Case Reflection of a Child With p.Phe312del/p.Phe508del Genotype Undetected on Newborn Screening and With No Clinical Features of Cystic Fibrosis Despite a Sweat Chloride Value in the Diagnostic Range

TL;DR

A child with two cystic fibrosis mutations showed no CF symptoms and was missed by newborn screening, highlighting limitations in current detection methods.

Contribution

Highlights a rare case where CF mutations were undetected by newborn screening and did not cause clinical CF symptoms.

Findings

The child had elevated sweat chloride but no clinical features of cystic fibrosis.

Newborn screening missed the CF mutations due to normal immunoreactive trypsinogen levels.

Elevated transaminases led to the discovery of Becker’s muscle dystrophy.

Abstract

This clinical overview reflects on a case of a nine-month-old boy presenting with mild bronchiolitis and persistently elevated transaminases. A total creatine kinase (CK) was requested to assess for dystrophinopathies, which was significantly elevated at 3000 U/L on repeat samples. Molecular testing confirmed the diagnosis of Becker’s muscle dystrophy (BMD). During molecular testing, two cystic fibrosis (CF) mutations were incidentally detected, a p.Phe312del mutation and the classic CF-causing mutation p.Phe508del. Sweat chloride testing was repeatedly elevated in keeping with the diagnosis of CF. Despite the significantly elevated sweat chloride and molecular genetic profile showing heterozygosity for p.Phe508del and p.Phe312del mutations, the patient did not show any clinical manifestation of CF. During the newborn screening, immunoreactive trypsinogen (IRT) was 26 ng/mL, below the upper limit value used for screening (54 ng/mL) at that time. This case illustrates two important points: firstly, patients heterozygous for p.Phe312del and p.Phe508del mutations may not be detected during newborn screening and may not have clinical manifestations of cystic fibrosis despite having unequivocally elevated sweat chloride. Secondly, an unexplained elevation of transaminases should trigger creatine kinase testing to check for dystrophinopathies.