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Cureus Jun 2024Beckwith-Wiedemann syndrome (BWS) is a genetic disorder that affects fetal growth in which those afflicted present with features pertaining to that, such as macrosomia,...
Beckwith-Wiedemann syndrome (BWS) is a genetic disorder that affects fetal growth in which those afflicted present with features pertaining to that, such as macrosomia, macroglossia, hemihypertrophy, and abdominal wall defects. This case reports the presentation of an infant diagnosed with BWS who was born with an extremely low birth weight of 980 grams, in contrast to the typical presentation of overgrowth and macrosomia. As a result, reaching a diagnosis of BWS was delayed until the patient reached eight months of age, when other clinical features of BWS, such as hemihypertrophy, became apparent on follow-up visits. Although genetic testing can be used to diagnose this condition, a clinical scoring system consisting of a patient's clinical features is sufficient, allowing for a timely and precise diagnosis, which is of great significance to allow for early screening and detection of the associated embryonal tumors with such a syndrome.
PubMed: 38919860
DOI: 10.7759/cureus.63099 -
Frontiers in Genetics 2024Overgrowth disorders comprise a group of entities with a variable phenotypic spectrum ranging from tall stature to isolated or lateralized overgrowth of body parts and... (Review)
Review
Overgrowth disorders comprise a group of entities with a variable phenotypic spectrum ranging from tall stature to isolated or lateralized overgrowth of body parts and or organs. Depending on the underlying physiological pathway affected by pathogenic genetic alterations, overgrowth syndromes are associated with a broad spectrum of neoplasia predisposition, (cardio) vascular and neurodevelopmental anomalies, and dysmorphisms. Pathologic overgrowth may be of prenatal or postnatal onset. It either results from an increased number of cells (intrinsic cellular hyperplasia), hypertrophy of the normal number of cells, an increase in interstitial spaces, or from a combination of all of these. The underlying molecular causes comprise a growing number of genetic alterations affecting skeletal growth and Growth-relevant signaling cascades as major effectors, and they can affect the whole body or parts of it (mosaicism). Furthermore, epigenetic modifications play a critical role in the manifestation of some overgrowth diseases. The diagnosis of overgrowth syndromes as the prerequisite of a personalized clinical management can be challenging, due to their clinical and molecular heterogeneity. Physicians should consider molecular genetic testing as a first diagnostic step in overgrowth syndromes. In particular, the urgent need for a precise diagnosis in tumor predisposition syndromes has to be taken into account as the basis for an early monitoring and therapy. With the (future) implementation of next-generation sequencing approaches and further technologies, clinical diagnoses can not only be verified, but they also confirm the clinical and molecular spectrum of overgrowth disorders, including unexpected findings and identification of atypical cases. However, the limitations of the applied assays have to be considered, for each of the disorders of interest, the spectrum of possible types of genomic variants has to be considered as they might require different methodological strategies. Additionally, the integration of artificial intelligence (AI) in diagnostic workflows significantly contribute to the phenotype-driven selection and interpretation of molecular and physiological data.
PubMed: 38894719
DOI: 10.3389/fgene.2024.1382371 -
Frontiers in Pediatrics 2024Genetic disposition is a major etiologic factor in childhood cancer. More than 100 cancer predisposing syndromes (CPS) are known. Surveillance protocols seek to mitigate...
INTRODUCTION
Genetic disposition is a major etiologic factor in childhood cancer. More than 100 cancer predisposing syndromes (CPS) are known. Surveillance protocols seek to mitigate morbidity and mortality. To implement recommendations in patient care and to ascertain that the constant gain of knowledge forces its way into practice specific pediatric CPS programs were established.
PATIENTS AND METHODS
We retrospectively analyzed data on children, adolescents, and young adults referred to our pediatric CPS program between October 1, 2021, and March 31, 2023. Follow-up ended on December 31, 2023.
RESULTS
We identified 67 patients (30 male, 36 female, 1 non-binary, median age 9.5 years). Thirty-five patients were referred for CPS surveillance, 32 for features suspicious of a CPS including café-au-lait macules ( = 10), overgrowth ( = 9), other specific symptoms ( = 4), cancer suspicious of a CPS ( = 6), and rare neoplasms ( = 3). CPS was confirmed by clinical criteria in 6 patients and genetic testing in 7 (of 13). In addition, 6 clinically unaffected at-risk relatives were identified carrying a cancer predisposing pathogenic variant. A total of 48 patients were eventually diagnosed with CPS, surveillance recommendations were on record for 45. Of those, 8 patients did not keep their appointments for various reasons. Surveillance revealed neoplasms ( = 2) and metachronous tumors ( = 4) by clinical ( = 2), radiological examination ( = 2), and endoscopy ( = 2). Psychosocial counselling was utilized by 16 (of 45; 35.6%) families.
CONCLUSIONS
The diverse pediatric CPSs pose several challenges necessitating interdisciplinary care in specified CPS programs. To ultimately improve outcome including psychosocial well-being joint clinical and research efforts are necessary.
