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A5593 - Gotta Catch ‘Em All: Delayed Diagnosis of Cystic Fibrosis (CF) in an Infant with a Novel CF Transmembrane Conductance Regulator (CFTR) Mutation
Author Block: N. Hong1, S. D. Sagel1, E. T. Zemanick1, Y. Shi2, J. Hoppe1; 1Pediatrics, University of Colorado School of Medicine, Aurora, CO, United States, 2Pediatrics, University of Colorado, Aurora, CO, United States.
Introduction: Although newborn screening (NBS) has greatly improved timely diagnosis of cystic fibrosis, CF infants with rare or novel mutations may be missed. We present a case of delayed CF diagnosis complicated by hypoelectrolytemia.
Case Summary: An elevated immunoreactive trypsinogen (IRT) (437 ng/mL) was identified on a newborn female's first NBS but a second sample was never sent. Genetic testing (39 mutations) identified one F508del mutation. Sweat testing was recommended but delayed due to parental choice. Mother was a known CF carrier but father had tested negative on a CF mutation panel. Sweat testing was performed at 5 months and was diagnostic for CF (61 mmol/L).
At her initial CF visit, electrolyte testing revealed mild hyponatremia (130 mmol/L) and hypochloremia (90 mmol/L). The parents started salt supplementation (¼ teaspoon daily), and three days later, her sodium (137 mmol/L) and chloride (96 mmol/L) normalized. Fecal elastase testing demonstrated pancreatic sufficiency (>500ug Elastase/g stool). CFTR gene sequencing was positive for one copy of the F508del mutation and one copy of the variant c.283A>G; p.Lys95Gl. This variant is not reported in the CFTR2 or the Toronto CF Mutation database, and there are no published case reports of this mutation in the literature. A functional study has been published on the Lysine-95 residue of the human CFTR protein (Linsdell P, J Biol Chem, 2005). Lysine-95 is localized to the CFTR chloride channel pore and plays a key role in the binding of chloride ions. When the positively charged lysine at position 95 was changed to a negatively charged glutamine, the normal function of the chloride channel pore was disrupted.
She is now 20 months old and has maintained a weight for length above the 50th percentile. Oropharyngeal cultures have grown methicillin sensitive Staphylococcus Aureus, Haemophilus influenzae and a Pseudomonas species (not aeruginosa).
Discussion: This case describes the clinical outcomes of an infant with a novel CFTR mutation and highlights the importance of NBS algorithms and timely sweat testing to identify patients with CF prior to the development of complications, including hypoelectrolytemia. Those with partial function CFTR mutations and pancreatic sufficiency remain at risk for hypoelectrolytemia. This case also emphasizes that prenatal screening and NBS are screens, not definitive tests, and could provide false reassurance against CF. Sweat testing remains the diagnostic gold standard and should be recommended in children with an inconclusive NBS or symptoms concerning for CF.