Case#: A.1, F, Age of Report: 9 y.o., Ethnicity: European-American.

CasePresentingHPOs: HP:0012378 (Fatigue), HP:0001878 (Hemolytic anemia), HP:0006510 (Chronic pulmonary obstruction/early obstructive pulmonary impairment), HP:0003651 (Foam cells), HP:0004313 (Decreased circulating antibody concentration/Hypogammaglobulinemia), HP:0001873 (Thrombocytopenia), HP:0001888 (Lymphopenia), HP:0001880 (Eosinophilia), HP:0100721 (Mediastinal lymphadenopathy), HP:0034388 (Hilar lymph node enlargement), HP:0001744 (Splenomegaly), HP:0004387 (Enterocolitis), HP:0002014 (Diarrhea), HP:0002027 (Abdominal pain), HP:0002583 (Colitis), HP:0005425 (Recurrent sinopulmonary infections), HP:0410018 (Recurrent ear infections), HP:0001581 (Recurrent skin infections), HP:0000010 (Recurrent urinary tract infections), HP:0001742 (Nasal congestion), HP:0011010 (Chronic), HP:0000964 (Eczematoid dermatitis/Eczema),

CaseHPOFreeText: A female patient (hereafter called A.1) from a European-American family presented at nine years of age with fatigue and hemolytic anemia followed by early obstructive pulmonary impairment. A subsequent chest CT scan revealed bilateral nodular infiltrates and areas of patchy, peripheral-basal consolidation in lungs, and histological examination revealed a pattern of interstitial CD3+ lymphocytic infiltration, foamy histiocytes, scattered noncaseating granulomas, and luminal obstruction initially characterized as cryptogenic organizing pneumonia (Fig. 1a–b). Further follow up and analysis revealed clinical progression to hypogammaglobulinemia, thrombocytopenia, various lymphopenias, eosinophilia, mediastinal and hilar lymphadenopathy, and splenomegaly (Table 1). More recently, at sixteen years of age, patient A.1 developed enterocolitis with diarrhea and abdominal pain. Histological assessment of gut tissue revealed interstitial infiltrate of more than 25 CD3+ lymphocytes per 100 epithelial cells (Fig. 1b, bottom). Episodes of pneumonitis and colitis continue to recur intermittently, have an apparent noninfectious etiology (with separate incidences of infectious colitis), and respond to pulse doses of corticosteroids and steroid-sparing measures including mycophenolate mofetil.

The childhood of patient A.1 was remarkable for recurrent sinopulmonary, ear, skin, and urinary tract infections (commonly with S. aureus), chronic nasal congestion, and eczema. Additional episodes of colitis were sometimes associated with stool cultures positive for C. difficile and Salmonella. Vaccination responses were protective for tetanus, borderline protective for diphtheria, and protective for 4 of 23 pneumococcal strains. Warm autoimmune hemolytic anemia at nine years of age (preceding the initial pneumonitis by several months) was treated with steroids and blood transfusions; a recurrence of autoimmune cytopenias at seventeen years prompted CD20+ B cell depletion with rituximab. Patient A.1 is currently treated with immunoglobulin replacement therapy to restore humoral protection and mycophenolate mofetil to suppress inflammation.

CaseNotHPOs: N/A.

CaseNotHPOFreeText: N/A.

CasePreviousTesting: N/A.

CaseMethod1: N/A.

CaseMethod2: N/A.

CaseGenotypingMethod: WES and Sanger.

Variant: NM_001282426.2:c.3062G>C (p.Arg1021Pro).

ClinVar: 1675218.

CAID: CA164129242.

gnomAD: Frequency: 0.00002988. Link: https://gnomad.broadinstitute.org/variant/chr7-106905140-G-C?dataset=gnomad_r4.

VariantEvidence: N/A.

CaseAddInfo: Patient A.1 inherited an allele from her healthy mother in whom a single base-pair deletion causes a frameshift beginning at R982 of p110γ, and an allele from her healthy father in whom a missense mutation results in an R1021P amino acid substitution in the kinase domain.

CasePMIDs: N/A.