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American Journal of Medical Genetics.... Dec 2019Congenital hyperinsulinism (HI) is the most frequent cause of persistent hypoglycemia in infants and children. Delays in diagnosis and initiation of appropriate... (Review)
Review
Congenital hyperinsulinism (HI) is the most frequent cause of persistent hypoglycemia in infants and children. Delays in diagnosis and initiation of appropriate treatment contribute to a high risk of neurocognitive impairment. HI represents a heterogeneous group of disorders characterized by dysregulated insulin secretion by the pancreatic beta cells, which in utero, may result in somatic overgrowth. There are at least nine known monogenic forms of HI as well as several syndromic forms. Molecular diagnosis allows for prediction of responsiveness to medical treatment and likelihood of surgically-curable focal hyperinsulinism. Timely genetic mutation analysis has thus become standard of care. However, despite significant advances in our understanding of the molecular basis of this disorder, the number of patients without an identified genetic diagnosis remains high, suggesting that there are likely additional genetic loci that have yet to be discovered.
Topics: Child; Congenital Hyperinsulinism; Epigenesis, Genetic; Genetic Testing; Humans; Infant; Mutation; Philadelphia; Syndrome
PubMed: 31414570
DOI: 10.1002/ajmg.c.31737 -
Blood Jan 2022
Topics: Adolescent; Adult; Child; Child, Preschool; Congenital Abnormalities; DNA Methyltransferase 3A; Female; Germ-Line Mutation; Hematologic Neoplasms; Humans; Male; Mutation; Syndrome; Young Adult
PubMed: 34788385
DOI: 10.1182/blood.2021014052 -
American Journal of Medical Genetics.... Aug 2016Clinical classification of overgrowth syndromes represents a challenge since a wide spectrum of disorders result in marked overgrowth. Therefore, there is a continuous... (Review)
Review
Clinical classification of overgrowth syndromes represents a challenge since a wide spectrum of disorders result in marked overgrowth. Therefore, there is a continuous effort to identify the genetic basis of these disorders that will eventually facilitate their molecular classification. Here, we have identified the genetic etiology and the pathogenetic mechanism underlying a rare autosomal recessive overgrowth syndrome in three affected siblings. The overgrowth phenotype in the patients was accompanied by developmental delay, learning disabilities, and variable congenital abnormalities. To elucidate the genetic etiology of the disorder, whole-genome genotyping and whole-exome sequencing were used. The disease was mapped to 3p21.1-p14.2 and 11q13.1-q13.4, where an in-frame insertion (c.175_176insTAA) in FIBP gene was revealed. The resulting indel (p.H59LN) was predicted to change the protein conformation with likely deleterious effect on its function as one of the fibroblast growth factor signaling mediators. In vitro cellular proliferation assay and in situ hypridization in vivo were then performed to understand the pathophysiology of the disease. The patients' skin fibroblasts showed an increased proliferation capacity compared to the controls' explaining the observed overgrowth phenotype. In addition, we detected Fibp expression most notably in the brains of mice embryos suggesting a possible effect on cognitive functions early in development. To date, only one patient has been reported with a homozygous nonsense mutation in FIBP exhibiting an overgrowth syndrome with multiple congenital abnormalities. Taken all together, these findings provide convincing evidence implicating FIBP aberrations in the newly recognized overgrowth syndrome and expand the associated phenotypes to include possible Wilms tumor predisposition. © 2016 Wiley Periodicals, Inc.
