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Physical Exam: Physical exam was notable for abnormal subcutaneous facial fat with normal fat distribution in the rest of her body. The rest of the exam was unremarkable with normal cardiac, pulmonary, abdominal, and skin exam.

Infectious complications and malignancy: A total of 1782 reported infectious conditions were sorted by organ system. Pulmonary infections were the most common (27%, n=478) followed by skin (26%, 470), ENT (21%, 381), gastrointestinal (8%, 147), systemic (8%, 145), genitourinary (2%, 42), CNS (2%, 33), oral (2%, 32), and musculoskeletal (2%, 30) infections. Pneumonia was the most commonly reported pulmonary infection (60%, n=285). Of all ENT infections, otitis media (44%, n = 167) was the most common, followed closely by sinusitis (42%, 160). A total of 943 infectious pathogens were recorded, of which 21% were Staphylococcus aureus (n=194), 13% Candida (123), 7% Pseudomonas (68), 6% Aspergillus (55), 5% common respiratory viruses (47), 4% other Staphylococcus (34), and 4% Streptococcus pneumoniae (34). Malignancy was diagnosed in 14% of patients (n=39), of which 51% (20) were lymphoma.

INTRODUCTION: DOCK8 deficiency (autosomal recessive hyper IgE syndrome) may present with features of combined immune deficiency (CID) early in life. Here we report a premature male infant of 24 weeks gestation who had generalized skin candidiasis within 2 weeks after delivery -- the youngest patient with DOCK8 deficiency ever identified by genetic testing.

CASE HISTORY: The infant was admitted to the neonatal intensive care unit for extreme prematurity (birthweight 585 g, vaginal delivery), respiratory failure, and possible sepsis. He was the first born to non-consanguineous parents without a family history of immunodeficiency. The infant was placed on a ventilator and given antibiotics for possible sepsis. During the first 2 weeks, candida skin infection was diagnosed (with a positive KOH preparation) and treated successfully with topical nystatin. Herpes simplex virus PCR of the skin and blood cultures for bacteria and fungi were negative. Subsequently, the infant developed conditions commonly associated with prematurity, including anemia, hyperbilirubinemia, patent ductus arteriosus, cardiac instability, acute urinary tract infection, and bilateral grade I intraventricular hemorrhages. Weight and length trended at 3%. Occurrence of severe candida infection with scalded skin and intractable unconjugated hyperbilirubinemia prompted whole exome sequencing (collected on day 10; reported on day 30). Results showed two heterozygous pathogenic DOCK8 variants, compatible with autosomal recessive hyper IgE syndrome: c.1963C>T (p.Gln655*) and a 33.39 kb DOCK8 deletion (exon 1 and intron 1). The mother carries the p.Gln655* variant. Testing for the 33.39 kb deletion in parents is pending, to confirm biallelic DOCK8 variants in the infant. Immune laboratory studies included: normal newborn Trec screening; normal IgG at 12 weeks (76 mg/dL), and borderline low T and B cells at 5, 9, and 12 weeks (PMIDs 31220471, 27548364) with an increasing trend (CD4+ T cells: 944 -> 965-> 1581; CD8+ T cells: 396 -> 519 -> 737; B cells: 234 -> 878 -> 1358). CD4 phenotypes at 9 weeks (by another laboratory) showed normal distributions of various subtypes including naive, memory (central and effector), and regulatory T cells.

A female child born to consanguineous parents, suffered from recurrent pneumonias, thrush, small vessel vasculitis and arthritis since early in infancy. At 16 months of life, she had a thrombotic stroke and left hemiparesis. Psychomotor developmental delay was noted. She continued to have recurrent flares of vasculitis and arthritis, multiple respiratory infections that required intubation, and chronic diarrhea requiring total parenteral nutrition. Physical exam revealed microcephaly, low height and weight, strabismus, beaked nose, hyper-extensible skin, pectus carinatum, and mild hepatomegaly. She had significant speech delay and was only able to walk with support.

Introduction: Mutations in the gene encoding signal transducer and activator of transcription 3 (STAT3) cause autosomal dominant hyperimmunoglobulin E syndrome (AD-HIES) characterized by recurrent skin and sinopulmonary infections, atopic dermatitis, and elevated serum immunoglobulin E (IgE) levels. Treatment is largely aimed at controlling symptoms and preventing infections with no standard of care. There is a paucity of literature describing the utilization of biologic therapies in the AD-HIES patient population. We present 3 patients from one family with AD-HIES successfully treated with monoclonal antibody therapies targeted at Il-5, Il-4 and Il-13.

