-
Zhonghua Yi Xue Yi Chuan Xue Za Zhi =... Oct 2021Perlman syndrome is a rare autosomal recessive congenital overgrowth syndrome caused by pathogenic variants of the DIS3L2 gene at 2q37 region. Clinically this syndrome...
Perlman syndrome is a rare autosomal recessive congenital overgrowth syndrome caused by pathogenic variants of the DIS3L2 gene at 2q37 region. Clinically this syndrome is characterized by polyhydramnios, macrosomia, distinctive facial appearance, and renal dysplasia. Prognosis of the disease is poor, and survivors usually have mental delay and a high risk of developing Wilms tumor. At present, the pathogenesis of this disease is still poorly understood. This article intends to provide a review for this disease.
Topics: Female; Fetal Macrosomia; Humans; Kidney Tubules, Proximal; Pregnancy; Syndrome; Wilms Tumor
PubMed: 34625946
DOI: 10.3760/cma.j.cn511374-20200717-00525 -
Current Opinion in Pediatrics Dec 2019To provide an update of vascular malformation syndromes by reviewing the most recent articles on the topic and following the new International Society for the Study of... (Review)
Review
PURPOSE OF REVIEW
To provide an update of vascular malformation syndromes by reviewing the most recent articles on the topic and following the new International Society for the Study of Vascular Anomalies (ISSVA) 2018 classification.
RECENT FINDINGS
This review discusses the main features and diagnostic approaches of the vascular malformation syndromes, the new genetic findings and the new therapeutic strategies developed in recent months.
SUMMARY
Some vascular malformations can be associated with other anomalies, such as tissue overgrowth. PIK3CA-related overgrowth spectrum (PROS) is a group of rare genetic disorders with asymmetric overgrowth caused by somatic mosaic mutations in PI3K-AKT-mTOR pathway that encompass a heterogeneous group of rare disorder that are associated with the appearance of overgrowth. CLOVES syndrome and Klippel-Trénaunay syndrome are PROS disease. Proteus syndrome is an overgrowth syndrome caused by a somatic activating mutation in AKT1. CLOVES, Klippel-Trénaunay and Proteus syndromes are associated with high risk of thrombosis and pulmonary embolism. Hereditary hemorrhagic telangiectasia is an autosomic dominant disorder characterized by the presence of arteriovenous malformations. New therapeutic strategies with bevacizumab and thalidomide have been employed with promising results.
Topics: Abnormalities, Multiple; Bevacizumab; Class I Phosphatidylinositol 3-Kinases; Growth Disorders; Humans; Musculoskeletal Abnormalities; Mutation; Phosphatidylinositol 3-Kinase; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Syndrome; TOR Serine-Threonine Kinases; Thalidomide; Vascular Malformations
PubMed: 31693582
DOI: 10.1097/MOP.0000000000000812 -
American Journal of Medical Genetics.... Jan 2017DNA methylation plays a critical role in both embryonic development and tumorigenesis and is mediated through various DNA methyltransferases. Constitutional mutations in... (Review)
Review
DNA methylation plays a critical role in both embryonic development and tumorigenesis and is mediated through various DNA methyltransferases. Constitutional mutations in the de novo DNA methyltransferase DNMT3A cause a recently identified Tatton-Brown-Rahman overgrowth syndrome (TBRS). Somatically acquired mutations in DNMT3A are causally associated with acute myeloid leukemia (AML), and p.Arg882His represents the most prevalent hotspot. So far, no patients with TBRS have been reported to have subsequently developed AML. Here, we report a live birth and the survival of a female with the TBRS phenotype who had a heterozygous constitutional DNMT3A mutation at the AML somatic mutation hotspot p.Arg882His in her DNA from peripheral blood and buccal tissue. Her characteristic features at birth included hypotonia, narrow palpebral fissures, ventricular septal defect, umbilical hernia, sacral cyst, Chiari type I anomaly. At the age of 6 years, she exhibited overgrowth (> 3 SD) and round face and intellectual disability. This report represents the first documentation of the same variant (DNMT3A p.Arg882His) as both the constitutional mutation associated with TBRS and the somatic mutation hotspot of AML. The observation neither confirms nor denies the notion that mutations responsible for TBRS and those for AML might share the same mode of action. Larger data sets are required to determine whether TBRS patients with constitutional DNMT3A mutations are at an increased risk for AML. © 2016 Wiley Periodicals, Inc.
