Musculoskeletal Issues in Children and Adolescents: Genetic Musculoskeletal Disorders.

Duchenne muscular dystrophy (DMD) is an X-linked recessive genetic disorder with progressive proximal weakness as the principal sign. Glucocorticoids and physical therapy are the mainstay of treatment. Exercise intolerance is the hallmark of metabolic myopathies, which require a combination of laboratory testing, electrodiagnostic testing, and muscle biopsy for diagnosis. Joint hypermobility may be an isolated finding or be associated with hypermobility Ehlers-Danlos syndrome (EDS), other variants of EDS, or marfanoid syndromes. The latter conditions are associated with aortic and cardiac valvular abnormalities. Osteogenesis imperfecta encompasses a group of disorders characterized by bone fragility presenting with a low-impact fracture as a result of minimal trauma. Management includes multidiscipline specialists. Down syndrome (DS), or trisomy 21, is the most common chromosome abnormality identified in live births. Routine evaluation of atlantoaxial instability with x-ray is no longer recommended for children with DS without symptoms of atlantoaxial instability; however, clinical evaluation of symptoms is required for sports preparticipation. Achondroplasia is the most common skeletal dysplasia. Clinical signs are macrocephaly, short limb, short stature with disproportionately shorter humerus and femur, along with characteristic findings in pelvis and lumbar spine x-rays. Caregivers should be educated on proper positioning and handling to avoid complications, including car seat-related deaths.

Diabetic mastopathy: about two cases.

Diabetic mastopathy is a rare and benign pathology affecting young individuals with type 1 diabetes or autoimmune diseases. It clinically resembles breast cancer, necessitating a histological examination for a definitive diagnosis. These cases underscore the diagnostic challenges and the importance of histological examination. This report details two cases of diabetic mastopathy at Mohammed VI Hospital in Marrakech. The first case involved a 35-year-old with type 1 diabetes and mastodynia, revealing a 4 x 3 cm nodule in the left breast. Biopsies confirmed fibrous breast tissue with lymphocytic infiltrates, characteristic of diabetic mastopathy, with no recurrence during follow-up. The second case featured a 38-year-old with trisomy 21 and type 1 diabetes presenting with a right breast abscess. Drainage revealed lymphocytic infiltrates, confirming diabetic mastopathy. Though diagnostically challenging, diabetic mastopathy lacks a direct link to breast cancer. Long-term cancer risks in affected patients mirror the general population.

JAK inhibition in Down Syndrome Regression Disorder.

Down Syndrome Regression Disorder (DRSD) is an uncommon but devastating condition affecting primarily adolescents and young adults with Down syndrome (DS). Individuals with DS display a dysregulated immune system associated with hyperactive interferon signaling, which is associated with a high incidence of autoimmune conditions. While the cause of DSRD is unknown, increasing evidence indicates that it may have an immune basis, and some individuals with DSRD have responded to intravenous immunoglobulin therapy. This case series describes three individuals with probable DSRD who received the JAK inhibitor tofacitinib and saw improvement in DSRD symptoms across multiple domains of neurological function.

Azacitidine treatment for myeloid leukemia associated with Down syndrome: A nationwide retrospective study in Japan.

Hypomethylating agent treatment for myeloid leukemia associated with Down syndrome (ML-DS) has been scarcely reported. Herein, we collected information on azacitidine treatment for ML-DS in Japan. Forty-eight cycles of azacitidine treatment were performed for 12 patients, including 11 relapsed or refractory (R/R) patients. In 40 cycles, azacitidine was used as monotherapy. No azacitidine-related death was observed. One cycle concurrently administered with methotrexate-based intrathecal therapy was discontinued due to toxicities. Only 4 of the 19 cycles given in non-remission achieved complete or partial remission. In conclusion, although most toxicities were acceptable, azacitidine monotherapy might be insufficient for R/R ML-DS cases.

Isolated pulmonary valve endocarditis in a pediatric patient with down syndrome.

