Diabetes Study of Children of Diverse Ethnicity and Race: Study design.

AIMS: Determining diabetes type in children has become increasingly difficult due to an overlap in typical characteristics between type 1 diabetes (T1D) and type 2 diabetes (T2D). The Diabetes Study in Children of Diverse Ethnicity and Race (DISCOVER) programme is a National Institutes of Health (NIH)-supported multicenter, prospective, observational study that enrols children and adolescents with non-secondary diabetes. The primary aim of the study was to develop improved models to differentiate between T1D and T2D in diverse youth. MATERIALS AND METHODS: The proposed models will evaluate the utility of three existing T1D genetic risk scores in combination with data on islet autoantibodies and other parameters typically available at the time of diabetes onset. Low non-fasting serum C-peptide (<0.6 nmol/L) between 3 and 10 years after diabetes diagnosis will be considered a biomarker for T1D as it reflects the loss of insulin secretion ability. Participating centres are enrolling youth (<19 years old) either with established diabetes (duration 3-10 years) for a cross-sectional evaluation or with recent onset diabetes (duration 3 weeks-15 months) for the longitudinal observation with annual visits for 3 years. Cross-sectional data will be used to develop models. Longitudinal data will be used to externally validate the best-fitting model. RESULTS: The results are expected to improve the ability to classify diabetes type in a large and growing subset of children who have an unclear form of diabetes at diagnosis. CONCLUSIONS: Accurate and timely classification of diabetes type will help establish the correct clinical management early in the course of the disease.

High Prevalence of A-ß+ Ketosis-Prone Diabetes in Children with Type 2 Diabetes and Diabetic Ketoacidosis at Diagnosis: Evidence from the Rare and Atypical Diabetes Network (RADIANT).

Background: A-ß+ ketosis-prone diabetes (KPD) in adults is characterized by presentation with diabetic ketoacidosis (DKA), negative islet autoantibodies, and preserved ß-cell function in persons with a phenotype of obesity-associated type 2 diabetes (T2D). The prevalence of KPD has not been evaluated in children. We investigated children with DKA at "T2D" onset and determined the prevalence and characteristics of pediatric A-ß+ KPD within this cohort. Methods: We reviewed the records of 716 children with T2D at a large academic hospital and compared clinical characteristics of those with and without DKA at onset. In the latter group, we identified patients with A-ß+ KPD using criteria of the Rare and Atypical Diabetes Network (RADIANT) and defined its prevalence and characteristics. Results: Mean age at diagnosis was 13.7 ± 2.4 years: 63% female; 59% Hispanic, 29% African American, 9% non-Hispanic White, and 3% other. Fifty-six (7.8%) presented with DKA at diagnosis and lacked islet autoantibodies. Children presenting with DKA were older and had lower C-peptide and higher glucose concentrations than those without DKA. Twenty-five children with DKA (45%) met RADIANT A-ß+ KPD criteria. They were predominantly male (64%), African American or Hispanic (96%), with substantial C-peptide (1.3 ± 0.7 ng/mL) at presentation with DKA and excellent long-term glycemic control (HbA1c 6.6% ± 1.9% at follow-up (median 1.3 years postdiagnosis)). Conclusions: In children with a clinical phenotype of T2D and DKA at diagnosis, approximately half meet criteria for A-ß+ KPD. They manifest the key characteristics of obesity, preserved ß-cell function, male predominance, and potential to discontinue insulin therapy, similar to adults with A-ß+ KPD.

Natural history of TANGO2 deficiency disorder: Baseline assessment of 73 patients.

PURPOSE: TANGO2 deficiency disorder (TDD), an autosomal recessive disease first reported in 2016, is characterized by neurodevelopmental delay, seizures, intermittent ataxia, hypothyroidism, and life-threatening metabolic and cardiac crises. The purpose of this study was to define the natural history of TDD. METHODS: Data were collected from an ongoing natural history study of patients with TDD enrolled between February 2019 and May 2022. Data were obtained through phone or video based parent interviews and medical record review. RESULTS: Data were collected from 73 patients (59% male) from 57 unrelated families living in 16 different countries. The median age of participants at the time of data collection was 9.0 years (interquartile range = 5.3-15.9 years, range = fetal to 31.8 years). A total of 24 different TANGO2 alleles were observed. Patients showed normal development in early infancy, with progressive delay in developmental milestones thereafter. Symptoms included ataxia, dystonia, and speech difficulties, typically starting between the ages of 1 to 3 years. A total of 46/71 (65%) patients suffered metabolic crises, and of those, 30 (65%) developed cardiac crises. Metabolic crises were significantly decreased after the initiation of B-complex or multivitamin supplementation. CONCLUSION: We provide the most comprehensive review of natural history of TDD and important observational data suggesting that B-complex or multivitamins may prevent metabolic crises.

