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Velocardiofacial syndrome, DiGeorge syndrome, and some other clinical syndromes have in common a high frequency of hemizygous deletions of chromosome 22q11.2. This deletion syndrome is very common, affecting nearly one in 3000 children. Here, we focus on recent advances in cardiac assessment, speech, immunology, and pathophysiology of velocardiofacial syndrome. The complex medical care of patients needs a multidisciplinary approach, and every patient has his own unique clinical features that need a tailored approach. Patients with chromosome 22q11.2 deletion syndrome might have high level of functioning, but most often need interventions to improve the function of many organ systems.

Newborn screening for severe combined immune deficiency (SCID) is the first inborn error of immunity (IEI) to be detected through population screening. It also represents the first newborn screening test to utilize molecular testing on DNA from newborn dried blood spots. Newborn screening for SCID has provided opportunities to measure the population prevalence of this disorder and evaluate the effect of early interventions on the overall outcomes in affected infants. The success of SCID newborn screening has increased interest in developing and implementing molecular testing for other clinically significant inborn errors of immunity. This methodology has been adapted to screen for another monogenic inborn defect, spinal muscle atrophy. Advances in the clinical care and new therapeutics for many inborn errors of immunity support the need for early diagnosis and prompt institution of therapies to reduce morbidity and mortality. Early diagnosis may also improve the quality of life for affected patients. This article provides an overview of newborn screening for SCID, recommended steps for follow-up testing and early intervention as well as long-term follow-up. Numerous challenges remain, including the development of clinical consensus regarding confirmatory and diagnostic testing, early interventions, and best practices for immune reconstitution in affected infants.

A hemizygous deletion of 1.5-3 Mb in 22q11.2 causes a distinct clinical syndrome with variable congenital defects. Current diagnostic methods use fluorescent in situ hybridization (FISH) or comparative genomic hybridization by microarray to detect the deletion. Neither method is suitable for newborn screening (NBS), since they cannot be performed on dried blood spots (DBS). We developed a MALDI-TOF-MS assay that uses DBS to measure the hemizygous deletion of UFD1L, located within the 22q11.2 region. We used DBS from 54 affected patients, previously tested by FISH or microarray, and 100 cord blood samples to evaluate the performance of the MALDI-TOF-MS assay. With a single primer pair, a 97-base oligonucleotide within UFD1L was amplified, as was a sequence on chromosome 18 that differs by 2 nucleotides. A multiplexed, single-base extension reaction created allele-specific products for MALDI-TOF-MS detection. The products were spotted onto a silicon chip, and the height of the spectral peaks identified the relative amounts of target and reference gene. The median ratio of the spectral peak for each UFD1L target:reference base was 0.96 and 0.99 for controls, compared with 0.35 and 0.53 for 22q11 deletion syndrome patients. There was 100% concordance between FISH/microarray and MALDI-TOF-MS in all patients with 22q11.2 deletion syndrome. This method can be reliably performed with DBS and is suitable for high sample throughput. This assay may be considered for use in population-based NBS for 22q11.2 deletion.

22q11 deletion syndrome (22qDS), also known as DiGeorge syndrome, is a copy number variant disorder that has a diverse clinical presentation including hypocalcaemia, learning disabilities, and psychiatric disorders. Many patients with 22q11DS present with signs that overlap with autism spectrum disorder (ASD) yet the possible physiological mechanisms that link 22q11DS with ASD are unknown. We hypothesized that early childhood hypocalcemia influences the neurobehavioral phenotype of 22q11DS. Drawing on a longitudinal cohort of 22q11DS patients, we abstracted albumin-adjusted serum calcium levels from 151 participants ranging in age from newborn to 19.5 years (mean 2.5 years). We then examined a subset of 20 infants and toddlers from this group for the association between the lowest calcium level on record and scores on the Communication and Symbolic Behavior Scales-Developmental Profile Infant-Toddler Checklist (CSBS-DP ITC). The mean (SD) age at calcium testing was 6.2 (8.5) months, whereas the mean (SD) age at the CSBS-DP ITC assessment was 14.7 (3.8) months. Lower calcium was associated with significantly greater impairment in the CSBS-DP ITC Social ( p  < 0.05), Speech ( p  < 0.01), and Symbolic domains ( p  < 0.05), in regression models adjusted for sex, age at blood draw, and age at the psychological assessment. Nevertheless, these findings are limited by the small sample size of children with combined data on calcium and CSBS-DP ITC, and hence will require replication in a larger cohort with longitudinal assessments. Considering the role of calcium regulation in neurodevelopment and neuroplasticity, low calcium during early brain development could be a risk factor for adverse neurobehavioral outcomes.

