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].