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Nephrologie & Therapeutique Apr 2017This review presents an overview of a recently characterized spectrum of overgrowth syndrome: phosphoinositide-3 kinase (PI3K)-related overgrowth spectrum (PROS). This... (Review)
Review
This review presents an overview of a recently characterized spectrum of overgrowth syndrome: phosphoinositide-3 kinase (PI3K)-related overgrowth spectrum (PROS). This spectrum encompasses overgrowth syndromes associated with somatic mosaic activating PIK3CA mutations such as megalencephaly-capillary malformation (MCAP) syndrome, dysplatic megalencephaly (DMEG), congenital lipomatous asymmetric overgrowth of the trunk, lymphatic, capillary, venous, and combined-type vascular malformations, epidermal nevi, skeletal and spinal anomalies (CLOVES) syndrome, hemihyperplasia-multiple lipomatosis (HHML), fibroadipose overgrowth and Klippel-Trenaunay syndrome. Mosaic gain of function mutation in PIK3CA gene leads to abnormal AKT-mTOR pathway activation and is responsible of the clinical manifestations. Here, we summarize the current knowledge on this disorder.
Topics: Abnormalities, Multiple; Biomarkers; Class I Phosphatidylinositol 3-Kinases; Growth Disorders; Humans; Lipomatosis; Musculoskeletal Abnormalities; Mutation; Phenotype; Syndrome; Vascular Malformations
PubMed: 28577738
DOI: 10.1016/j.nephro.2017.02.004 -
Pediatrics and Neonatology Apr 2017With the growing understanding of the magnitude of genetic diseases in newborns and equally rapid advancement of tools used for genetic diagnoses, healthcare providers... (Review)
Review
With the growing understanding of the magnitude of genetic diseases in newborns and equally rapid advancement of tools used for genetic diagnoses, healthcare providers must have a sufficient knowledge base to both recognize and evaluate genetic diseases in the neonatal period. Genetic assessment has become an essential aspect of medicine, and professionals need to know when genetic evaluation is indispensable. Much progress has been made in recent years in utilizing massively parallel sequencing for rapid diagnosis of genetic conditions in neonates. Next-generation sequencing is increasingly being used for noninvasive prenatal diagnosis, and it may become an essential component of newborn screening. This review will define some basic genetic terms and concepts, explain the gamut of genetic testing available for early diagnosis of genetic diseases, and describe some common chromosomal abnormalities, genomic disorders, and single-gene diseases relevant to neonatal medicine.
Topics: Chromosome Aberrations; Congenital Abnormalities; Early Diagnosis; Genetic Testing; Humans; Infant, Newborn; Microarray Analysis; Mitochondrial Diseases; Neonatal Screening; Neonatology; Sequence Analysis
PubMed: 28277305
DOI: 10.1016/j.pedneo.2016.07.002 -
Seminars in Pediatric Neurology Dec 2015Neurocutaneous disorders are a heterogeneous group of conditions (mainly) affecting the skin [with pigmentary/vascular abnormalities and/or cutaneous tumours] and the... (Review)
Review
Neurocutaneous disorders are a heterogeneous group of conditions (mainly) affecting the skin [with pigmentary/vascular abnormalities and/or cutaneous tumours] and the central and peripheral nervous system [with congenital abnormalities and/or tumours]. In a number of such disorders, the skin abnormalities can assume a mosaic patterning (usually arranged in archetypical patterns). Alternating segments of affected and unaffected skin or segmentally arranged patterns of abnormal skin often mirror similar phenomena occurring in extra-cutaneous organs/tissues [eg, eye, bone, heart/vessels, lung, kidney and gut]. In some neurocutaneous syndromes the abnormal mosaic patterning involve mainly the skin and the nervous system configuring a (true) mosaic neurocutaneous disorder; or an ordinary trait of a neurocutaneous disorder is sometimes superimposed by a pronounced linear or otherwise segmental involvement; or, lastly, a neurocutaneous disorder can occur solely in a mosaic pattern. Recently, the molecular genetic and cellular bases of an increasing number of neurocutaneous disorders have been unravelled, shedding light on the interplays between common intra- and extra-neuronal signalling