BACKGROUND: Isolated pulmonary valve endocarditis (IPE) accounts for less than 2% of all infective endocarditis patients. It is commonly associated with several predisposing factors, including intravenous drug use (IVDU) and congenital heart disease. The most common causative pathogens of IPE are Staphylococcus aureus and Streptococcus viridans. We report a Down's syndrome patient with IPE and with no standard risk factors caused by the rare pathogen Acinetobacter spp. This led to respiratory failure and systemic infection due to septic pulmonary emboli. Early elective surgery was decided upon as the patient was no longer responding to medical therapy, and his clinical condition was worsening over time. CASE PRESENTATION: A 15-year-old male with Down syndrome and no underlying heart defect presented with a 3-month history of episodic fever, nausea, vomiting, and diarrhea. Transthoracic echocardiography (TTE) revealed large vegetation on the pulmonary valve leaflet, another mobile mass at the pulmonary artery bifurcation, and severe pulmonary regurgitation. Serial blood cultures isolated Acinetobacter spp. Despite initial antibiotic therapy, the patient continued to have sepsis, unresolved vegetations, and developed life-threatening complications and respiratory distress, which convinced us to perform a pulmonary valve replacement surgery with a homograft. After surgery, the patient recovered and was discharged on the ninth postoperative day (POD). CONCLUSION: This report highlights IPE's diagnostic and therapeutic challenges, alongside the importance of a comprehensive cardiopulmonary workup in patients with unexplained fever, sepsis, and pulmonary symptoms, even without typical risk factors. Based on the patient's aggravating condition despite medical treatment, early surgical intervention and pulmonary valve replacement were deemed crucial. However, there still needs to be a definitive guideline on when and how surgery should be performed in patients with complicated IPE, especially in pediatric patients.

Word of caution: early life-threatening complication linked to pulmonary flow restrictors.

A 2-month-old female (3.4 kg, 50 cm) with Down syndrome and left-to-right shunting congenital heart defects underwent an unsuccessful transcatheter ductal closure, followed by bilateral implantation of manually modified microvascular plugs (MVP-9Q) from Medtronic (Minneapolis, MN, USA), used as pulmonary flow restrictors. Post-procedure, she developed febrile respiratory distress, leading to admission to the intensive care unit. Despite initial improvement, she was readmitted with respiratory syncytial virus infection, progressing to bilateral pneumonic consolidation. Subsequent complications included pulmonary artery aneurysmal dilatation attributed to pulmonary flow restrictors, which necessitated urgent surgery two months after their implantation. The surgery involved removing the pulmonary flow restrictors and repairing the injuries to the pulmonary artery, followed by management with extracorporeal support and targeted antibiotics. The patient recovered over 12 months.

Opioid and benzodiazepine requirements in critically ill post-surgical children with down syndrome: a systematic review and meta-analysis.

BACKGROUND: Down syndrome (DS), or Trisomy 21, is defined by the existence of an additional chromosome 21. Various physiological considerations in DS patients might lead to challenges in adequate pain management and sedation after surgery. The aim of this systematic review and meta-analysis is to evaluate the variations of the requirement needed for pain management and sedation in patients with DS who have undergone surgery compared to patients without DS. METHODS: A systematic review and meta-analysis of studies were conducted, focusing on critically ill patients with DS who were admitted to Intensive care units (ICUs) post-surgery and received opioids and/or benzodiazepines. Searches were conducted in four databases from their inception to November 18, 2023 (Pubmed, Scopus, Cochrane Library, and Web of Science). The primary outcome measured was the dosage of Oral Morphine Equivalent (OME) administered in the days following surgery. Fixed-effect models were used, an approach advisable when only a limited number of studies are available. RESULTS: Out of the 992 studies initially screened, the systematic review included ten studies, encompassing 730 patients, while the meta-analysis consisted of seven studies, encompassing 533 patients. Of the seven studies included in the analysis, 298 patients were identified to have DS, and 235 patients served as controls. Patients with DS showed a slight increase in OME needs on the first day, but this increase was not statistically significant (mean difference [MD] = 0.09; 95% Confidence Interval [CI]: [-0.02, 0.20]; P = 0.11). There was also no significant difference in the requirement for Midazolam on the first day among DS patients (MD = 0.01; CI [-0.16, 0.19]; P = 0.88). In addition, the duration of mechanical ventilation was not statistically significant in patients with DS compared with the control group (MD = -1.46 hours; 95% CI [-9.74, 6.82]; P = 0.73). CONCLUSION: Patients with Down syndrome did not require more sedation or analgesia in the first three days after surgery than patients without Down syndrome. Additionally, the two groups showed no significant difference in the duration of mechanical ventilation.

Informing creation of the FEEDS Toolkit to support parent-delivered interventions for eating, drinking and swallowing difficulties in young children with neurodisability: intervention use by neurodevelopmental diagnosis and healthcare professional role.

