Family History of Early Infant Death Correlates with Earlier Age at Diagnosis But Not Shorter Time to Diagnosis for Severe Combined Immunodeficiency

Abstract

BackgroundSevere combined immunodeficiency (SCID) is fatal unless treated with hematopoietic stem cell transplant. Delay in diagnosis is common without newborn screening. Family history of infant death due to infection or known SCID (FH) has been associated with earlier diagnosis.ObjectiveThe aim of this study was to identify the clinical features that affect age at diagnosis (AD) and time to the diagnosis of SCID.MethodsFrom 2005 to 2016, 147 SCID patients were referred to the Asian Primary Immunodeficiency Network. Patients with genetic diagnosis, age at presentation (AP), and AD were selected for study.ResultsA total of 88 different SCID gene mutations were identified in 94 patients, including 49 IL2RG mutations, 12 RAG1 mutations, 8 RAG2 mutations, 7 JAK3 mutations, 4 DCLRE1C mutations, 4 IL7R mutations, 2 RFXANK mutations, and 2 ADA mutations. A total of 29 mutations were previously unreported. Eighty-three of the 94 patients fulfilled the selection criteria. Their median AD was 4 months, and the time to diagnosis was 2 months. The commonest SCID was X-linked (n = 57). A total of 29 patients had a positive FH. Candidiasis (n = 27) and bacillus Calmette–Guérin (BCG) vaccine infection (n = 19) were the commonest infections. The median age for candidiasis and BCG infection documented were 3 months and 4 months, respectively. The median absolute lymphocyte count (ALC) was 1.05 × 109/L with over 88% patients below 3 × 109/L. Positive FH was associated with earlier AP by 1 month (p = 0.002) and diagnosis by 2 months (p = 0.008), but not shorter time to diagnosis (p = 0.494). Candidiasis was associated with later AD by 2 months (p = 0.008) and longer time to diagnosis by 0.55 months (p = 0.003). BCG infections were not associated with age or time to diagnosis.ConclusionFH was useful to aid earlier diagnosis but was overlooked by clinicians and not by parents. Similarly, typical clinical features of SCID were not recognized by clinicians to shorten the time to diagnosis. We suggest that lymphocyte subset should be performed for any infant with one or more of the following four clinical features: FH, candidiasis, BCG infections, and ALC below 3 × 109/L.

Disseminated Bacille Calmette‐Guérin infection in a patient with severe combined immunodeficiency caused by JAK3 gene mutation

“…In conclusion, the diagnosis of disseminated BCG disease should be considered when a BCG vaccinated infant presents with cutaneous papules, pustules, and nodules, especially in infants with immunodeficiency. One study from the Asian Primary Immunodeficiency Network found typical clinical features of SCID, like candidiasis, BCG infections, pneumonia, chronic diarrhea, severe infections, and absolute lymphocyte count below 3 × 109/L were often not recognized by clinicians, thereby prolonging the time to diagnosis . The only solution for early diagnosis of SCID is newborn screening.…”

“…One study from the Asian Primary Immunodeficiency Network found typical clinical features of SCID, like candidiasis, BCG infections, pneumonia, chronic diarrhea, severe infections, and absolute lymphocyte count below 3 × 109/L were often not recognized by clinicians, thereby prolonging the time to diagnosis. 11 The F I G U R E 4 Black arrow designates the proband. Sequencing identified de novo compound heterozygous mutation c. 1934 A > G in the JAK3 gene and heterozygous variant c. 1899 C > A in the JAK3 gene carried by both the proband and her mother…”

Mutational landscape of severe combined immunodeficiency patients from Turkey

“…The SCIDX1 patients with IL2RG deficiency are the largest group in the populations with low‐consanguinity rates like European or far east countries (Fischer et al., 2015; Luk et al., 2017), but we found RAG1/2 deficiency (47%) which leads to T‐B‐NK+ phenotype is the most common group in our Turkish SCID cohort. Due to the high consanguineous marriage rates in our country, autosomal‐recessive inherited genes might be the most effected genes among the SCID patients in our cohort.…”

The IL-2RG R328X nonsense mutation allows partial STAT-5 phosphorylation and defines a critical region involved in the leaky-SCID phenotype

“…The R328X mutation was first reported in 2017 in a cohort of 147 Asiatic SCID patients , but detailed clinical and immunological information has only been described recently in two patients with the same mutation . Lim et al reported the R328X mutation in a 16‐year‐old Kurdish boy with chronic airway hypersensitivity and recurrent sinopulmonary infections and Tanita et al described the same mutation in a 21‐year‐old Japanese male with recurrent respiratory infections, EBV‐associated leiomyoma during childhood and invasive Haemophilus influenzae infection .…”

“…Until very recently, mutations in exon 8 have been described only in association with the typical X-SCID phenotype [28], thus suggesting a critical role on the C-terminal part of the cytoplasmic domain of γ c for correct signal transmission. Up to the present, two case reports and a cohort study have reported a hypomorphic mutation located in exon 8 (c.C982T/ p.328X) [19,21,29].…”