TY  - JOUR
AB  - Blue diaper syndrome (BDS) (Online Mendelian Inheritance in Man number 211000) is an extremely rare disorder that was first described in 1964. The characteristic finding is a bluish discoloration of urine spots in the diapers of affected infants. Additional clinical features of the first described patients included diarrhea, inadequate weight gain, hypercalcemia, and nephrocalcinosis. An intestinal defect of tryptophan absorption was postulated as the underlying pathology. However, functional evidence for this theory is lacking. No genetic cause has been identified so far. Here, we report on a boy who presented with neonatal-onset diarrhea, metabolic acidosis, transient hepatopathy, recurrent hypoglycemia, and blue-stained urine spots in his diapers. An ultra-performance liquid chromatography-electrospray ionization-tandem mass spectrometry analysis of urine samples at different time points demonstrated the constant presence of indigo derivatives, thereby confirming the diagnosis of BDS. Of note, the visibility of indigo derivatives in the urine was highly dependent on the urine's pH. To identify the underlying genetic cause of the disease, whole-exome sequencing was performed, leading to the identification of a homozygous frameshift mutation in proprotein convertase subtilisin/kexin type 1 (PCSK1; NM_000439.4: c.679del, p.[Val227Leufs*12]). PCSK1 encodes prohormone convertase 1/3, and mutations within this gene have been reported as a rare cause of early-onset malabsorptive diarrhea and multiple endocrine dysfunction. In our report, we suggest that BDS can be caused by PCSK1 mutations.
AU  - Distelmaier, F.*
AU  - Herebian, D.*
AU  - Atasever, C.*
AU  - Beck-Woedl, S.*
AU  - Mayatepek, E.*
AU  - Strom, T.M.
AU  - Haack, T.B.
C1  - 53905
C2  - 45137
CY  - 141 North-west Point Blvd,, Elk Grove Village, Il 60007-1098 Usa
SP  - S501-S505
TI  - Blue diaper syndrome and PCSK1 mutations.
JO  - Pediatrics
VL  - 141
PB  - Amer Acad Pediatrics
PY  - 2018
SN  - 0031-4005
ER  - 

TY  - JOUR
AB  - CONTEXT: The association between acid-suppressive drug exposure during pregnancy and childhood asthma has not been well established. OBJECTIVE: To conduct a systematic review and meta-analysis on this association to provide further justification for the current studies. DATA SOURCES: We searched PubMed, Medline, Embase, the Cochrane Database of Systematic Reviews, EBSCO Information Services, Web of Science, and Google Scholar from inception until June 2017. STUDY SELECTION: Observational studies in which researchers assessed acid-suppressive drug use during pregnancy and the risk of childhood asthma were included. DATA EXTRACTION: Of 556 screened articles, 8 population-based studies were included in the final analyses. RESULTS: When all the studies were pooled, acid-suppressive drug use in pregnancy was associated with an increased risk of asthma in childhood (relative risk [RR] = 1.45; 95% confidence interval [CI] 1.35-1.56; I-2 = 0%; P <.00001). The overall risk of asthma in childhood increased among proton pump inhibitor users (RR = 1.34; 95% CI 1.18-1.52; I-2 = 46%; P <.00001) and histamine-2 receptor antagonist users (RR = 1.57; 95% CI 1.46-1.69; I-2 = 0%; P <.00001). LIMITATIONS: None of the researchers in the studies in this meta-analysis adjusted for the full panel of known confounders in these associations. CONCLUSIONS: The evidence suggests that prenatal, maternal, acid-suppressive drug use is associated with an increased risk of childhood asthma. This information may help clinicians and parents to use caution when deciding whether to take acid-suppressing drugs during pregnancy because of the risk of asthma in offspring.
AU  - Lai, T.*
AU  - Wu, M.*
AU  - Liu, J.
AU  - Luo, M.C.*
AU  - He, L.*
AU  - Wang, X.*
AU  - Wu, B.L.*
AU  - Ying, S.*
AU  - Chen, Z.*
AU  - Li, W.*
AU  - Shen, H.*
C1  - 52972
C2  - 44392
CY  - Elk Grove Village
TI  - Acid-suppressive drug use during pregnancy and the risk of childhood asthma: A meta-analysis.
JO  - Pediatrics
VL  - 141
IS  - 2
PB  - Amer Acad Pediatrics
PY  - 2018
SN  - 0031-4005
ER  - 

