Impact of Deletion on Angelman Syndrome Phenotype Variability: Phenotype-Genotype Correlation in 97 Patients with Motor Developmental Delay.

Angelman syndrome (AS) is a rare neurodevelopmental disorder due to genetic defects involving chromosome 15, known by intellectual disability, cognitive and behavioral disorders, ataxia, delayed motor development, and seizures. This study highlights the clinical spectrum and molecular research to establish the genotype-phenotype correlation in the pediatric Moroccan population. Methylation-specific-polymerase chain reaction (MS-PCR) is a primordial technique not only to identify the genetic mechanism of AS but also to characterize the different molecular classes induced in the appearance of the clinical symptoms. Patients with positive methylation profile were additionally studied by fluorescent in situ hybridization. Sequencing analysis of the UBE3A gene was performed for patients with negative MS-PCR. We used Fisher's test to assess differences in the distribution of features frequencies among the deletional and the nondeletional group. Statistical analysis was performed using R project. We identified from 97 patients diagnosed with AS, 14 (2.06%) had a classical AS phenotype, while 70 (84.5%) patients displayed a subset of consistent and frequent criteria. Development delay was shown severe in 63% and moderate in 37%. Nineteen out of 97 of them had MS-PCR positive in which 17 (89.47%) had 15q11-q13 deletion. Deletion patients presented a higher incidence of epileptic seizures ( p = 0.04), ataxia ( p = 0.0008), and abnormal electroencephalogram (EEG) profile ( p = 0.003). We further found out a frameshift deletion located at exon 9 of the UBE3A gene discovered in a 5 years old patient. We report in this study the genotype-phenotype correlation using different molecular testing. Correlation analysis did not reveal any statistical differences in phenotypic dissimilarity between deletion and nondeletion groups for most clinical features, except the correlation was highly significant in the abnormal EEG. According to our findings, we recommend offering MS-PCR analysis to all patients with severe intellectual disability, developmental delay, speech impairment, happy demeanor, and hypopigmentation.

Identification of novel and de novo variant in the SCN1A gene confirms Dravet syndrome in Moroccan child: a case report.

Dravet syndrome is a severe form of epilepsy characterised by recurrent seizures and cognitive impairment. It is mainly caused by variant in the SCN1A gene in 90% of cases, which codes for the α subunit of the voltage-gated sodium channel. In this study, we present one suspected case of Dravet syndrome in Moroccan child that underwent exome analysis and were confirmed by Sanger sequencing. The variant was identified in the SCN1A gene, and is a new variant that has never been described in the literature. The variant was found de nova in our case, indicating that it was not inherited from the parents. The variant, SCN1A c.965-2A>G p.(?), is located at the splice site and results in an unknown modification of the protein. This variant is considered pathogenic on the basis of previous studies. These results contribute to our knowledge of the SCN1A gene mutations associated with Dravet syndrome and underline the importance of genetic analysis in the diagnosis and confirmation of this disorder. Further studies are needed to better understand the functional consequences of this variant and its implications for therapeutic strategies in Dravet syndrome.

Autosomal Dominant Intellectual Development Disorder-6 (MRD6) Without Seizures Linked to a De Novo Mutation in the grin2b Gene Revealed by Exome Sequencing: A Case Report of a Moroccan Child.

Autosomal dominant intellectual development disorder-6 (MRD6) arises from a grin2b gene mutation, inducing neurodevelopmental issues. The effects of MRD6 encompass cognitive disabilities, seizures, muscle tone decline, and autism-like traits. Its severity ranges from mild impairment to severe epilepsy. The disorder's rarity is emphasized by roughly 100 reported GRIN2B-related cases, spotlighting the gene's significance in brain development. We present the case of a three-year-old Moroccan boy who was referred to a neuropediatric department for a molecular diagnosis. Initial genetic testing yielded inconclusive results, and subsequent tests for Angelman syndrome and metabolic diseases showed no abnormalities. Given the complexity of the disorder, exome sequencing was employed to identify the underlying genetic cause. Exome sequencing identified a nonsense (STOP) mutation c.3912C>G (p.Tyr1304Ter) in the grin2b gene in the heterozygous state known to be present in MRD6 (Online Mendelian Inheritance in Man (OMIM) 613970). The family segregation study shows that this is a de novo variant, which is confirmed by Sanger sequencing. This variant has not been previously reported in the GnomAD database. Based on current scientific knowledge, the variant is considered pathogenic (PVS1, PS2, PM2, PP3, PP5) according to the criteria of the American College of Medical Genetics and Genomics (ACMG). The mutation in the grin2b gene (p.Tyr1304Ter) was predicted to be deleterious through bioinformatics analysis tools. This study highlights the crucial role of the grin2b gene in normal brain development and communication within the nervous system. It also sheds light on the impact of a novel genetic mutation, identified through exome sequencing, on causing an intellectual developmental disorder in a child patient from Morocco.