Topics: Adolescent; Animals; Carrier Proteins; Cell Proliferation; Child; Child, Preschool; Chromosome Mapping; DNA Mutational Analysis; Exome; Female; Gene Expression; Gene Expression Regulation, Developmental; Genes, Recessive; Genetic Association Studies; Genotype; Growth Disorders; High-Throughput Nucleotide Sequencing; Homozygote; Humans; Intellectual Disability; Kidney; Male; Membrane Proteins; Mice; Mice, Transgenic; Mutation; Pedigree; Phenotype; Syndrome; Wilms Tumor
PubMed: 27183861
DOI: 10.1002/ajmg.a.37741 -
Current Opinion in Pediatrics Dec 2005The clinical importance of overgrowth syndromes in the pediatric patient population has been increasingly recognized during the past decade, but clinical overlap among... (Review)
Review
PURPOSE OF REVIEW
The clinical importance of overgrowth syndromes in the pediatric patient population has been increasingly recognized during the past decade, but clinical overlap among overgrowth syndromes often makes diagnostic categorization difficult. Advances in the molecular delineation of overgrowth syndromes in recent years have furthered our knowledge of the phenotypic spectrum of this group of conditions. This review focuses on developments in our understanding of the molecular mechanisms and phenotype-genotype correlations in the two most common overgrowth syndromes, Beckwith-Wiedemann syndrome and Sotos syndrome. The implications of these findings with respect to clinical diagnosis, medical management, and genetic counseling are discussed.
RECENT FINDINGS
Recent reports have redefined the cardinal clinical features of Sotos syndrome, and the identification of two distinct types of molecular alterations in patients with this syndrome has enabled assessment of phenotype-genotype correlations. Recent studies in patients with Beckwith-Wiedemann syndrome have further expanded our understanding of the causative molecular mechanisms of this condition and provide evidence for specific genotype-phenotype correlations, most notably with respect to tumor risk.
SUMMARY
Recognition of childhood overgrowth and investigation of diagnostic causes is important in anticipating appropriate medical management and facilitating the provision of genetic counseling. New developments in our understanding of the molecular basis and phenotypic expression of overgrowth syndromes provide additional tools in this often challenging process.
Topics: Beckwith-Wiedemann Syndrome; Child; Chromosomes, Human, Pair 11; Genomic Imprinting; Genotype; Growth Disorders; Histone Methyltransferases; Histone-Lysine N-Methyltransferase; Humans; Intracellular Signaling Peptides and Proteins; Mutation; Nuclear Proteins; Phenotype; Syndrome; Translocation, Genetic; Uniparental Disomy
PubMed: 16282780
DOI: 10.1097/01.mop.0000187191.74295.97 -
Current Opinion in Pediatrics Aug 2012Human growth ensues from a complex interplay of physiological factors, in the wider setting of varying genetic traits and environmental influences. Intensive research in... (Review)
Review
PURPOSE OF REVIEW
Human growth ensues from a complex interplay of physiological factors, in the wider setting of varying genetic traits and environmental influences. Intensive research in these divergent areas, and particularly in the field of genetics, continues to clarify the molecular basis of disorders which result in overgrowth, and it is therefore timely to provide a review of these findings.
RECENT FINDINGS
This article provides an overview of the factors which regulate growth, followed by a discussion of the more commonly encountered overgrowth syndromes and their genetic basis as it is understood at the current time. There is also an added focus on recently discovered genetic associations in some conditions, such as Weaver, Perlman and Proteus syndromes.
SUMMARY
New discoveries continue to be made regarding the genetic basis for many overgrowth syndromes and the development of a much needed molecular classification system for overgrowth may become possible as the interlinking functions of these genes on growth are unravelled. As there exists a wide spectrum of syndromes, disorders resulting in overgrowth can represent a diagnostic and therapeutic challenge, from those causing prenatal overgrowth with a poor prognosis to less severe genetic aberrations which are identified in later childhood or adult life.
