Mary Hintermeyer

Newborn Screening for Severe Combined Immunodeficiency; The Wisconsin Experience (2008–2011)

Severe combined immunodeficiency is a life-threatening primary immune deficiency characterized by low numbers of naïve T cells. Early diagnosis and treatment of this disease decreases mortality. In 2008, Wisconsin began newborn screening of infants for severe combined immunodeficiency and other forms of T-cell lymphopenia by the T-cell receptor excision circle assay. In total, 207,696 infants were screened. Seventy-two infants had an abnormal assay. T-cell numbers were normal in 38 infants, abnormal in 33 infants, and not performed in one infant, giving a positive predictive value for T-cell lymphopenia of any cause of 45.83% and a specificity of 99.98%. Five infants with severe combined immunodeficiency/severe T-cell lymphopenia requiring hematopoietic stem cell transplantation or other therapy were detected. In summary, the T-cell receptor excision circle assay is a sensitive and specific test to identify infants with severe combined immunodeficiency and severe T-cell lymphopenia that leads to life-saving therapies such as hematopoietic stem cell transplantation prior to the acquisition of severe infections.

Gain of Function Mutations of PIK3CD as a Cause of Primary Sclerosing Cholangitis

Gain of function (GOF) mutation in the p110δ catalytic subunit of the phosphatidylinositol-3-OH kinase (PIK3CD) is the cause of a primary immunodeficiency (PID) characterized by recurrent sinopulmonary infections and lymphoproliferation. We describe a family of two adults and three children with GOF mutation in PIK3CD, all with recurrent sinopulmonary infections and varied infectious and non-infectious complications. The two adults have Primary Sclerosing Cholangitis (PSC) without evidence of Cryptosporidium parvum infection and have required liver transplantation. PSC is a novel phenotype of GOF mutation in PIK3CD.

Autoantibody stabilization of the classical pathway C3 convertase leading to C3 deficiency and Neisserial sepsis: C4 nephritic factor revisited.

C3 deficiency is a rare disorder that leads to recurrent pyogenic infections. Here we describe a previously healthy 18 y/o Caucasian male with severe meningococcal disease. Total hemolytic activity was zero secondary to an undetectable C3. The C3 gene was normal by sequencing. Mixing the patients serum with normal human serum led to C3 consumption. An IgG autoantibody in the patients serum was identified that stabilized the classical pathway C3 and C5 convertases, thus preventing decay of these enzyme complexes. This autoantibody is an example of a C4 nephritic factor, with an additional feature of stabilizing the C5 convertase. Previous patients with C4 nephritic factor had membranoproliferative glomerulonephritis. Two years after presentation, this patients C3 remains undetectable with no evidence of renal disease. We revisit the role of autoantibodies to classical pathway convertases in disease, review the literature on C4-NeF and comment on its detection in the clinical laboratory.

IRAK4 Deficiency in a Patient with Recurrent Pneumococcal Infections: Case Report and Review of the Literature

Primary immunodeficiencies are genetic defects of the innate or adaptive immune system, resulting in a propensity to infections. The innate immune system is the first line of defense against pathogens and is critical to recognize microbes and start the inflammatory cascade. Sensing of microbes occurs by a number of pathogen-recognition receptors, resulting in the activation of inflammatory signal transduction pathways, such as the activation of NF-κB. Herein, we describe a case of IRAK4 deficiency, a key signal transduction molecule of toll-like and IL-1 receptors. We highlight the complexities in diagnosis of these disorders and review genetic defects of the NF-κB pathway.

X-linked Hyper IgM Syndrome Presenting as Pulmonary Alveolar Proteinosis.

PurposeX-linked hyper IgM syndrome (XHIGM) is a combined immunodeficiency caused by mutations in the CD40 ligand (CD40L) gene that typically results in decreased or absent CD40L expression on activated T cells, leading to defective class switching and somatic hypermutation. We describe an infant who presented with respiratory failure due to pulmonary alveolar proteinosis (PAP) with a novel damaging missense mutation in the CD40L gene.MethodsWhole exome sequencing (WES) was used to identify a mutation in the CD40L gene. CD40L expression and function were determined by flow cytometry.ResultsA 5-month-old previously-healthy male presented with respiratory failure and diffuse pulmonary ground glass opacities on CT scan of the chest. Laboratory evaluation revealed an undetectable IgG, normal IgA, and elevated IgM. A bronchoalveolar lavage demonstrated pulmonary alveolar proteinosis. WES demonstrated a c.608G > C mutation in the CD40L gene resulting in p.R203T. Flow cytometry demonstrated normal CD40L expression on activated T cells but absent binding of CD40-Ig to CD40L on activated patient T cells.ConclusionsThe clinical manifestations of XHIGM in our patient had several unique features, including the presentation with PAP, normal serum IgA, and expression of non-functional CD40L on activated T cells. To our knowledge, this is the first published case of PAP in a patient with XHIGM.