TY  - JOUR
AB  - BACKGROUND AND OBJECTIVES: Few birth cohorts have prospectively followed development of type 1 diabetes (T1D) and celiac disease (CD) autoimmunities to determine timing, extent of co-occurrence, and associated genetic and demographic factors. METHODS: In this prospective birth cohort study, 8676 children at high genetic risk of both diseases were enrolled and 5891 analyzed in median follow-up of 66 months. Along with demographic factors and HLA-DR-DQ, genotypes for HLA-DPB1 and 5 non-HLA loci conferring risk of both T1D and CD were analyzed. RESULTS: Development of persistent islet autoantibodies (IAs) and tissue transglutaminase autoantibodies (tTGAs), as well as each clinical disease, was evaluated quarterly from 3 to 48 months of age and semiannually thereafter. IAs alone appeared in 367, tTGAs alone in 808, and both in 90 children. Co-occurrence significantly exceeded the expected rate. IAs usually, but not always, appeared earlier than tTGAs. IAs preceding tTGAs was associated with increasing risk of tTGAs (hazard ratio [HR]: 1.48; 95% confidence interval [CI]: 1.15-1.91). After adjusting for country, sex, family history, and all other genetic loci, significantly greater co-occurrence was observed in children with a T1D family history (HR: 2.80), HLA-DR3/4 (HR: 1.94) and single-nucleotide polymorphism rs3184504 at SH2B3 (HR: 1.53). However, observed co-occurrence was not fully accounted for by all analyzed factors. CONCLUSIONS: In early childhood, T1D autoimmunity usually precedes CD autoimmunity. Preceding IAs significantly increases the risk of subsequent tTGAs. Co-occurrence is greater than explained by demographic factors and extensive genetic risk loci, indicating that shared environmental or pathophysiological mechanisms may contribute to the increased risk.
AU  - Hagopian, W.*
AU  - Lee, H.S.*
AU  - Liu, E.*
AU  - Rewers, M.*
AU  - She, J.X.*
AU  - Ziegler, A.-G.
AU  - Lernmark, A.*
AU  - Toppari, J.*
AU  - Rich, S.S.*
AU  - Krischer, J.P.*
AU  - Erlich, H.*
AU  - Akolkar, B.*
AU  - Agardh, D.*
C1  - 52088
C2  - 43701
TI  - Co-occurrence of type 1 diabetes and celiac disease autoimmunity.
JO  - Pediatrics
VL  - 140
IS  - 5
PY  - 2017
SN  - 0031-4005
ER  - 

TY  - JOUR
AB  - BACKGROUND AND OBJECTIVES: Psychological symptoms can be associated with celiac disease; however, this association has not been studied prospectively in a pediatric cohort. We examined mother report of psychological functioning in children persistently positive for tissue transglutaminase autoantibodies (tTGA), defined as celiac disease autoimmunity (CDA), compared with children without CDA in a screening population of genetically at-risk children. We also investigated differences in psychological symptoms based on mothers' awareness of their child's CDA status. METHODS: The Environmental Determinants of Diabetes in the Young study followed 8676 children to identify triggers of type 1 diabetes and celiac disease. Children were tested for tTGA beginning at 2 years of age. The Achenbach Child Behavior Checklist assessed child psychological functioning at 3.5 and 4.5 years of age. RESULTS: At 3.5 years, 66 mothers unaware their child had CDA reported more child anxiety and depression, aggressive behavior, and sleep problems than 3651 mothers of children without CDA (alls ≤ .03). Unaware-CDA mothers also reported more child anxiety and depression, withdrawn behavior, aggressive behavior, and sleep problems than 440 mothers aware of their child's CDA status (alls ≤.04). At 4.5 years, there were no differences. CONCLUSIONS: In 3.5-year-old children, CDA is associated with increased reports of child depression and anxiety, aggressive behavior, and sleep problems when mothers are unaware of their child's CDA status. Mothers' knowledge of their child's CDA status is associated with fewer reports of psychological symptoms, suggesting that awareness of the child's tTGA test results affects reporting of symptoms.
AU  - Smith, L.B.*
AU  - Lynch, K.F.*
AU  - Kurppa, K.*
AU  - Koletzko, S.
AU  - Krischer, J.*
AU  - Liu, E.*
AU  - Johnson, S.B.*
AU  - Agardh, D.*
AU  - TEDDY Study Group (Ziegler, A.-G.
AU  - Beyerlein, A.
AU  - Hummel, M.
AU  - Hummel, S.
AU  - Janz, N.
AU  - Knopff, A.
AU  - Peplow, C.
AU  - Roth, R.
AU  - Scholz, M.
AU  - Stock, J.
AU  - Strauss, E.
AU  - Warncke, K.
AU  - Wendel, L.
AU  - Winkler, C.)
C1  - 53021
C2  - 44273
TI  - Psychological manifestations of celiac disease autoimmunity in young children.
JO  - Pediatrics
VL  - 139
IS  - 3
PY  - 2017
SN  - 0031-4005
ER  - 