PubMed: 38887560
DOI: 10.3389/fped.2024.1410061 -
Signal Transduction and Targeted Therapy Jun 2024Sporadic venous malformations are genetic conditions primarily caused by somatic gain-of-function mutation of PIK3CA or TEK, an endothelial transmembrane receptor...
Sporadic venous malformations are genetic conditions primarily caused by somatic gain-of-function mutation of PIK3CA or TEK, an endothelial transmembrane receptor signaling through PIK3CA. Venous malformations are associated with pain, bleedings, thrombosis, pulmonary embolism, esthetic deformities and, in severe cases, life-threatening situations. No authorized medical treatment exists for patients with venous malformations. Here, we created a genetic mouse model of PIK3CA-related capillary venous malformations that replicates patient phenotypes. We showed that these malformations only partially signal through AKT proteins. We compared the efficacy of different drugs, including rapamycin, a mTORC1 inhibitor, miransertib, an AKT inhibitor and alpelisib, a PI3Kα inhibitor at improving the lesions seen in the mouse model. We demonstrated the effectiveness of alpelisib in preventing vascular malformations' occurrence, improving the already established ones, and prolonging survival. Considering these findings, we were authorized to treat 25 patients with alpelisib, including 7 children displaying PIK3CA (n = 16) or TEK (n = 9)-related capillary venous malformations resistant to usual therapies including sirolimus, debulking surgical procedures or percutaneous sclerotherapies. We assessed the volume of vascular malformations using magnetic resonance imaging (MRI) for each patient. Alpelisib demonstrated improvement in all 25 patients. Vascular malformations previously considered intractable were reduced and clinical symptoms were attenuated. MRI showed a decrease of 33.4% and 27.8% in the median volume of PIK3CA and TEK malformations respectively, over 6 months on alpelisib. In conclusion, this study supports PI3Kα inhibition as a promising therapeutic strategy in patients with PIK3CA or TEK-related capillary venous malformations.
Topics: Class I Phosphatidylinositol 3-Kinases; Animals; Mice; Humans; Vascular Malformations; Capillaries; Female; Male; Sirolimus; Child; Disease Models, Animal; Molecular Targeted Therapy; Thiazoles
PubMed: 38880808
DOI: 10.1038/s41392-024-01862-9 -
Frontiers in Surgery 2024Terminal osseous overgrowth is a common complication after trans-diaphyseal amputation in children, leading to pain, soft tissue problems, and recurrent surgical...
Terminal osseous overgrowth is a common complication after trans-diaphyseal amputation in children, leading to pain, soft tissue problems, and recurrent surgical procedures. We report three different cases with post-amputation issues of osseous overgrowth, ulceration, and deformity over the amputation site. The first case involves a 9-year-old boy with a right leg congenital amputation secondary to amniotic band syndrome. The right below-knee stump later experienced recurrent episodes of osseous overgrowth, leading to ulceration. After the prominent tibia was resected and capped with the ipsilateral proximal fibula, a positive outcome was achieved with no more recurrent overgrowth over the right leg stump. The second case involves a 9-year-old girl born with an amniotic constriction band over both legs. Her left leg remained functional after a circumferential Z-plasty, but the right leg was a congenital below-knee amputation. Multiple refashioning surgeries were performed on the right leg due to osseous overgrowth but the patient continued to experience recurrent overgrowth causing pain and difficulty fitting into a prosthesis. We performed osteocartilaginous transfer of the proximal part of the ipsilateral fibula to the right tibial end, successfully preventing the overgrowth of the tibia without any complications. The third case involves an 11-year-old boy with a history of meningococcal septicemia who underwent a right below-knee amputation and left ankle disarticulation due to complications of septic emboli. He experienced a prominent right distal tibia stump, which later developed into valgus deformity as a result of the previous insult to the proximal tibial growth plate. We performed a corrective osteotomy over the proximal right tibia and capped the entire tibia with the ipsilateral fibula as an intramedullary splint for the osteotomy site. Post-operatively, we achieved satisfactory deformity correction and successfully halted the recurrent overgrowth over the right tibia stump. The method of ipsilateral fibula capping is safe and effective in managing the osseous overgrowth complications in trans-diaphyseal amputations among children. Therefore, it is a reasonable option during primary below-knee amputations in children compared to multiple refashioning surgeries.
PubMed: 38854925
DOI: 10.3389/fsurg.2024.1320661 -
Gastroenterologia Y Hepatologia Jun 2024The recognition and treatment of intestinal bacterial overgrowth syndrome are matters of controversy. The symptoms that have guided the search for the disorder suffer...
The recognition and treatment of intestinal bacterial overgrowth syndrome are matters of controversy. The symptoms that have guided the search for the disorder suffer from lack of specificity, especially in the absence of well-defined predisposing factors. The accuracy of diagnostic procedures has been questioned and the proposed therapies achieve generally low effectiveness figures, with large differences between available studies. It is also unknown whether the normalization of tests is really a guarantee of cure. Within this framework of uncertainty, and in order to contribute to the guidance and homogenization of medical practice, a group of experts from the AEG and ASENEM have formulated the key questions on the management of this pathology and have provided answers to them, in accordance with the available scientific evidence. In addition, they have drawn up statements based on the conclusions of the review and have voted on them individually to reflect the degree of consensus for each statement.
