Alternative titles; symbols
SNOMEDCT: 5388008; ICD10CM: E73.0; ORPHA: 53690; DO: 0111646;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 2q21.3 | Lactase deficiency, congenital | 223000 | Autosomal recessive | 3 | LCT | 603202 |
A number sign (#) is used with this entry because congenital lactase deficiency is caused by homozygous or compound heterozygous mutation in the LCT gene (603202) on chromosome 2q21.
Congenital lactase deficiency is a severe gastrointestinal disorder characterized by watery diarrhea in infants fed with breast milk or other lactose-containing formulas.
In disaccharide intolerance II, cellobiose intolerance would be expected as well as that for lactose. Sucrose, maltose, and starch are well tolerated. In a breastfed infant who developed watery diarrhea on the third day of life, Levin et al. (1970) demonstrated absent lactase in a specimen of duodenal mucosa which was histologically normal and showed normal maltase isomaltase and sucrase activities. Convincing direct demonstration of absent lactase in biopsies obtained in infancy has been achieved only twice before, according to the authors. A sister of the proband was probably identically affected.
Savilahti et al. (1983) reported 16 Finnish cases (10 male, 6 female) discovered during the previous 17 years. In each case the mother noted watery diarrhea, generally after the first feed of breast milk but at the latest by age 10 days. The 16 cases included 4 pairs of sibs. With the virtual disappearance of diarrhea as a cause of death in the first year of life, the authors believed that every case of congenital lactase deficiency in their population was discovered. Segregation analysis, assuming complete ascertainment, showed agreement with the number expected. The Finnish collection of 16 patients was especially impressive in light of the fact that only 18 cases had been reported elsewhere. The late consequences of this genetic disorder were not fully known. Affected persons might have less atherosclerosis than the average because they avoid dairy products, just as persons with fructose intolerance (229600) have fewer dental caries.
Jarvela et al. (1998) stated that, since 1966, 42 patients with congenital lactase deficiency had been diagnosed in Finland. In this disorder an almost total lack of lactase-phlorizin hydrolase activity is found in jejunal biopsy material. In adult-type hypolactasia (223100), the most common genetic enzyme deficiency in humans, this enzyme activity is reduced to 5 to 10%.
Congenital lactase deficiency is one of the approximately 30 rare recessive disorders that are relatively common in Finland.
Affected sibs were reported by Holzel et al. (1959), Weijers and Van De Kamer (1964), Launiala et al. (1969), and Savilahti et al. (1983).
By linkage analysis in 19 Finnish families, Jarvela et al. (1998) assigned the locus for congenital lactase deficiency to 2q21.
Poggi and Sebastio (1991) sequenced the exons, the exon-intron boundaries, and the promoter region of the lactase gene of a Finnish patient with congenital lactase deficiency. No mutation leading to a missense, frameshift, or other change in amino acid sequence was found. They raised the question of a defect in a control mechanism 'in trans' as the basis of the abnormality.
Enattah et al. (2002) identified 2 variants upstream from the LCT gene (see 601806.0001-601806.0002) that were completely associated with hypolactasia of the adult type (223100). However, no association was found between these variants and congenital lactase deficiency in 19 Finnish families.
In patients with congenital lactase deficiency, Kuokkanen et al. (2006) identified 5 distinct mutations in the coding region of the LCT gene. In 27 of 32 patients (84%), they found homozygosity for a nonsense mutation, 4170T-A (Y1390X; 603202.0001), designated 'Fin(major).' In the other patients, they identified compound heterozygosity. The data demonstrated that, in contrast to adult-type hypolactasia (lactose intolerance) caused by a variant of the regulatory element, the severe infancy type represents the outcome of mutations affecting the structure of the protein with inactivation of the enzyme.
Several groups described what may be a distinct disorder.
Congenital lactose intolerance was first described by Durand (1958). Severe congenital lactose intolerance was viewed by some as a transient form of congenital lactase deficiency. However, the disease has distinct features. It is a more serious disorder with vomiting, failure to thrive, dehydration, disacchariduria including lactosuria, renal tubular acidosis, and amino aciduria. Liver damage is also observed. Abnormal absorption of lactose and other disaccharides was suggested by the work of Berg et al. (1969). Lactose, not normally found in the blood, may have toxic effects as does fructose-1-phosphate in fructose intolerance (229600) and galactose-1-phosphate in galactosemia (230400). Russo et al. (1974) documented that lactosuria is due to gastric absorption because it disappeared when lactose was given intraduodenally. They made the additional important observation of cataracts in the male proband, his father, 2 paternal uncles, and his paternal grandfather, all of whom had lactosuria. Hirashima et al. (1979) also observed cataract and described brain damage which may have been due to lactosemia. The disorder occurs with breastfeeding as well as bottle-feeding. Although the disorder can be fatal if not recognized, change to a milk-free diet leads to rapid recovery, and after 6 months of age a normal diet (with milk) is well tolerated (Hoskova et al., 1980).
