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Human Mutation Sep 2018Malan syndrome is an overgrowth disorder described in a limited number of individuals. We aim to delineate the entity by studying a large group of affected individuals....
Malan syndrome is an overgrowth disorder described in a limited number of individuals. We aim to delineate the entity by studying a large group of affected individuals. We gathered data on 45 affected individuals with a molecularly confirmed diagnosis through an international collaboration and compared data to the 35 previously reported individuals. Results indicate that height is > 2 SDS in infancy and childhood but in only half of affected adults. Cardinal facial characteristics include long, triangular face, macrocephaly, prominent forehead, everted lower lip, and prominent chin. Intellectual disability is universally present, behaviorally anxiety is characteristic. Malan syndrome is caused by deletions or point mutations of NFIX clustered mostly in exon 2. There is no genotype-phenotype correlation except for an increased risk for epilepsy with 19p13.2 microdeletions. Variants arose de novo, except in one family in which mother was mosaic. Variants causing Malan and Marshall-Smith syndrome can be discerned by differences in the site of stop codon formation. We conclude that Malan syndrome has a well recognizable phenotype that usually can be discerned easily from Marshall-Smith syndrome but rarely there is some overlap. Differentiation from Sotos and Weaver syndrome can be made by clinical evaluation only.
Topics: Abnormalities, Multiple; Adolescent; Adult; Bone Diseases, Developmental; Child; Child, Preschool; Chromosome Deletion; Congenital Hypothyroidism; Craniofacial Abnormalities; Developmental Disabilities; Exons; Female; Hand Deformities, Congenital; Humans; Intellectual Disability; Male; Megalencephaly; Mutation, Missense; NFI Transcription Factors; Phenotype; Septo-Optic Dysplasia; Sotos Syndrome; Young Adult
PubMed: 29897170
DOI: 10.1002/humu.23563 -
Ryoikibetsu Shokogun Shirizu 2000
Review
Topics: Abnormalities, Multiple; Bone and Bones; Craniofacial Abnormalities; Diagnosis, Differential; Genes, Dominant; Growth Disorders; Humans; Intellectual Disability; Limb Deformities, Congenital; Prognosis; Syndrome
PubMed: 11057220
DOI: No ID Found -
Ryoikibetsu Shokogun Shirizu 2001
Review
Topics: Abnormalities, Multiple; Bone Diseases, Developmental; Craniofacial Abnormalities; Female; Growth Disorders; Humans; Infant, Newborn; Male; Syndrome
PubMed: 11529033
DOI: No ID Found -
Journal of Medical Genetics May 1992
Topics: Adult; Aging; Behavior; Child, Preschool; Diagnosis, Differential; Endocrine Glands; Face; Female; Growth Disorders; Humans; Infant; Male; Skull; Syndrome
PubMed: 1583661
DOI: 10.1136/jmg.29.5.332 -
Clinical Genetics Apr 2023The SUZ12 gene encodes a subunit of polycomb repressive complex 2 (PRC2) that is essential for development by silencing the expression of multiple genes. Germline... (Review)
Review
The SUZ12 gene encodes a subunit of polycomb repressive complex 2 (PRC2) that is essential for development by silencing the expression of multiple genes. Germline heterozygous variants in SUZ12 have been found in Imagawa-Matsumoto syndrome (IMMAS) characterized by overgrowth and multiple dysmorphic features. Similarly, both EZH2 and EED also encode a subunit of PRC2 each and their pathogenic variants cause Weaver syndrome and Cohen-Gibson syndrome, respectively. Clinical manifestations of these syndromes significantly overlap, although their different prevalence rates have recently been noted: generalized overgrowth, intellectual disability, scoliosis, and excessive loose skin appear to be less prevalent in IMMAS than in the other two syndromes. We could not determine any apparent genotype-phenotype correlation in IMMAS. The phenotype of neurofibromatosis type 1 arising from NF1 deletion was also shown to be modified by the deletion of SUZ12, 560 kb away. This review deepens our understanding of the clinical and genetic characteristics of IMMAS together with other overgrowth syndromes related to PRC2. We also report on a novel IMMAS patient carrying a splicing variant (c.1023+1G>C) in SUZ12. This patient had a milder phenotype than other previously reported IMMAS cases, with no macrocephaly or overgrowth phenotypes, highlighting the clinical variation in IMMAS.
Topics: Humans; Abnormalities, Multiple; Craniofacial Abnormalities; Intellectual Disability; Phenotype; Polycomb Repressive Complex 2
PubMed: 36645289
DOI: 10.1111/cge.14296 -
Journal of Pediatric Hematology/oncology Oct 2008Overgrowth syndromes such as Beckwith-Wiedemann syndrome, Sotos syndrome, and Weaver syndrome have an increased risk of neoplasia. Two previous cases of neuroblastoma...
