Congenital lactase deficiency

Congenital lactase deficiency (CLD) is an extremely rare, lifelong gastrointestinal disorder of neonatal onset. Affected neonates present within the first week of life with watery osmotic diarrhoea on first exposure to lactose-containing milk, including breast milk. The diarrhoea is a classic example of diet-induced osmotic diarrhoea, with undigested intraluminal lactose drawing fluid into the small-bowel lumen and producing high-volume watery stools. Continued lactose ingestion produces severe, potentially life-threatening dehydration, metabolic acidosis and failure to thrive within the first weeks of life.

Small-intestinal histology is characteristically normal, with no villus atrophy and no mucosal inflammation, which distinguishes CLD on biopsy from other neonatal-onset congenital enteropathies that present with similar diarrhoeal symptoms. CLD persists across the lifespan, but with early clinical recognition and strict avoidance of dietary lactose, it is regarded as one of the most treatable forms of congenital enteropathy.

Reliable data on the global prevalence are not available. CLD is considered an extremely rare disorder. A higher frequency has been reported in Finland, likely due to a founder effect, with historical estimates of approximately 1:60,000 live births.

Congenital lactase deficiency is caused by biallelic germline pathogenic variants in LCT. LCT (2q21.3) encodes lactase-phlorizin hydrolase, the enzyme that hydrolyses lactose at the small-intestinal brush border. Reported variants span nonsense, frameshift (duplications and deletions) and missense changes distributed across the trafficking and catalytic domains of the enzyme. Functional studies show that mutant lactase-phlorizin hydrolase is trafficking-incompetent and enzymatically inactive and that certain missense variants can additionally impair the wild-type enzyme through hetero-complex assembly. Undigested intraluminal lactose then drives the osmotic diarrhoea and dehydration that define the clinical picture.

Congenital lactase deficiency is inherited in an autosomal recessive manner. Both biological parents are typically asymptomatic heterozygous carriers, and the recurrence risk for each subsequent pregnancy of a carrier couple is 25%. Once the familial pathogenic variants in LCT have been identified, prenatal molecular testing and preimplantation genetic testing are technically possible. Carrier testing of at-risk adult relatives is also technically possible.

In congenital lactase deficiency, the diagnosis is established by demonstrating low or absent lactase (disaccharidase) activity in a small-intestinal biopsy that otherwise shows normal mucosal architecture, without villus atrophy or inflammation; molecular genetic testing of LCT confirms the diagnosis by identifying biallelic pathogenic variants.

• Establishing the diagnosis: confirming the molecular diagnosis ends the diagnostic odyssey, secures the clinical suspicion, and provides the foundation for informed genetic counselling.
• Clinical management: a confirmed molecular diagnosis is a prerequisite for individualised, condition-tailored clinical management and supportive care, planned by the treating physicians in consultation with the affected individual.
• Family member testing: once the familial pathogenic variants have been identified, targeted carrier testing of at-risk relatives is technically possible within established human-genetic counselling.

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