Germline gain-of-function (GOF) variants in ABL1 cause congenital heart defects and skeletal malformations syndrome (CHDSKM), a multisystem developmental disorder characterized by congenital heart disease, skeletal abnormalities, dysmorphic features, and variable developmental delay. More recently, biallelic loss-of-function variants and ABL haploinsufficiency have been associated with distinct phenotypes, expanding the allelic spectrum of ABL1-related disorders. We report three individuals with ABL1 variants. A female infant with tetralogy of Fallot, critical pulmonary stenosis, covered omphalocele, and a lethal outcome was found by rapid trio genome sequencing to harbor a de novo likely pathogenic ABL1 variant, NM_007313.2:c.354G>T p.(Trp118Cys). We also provide updated clinical follow-up of a previously reported individual and describe a third individual, both carrying the recurrent p.(Tyr245Cys) variant. Functional studies were performed and support a GOF mechanism. Similar activation was observed for Tyr245Cys despite the differences in clinical severity. Our findings expand the phenotypic spectrum of ABL1-related CHDSKM to include severe conotruncal heart disease and covered omphalocele. The comparison of two biochemically activating ABL1 variants demonstrates substantial clinical variability despite a shared molecular mechanism. Furthermore, the overlap between ventral body wall abnormalities in GOF disease and omphalocele associated with ABL1 haploinsufficiency suggests that precise regulation of ABL1 signaling is critical for normal ventral body wall formation.

BACKGROUND:Hypochondroplasia, a fibroblast growth factor receptor 3 (FGFR3)-related skeletal condition characterized by disproportionate short stature and a spectrum of clinical features, has no available targeted therapies. Vosoritide, a C-type natriuretic peptide analogue approved for the treatment of achondroplasia, is being investigated for hypochondroplasia. METHODS:In this phase 3, multicenter trial, children with hypochondroplasia who were 3 to less than 18 years of age were randomly assigned to receive once-daily subcutaneous injections of vosoritide or placebo for 52 weeks per weight-band dosing regimen. The primary end point was change from baseline in annualized growth velocity at week 52 versus placebo. Confirmatory statistical testing using hierarchical procedures to control for type I error at the one-sided 0.025 significance level (equivalent to the two-sided 0.05 level) was performed for the primary and six key secondary efficacy end points. The safety and side effect profile of vosoritide versus placebo was assessed. RESULTS:A total of 81 participants were randomly assigned to receive vosoritide (n=41) or placebo (n=40). At week 52, the least squares mean (LSM) change from baseline in annualized growth velocity was 1.95 cm/year with vosoritide versus -0.39 cm/year with placebo (LSM difference of 2.33 cm/year; 95% confidence interval, 1.85-2.82 cm/year; two-sided P<0.0001). Most participants in the vosoritide group (87.8%) and the placebo group (72.5%) experienced at least one adverse event (AE). There were no reports of grade 3 or higher AEs, AEs leading to treatment discontinuation, or deaths. CONCLUSIONS:One year of vosoritide treatment significantly increased linear growth in children with hypochondroplasia. (Funded by BioMarin Pharmaceutical; ClinicalTrials.gov number, NCT06455059.).

BACKGROUND:Children and youth with neurofibromatosis type 1 (NF1) commonly experience motor, behavioral, and cognitive problems. Promising findings from an NF1 mouse model suggested that the antioxidant N-acetylcysteine (NAC) might address underlying mechanistic deficits. METHODS:We conducted a 12-week (8-week treatment, 4-week washout), double-blind, placebo-controlled randomized trial of NAC in 8-16-year-olds with NF1. We screened 481 children, identified 203 eligible, and randomized 25; 23 received at least one dose (10 NAC at ∼70 mg/kg/day; 13 placebo). Outcomes were safety, tolerability, motor function (primary: Physical and Neurological Examination for Subtle Signs), cognitive function (secondary: attention deficit/hyperactivity disorder symptom scores and executive function measures), and exploratory biomarkers (transcranial magnetic stimulation and magnetic resonance spectroscopy measures). RESULTS:In the modified intention to treat analysis, no significant difference in Physical and Neurological Examination for Subtle Signs was observed between groups. In completer analyses, NAC did not improve any secondary or exploratory outcome at 8 weeks. NAC was generally well tolerated, although two participants were withdrawn by parents because of worsening behavior. Test-retest reliability of scales, measures, and biomarkers over 12 weeks was generally moderate. CONCLUSIONS:NAC was generally well tolerated but did not improve motor or behavioral outcomes in youth with NF1. Larger, longer trials with preceding dose-escalation and target-engagement studies are needed to evaluate new therapies.