BACKGROUND: The FEEDS (Focus on Early Eating, Drinking and Swallowing) study focused on interventions used to improve feeding for children with neurodisability and eating, drinking and swallowing difficulties (EDSD), and the outcomes viewed as important by healthcare professionals (HPs) and parent carers. The FEEDS Toolkit was created subsequently as an intervention decision aid to be used collaboratively by parent carers and HPs. This study aimed to inform on current intervention practices and influence toolkit design by ascertaining whether specific intervention use varied by a child's main diagnosis and by specific HP role. METHODS: FEEDS survey data were grouped by child's main diagnosis and HP role. Main diagnoses included autism spectrum disorder (ASD) n=183; Down syndrome (DS) n=69; cerebral palsy (CP) n=30). HPs included were speech and language therapists (SLT) n=131; occupational therapists (OT) n=63; physiotherapists (PT) n=57; paediatricians n=50; dieticians n=40; nurses n=32 and health visitors n=14. RESULTS: Most interventions were used commonly across diagnoses. However, some interventions were used more commonly with specific conditions, for example, positioning (CP 85%, DS 70%, ASD 23%, strategies/programmes aimed at changing behaviour at mealtimes (ASD 52%, CP 8%, DS 11%); visual supports (ASD 58%, CP 0%, DS 21%). HPs reported using a broad range of interventions, SLTs (mean=13.9), dieticians (12.3), OTs (12.7) and paediatricians (11.1). There was overlap between intervention use and HP role, for example, positioning (100% PT, 97% SLT, 94% OT, 73% paediatricians and 69% nurses). CONCLUSIONS: Interdisciplinary working is common when managing EDSD, with all HP types using multiple interventions. A child's main diagnosis does not substantially influence intervention use, and the individual context of each child requires consideration in intervention selection. Study findings have supported development of the FEEDS Toolkit for use in feeding services.

Associations of Microbleeds and Their Topography With Imaging and CSF Biomarkers of Alzheimer Pathology in Individuals With Down Syndrome.

BACKGROUND AND OBJECTIVES: Cerebral hemorrhages are an exclusion criterion and potential adverse effect of antiamyloid agents. It is, therefore, critical to characterize the natural history of cerebral microbleeds in populations genetically predisposed to Alzheimer disease (AD), such as Down syndrome (DS). We aimed to assess microbleed emergence in adults with DS across the AD spectrum, defining their topography and associations with clinical variables, cognitive outcomes, and fluid and neuroimaging biomarkers. METHODS: This cross-sectional study included participants aged 18 years or older from the Down-Alzheimer Barcelona Neuroimaging Initiative and Sant Pau Initiative on Neurodegeneration with T1-weighted and susceptibility-weighted images. Participants underwent comprehensive assessments, including apolipoprotein E (APOE) genotyping; fluid and plasma determinations of beta-amyloid, tau, and neurofilament light; cognitive outcomes (Cambridge Cognitive Examination and modified Cued Recall Test); and vascular risk factors (hypertension, diabetes mellitus, and dyslipidemia). We manually segmented microbleeds and characterized their topography. Associations between microbleed severity and AD biomarkers were explored using between-group comparisons (none vs 1 vs 2+) and multivariate linear models. RESULTS: We included 276 individuals with DS and 158 healthy euploid controls (mean age = 47.8 years, 50.92% female). Individuals with DS were more likely to have microbleeds than controls (20% vs 8.9%, p < 0.001), with more severe presentation (12% with 2+ vs 1.9%). Microbleeds increased with age (12% 20-30 years vs 60% > 60 years) and AD clinical stage (12.42% asymptomatic, 27.9% prodromal, 35.09% dementia) were more common in APOEε4 carriers (26% vs 18.3% noncarriers, p = 0.008), but not associated with vascular risk factors (p > 0.05). Microbleeds were predominantly posterior (cerebellum 33.66%; occipital 14.85%; temporal 21.29%) in participants with DS. Associations with microbleed severity were found for neuroimaging and fluid AD biomarkers, but only hippocampal volumes (standardized ß = -0.18 [-0.31, -0.06], p < 0.005) and CSF p-tau-181 concentrations (ß = 0.26 [0.12, 0.41], p < 0.005) survived regression controlling for age and disease stage, respectively. Microbleeds had limited effect on cognitive outcomes. DISCUSSION: In participants with DS, microbleeds present with a posterior, lobar predominance, are associated with disease severity, but do not affect cognitive performance. These results suggest an interplay between AD pathology and vascular lesions, implicating microbleeds as a risk factor limiting the use of antiamyloid agents in this population.