Topics: Amino Acid Substitution; Child, Preschool; Codon; DNA (Cytosine-5-)-Methyltransferases; DNA Methylation; DNA Methyltransferase 3A; DNA Mutational Analysis; Female; Genetic Association Studies; Growth Charts; High-Throughput Nucleotide Sequencing; Humans; Leukemia, Myeloid, Acute; Mutation; Phenotype; Syndrome
PubMed: 27991732
DOI: 10.1002/ajmg.a.37995 -
Pediatric Endocrinology Reviews : PER Jun 2020Hypoglycaemia is the most common metabolic health complication in newborns. Persistent and severe hypoglycaemia in a neonate is correlated with morbidity and could... (Review)
Review
Hypoglycaemia is the most common metabolic health complication in newborns. Persistent and severe hypoglycaemia in a neonate is correlated with morbidity and could represent an early clinical manifestation of an endocrine or metabolic, genetically determined disorder. Besides this, the most common reason for neonatal hypoglycaemia is the inmature liver storage of glucose seen in preterms or children born intrauterine growth retarded. The genetic determination of hypoglycaemia is gene- and allele- heterogeneous, and thus complex to diagnose. Nevertheless its contribution to brain damage and intellectual disability in children provides a strong rationale for comprehensive and rapid testing. Hypoglycaemia may contribute directly to the phenotype of various genetic syndromes but because of their rarity, it has been not always included in differential diagnosis and its frequency has been underestimated. In clinical practice but also with the growing attention to improved neonatal helathcare and to neonatal genetic screening programmes, the detailed classification of genotype to phenotype is of great importance. This review provides a catalogue of syndromic forms of neonatal hypoglycaemia.
Topics: Genetic Testing; Genotype; Glucose; Humans; Hypoglycemia; Infant, Newborn; Phenotype
PubMed: 32741157
DOI: 10.17458/per.vol17.2020.z.geneticsneonatalhypoglycaemia -
Annals of Plastic Surgery May 2023Hyperactivation of the PI3K/AKT/mTOR signaling pathway caused by PIK3CA mutations is associated with a category of overgrowth syndromes that are defined as PIK3CA... (Review)
Review
Hyperactivation of the PI3K/AKT/mTOR signaling pathway caused by PIK3CA mutations is associated with a category of overgrowth syndromes that are defined as PIK3CA -related overgrowth spectrum (PROS). The clinical features of PROS are highly heterogeneous and usually present as vascular malformations, bone and soft tissue overgrowth, and neurological and visceral abnormalities. Detection of PIK3CA variants is necessary for diagnosis and provides the basis for targeted therapy for PROS. Drugs that inhibit the PI3K pathway offer alternatives to conventional therapies. This article reviews the current knowledge of PROS and summarizes the latest progress in precise treatment, providing new insights into future therapies and research goals.
Topics: Humans; Phosphatidylinositol 3-Kinases; Mutation; Signal Transduction; Class I Phosphatidylinositol 3-Kinases; Syndrome; Vascular Malformations
PubMed: 36729078
DOI: 10.1097/SAP.0000000000003389 -
Radiographics : a Review Publication of... 2019Congenital limb length discrepancy disorders are frequently associated with a variety of vascular anomalies and have unique genetic and phenotypic features. Many of... (Review)
Review
Congenital limb length discrepancy disorders are frequently associated with a variety of vascular anomalies and have unique genetic and phenotypic features. Many of these syndromes have been linked to sporadic somatic mosaicism involving mutations of the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway, which has an important role in tissue growth and angiogenesis. Radiologists who are aware of congenital limb length discrepancies can make specific diagnoses based on imaging findings. Although genetic confirmation is necessary for a definitive diagnosis, the radiologist serves as a central figure in the identification and treatment of these disorders. The clinical presentations, diagnostic and imaging workups, and treatment options available for patients with Klippel-Trenaunay syndrome, CLOVES (congenital lipomatous overgrowth, vascular anomalies, epidermal nevi, and scoliosis/spinal deformities) syndrome, fibroadipose vascular anomaly, phosphatase and tensin homolog mutation spectrum, Parkes-Weber syndrome, and Proteus syndrome are reviewed. RSNA, 2019.