Pathogenic missense variants in PRKACA cause craniofacial, skeletal, and cardiac defects similar to Ellis-van Creveld syndrome. We report an individual with a previously unreported, de novo 3-amino-acid deletion in PRKACA, identified on trio genome sequencing, and phenotypic features including severe neonatal hypotonia, appendicular skeletal abnormalities, osteopenia, aortic dilation, coronary dilation, and vascular tortuosity. To assess this variant's effects, we performed in vitro and in vivo studies, generated an in silico model, and assessed cell ciliation in induced pluripotent stem cells from the patient. Although the protein product of the PRKACA (Protein kinase A [PKA]-Cα) 3-amino-acid-deletion variant is catalytically active, it shows reduced interaction with the regulatory subunits of PKA (particularly type II), resulting in overactivation of the PKA pathway and/or an inability to initiate Hedgehog signaling. The deletion affects a key portion of PKA-C important for substrate tethering. Patient-derived induced pluripotent stem cells (iPSCs) have reduced ciliation compared to controls. Collectively, this supports that the PRKACA variant is pathogenic, and we propose that it is causal for our patient's unique skeletal dysplasia and vasculopathy phenotypes. This expands the phenotypic spectrum of pathogenic variants in PRKACA and suggests that affected individuals may require periodic screening for aortic and coronary dilation as well as osteopenia.

BACKGROUND:Phenylketonuria (PKU) is an inborn error of metabolism caused by phenylalanine hydroxylase (PAH) deficiency. Sepiapterin, the most recently FDA-approved therapeutic for PKU, is indicated for sepiapterin-responsive PKU in individuals >1 month of age. Real-world experience is needed to characterize clinical impact across patient subsets. METHODS:A retrospective chart review was conducted for PKU patients at Lurie Children's Hospital prescribed sepiapterin from August 2025 through January 2026. Baseline characteristics, genotypic phenotype values (GPV), historical sapropterin responsiveness, and treatment outcomes were analyzed. RESULTS:Of 63 patients prescribed sepiapterin, 53 initiated treatment. The cohort included 34 sapropterin-responsive, 12 non-sapropterin-responsive, and 7 treatment-naïve patients. Of 50 patients who submitted blood samples, 76% (n = 38) responded to sepiapterin. Mean Phe reductions were 46% (GPV ≤2.7), 53% (GPV 2.8-6.6), and 41% (GPV >6.6). Notably, a mean 46% reduction occurred in sapropterin-responsive patients already receiving sapropterin. Within the non-sapropterin responsive cohort 27% (3/11) had a mean blood Phe reduction ≥15% (16%-76%; mean 56%). Dietary liberalization occurred in 64% of patients, with 88% increasing natural protein intake and 5 patients discontinuing medical nutrition therapy. The discontinuation rate was 10% due to inadequate response. Side effects were predominantly gastrointestinal (loose stools 8%, abdominal pain 9%). CONCLUSIONS:Real-world experience with sepiapterin demonstrates a 76% response rate in the group of PKU patients tested which included a disproportionate number of sapropterin-responsive subjects. Clinical benefit was observed in individuals across the PKU severity spectrum, including a proportion of patients with classical PKU and those historically non-responsive to cofactor therapy. The favorable safety profile and potential for dietary liberalization support sepiapterin as a valuable treatment option for individuals with PKU.