Orthodontic findings in adults with Trisomy 21.

OBJECTIVES: Objective of this study was to describe orthodontic findings in adults with Down's syndrome, a matter insufficiently regarded in literature. MATERIALS AND METHODS: A group of 104 adults (33.8 ± 15 years) with trisomy 21 had an orthodontic check-up in their accustomed environment. Anamnestic and dental findings completed the examination and descriptive analysis was performed using SPSS23. Relative frequencies with 95% confidence intervals were compared to the average population (SHIP-study, 2003; DMS IV, 2006). RESULTS: Among the participants 46.2% (36.3-56.2%) (SHIP 36.7%) had already undergone orthodontic treatment. In 87.5% (79.6-93%) of the patients, less than 25.6 properly functioning permanent teeth (DMS IV's mean) were found. Gingival bleeding and recessions, as well as periodontal disease, were increasingly found in older affected persons. Patients with Down's syndrome showed less crowding, e.g., maxillary incisors 28% (19.3-39%) versus 41.9% (SHIP). Frontal open bite (35.2% (25.3-46.1%) versus 3.6% (SHIP)) and frontal crossbite (40.9% (30.5-51.9%) versus 4.2% (SHIP)) were more often observed. No considerable differences in frequencies of orthodontic findings were detected in the comparison of the subgroups "18-28 years" versus ">28 years", "with" versus "without orthodontic treatment", "male" versus "female", "with" versus "without periodontal problems", or "with" versus "without orofacial disturbances". CONCLUSIONS: Within the bounds of this study, we gathered orthodontic findings in adults with trisomy 21 for the first time. In comparison to the average population, the subject group showed a greater number of complex orthodontic findings. CLINICAL RELEVANCE: These persisting dental and orofacial problems must be considered when treating patients with Down's syndrome.

Giant Urinary Bladder in a Woman with Down Syndrome: A Case Report.

BACKGROUND Non-neurogenic neurogenic bladder involves fluctuating flow rates due to involuntary muscle contractions during voiding in those with normal neurological function. The diagnostic challenge lies in distinguishing between massive urinary bladder distension and ovarian tumors. While various pathologies mimicking ovarian tumors are documented, cases of a massively distended urinary bladder, known as giant urinary bladder, posing as such are notably scarce. CASE REPORT This case report presents the unique clinical scenario of a 31-year-old woman with Down syndrome who was initially misdiagnosed with an ovarian tumor due to progressive abdominal distention, reduced appetite, and weight loss. On presentation, she appeared dehydrated, with an abnormal renal profile. Despite hydration, the renal profile worsened. Initial ultrasound showed a large, uniloculated cystic lesion measuring 11×15 cm in the pelvis. Due to the size of the cyst, which appeared to be ovarian in origin, ovarian tumor was suspected. However, tumor markers were normal. A computed tomography scan subsequently showed a massively distended urinary bladder measuring 11.6×13.6×17.6 cm causing bilateral obstructive uropathy, with moderate hydronephrosis and hydroureter. Needing intermittent catheterization at first, the patient subsequently passed urine on her own following behavioral modification. CONCLUSIONS This rare case of non-neurogenic neurogenic bladder causing a giant urinary bladder in a patient with Down syndrome highlights the importance of an awareness of this condition for effective assessment and patient treatment.

Recurrence of anterior congenital diaphragmatic hernia after laparoscopic repair in children.

PURPOSE: To report our experience with laparoscopic repair of anterior congenital diaphragmatic hernia (CDH) using extracorporeal subcutaneous knot tying and to define recurrence risk factors. METHODS: This retrospective unicentric study included children who underwent laparoscopic repair of anterior CDH without patch, using extracorporeal knot tying of sutures passed through the full thickness of the abdominal wall (2013-2020). A systematic review of the literature with meta-analysis was performed using the MEDLINE database since 2000. RESULTS: Eight children were included (12 months [1-183]; 10.6 kg [3.6-65]). Among the two patients with Down syndrome, one with previous cardiac surgery had a recurrence at 17 months postoperatively. In our systematic review (26 articles), among the 156 patients included, 10 had a recurrence (none with patch). Recurrence was statistically more frequent in patients with Down syndrome (19.4%) than without (2.5%) (p < 0.0001), and when absorbable sutures were used (50%) instead of non-absorbable sutures (5.3%) (p < 0.0001). CONCLUSION: Laparoscopic repair of anterior CDH without patch was a safe and efficient surgical approach in our patients. The use of a non-absorbable prosthetic patch should be specifically discussed in anterior CDH associated with Down syndrome and/or in case of previous cardiac surgery to perform a diaphragmatic tension-free closure.