pathways encompassing receptor-protein and protein-to-protein cascades (eg, RAS, MAPK, mTOR, PI3K/AKT and GNAQ pathways), which are often responsible of the mosaic distribution of cutaneous and extra-cutaneous features. In this article we will focus on the well known, and less defined mosaic neurocutaneous phenotypes and their related molecular/genetic bases, including the mosaic neurofibromatoses and their related forms (ie, spinal neurofibromatosis and schwannomatosis); Legius syndrome; segmental arrangements in tuberous sclerosis; Sturge-Weber and Klippel-Trenaunay syndromes; microcephaly/megalencephaly-capillary malformation; blue rubber bleb nevus syndrome; Wyburn-Mason syndrome; mixed vascular nevus syndrome; PHACE syndrome; Incontinentia pigmenti; pigmentary mosaicism of the Ito type; neurocutaneous melanosis; cutis tricolor; speckled lentiginous syndrome; epidermal nevus syndromes; Becker's nevus syndrome; phacomatosis pigmentovascularis and pigmentokeratotica; Proteus syndrome; and encephalocraniocutaneous lipomatosis.
Topics: Animals; Humans; Mosaicism; Neurocutaneous Syndromes
PubMed: 26706010
DOI: 10.1016/j.spen.2015.11.001 -
Clinics in Perinatology Jun 2015In the perinatal setting, chromosome imbalances cause a range of clinically significant disorders and increase the risk for other particular phenotypes. As technologies... (Review)
Review
In the perinatal setting, chromosome imbalances cause a range of clinically significant disorders and increase the risk for other particular phenotypes. As technologies have improved to detect increasingly smaller deletions and duplications, collectively referred to as copy number variants (CNVs), clinicians are learning the significant role that these types of genomic variants play in human disease and their high frequency in ∼ 1% of all pregnancies. This article highlights key aspects of CNV detection and interpretation used during the course of clinical care in the prenatal and neonatal periods. Early diagnosis and accurate interpretation are important for targeted clinical management.
Topics: Aneuploidy; Congenital Abnormalities; DNA Copy Number Variations; Genetic Testing; Genome, Human; Humans; Infant, Newborn
PubMed: 26042902
DOI: 10.1016/j.clp.2015.03.001 -
American Journal of Medical Genetics.... May 2021Trisomy 13 is one of the three most common aneuploidy syndromes in live-born infants. It is associated with mortality rates as high as 90% within the first year of life,... (Review)
Review
Trisomy 13 is one of the three most common aneuploidy syndromes in live-born infants. It is associated with mortality rates as high as 90% within the first year of life, in large part, due to the high prevalence of severe congenital abnormalities that increase mortality and morbidity. However, life-saving and life-prolonging medical interventions are being performed at a higher rate for these infants, resulting in increased rates of survival. Although cardiac complications have been well described in infants with trisomy 13, these patients also experience other complications such as respiratory, neurological, genitourinary, abdominal, otolaryngologic, and orthopedic complications that can impact their quality of life. The goal of this review is to present a comprehensive description of complications in children with trisomy 13 to aid in the development of monitoring and treatment guidelines for the increasing number of providers who will be caring for these patients throughout their lives. Where the evidence is available, this review presents screening recommendations to allow for more rapid detection and documentation of these complications.
Topics: Aneuploidy; Congenital Abnormalities; Early Medical Intervention; Female; Guidelines as Topic; Humans; Infant, Newborn; Male; Trisomy 13 Syndrome
PubMed: 33709620
DOI: 10.1002/ajmg.a.62133 -
International Ophthalmology Jul 2022Congenital ectopia lentis (CEL) is a rare but serious disease. We use next-generation sequencing to detect genes associated with lens abnormalities in 24 patients with...
BACKGROUND
Congenital ectopia lentis (CEL) is a rare but serious disease. We use next-generation sequencing to detect genes associated with lens abnormalities in 24 patients with bilateral CEL and search for pathogenic genes and mutation sites.
