Further delineation of the rare GDACCF (global developmental delay, absent or hypoplastic corpus callosum, dysmorphic facies syndrome): genotype and phenotype of 22 patients with ZNF148 mutations.

BACKGROUND: Pathogenic variants in the zinc finger protein coding genes are rare causes of intellectual disability and congenital malformations. Mutations in the ZNF148 gene causing GDACCF syndrome (global developmental delay, absent or hypoplastic corpus callosum, dysmorphic facies; MIM #617260) have been reported in five individuals so far. METHODS: As a result of an international collaboration using GeneMatcher Phenome Central Repository and personal communications, here we describe the clinical and molecular genetic characteristics of 22 previously unreported individuals. RESULTS: The core clinical phenotype is characterised by developmental delay particularly in the domain of speech development, postnatal growth retardation, microcephaly and facial dysmorphism. Corpus callosum abnormalities appear less frequently than suggested by previous observations. The identified mutations concerned nonsense or frameshift variants that were mainly located in the last exon of the ZNF148 gene. Heterozygous deletion including the entire ZNF148 gene was found in only one case. Most mutations occurred de novo, but were inherited from an affected parent in two families. CONCLUSION: The GDACCF syndrome is clinically diverse, and a genotype-first approach, that is, exome sequencing is recommended for establishing a genetic diagnosis rather than a phenotype-first approach. However, the syndrome may be suspected based on some recurrent, recognisable features. Corpus callosum anomalies were not as constant as previously suggested, we therefore recommend to replace the term 'GDACCF syndrome' with 'ZNF148-related neurodevelopmental disorder'.

Neurofibromatosis type 1 mosaicism in patients with constitutional mismatch repair deficiency.

Differential diagnosis between constitutional mismatch repair deficiency (CMMRD) and neurofibromatosis type 1 (NF1) is crucial as treatment and surveillance differ. We report the case of a girl with a clinical diagnosis of sporadic NF1 who developed a glioblastoma. Immunohistochemistry for MMR proteins identified PMS2 loss in tumour and normal cells and WES showed the tumour had an ultra-hypermutated phenotype, supporting the diagnosis of CMMRD. Germline analyses identified two variants (one pathogenic variant and one classified as variant(s) of unknown significance) in the PMS2 gene and subsequent functional assays on blood lymphocytes confirmed the diagnosis of CMMRD. The large plexiform neurofibroma of the thigh and the freckling were however more compatible with NF1. Indeed, a NF1 PV (variant allele frequencies of 20%, 3% and 9% and in blood, skin and saliva samples, respectively) was identified confirming a mosaicism for NF1. Retrospective analysis of a French cohort identified NF1 mosaicism in blood DNA in 2 out of 22 patients with CMMRD, underlining the existence of early postzygotic PV of NF1 gene in patients with CMMRD whose tumours have been frequently reported to exhibit somatic NF1 mutations. It highlights the potential role of this pathway in the pathogenesis of CMMRD-associated gliomas and argues in favour of testing MEK inhibitors in this context.

Early-life diet and risk of inflammatory bowel disease: a pooled study in two Scandinavian birth cohorts.

OBJECTIVE: We assessed whether early-life diet quality and food intake frequencies were associated with subsequent IBD. DESIGN: Prospectively recorded 1-year and 3-year questionnaires in children from the All Babies in Southeast Sweden and The Norwegian Mother, Father and Child Cohort Study were used to assess diet quality using a Healthy Eating Index and intake frequency of food groups. IBD was defined as >2 diagnoses in national patient registers. Cox regression yielded HRs adjusted (aHRs) for child's sex, parental IBD, origin, education level and maternal comorbidities. Cohort-specific results were pooled using a random-effects model. RESULTS: During 1 304 433 person-years of follow-up, we followed 81 280 participants from birth through childhood and adolescence, whereof 307 were diagnosed with IBD. Compared with low diet quality, medium and high diet quality at 1 year of age were associated with a reduced risk of IBD (pooled aHR 0.75 (95% CI=0.58 to 0.98) and 0.75 (95% CI=0.56 to 1.00)). The pooled aHR per increase of category was 0.86 (0.74 to 0.99). Pooled aHR for children 1 year old with high versus low fish intake was 0.70 (95% CI=0.49 to 1.00) for IBD, and showed association with reduced risk of UC (pooled aHR=0.46; 95% CI=0.21, 0.99). Higher vegetable intake at 1 year was associated with a risk reduction in IBD. Intake of sugar-sweetened beverages was associated with an increased risk of IBD. Diet quality at 3 years was not associated with IBD. CONCLUSION: In this Scandinavian birth cohort, high diet quality and fish intake in early life were associated with a reduced risk of IBD.

Associations between type 1 diabetes and educational outcomes: an Aotearoa/New Zealand nationwide birth cohort study using the Integrated Data Infrastructure.