Topics: Abnormalities, Multiple; Female; Humans; Klippel-Trenaunay-Weber Syndrome; Limb Deformities, Congenital; Lipoma; Lower Extremity; Male; Musculoskeletal Abnormalities; Nevus; Proteus Syndrome; Sturge-Weber Syndrome; Syndrome; Vascular Malformations
PubMed: 30844349
DOI: 10.1148/rg.2019180136 -
Frontiers in Endocrinology 2023Congenital hyperinsulinism (CHI), also called hyperinsulinemic hypoglycemia (HH), is a very heterogeneous condition and represents the most common cause of severe and... (Review)
Review
Congenital hyperinsulinism (CHI), also called hyperinsulinemic hypoglycemia (HH), is a very heterogeneous condition and represents the most common cause of severe and persistent hypoglycemia in infancy and childhood. The majority of cases in which a genetic cause can be identified have monogenic defects affecting pancreatic β-cells and their glucose-sensing system that regulates insulin secretion. However, CHI/HH has also been observed in a variety of syndromic disorders. The major categories of syndromes that have been found to be associated with CHI include overgrowth syndromes (e.g. Beckwith-Wiedemann and Sotos syndromes), chromosomal and monogenic developmental syndromes with postnatal growth failure (e.g. Turner, Kabuki, and Costello syndromes), congenital disorders of glycosylation, and syndromic channelopathies (e.g. Timothy syndrome). This article reviews syndromic conditions that have been asserted by the literature to be associated with CHI. We assess the evidence of the association, as well as the prevalence of CHI, its possible pathophysiology and its natural course in the respective conditions. In many of the CHI-associated syndromic conditions, the mechanism of dysregulation of glucose-sensing and insulin secretion is not completely understood and not directly related to known CHI genes. Moreover, in most of those syndromes the association seems to be inconsistent and the metabolic disturbance is transient. However, since neonatal hypoglycemia is an early sign of possible compromise in the newborn, which requires immediate diagnostic efforts and intervention, this symptom may be the first to bring a patient to medical attention. As a consequence, HH in a newborn or infant with associated congenital anomalies or additional medical issues remains a differential diagnostic challenge and may require a broad genetic workup.
Topics: Infant; Infant, Newborn; Humans; Child; Congenital Hyperinsulinism; Beckwith-Wiedemann Syndrome; Insulin Secretion; Glucose
PubMed: 37065762
DOI: 10.3389/fendo.2023.1013874 -
Journal of Pediatric Surgery Jul 2002Proteus syndrome is a rare, sporadic disorder consisting of disproportionate overgrowth of multiple tissues, vascular malformations, and connective tissue or epidermal... (Review)
Review
BACKGROUND
Proteus syndrome is a rare, sporadic disorder consisting of disproportionate overgrowth of multiple tissues, vascular malformations, and connective tissue or epidermal nevi. Patients with Proteus syndrome present with diverse and variable phenotypes because of the syndrome's mosaic pattern of distribution.
METHODS
Eighty patients with Proteus syndrome, satisfying published diagnostic criteria, and 51 patients with overgrowth not meeting Proteus criteria were identified from the literature. Three additional patients, one patient with Proteus syndrome and 2 patients with overgrowth, were treated at the author's institutions and are discussed in detail. All nonorthopedic and noncutaneous surgical interventions were reviewed.
