Clinical Features
The timing of presentation of interstitial lung disease can provide some indication towards the type of mutation causing surfactant protein deficiency. SP-B deficiency typically presents in full-term infants with diffuse lung disease which clinically and radiologically mimics the features of a pre-term infant with hyaline membrane disease. The disease rapidly progresses and results in respiratory failure and death within the first 3-6 months of life despite optimal medical treatment, although rarely some infants with partial deficiency of SP-B have survived longer. Longer survival could be attributed to a mild phenotype of the disease that allows for partial production of SP-B[35].
SP-C deficiency can present at various age groups particularly in later childhood, although there has been presentation as pulmonary fibrosis at the 5th or 6th decade of life [55]. This deficiency has a wide spectrum of clinical manifestation even in patients with the same genotype[56].SP-C deficiency is thought to be much rarer than SP-B deficiency or ABCA3 deficiency. In a case series of 22 patients with a median age of 3 months, patients presented with tachypnoea and hypoxemia with other symptoms that included failure to thrive and persistent cough[57]. Some children with SP-C deficiency can also present with recurrent non-resolving RSV bronchiolitis. Animal models that explored this relationship have shown that there is a demonstrable increase in severity in RSV- induced pulmonary inflammation[58]. It has also been suggested that RSV infection trigger severe lung injury or respiratory failure in SP-C carriers that have been previously asymptomatic[59]. In adults with idiopathic pulmonary fibrosis, a small case series showed only mild respiratory symptoms and almost normal lung function and survival after 27 years of follow up[60, 61].
The most common cause of surfactant protein deficiency is ABCA3 deficiency. Although it varies in presentation and severity, ABCA3 deficiency can either be identical to SF-B deficiency in terms of severity and high mortality or may manifest as subacute progressive lung disease in childhood. Genotype-phenotype correlations have been demonstrated in ABCA3 mutations. Patients with two frameshift and/or nonsense mutations have ~100% mortality or lung transplant by the age of one year while infants with only one frameshift and nonsense mutation with another mutation either a missense splice site or insertion/deletion have a milder phenotype and better outcomes[52]. In some instances, patients with ABCA3 deficiency may stabilise or even improve. In later childhood or early adulthood, the presentation can be cough, dyspnoea, reduced effort tolerance and chest wall deformities[62].
Patients with NKX2.1 related disease classically present with a triad of neurological dysfunction, hypothyroidism and lung disease. Chorea is the most common form of neurological involvement, followed by ataxia, developmental delay or hypotonia. Lung involvement typically causes respiratory distress in the neonatal period or early infancy [63]. Similar to the ABCA3 deficiency and SP-C deficiency, there has also been description of chronic phenotypes with patients surviving into adulthood characterized with recurrent pulmonary infections[64].