Low Gamma-Glutamyl Transferase Cholestasis in a Patient With X-Linked Myotubular Myopathy and Crohn's Disease.

X-linked myotubular myopathy (XLMTM) is a neuromuscular disorder manifesting at birth with hypotonia and respiratory distress. We describe the XLMTM case presenting at birth who developed normal gamma-glutamyl transferase cholestasis at 1 year of age. He was also diagnosed with Crohn's disease 4 years later. His cholestasis could be attributed to progressive familial intrahepatic cholestasis (PFIC) or primary sclerosing cholangitis in the setting of Crohn's disease. However, genetic testing ruled-out PFIC, and his radiographic and liver biopsy findings were not suggestive of primary sclerosing cholangitis. We believe that this cholestasis is related to XLMTM leading to a PFIC-like state.

Metabolic-Associated Fatty Liver Disease in Childhood and Adolescence.

Metabolic-associated fatty liver disease (MAFLD) has become the most common cause for chronic liver disease among children and adolescents globally. Although liver biopsy remains the gold standard for diagnosis, emerging technology, like velocity controlled transient elastography, a noninvasive method, is being utilized to evaluate degree of fibrosis in these patients. The discovery of multiple gene polymorphisms has brought new hope for possible treatment targets. However, this research is still ongoing, making lifestyle changes and weight reduction the current mainstay of treatment. This review briefly reviews the most recent data regarding the epidemiology, pathophysiology, diagnostic modalities, and treatment of pediatric MAFLD.

Longitudinal Analysis of Cancer Risk in Children and Adults With Germline PTEN Variants.

Importance: Identifying hereditary cancer predisposition facilitates high-risk organ-specific cancer surveillance and prevention. In PTEN hamartoma tumor syndrome (PHTS), longitudinal studies remain lacking, and there are insufficient data on cancers in children and young adults, as well as individuals with neurodevelopmental disorders (NDD). Objective: To evaluate lifetime cancer risks, including second malignant neoplasms (SMN), among patients with PHTS. Design, Setting, and Participants: Prospective longitudinal cohort study (September 1, 2005, through January 6, 2022). General population risks from the Surveillance, Epidemiology, and End Results database. Patients with PHTS, molecularly defined as carrying germline PTEN variants, were accrued from community and academic medical centers throughout North America, South America, Europe, Australia, and Asia. Data were analyzed from July 2022 to February 2023. Exposures: Review of physical and electronic medical records, and follow-up through clinical visits or telephone interviews. Main Outcomes and Measures: Lifetime cancer risks in PHTS relative to the general population. Results: A total of 7302 patients were prospectively accrued, 701 of whom had germline PTEN variants (median [IQR] age at consent, 38 [12-52] years; 413 female patients [59%]). Longitudinal follow-up data could be obtained for 260 patients (37%), with a median (IQR) follow-up of 4 (2-8) years. Of the 701 patients, 341 (49%) received at least 1 cancer diagnosis, with 144 (42%) of those having SMN. The study found significantly elevated lifetime risks for breast (91%), endometrial (48%), thyroid (33%), kidney (30%), and colorectal cancers (17%), as well as melanoma (5%). Cancer diagnoses were also observed in children and young adults with PHTS (15%) and in patients with PHTS with neurodevelopmental disorders (11%). Elevated risks (P < .001) of thyroid (age-adjusted standardized incidence ratios [SIR], 32.1; 95% CI, 26.0-39.0), kidney (SIR, 26.5; 95% CI, 18.8-36.3), endometrial (SIR, 26.0; 95% CI, 19.5-34.1), breast (SIR, 20.3; 95% CI, 17.3-23.7), and colorectal (SIR, 7.9; 95% CI, 5.2-11.7) cancers, and melanoma (SIR, 6.3; 95% CI, 3.5-10.5) were observed. Of the 341 patients with PHTS with cancer, 51 (15%) had 1 or more cancers diagnosed at age 29 years or younger, and 16 (31.4%) of those developed SMN at final follow-up. Twenty-three patients with PHTS with NDD and cancer were identified, with 5 (22%) having developed SMN at final follow-up. Individuals with PHTS and NDD showed higher lifetime cancer risks compared with individuals with PHTS but without NDD (hazard ratio, 2.7; 95% CI, 1.7-4.2; P < .001). Conclusions and Relevance: This cohort study found consistently elevated lifetime cancer risks in PHTS. Organ-specific surveillance should continue in patients with PHTS. Additional study is required to ascertain elevated cancer risks in patients with PHTS with NDD.

