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.