Children's Specialized Hospital

PURPOSE:Gene-disease relationship (GDR) is a key concept in monogenic disease diagnostics. Although functional analysis and disease modeling play important supporting roles, human genetics evidence remains key to supporting or challenging a proposed GDR. Such evidence typically comes from individual publications that address one GDR at a time. We hypothesized that a large cohort composed primarily of Mendelian phenotypes and enriched for consanguinity and founder effect can accelerate evidence generation by enabling high-throughput discovery of homozygous loss-of-function (LOF) variants as well as strong segregation data. METHODS:To test this hypothesis, we analyzed our Lifera Omics Database (LODB) for homozygous high-impact missense variants that are observed in 2 or more unrelated individuals to exploit the power of founder variants, as well as homozygous presumptive LOF variants. The search spanned 2904 genes with tentative GDRs in the literature. RESULTS:The analysis revealed 154 individuals with 119 homozygous LOF variants that support GDRs for 95 genes. Additionally, we identified 13 founder missense variants (33 homozygous individuals) that support GDR for 13 genes. Our data expand the mode of inheritance (MOI) of 19 genes for which the tentative GDRs were based on dominant variants. Phenotypic expansion was encountered in 18 of the supported GDRs, including those in which the full syndromic constellation has not been previously delineated. We also report four novel allelic disorders of reported GDRs. CONCLUSION:This work highlights the potential of diagnostic laboratories to accelerate GDR refinement through data sharing and working closely with referring physicians. It also showcases the added advantage concerning autosomal recessive GDR when the study population is enriched for consanguinity and founder effect.

BackgroundMembranoproliferative glomerulonephritis (MPGN) is a rare glomerular disorder characterized by immune complex or complement-mediated injury, often leading to nephrotic syndrome, hypertension, and progressive renal dysfunction. Its management remains challenging, particularly in pediatric patients with coexisting renal pathologies.Case presentationWe report a case of an 11-years-old girl who presented with nephrotic syndrome, severe hypertension, and impaired renal function. Renal biopsy confirmed immune complex-mediated MPGN (IC-MPGN), and genetic testing revealed a homozygous, pathogenic missense PKHD1 variant (NM_138694.3:c.4870C > T; p.(Arg1624Trp), leading to a diagnosis of autosomal recessive polycystic kidney disease (ARPKD). Initial treatment with prednisolone and mycophenolate mofetil failed to halt disease progression, and the patient became dialysis dependent. Pegcetacoplan, a complement C3 inhibitor, was subsequently initiated. After 11 weeks of pegcetacoplan therapy, the patient achieved renal recovery and was successfully weaned from dialysis. Proteinuria decreased from nephrotic to sub-nephrotic levels without significant adverse effects.ConclusionTo our knowledge, this is the first pediatric case of IC-MPGN with genetically confirmed ARPKD successfully treated with pegcetacoplan. The case illustrates that renal recovery occurred following initiation of proximal complement inhibition with pegcetacoplan.

Background and Objectives:Mutations in the GPD1 gene, which encodes glycerol-3-phosphate dehydrogenase 1 (GPD1), are a rare cause of monogenic hypertriglyceridemia (HTG) during childhood. This study is aimed at providing a detailed analysis of the clinical, laboratory, and molecular characteristics of all patients affected by biallelic GPD1 gene variants, including three cases from our center. Methods:A literature search was conducted across the English MEDLINE, PubMed, and Embase databases from 1966 to 2023 for the studies that reported on GPD1 deficiency with confirmed GPD1 gene variants using the search words HTG and GPD1 gene. Results:A total of 39 children (including three from our center) were identified with 15 pathogenic mutations in GPD1 reported in 14 articles from 5 ethnicities (15 Arabs, 14 Caucasians, 4 Chinese, 5 Indian/South Asian, and 1 Turkish): 8 missense variants (one compound heterozygous), 3 nonsense, 3 frameshifts, and 1 splicing. Three of the 15 variants likely originated from a common ancestor, "that is, founder in nature": p.I119fs∗94 (Palestinian Arabs), p.Gly299Arg (Czech population), and p.Thr251Asnfs∗10 (Saudi Arabia). The median age at presentation was 9 months. All patients manifested hepatomegaly, elevated transaminases, and HTG. Nineteen patients underwent liver biopsy; all showed micro- and macrosteatosis, mild to moderate portal fibrosis in 58% (11 out of 19), and cirrhosis in the remaining eight cases (42%). Follow-up data showed that HTG normalized in 28% of patients (11 out of 39) but persisted mildly in the remaining 72% (28 out of 39). Conclusion:Mutations in the GPD1 gene should be considered in children with hepatomegaly, hepatic steatosis, and HTG. This study indicates that GPD1 deficiency may not be a transient or benign condition, as previously considered, due to the persistence of HTG and liver pathology in a significant proportion of cases. Identifying specific GPD1 variants may expedite targeted molecular analysis.