The outcome in pediatric acute myeloblastic leukemia; results of the first-line treatment and contribution of hematopoietic stem cell transplantation to survival of relapsed patients.

Background/aim: To analyze the long-term outcome of pediatric patients with acute myeloblastic leukemia. Materials and methods: Data from 69 patients 0-18 years of age diagnosed between December 2001 and October 2019 were analyzed in April 2023. Patients received MRC-AML10 chemotherapy (2ADE+MACE+MidAC). No maintenance chemotherapy or preventive cranial radiotherapy was administered. Twelve patients with Down syndrome and 15 patients with promyelocytic leukemia were in the cohort. Patients with Down syndrome received reduced chemotherapy (cumulative anthracycline 420 mg/m2, cytarabine 3.4 g/m2, etoposide 1400 mg/m2). ATRA was added to chemotherapy in promyelocytic leukemia. Results: Four patients (5.8%) died in the induction (two typhlitis, one intracranial hemorrhage, and one resistant disease). The complete remission rate of 66 patients was 87.8%. There was one death due to cardiotoxicity. Total infection-related deaths were 7.2%. Seven patients with high-risk criteria and one with resistant disease underwent hematopoietic stem cell transplantation (HSCT) following the first-line treatment. All seven patients in remission were alive and disease-free. The relapse rate was 34.4% (n = 21). Four patients developing marrow relapse were disease-free in the second remission after salvage and maintenance chemotherapy. Thirteen patients (18.84%) underwent HSCT in the second remission and 8 are alive and disease-free. The mean follow-up period of patients from diagnosis was 185 ± 13 months. Thirty-four patients (49.2%) were alive and disease-free in the first remission whereas another two patients in the first remission developed secondary malignancy. In good, standard, and poor risk groups, event-free survival (EFS) rates were 68.2%, 52.9%, and 10%, and overall survival (OS) rates were 86.4%, 79.4%, and 20%, respectively. Fifteen years of EFS and OS of the whole cohort were 49.3% and 69.6%, respectively. Conclusion: When compared with national data and multicenter studies of developed countries, survival rates were acceptable.

The use of hearing tests to assess otitis media with effusion in children with Down syndrome.

BACKGROUND: Down syndrome is associated with an increased risk for otitis media with effusion (OME), a childhood condition in which fluid accumulates in the middle ear, potentially leading to hearing loss. The American Academy of Pediatrics Down syndrome guidelines and the American Academy of Otolaryngology - Head and Neck Surgery OME guidelines recommend hearing testing to assess the hearing status of children with Down syndrome diagnosed with OME. METHODS: Through an Institutional Review Board approved retrospective chart review at Children's Mercy, this project assessed how clinical factors affect the frequency in which children with Down syndrome receive hearing testing after diagnosis of OME. The study included data from all children with Down syndrome between 1 and 8 years old diagnosed with OME in the Down syndrome, general pediatrics, and otolaryngology clinics between 2018 and 2020. Demographics and clinical factors, including clinic setting, were collected. RESULTS: Of the 124 patients identified, 91.1 % were diagnosed with OME in the otolaryngology clinic and 33.1 % received hearing testing. While most diagnoses occurred in the otolaryngology clinic, a higher proportion of hearing testing at the time of diagnosis occurred in the Down syndrome clinic. This could be explained by the fact that the Down syndrome clinic is a multidisciplinary clinic, where yearly visits include hearing screening. Bivariate analysis using chi-square or Fisher's tests showed that clinic setting had a significant association (p-value <0.001) with hearing testing. However, logistic regression depicted all clinical factors had an insignificant effect on hearing testing at 5 % significance. CONCLUSION: While results indicate hearing testing is largely not performed to assess OME early in otolaryngology clinics, they may be used to assess intervention efficacy post-diagnosis. Results point to the importance of Down syndrome clinics in early diagnosis of hearing loss leading to timely referrals to otolaryngology clinics which diagnose and manage OME in children with Down syndrome.