Glycogen storage disease type 1a in the Ohio Amish.

Glycogen storage disease type 1a (GSD1a) is an inborn error of glucose metabolism characterized by fasting hypoglycemia, hepatomegaly, and growth failure. Late complications include nephropathy and hepatic adenomas. We conducted a retrospective observational study on a cohort of Amish patients with GSD1a. A total of 15 patients cared for at a single center, with a median age of 9.9 years (range 0.25-24 years) were included. All patients shared the same founder variant in GCPC c.1039 C > T. The phenotype of this cohort demonstrated good metabolic control with median cohort triglyceride level slightly above normal, no need for continuous overnight feeds, and a higher quality of life compared to a previous GSD cohort. The most frequent complications were oral aversion, gross motor delay, and renal hyperfiltration. We discuss our unique care delivery at a single center that cares for Amish patients with inherited disorders.

Heterozygous CTLA4 splice site mutation c.458-1G > C presenting with immunodeficiency and variable degree of immune dysregulation in three generation kindred of Caribbean descent.

Cytotoxic T-lymphocyte-associated protein 4 (CTLA4) is an immune checkpoint, which downregulates T cell activation and T regulatory cell function. CTLA4 haploinsufficiency (CTLA4 HI) leads to T cell hyperactivation, immunodeficiency and variable degree of immune dysregulation. Furthermore, CTLA4 HI predisposes affected individuals to development of various cancers. Less well understood is the penetrance and expressivity of CTLA4 mutations. We describe five members of a single family with heterozygous CTLA4 splice site mutation c.458-1G > C, previously shown to result in CTLA-4 HI, who presented with immunodeficiency and variable degree of immune dysregulation. The host, environmental and the epigenetic factors affecting the penetrance and expressivity of CTLA4 mutations merits further investigation.

Vascular anomalies associated with hepatic shunting.

Congenital vascular anomalies affecting the liver have been described in the scientific literature for decades. Understanding these malformations begins with knowledge of hepatic vascular embryology. Surgeons have applied numerous classification systems to describe both intrahepatic and extrahepatic shunts, which can confuse the reader and clinician. In our experience, focusing on one classification system for extrahepatic shunts and one for intrahepatic shunts is better. Today many patients with these shunts carry good long-term prognosis thanks to advances in imaging to better detect shunts earlier and classify them. Timely intervention by skilled radiologists and surgeons have also limited complications arising from dynamic shunts and can avoid a liver transplant. Congenital hepatic shunts are not the only vascular condition affecting the liver. Hereditary hemorrhagic telangiectasia, also known as Osler Weber Rendu syndrome, particularly type 2, may have varying severity of hepatic involvement which warrants longitudinal care from an experienced hepatologist. Lastly, congenital hemangiomas, often first identified on the skin and oral mucosa, also can affect the liver. While most will resolve in infancy and childhood, the pediatric hepatologist must understand how and when to treat persistent lesions and their complications. This article serves as a concise reference to help clinicians better care for patients with these rare conditions.

A Review of Autoimmune Enteropathy and Its Associated Syndromes.

Autoimmune enteropathy is an extremely rare condition characterized by an abnormal intestinal immune response which typically manifests within the first 6 months of life as severe, intractable diarrhea that does not respond to dietary modification. Affected individuals frequently present with other signs of autoimmunity. The diagnosis is made based on a characteristic combination of clinical symptoms, laboratory studies, and histological features on small bowel biopsy. Autoimmune enteropathy is associated with a number of other conditions and syndromes, most notably immunodysregulation polyendocrinopathy enteropathy X-linked (IPEX) syndrome and autoimmune polyglandular syndrome type 1 (APS-1). Diagnosis and treatment is challenging, and further research is needed to better understand the pathogenesis, disease progression, and long-term outcomes of these conditions.