BACKGROUND:Autism spectrum disorder (ASD) is common in individuals with Down syndrome (DS), with an estimated prevalence of 16%-18%. However, receiving a dual diagnosis of Down syndrome and ASD (DS + ASD) is often delayed. Little evidence exists on the path to ASD diagnosis nor interventions to support individuals with DS + ASD. Barriers to diagnosis and treatment for this unique patient population have yet to be described. This study explores clinicians' practices and perceptions regarding the diagnosis and treatment DS + ASD, and the barriers their patients face in connecting to recommended evaluations and services. METHODS:The study used an anonymous web-based survey developed by a group of physicians, psychologists and researchers who work with individuals with DS, ASD and DS + ASD. The survey queried clinicians from various specialties about their practice patterns regarding assessment of suspected ASD in individuals with DS. The survey inquired about treatment recommendations for DS + ASD and perceived barriers to connecting families with evaluations and services. Data analysis involved descriptive statistics and Mann-Whitney U tests. RESULTS:Most respondents believe diagnosing ASD in individuals with DS significantly impacts management. Challenges were reported in accessing diagnostic evaluations, with heavy reliance on highly specialised DS and ASD clinics. Communication impairment (n = 64, 65%), aggressive behaviours (n = 38, 39%), self-injurious behaviours (n = 33, 34%) and adaptive skills (n = 27, 28%) are priority targets for intervention, and applied behavioural analysis (ABA) (n = 80, 82%), speech therapy through insurance (n = 60, 61%), augmentative and alternative communication evaluation through insurance (n = 59, 60%), and occupational therapy through insurance (n = 57, 58%) are the most frequent referrals following a diagnosis of DS + ASD. All respondents identified multiple barriers to care for individuals with DS + ASD, including waitlists, insurance networks and requirements, lack of experienced providers and high turnover. CONCLUSION:This study highlighted the complexity of caring for individuals with DS + ASD, revealed the heterogeneity of practice patterns among providers, and reported multiple barriers to care for this underserved patient population. Results should prompt work aimed at redressing barriers to care and additional research in the field of effective interventions for individuals with DS + ASD.

Abstract Background Preterm birth remains a significant global health concern, with long-term outcomes closely linked to postnatal growth trajectories. Data regarding the timing of catch-up growth in preterm infants from Middle Eastern populations are limited. This study aimed to assess the time required to achieve catch-up weight and to characterize postnatal growth trajectories across birth-weight categories at a tertiary care hospital in Riyadh, Saudi Arabia. Methods This retrospective cohort study included 134 preterm infants (< 37 weeks’ gestational age) and 193 term infants born between January 2018 and early 2019 at King Saud University Medical City. Anthropometric measurements were recorded at predefined intervals up to 24 months of corrected age. Growth was evaluated using sex-specific Z-scores based on WHO Child Growth Standards. Catch-up growth was defined as a Z-score increase > 0.67 between two consecutive time points. Longitudinal weight and length trajectories were analyzed using linear mixed-effects models with subject-specific random intercepts and a first-order autoregressive covariance structure, with adjusted estimated marginal means derived over time. Reporting followed the STROBE statement for cohort studies. Results Preterm infants had significantly lower birth weight (1.72 ± 0.60 kg vs. 2.97 ± 0.66 kg; p < 0.001) and birth length (40.65 ± 5.36 cm vs. 48.27 ± 3.55 cm; p < 0.001) compared with term infants. In mixed-effects models, preterm infants had lower adjusted weight overall ( p = 0.006), but the group-by-age interaction was not significant ( p = 0.271), indicating parallel weight gain over time. For length, a significant group-by-age interaction ( p < 0.001) indicated that linear-growth trajectories differed between groups, with preterm infants remaining shorter throughout follow-up. Weight-for-age Z-scores converged across birth-weight categories by 24 months. Catch-up growth rates were highest among very low birth weight infants (31.8% by 24 months). Conclusions Preterm infants demonstrate significant early growth deficits with weight catch-up achieved within the first year of corrected age, while linear growth recovery extends closer to 24 months. These findings underscore the importance of vigilant growth monitoring and individualized nutritional strategies during early infancy.