Topics: Abnormalities, Multiple; Adolescent; Child; Child, Preschool; Congenital Hypothyroidism; Craniofacial Abnormalities; Female; Fetal Macrosomia; Growth Disorders; Hand Deformities, Congenital; Humans; Infant; Male; Mutation; Phenotype; Prognosis; Proteus Syndrome; Wilms Tumor
PubMed: 22705997
DOI: 10.1097/MOP.0b013e3283558995 -
Orphanet Journal of Rare Diseases Sep 2007Sotos syndrome is an overgrowth condition characterized by cardinal features including excessive growth during childhood, macrocephaly, distinctive facial gestalt and... (Review)
Review
Sotos syndrome is an overgrowth condition characterized by cardinal features including excessive growth during childhood, macrocephaly, distinctive facial gestalt and various degrees of learning difficulty, and associated with variable minor features. The exact prevalence remains unknown but hundreds of cases have been reported. The diagnosis is usually suspected after birth because of excessive height and occipitofrontal circumference (OFC), advanced bone age, neonatal complications including hypotonia and feeding difficulties, and facial gestalt. Other inconstant clinical abnormalities include scoliosis, cardiac and genitourinary anomalies, seizures and brisk deep tendon reflexes. Variable delays in cognitive and motor development are also observed. The syndrome may also be associated with an increased risk of tumors. Mutations and deletions of the NSD1 gene (located at chromosome 5q35 and coding for a histone methyltransferase implicated in transcriptional regulation) are responsible for more than 75% of cases. FISH analysis, MLPA or multiplex quantitative PCR allow the detection of total/partial NSD1 deletions, and direct sequencing allows detection of NSD1 mutations. The large majority of NSD1 abnormalities occur de novo and there are very few familial cases. Although most cases are sporadic, several reports of autosomal dominant inheritance have been described. Germline mosaicism has never been reported and the recurrence risk for normal parents is very low (<1%). The main differential diagnoses are Weaver syndrome, Beckwith-Wiedeman syndrome, Fragile X syndrome, Simpson-Golabi-Behmel syndrome and 22qter deletion syndrome. Management is multidisciplinary. During the neonatal period, therapies are mostly symptomatic, including phototherapy in case of jaundice, treatment of the feeding difficulties and gastroesophageal reflux, and detection and treatment of hypoglycemia. General pediatric follow-up is important during the first years of life to allow detection and management of clinical complications such as scoliosis and febrile seizures. An adequate psychological and educational program with speech therapy and motor stimulation plays an important role in the global development of the patients. Final body height is difficult to predict but growth tends to normalize after puberty.
Topics: Abnormalities, Multiple; Animals; Craniofacial Abnormalities; Gigantism; Humans; Mutation; Syndrome
PubMed: 17825104
DOI: 10.1186/1750-1172-2-36 -
JCI Insight May 2023Overgrowth syndromes can be caused by pathogenic genetic variants in epigenetic writers, such as DNA and histone methyltransferases. However, no overgrowth disorder has...
Overgrowth syndromes can be caused by pathogenic genetic variants in epigenetic writers, such as DNA and histone methyltransferases. However, no overgrowth disorder has previously been ascribed to variants in a gene that acts primarily as an epigenetic reader. Here, we studied a male individual with generalized overgrowth of prenatal onset. Exome sequencing identified a hemizygous frameshift variant in Spindlin 4 (SPIN4), with X-linked inheritance. We found evidence that SPIN4 binds specific histone modifications, promotes canonical WNT signaling, and inhibits cell proliferation in vitro and that the identified frameshift variant had lost all of these functions. Ablation of Spin4 in mice recapitulated the human phenotype with generalized overgrowth, including increased longitudinal bone growth. Growth plate analysis revealed increased cell proliferation in the proliferative zone and an increased number of progenitor chondrocytes in the resting zone. We also found evidence of decreased canonical Wnt signaling in growth plate chondrocytes, providing a potential explanation for the increased number of resting zone chondrocytes. Taken together, our findings provide strong evidence that SPIN4 is an epigenetic reader that negatively regulates mammalian body growth and that loss of SPIN4 causes an overgrowth syndrome in humans, expanding our knowledge of the epigenetic regulation of human growth.
