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Medicina Clinica Nov 2021The overgrowth syndromes related to phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) are grouped under the concept of PROS (PIK3CA-related overgrowth spectrum). It... (Review)
Review
The overgrowth syndromes related to phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) are grouped under the concept of PROS (PIK3CA-related overgrowth spectrum). It is a heterogeneous group of diseases, considered a rare disease (ORPHA: 530313), which combines the presence of vascular malformations with segmental overgrowth of some parts of the body. All these diseases are caused by mutations in the gene that encodes for the alpha subunit of PI3K. These mutations are somatic and take place during the embryonic stage. Depending on the stage of embryonic development and the affected germ layers, the phenotype will be very different, from syndromes with extensive involvement to isolated forms. Although there are clinical criteria, identification of the mutation by biopsy, although complex, confirms the diagnosis. The objective of the present study is to review the pathophysiological, clinical, diagnostic, and therapeutic aspects of PROS, in order to optimize its identification.
Topics: Class I Phosphatidylinositol 3-Kinases; Humans; Mutation; Phenotype; Syndrome; Vascular Malformations
PubMed: 34281706
DOI: 10.1016/j.medcli.2021.03.036 -
Endocrine Development 2009Overgrowth syndromes are characterized by macrosomia, congenital anomalies, mental retardation and an increased risk of tumors. In this article we will analyze what we... (Review)
Review
Overgrowth syndromes are characterized by macrosomia, congenital anomalies, mental retardation and an increased risk of tumors. In this article we will analyze what we define 'classical' overgrowth.
Topics: Beckwith-Wiedemann Syndrome; Growth Disorders; Humans; Syndrome
PubMed: 19293574
DOI: 10.1159/000207476 -
Ultrasound (Leeds, England) Nov 2022Syndromes associated with vascular malformation and soft tissue overgrowth in the paediatric population present with multiple soft tissue swellings. Ultrasound is the...
INTRODUCTION
Syndromes associated with vascular malformation and soft tissue overgrowth in the paediatric population present with multiple soft tissue swellings. Ultrasound is the initial investigation of choice for paediatric soft tissue swellings. Ultrasound evaluation can accurately assess the nature of vascular malformations and pattern of lipomatous hypertrophy in areas of soft tissue overgrowth to facilitate early diagnosis of such syndromes.
CASE REPORT
Here, we report a case of CLOVES (congenital lipomatous overgrowth (CLO), vascular malformations (V), epidermal nevi (E), and spinal/skeletal anomalies/scoliosis (S)) syndrome in a 6-year-old girl referred for evaluation of soft tissue swellings. CLOVES syndrome is a rare overgrowth syndrome in the paediatric population which presents with multiple soft tissue swellings. The ultrasound and clinical features of the syndrome have been illustrated to help radiologists accurately diagnose this rare syndrome based on detailed ultrasound and clinical evaluation.
DISCUSSION
Radiological features of CLOVES syndrome and differentiating ultrasound features of other such syndromes have been described in detail. A systematic stepwise approach to diagnosing complex syndromic associations of vascular malformations with lipomatous overgrowth has been proposed. Role of ultrasound in the management, Wilms tumour screening and follow-up of CLOVES syndrome have also been discussed.
CONCLUSION
Ultrasound plays a crucial role in the early diagnosis and management of complex syndromes presenting with soft tissue swelling in the paediatric population. It also aids in the differentiation of such syndromes, tumour screening, guided sclerotherapy and follow-up of vascular lesions encountered in such syndromes.
PubMed: 36969529
DOI: 10.1177/1742271X221091714 -
Journal of Indian Society of... 2023Hereditary gingival fibromatosis (HGF) is an uncommon slow-growing fibrous overgrowth characterized by connective tissue accumulation. It presents as an isolated feature...
Hereditary gingival fibromatosis (HGF) is an uncommon slow-growing fibrous overgrowth characterized by connective tissue accumulation. It presents as an isolated feature or as a manifestation of any syndrome. Various syndromes associated with HGF are inherited by autosomal dominant/recessive/X-linked traits. Zimmermann-Laband syndrome (ZLS) is a rare, autosomal dominant inherited disease manifested with gingival fibromatosis (GF), nose and ears abnormalities, and hypoplastic/dysplastic nails or terminal phalanges of hand and feet. Although the pattern of inheritance was found to be both autosomal dominant and recessive traits, the molecular basis is still unclear. This report presents a possible case of ZLS-associated HGF in a 25-year-old female patient who presents with GF, hypertrichosis, and other syndrome-related features. Her father was similarly affected whereas her mother and sibling were asymptomatic. The patient and her family members were explained about the condition and surgical periodontal therapy was carried out for the patient to improve esthetics and was followed up regularly. Esthetics was significantly improved and no recurrence was noted at the end of 6 months.
