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 omic 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.

暂无摘要。

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.
Working together to speed up treatments for rare genetic syndromes linked to excessive growth and intellectual disability To address the shared challenges experienced among those affected by overgrowth–intellectual disability (OGID) syndromes, we recently formed the Overgrowth Syndromes Alliance (OSA). The OSA unites patient advocacy organizations that have typically worked independently of one another, in hopes of accelerating our progress toward treatments. Here, we summarize the OGID syndromes represented by the OSA, the prevalence of seizures in these disorders, and efforts by the OSA to tackle the most pressing needs of the overgrowth community. We also present the steps patient organizations can take in pursuit of developing treatments. We hope the work of our alliance can be a template for creating collaborative, patient-led advances in diagnosis, management guidelines, and, eventually, treatment of rare genetic disorders.

Beckwith-Wiedemann spectrum (BWSp) is caused by genetic and epigenetic alterations on chromosome 11 that regulate cell growth and division. Considering the diverse phenotypic landscape in BWSp, the characterization of the CDKN1C molecular subtype remains relatively limited. Here, we investigate the role of CDKN1C in the broader BWSp phenotype. Notably, patients with CDKN1C variants appear to exhibit a different tumor risk than other BWSp molecular subtypes. We performed a comprehensive literature review using the search term \"CDKN1C Beckwith\" to identify 113 cases of patients with molecularly confirmed CDKN1C-BWSp. We then assessed the genotype and phenotype in a novel cohort of patients with CDKN1C-BWSp enrolled in the BWS Research Registry. Cardinal and suggestive features were evaluated for all patients reported, and tumor risk was established based on available reports. The most common phenotypes included macroglossia, omphalocele, and ear creases/pits. Tumor types reported from the literature included neuroblastoma, acute lymphocytic leukemia, superficial spreading melanoma, and intratubular germ cell neoplasia. Overall, this study identifies unique features associated with CDKN1C variants in BWSp, enabling more accurate clinical management. The absence of Wilms tumor and hepatoblastoma suggests that screening for these tumors may not be necessary, while the neuroblastoma risk warrants appropriate screening recommendations.

Macrocephaly, characterized by an abnormally large head circumference, often co-occurs with distinctive finger changes, presenting a diagnostic challenge for clinicians. This review aims to provide a current synthetic overview of the main acquired and genetic etiologies associated with macrocephaly and finger changes. The genetic cause encompasses several categories of diseases, including bone marrow expansion disorders, skeletal dysplasias, ciliopathies, inherited metabolic diseases, RASopathies, and overgrowth syndromes. Furthermore, autoimmune and autoinflammatory diseases are also explored for their potential involvement in macrocephaly and finger changes. The intricate genetic mechanisms involved in the formation of cranial bones and extremities are multifaceted. An excess in growth may stem from disruptions in the intricate interplays among the genetic, epigenetic, and hormonal factors that regulate human growth. Understanding the underlying cellular and molecular mechanisms is important for elucidating the developmental pathways and biological processes that contribute to the observed clinical phenotypes. The review provides a practical approach to delineate causes of macrocephaly and finger changes, facilitate differential diagnosis and guide for the appropriate etiological framework. Early recognition contributes to timely intervention and improved outcomes for affected individuals.

OBJECTIVE: Sotos syndrome (SOTOS) is an uncommon genetic condition that manifests itself with the following distinctive features: prenatal overgrowth, facial abnormalities, and intellectual disability. This disorder is often associated with haploinsufficiency of the nuclear receptor-binding SET domain protein 1 (NSD1)gene. We investigated four pediatric cases characterized by early-onset overgrowth and developmental delay. The primary objective of this study was to achieve accurate genetic diagnoses.
UNASSIGNED: A sequential analysis approach comprising chromosomal karyotyping, whole exome sequencing, and microarray analysis was conducted.
RESULTS: All four cases exhibited variations in the NSD1 gene, with the identification of four previously unreported de novo variants, each specific to one case.Specifically, Case 1 carried the NSD1 (NM_022455): c.2686 C > T(p.Q896X) variant, Case 2 had the NSD1 (NM_022455): c.2858_2859delCT(p.S953X) variant, Case 3 displayed a chromosomal aberration, chr5: 5q35.2q35.3(176,516,604-176,639,249)×1, which encompassed the 5\'-untranslated region of NSD1, and Case 4 harbored the NSD1 (NM_022455): c.6397T > G(p.C2133G) variant.
CONCLUSIONS: This study not only provided precise diagnoses for these cases but also supplied significant evidence to facilitate informed consultations. Furthermore, our findings expanded the spectrum of mutations associated with SOTOS.

