Intermediate sweat chloride and faltering growth in an infant
A 9-month-old girl is referred with faltering growth and three episodes of productive cough treated as pneumonia since 4 months of age. Birth weight 3.2 kg; current weight 6.8 kg (0.4th centile), length 68 cm (2nd centile). She was exclusively breastfed to 6 months and is now on formula and solids. Her stools are bulky, pale and float, and her abdomen is distended. Sweat chloride by pilocarpine iontophoresis is 36 mmol/L on one occasion and 42 mmol/L on a repeat. Faecal elastase is 48 micrograms/g (normal >200). Chest radiograph shows hyperinflation and peribronchial thickening. CFTR sequencing reports c.1521_1523delCTT (F508del) on one allele and c.2657+5G>A on the other. Newborn screening was not performed. Her parents are consanguineous and have no symptoms.
1. How do you interpret the sweat chloride results and the genetic findings? What is your diagnosis?
Read the worked answer
A sweat chloride of 30-59 mmol/L is intermediate, not diagnostic. A single value in this range requires repeat testing, and the second value of 42 mmol/L remains intermediate. However, the clinical picture is strongly suggestive: faltering growth, recurrent chest infections, abdominal distension, and bulky pale stools. Faecal elastase of 48 micrograms/g confirms exocrine pancreatic insufficiency.
CFTR sequencing shows two variants: F508del, a well-established severe mutation, and c.2657+5G>A, a splice-site variant. The combination of compatible clinical features, pancreatic insufficiency, and two CFTR variants is sufficient to diagnose cystic fibrosis even when sweat chloride is intermediate, provided the second variant is confirmed pathogenic. I would check the splice variant in a CFTR database and, if needed, use functional testing such as nasal potential difference or intestinal current measurement. The diagnosis is cystic fibrosis; the intermediate sweat chloride reflects residual CFTR function rather than excluding disease.
2. Outline the first-line management plan for this child.
Read the worked answer
Respiratory: start airway clearance with chest physiotherapy twice daily, hypertonic saline 7% nebulised, and consider dornase alfa if there is persistent secretions or evidence of benefit. Send sputum or cough swab cultures every clinic visit; treat new Pseudomonas aeruginosa isolation with eradication therapy (for example inhaled tobramycin plus oral ciprofloxacin). Give annual influenza vaccination and routine immunisations. Monitor spirometry when old enough, chest radiographs as needed, and growth.
Nutrition: pancreatic enzyme replacement with every fat-containing feed, typically 500-2,500 lipase units per gram of fat, and fat-soluble vitamins A, D, E and K. Dietitian review for energy and protein intake, salt supplementation especially in hot weather, and growth monitoring. Check liver function and consider liver ultrasound; CF-related liver disease can be silent. Refer to a specialist CF centre. CFTR modulator eligibility depends on the specific variants and local approval; the F508del plus splice variant may qualify for a modulator, but this needs confirmation by the CF team.
3. What genetic counselling and family screening would you arrange?
Read the worked answer
Cystic fibrosis is autosomal recessive; both parents are obligate carriers if the variants are in trans, which should be confirmed by parental testing. Each sibling has a 25% chance of cystic fibrosis, 50% of being a carrier, and 25% of being unaffected and not a carrier. Offer carrier testing to parents and, when appropriate, to siblings after counselling. Discuss recurrence risk for future pregnancies and options including prenatal diagnosis by chorionic villus sampling or amniocentesis, and preimplantation genetic testing.
The parents are consanguineous, which increases the risk of other autosomal recessive conditions; the geneticist should take a three-generation pedigree and consider whether additional testing is indicated. Explain that the child's diagnosis is confirmed and that carrier status is not a disease. Provide written information and a follow-up appointment, and ensure the family has access to a clinical genetics service. Newborn screening was missed, so consider whether other children in the family need testing.