MATERIALS AND METHODS
A total of 24 patients diagnosed with CEL from January 2019 to November 2019 were enrolled in this study, and their clinical data were collected and genome-wide deoxyribonucleic acid was extracted from peripheral venous blood. Targeted gene capture technology was used to obtain 188 exons of lens abnormality-related genes, which were sequenced using a high-throughput method. The mutation sites were determined through data analysis and verified by the Sanger method. According to the data from previous studies, the association between the genotype and clinical phenotype was analysed.
RESULT
Of the 24 patients, 23 had mutations in the fibrillin-1 (FBN1) gene, and 20 were diagnosed with Marfan syndrome. The 23 cases of FBN1 mutations were all heterozygous mutations, including 17 missense mutations, 3 splicing variants, 2 exon deletion mutations, 1 codon mutation, and 9 new mutations. A total of 17 mutations were located in the calcium-binding epidermal growth factor domain, including 16 mutations that contained missense mutations of cysteine. In addition, a heterozygous mutation of the gap junction protein alpha 8 (GJA8) gene was detected in one patient.
CONCLUSION
In this study, we identified 23 FBN1 gene mutations and 1 GJA8 gene mutation in 24 patients with CEL. Of these, 9 new FBN1 mutations and 14 known mutations were found. The results expanded the mutation spectrum of the FBN1 gene, suggesting that FBN1 mutation may be the main cause of CEL in Chinese patients.
Topics: China; DNA Mutational Analysis; Ectopia Lentis; Fibrillin-1; Fibrillins; High-Throughput Nucleotide Sequencing; Humans; Marfan Syndrome; Microfilament Proteins; Mutation; Pedigree; Phenotype
PubMed: 35612688
DOI: 10.1007/s10792-022-02224-6 -
Otolaryngologic Clinics of North America Feb 2018The detection of somatic, activating genetic mutations to underlie development of vascular tumors and malformations led to a better understanding of their... (Review)
Review
The detection of somatic, activating genetic mutations to underlie development of vascular tumors and malformations led to a better understanding of their pathophysiology. Proteins encoded by the detected mutated genes activate the two major signaling pathways, also involved in cancer: the RAS/MAPK/ERK pathway and/or the PI3K/AKT/mTOR pathway. This gives a strong basis for studies to repurpose cancer therapeutics to patients with vascular tumors and malformations.
Topics: Arteriovenous Malformations; Capillaries; Head and Neck Neoplasms; Hemangioma; Humans; Lymphatic Abnormalities; Mutation; Signal Transduction
PubMed: 29217067
DOI: 10.1016/j.otc.2017.09.006 -
Birth Defects Research Jan 2018Many different causes of malformations have been established. The surveillance of a consecutive population of births, including stillbirths and elective terminations of...
BACKGROUND
Many different causes of malformations have been established. The surveillance of a consecutive population of births, including stillbirths and elective terminations of pregnancy because of fetal anomalies, can identify each infant with malformations and determine the frequency of the apparent etiologies. This report is a sequel to the first such analysis in the first 10 years of this Active Malformations Surveillance Program (Nelson and Holmes, ).
METHODS
The presence of malformations was determined among 289,365 births over 41 years (1972-2012) at the Brigham and Women's Hospital in Boston. The abnormalities were identified from the review of the examination findings of the pediatricians and consultants and diagnostic testing for the live-born infants and the autopsies of the fetuses in elective terminations and stillbirths.
RESULTS
A total of 7020 (2.4%) infants and fetuses with one or more malformations were identified with these apparent etiologies in 26.6%: Mendelian disorders, including infants with postaxial polydactyly, type B; chromosome abnormalities; vascular disruption; complications of monozygous twinning; and environmental factors. The malformations of unknown etiology were a much larger group.
CONCLUSION
While several causes of malformations have been identified, many remain unexplained. Combining the ascertainment in a future surveillance programs with genome sequencing and chromosome microarray analysis will increase significantly the number of malformations attributed to genetic mechanisms. Birth Defects Research 110:87-91, 2018.© 2018 Wiley Periodicals, Inc.