AIMS/HYPOTHESIS: Type 1 diabetes is one of the most common chronic diseases of childhood. It is hypothesised that the metabolic and psychosocial consequences of type 1 diabetes may affect educational outcomes; however, existing literature presents conflicting results. This study aimed to assess whether educational outcomes differ for young people with and without type 1 diabetes in Aotearoa/New Zealand (NZ). METHODS: This was a nationwide 9 year birth cohort study of all people born in NZ from 1993 to 2001 using linked administrative data held within the Integrated Data Infrastructure, a national research database containing linked health and non-health data. Educational outcomes of high school attainment, high school attendance and university enrolment were measured from age 13 years until 20 years. Generalised linear regression models with log link and Gaussian distributions were used to compare educational outcomes between those with and those without type 1 diabetes, adjusting for sociodemographic and maternal characteristics. RESULTS: Of the 442,320 children in the birth cohort, type 1 diabetes was identified in 2058 (0.47%) (mean [SD] age of type 1 diabetes diagnosis 7.7 [3.4] years). Educational outcomes were significantly lower for children with type 1 diabetes than for those without type 1 diabetes, including for any high school qualification (RR 0.97 [95% CI 0.95, 0.99]), university entrance-level high school attainment (RR 0.88 [95% CI 0.84, 0.92]), regular high school attendance (RR 0.91 [95% CI 0.85, 0.97]) and university enrolment (RR 0.93 [95% CI 0.88, 0.98]), even after adjusting for sociodemographic and maternal factors. In addition, educational outcomes were substantially lower for those with post type 1 diabetes diagnosis hospitalisations for diabetic ketoacidosis and hypoglycaemia. CONCLUSIONS/INTERPRETATION: In this whole NZ birth cohort study, type 1 diabetes was associated with lower educational outcomes spanning secondary school and into university enrolment. Ongoing efforts to support students with type 1 diabetes are needed, particularly for those with a greater risk profile.

The CAR T-cell race: The rules of the game.

The management of paediatric patients with refractory acute lymphoblastic leukaemia eligible for the CAR T cell product tisagenlecleucel involves multiple decision points between the process of patient referral to product infusion. How to address the individual patient's circumstances, optimize apheresis yields and, above all, plan the best bridging chemotherapy is clearly detailed in these comprehensive and practical recommendations by Kumar Mishra and colleagues. Commentary on: Mishra et al. Practice guideline: Preparation for CAR T-cell therapy in children and young adults with B-acute lymphoblastic leukaemia. Br J Haematol 2024;204:1687-1696.

Exploratory study on the individualized application of eltrombopag in paediatric immune thrombocytopaenia guided by therapeutic drug monitoring.

There are variations in individual eltrombopag concentrations that may impact efficacy and adverse drug reactions (ADRs) in paediatric immune thrombocytopaenia (ITP). To solve this problem, we tailored the eltrombopag dosage refer to concentration, then followed up to assess concentration value in paediatric ITP. This is a single-centre, prospective, observational study. The eltrombopag dosage was adjusted, and children were divided into three groups: the maintenance, discontinuation, and increase groups. Concentration and other data were compared to explore concentration value in guiding the individualized treatment of paediatric ITP. Thirty-nine patients were enrolled, including 23 in the maintenance group, 3 in the discontinued group and 13 in the increase group. 3 patients discontinued eltrombopag due to ADRs, which was significantly higher than patients in the maintenance group (t = 3.606, p = 0.001). In all, 13 patients increased their dosage due to poor response, whose concentration and platelet count were significantly lower than patients in the maintenance group (t = 2.461, p = 0.019; t = 4.633, p < 0.001). Two months after the increase, the number of patients reaching CR and R respectively increased by 2 and 3, while the median platelet count was significantly raised (Z = -2.411, p = 0.016). Concentration could be used as a reference index for the individualized treatment of eltrombopag in paediatric ITP.

Acquired haemophilia A in paediatric patients: A retrospective French cohort of eight cases.

Acquired haemophilia A (AHA) is a rare haemorrhagic disease characterised by new-onset haemorrhagic symptoms associated with a dramatic decrease in factor VIII levels and an anti-factor VIII neutralising autoantibody concentration >0.6 Bethesda units. Elderly people are often affected, whereas children are rarely affected; the paediatric incidence reported in the literature is about 0.045 case/million/year. For some time, the paediatric standard of care has been that for adults, but clinicians have often reported poor outcomes. Here, we describe the largest retrospective paediatric AHA cohort assembled to date, including eight patients diagnosed in France from 2000 to 2020.

An integrated molecular risk score early in life for subsequent childhood asthma risk.