Overgrowth syndromes such as Beckwith-Wiedemann syndrome, Sotos syndrome, and Weaver syndrome have an increased risk of neoplasia. Two previous cases of neuroblastoma have been reported in children with Weaver syndrome. We present a third description of a patient with Weaver syndrome and neuroblastoma. In a child with phenotypic characteristics consistent with Weaver syndrome, evaluation for neuroblastoma should be considered.
Topics: Abnormalities, Multiple; Female; Histone Methyltransferases; Histone-Lysine N-Methyltransferase; Humans; Infant; Intracellular Signaling Peptides and Proteins; Neuroblastoma; Nuclear Proteins; Syndrome
PubMed: 19011474
DOI: 10.1097/MPH.0b013e3181758974 -
Pediatrics Dec 1991A female child with Weaver syndrome is described. She did not show the excessive growth characteristic of this syndrome until after adequate caloric intake was achieved... (Review)
Review
A female child with Weaver syndrome is described. She did not show the excessive growth characteristic of this syndrome until after adequate caloric intake was achieved by feeding through a gastric feeding tube. Her inadequate nutrition was a result of feeding difficulties during infancy. In addition, she had recurrent pulmonary infections, apneic spells, and severe developmental delay. She died at 16 months of sepsis, congestive heart failure, and respiratory arrest. The autopsy revealed marked atrophy of the brain and cardiac ventricular hypertrophy. Most of the brain changes were thought to be from hypoxia.
Topics: Congenital Abnormalities; Female; Growth Disorders; Humans; Infant, Newborn; Syndrome
PubMed: 1956726
DOI: No ID Found -
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 -
American Journal of Medical Genetics.... Dec 2013Weaver syndrome, first described in 1974, is characterized by tall stature, a typical facial appearance, and variable intellectual disability. In 2011, mutations in the...
Weaver syndrome, first described in 1974, is characterized by tall stature, a typical facial appearance, and variable intellectual disability. In 2011, mutations in the histone methyltransferase, EZH2, were shown to cause Weaver syndrome. To date, we have identified 48 individuals with EZH2 mutations. The mutations were primarily missense mutations occurring throughout the gene, with some clustering in the SET domain (12/48). Truncating mutations were uncommon (4/48) and only identified in the final exon, after the SET domain. Through analyses of clinical data and facial photographs of EZH2 mutation-positive individuals, we have shown that the facial features can be subtle and the clinical diagnosis of Weaver syndrome is thus challenging, especially in older individuals. However, tall stature is very common, reported in >90% of affected individuals. Intellectual disability is also common, present in ~80%, but is highly variable and frequently mild. Additional clinical features which may help in stratifying individuals to EZH2 mutation testing include camptodactyly, soft, doughy skin, umbilical hernia, and a low, hoarse cry. Considerable phenotypic overlap between Sotos and Weaver syndromes is also evident. The identification of an EZH2 mutation can therefore provide an objective means of confirming a subtle presentation of Weaver syndrome and/or distinguishing Weaver and Sotos syndromes. As mutation testing becomes increasingly accessible and larger numbers of EZH2 mutation-positive individuals are identified, knowledge of the clinical spectrum and prognostic implications of EZH2 mutations should improve.
Topics: Abnormalities, Multiple; Adolescent; Child; Child, Preschool; Chromosome Deletion; Congenital Hypothyroidism; Craniofacial Abnormalities; Developmental Disabilities; Enhancer of Zeste Homolog 2 Protein; Female; Growth Disorders; Hand Deformities, Congenital; Humans; Intellectual Disability; Male; Mutation; Phenotype; Polycomb Repressive Complex 2; Sotos Syndrome
PubMed: 24214728
DOI: 10.1002/ajmg.a.36229 -
American Journal of Medical Genetics Nov 1991We report on 2 Japanese patients (a 3-year-old girl and an 20-month-old boy) with the Weaver syndrome. The clinical manifestations are mild mental retardation,... (Review)
Review
We report on 2 Japanese patients (a 3-year-old girl and an 20-month-old boy) with the Weaver syndrome. The clinical manifestations are mild mental retardation, overgrowth with accelerated bone age, minor facial anomalies including broad forehead, mild hypertelorism, depressed nasal bridge, accentuated philtrum, micrognathia and large ears, and unique behavior characteristics with some social withdrawal. The nosology of the Weaver and Simpson-Golabi-Behmel syndromes is discussed.
Topics: Abnormalities, Multiple; Age Determination by Skeleton; Child, Preschool; Face; Female; Growth Disorders; Humans; Infant; Intellectual Disability; Male; Shyness; Syndrome
PubMed: 1785638
DOI: 10.1002/ajmg.1320410218