BESC1 is a progressive lung disorder that results in a phenotype closely resembling Cystic Fibrosis. However, affected individuals do not carry mutations in the Cystic Fibrosis-associated CFTR gene. The condition is hence known as Cystic-Fibrosis like Syndrome or Atypical Cystic Fibrosis. It is characterized by chronic dilation of the bronchi (bronchiectasis) and chronic inflammation of the bronchial tubes (bronchitis). Patients may exhibit elevated levels of sweat chloride resulting in episodes of hyponatremic dehydration. They may also have an increased nasal potential difference but with normal exocrine pancreatic function.
The condition is rare, with only a handful of cases reported worldwide. The disorder is diagnosed based on laboratory investigations of sweat chloride levels, nasal potential difference (NPD) testing, spirometry studies to analyze lung function and chest CT scans to detect bronchiectasis. The differential diagnosis of cystic fibrosis is eliminated based on the normal pancreatic function and lack of CFTR mutations. Treatment of the condition is currently limited to symptomatic management. Hyponatremic dehydration is treated by administration of Pedialyte and unrestricted access to dietary salt.
The condition follows an autosomal dominant pattern of inheritance and is caused by mutations in the SCNN1B gene. This gene encodes the beta subunit of the epithelial sodium channel. Variants that are associated with BESC1 mainly include missense mutations that disrupt sodium transport and fluid balance.
A recent study has also suggested the role of CA12 gene mutations in developing a BESC1-like phenotype. The CA12 gene encodes Carbonic Anhydrase 12, a zinc metalloenzyme responsible for catalyzing the reversible hydration of carbon dioxide.
Lee et al. (2016) described a consanguineous Omani family with two children affected by elevated sweat chloride, infantile FTT, recurrent hyponatremia and bilateral hyperkeratosis of the heels. Genetic analysis identified a novel homozygous c.363C>A mutation in exon 4 of the CA12 gene of both patients. It segregated in an autosomal recessive pattern in the family and was predicted to result in a p.His121Gln substitution. Studies of the mutation along with a previously reported p.Glu143Lys variant found that while they did not affect CA12 protein localization, they resulted in a near complete loss of enzyme activity at physiologic concentrations of extracellular chloride. CA12 deleterious variants were also identified in a 25-year-old Caucasian female with elevated sweat chloride and pulmonary airway disease. Hence, while spirometry and chest X-rays of the Omani proband were normal, it was suggested that bronchiectasis might be present but was undetected due to lack of CT-scan analysis. This study highlighted the importance of screening for CA12 mutations in individuals that have CF-like features in the sweat gland and lung but no CFTR mutations.
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