PMID: 39689284 Gene: CTLA4 HGNC: 2505

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.

PMID: 41608053 Gene: CTLA4 HGNC: 2505

Case#: Patient 16 (P16) is a female child, ethnicity not specified.

DiseaseAssertion: The patient is asserted to have CTLA-4 haploinsufficiency with autoimmune infiltration (CHAI)

FamilyInfo: Sanger sequencing of other family members revealed the same CTLA4 variant in seven females across four generations, all of whom are symptomatic with autoimmunity and/or recurrent infections. See Figure 1A for pedigree.

CasePresentingHPOs: HP:0004880 (Respiratory infections in early life), HP:0003256 (Abnormality of te coagulation cascade), HP:0001954 (recurrent fever), HP:0000967 (Petechiae), HP:0002014 (Diarrea), HP:0003270 (Abdominal distention), HP:0025085 (Bloody diarrhea), HP:0001943 (Hypoglycemia), HP:0034315 (Chronic cough), HP:0000010 (Recurrent urinary tract infections), HP:0000076 (Vesicoureteral reflux)

CaseHPOFreeText: In infancy the patient was hospitalized multiple times for respiratory viral infections and an episode of transient coagulopathy. She continued to experience respiratory infections, prolonged bleeding with transient coagulopathy, and intermittent bloody diarrhea. Patient had intermittent elevated lactate. Flow cytometry demonstrated normal lymphocyte subsets and immunoglobulin concentrations were within normal limits. Soluble IL-2 receptor levels were elevated. Gastrostomy tube was placed at 26 months due to recurrent hypoglycemia and poor growth.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Whole exome sequencing performed at 18 months old reported no diagnostic variants. Mitochondrial genome analysis was normal.

GenotypingMethod: Genotyping was performed via whole exome sequencing, which initially did not identify any diagnostic variants. Research analysis of the clinical exome data identified the CTLA4 variant.

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

Variant: The patient is heterozygous for the NM_005214.5: c.654T>A (p.Tyr218*) variant.

ClinVar: 2440604

gnomAD: This variant has an allele frequency of 0.0006536 in gnomAD v4.1.1 (https://gnomad.broadinstitute.org/variant/chr3-38011318-G-A?dataset=gnomad_r4)

SupplementalData: N/A

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

PMID: 39624103 Gene: CTLA4 HGNC: 2505