Case#: Grammatikos_2021_Case 1, female, 35 y.o. (onset) 51 y.o. (report), origin not reported

DiseaseAssertion: CTLA4 haploinsufficiency

FamilyInfo: affected younger daughter (case 2), affected son (case 3). 2 brothers of case 1 were affected by Evans syndrome. Another brother was affected by unexplained lymphadenopathy. Deceased brother passed due to eft ventricular fibrosis at age 40. Case 1 also had a niece with recurrent cutaneous ulceration and was a LRBA mutation carrier. The eldest daughter of case 1 developed AML (age 14).

CasePresentingHPOs: HP:0001903, HP:0002716, HP:0001945,HP:0003326, HP:0002829, HP:0031457, HP:0033608, HP:0002110, HP:0001744, HP:0033805, HP:0040312, HP:0002840, HP:0002113, HP:0005479, HP:0010976, HP:0025379, HP:0002922, HP:0001974, HP:0032289, HP:0002321, HP:0002013, HP:0001250, HP:0012534, HP:0001260, HP:0001310 (anaemia, lymphadenopathy, fevers, myalgia, arthralgia, scattered opacification, nodules in lung, bronchiectasis, splenomegaly, non-necrotising granulomas, arthritis of left temporomandibular joint, granulomatous lymphadenitis, migratory infiltrates, decreased IgE, low b-cell count, increased TPO antibodies, increased protein CSF, increased WBC, IgG oligoclonoal pattern, vertigo, vomiting, seizures, right-facial dysesthesia, dysarthria, right-sided dysmetria)

CaseHPOFreeText: mass of 1.4 cm resolving spontaneously behind tibialis posterior tendon. MRI revealed mass in the right middle cerebellar peduncle with surrounding edema. Cellular infiltration by CD4:CD* T cells, plasma cells, microglia (2:1 ratio). Neutrophilic infiltrate of the lymphatic system, EBV-related lymphoprliferation, bile salt malabsorption

CaseNotHPOs: HP:0031693, HP:0005344, HP:0003116 (serum EBV, abnormal carotid ultrasound, abnormal echocardiogram)

CaseNotHPOFreeText: presence of inflammatory markers

CasePreviousTesting: 194 genes associated with immune deficiency, next-gen sequencing. Heterozygous VUS found in LRBA.

GenotypingMethod: confirmation of CTLA4 c.81dup by Sanger sequencing

PreviouslyPublished: not reported

Variant: Heterozygous NM_005214.4(CTLA4):c.81_82insT (p.Leu28fs), Heterozygous NM_006726.4(LRBA):c.6424T>C (p.Phe2142Leu)

ClinVarID: 644629, 1038663

CAID: CA645516071, CA358607456

gnomAD: not found, not found

SupplementalData: Figure S1 shows extensive family history