This multi-institutional, natural language processing-based analysis of 273 children with neurofibromatosis 1-associated optic pathway gliomas examines the impact of ancestral background on clinical presentation and progression. We report that White children had a greater prevalence of optic pathway glioma than Black or Asian children, but clinical features and outcomes did not differ across groups.

Germline pathogenic variants that activate the Ras/mitogen-activated protein kinase (MAPK) pathway cause neurodevelopmental disorders called 'Rasopathies'. Because many affected proteins directly regulate Ras, causative mutations may alter other Ras-dependent pathways in addition to MAPK signaling. To better understand which Rasopathy sequelae result from hyperactivation of downstream MAP kinases, we engineered mice with a gain-of-function mutation in the terminal MAP kinase gene Mapk1, which encodes ERK2 and is associated with the recently described genetic syndrome MAPK1-related Rasopathy (MRR). Mapk1 mutant mice successfully modeled key aspects of the human MRR phenotype, including small stature, facial dysmorphism, and impaired cognitive function. Importantly, they recapitulated phenotypes identified in Rasopathy models with upstream Ras activation, such as neurofibromatosis type 1 (NF1): oligodendrocyte lineage defects, reactive astrogliosis, memory deficits, and hypersensitivity to sensory stimuli. These findings emphasize the importance of downstream MAPK signaling in the pathophysiology of neurocognitive symptoms observed in Rasopathy syndromes.

Pathogenic variants in LZTR1 are an established cause of Noonan syndrome (NS) and uniquely exhibit both autosomal dominant (AD) and autosomal recessive (AR) inheritance. However, the phenotypic spectrum and genotype-phenotype correlations remain incompletely defined. We conducted a multi-center retrospective chart review of patients diagnosed with LZTR1-NS evaluated at three tertiary care centers. Clinical, molecular, and imaging data were systematically collected. A comprehensive literature review (2015-2025) identified 100 additional individuals meeting inclusion criteria. Comparative analyses were performed to evaluate phenotypic patterns by inheritance. Among 21 previously unreported patients aged 6 months to 49 years, 15 had AD NS and 6 had AR NS. Clinical features were largely consistent with prior reports, including high prevalence of craniofacial dysmorphism, neurodevelopmental and multisystem involvement. Cardiac manifestations were frequent, with pulmonary valve stenosis as the most common lesion. Hypertrophic cardiomyopathy appeared more prominent among AR NS. Notably, lymphatic abnormalities were observed at a higher frequency than previously reported. Compared to the literature, our cohort highlights novel findings, including the co-occurrence of AD LZTR1-NS with 22q11.2 deletion and two patients with AR NS with features suggestive of schwannomatosis. These findings expand the clinical spectrum of LZTR1-NS and have important implications for diagnosis, surveillance, and genetic counseling.

PURPOSE OF REVIEW:Noonan syndrome and related disorders (RASopathies) affect ~1 in 2000 individuals and are associated with a wide range of phenotypic manifestations. It is highly likely that pediatricians and other pediatric subspecialists will encounter multiple patients with these diagnoses in their clinical practice. It is important that pediatric providers recognize common diagnostic features and are informed regarding recent advances in diagnosis and emerging treatment options for patients with these conditions. RECENT FINDINGS:Major themes of research articles published about RASopathies in the past 18 months include the utilization of pathway targeted drugs such as trametinib for treatment-refractory cardiac and lymphatic manifestations, emerging genotype-phenotype correlations, and detailed characterization of neurologic manifestations. SUMMARY:The potential for pathway targeted therapy, with increasing reported use of trametinib for severe cardiac and lymphatic manifestations of RASopathies, exemplifies the importance of recognizing RASopathy diagnoses and of clearly defining natural history and treatment endpoints. Further refinement of genotype-phenotype correlations and the phenotypic spectrum, particularly the delineation of neurologic manifestations clinically and radiographically, are likely to be areas of significant knowledge growth in upcoming years.