Incidence Trends, Comorbidities, and Outcomes of Pyogenic Liver Abscess Among Children: A Nationwide Population-based Analysis.

OBJECTIVES: Population-based analysis of incidence, comorbid conditions, microbiological characteristics, and outcomes of pyogenic liver abscess (PLA) in children. METHODOLOGY: Retrospective analysis of National Inpatient Sample (NIS) and Kids Inpatient database (KID) database from 2003 to 2014 and included patients between 1 and 20 years of age. Using ICD-9 codes, we identified all hospitalizations with PLA and compared them with 1 : 10 age- and gender-matched controls. Amebic liver abscess and Candida infections were excluded. RESULTS: Total number of PLA admissions is 4075. The overall incidence of PLA is 13.5 per 100,000 hospitalizations, which increased by 60% between 2003 and 2014. The mean age of patients was 13.03 ±â€Š6.1 years and were predominantly boys-61%. Of the comorbid conditions, hepatobiliary malignancy had the highest odds ratio (OR 71.8) followed by liver transplant (OR 38.4), biliary disease (OR 29.9), inflammatory bowel disease (IBD) (OR 5.35), other GI malignancies (OR 4.74), primary immune deficiency disorder (OR 4.13). Patients with PLA had 12 times increased odds of having associated severe sepsis. Infective endocarditis (IE) (OR 4.5), appendicitis (OR 1.8), and diverticulitis (OR 8.1) were significantly associated with PLA. Almost 39% (1575) of the PLA patients had positive culture, whereas Streptococcus (10.8%) and Staphylococcus spp (9.2%) were the most common pathogens. About 45% of PLA patients underwent percutaneous liver abscess aspiration whereas 4.1% had hepatic resection for PLA. The mortality rate of PLA was 0.8% (n = 32). CONCLUSIONS: The incidence of PLA is steadily increasing over the last decade among pediatric population in the United States. Hepatobiliary malignancy and liver transplant are the most common comorbid conditions associated with PLA.

Increased Needs for Copper in Parenteral Nutrition for Children in the Neonatal Intensive Care Unit With an Ostomy.

BACKGROUND: Copper (Cu) is an essential trace element, with deficiency causing anemia, neutropenia, and other abnormalities. Cu is mainly absorbed in the small intestine. Patients with intestinal failure or jejunostomy have increased Cu losses and require additional Cu supplementation in parenteral nutrition (PN). The American Society for Clinical Nutrition standards for trace element recommendations in PN, including Cu, were created in 1988, and the American Society for Parenteral and Enteral Nutrition currently follows the same recommendations. METHODS: Patients admitted to the neonatal intensive care unit for surgical intervention resulting in an ostomy (ileal or jejunal) were included in this retrospective study. Patients received PN support with Cu dosed individually, rather than in a multi-trace element package. Cu and ostomy output were analyzed daily. Serum Cu was obtained 2 months postsurgical intervention. RESULTS: Out of the 7 patients enrolled, 71% had low serum Cu. Weekly mean Cu intake for all 7 patients ranged from 5.3 to 154.8 µg/kg/day from enteral and parenteral sources, with individual mean weekly Cu intake ranging from 18.9 to 74.4 µg/kg/day from surgical intervention to 2 months post-surgery. Patients' weekly ostomy outputs ranged from 0 mL/kg/day to 77.2 mL/kg/day, with individual mean weekly output ranging from 3.7 to 41.6 mL/kg/day. CONCLUSION: Providing 20 µg/kg/day of Cu in PN to neonates with ostomies is insufficient to prevent Cu deficiency. Further studies are warranted to determine an optimal dosage of parenteral Cu to prevent Cu deficiency.

Pediatric Inflammatory Myofibroblastic Tumor of the Liver: A Rare Cause of Portal Hypertension.

Hepatic inflammatory pseudotumors or myofibroblastic tumors are benign neoplasms rarely seen in children. We report a case of a previously healthy 10-year-old girl with prolonged fever and abdominal pain who was found to have hepatosplenomegaly and pancytopenia. Imaging revealed a periportal mass along with thrombosis of portal vein and splenomegaly. Liver biopsy showed normal hepatic architecture with no evidence of cirrhosis. She underwent endoscopic banding of esophageal varices. Biopsy of the mass was suggestive of inflammatory myofibroblastic tumor without malignant changes. She has been successfully managed with nonsteroidal anti-inflammatory drug and pulse steroids with resolution of symptoms and decrease in size of the tumor with more than 2 years of follow-up.

