Case#: 14-year old female index patient, F, Age of Report:, Ethnicity: Austrian.

CasePresentingHPOs: HP:0001252 (Hypotonia), HP:0001945 (Fever), HP:0025297 (Prolonged), HP:0001873 (Thrombocytopenia), HP:0002155 (Hypertriglyceridemia), HP:0025435 (Increased circulating lactate dehydrogenase concentration/increased lactate dehydrogenase), HP:0003281 (Increased circulating ferritin concentration/markedly elevated ferritin), HP:0012156 (Hemophagocytosis),

CaseHPOFreeText: Here we investigated a 14-year old female index patient, born to non-consanguineous healthy Austrian parents, who was hospitalized with severe hypotonia and prolonged fever. She had neither lymphadenopathy nor hepatosplenomegaly, and no infectious agent was found. Initial laboratory findings showed a mild thrombocytopenia, hypertriglyceridemia, increased lactate dehydrogenase (LDH) and markedly elevated ferritin (Table 1 and Figure 1A), prompting work up for hemophagocytic lymphohistiocytosis (HLH). Hemophagocytosis was indeed visible in the bone marrow aspirate (Figure 1B). Soluble CD25 was mildly elevated at 2204 U mL-1 (Table 1) but below the levels typically seen in HLH.6 NK-cell activity as measured by CD107a expression upon stimulation was in the low normal range in the initial diagnostic (Table 1). The presence of fever, hypertriglyceridemia, hyperferritinemia and hemophagocytosis, did not allow the diagnosis of HLH, but gave evidence of macrophage activation in the context of a hyperferritinemic inflammatory syndrome (Table 1).6We initiated treatment with dexamethasone, leading to clinical improvement and normalization of LDH and ferritin levels. Tapering of dexamethasone resulted in clinical deterioration and rise in ferritin (Figure 1A), and was accompanied by the development of autoimmune neutropenia as documented by HNA-1b antibodies. As the disease was distinct from classical HLH,6 we decided to treat the patient with recombinant human anti-IL-1β (Anakinra, 100 mg twice daily) in combination with dexamethasone, rather than using the etoposide-based HLH-94 protocol. We discontinued dexamethasone treatment after eight weeks and, one month later, reduced the Anakinra dose to a maintenance dose of 100 mg daily. The patient has remained clinically stable and is currently receiving Anakinra (decreased to 60 mg once daily) without any inflammatory manifestations. Immunological characterization of patient peripheral blood in the asymptomatic phase after ceasing dexamethasone revealed reduced absolute natural killer (NK)-cell counts and low frequency of monocytes, and slightly low absolute lymphocyte counts (Table 1)..

CaseNotHPOs: N/A.

CaseNotHPOFreeText: She had neither lymphadenopathy nor hepatosplenomegaly, and no infectious agent was found.

CasePreviousTesting: N/A.

CaseMethod1: N/A.

CaseMethod2: N/A.

CaseGenotypingMethod: WES.

Variant: Variant 1: NM_001282426.2:c.145C>A (p.Arg49Ser) . Variant 2: NM_001282426.2:c.3254A>G (p.Asn1085Ser).

ClinVar: Variant 1: 1675220. Variant 2: 1675219.

CAID: Variant 1: CA4429087. Variant 2: CA368817268.

gnomAD: Variant 1: Frequency: 0.001519. Link: https://gnomad.broadinstitute.org/variant/chr7-106867706-C-A?dataset=gnomad_r4. Variant 2: N/A.

VariantEvidence: N/A.

CaseAddInfo: N/A.

CasePMIDs: N/A.

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.