Case#: The patient is a 39-year-old female with symptom onset at 14.

DiseaseAssertion: The patient is asserted to have "CTLA-4 happloinsufficiency." "Affected patients develop cytopenia, lymphoproliferative disorders, and hypogammaglobulinemia and are prone to a variety of autoimmune phenomena."

FamilyInfo: None provided

CasePresentingHPOs: HP:0001873 (Thrombocytopenia), HP:0001888 (Lymphopenia), HP:0001903 (Anemia), HP:0004313 (Decreased circulating immunoglobulin concentration), HP:0002028 (Chronic diarrhea), HP:0002024 (Malabsorption), HP:0001596 (Alopecia), HP:4000055 (Intestinal inflammation), HP:0006824 (Cranial nerve paralysis), HP:0002090 (Pneumonia), HP:0001269 (Hemiparesis)

CaseHPOFreeText: CSF analysis showed intrathecal synthesis of immunoglobulins G and M. MRI showed disseminated T2-hyperintense lesions, some lesions indicated long-lasting gadolinium enhancement (Figure 1A). PET scan-guided brain biopsy showed sustained myeline integrity, massive infiltration of T cells, and presence of few perivascular B cells. Infectious or neoplastic conditions were ruled out.

CaseNotHPOs: N/A

CaseNotHPOFreeText: Laboratory testing was negative for infectious or rheumatologic conditions. Brain vessel angiography was normal.

CasePreviousTesting: None reported.

GenotypingMethod: Sequencing of the LRBA and CTLA4 genes was performed. Authors did not elaborate on methodology or assay.

PreviouslyPublished No prior article is known to contain information on the same proband.

Variant: The patient is heterozygous for the NM_005214.5(CTLA4):c.322_323insT (p.Ser108MetfsTer46) variant.

CAID: CA3270658428

gnomAD: This variant is not found in gnomAD v4.1.1.

SupplementalData: Figure 1A shows MRI scans from 2014-2021. Figure 1B shows immunomodulatory treatment of the patient. Figure 1C shows blood lymphocyte count and lymphocyte subsets over time. Figure 1D shows Crohn disease activity index, blood platelet count, and serum immunoglobulins. Figure 2 shows single-cell RNA sequencing of peripheral blood monocular cells.

Case#: A 51-year-old woman

FamilyInfo: the patient (and her affected family members) were heterozygous for a novel, likely pathogenic frameshift deletion variant in CLTA-4 exon

CasePresentingHPOs: HP:0002018, HP:0002141, HP:0003474, HP:0002110, HP:0001891, HP:0000964, HP:0001973, HP:0011108, HP:0100512

CaseHPOFreeText: necrotising granulomatous lymphadenitis, osteonecrosis of the jaw induced by bisphosphonates, diverticulitis, and bowel salt malabsorption. The patient’s daughter had recurrent episodes of CNS inflammation as a child and in adulthood she developed autoimmune hepatitis, autoimmune haemolytic anaemia and bronchiectasis.

FamilyInfo: The patient’s daughter had recurrent episodes of CNS inflammation as a child and in adulthood she developed autoimmune hepatitis, autoimmune haemolytic anaemia and bronchiectasis. The patient’s son was known to have type I diabetes, thyroid disease, pernicious anaemia and autoimmune encephalitis. FAS sequencing for autoimmune lymphoproliferative syndrome (ALPS) was normal and, at the time of presentation, extended panel screening for primary immunodeficiency was ongoing. There was prior exposure to corticosteroids but no other immunomodulatory treatment.

Variant: c.81dup p.(leu28Serfs*32)

ClinVar: 644629

GenotypingMethod: a virtual sub-panel of 194 genes associated with primary immunodeficiencies screened using Agilent ‘Focused Exome’ custom target enrichment system (SureSelectXT) and Next Generation Sequencing demonstrated that the patient (and her affected family members) were heterozygous for a novel, likely pathogenic frameshift deletion variant