Retrotransposition has generated thousands of intronless gene copies in mammalian genomes, yet their contribution to brain development and evolution remains largely unexplored. Here we uncover a critical role for RBMX retrocopy in shaping neurodevelopment and modulating disease. Pathogenic variants in RBMX , an X-linked splicing regulator, cause intellectual disability, microcephaly, and cortical malformations. Through integrated human genetic, cellular, and mouse model studies, we show that RBMX pathogenic variants disrupt cortical development through both loss- and gain-of-function mechanisms. Surprisingly, despite severe phenotypes in humans, Rbmx -deficient mice display only mild cortical abnormalities, a discrepancy likely due to compensation by Rbmxl1 , a retrocopy that arose independently in mice and humans. We demonstrate that RBMX and RBMXL1 share protein and RNA partners and act redundantly in brain development, with RBMXL1 buffering the impact of RBMX deficiency. These findings establish retrocopies as functional paralogs safeguarding neurodevelopment, and suggest that functional RBMX retrocopy could contribute to the robustness and evolutionary diversification of mammalian brain.

NF1-related bone dysplasia in children and young adults with neurofibromatosis type 1 (NF1) involving the sacroiliac joint has been rarely described. We report four participants who underwent whole-body magnetic resonance imaging (WB-MRI) as part of a longitudinal imaging and plexiform neurofibroma (PN) biomarker study (NCT05238909) at Ann & Robert H. Lurie Children's Hospital of Chicago in collaboration with the National Institutes of Health. The four participants were aged 12, 17, 32, and 34 at the time of WB-MRI; three out of four were female. In cases 1 through 3, there was an underlying internal PN on the side of sacroiliac dysplasia. All cases were unilateral and intraarticular, and two involved subcutaneous tissue. The PNs were too small to measure in two cases. Among the measurable lesions, one was localized, and one was diffuse with extension into the lower extremity. The localized PN showed a 20% increase in size over a one-year follow-up period. In cases 1 through 3, no sequelae such as pain or fractures were observed during the follow-up period. Case 4 was referred for surgical evaluation due to persistent pain. Our findings highlight a potentially underreported developmental abnormality of the sacroiliac joint in individuals with NF1.

The calcium/calmodulin-dependent protein kinase type 2 (CAMK2) family consists of four different isozymes, encoded by four different genes-CAMK2A, CAMK2B, CAMK2G, and CAMK2D-of which the first three have been associated recently with neurodevelopmental disorders. CAMK2D is one of the major CAMK2 proteins expressed in the heart and has been associated with cardiac anomalies. Although this CAMK2 isoform is also known to be one of the major CAMK2 subtypes expressed during early brain development, it has never been linked with neurodevelopmental disorders until now. Here we show that CAMK2D plays an important role in neurodevelopment not only in mice but also in humans. We identified eight individuals harboring heterozygous variants in CAMK2D who display symptoms of intellectual disability, delayed speech, behavioral problems, and dilated cardiomyopathy. The majority of the variants tested lead to a gain of function (GoF), which appears to cause both neurological problems and dilated cardiomyopathy. In contrast, loss-of-function (LoF) variants appear to induce only neurological symptoms. Together, we describe a cohort of individuals with neurodevelopmental disorders and cardiac anomalies, harboring pathogenic variants in CAMK2D, confirming an important role for the CAMK2D isozyme in both heart and brain function.

BACKGROUND:In 2015, Illinois added Fabry disease to the newborn screening (NBS) panel, and numerous individuals who have the controversial p.A143T GLA variant were identified. Ann & Robert H. Lurie Children's Hospital of Chicago identified 80 individuals with this variant. SUMMARY:Of the 80 individuals, 34/80 were identified by NBS, 2/80 were identified by gene panel testing, and 44/80 were identified by cascade testing. These individuals were from 36 families and ranged in age from 7 months to 71 years. Most individuals identified by NBS were male (90.9%) and 35.96% had the p.A143T variant. All newborns with known pathogenic or likely pathogenic variants in GLA had enzyme leukocyte activities below 20% of the percentage of mean of normal. This threshold could serve as a guideline for determining risk of symptom development for p.A143T and other variants of unknown significance. No person with p.A143T had significant lyso-GL3 elevation in this cohort. KEY MESSAGES:These data suggest the variant impacts enzyme levels, but its effect on health outcomes remains unclear. We further characterize clinical and biochemical data on individuals with the p.A143T GLA variant to help provide guidance on its clinical significance.