Clinical Characterization of Data-Driven Diabetes Clusters of Pediatric Type 2 Diabetes.

Background: Pediatric Type 2 diabetes (T2D) is highly heterogeneous. Previous reports on adult-onset diabetes demonstrated the existence of diabetes clusters. Therefore, we set out to identify unique diabetes subgroups with distinct characteristics among youth with T2D using commonly available demographic, clinical, and biochemical data. Methods: We performed data-driven cluster analysis (K-prototypes clustering) to characterize diabetes subtypes in pediatrics using a dataset with 722 children and adolescents with autoantibody-negative T2D. The six variables included in our analysis were sex, race/ethnicity, age, BMI Z-score and hemoglobin A1c at the time of diagnosis, and non-HDL cholesterol within first year of diagnosis. Results: We identified five distinct clusters of pediatric T2D, with different features, treatment regimens and risk of diabetes complications: Cluster 1 was characterized by higher A1c; Cluster 2, by higher non-HDL; Cluster 3, by lower age at diagnosis and lower A1c; Cluster 4, by lower BMI and higher A1c; and Cluster 5, by lower A1c and higher age. Youth in Cluster 1 had the highest rate of diabetic ketoacidosis (DKA) (p = 0.0001) and were most prescribed metformin (p = 0.06). Those in Cluster 2 were most prone to polycystic ovarian syndrome (p = 0.001). Younger individuals with lowest family history of diabetes were least frequently diagnosed with diabetic ketoacidosis (p = 0.001) and microalbuminuria (p = 0.06). Low-BMI individuals with higher A1c had the lowest prevalence of acanthosis nigricans (p = 0.0003) and hypertension (p = 0.03). Conclusions: Utilizing clinical measures gathered at the time of diabetes diagnosis can be used to identify subgroups of pediatric T2D with prognostic value. Consequently, this advancement contributes to the progression and wider implementation of precision medicine in diabetes management.

Characteristics of Type 2 Diabetes in Female and Male Youth.

The incidence of type 2 diabetes in children is rising and carries a worse prognosis than in adults. The influence of sex on pediatric type 2 diabetes outcomes has not been well investigated. We studied 715 youth with type 2 diabetes diagnosed at a median age of 13.7 years and compared sex differences in demographic, clinical, and laboratory characteristics within the first year of diagnosis. Females diagnosed with type 2 diabetes were younger and at a higher stage of pubertal development than males, yet presented with lower A1Cs, a lower prevalence of diabetic ketoacidosis, and higher HDL cholesterol levels.

The germline p53 activation syndrome: A new patient further refines the clinical phenotype.

The tumor suppressor p53 has well known roles in cancer development and germline cancer predisposition disorders, but increasing evidence supports the role of activation of this transcription factor in the pathogenesis of inherited bone marrow failure and chromosomal instability disorders. Here we report a patient with red cell aplasia, which was steroid responsive, as well as intellectual disability, seizures, microcephaly, short stature, cellular radiosensitivity, and normal telomere lengths, who had a germline heterozygous C-terminal frameshift variant in TP53 similar to others that activate the transcription factor. This is the third reported individual with a germline p53 activation syndrome, with several unique features that refine the clinical disease associated with these variants.

Optimizing maturity-onset diabetes of the young detection in a pediatric diabetes population.

