Scientific Background

Interstitial lung disease (ILD) is a heterogeneous group of rare diseases with varied and often unknown causes that have acute or chronic respiratory symptoms as a result of pathological changes in the lung interstitium. Since other structures of the lung are often affected as well, the term diffuse parenchymatous lung disease (DPLD) is used synonymously. Childhood ILD (chILD) differs significantly from the ILD in adults in terms of pathology and clinical progression. Due to the rarity of these diseases, research in this area is not yet sufficiently advanced. The typical presentation of ILD in childhood is a full-term infant with unexplained respiratory distress syndrome, which is clinically and radiologically similar to respiratory distress syndrome in premature infants. ILD can also occur in older infants and children without a history of neonatal lung disease. The clinical symptoms with more or less severe respiratory insufficiency at diagnosis are very variable and the disease course is very different. The frequency of the disease is difficult to assess, especially because in many cases the diagnosis remains uncertain without a clear cause. This is reflected in prevalence estimates ranging from 0.1 to 16.2 cases per 100,000.


About 20% of chILD cases are caused by a genetic surfactant dysfunction. Surfactant is a complex mixture of lipids and proteins with a high lipid content, which serves to lower the surface tension in the alveoli and thus prevent atelectasis. Congenital disorders of surfactant metabolism are genetically and clinically heterogeneous and are triggered by causative variants in various genes, for example that code for protein components of the surfactant (SFTPB, SFTPC), which regulate the expression of genes involved in lung development and function (NKX2-1), are responsible for lipid transport in lamellar bodies (ABCA3), or are important for signal transduction in the surfactant metabolism and pulmonary macrophages (CSF2RA, CSF2RB). The diseases follow different modes of inheritance: autosomal recessive (SFTPB, ABCA3, CSF2RB), autosomal dominant or sporadic due to a dominant new mutation (SFTPC, NKX2-1), or X-linked (CSF2RA).


The FLNA gene on Xq28 encodes filamine A, which is an actin-binding protein that is important for maintaining the cellular actin cytoskeleton. Pathogenic variants in FLNA cause a broad spectrum of diseases, including various malformation syndromes affecting the skeleton, craniofacial region, brain, abdominal organs, and the urogenital tract. Several diseases are considered to be a lethal in males and only female sufferers are seen. Other FLNA-associated syndromes are associated with a symptomatology that is only seen in males and female mutation carriers are symptom-free. Loss-of-function variants cause, for example, an X-linked dominant inherited form of periventricular nodular heterotopy (PNH), which occurs mainly in women. Occasional male PNH patients have also been reported due to residual protein function. In contrast, missense substitutions or in-frame deletions lead to diseases with skeletal involvement such as Melnick-Needles syndrome and otopalatodigital syndrome type I and II. Recently, ILD in childhood has also been reported in connection with FLNA variants.


Heterozygous pathogenic sequence alterations of the FOXF1 gene and genomic deletions of the chromosomal region 16q24.1 including the FOXF1 gene and it’s regulatory regions lead to a rare, lethal developmental condition of the lung and associated vasculature, congenital alveolar capillary dysplasia. Affected patients typically develop a severe respiratory distress syndrome shortly after birth with pulmonary hypertension and death within the first months of life. However, rare atypical cases with later onset of disease and longer survival have also been described. Histology shows abnormal development of the alveolar capillaries and veins with a lack of contact between capillaries and epithelium, thickened arteriole and alveolar wall muscle and an abnormal course of the pulmonary veins together with the arterioles. Approximately 80% of those affected have additional malformations that are mainly cardiovascular, gastrointestinal and urogenital; about 1/3 are a loss of normal right-left asymmetry of the thoracic and intra-abdominal organs. FOXF1 encodes a transcription factor that plays a role in the development of the pulmonary, cardiovascular, gastrointestinal and urogenital systems. It is a dose-sensitive transcription factor that binds to the promoter regions of other genes involved in organogenesis. The gene seems to be subject to paternal imprinting, since in the patients examined so far, the maternal allele was almost exclusively affected. Most cases have been sporadic; the few familial cases showed inheritance via the mother, which is also compatible with paternal imprinting of the gene.


The three main symptoms of the rare autosomal dominant inherited brain-lung-thyroid syndrome occur in variable combination. In one study, 50% of affected persons showed full brain-lung-thyroid syndrome, 30% had brain and thyroid involvement and 13% had isolated chorea. Neurological signs appear in the first year of life with muscle hypotonia and psychomotor retardation. Between the first and fifth year of life, benign hereditary chorea (BHC) develops. Non-progressive BHC after the age of five is the most common disease feature. The second most common symptom, lung disease, can manifest in a newborn as respiratory distress syndrome or later as chronic interstitial pneumonia or recurrent lung infections. Congenital hypothyroidism is due to a developmental disorder of the thyroid gland; accordingly, athyroidism or partial agenesis also occurs. Up to 50% of patients with a causative NKX2-1 variant develop (variable) pulmonary symptoms. They have an increased risk of recurrent pulmonary infections and as young adults are likely to have an increased risk of lung cancer. The NKX2-1 gene codes for a transcription factor that is expressed during early embryonic development, particularly in the thyroid, lung, basal ganglia and hypothalamus. The disease is caused by loss-of-function variants and deletions (approximately 10%), which lead to haploinsufficiency.



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