Non-ketotic hyperglycinemia (NKH) is a rare autosomal recessive disorder caused by defects in the mitochondrial glycine cleavage system, most commonly involving variants in GLDC. Clinical presentation is heterogeneous, ranging from severe neonatal encephalopathy with intractable epilepsy to attenuated forms with variable neurodevelopmental outcomes. We conducted a comprehensive clinical, biochemical, molecular, and genealogical analysis of eight Colombian patients with NKH, all of whom shared ancestry from the Paisa population. All patients were born at term after uncomplicated pregnancies and presented in the neonatal period with hypotonia, lethargy, feeding difficulties, and treatment-resistant seizures. Elevated glycine levels were detected in plasma for all patients and cerebrospinal fluid in three cases. Molecular testing identified the same homozygous GLDC variant (NM_000170.3:c.2714 T>G; p.Val905Gly) in all individuals. Although no consanguinity was reported, shared surname and regional ancestry suggested intra- and interfamilial isonymy, raising the possibility of a founder effect. Clinical outcomes varied despite the implementation of early supportive interventions. This is the first report of a recurrent GLDC variant in Colombian patients, supporting a potential founder effect in the Paisa population. These findings highlight the importance of regional genetic studies in enhancing diagnostic precision and guiding population-specific strategies for rare disease management.

Smith-Kingsmore syndrome (SKS) is a rare autosomal dominant condition characterized by neurodevelopmental differences, macrocephaly/megalencephaly, describable facial features, sleep-wake abnormalities, hyperphagia, and overgrowth. SKS is caused by pathogenic gain-of-function variants in MTOR which lead to hyperactivation of the mTOR pathway. In this review, we discuss the history, epidemiology, molecular basis, clinical features, and management considerations for Smith-Kingsmore syndrome. In addition, we provide insight on early developmental milestones through a report on 14 individuals with a confirmed diagnosis of SKS. Among these individuals, 8/12 (67%) achieved crawling at an average age of 23 months, 9/14 (64%) achieved walking with an average age of 32 months, 5/9 (56%) achieved a pincer grasp at an average age of 23 months, 8/12 (67%) achieved the ability to use a device or utensil with an average age of 3.4 years, 10/13 (77%) achieved babbling at an average age of 20 months, 8/14 (57%) achieved their first word at an average age of 34 months, and 4/14 (29%) achieved the use of short phrases at an average age of 4.6 years. This review highlights advances in characterizing the natural history of SKS since it was first described 12 years ago and the need for additional research to inform genotype-phenotype correlations and targeted therapies to support individuals with SKS.

The UNC13A gene encodes a presynaptic protein that is crucial for setting the strength and dynamics of information transfer between neurons. Here we describe a neurodevelopmental syndrome caused by germline coding or splice-site variants in UNC13A. The syndrome presents with variable degrees of developmental delay and intellectual disability, seizures of different types, tremor and dyskinetic movements and, in some cases, death in early childhood. Using assays with expression of UNC13A variants in mouse hippocampal neurons and in Caenorhabditis elegans, we identify three mechanisms of pathogenicity, including reduction in synaptic strength caused by reduced UNC13A protein expression, increased neurotransmission caused by UNC13A gain-of-function and impaired regulation of neurotransmission by second messenger signalling. Based on a strong genotype-phenotype-functional correlation, we classify three UNC13A syndrome subtypes (types A-C). We conclude that the precise regulation of neurotransmitter release by UNC13A is critical for human nervous system function.