INTRODUCTION: Maturity-onset diabetes of the young (MODY) is often misdiagnosed as type 1/type 2 diabetes. We aimed to define patient characteristics to guide the decision to test for MODY in youth with diabetes. RESEARCH DESIGN AND METHODS: Of 4750 patients enrolled in the Diabetes Registry at Texas Children's Hospital between July 2016 and July 2019, we selected ("Study Cohort", n = 350) those with: (1) diabetes diagnosis <25 years, (2) family history of diabetes in three consecutive generations, and (3) absent islet autoantibodies except for GAD65. We retrospectively studied their clinical and biochemical characteristics and available MODY testing results. Cluster analysis was then performed to identify the cluster with highest rate of MODY diagnosis. RESULTS: Patients in the Study Cohort were 3.5 times more likely to have been diagnosed with MODY than in the overall Diabetes Registry (4.6% vs. 1.3%, p < 0.001). The cluster (n = 16) with the highest rate of clinician-diagnosed MODY (25%, n = 4/16) had the lowest age (10.9 ± 2.5 year), BMI-z score (0.5 ± 0.9), C-peptide level (1.5 ± 1.2 ng/ml) and acanthosis nigricans frequency (12.5%) at diabetes diagnosis (all p < 0.05). In this cluster, three out of five patients who underwent MODY genetic testing had a pathogenic variant. CONCLUSIONS: Using a stepwise approach, we identified that younger age, lower BMI, lower C-peptide, and absence of acanthosis nigricans increase likelihood of MODY in racially/ethnically diverse children with diabetes who have a multigenerational family history of diabetes and negative islet autoantibodies, and can be used by clinicians to select patients for MODY testing.

Islet autoantibody types mark differential clinical characteristics at diagnosis of pediatric type 1 diabetes.

BACKGROUND: We aimed to study whether islet autoantibody type marks differential characteristics at the time of type 1 diabetes (T1D) diagnosis. METHODS: We studied 711 children with newly diagnosed autoimmune T1D. We compared demographic (sex, age, race/ethnicity), clinical (pubertal development, BMI percentile, diabetic ketoacidosis [DKA]) and laboratory (glucose, hemoglobin A1c [HbA1c], C-peptide, tissue transglutaminase antibodies [tTGA], thyroglobulin antibodies, and thyroid peroxidase antibodies [TPOA]) characteristics by presence/absence of autoantibodies to insulin (IAA), GAD65 (GADA), or IA-2/ICA512 (IA-2A). Islet autoantibody titers were evaluated among the children positive for the relevant autoantibody type. We used multivariable analysis to adjust for potential confounders. RESULTS: IAA+ was statistically associated with younger age (p < 0.0001) and lower HbA1c (p = 0.049) while Tanner stage, GADA status and number of positive islet autoantibodies were not significant in the multivariable model. GADA+ was associated with female sex (OR = 4.0, p = 0.002) and negatively with elevated tTGA titers (>50 U/mL) (OR = 0.21, p = 0.026) but not with age, IAA status, IA-2A status, islet autoantibody number, or thyroid autoimmunity. None of the associations with IA-2A positivity was statistically significant in the multivariable analysis. In multivariable models, IAA titer was significantly associated with younger age (p = 0.006), DKA (p = 0.017) and higher tTGA levels (p = 0.002); GADA titer with female sex (p = 0.028), racial minority (p = 0.046) and TPOA positivity (p = 0.021); and IA-2A titer with older age (p = 0.001) and not being African American (p = 0.024). CONCLUSIONS: Islet autoantibody type is associated with differential characteristics at diagnosis of pediatric T1D. Longitudinal and mechanistic studies are needed to evaluate T1D endotypes by autoantibody type.

Type 2 diabetes in prepubertal children.

