Case#: N/A. This patient is the only one studied in this paper. Female. Age of Onset: 11 y.o. Age of evaluation: 13 y.o. Origin not specified but looking at the author information, I believe it can be safely inferred that the patient is originally from Japan.
DiseaseAssertion: Autoimmune enteropathy with CTLA4 haploinsufficiency
FamilyInfo: Patient had no family history of autoimmune diseases, except for hypothyroidism in her mother and hyperthyroidism in her sister. The patient’s mother and sister were found to have the same heterozygous mutation, but they showed only thyroid gland dysfunction that was manageable with medication, which suggests incomplete penetrance.
CasePresentingHPOs: HP:0002720 (low IgA), OMIM:188030 (immune thrombocytopenic purpura (ITP)), sometimes accompanied by HP:0001890 (autoimmune hemolytic anemia), HP:0001882 (leukopenia), and ORPHA:56425 (cold agglutinin disease).
CaseHPOFreeText: Persistent watery diarrhea, immunoglobulin A (IgA) deficiency with low IgG2 and IgG4 subclass, recurrent immune thrombocytopenic purpura (ITP).
The patient had CTLA4 haploinsufficiency and was positive for anti-AIE-75 autoantibody but was successfully treated with 6-mercaptopurine (6-MP)
Patient was suspected of having interstitial nephritis
The patient responded well to prednisolone (PSL; 2 mg/kg/day) that was used to treat ITP at every onset, and the treatment was successfully tapered off. However, watery diarrhea appeared during the tapering of PSL while the treatment for the fifth episode of ITP was ongoing.
Her height was 155 cm (third to fifth percentile) and weight was 48 kg (fifth percentile)
In our patient, clinical remission was achieved with 40 mg/day of PSL. Clinical remission was maintained on 6-MP even after cessation of PSL for 4 years.
CaseNotHPOs: N/A.
CaseNotHPOFreeText: After analyzing the patient’s past laboratory data, we found that following cessation of PSL, ITP relapsed in association with the normalization of IgG levels (861–1,747 mg/dL). In addition, we found that serum levels of sIL-2R were extremely elevated at the onset of AIE. There was no manifestation of AIE, ITP, or other autoimmune diseases for 4 years, while the dose of 6-MP was adjusted to keep the levels of IgG and sIL-2R below 700 mg/dL and 1,500 U/mL, respectively (Fig. 3).
Flow cytometry analysis showed reduced frequency of CD4+ CD25+ FOXP3+ Tregs (Fig. 4) [10]. Consistent with clinical remission of AIE, an endoscopy and histological study 3 years after the achievement of remission demonstrated recovery from villous atrophy (Fig. 5). After 4 years of 6-MP administration, we tried to reduce the amount of 6-MP because we were concerning about the risk of secondary malignancies such as malignant lymphoma caused by 6-MP. Unfortunately, it led to the relapse of diarrhea and ITP along with soar up of serum level of rIL-2 receptor (Fig. 3).
CasePreviousTesting: The patient underwent many different types of testing:
None of the viruses, namely, adenovirus, enterovirus, cytomegalovirus, Epstein-Barr virus, norovirus, and rotavirus, were detected in the patient’s stool sample using polymerase chain reaction. In addition, no pathogenic bacteria were cultured from the stool. Besides, a toxin detection test for Clostridium difficile also yielded negative results. A computed tomography scan of her abdomen revealed a small volume of ascites.
An esophagogastroduodenoscopy and a colonoscopy demonstrated prominent atrophy of the villus in the duodenum (Fig. 1A) and terminal ileum. Colon was intact endoscopically (Fig. 1B). Histopathological examinations of the duodenum and ileum showed severe villous atrophy. Crypt apoptosis, and infiltration of lymphoplasmacytes into the lamina propria were seen in the biopsies of duodenum, ileum, and colon (Fig. 1C--E).E). Immunostaining of the normal small intestine tissue with the patient’s serum showed positive staining of the brush borders of the intestinal epithelium, indicating the presence of anti-enterocyte autoantibodies in the serum of the patient (Fig. 2A and andB).B). Furthermore, autoantibodies against AIE-75 were detected by Western blotting, using a recombinant protein as an antigen (Fig. 2C). The patient was diagnosed with AIE and was administered an increased dose of PSL (40 mg/day) as induction therapy.
Whole-exome sequencing demonstrated a heterozygous missense mutation in the CTLA4 gene. Flow cytometry analysis showed reduced frequency of CD4+ CD25+ FOXP3+ Tregs
GenotypingMethod: Whole-exome sequencing demonstrated a heterozygous missense mutation in the CTLA4 gene
PreviouslyPublished: Yes, PMID: 29729943. Schwab et al.
Variant: NM_001037631.2:c.119T>C
ClinVarID: None found
CAID: CA350138103
gnomAD: None found
SupplementalData: N/A
Note: Not functionally tested using transendocytosis