Glycogen storage disease type I (GSD I) is a rare disease of variable clinical severity that primarily affects the liver and kidney. It is caused by deficient activity of the glucose 6-phosphatase ...enzyme (GSD Ia) or a deficiency in the microsomal transport proteins for glucose 6-phosphate (GSD Ib), resulting in excessive accumulation of glycogen and fat in the liver, kidney, and intestinal mucosa. Patients with GSD I have a wide spectrum of clinical manifestations, including hepatomegaly, hypoglycemia, lactic acidemia, hyperlipidemia, hyperuricemia, and growth retardation. Individuals with GSD type Ia typically have symptoms related to hypoglycemia in infancy when the interval between feedings is extended to 3–4 hours. Other manifestations of the disease vary in age of onset, rate of disease progression, and severity. In addition, patients with type Ib have neutropenia, impaired neutrophil function, and inflammatory bowel disease. This guideline for the management of GSD I was developed as an educational resource for health-care providers to facilitate prompt, accurate diagnosis and appropriate management of patients.
A national group of experts in various aspects of GSD I met to review the evidence base from the scientific literature and provided their expert opinions. Consensus was developed in each area of diagnosis, treatment, and management.
This management guideline specifically addresses evaluation and diagnosis across multiple organ systems (hepatic, kidney, gastrointestinal/nutrition, hematologic, cardiovascular, reproductive) involved in GSD I. Conditions to consider in the differential diagnosis stemming from presenting features and diagnostic algorithms are discussed. Aspects of diagnostic evaluation and nutritional and medical management, including care coordination, genetic counseling, hepatic and renal transplantation, and prenatal diagnosis, are also addressed.
A guideline that facilitates accurate diagnosis and optimal management of patients with GSD I was developed. This guideline helps health-care providers recognize patients with all forms of GSD I, expedite diagnosis, and minimize adverse sequelae from delayed diagnosis and inappropriate management. It also helps to identify gaps in scientific knowledge that exist today and suggests future studies.
D‐2‐hydroxyglutaric aciduria (D‐2‐HGA) is a rare neurometabolic disease with two main subtypes, caused by either inactivating variants in D2HGDH (type I) or germline gain of function variants in IDH2 ...(type II), that result in accumulation of the same toxic metabolite, D‐2‐hydroxyglutarate. The main clinical features of both are neurologic, including developmental delay, hypotonia, and seizures. Dilated cardiomyopathy is a unique feature thus far only reported in type II. As somatic variants in IDH2 are frequently identified in several different types of cancer, including acute myeloid leukemia (AML), a link between cancer and this metabolic disease has been proposed; however, there is no reported cancer in patients with either type of D‐2‐HGA. Murine models have demonstrated how D‐2‐hydroxyglutarate alters metabolism and epigenetics, a potential mechanism by which this metabolite may cause cancer and cardiomyopathy. Here, we report the first case of both AML and dilated cardiomyopathy in a pediatric patient with D‐2‐HGA type I, who was treated with an anthracycline‐free regimen. This report may expand the clinical spectrum of this rare metabolic disease and provide insight on long‐term surveillance and care. However, this case is complicated by the presence of a complex chromosomal rearrangement resulting in a 25.5 Mb duplication of 1q41 and a 2.38 Mb deletion of 2q37.3. Thus, the direct causal relationship between D‐2‐HGA and leukemogenesis or cardiomyopathy warrants further scrutiny.
Background Chromosomal microarray analysis (CMA) provides an opportunity to understand genetic causes of congenital heart disease (CHD). The methods for describing cardiac phenotypes in patients with ...CMA abnormalities have been inconsistent, which may complicate clinical interpretation of abnormal testing results and hinder a more complete understanding of genotype–phenotype relationships. Methods and Results Patients with CHD and abnormal clinical CMA were accrued from 9 pediatric cardiac centers. Highly detailed cardiac phenotypes were systematically classified and analyzed for their association with CMA abnormality. Hierarchical classification of each patient into 1 CHD category facilitated broad analyses. Inclusive classification allowing multiple CHD types per patient provided sensitive descriptions. In 1363 registry patients, 28% had genomic disorders with well‐recognized CHD association, 67% had clinically reported copy number variants (CNVs) with rare or no prior CHD association, and 5% had regions of homozygosity without CNV. Hierarchical classification identified expected CHD categories in genomic disorders, as well as uncharacteristic CHDs. Inclusive phenotyping provided sensitive descriptions of patients with multiple CHD types, which occurred commonly. Among CNVs with rare or no prior CHD association, submicroscopic CNVs were enriched for more complex types of CHD compared with large CNVs. The submicroscopic CNVs that contained a curated CHD gene were enriched for left ventricular obstruction or septal defects, whereas CNVs containing a single gene were enriched for conotruncal defects. Neuronal‐related pathways were over‐represented in single‐gene CNVs, including top candidate causative genes NRXN3 , ADCY2 , and HCN1 . Conclusions Intensive cardiac phenotyping in multisite registry data identifies genotype–phenotype associations in CHD patients with abnormal CMA.