OBJECTIVE: Puberty-induced insulin resistance is considered critical in the pathogenesis of type 2 diabetes (T2D) in youth. The development of T2D before puberty suggests distinct risk factors and pathophysiology but, because of its rarity, this has not been well studied. We aimed to describe the clinical characteristics of children with T2D diagnosed before the onset of puberty. RESEARCH DESIGN AND METHODS: We retrospectively studied all children with autoantibody-negative T2D and available pubertal development assessment seen at our center between July 2016 and July 2019, and compared characteristics of those at Tanner stage I (prepubertal, n = 35) versus those at Tanner II-V of pubertal development (n = 341). RESULTS: At T2D diagnosis, prepubertal children compared with those at Tanner II-V had higher body mass index z-score (p = 0.003) and higher C-peptide (p = 0.003) (while glucose levels were not significantly different), with differences retaining significance after adjustment for glucose, race/ethnicity and sex. Dyslipidemia occurred in 100% of prepubertal children versus 89.7% of those diagnosed later (p = 0.036). Of the prepubertal children diagnosed under age 10 (n = 13), 69.2% were female, 100% racial/ethnic minority, 100% had obesity with history of dyslipidemia and none with diabetic ketoacidosis. CONCLUSIONS: T2D, although rarely, can develop before puberty. Children with T2D diagnosed in the prepubertal period have more severe obesity, greater insulin resistance, and more frequent dyslipidemia than older youth. These findings suggest that children with prepubertal T2D are at increased risk for associated morbidity compared with older youth and underscore the significance of interventions to prevent and treat obesity in early childhood.

Exome sequencing in children with clinically suspected maturity-onset diabetes of the young.

OBJECTIVE: Commercial gene panels identify pathogenic variants in as low as 27% of patients suspected to have MODY, suggesting the role of yet unidentified pathogenic variants. We sought to identify novel gene variants associated with MODY. RESEARCH DESIGN AND METHODS: We recruited 10 children with a clinical suspicion of MODY but non-diagnostic commercial MODY gene panels. We performed exome sequencing (ES) in them and their parents. RESULTS: Mean age at diabetes diagnosis was 10 (± 3.8) years. Six were females; 4 were non-Hispanic white, 5 Hispanic, and 1 Asian. Our variant prioritization analysis identified a pathogenic, de novo variant in INS (c.94G > A, p.Gly32Ser), confirmed by Sanger sequencing, in a proband who was previously diagnosed with "autoantibody-negative type 1 diabetes (T1D)" at 3 y/o. This rare variant, absent in the general population (gnomAD database), has been reported previously in neonatal diabetes. We also identified a frameshift deletion (c.2650delC, p.Gln884AsnfsTer57) in RFX6 in a child with a previous diagnosis of "autoantibody-negative T1D" at 12 y/o. The variant was inherited from the mother, who was diagnosed with "thin type 2 diabetes" at 25 y/o. Heterozygous protein-truncating variants in RFX6 gene have been recently reported in individuals with MODY. CONCLUSIONS: We diagnosed two patients with MODY using ES in children initially classified as "T1D". One has a likely pathogenic novel gene variant not previously associated with MODY. We demonstrate the clinical utility of ES in patients with clinical suspicion of MODY.

Challenges in the diagnosis of diabetes type in pediatrics.

The incidence of diabetes, both type 1 and type 2, is increasing. Health outcomes in pediatric diabetes are currently poor, with trends indicating that they are worsening. Minority racial/ethnic groups are disproportionately affected by suboptimal glucose control and have a higher risk of acute and chronic complications of diabetes. Correct clinical management starts with timely and accurate classification of diabetes, but in children this is becoming increasingly challenging due to high prevalence of obesity and shifting demographic composition. The growing obesity epidemic complicates classification by obesity's effects on diabetes. Since the prevalence and clinical characteristics of diabetes vary among racial/ethnic groups, migration between countries leads to changes in the distribution of diabetes types in a certain geographical area, challenging the clinician's ability to classify diabetes. These challenges must be addressed to correctly classify diabetes and establish an appropriate treatment strategy early in the course of disease for all. This may be the first step in improving diabetes outcomes across racial/ethnic groups. This review will discuss the pitfalls in the current diabetes classification scheme that is leading to increasing overlap between diabetes types and heterogeneity within each type. It will also present proposed alternative classification schemes and approaches to understanding diabetes type that may improve the timely and accurate classification of pediatric diabetes type.

Ethnic differences in progression of islet autoimmunity and type 1 diabetes in relatives at risk.