Bilateral lung transplant in Gauchers type-1 disease

Abstract:  We report a case of a patient who received a bilateral lung transplant for end‐stage lung disease secondary to Gauchers type‐1 disease with no evidence of recurrence of the disease in the transplanted lung.

A Practical Approach to Newborn Screening for Severe Combined Immunodeficiency Using the T Cell Receptor Excision Circle Assay

Severe combined immunodeficiency (SCID) is a life-threatening condition of newborns and infants caused by defects in genes involved in T cell development. Newborn screening (NBS) for SCID using the T cell receptor excision circle (TREC) assay began in Wisconsin in 2008 and has been adopted or is being implemented by all states in 2017. It has been established that NBS using the TREC assay is extremely sensitive to detect SCID in the newborn period. Some controversies remain regarding how screening positives are handled by individual states, including when to perform confirmatory flow cytometry, what is the necessary diagnostic workup of patients, what infection prophylaxis measures should be taken, and when hematopoietic stem cell transplantation should occur. In addition, the TREC can also assay detect infants with T cell lymphopenia who are not severe enough to be considered SCID; management of these infants is also evolving.

Lack of Clinical Hypersensitivity to Penicillin Antibiotics in Common Variable Immunodeficiency

To the Editor, Common variable immunodeficiency (CVID) is a heterogeneous primary immunodeficiency defined by low serum immunoglobulins (low IgG and low IgA and/or IgM) and poor specific antibody response to vaccines [1]. Although prevalence of IgE-mediated allergic disease in CVID appears to be uncommon, there has been no prior report on the presence or rate of IgE-mediated drug allergy in the CVID population. More specifically, no study has been conducted in CVID to evaluate beta-lactam hypersensitivity. Although it is not part of current diagnostic criteria for CVID [1], many patients with CVID have low or undetectable levels of IgE [2]. Rates of specific IgE (serum and/or skin testing) measurement vary from 3 to 16% [2, 3] while as many as 82% of patients with CVID report symptoms consistent with allergies [2]. Because patients with CVID have low levels of total and antigen-specific IgE, the presence of allergic diseases should theoretically be rare or non-existent. Based on these prior observations, we hypothesized that patients with CVID would not have IgE-mediated hypersensitivity reactions to beta-lactam medication. We set out to determine the rates of self-reported beta-lactam allergy in the CVID population and test for clinical hypersensitivity with skin testing and in-office dose challenge. The study was approved by the Children’s Hospital of Wisconsin Institutional Review Board. Funding was provided by the Division of Allergy and Clinical Immunology. All patients were recruited from July 2015 to June 2016. Informed consent was obtained from all individual participants included in the study. Patients were selected based on diagnosis of CVID by internationally agreed upon diagnostic criteria [1]. Patients were then screened for self-reported beta-lactam (ex: penicillin, amoxicillin, ampicillin) allergy in the hospital electronic medical record. Patients were excluded from the study if they had chronic severe respiratory compromise (supplemental oxygen requirement or dependence on positive pressure ventilation), beta-blocker use, pregnancy, history of non-IgE-mediated beta-lactam reactions, or prior exclusion of beta-lactam hypersensitivity. Eligible patients underwent a two-step skin testing procedure with PRE-PEN® (AllerQuest LLC, Plainville, CT) and penicillin G per the American Academy of Allergy, Asthma and Immunology (AAAAI) drug allergy practice parameters [4]. If intradermal testing was negative, a single dose * John Routes jroutes@mcw.edu

Primary immunodeficiency diseases: a primer for PCPs.

Primary care providers (PCPs) play a key role in identifying patients with primary immunodeficiency diseases (PIDDs). This diagnosis has implications for PCPs, as patients continue to require primary care and management after a PIDD diagnosis has been made. This review presents essential information for PCPs regarding PIDDs.

A172: Metaphyseal Chondrodysplasia, Ectodermal Dysplasia, Short Stature, Hypergammaglobulinemia, and Spontaneous Inflammation Without Infections in an Extended Family Due to Mutation in NFKB1A

Autoinflammatory disorders are characterized by chronic inflammation and a variety of systemic complaints. Defects in the NF‐kB essential modifier pathway, or NEMO, are associated with an immune deficiency characterized by ectodermal dysplasia. We investigated an extended family with features of both chronic inflammation and NEMO following an autosomal dominant inheritance.