The disconnected (disco)‐interacting protein 2 (DIP2) gene was first identified in D. melanogaster and contains a DNA methyltransferase‐associated protein 1 (DMAP1) binding domain, Acyl‐CoA ...synthetase domain and AMP‐binding sites. DIP2 regulates axonal bifurcation of the mushroom body neurons in D. melanogaster and is required for axonal regeneration in the neurons of C. elegans. The DIP2 homologues in vertebrates, Disco‐interacting protein 2 homolog A (DIP2A), Disco‐interacting protein 2 homolog B (DIP2B), and Disco‐interacting protein 2 homolog C (DIP2C), are highly conserved and expressed widely in the central nervous system. Although there is evidence that DIP2C plays a role in cognition, reports of pathogenic variants in these genes are rare and their significance is uncertain. We present 23 individuals with heterozygous DIP2C variants, all manifesting developmental delays that primarily affect expressive language and speech articulation. Eight patients had de novo variants predicting loss‐of‐function in the DIP2C gene, two patients had de novo missense variants, three had paternally inherited loss of function variants and six had maternally inherited loss‐of‐function variants, while inheritance was unknown for four variants. Four patients had cardiac defects (hypertrophic cardiomyopathy, atrial septal defects, and bicuspid aortic valve). Minor facial anomalies were inconsistent but included a high anterior hairline with a long forehead, broad nasal tip, and ear anomalies. Brainspan analysis showed elevated DIP2C expression in the human neocortex at 10–24 weeks after conception. With the cases presented herein, we provide phenotypic and genotypic data supporting the association between loss‐of‐function variants in DIP2C with a neurocognitive phenotype.
Loeys-Dietz syndrome (LDS) results from mutations in receptors for the cytokine transforming growth factor-β leading to aggressive aortic pathology sometimes accompanied by specific phenotypic ...features including bifid uvula, hypertelorism, cleft palate, and generalized arterial tortuosity. We reviewed our adult surgical experience with LDS in order to validate current recommendations regarding management of this newly described disease.
All adult (≥ 18 years old) patients with LDS undergoing surgical treatment at a single referral institution from September 1999 to May 2013 were retrospectively reviewed.
Eleven adult LDS patients were identified by clinical criteria and genotyping. Seven (64%) experienced acute type A dissection at some point in their lives. All eventually required aortic root replacement, and 73% required multiple vascular surgical interventions. Over a mean follow-up of 65 ± 49 months, 2.8 cardiovascular procedures per patient were performed. In patients with type A dissection, a mean of 3.4 operations were performed versus 1.8 operations for patients without dissection. Total aortic replacement was required in 5 patients (45%) and 2 (18%) required neurosurgical intervention for cerebrovascular pathology. There was 1 late death from infectious complications, and no deaths from vascular catastrophe.
These results confirm the aggressive nature of LDS aortic pathology. However, the improved survival compared with earlier LDS reports suggest that aggressive treatment strategies may alter outcomes and improve the natural history of this syndrome.
To evaluate long-term survival in patients with Turner syndrome after congenital heart surgery with a focus on left heart obstructive lesions (LHOLs).
We queried the Pediatric Cardiac Care ...Consortium, a US-based registry of congenital heart surgery, for patients with Turner syndrome undergoing congenital heart surgery at <21 years of age between 1982 and 2011. Outcomes were obtained from the Pediatric Cardiac Care Consortium and from national death and transplant registries through 2019. Survival of patients with Turner syndrome and nonsyndromic patients with similar LHOL was compared by Kaplan-Meier survival curves and Cox regression adjusted for age, congenital heart disease, and era.
We identified 179 patients with Turner syndrome operated for LHOL: 161 with 2-ventricle lesions (coarctation n = 149, aortic stenosis n = 12) and 18 with hypoplastic left heart (HLH) variants. There were 157 with 2-ventricle LHOL and 6 with HLH survived to discharge. Among survivors to hospital discharge, the 30-year transplant-free survival was 90.4% for Turner syndrome with 2-ventricle lesions and 90.9% for nonsyndromic comparators (adjusted hazard ratio aHR 1.15, 95% CI 0.64-2.04). The postdischarge survival for HLH was 33% for Turner syndrome and 51% for nonsyndromic patients, with these numbers being too small for meaningful comparisons. There was a higher risk for cardiovascular disease events in patients with Turner syndrome vs male (aHR 3.72, 95% CI 1.64-8.39) and female comparators (aHR 4.55, 95% CI 1.87-11.06) excluding heart failure deaths.
The 30-year transplant-free survival is similar for patients with Turner syndrome and nonsyndromic comparators with operated 2-ventricle LHOL without excess congenital heart disease risk. However, patients with Turner Syndrome still face increased cardiovascular disease morbidity, stressing the importance of lifelong comorbidity surveillance in this population.