Anaphylaxis is a clinical syndrome characterized by an abrupt, severe, life-threatening event with cutaneous, respiratory, cardiovascular, and gastrointestinal symptoms mediated by IgE and non-IgE immunologic reactions to a particular antigen. Several other syndromes have symptoms that may mimic those of anaphylaxis, and a rapid diagnostic laboratory test is not readily available in most emergency departments. Thus, it is important that physicians in the emergency department are familiar with the signs and symptoms of anaphylaxis and are able to distinguish this condition from disorders presenting with similar symptoms. Prompt recognition of anaphylaxis and initiation of treatment with epinephrine in a timely fashion is critical to prevent fatalities. This article will review the pathophysiology of anaphylaxis, the common triggers, the clinical findings, the treatment and prevention of this disorder.

PurposeThe Primary Immune Deficiency Treatment Consortium (PIDTC) enrolled children with severe combined immunodeficiency (SCID) in a prospective natural history study of hematopoietic stem cell transplant (HSCT) outcomes over the last decade. Despite newborn screening (NBS) for SCID, infections occurred prior to HSCT. This study’s objectives were to define the types and timing of infection prior to HSCT in patients diagnosed via NBS or by family history (FH) and to understand the breadth of strategies employed at PIDTC centers for infection prevention.MethodsWe analyzed retrospective data on infections and pre-transplant management in patients with SCID diagnosed by NBS and/or FH and treated with HSCT between 2010 and 2014. PIDTC centers were surveyed in 2018 to understand their practices and protocols for pre-HSCT management.ResultsInfections were more common in patients diagnosed via NBS (55%) versus those diagnosed via FH (19%) (p = 0.012). Outpatient versus inpatient management did not impact infections (47% vs 35%, respectively; p = 0.423). There was no consensus among PIDTC survey respondents as to the best setting (inpatient vs outpatient) for pre-HSCT management. While isolation practices varied, immunoglobulin replacement and antimicrobial prophylaxis were more uniformly implemented.ConclusionInfants with SCID diagnosed due to FH had lower rates of infection and proceeded to HSCT more quickly than did those diagnosed via NBS. Pre-HSCT management practices were highly variable between centers, although uses of prophylaxis and immunoglobulin support were more consistent. This study demonstrates a critical need for development of evidence-based guidelines for the pre-HSCT management of infants with SCID following an abnormal NBS.Trial RegistrationNCT01186913

Primary immunodeficiencies are intrinsic defects in the immune system that result in a predisposition to infection and are frequently accompanied by a propensity to autoimmunity and/or immunedysregulation. Primary immunodeficiencies can be divided into innate immunodeficiencies, phagocytic deficiencies, complement deficiencies, disorders of T cells and B cells (combined immunodeficiencies), antibody deficiencies and immunodeficiencies associated with syndromes. Diseases of immune dysregulation and autoinflammatory disorder are many times also included although the immunodeficiency in these disorders are often secondary to the autoimmunity or immune dysregulation and/or secondary immunosuppression used to control these disorders. Congenital primary immunodeficiencies typically manifest early in life although delayed onset are increasingly recognized. The early diagnosis of congenital immunodeficiencies is essential for optimal management and improved outcomes. In this International Consensus (ICON) document, we provide the salient features of the most common congenital immunodeficiencies.

Genetic testing plays a critical role in diagnosis for many primary immunodeficiency diseases. The goals of this report are to outline some of the challenges that clinical immunologists face routinely in the use of genetic testing for patient care. In addition, we provide a review of the types of genetic testing used in the diagnosis of PID, including their strengths and limitations. We describe the strengths and limitations of different genetic testing approaches for specific clinical contexts that raise concern for specific PID disorders in light of the challenges reported by the clinical immunologist members of the CIS in a recent membership survey. Finally, we delineate the CIS’s recommendations for the use of genetic testing in light of these issues.