BACKGROUND: Numerous children present with early wheeze symptoms, yet solely a subgroup develops childhood asthma. Early identification of children at risk is key for clinical monitoring, timely patient-tailored treatment, and preventing chronic, severe sequelae. For early prediction of childhood asthma, we aimed to define an integrated risk score combining established risk factors with genome-wide molecular markers at birth, complemented by subsequent clinical symptoms/diagnoses (wheezing, atopic dermatitis, food allergy). METHODS: Three longitudinal birth cohorts (PAULINA/PAULCHEN, n = 190 + 93 = 283, PASTURE, n = 1133) were used to predict childhood asthma (age 5-11) including epidemiological characteristics and molecular markers: genotype, DNA methylation and mRNA expression (RNASeq/NanoString). Apparent (ap) and optimism-corrected (oc) performance (AUC/R2) was assessed leveraging evidence from independent studies (Naïve-Bayes approach) combined with high-dimensional logistic regression models (LASSO). RESULTS: Asthma prediction with epidemiological characteristics at birth (maternal asthma, sex, farm environment) yielded an ocAUC = 0.65. Inclusion of molecular markers as predictors resulted in an improvement in apparent prediction performance, however, for optimism-corrected performance only a moderate increase was observed (upto ocAUC = 0.68). The greatest discriminate power was reached by adding the first symptoms/diagnosis (up to ocAUC = 0.76; increase of 0.08, p = .002). Longitudinal analysis of selected mRNA expression in PASTURE (cord blood, 1, 4.5, 6 years) showed that expression at age six had the strongest association with asthma and correlation of genes getting larger over time (r = .59, p < .001, 4.5-6 years). CONCLUSION: Applying epidemiological predictors alone showed moderate predictive abilities. Molecular markers from birth modestly improved prediction. Allergic symptoms/diagnoses enhanced the power of prediction, which is important for clinical practice and for the design of future studies with molecular markers.

HIV drug resistance, viral suppression, and survival in children living with HIV in Brazil.

INTRODUCTION: Mutations associated with HIV drug resistance (DR) affect clinical outcomes. Understanding the prevalence of HIV DR and its association with viral suppression and survival in the paediatric population is key to inform patient care and health policies. METHODS: We used Brazilian monitoring systems to identify genotyping tests performed in children living with HIV aged ≤18 months between 2009 and 2020. We categorized HIV DR using three criteria: any HIV DR (R1), DR to nevirapine or efavirenz (R2), and DR to at least one antiretroviral recommended for children with HIV in Brazilian guidelines (R3). We investigated factors associated with HIV DR, viral suppression, and survival up to 3 years old using multivariable models. Lastly, we describe the annual prevalence of each type of HIV DR in Brazilian children with HIV between 2009 and 2020. RESULTS: We included 1152 children with HIV with a median age of 5 months at genotype testing; 57% were females. R1 was observed in 30%, R2 in 17%, and R3 in 21%. Children with HIV whose birth parents were exposed to nevirapine or efavirenz before delivery had higher odds of R2 (odds ratio 3.4; 95% confidence interval [CI] 1.1-10.8). Children with HIV with R1 or R3 had higher rates of death than those with HIV with no HIV DR in the adjusted models (adjusted hazard ratios 4.7 [95% CI 1.6-13.9] and 4.1 [95% CI 1.4-12.4], respectively). The prevalence of resistance to nevirapine and efavirenz peaked in 2015. Over time, the prevalence of genotyping tests with no detected resistance varied between 57% and 87%. CONCLUSION: HIV DR is highly prevalent in children with HIV and is associated with lower survival.

Pituitary deficiencies related to optic nerve hypoplasia and visual acuity.

OBJECTIVE: Optic nerve hypoplasia (ONH), the congenital underdevelopment of the optic nerve, is an increasing cause of visual impairment and is associated with pituitary dysfunction. Past studies have focused on the relationship between ONH, pituitary deficiencies, and brain imaging. However, recent studies have demonstrated the true risk for hypopituitarism lies with the presence or absence of ONH, irrespective of midline brain findings. This study reviewed the relationship between the health of the optic nerve (visual acuity) and pituitary gland (number and age of development of pituitary deficiencies) as a way to stratify risk, regardless of imaging findings. DESIGN, PATIENTS AND MEASUREMENTS: Retrospective chart review of 197 patients seen at a single center from 2013 to 2022. Visual assessment was defined by distance acuity, and the presence of nystagmus or afferent pupillary defect. Pituitary deficiencies were diagnosed per Endocrine Society guidelines. RESULTS: In children with bilateral ONH (bONH), profound visual impairment was associated with more pituitary deficiencies between 0 and 15 years of age. The odds of having any pituitary deficiency were 4.9 times higher (95% confidence interval [95% CI]: 2.4-10.1) for patients with bONH versus unilateral ONH (uONH). Central hypothyroidism was the most common first presenting pituitary deficiency followed by growth hormone across all patients. CONCLUSION: This study shows a significant association between severity of visual impairment and increased probability of pituitary deficiencies in children with bONH versus uONH. Children with ONH require urgent endocrine evaluation due to risk of pituitary deficiencies, but risk stratification may also be based on severity of visual impairment.