RESULTS
Fourteen genitourinary, 9 gastrointestinal, and 5 otolaryngologic operations were performed on patients with Proteus syndrome. Six genitourinary, 5 gastrointestinal, and 2 otolaryngologic operations were performed on patients with overgrowth not meeting Proteus criteria. Eight patients with Proteus syndrome and 4 patients with overgrowth experienced thoracic manifestations, generally diffuse cystic pulmonary lesions, but only 1 of 12 underwent surgical treatment.
CONCLUSIONS
Patients with visceral manifestations of either Proteus syndrome or overgrowth not meeting Proteus criteria should be treated in a similar manner. Lesions involving the ovaries and testes, because of the high incidence of neoplasm, should be managed aggressively. Gastrointestinal and renal lesions may be managed conservatively with frequent follow-up to minimize abdominal explorations. All patients undergoing surgery should have a thorough preoperative assessment of their airway and pulmonary reserve because of the relatively high frequency of tonsillar hypertrophy and pulmonary cystic involvement.
Topics: Adolescent; Female; Humans; Infant; Laparotomy; Male; Proteus Syndrome
PubMed: 12077761
DOI: 10.1053/jpsu.2002.33832 -
Nature Communications Jul 2021Germline pathogenic variants in DNMT3A were recently described in patients with overgrowth, obesity, behavioral, and learning difficulties (DNMT3A Overgrowth...
Germline pathogenic variants in DNMT3A were recently described in patients with overgrowth, obesity, behavioral, and learning difficulties (DNMT3A Overgrowth Syndrome/DOS). Somatic mutations in the DNMT3A gene are also the most common cause of clonal hematopoiesis, and can initiate acute myeloid leukemia (AML). Using whole genome bisulfite sequencing, we studied DNA methylation in peripheral blood cells of 11 DOS patients and found a focal, canonical hypomethylation phenotype, which is most severe with the dominant negative DNMT3A mutation. A germline mouse model expressing the homologous Dnmt3a mutation phenocopies most aspects of the human DOS syndrome, including the methylation phenotype and an increased incidence of spontaneous hematopoietic malignancies, suggesting that all aspects of this syndrome are caused by this mutation.
Topics: Abnormalities, Multiple; Adolescent; Adult; Animals; Behavior, Animal; Body Weight; Bone Marrow Cells; Child; Child, Preschool; CpG Islands; DNA (Cytosine-5-)-Methyltransferases; DNA Methylation; DNA Methyltransferase 3A; Epigenesis, Genetic; Female; Gene Expression Profiling; Germ-Line Mutation; Hematopoiesis; Hematopoietic Stem Cells; Humans; Infant; Leukemia; Male; Mice, Inbred C57BL; Obesity; Phenotype; Syndrome; Transcription, Genetic; Mice
PubMed: 34315901
DOI: 10.1038/s41467-021-24800-7 -
American Journal of Medical Genetics Feb 1998We report on a patient with Nevo syndrome manifesting intrauterine and postpartum overgrowth, accelerated osseous maturation, dolichocephaly, highly arched palate,...
We report on a patient with Nevo syndrome manifesting intrauterine and postpartum overgrowth, accelerated osseous maturation, dolichocephaly, highly arched palate, large, low-set ears, cryptorchidism, delayed neuropsychological development, hypotonia, adema, contractures of the hands and feet, a single a transverse palmar crease, and tapering digits. After meningococcal sepsis at age 6 months, he remained decerebrate. Thereafter, overgrowth and especially weight gain were extremely accelerated until his death at age 18 months, at which time his height was 103 cm and his weight was 23 kg. In addition to low plasma concentrations of growth hormone and insulin-like growth factor, severe insulin resistance was observed. It is presumed that a selective defect in insulin-stimulated glucose uptake, with preservation of anabolic effect, was one of the causes of his "overgrowth without growth hormone," at least in the last 12 months of life after severe brain damage.
Topics: Blood Glucose; Edema; Growth Disorders; Human Growth Hormone; Humans; Infant; Insulin Resistance; Islets of Langerhans; Male; Muscle Hypotonia; Somatomedins; Syndrome
PubMed: 9508068
DOI: 10.1002/(sici)1096-8628(19980226)76:1<67::aid-ajmg12>3.3.co;2-u