Management of Five Hundred Patients With Gut Failure at a Single Center: Surgical Innovation Versus Transplantation With a Novel Predictive Model.

OBJECTIVE(S): To define the evolving role of integrative surgical management including transplantation for patients gut failure (GF). METHODS: A total of 500 patients with total parenteral nutrition-dependent catastrophic and chronic GF were referred for surgical intervention particularly transplantation and comprised the study population. With a mean age of 45 ±â€Š17 years, 477 (95%) were adults and 23 (5%) were children. Management strategy was guided by clinical status, splanchnic organ functions, anatomy of residual gut, and cause of GF. Surgery was performed in 462 (92%) patients and 38 (8%) continued medical treatment. Definitive autologous gut reconstruction (AGR) was achievable in 378 (82%), primary transplant in 42 (9%), and AGR followed by transplant in 42 (9%). The 84 transplant recipients received 94 allografts; 67 (71%) liver-free and 27 (29%) liver-contained. The 420 AGR patients received a total of 790 reconstructive and remodeling procedures including primary reconstruction, interposition alimentary-conduits, intestinal/colonic lengthening, and reductive/decompressive surgery. Glucagon-like peptide-2 was used in 17 patients. RESULTS: Overall patient survival was 86% at 1-year and 68% at 5-years with restored nutritional autonomy (RNA) in 63% and 78%, respectively. Surgery achieved a 5-year survival of 70% with 82% RNA. AGR achieved better long-term survival and transplantation better (P = 0.03) re-established nutritional autonomy. Both AGR and transplant were cost effective and quality of life better improved after AGR. A model to predict RNA after AGR was developed computing anatomy of reconstructed gut, total parenteral nutrition requirements, cause of GF, and serum bilirubin. CONCLUSIONS: Surgical integration is an effective management strategy for GF. Further progress is foreseen with the herein-described novel techniques and established RNA predictive model.

Health-related quality of life in children with autoimmune liver disease.

BACKGROUND AND AIM: Health-related quality of life (HRQOL), a pivotal outcome indicator of health care interventions, has not been evaluated in children with autoimmune liver disease (AILD). The aim of this study was to determine HRQOL in children with AILD and the factors affecting it. METHODS: The Pediatric Quality Of Life Inventory, generic core scale, was used to collect HRQOL data on children with AILD. Specific liver disease-related questions were added. RESULTS: Survey responses were received from 30 of 40 patients. Patients' mean age at diagnosis was 11.6 ± 4.5 years, with M:F ratio of 1:1.3, and AILD for average of 4.6 ± 4.3 years. Seventy-three percent of patients had advanced liver disease. Mean overall health summary scores for the group per child and parent reports were 71.6 ± 19.0 and 71.3 ± 17.1, respectively, which were lower than healthy controls: 83.9 ± 12.5 and 82.3 ± 15.6 (P = 0.002). Frequent liver-related symptoms were associated with impaired physical and school functioning by child (P = 0.034 and 0.047) and parent reports (P = 0.051 and P = 0.018). Abdominal pain, fatigue, and psychological symptoms were found to adversely affect the HRQOL. Although it was difficult to estimate the effect of individual features of advanced liver disease such as cirrhosis, history of upper gastrointestinal bleed, and portal hypertension on the HRQOL, because of a relatively small sample size, the presence of ascites revealed lower social functioning score per parent report (P = 0.036). In an analysis of patients with any of the above complications versus those without, however, children reported lower social functioning scores (P = 0.018). There were no differences in HRQOL scores in children with autoimmune hepatitis versus primary sclerosing cholangitis versus autoimmune hepatitis/primary sclerosing cholangitis overlap syndrome. CONCLUSIONS: First study to date shows that AILD in children significantly affects HRQOL, especially with frequent liver disease-related symptoms, even in early stages of disease. Findings need to be validated in larger, multicenter studies and will help practitioners understand their patients better and optimize care.