AIMS/HYPOTHESIS: We hypothesised that progression of islet autoimmunity and type 1 diabetes mellitus differs among races/ethnicities in at-risk individuals. METHODS: In this study, we analysed the data from the Type 1 Diabetes TrialNet Pathway to Prevention Study. We studied 4873 non-diabetic, autoantibody-positive relatives of individuals with type 1 diabetes followed prospectively (11% Hispanic, 80.9% non-Hispanic white [NHW], 2.9% non-Hispanic black [NHB] and 5.2% non-Hispanic other [NHO]). Primary outcomes were time from single autoantibody positivity confirmation to multiple autoantibody positivity, and time from multiple autoantibody positivity to type 1 diabetes mellitus diagnosis. RESULTS: Conversion from single to multiple autoantibody positivity was less common in Hispanic individuals than in NHW individuals (HR 0.66 [95% CI 0.46, 0.96], p = 0.028) adjusting for autoantibody type, age, sex, Diabetes Prevention Trial Type 1 Risk Score and HLA-DR3-DQ2/DR4-DQ8 genotype. In participants who screened positive for multiple autoantibodies (n = 2834), time to type 1 diabetes did not differ by race/ethnicity overall (p = 0.91). In children who were <12 years old when multiple autoantibody positivity was determined, being overweight/obese had differential effects by ethnicity: type 1 diabetes risk was increased by 36% in NHW children (HR 1.36 [95% CI 1.04, 1.77], p = 0.024) and was nearly quadrupled in Hispanic children (HR 3.8 [95% CI 1.6, 9.1], p = 0.0026). We did not observe this interaction in participants who were ≥12 years old at determination of autoantibody positivity, although this group size was limited. No significant differential risks were observed between individuals of NHB and NHW ethnicity. CONCLUSIONS/INTERPRETATION: The risk and rate of progression of islet autoimmunity were lower in Hispanic compared with NHW at-risk individuals, while significant differences in the development of type 1 diabetes were limited to children <12 years old and were modified by BMI.

Adjuvant Pharmacotherapies to Insulin for the Treatment of Type 1 Diabetes.

PURPOSE OF REVIEW: Insulin therapy alone fails to achieve target glycemic control in the majority of individuals with type 1 diabetes (T1D), motivating the investigation of additive medications. This review focuses on the recent findings on the use of adjunctive pharmacotherapy in T1D. RECENT FINDINGS: Metformin and glucagon-like peptide-1 receptor agonists have been associated with weight reduction and decrease in daily insulin requirements without sustainable improvement in glycemic control. Sodium-glucose cotransporter (SGLT)-2 inhibitors, dual SGLT-1/2 inhibitors, and pramlintide have been shown to reduce hemoglobin A1c, induce weight loss, and lower insulin dose. The benefits of dipeptidyl peptidase-4 inhibitors, thiazolidinediones, and alpha glucosidase inhibitors appear to be more limited. Gastrointestinal symptoms and increased hypoglycemia are adverse effects of certain classes. Although not devoid of side effects, additive pharmacotherapies in T1D can improve glycemic control and lower body weight and insulin requirement. Longer studies are needed before consideration for widespread clinical care.

Persistence of müllerian duct structures in a genetic male with distal monosomy 10q.

Persistent müllerian duct syndrome (PMD) with antimüllerian hormone (AMH) deficiency is usually associated with mutations or deletions of the AMH gene, although many cases have no identified gene association. We report on a genetic male with PMD and AMH deficiency associated with distal monosomy 10q. A term 3,230 g infant was born to a healthy 27-year-old. Fetal ultrasound had shown possible genital ambiguity. Postnatal exam showed a 0.5 cm phallus with basal meatus, normal scrotum with no palpable gonads, no vaginal orifice, and a rectal fistula with an imperforate anus. Voiding cystourethrogram with ultrasound, cystoscopy, and laparoscopy showed normal bladder, urethral orifice, distal vagina, cervix, and bilateral abdominal testis. At 24 hours of life, testosterone was within normal range with low AMH level. Chromosome microarray analysis showed 46, XY, del10(10q25.3q26.13) involving an 8.2 MB interstitial deletion. Whole exome sequencing identified a NOTCH2 variant (1p11.2). AMH sequencing revealed no abnormalities. Following multidisciplinary team and parent discussion, male gender was assigned. Testosterone treatment resulted in penile length of 1.5 cm. Bilateral orchiopexy and posterior sagittal anorectoplasty were performed at 11 months of age; rudimentary müllerian structures were identified. This observation suggests an association of 10qter elements with male differentiation including AMH expression and is similar to a patient with 46, XY, del(10q26.1) in which AMH levels were not reported. Regional candidate genes include FGFR2 (10q26.13). The possible contribution of a NOTCH2 variant cannot be excluded.