The Diagnosis and Genetic Mechanisms of Prader-Willi Syndrome: Findings From a Moroccan Population Study.

Background Prader-Willi syndrome (PWS) is a complex genetic disorder caused by a deficit in gene expression on the paternal inherited chromosome 15q11.2-q13. It affects various aspects of growth and development, including feeding, cognitive function, and behavior. Early diagnosis and management of PWS can significantly improve outcomes for patients and their families. Methods In this study, we analyzed a group of 29 clinically diagnosed patients suspected of PWS. All patients were referred to the medical genetics and onco-genetics service for genetic consultation and molecular analysis. We used DNA methylation analysis and fluorescence in situ hybridization (FISH) to confirm the diagnosis and identify the underlying genetic mechanisms. Results Our analysis showed that five out of seven patients (71.43%) with a positive methylation-specific PCR (MSP) had chromosomal deletion by FISH and presented major clinical signs summarized by morbid obesity in 65.21% of cases and neonatal hypotonia in 42.85% of cases. This finding indicates that paternal 15q11-q13 deletion is the most common genetic mechanism involved in PWS. Conclusion The results of this study highlight the importance of early diagnosis and molecular analysis in the management of Prader-Willi syndrome. Our findings contribute to a better understanding of the genotype-phenotype correlation in the Moroccan population and provide families with a rigorous molecular diagnosis, relevant genetic counseling, and multidisciplinary support. Further research is needed to explore the underlying mechanisms of PWS and develop effective interventions to improve outcomes for affected individuals.

[Macrophage activation syndrome revealing subcutaneous T-cell lymphoma in a 16-year old adolescent]. / Syndrome d'activation macrophagique révélant un lymphome T sous-cutané chez un adolescent de 16 ans.

Macrophage activation syndrome (MAS) is a multisystemic disorder resulting from an over-activation of the immune system leading to a more or less diffuse macrophagic infiltration into the tussues. Clinical signs including fever, hepatosplenomegaly, adenopathy are associated with abnormal values in laboratory test results (bi or pancytopenia, hepatic cytolysis, elevated LDH levels, coagulopathy) and hemophagocytosis. In children, it can be primary or secondary to several disorders. We report the case of a 16-year old patient admitted to the Department of Pediatrics with febrile leukopenia associated with impaired general condition and circular erythematous lesions spread to the lower limbs. The diagnosis of macrophage activation syndrome was retained based on clinical signs, laboratory test results and cytological results. Skin biopsy of these lesions showed subcutaneous panniculitis-like T-cell lymphoma. The purpose of this study is to insists on the peculiarities of this clinical case given the rarity of this type of subcutaneous T-cell lymphoma, much more in this age group. We want to highlight the importance of suspecting subcutaneous T-cell lymphoma in patients with MAS associated with subcutaneous erythematous lesions because this could be life threatening.

Cutis Laxa syndrome: a case report.

Cutis laxa (CL) is a heterogeneous group of inherited and acquired connective tissue disorders characterized by a loose skin and variable systemic involvement (inguinal hernia, cardiopulmonary disease, and emphysema). Autosomal dominant, autosomal recessive and x-linked recessive patterns have been described in the inherited forms. Acquired forms of this disease have been associated with a previous inflammatory skin disorder (urticaria…). The characteristic symptomatological pattern is resulting from paucity of elastic fibers. We report an 18 months old baby boy with a congenital cutis laxa. He was admitted in pediatric unit for respiratory disorders. The diagnosis of CL syndrome is based on clinical assessment of typical skin features and the associated extracutaneous finding.

Multicentric Castleman's Disease in a Child Revealed by Chronic Diarrhea.

Multicentric Castleman's disease is a rare benign and unexplained lymphoproliferative disorder that is extremely uncommon in children. It presents with fever, systemic symptoms, generalized lymphadenopathy, and laboratory markers of inflammation. Its treatment is not standardized and its prognosis is poor. We report a novel case of multicentric Castleman's disease in a 13-year-old girl who had presented with chronic diarrhea as the only initial presenting symptom. The diagnosis of celiac or inflammatory bowel diseases was suspected, but two and a half years later, the diagnosis of multicentric Castleman's disease was brought following the appearance of abdominal mass whose biopsy revealed Castleman's disease in the plasma cell form. The outcome was favorable after treatment by corticosteroid, chemotherapy, and surgery. The occurrence of diarrhea as the initial symptom of multicentric Castleman's disease without lymph node involvement is very rare. This case report underlines the diagnostic difficulties and the long interval between onset and diagnosis when diarrhea occurs first.

Hodgkin's Lymphoma Revealed by Hemophagocytic Lymphohistiocytosis in a Child.