Short bowel syndrome in children: current and potential therapies.

Short bowel syndrome (SBS) reflects a state of malabsorption that occurs due to loss of a significant portion of the small bowel. The pathophysiology of SBS is determined largely by the process of adaptation, which is the innate attempt by the remnant portions of the intestine to increase fluid and nutrient reabsorption. In recent years, emphasis has been placed on intestinal rehabilitation with multidisciplinary teams as a comprehensive approach to the management of patients with SBS. In our institution, the multidisciplinary team members include pediatric gastroenterologists, pediatric surgeons, pediatric dieticians, physical therapists, occupational therapists, neonatologists (especially for patients still under their care), transplant surgeons, transplant coordinators and social workers. Parenteral nutrition plays a significant role in the management of SBS, but its use is associated with many potential complications, including cholestatic liver disease. Fish oil-based lipid emulsions have shown promise in their ability to reverse and also prevent the development of cholestasis in these patients. Clinical trials have shown that growth factors and other trophic hormones facilitate the process of adaptation. The most significant impact has been shown with the use of glucagon-like peptide-2 and its analog (teduglutide). Surgical interventions remain an important part of the management of SBS to facilitate adaptation and treat complications. Intestinal transplantation is a last resort option when the process of adaptation is unsuccessful. This review article is intended to provide an overview of the conventional and emerging therapies for pediatric SBS.

Autoimmune hepatitis in children--impact of cirrhosis at presentation on natural history and long-term outcome.

UNLABELLED: Little is known regarding the natural history of autoimmune hepatitis in children. The aims of this longitudinal cohort study were to determine the long-term prognosis of children with autoimmune hepatitis and to determine the effect of cirrhosis at presentation on survival. METHODS: Thirty-three children with autoimmune hepatitis who were seen at our institution over a 25-year period were studied retrospectively. RESULTS: The median age of diagnosis was 12.9 years (2.7-18.1) with a female predominance of 3:1. Liver biopsies showed cirrhosis in 18 (55%) patients at time of diagnosis. Patients with cirrhosis at baseline had a similar 10-year survival 85% (70-100%) to those without cirrhosis 75% (49-100%) (p=0.97). The overall survival was significantly lower than the expected in the age- and gender-matched U.S. population (log-rank test; p<0.001). In Cox regression models, weight loss (p=0.037), baseline elevated bilirubin (p=0.028), prolonged International Normalized Ratio (INR) (p=0.013), and positive LKM-1 antibodies (p=0.007) were associated with shorter survival. CONCLUSION: AIH in children is associated with a significant shorter survival rate than the expected in the general population. Cirrhosis on initial liver biopsy does not seem to impact long-term survival in children with AIH.

Severe chest pain in a pediatric ulcerative colitis patient after 5-aminosalicylic acid therapy.

Severe reactions to mesalamine products are rarely seen in pediatric patients. We report a case of a 12-year-old boy who had a severe cardiac reaction to a mesalamine product Asacol. Past medical history is significant for ulcerative colitis (UC) diagnosed at 9 years of age. Colonoscopy one week prior to admission revealed pancolitis. He was treated with Asacol 800 mg three times per day and prednisone 20 mg/d. He was subsequently admitted to the hospital for an exacerbation of his UC and started on intravenous solumedrol. He had improvement of his abdominal pain and diarrhea. The patient complained of new onset of chest pain upon initiating Asacol therapy. Electrocardiogram (ECG) revealed non-specific ST-T wave changes with T-wave inversion in the lateral leads. Echocardiogram (ECHO) revealed low-normal to mildly depressed left ventricular systolic function. The left main coronary artery and left anterior descending artery were mildly prominent measuring 5 mm and 4.7 mm, respectively. His chest pain completely resolved within 24-36 h of discontinuing Asacol. A repeat echocardiogram performed two days later revealed normal left ventricular function with normal coronary arteries (< 3.5 mm). Onset of chest pain after Asacol and immediate improvement of chest pain, as well as improvement of echocardiogram and ECG findings after discontinuing Asacol suggests that our patient suffered from a rare drug-hypersensitivity reaction to Asacol.