PubMed: 38434504
DOI: 10.4103/jisp.jisp_582_22 -
Annals of Pediatric Endocrinology &... Sep 2013Overgrowth syndromes comprise a diverse group of conditions with unique clinical, behavioral and molecular genetic features. While considerable overlap in presentation... (Review)
Review
Overgrowth syndromes comprise a diverse group of conditions with unique clinical, behavioral and molecular genetic features. While considerable overlap in presentation sometimes exists, advances in identification of the precise etiology of specific overgrowth disorders continue to improve clinicians' ability to make an accurate diagnosis. Among them, this paper introduces two classic genetic overgrowth syndromes: Sotos syndrome and Beckwith-Wiedemann syndrome. Historically, the diagnosis was based entirely on clinical findings. However, it is now understood that Sotos syndrome is caused by a variety of molecular genetic alterations resulting in haploinsufficiency of the NSD1 gene at chromosome 5q35 and that Beckwith-Wiedemann syndrome is caused by heterogeneous abnormalities in the imprinting of a number of growth regulatory genes within chromosome 11p15 in the majority of cases. Interestingly, the 11p15 imprinting region is also associated with Russell-Silver syndrome which is a typical growth retardation syndrome. Opposite epigenetic alterations in 11p15 result in opposite clinical features shown in Beckwith-Wiedemann syndrome and Russell-Silver syndrome. Although the exact functions of the causing genes have not yet been completely understood, these overgrowth syndromes can be good models to clarify the complex basis of human growth and help to develop better-directed therapies in the future.
PubMed: 24904861
DOI: 10.6065/apem.2013.18.3.101 -
Pediatric Blood & Cancer Aug 2022Vascular anomalies, both vascular tumors and vascular malformations, can occur in isolation or as part of syndromes including those which feature phenotypic overgrowth.... (Review)
Review
Vascular anomalies, both vascular tumors and vascular malformations, can occur in isolation or as part of syndromes including those which feature phenotypic overgrowth. To update what is known about vascular anomalies associated with overgrowth, PubMed was searched for "overgrowth syndromes and vascular anomalies or malformations." PubMed, OMIM, and the Rare Disease Database also were searched for specific diagnoses. We review individual overgrowth syndromes, provide a case-based approach to the clinical, radiographic, pathologic, and genetic basis for diagnosis, to complications of both the vascular anomalies and the overgrowth, and emphasize the need for a multidisciplinary approach to care.
Topics: Humans; Syndrome; Vascular Malformations
PubMed: 36070209
DOI: 10.1002/pbc.29273 -
Journal of Pediatric Ophthalmology and... 1988Proteus syndrome is a recently recognized hamartoneoplastic malformation syndrome of uncertain etiology and variable expression, whose cardinal manifestations are... (Review)
Review
Proteus syndrome is a recently recognized hamartoneoplastic malformation syndrome of uncertain etiology and variable expression, whose cardinal manifestations are pigmented nevi, hemihypertrophy, macrodactly, lipomata, and cerebroid-gyriform configuration of the skin on the soles of the feet. The characteristic features may be present at birth but become more apparent with time. In the past this syndrome has been confused with other overgrowth disorders such as neurofibromatosis, Klippel-Trenaunay-Weber syndrome, Maffucci syndrome, and Bannayan syndrome. The ophthalmic features of the proteus syndrome require clarification. We review the ocular findings in 16 previously described cases and describe the findings unique to our patient, in particular, unilateral epibulbar and suspected posterior segment hamartomas.
Topics: Child; Eye Diseases; Female; Foot Deformities, Congenital; Gigantism; Hamartoma; Hand Deformities, Congenital; Humans; Nystagmus, Pathologic; Orbital Neoplasms; Skin Diseases; Syndrome
PubMed: 3282059
DOI: 10.3928/0191-3913-19880301-12 -
Nature Reviews. Endocrinology May 2019Overgrowth syndromes are a heterogeneous group of rare disorders characterized by generalized or segmental excessive growth commonly associated with additional features,... (Review)
Review
Overgrowth syndromes are a heterogeneous group of rare disorders characterized by generalized or segmental excessive growth commonly associated with additional features, such as visceromegaly, macrocephaly and a large range of various symptoms. These syndromes are caused by either genetic or epigenetic anomalies affecting factors involved in cell proliferation and/or the regulation of epigenetic markers. Some of these conditions are associated with neurological anomalies, such as cognitive impairment or autism. Overgrowth syndromes are frequently associated with an increased risk of cancer (embryonic tumours during infancy or carcinomas during adulthood), but with a highly variable prevalence. Given this risk, syndrome-specific tumour screening protocols have recently been established for some of these conditions. Certain specific clinical traits make it possible to discriminate between different syndromes and orient molecular explorations to determine which molecular tests to conduct, despite the syndromes having overlapping clinical features. Recent advances in molecular techniques using next-generation sequencing approaches have increased the number of patients with an identified molecular defect (especially patients with segmental overgrowth). This Review discusses the clinical and molecular diagnosis, tumour risk and recommendations for tumour screening for the most prevalent generalized and segmental overgrowth syndromes.
