Case#: Case 1, 12 year old, male

DiseaseAssertion: APDS-1 presenting as MAS/HL

FamilyInfo: born to not consanguineous parents of Rumenian origin

CaseHPOFreeText: His clinical history was uneventful until the age of 12, when he presented arthralgias and arthritis of the right ankle. After 4 months, the patient was admitted in a peripheral hospital due to fever, diffuse rash followed by desquama- tion. Initial blood work-up revealed increased ferritin (40.000 μg/L; normal values: 30–400 μg/L) and increased AST (88 U/L; normal va- lues: 18–32 U/L). The index patient was transferred to our clinic where additional blood work-up confirmed increased ferritin and AST. Radiologic evaluation revealed splenomegaly and lymphadenomegaly. Bone marrow aspirate revealed the presence of rare hemophagocytes. Based on available diagnostic criteria, MAS/HLH was suspected (Supplemental Table 1). Natural killer (NK) cell activity was normal, and genetic screening for HLH-related genes did not yield any patho- genic variants. The patient was put on high-dose steroid treatment with good clinical response. Progressive reduction of steroids upon dismission led to a novel flair of the febrile condition, requiring a novel admission. High dose steroid treatment was repeated with good clinical response. Considering the initial articular involvement, anakinra was also added for a period of 8 weeks. Upon progressive treatment sus- pension, another flair of fever associated with malaise, diffuse lym- phadenopathies, pruritus and arthralgias occurred. Screening for in- fectious aetiologies (including Epstein Barr Virus (EBV), Cytomegalovirus (CMV)) yielded negative results. Whole body mag- netic resonance imaging (MRI) revealed diffuse lymphadenopathies (Fig. 1A, upper panels). Positron emission tomography (PET) confirmed increased glucose metabolism in lymph nodes and spleen, suggestive of lymphoma (Fig. 1A, lower panels). In order to exclude lymphoid ma- lignancies, a lymph node excision was performed. The inguinal lymph node (1.2 cm in maximum diameter) that was removed showed a pre- served architecture, with reactive B-cell follicles and expanded para- cortex (Supplemental Text and Supplemental Fig. S1).

CasePreviousTesting: NGS (not specified if any other genes were sequenced).

GenotypingMethod: NGS

Variant: Next generation sequencing revealed the novel c.323G > T: p.R108L mutation in the linker region of the adaptor binding domain (ABD) of p110δ. monoallelic

CAID: CA576828

gnomAD: Largest allele frequency in gnomAD v2.1.1 is 0.00002823 (1/35426 alleles) in the Latino/Admixed population