diagnose rapidly and broadly because the result determines transplant referral, counselling and palliative care decisions; enrol patients in registries, the only robust natural history source in such rare disease; prescribe empirical drugs with quantitative repeated response assessment, limited duration and adverse-effect surveillance; and ensure active transition to adult care for all survivors, even asymptomatic individuals, as one fifth of European chILD survivors have surfactant-related disease, most retain significant functional impairment and diagnosis or treatment is revised in some after transition.

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