We conducted WGS on a 20-year-old Spanish proband (only child), who exhibited classical symptoms of IDAIL, including early-onset type 1 diabetes (diagnosed at 15 months old), severe enteritis, genital vitiligo and atopic dermatitis. Throughout his childhood, he faced recurrent respiratory infections, including pneumonia, alongside pronounced reactive hypereosinophilia, which constituted up to approximately 65% of total peripheral blood mononuclear cells (PBMCs) at times. Notably, at the age 13, he experienced severe diarrhea and ascites, accompanied by eosinophil infiltration in the esophagus, stomach, and bone marrow. Medical investigations revealed a clonal γδ T cell band, characterized as reactive, with subsequent exclusion of FIP1L1-PDGFRA and PDGFRB rearrangements, as well as any abnormal karyotype. Over time, he developed esophageal candidiasis and sepsis due to Salmonella typhi and Clostridium difficile infection, which was accompanied by a gradual development of hypogammaglobulinemia. A complete clinical case description is included in the Supplementary Materials.Bioinformatic analysis revealed a known pathogenic maternally inherited missense variant in CTLA4, c.208C>T p.R70W, confirmed by Sanger sequencing (Fig. 1, A to D). This heterozygous variant has been previously reported to be causative of CTLA4-h with incomplete penetrance (1, 2). The R70W variant was also present in the patient’s mother who had been diagnosed with mild sarcoidosis, dysphagia with eosinophilic infiltrates of esophagus, low IgM, and decreased percentages of memory B cells.
Case#: 20-year-old Spanish man
DiseaseAssertion: Immune dysregulation with autoimmunity, immunodeficiency, and lymphoproliferation
FamilyInfo: Maternally inherited CTLA4 variant and paternally inherited CLEC7A variant. Patient's mother had been diagnosed with mild sarcoidosis, dysphagia with eosinophilic infiltrates of esophagus, low IgM, and decreased percentages of memory B cells.
CasePresentingHPOs: HP:0100651 (Type I diabetes mellitus) HP:0001045 (Vitiligo) HP:0001047 (Atopic dermatitis) HP:0002205 (Recurrent respiratory infections) HP:0001541 (Ascites) HP:0002014 (Diarrhea) HP:0410151 (Eosinophilic infiltration of the esophagus) HP:0410147 (Eosinophilic infiltration in the stomach mucosa) HP:0033351 (Candida esophagitis) HP:0100806 (Sepsis) HP:0032061 (Hypereosinophilia) HP:0032064 (Gastrointestinal eosinophilia)
CaseHPOFreeText: Type 1 diabetes was diagnosed at 15 months old. Patient has a history of severe enteritis. Investigations, which were undertaken due to hypereosinophilia and eosinophilic infiltration, revealed a clonal γδ T cell band, characterized as reactive, with subsequent exclusion of FIP1L1-FDGFRA and PDGFRB rearrangements, as well as any abnormal karyotype. Sepsis was due to Salmonella typhi and Clostridium difficile infection.
Article provides functional evidence of CLEC7A variant affecting phenotype of this patient. Their data suggest that partial loss of DECTIN-1 in a patient with CTLA-4h may enhance IDAIL penetrance and confer additional unique phenotypes, with persistent marked hypereosinophilia as the most remarkable uncommon clinical manifestation.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: Whole-genome sequencing was performed on the patient's whole blood sample. The variants were confirmed with Sanger sequencing. Presence of a somatic CTLA4 variant was ruled out with high-coverage WGS of sorted peripheral T cells.
GenotypingMethod: Whole-genome sequencing was performed on the patient's whole blood sample. The variants were confirmed with Sanger sequencing. Presence of a somatic CTLA4 variant was ruled out with high-coverage WGS of sorted peripheral T cells.
PreviouslyPublished: No
Variant: NM_005214.5:c.208C>T p.Arg70Trp
ClinVar: 161114
CAID: CA173999
gnomAD: 0.000001313 https://gnomad.broadinstitute.org/variant/2-203870684-C-T?dataset=gnomad_r4
Variant: NM_197947.3:c.547C>T p.Leu183Phe
ClinVar: 717363
CAID: CA6443934
gnomAD: 0.01719 https://gnomad.broadinstitute.org/variant/12-10123309-G-A?dataset=gnomad_r4
SupplementalData: Detailed clinical info and and immunological test results can be found in Supplementary Materials.f