A number sign (#) is used with this entry because of evidence that congenital malabsorptive diarrhea-11 (DIAR11) is caused by homozygous or compound heterozygous deletions encompassing the intestine critical region (ICR) on chromosome 16p13, which flanks and controls gastrointestinal expression of the PERCC1 gene (618656).

Diarrhea-11 (DIAR11) is characterized by onset of intractable malabsorptive diarrhea within the first few weeks of life (Oz-Levi et al., 2019).

For a discussion of genetic heterogeneity of diarrhea, see DIAR1 (214700).

Intractable diarrhea of infancy (IDIF) was first defined by Avery et al. (1968) as a noninfectious diarrhea lasting for more than 2 weeks, with onset before a few months of age, with consequent malabsorption and failure to thrive. It comprises a heterogeneous group of conditions; while the great majority of cases have no known etiology, several reports distinguished 2 subgroups. Straussberg et al. (1997) noted that in one subgroup, there is evidence of autoimmune involvement of the gastrointestinal tract as part of a systemic immune response. A second subgroup is characterized by a genetic basis, as indicated by parental consanguinity and a pattern of autosomal recessive inheritance. In this form, onset is usually before 2 months of age, extraintestinal involvement is infrequent, and there is no improvement of the diarrhea with diet and/or immunosuppression.

Straussberg et al. (1997) reported a cluster of cases with Jewish Iraqi ancestry who showed no evidence of antienterocyte antibodies, did not respond to an elemental diet or to steroid or immunosuppression therapy, and were dependent on total parenteral nutrition for years. Their 5 Iraqi Jewish patients with intractable diarrhea beginning during the first days of life belonged to 4 families. The parents were consanguineous in 3 families. Two of the patients were brothers (patients 4 and 5), and another (patient 3) had a brother who died at an early age from protracted diarrhea. The patients were all born after uneventful pregnancy and labor, with birth weight in the normal range. There were no dysmorphic features. Three patients were breastfed. Diarrhea was of the secretory type. Jejunal biopsies performed on all patients ranged from normal to severe partial villus atrophy. No similar cases were known in other ethnic groups in Israel, suggesting a possibly high gene frequency among Jews of Iraqi origin. Straussberg et al. (1997) concluded that the suggestion of a hereditary inborn defect of enterocyte differentiation as the pathogenetic mechanism is not certain, and pointed out that the reports are probably based on a heterogeneous population of patients.

Oz-Levi et al. (2019) studied 8 patients with malabsorptive diarrhea from 7 unrelated families of Jewish Iraqi origin. All but 1 patient were born at term with normal birth weight, and all presented with intractable diarrhea within the first 3 weeks of life. Ages ranged from 2 years to 28 years, and most patients were able to forgo parenteral nutrition by the second decade of life, although the oldest patient still received parenteral nutrition 4 times per week. Small intestine imaging appeared normal in most patients, but partial villous atrophy was observed in 2 of them.

Straussberg et al. (1997) found that the activity of prostaglandin synthetase (176805), which catalyzes the conversion of arachidonic acid to PGE2, was 2 to 3 times the control values in their Iraqi Jewish patients with intractable malabsorptive diarrhea.

The transmission pattern of DIAR11 in the families reported by Oz-Levi et al. (2019) was consistent with autosomal recessive inheritance.

By whole-genome linkage analysis in patients of Jewish Iraqi origin (families 1 to 5) with intractable congenital malabsorptive diarrhea, Oz-Levi et al. (2019) detected a single significant telomeric linkage interval on chromosome 16 (lod = 4.26). Haplotype reconstruction confirmed the interval, with flanking marker rs207435, and showed 2 distinct disease haplotypes, in either a homozygous or in a compound heterozygous setting.

In 8 patients from 7 families of Jewish Iraqi origin with intractable malabsorptive diarrhea of infancy, Oz-Levi et al. (2019) identified either homozygosity for a 7,013-bp long deletion (del-L) on chromosome 16 (618656.0001), or compound heterozygosity for del-L and a shorter, partially overlapping 3,101-bp deletion (del-S; 618656.0002). The overlap of del-L and del-S defined a minimal sequence of 1,528 bp that the authors designated the intestine critical region (ICR), deletion of which was not detected in control groups. Functional analysis in a mouse model demonstrated that the ICR contains a regulatory sequence that activates transcription during development of the gastrointestinal system, and targeted deletion of the ICR resulted in symptoms recapitulating the human disease. The ICR was shown to drive expression of the flanking gene PERCC1 (618656), and Percc1 knockout mice displayed a phenotype similar to that of ICR-deleted mice and humans, which was rescued by an ICR-driven Percc1 transgene. The authors concluded that PERCC1 is critical for intestinal function.

Oz-Levi et al. (2019) generated human intestinal organoids (HIOs) from pluripotent stem cells from a patient with intractable malabsorptive diarrhea of infancy who was homozygous for the del-L deletion on chromosome 16 (see MOLECULAR GENETICS), as well as from an unaffected heterozygous carrier of del-L and a wildtype sib. The authors observed that gross morphology of the HIOs was similar at early stages of development, but by day 42 the number of enteroendocrine cells (EECs) was severely reduced in patient HIOs compared to control HIOs, and expression of EEC markers was also reduced. The results suggested that disruption of the ICR does not affect initial formation of EECs, but interferes with their subsequent development.