A number sign (#) is used with this entry because of evidence that inflammatory bowel disease, immunodeficiency, and encephalopathy (IBDIMDE) is caused by homozygous or compound heterozygous mutation in the TGFB1 gene (190180) on chromosome 19q13.

Kotlarz et al. (2018) reported 3 patients from 2 unrelated families who presented in infancy with severe inflammatory bowel disease manifest as bloody diarrhea and failure to thrive. Colonoscopy showed chronic active inflammation with abscesses, crypt formation, inflammatory infiltration, and pseudopolyps. One patient also had eosinophilic esophagitis and esophageal candidiasis. All patients also showed global developmental delay associated with impaired speech and delayed intellectual development. One patient had hypotonia, and 2 sibs from family 2 developed myoclonic or complex partial seizures and had hypsarrhythmia on EEG. Brain imaging showed global atrophy, thin corpus callosum, posterior leukoencephalopathy, and delayed myelination. Two patients, one from each family, had recurrent infections, including respiratory infections, dermatitis, and varicella. Both of these patients had reduced T-cell responses to stimulation, and one had decreased T-cell subsets, including regulatory and helper T cells. The sole patient from family 1 was alive in stable condition at age 11 years. Both sibs in family 2 showed severe neurologic deterioration with loss of communication and increased spasticity, resulting in death at ages 25 and 39 months.

The transmission pattern of IBDIMDE in the families reported by Kotlarz et al. (2018) was consistent with autosomal recessive inheritance.

In 3 patients from 2 unrelated families with IBDIMDE, Kotlarz et al. (2018) identified homozygous or compound heterozygous missense mutations in the TFGB1 gene (190180.0008-190180.0010). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in both families. In vitro functional expression studies in HEK293 cells showed that the mutations resulted in reduced levels of secreted TGFB1 and reduced downstream signaling compared to controls, consistent with a loss of function. Colonic biopsy from 1 patient showed reduced levels of phosphorylated SMAD2 (601366)/SMAD3 (603109) in lamina propria mononuclear cells. Reduced levels of phosphorylated SMAD2/3 were also seen in mononuclear cells from an unrelated patient with Crohn disease (see 266600), suggesting a common pathophysiology.