Topics: Male; Humans; Mice; Animals; Epigenesis, Genetic; Genes, X-Linked; Syndrome; Cell Cycle Proteins; Mammals
PubMed: 36927955
DOI: 10.1172/jci.insight.167074 -
American Journal of Medical Genetics.... Dec 2019Specific classes of de novo heterozygous gain-of-function pathogenic variants of the PDGFRB (platelet-derived growth factor receptor-beta) cause a distinctive overgrowth...
Specific classes of de novo heterozygous gain-of-function pathogenic variants of the PDGFRB (platelet-derived growth factor receptor-beta) cause a distinctive overgrowth syndrome, named the Kosaki overgrowth syndrome (KOGS) (OMIM #616592). Until now, six patients with this condition have been reported in the literature. In addition to skeletal overgrowth, these patients exhibit hyperelastic, translucent, and fragile skin, scoliosis, progressive loss of subcutaneous adipose tissue, skull deformity, infantile myofibromas, neuropsychiatric symptoms, and arachnoid cysts in the posterior fossa and periventricular white matter signal abnormalities on neuroimaging. This constellation of phenotypes clearly distinguishes KOGS from other PDGFRB-related disorders, including idiopathic basal ganglia calcification, infantile myofibroma, and Penttinen-type premature aging syndrome. From a molecular standpoint, PDGFRB is a dimeric receptor tyrosine kinase that plays critical roles in cell growth and tumorigenesis. The two known types of pathogenic variants (p.(Pro584Arg) and p.(Trp566Arg)) of the PDGFRB that cause KOGS are exclusively located in the juxtaglomerular domain that regulates autoactivation/inhibition of PDGFRB. In-vitro evidence suggests that p.(Pro584Arg) represents a gain-of-function pathogenic variant. Inhibition of PDGFRB activity using multi-kinase inhibitors appears to be a potentially promising therapeutic approach. Investigation of the molecular mechanisms underlying the pathogenesis of this disease using induced pluripotent stem cells is under way. Presence of skeletal overgrowth, distinctive facial features, characteristic hyperelastic and fragile skin, and cerebral white matter lesions with neuropsychiatric symptoms should prompt genetic analysis of the PDGFRB.
Topics: Adolescent; Child; Child, Preschool; Female; Growth Disorders; Humans; Male; Musculoskeletal Abnormalities; Psychomotor Performance; Receptor, Platelet-Derived Growth Factor beta; Syndrome; Young Adult
PubMed: 31710779
DOI: 10.1002/ajmg.c.31755 -
Trends in Genetics : TIG Apr 2008Human growth is a complex process that requires the appropriate interaction of many players. Central members in the growth pathways are regulated epigenetically and... (Review)
Review
Human growth is a complex process that requires the appropriate interaction of many players. Central members in the growth pathways are regulated epigenetically and thereby reflect the profound significance of imprinting for correct mammalian ontogenesis. In this review, we show that the growth retardation disorder Silver-Russell syndrome (SRS) is a suitable model to decipher the role of imprinting in growth. As we will show, SRS should not only be regarded as the genetically (and clinically) opposite disease to Beckwith-Wiedemann syndrome, but it also represents the first human disorder with imprinting disturbances that affect two different chromosomes (i.e. chromosomes 7 and 11). Thus, a functional interaction between factors encoded by chromosomes 7 and 11 is likely.
Topics: Abnormalities, Multiple; Beckwith-Wiedemann Syndrome; DNA Methylation; Genomic Imprinting; Growth Disorders; Humans; Syndrome
PubMed: 18329128
DOI: 10.1016/j.tig.2008.01.003 -
Clinical Genetics Jan 2022
Topics: Genetic Association Studies; Genetic Predisposition to Disease; Growth Disorders; Humans; Mutation; Phenotype; Quality of Life; Receptor, Platelet-Derived Growth Factor beta; Structure-Activity Relationship; Syndrome
PubMed: 34708400
DOI: 10.1111/cge.14078