Patient 1: 13-year-old female with STAT3 LOF c.1003C>T (p.Arg335Trp) with a history of atopic dermatitis and asthma requiring 2-5 steroid courses per year with frequent school absences. She developed a severe pruritic rash covering her upper body 18 months ago that failed to respond to antihistamines and topical antibiotics prescribed by her primary care provider. Given her poorly controlled asthma and our concern for a follicular type morphologic variant of atopic dermatitis, dupilumab was initiated. Her scoring atopic dermatitis (SCORAD) prior to initiation of biologic therapy was 53.8 and improved to 4.5 following 12 doses (24 weeks) of dupilumab with clear dramatic improvement in her skin and quality of life (Figure 1). She also reports decreased asthma severity with no steroid courses, reduced albuterol usage, and significant decline in school absences since initiation of dupilumab.

Patient 3: 15-year-old female with STAT3 LOF c.1003C>T (p.Arg335Trp) who is the paternal first cousin of Patients 1&2. She has a history of severe atopic dermatitis with associated pruritus and picking behaviors, poorly controlled despite daily triamcinolone application. She previously failed ultraviolet therapy and crisaborole. She also has a history of severe asthma requiring 2-5 steroid courses per year despite high-dose fluticasone-salmeterol. Dupilumab was started in May 2019. SCORAD prior to initiation monoclonal antibody therapy was 80.3 and declined to 21.2 following 13 weeks (7 doses) of dupilumab therapy with marked improvement in skin appearance and pruritus (Figure 2).

Subjects and Methods: Five patients with severe WAS (clinical score 3-5) were enrolled (Table 1). CD34+ cells were transduced ex-vivo and re-infused after conditioning with busulfan and fludarabine. Two subjects (P4, P5) had autoimmunity pre-GT, manifested as skin vasculitis and autoimmune cytopenias.

The reported case represents the first case of NBAS disease detected by newborn screening program for primary immunodeficiency, based on KREC assay. The patient came to our attention due to the complete absence of KRECs and normal TRECs on DBS (dried blood spot) while hospitalized for low weight at birth (1,520 g), intolerance for enteral feeding, hepatosplenomegaly, slightly elevated liver transaminase, head and face eczematous dermatitis. During the 1st month, he also presented Klebsiella pneumoniae urinary tract infection and methicillin-resistant Staphylococcus aureus sepsis. Peculiar phenotypic features including triangular face, proptosis, flat philtrum, mild retrognatia, hirsutism, loose and slightly wrinkled skin, and apparent reduction of subcutaneous fat were noticed at birth. Complete blood count showed lymphocytopenia, marked hypereosinophilia. Serum immunoglobulin G (IgG) were markedly decreased, IgA and IgM were undetectable. Extended immune-phenotyping showed complete absence of CD19+ cells, low count of CD8+ lymphocytes, and reduced natural killer (NK) levels. At 9month of age a colonoscopy was carried out for persistent diarrhea and reduced tolerance to enteral feeding. The histological examination of mucosal intestinal biopsies showed signs compatible with autoimmune enteropathy. For this reason immunosuppressive therapy with rapamycin was started without consistent clinical amelioration. Many CVC-sepsis occurred in the last months, associated with persistent gastrointestinal symptoms and severe growth restriction. Despite the absence of experience data in literature for NBAS syndrome, we retain that HSCT represents the only resolutive therapy for him.

Cases 1.1 and 1.2 identify 2 sisters of Spanish descent with a classical hyper-IgE phenotype. The younger sibling demonstrated severe atopic dermatitis, mild-moderate asthma, multiple food allergies, one episode of ITP, and ADHD. The older sibling demonstrated atopic dermatitis, skin infections, and C. albicans otomastoiditis. The siblings were found to have the damaging compound heterozygous variants p.T492I and p.Q506X in PGM3. Case 2 is a 15 year-old Guatemalan boy with prominent atopy including asthma, allergic rhinitis, food allergy, elevated IgE, atopic dermatitis, as well as oral HSV who was found to be homozygous for the damaging PGM3 variant p.I350T.

Case 3 is a 10-year-old Turkish girl who is the daughter of a consanguineous union. She presented with infantile nephrotic syndrome at 6 months of age, and subsequently developed leukopenia, neutropenia, and low IgG. Complications include bronchiectasis, sinusitis, Pseudomonas urinary tract infection, and inflammatory skin lesions without atopy. She was found to be homozygous for the damaging PGM3 variant p.R69H

Methods: Following enrollment in a NIAID IRB-approved protocol (11-I-0187) the patient was evaluated with history and physical examination, AIRE sequencing, measurement of interferon- autoantibodies, and skin biopsy with immunohistochemical analyses.

Päivi Kokkonen, 1, Anni Niskakoski, 1, Inka Saarienen, 2, Johanna Sistonen, 3, Heidi Junnila, 4, Annakarin Kere, 4, Margarita Andreevskaya, 5, Mikko Muona, 6, Janica Djupsjöbacka, 7, Lotta Koskinen, 8, Hatice Duzkale, 9, Joe Jacher, MS, CGC10, Samuel Myllykangas, 11, Juha Koskenvuo, 12, Tero-Pekka Alastalo, 12

Introduction: Dominant negative mutations in STAT3 (L