TY  - JOUR
AB  - OBJECTIVES: To investigate clinical features of celiac disease (CD) and their association with risk factors for CD in a genetic risk birth cohort. METHODS: Children from 6 clinical centers in 4 countries positive for HLA-DR3-DQ2 or DR4-DQ8 were annually screened for tissue transglutaminase antibodies (tTGA) and assessed for symptoms by questionnaires. Associations of symptoms with anthropometrics, known risk factors for CD, tTGA levels, and mucosal lesions in those biopsied were examined. RESULTS: Of 6706 screened children, 914 developed persistent positive tTGA, 406 underwent biopsies, and 340 had CD. Compared with age-matched tTGA-negative children, those with persistent tTGA were more likely to have symptoms at 2 (34% vs 19%, P < .001) and 3 years of age (28% vs 19%, P = .009) but not at 4 years (27% vs 21%, NS). Z-scores for height, weight, and BMI did not differ between groups. In children with persistent tTGA, having ≥1 symptom was associated with family history of CD (odds ratio = 2.59, 95% confidence interval, 1.21-5.57) but not with age, gender, or HLA-DR3-DQ2 homozygosity. At seroconversion, tTGA levels were higher in symptomatic than asymptomatic children (P < .001), in those from CD families (P < .001), and in US participants (P < .001) but not associated with age, gender, or HLA genotype. tTGA levels correlated with severity of mucosal lesions both in symptomatic (r = 0.53, P < .001) and asymptomatic children (r = 0.22, P = .01). CONCLUSIONS: A majority of children detected with persistent tTGA in screenings are asymptomatic and have normal growth by age 4 years. tTGA levels correlate more strongly with severity of mucosal lesions in symptomatic as compared with asymptomatic children.
AU  - Agardh, D.*
AU  - Lee, H.S.*
AU  - Kurppa, K.*
AU  - Simell, V.*
AU  - Aronsson, C.A.*
AU  - Jörneus, O.*
AU  - Hummel, M.
AU  - Liu, E.*
AU  - Koletzko, S.*
AU  - TEDDY Study Group (Ziegler, A.-G.
AU  - Beyerlein, A.
AU  - Hummel, S.
AU  - Knopff, A.
AU  - Peplow, C.
AU  - Roth, R.
AU  - Stock, J.
AU  - Strauss, E.
AU  - Warncke, K.
AU  - Winkler, C.)
C1  - 43551
C2  - 36672
CY  - Elk Grove Village
SP  - 627-634
TI  - Clinical features of celiac disease: A prospective birth cohort.
JO  - Pediatrics
VL  - 135
IS  - 4
PB  - Amer Acad Pediatrics
PY  - 2015
SN  - 0031-4005
ER  - 

TY  - JOUR
AB  - OBJECTIVES: The goal of this study was to determine whether age at introduction to gluten was associated with risk for celiac disease (CD) in genetically predisposed children. METHODS: TEDDY (The Environmental Determinants of Diabetes in the Young) is a prospective birth cohort study. Newborn infants (N = 6436) screened for high-risk HLA-genotypes for CD were followed up in Finland, Germany, Sweden, and the United States. Information about infant feeding was collected at clinical visits every third month. The first outcome was persistent positive for tissue transglutaminase autoantibodies (tTGA), the marker for CD. The second outcome was CD, defined as either a diagnosis based on intestinal biopsy results or on persistently high levels of tTGA. RESULTS: Swedish children were introduced to gluten earlier (median: 21.7 weeks) compared with children from Finland (median: 26.1 weeks), Germany, and the United States (both median: 30.4 weeks) (P < .0001). During a median follow-up of 5.0 years (range: 1.7-8.8 years), 773 (12%) children developed tTGA and 307 (5%) developed CD. Swedish children were at increased risk for tTGA (hazard ratio: 1.74 [95% CI: 1.47-2.06]) and CD (hazard ratio: 1.76 [95% CI: 1.34-2.24]) compared with US children, respectively (P < .0001).Gluten introduction before 17 weeks or later than 26 weeks was not associated with increased risk for tTGA or CD, adjusted for country, HLA, gender, and family history of CD, neither in the overall analysis nor on a country-level comparison. CONCLUSIONS: In TEDDY, the time to first introduction to gluten introduction was not an independent risk factor for developing CD.
AU  - Aronsson, C.A.*
AU  - Lee, H.S.*
AU  - Liu, E.*
AU  - Uusitalo, U.*
AU  - Hummel, S.
AU  - Yang, J.*
AU  - Hummel, M.
AU  - Rewers, M.*
AU  - She, J.X.*
AU  - Simell, O.*
AU  - Toppari, J.*
AU  - Ziegler, A.-G.
AU  - Krischer, J.*
AU  - Virtanen, S.M.*
AU  - Norris, J.M.*
AU  - Agardh, D.*
AU  - TEDDY Study Group (Beyerlein, A.
AU  - Knopff, A.
AU  - Peplow, C.
AU  - Roth, R.
AU  - Stock, J.
AU  - Strauss, E.
AU  - Warncke, K.
AU  - Winkler, C.)
C1  - 43135
C2  - 36302
CY  - Elk Grove Village
SP  - 239-245
TI  - Age at gluten introduction and risk of celiac disease.
JO  - Pediatrics
VL  - 135
IS  - 2
PB  - Amer Acad Pediatrics
PY  - 2015
SN  - 0031-4005
ER  - 