Berg, N. O., Dahlqvist, A., Lindberg, T., Studnitz, W. Severe familial lactose intolerance--a gastrogen disorder? Acta Paediat. Scand. 58: 525-527, 1969. [PubMed: 5365173] [Full Text: https://doi.org/10.1111/j.1651-2227.1969.tb04754.x]
Dahlqvist, A. Specificity of the human intestinal disaccharidases and implications for hereditary disaccharide intolerance. J. Clin. Invest. 41: 463-470, 1962. [PubMed: 13883118] [Full Text: https://doi.org/10.1172/JCI104499]
Darling, S., Mortensen, O., Sondergaard, G. Lactosuria and amino-aciduria in infancy: a new inborn error of metabolism? Acta Paediat. (Stockh.) 49: 281-290, 1960. [PubMed: 13814131] [Full Text: https://doi.org/10.1111/j.1651-2227.1960.tb07735.x]
Durand, P. Lactosuria idiopatica in una paziente con diarrea ad acidi. Minerva Pediat. 10: 706-711, 1958. [PubMed: 13565838]
Enattah, N. S., Sahi, T., Savilahti, E., Terwilliger, J. D., Peltonen, L., Jarvela, I. Identification of a variant associated with adult-type hypolactasia. Nature Genet. 30: 233-237, 2002. [PubMed: 11788828] [Full Text: https://doi.org/10.1038/ng826]
Hirashima, Y., Shinozuka, S., Ieiri, T., Matsuda, I., Ono, Y., Murata, T. Lactose intolerance associated with cataracts. Europ. J. Pediat. 130: 41-45, 1979. [PubMed: 759181] [Full Text: https://doi.org/10.1007/BF00441897]
Holzel, A., Schwarz, V., Sutcliffe, K. W. Defective lactose absorption causing malnutrition in infancy. Lancet 273: 1126-1128, 1959. Note: Originally Volume I. [PubMed: 13665980] [Full Text: https://doi.org/10.1016/s0140-6736(59)90710-x]
Hoskova, A., Sabacky, J., Mrskos, A., Pospisil, R. Severe lactose intolerance with lactosuria and vomiting. Arch. Dis. Child. 55: 304-316, 1980. [PubMed: 7416780] [Full Text: https://doi.org/10.1136/adc.55.4.304]
Jarvela, I., Enattah, N. S., Kokkonen, J., Varilo, T., Savilahti, E., Peltonen, L. Assignment of the locus for congenital lactase deficiency to 2q21, in the vicinity of but separate from the lactase-phlorizin hydrolase gene. Am. J. Hum. Genet. 63: 1078-1085, 1998. [PubMed: 9758622] [Full Text: https://doi.org/10.1086/302064]
Kuokkanen, M., Kokkonen, J., Enattah, N. S., Ylisaukko-oja, T., Komu, H., Varilo, T., Peltonen, L., Savilahti, E., Jarvela, I. Mutations in the translated region of the lactase gene (LCT) underlie congenital lactase deficiency. Am. J. Hum. Genet. 78: 339-344, 2006. [PubMed: 16400612] [Full Text: https://doi.org/10.1086/500053]
Launiala, K., Perheentupa, J., Hallman, N. Congenital sugar malabsorption. In: Gardner, L. I.: Endocrine and Genetic Diseases of Childhood. Philadelphia: W. B. Saunders (pub.) 1969. Pp. 830-843.
Levin, B., Abraham, J. M., Burgess, E. A., Wallis, P. G. Congenital lactose malabsorption. Arch. Dis. Child. 45: 173-177, 1970. [PubMed: 5419986] [Full Text: https://doi.org/10.1136/adc.45.240.173]
Poggi, V., Sebastio, G. Molecular analysis of the lactase gene in the congenital lactase deficiency. (Abstract) Am. J. Hum. Genet. 49 (suppl.): 105, 1991.
Rinaldi, E., Albini, L., Costagliola, C., De Rosa, G., Auricchio, G., De Vizia, B., Auricchio, S. High frequency of lactose absorbers among adults with idiopathic senile and presenile cataract in a population with a high prevalence of primary adult lactose malabsorption. Lancet 323: 355-357, 1984. Note: Originally Volume I. [PubMed: 6141422] [Full Text: https://doi.org/10.1016/s0140-6736(84)90409-4]
Russo, G., Mollica, F., Mazzone, D., Santonocito, B. Congenital lactose intolerance of gastrogen origin associated with cataracts. Acta Paediat. Scand. 63: 457-460, 1974. [PubMed: 4209121] [Full Text: https://doi.org/10.1111/j.1651-2227.1974.tb04830.x]
Savilahti, E., Launiala, K., Kuitunen, P. Congenital lactase deficiency: a clinical study on 16 patients. Arch. Dis. Child. 58: 246-252, 1983. [PubMed: 6847226] [Full Text: https://doi.org/10.1136/adc.58.4.246]
Weijers, H. A., Van de Kamer, J. H. Fermentative diarrhoeas. In: Durand, P.: Disorders Due to Intestinal Defective Carbohydrate Digestion and Absorption. Rome: Il Pensiero Scientifico (pub.) 1964.