UNASSIGNED: Weaver syndrome (WS) is a rare autosomal dominant disorder characterized by distinctive facial features, pre- and post-natal overgrowth, macrocephaly, and variable developmental delay. The characteristic facial features are ocular hypertelorism, a broad forehead, almond-shaped palpebral fissures and, in early childhood, large, fleshy ears, a pointed \"stuck-on\" chin with horizontal skin creases, and retrognathia. Heterozygous pathogenic/likely pathogenic variants in the enhancer of zeste homolog 2 (EZH2) gene are responsible for WS.
UNASSIGNED: Here, we report a male patient with a heterozygous likely pathogenic variant in EZH2 gene who has tall stature, distinctive facial features, mild development delay, hypoxic-ischemic encephalopathy with a MRI finding of periventricular leukomalacia, gingival hypertrophy, and early onset high hypermetropia.
UNASSIGNED: This case demonstrates the importance of reporting detailed molecular and clinical findings in patients to expand the genotypic and phenotypic findings of this rare syndrome.

The PI3K enzymes modify phospholipids to regulate cell growth and differentiation. Somatic variants in PI3K are recurrent in cancer and drive a proliferative phenotype. Somatic mosaicism of PIK3R1 and PIK3CA are associated with vascular anomalies and overgrowth syndromes. Germline PIK3R1 variants are associated with varying phenotypes, including immunodeficiency or facial dysmorphism with growth delay, lipoatrophy, and insulin resistance associated with SHORT syndrome. There has been limited study of the molecular mechanism to unify our understanding of how variants in PIK3R1 drive both undergrowth and overgrowth phenotypes. Thus, we compiled genomic variants from cancer and rare vascular anomalies and sought to interpret their effects using an unbiased physics-based simulation approach for the protein complex. We applied molecular dynamics simulations to mechanistically understand how genetic variants affect PIK3R1 and its interactions with PIK3CA. Notably, iSH2 genetic variants associated with undergrowth destabilize molecular interactions with the PIK3CA receptor binding domain in simulations, which is expected to decrease activity. On the other hand, overgrowth and cancer variants lead to loss of inhibitory interactions in simulations, which is expected to increase activity. We find that all disease variants display dysfunctions on either structural characteristics or intermolecular interaction energy. Thus, this comprehensive characterization of novel mosaic somatic variants associated with two opposing phenotypes has mechanistic importance and biomedical relevance and may aid in future therapeutic developments.

Gingival overgrowth, localized or generalized, is one of the leading causes of poor maintenance of oral hygiene. Excision of growth using laser should be the choice of treatment because laser helps maintain a blood-free surgical site during treatment and provides more patient comfort during and after the procedure. Lasers are commonly employed in many different applications, including scaling, root planning, cavity preparation, and excision of soft tissue growths in surgery. Laser therapy offers numerous benefits over traditional methods of treatment. These benefits have led to the growing use of lasers as dental treatment options in a variety of dental fields. In this case report, we are presenting a case of excision of localized gingival growth using a laser. Postoperative healing and maintenance of oral health were satisfied after laser surgery.

Sotos syndrome belongs to the group of diseases characterised by features such as facial dysmorphism, intellectual disability, hypotonia and overgrowth. Usually, Sotos syndrome is caused by heterozygous mutations in the NSD1 gene at chromosome 5q35 or by large genomic deletions of the same region. Genotype-phenotype correlations have mainly been reported as an association of significant or major abnormalities and presence of 5q35 deletions rather than intragenic deletions or point mutations in NSD1. The congenital hyperinsulinaemic hypoglycaemia (CHI) has been described as an uncommon feature in the presentation of Sotos syndrome. Most of the patients with Sotos syndrome and transient CHI were carriers of 5q35 deletions while persistent CHI has been recently reported in individuals with point mutations or small NSD1 deletions. We report the clinical features and medical treatment in a new-born child with Sotos syndrome and CHI that was present for almost two years. Genetic cause of Sotos syndrome in this case was a novel, large genomic deletion encompassing 24 OMIM genes including the entire NSD1 gene and 6 other Morbid genes. Our report shows challenges in diagnostics and management of this rare genetic condition. We propose, that in neonatal diagnostics, the phenotypic spectrum of Sotos syndrome should include CHI as a characteristic feature and molecular genetic testing should be done by whole genome analysis.