Inaccurate diagnosis of diabetes type in youth: prevalence, characteristics, and implications.

Classifying diabetes at diagnosis is crucial for disease management but increasingly difficult due to overlaps in characteristics between the commonly encountered diabetes types. We evaluated the prevalence and characteristics of youth with diabetes type that was unknown at diagnosis or was revised over time. We studied 2073 youth with new-onset diabetes (median age [IQR] = 11.4 [6.2] years; 50% male; 75% White, 21% Black, 4% other race; overall, 37% Hispanic) and compared youth with unknown versus known diabetes type, per pediatric endocrinologist diagnosis. In a longitudinal subcohort of patients with data for ≥ 3 years post-diabetes diagnosis (n = 1019), we compared youth with steady versus reclassified diabetes type. In the entire cohort, after adjustment for confounders, diabetes type was unknown in 62 youth (3%), associated with older age, negative IA-2 autoantibody, lower C-peptide, and no diabetic ketoacidosis (all, p < 0.05). In the longitudinal subcohort, diabetes type was reclassified in 35 youth (3.4%); this was not statistically associated with any single characteristic. In sum, among racially/ethnically diverse youth with diabetes, 6.4% had inaccurate diabetes classification at diagnosis. Further research is warranted to improve accurate diagnosis of pediatric diabetes type.

Variants of Unknown Significance in Maturity-Onset Diabetes of the Young: High Rate of Conundrum Resolution via Variants of Unknown Significance Reanalysis.

INTRODUCTION: In the era of next-generation sequencing, clinicians frequently encounter variants of unknown significance (VUS) in genetic testing. VUS may be reclassified over time as genetic knowledge grows. We know little about how best to approach VUS in the maturity-onset diabetes of the young (MODY). Therefore, our study aimed to determine the utility of reanalysis of previous VUS results in genetic confirmation of MODY. METHODS: A single-center retrospective chart review identified 85 subjects with a MODY clinical diagnosis. We reanalyzed genetic testing in 10 subjects with 14 unique VUS on MODY genes that was performed >3 years before the study. Demographic, clinical, and biochemical data was collected for those individuals. RESULTS: After reanalysis, 43% (6/14) of the gene variants were reclassified to a different category: 7% (1/14) were "likely pathogenic" and 36% (5/14) were "benign" or "likely benign." The reclassified pathogenic variant was in HNF1A and all reclassified benign variants were in HNF1A, HNF1B and PDX1. The median time between MODY testing and reclassification was 8 years (range: 4-10 years). CONCLUSION: In sum, iterative reanalyzing the genetic data from VUS found during MODY testing may provide high-yield diagnostic information. Further studies are warranted to identify the optimal time and frequency for such analyses.

Genetic Associations with C-peptide Levels before Type 1 Diabetes Diagnosis in At-Risk Relatives.

OBJECTIVE: We sought to determine whether the type 1 diabetes genetic risk score-2 (T1D-GRS2) and single nucleotide polymorphisms (SNPs) are associated with C-peptide preservation before type 1 diabetes diagnosis. METHODS: We conducted a retrospective analysis of 713 autoantibody-positive participants who developed type 1 diabetes in the TrialNet Pathway to Prevention Study who had T1DExomeChip data. We evaluated the relationships of 16 known SNPs and T1D-GRS2 with area under the curve (AUC) C-peptide levels during oral glucose tolerance tests conducted in the 9 months before diagnosis. RESULTS: Higher T1D-GRS2 was associated with lower C-peptide AUC in the 9 months before diagnosis in univariate (ß=-0.06, P<0.0001) and multivariate (ß=-0.03, P=0.005) analyses. Participants with the JAZF1 rs864745 T allele had lower C-peptide AUC in both univariate (ß=-0.11, P=0.002) and multivariate (ß=-0.06, P=0.018) analyses. CONCLUSIONS: The type 2 diabetes-associated JAZF1 rs864745 T allele and higher T1D-GRS2 are associated with lower C-peptide AUC prior to diagnosis of type 1 diabetes, with implications for the design of prevention trials.