Hemophagocytic lymphohistiocytosis (HLH) is a severe life-threatening disorder, responsible for extensive phagocytosis of hematopoietic cells and causing a multisystem organ failure. If lymphomas are common causes of HLH, the association with Hodgkin's lymphoma is rarely described in children. We report a case of a 9-year-old boy presenting with HLH as an initial manifestation of Hodgkin's lymphoma. He has been suffering from persistent high fever, asthenia, weight loss, and hepatosplenomegaly with no lymphadenopathy. The diagnosis of HLH secondary to infectious disease was initially worn. The patient received high-dose intravenous immunoglobulin with broad-spectrum antibiotics. However, his state got worse with the onset of dry cough and pleural effusion. Histopathologic examination of pleural fluid showed the presence of Reed-Sternberg cells. The outcome was favorable after treatment by corticosteroid and chemotherapy. Hodgkin's lymphoma revealed by HLH is a source of delayed diagnosis and should be borne in mind in children.

Neonatal hyperekplexia with homozygous p.R392H mutation in GLRA1.

Hyperekplexia is a rare neurogenetic disorder, frequently misdiagnosed in neonates with a risk of apnoea, asphyxia, and sudden infant death. We present video sequences of a male newborn, admitted on the second day of life to the neonatal intensive care unit, due to tonic-clonic movements. Following clinical and paraclinical investigations, a final diagnosis of hyperekplexia was made. Genetic analysis revealed a homozygous mutation in GLRA1 resulting in a R392H amino acid substitution and altered receptor dynamics, as indicated from previous work. The infant showed a marked improvement of the startle response and muscle hypertonia with clonazepam which is a strong clinical feature of GLRA1-mediated hyperekplexia. [Published with video sequences].

Gelastic seizures and fever originating from a parietal cortical dysplasia.

Gelastic seizures (GS) is an uncommon seizure type characterized by sudden inappropriate attacks of uncontrolled and unmotivated laugh and its diagnostic criteria were elaborated by Gascon. These criteria included stereotypical recurrence of laugh, which is unjustified by the context, associated signs compatible with seizure, and ictal or interictal abnormalities. GS can be cryptogenic or symptomatic of a variety of cerebral lesions, the most common being hypothalamic hamartoma. However, GS associated with other types of cerebral lesions are exceedingly rare. The physiopathologic mechanisms of this type of seizure are still undefined. Two reports have described a non-lesional GS arising from a parietal focus. In this paper, we report the first case of lesional GS associated to the parietal area of the brain in a child and this case has associated fever that is likely an ictal symptom.

Actuality of juvenile dermatomyositis.

Juvenile dermatomyositis is a rare disorder, but remains the most commonly occurring chronic inflammatory myopathy among children. Other than the proximal muscles and skin, which are routinely affected, vasculopathy may affect other viscera and can be multisystemic. A redefinition of the diagnostic criteria is currently underway and is likely to lead to other clinical signs and to sensitive and non-invasive examinations such as MRI. The impact of juvenile dermatomyositis on health and quality of life remains significant despite systemic corticosteroid therapy and immunosuppressor treatment, which have considerably improved the prognosis. Numerous predictors for favourable and pejorative evolution have been identified. The standardisation and the generalisation of clinical assessment tools will make it possible to carry out the clinical trials required to determine the relevance of the new therapeutic options available for children.

[Lemierre syndrome]. / Syndrome de Lemierre.

Lemierre's syndrome is a rare and severe condition, with a primary focus in the cervicofacial area and followed by thrombosis of the internal jugular vein and metastatic infections, most often pulmonary. The principal pathogen is Fusobacterium necrophorum. Less rare and associated with high mortality before antibiotics, Lemierre syndrome had became exceptional until the increase in the number of cases in recent years. Recovery is usually the rule, but often only after long convalescence and often surgical intervention. The reemergence of this disease calls for a review of the literature to update knowledge about its epidemiologic, clinical, and therapeutic aspects.

Lemierre syndrome: once seen it can never be mistaken.

Lemierre syndrome is a rare but severe septicaemia due most frequently to Fusobacterium necrophorum, with primary foci in the head, internal jugular vein thrombosis and metastatic infections, mainly in the lungs. We report two cases of Lemierre syndrome admitted to the paediatric unit of our hospital at 2-month intervals. The first was 10 years old and the second one was a 3-month-old infant. They were diagnosed on the 25th hospital day and at the time of admission, respectively. In the first case, diagnosis was delayed due to unfamiliarity with this disease. In the second patient the diagnosis was established on the first day because of the recent experience with patient 1. In both cases, bacteriological investigations were not helpful. Both patients had a favourable outcome after prolonged antibiotic treatment, anticoagulation and surgical drainage.