TY  - JOUR
AB  - Current prophylactic feeding guidelines recommend a delayed introduction of solids for the prevention of atopic diseases. This study investigates whether a delayed introduction of solids (past 4 or 6 months) is protective against the development of eczema, asthma, allergic rhinitis, and food or inhalant sensitization at the age of 6 years. METHODS: Data from 2073 children in the ongoing LISA birth cohort study were analyzed at 6 years of age. Multivariate logistic regression analyses were performed for all children and for children without skin or allergic symptoms within the first 6 months of life to take into account reverse causality. RESULTS: A delayed introduction of solids (past 4 or 6 months) was not associated with decreased odds for asthma, allergic rhinitis, or sensitization against food or inhalant allergens at 6 years of age. On the contrary, food sensitization was more frequent in children who were introduced to solids later. The relationship between the timing of solid food introduction and eczema was not clear. There was no protective effect of a late introduction of solids or a less diverse diet within the first 4 months of life. However, in children without early skin or allergic symptoms were considered, eczema was significantly more frequent in children who received a more diverse diet within the first 4 months. CONCLUSIONS: This study found no evidence supporting a delayed introduction of solids beyond 4 or 6 months for the prevention of asthma, allergic rhinitis, and food or inhalant sensitization at the age of 6 years. For eczema, the results were conflicting, and a protective effect of a delayed introduction of solids cannot be excluded. Positive associations between late introduction of solids and food sensitization have to be interpreted with caution. A true protective effect of a delayed introduction of solids on food sensitization seems unlikely.
AU  - Zutavern, A.
AU  - Brockow, I.
AU  - Schaaf, B.*
AU  - von Berg, A.*
AU  - Diez, U.*
AU  - Borte, M.*
AU  - Kraemer, U.*
AU  - Herbarth, O.*
AU  - Behrendt, H.
AU  - Wichmann, H.-E.
AU  - Heinrich, J.
AU  - LISAplus Study Group (Wichmann, H.-E.
AU  - Heinrich, J.
AU  - Bolte, G.
AU  - Belcredi, P.
AU  - Jacob, B.
AU  - Schoetzau, A.
AU  - Mosetter, M.
AU  - Schindler, J.
AU  - Höhnke, A.
AU  - Franke, K.
AU  - Laubereau, B.
AU  - Sausenthaler, S.
AU  - Thaqi, A.
AU  - Zirngibl, A.
AU  - Zutavern, A.)
C1  - 2722
C2  - 25183
SP  - e44-e52
TI  - Timing of solid food introduction in relation to eczema, asthma, allergic rhinitis, and food and inhalant sensitization at the age of 6 years: Results from the prospective birth cohort study LISA.
JO  - Pediatrics
VL  - 121
IS  - 1
PB  - American Academy of Pediatrics
PY  - 2008
SN  - 0031-4005
ER  - 

TY  - JOUR
AU  - Zutavern, A.
AU  - Brockow, I.
AU  - Bolte, G.
AU  - von Berg, A.*
AU  - Diez, U.*
AU  - Borte, M.*
AU  - Herbarth, O.*
AU  - Wichmann, H.-E.
AU  - Heinrich, J.
C1  - 3524
C2  - 23609
SP  - 401-411
TI  - Timing of solid food introduction in relation to atopic dermatitis and atopic sensitization: Results from a prospective birth cohort study.
JO  - Pediatrics
VL  - 117
PY  - 2006
SN  - 0031-4005
ER  -