Loeys–Dietz syndrome (LDS) is a recently described connective tissue disorder characterized by generalized arterial tortuosity and aggressive aortopathy that untreated leads to early death even at ...aortic dimensions as small as 4 cm. We report the case of a young man with LDS successfully treated for aortic root, arch, and thoracoabdominal pathology. (J Card Surg 2010;25:223‐224)
Glycogen storage disease type III is a rare disease of variable clinical severity affecting primarily the liver, heart, and skeletal muscle. It is caused by deficient activity of glycogen debranching ...enzyme, which is a key enzyme in glycogen degradation. Glycogen storage disease type III manifests a wide clinical spectrum. Individuals with glycogen storage disease type III present with hepatomegaly, hypoglycemia, hyperlipidemia, and growth retardation. Those with type IIIa have symptoms related to liver disease and progressive muscle (cardiac and skeletal) involvement that varies in age of onset, rate of disease progression, and severity. Those with type IIIb primarily have symptoms related to liver disease. This guideline for the management of glycogen storage disease type III was developed as an educational resource for health care providers to facilitate prompt and accurate diagnosis and appropriate management of patients.
An international group of experts in various aspects of glycogen storage disease type III met to review the evidence base from the scientific literature and provided their expert opinions. Consensus was developed in each area of diagnosis, treatment, and management.
This management guideline specifically addresses evaluation and diagnosis across multiple organ systems (cardiovascular, gastrointestinal/nutrition, hepatic, musculoskeletal, and neuromuscular) involved in glycogen storage disease type III. Conditions to consider in a differential diagnosis stemming from presenting features and diagnostic algorithms are discussed. Aspects of diagnostic evaluation and nutritional and medical management, including care coordination, genetic counseling, hepatic transplantation, and prenatal diagnosis, are addressed.
A guideline that will facilitate the accurate diagnosis and appropriate management of individuals with glycogen storage disease type III was developed. This guideline will help health care providers recognize patients with all forms of glycogen storage disease type III, expedite diagnosis, and minimize stress and negative sequelae from delayed diagnosis and inappropriate management. It will also help identify gaps in scientific knowledge that exist today and suggest future studies.
Neurodevelopmental disorders are highly heterogenous conditions resulting from abnormalities of brain architecture and/or function. FBXW7 (F-box and WD-repeat-domain-containing 7), a recognized ...developmental regulator and tumor suppressor, has been shown to regulate cell-cycle progression and cell growth and survival by targeting substrates including CYCLIN E1/2 and NOTCH for degradation via the ubiquitin proteasome system. We used a genotype-first approach and global data-sharing platforms to identify 35 individuals harboring de novo and inherited FBXW7 germline monoallelic chromosomal deletions and nonsense, frameshift, splice-site, and missense variants associated with a neurodevelopmental syndrome. The FBXW7 neurodevelopmental syndrome is distinguished by global developmental delay, borderline to severe intellectual disability, hypotonia, and gastrointestinal issues. Brain imaging detailed variable underlying structural abnormalities affecting the cerebellum, corpus collosum, and white matter. A crystal-structure model of FBXW7 predicted that missense variants were clustered at the substrate-binding surface of the WD40 domain and that these might reduce FBXW7 substrate binding affinity. Expression of recombinant FBXW7 missense variants in cultured cells demonstrated impaired CYCLIN E1 and CYCLIN E2 turnover. Pan-neuronal knockdown of the Drosophila ortholog, archipelago, impaired learning and neuronal function. Collectively, the data presented herein provide compelling evidence of an F-Box protein-related, phenotypically variable neurodevelopmental disorder associated with monoallelic variants in FBXW7.
Children with complex chronic conditions (CCCs) require a disproportionate amount of inpatient resources and are at increased risk of mortality during hospital admissions. This study examines the ...impact of non-cardiac, comorbid complex chronic conditions on outcomes in children undergoing congenital heart surgery. All admissions associated with a congenital cardiac surgical procedure in the Kids’ Inpatient Database from 1997 to 2012 were examined. Children were classified by the number as well as type (genetic vs. non-genetic) of CCC. Baseline demographics as well as proportion of total inpatient days and total hospitalization charges was assessed. Multivariate regression models examining occurrence of a complication, mortality, prolonged length of stay and high hospitalization charges were constructed. In multivariate models, an increasing number of CCC was associated with increased risk of mortality and complications (mortality: 1 CCC: odds ratio (OR) = 1.17, 95 % CI = 1.03–1.33); ≥2 CCC: OR = 1.54, 95 % CI = 1.26–1.87). Additionally, the presence of a genetic CCC was protective against mortality (OR = 0.71, 95 % CI = 0.56–0.89) while non-genetic CCCs were associated with mortality (OR = 1.62, 95 % CI = 1.41–1.88) and high resource utilization. Over time, the proportion of genetic CCC remained stable while non-genetic CCC increased in prevalence. Complex chronic conditions have a varying association with mortality, morbidity and resource utilization in children undergoing congenital heart surgery. While genetic CCCs were not associated with poor outcomes, non-genetic CCCs were risk factors for morbidity and mortality. These findings suggest that pre-surgical counseling and surgical planning should account for the type of non-cardiac comorbid conditions.
PDF