PubMed: 38852778
DOI: 10.1016/j.gastrohep.2024.502216 -
Journal of Neuroradiology = Journal de... Jun 2024
PubMed: 38850627
DOI: 10.1016/j.neurad.2024.101210 -
Indian Dermatology Online Journal 2024International Society for the Study of Vascular Anomalies classification defines Congenital Limb Overgrowth Vascular Syndromes (CLOS) as a subset of vascular syndromes...
International Society for the Study of Vascular Anomalies classification defines Congenital Limb Overgrowth Vascular Syndromes (CLOS) as a subset of vascular syndromes with other abnormalities that present with unilateral limb overgrowth. It includes Klippel-Trenaunay Syndrome, Parkes-Weber Syndrome, CLOVES (Congenital Lipomatous Overgrowth, Vascular Malformations, Epidermal Nevi, Spinal/Skeletal Anomalies/Scoliosis) Syndrome, Proteus Syndrome, PTEN Hamartomatous Syndrome, and Fibroadipose Vascular Anomaly. Due to their rare and complex nature, a multidisciplinary approach to diagnosis and treatment is required. A thorough clinical and radiological workup can go miles in reflecting on the patient's outcome. Here we report five cases of CLOS with their detailed dermato-radiological profiles.
PubMed: 38845672
DOI: 10.4103/idoj.idoj_500_23 -
Clinical Epigenetics Jun 2024Tatton-Brown-Rahman syndrome (TBRS) is a rare congenital genetic disorder caused by autosomal dominant pathogenic variants in the DNA methyltransferase DNMT3A gene....
Tatton-Brown-Rahman syndrome (TBRS) is a rare congenital genetic disorder caused by autosomal dominant pathogenic variants in the DNA methyltransferase DNMT3A gene. Typical TBRS clinical features are overgrowth, intellectual disability, and minor facial anomalies. However, since the syndrome was first described in 2014, a widening spectrum of abnormalities is being described. Cardiovascular abnormalities are less commonly reported but can be a major complication of the syndrome. This article describes a family of three individuals diagnosed with TBRS in adulthood and highlights the variable expression of cardiovascular features. A 34-year-old proband presented with progressive aortic dilatation, mitral valve (MV) regurgitation, left ventricular (LV) dilatation, and ventricular arrhythmias. The affected family members (mother and brother) were diagnosed with MV regurgitation, LV dilatation, and arrhythmias. Exome sequencing and computational protein analysis suggested that the novel familial DNMT3A mutation Ser775Tyr is located in the methyltransferase domain, however, distant from the active site or DNA-binding loops. Nevertheless, this bulky substitution may have a significant effect on DNMT3A protein structure, dynamics, and function. Analysis of peripheral blood cfDNA and transcriptome showed shortened mononucleosome fragments and altered gene expression in a number of genes related to cardiovascular health and of yet undescribed function, including several lncRNAs. This highlights the importance of epigenetic regulation by DNMT3A on cardiovascular system development and function. From the clinical perspective, we suggest that new patients diagnosed with congenital DNMT3A variants and TBRS require close examination and follow-up for aortic dilatation and valvular disease because these conditions can progress rapidly. Moreover, personalized treatments, based on the specific DNMT3A variants and the different pathways of their function loss, can be envisioned in the future.
Topics: Humans; DNA Methyltransferase 3A; Adult; Male; DNA (Cytosine-5-)-Methyltransferases; Female; Pedigree; Cardiomyopathies; Aortic Diseases; Exome Sequencing; Intellectual Disability; Mutation
PubMed: 38845031
DOI: 10.1186/s13148-024-01686-y -
Therapeutic Advances in Rare Disease 2024Overgrowth-intellectual disability (OGID) syndromes are a collection of rare genetic disorders with overlapping clinical profiles. In addition to the cardinal features... (Review)
Review
Overgrowth-intellectual disability (OGID) syndromes are a collection of rare genetic disorders with overlapping clinical profiles. In addition to the cardinal features of general overgrowth (height and/or head circumference at least two standard deviations above the mean) and some degree of intellectual disability, the OGID syndromes are often associated with neurological anomalies including seizures. In an effort to advance research in directions that will generate meaningful treatments for people with OGID syndromes, a new collaborative partnership called the Overgrowth Syndromes Alliance (OSA) formed in 2023. By taking a phenotype-first approach, OSA aims to unite research and patient communities traditionally siloed by genetic disorder. OSA has galvanized OGID patient organizations around shared interests and developed a research roadmap to identify and address our community's greatest unmet needs. Here, we describe the literature regarding seizures among those with overgrowth syndromes and present the OSA Research Roadmap. This patient-driven guide outlines the milestones essential to reaching the outcome of effective treatments for OGID syndromes and offers resources for reaching those milestones.
PubMed: 38827639
DOI: 10.1177/26330040241254123