Topics: Arrhythmias, Cardiac; Female; Genetic Diseases, X-Linked; Gigantism; Heart Defects, Congenital; Humans; Intellectual Disability; Megalencephaly; Neoplasms; Pregnancy; Risk Factors; Sotos Syndrome; Syndrome
PubMed: 30842651
DOI: 10.1038/s41574-019-0180-z -
Medical and Pediatric Oncology Nov 1996Beckwith-Wiedemann syndrome (BWS) is an overgrowth syndrome associated with a predisposition to embryonal tumors, most commonly Wilms' (WT). Overlapping clinical... (Review)
Review
Beckwith-Wiedemann syndrome (BWS) is an overgrowth syndrome associated with a predisposition to embryonal tumors, most commonly Wilms' (WT). Overlapping clinical phenotypes are seen in two other disorders, Simpson-Golabi-Behmel syndrome (SGBS) and Perlman syndrome (PS). BWS is a genetically heterogeneous disorder most often associated with normal chromosomes and a negative family history. However, autosomal dominant transmission of BWS is reported, as are chromosome 11p15.5 abnormalities, uniparental paternal disomy (UPD) of chromosome 11p15.5, and altered expression of the imprinted gene insulin-like growth factor 2 (IGF2) from the normally repressed maternal allele. Crucial to our understanding of the large variety of genetic presentations in BWS is the concept of genomic imprinting, a process in which gene expression specific to parent-of-origin is observed. The current genetic and molecular data for BWS are best explained by a model assuming an imprinted domain for 11p15.5, whereby altered expression of one or more genes in this region contributes to the BWS phenotype. In this model, a defined chromatin structure is reflected in coordinated control of multiple genes in the domain, as well as specific patterns of replication timing and gene expression. Data supporting this viewpoint include the maternally derived 11p15.5 translocation breakpoints associated with BWS, and the recent finding that the normally asynchronous pattern of replication timing for the imprinted gene IGF2 can be disrupted, shifted by a BWS-associated translocation 400 kh from IGF2. As we unravel the molecular basis of the different BWS patient subgroups, we will achieve a better understanding of this overgrowth syndrome and its relationship to WT.
Topics: Beckwith-Wiedemann Syndrome; Chromatin; Chromosomes, Human, Pair 11; DNA Replication; Gene Expression Regulation, Neoplastic; Genes, Dominant; Genomic Imprinting; Humans; Insulin-Like Growth Factor II; Models, Genetic; Molecular Biology; Neoplasms, Germ Cell and Embryonal; Phenotype; Syndrome; Translocation, Genetic; Wilms Tumor
PubMed: 8827075
DOI: 10.1002/(SICI)1096-911X(199611)27:5<462::AID-MPO13>3.0.CO;2-C -
American Journal of Human Genetics Jan 2003Sotos syndrome is a childhood overgrowth syndrome characterized by a distinctive facial appearance, height and head circumference >97th percentile, advanced bone age,...
Sotos syndrome is a childhood overgrowth syndrome characterized by a distinctive facial appearance, height and head circumference >97th percentile, advanced bone age, and developmental delay. Weaver syndrome is characterized by the same criteria but has its own distinctive facial gestalt. Recently, a 2.2-Mb chromosome 5q35 microdeletion, encompassing NSD1, was reported as the major cause of Sotos syndrome, with intragenic NSD1 mutations identified in a minority of cases. We evaluated 75 patients with childhood overgrowth, for intragenic mutations and large deletions of NSD1. The series was phenotypically scored into four groups, prior to the molecular analyses: the phenotype in group 1 (n=37) was typical of Sotos syndrome; the phenotype in group 2 (n=13) was Sotos-like but with some atypical features; patients in group 3 (n=7) had Weaver syndrome, and patients in group 4 (n=18) had an overgrowth condition that was neither Sotos nor Weaver syndrome. We detected three deletions and 32 mutations (13 frameshift, 8 nonsense, 2 splice-site, and 9 missense) that are likely to impair NSD1 functions. The truncating mutations were spread throughout NSD1, but there was evidence of clustering of missense mutations in highly conserved functional domains between exons 13 and 23. There was a strong correlation between presence of an NSD1 alteration and clinical phenotype, in that 28 of 37 (76%) patients in group 1 had NSD1 mutations or deletions, whereas none of the patients in group 4 had abnormalities of NSD1. Three patients with Weaver syndrome had NSD1 mutations, all between amino acids 2142 and 2184. We conclude that intragenic mutations of NSD1 are the major cause of Sotos syndrome and account for some Weaver syndrome cases but rarely occur in other childhood overgrowth phenotypes.
Topics: Abnormalities, Multiple; Amino Acid Sequence; Carrier Proteins; Child; Chromosome Deletion; Chromosomes, Human, Pair 5; Craniofacial Abnormalities; DNA Mutational Analysis; Developmental Disabilities; Exons; Female; Growth Disorders; Histone Methyltransferases; Histone-Lysine N-Methyltransferase; Humans; Intracellular Signaling Peptides and Proteins; Introns; Male; Molecular Sequence Data; Mutation; Nuclear Proteins; Pedigree; Phenotype; Polymorphism, Genetic; Protein Structure, Tertiary; Sequence Deletion; Syndrome
PubMed: 12464997
DOI: 10.1086/345647