Topics: Boston; Chromosome Aberrations; Congenital Abnormalities; Female; Fetal Development; Fetus; Humans; Infectious Disease Transmission, Vertical; Maternal Exposure; Pregnancy; Prenatal Diagnosis
PubMed: 29377643
DOI: 10.1002/bdr2.1105 -
European Journal of Medical Genetics Nov 2022Associated congenital anomalies may be observed in cases with achondroplasia. The prevalence reported in the literature and the types of co-occurring congenital...
Associated congenital anomalies may be observed in cases with achondroplasia. The prevalence reported in the literature and the types of co-occurring congenital anomalies are variable between the reported studies. The aim of this study was to establish the prevalence and to describe the associated anomalies in cases with achondroplasia. This study included 25 cases ascertained from our registry of congenital anomalies including all terminations of pregnancy, stillbirths and live births between 1979 and 2007 in 387,067 consecutive births (the prevalence of achondroplasia was 6.4 per 100,000 births), and 223 cases ascertained from the French Little People organization built on the model of LPA (Little People of America, Inc.). Out of these 248 cases of achondroplasia 37 (14.9%) had associated anomalies including 4 (1.6%) cases with chromosomal abnormalities (2 trisomies 21, one 22 q11.2 deletion, and one 47, XXX), 2 (0.8%) cases with recognizable non-chromosomal conditions (one Moebius syndrome and one Pierre Robin sequence) and 31(12.5%) cases with MCA (multiple congenital anomalies). The 31 cases with MCA had 45 anomalies. Anomalies in the urogenital system (24.4%), the cardiovascular system (20.0%), the musculoskeletal system (15.5%), the central nervous system (11.1%), the eye (11.1%), and the orofacial system (8.8%) were the most common MCA. The overall prevalence of associated anomalies shows that the individuals with achondroplasia need a careful screening for other congenital anomalies.
Topics: Abnormalities, Multiple; Achondroplasia; Chromosome Aberrations; Congenital Abnormalities; Down Syndrome; Female; Humans; Pregnancy; Prevalence; Registries; Trisomy
PubMed: 36150686
DOI: 10.1016/j.ejmg.2022.104612 -
Clinical Genetics Jan 2017Overgrowth syndromes are characterized by global or localized disproportionate growth associated with other anomalies, including vascular malformations and neurological... (Review)
Review
Overgrowth syndromes are characterized by global or localized disproportionate growth associated with other anomalies, including vascular malformations and neurological and/or visceral disorders. CLOVES (Congenital Lipomatous asymmetric Overgrowth of the trunk with lymphatic, capillary, venous, and combined-type Vascular malformations, Epidermal naevi, Scoliosis/Skeletal and spinal anomalies) is an overgrowth syndrome caused by mosaic activating mutation in gene PIK3CA, which gives rise to abnormal PI3K-AKT-mTOR pathway activation. These mutations are responsible for the clinical manifestations of the syndrome, which include low- and high-flow vascular malformations, thoracic lipomatous hyperplasia, asymmetric growth, and visceral and neurological disorders. These common anomalies are illustrated with figures from two personal cases. Identification of the clinical and genetic characteristics of CLOVES syndrome is crucial for the differential diagnosis with other overgrowth syndromes, such as Proteus or Klippel-Trenaunay (K-T) syndromes, and for the therapeutic management of the different anomalies. In this context, a new entity comprising different syndromes with phenotypic mutations in PIK3CA has been proposed, designated PIK3CA-related overgrowth spectrum (PROS), with the aim of facilitating clinical management and establishing appropriate genetic study criteria.
Topics: Abnormalities, Multiple; Class I Phosphatidylinositol 3-Kinases; Growth Disorders; Humans; Lipoma; Musculoskeletal Abnormalities; Mutation; Nevus; Phosphatidylinositol 3-Kinases; Syndrome; Vascular Malformations
PubMed: 27426476
DOI: 10.1111/cge.12832