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A 22 year old female with Sotos syndrome and a small cell lung carcinoma is described. This case is of interest not only because of the somatic growth pattern, atypical of Sotos syndrome, but also because of the association with a rare tumour. Of significance is the possible role of mutations at 3p21 in the aetiology of Sotos syndrome and tumour de...
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Background: Genetic studies of late-onset sporadic ataxias (>40 years of age) are not routinely indicated. For unresolved cases, next-generation sequencing (NGS) tools, such as whole-exome sequencing (WES), are available for a definitive diagnosis.
Case presentation: Our patient is a woman with a usual facial phenotype and anthropometry, who develo...
Background
Extremely tall children (defined as height SDS (HSDS) ≥+3) are frequently referred to specialized healthcare for diagnostic work-up. However, no systematic studies focusing on such children currently exist. We investigated the aetiology, clinical features, and auxological clues indicative of syndromic tall stature in extremely tall child...
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 the...
Background:
Research investigating cognition and behaviour in Sotos syndrome has been sporadic and to date, there is no published overview of study findings.
Method:
A systematic review of all published literature (1964-2015) presenting empirical data on cognition and behaviour in Sotos syndrome. Thirty four journal articles met inclusion criter...
Citations
... Targeted studies are needed to assess the real risk of lung cancer in persons with ID. Various histological types have been reported: adenocarcinoma [14], small cell carcinoma [15], carcinoid [16], synovial sarcoma [17], and lymphoma of the lung [18]. ...
... Because he had a history of imagining illnesses, his family and doctors did not believe him when he first complained of chest pain [45,46]. The eighth patient, a 22-year-old woman with Sotos syndrome, was admitted at a metastatic stage one month before death with significant weight loss, cough, dyspnea, and lethargy [15]. ...
As the life expectancy of people with intellectual disability (ID) has progressed, they have become similarly at risk of cancer as individuals of the general population. Epidemiological studies indicate a reduced incidence and mortality from lung cancer in the total population of persons with ID. However, the pattern is heterogeneous and the risk is strongly correlated with the impairment level; persons with mild intellectual impairment have higher cancer risk, and this subgroup also has the highest tobacco consumption (the major risk factor for lung cancer) compared to individuals with more severe impairment. Clinical
presentation of lung cancer in persons with ID is often atypical, with symptoms frequently hidden by the mental state and communication impairments. Treatment can be impeded by incomplete understanding and lack of cooperation on the part of the patient; nevertheless, general principles for treating lung cancer must be applied to persons with ID. Early diagnosis and implementation of an adapted treatment plan may result in lung cancer outcomes similar to those of individuals in the general population. Physicians facing the difficult task of treating lung cancer in persons with ID are called to carry out their mission of care in a responsible, free, and creative way.
... У 1992 р. Cole and Hughes в огляді, що базувався на спостереженні 79 пацієнтів віком від 1 до 6 років, запропонували такі критерії захворювання: специфічний фенотип обличчя, прискорений соматичний розвиток, прискорений кістковий вік, затримка інтелектуального розвитку [8]. ...
Стаття присвячена проблемі орфанних (рідкісних) захворювань у нейропедіатричній практиці, а саме синдрому Сотоса. На підставі аналізу сучасної літератури подано детальний опис клінічної картини, підходів до діагностики і лікування цього захворювання. Особливу увагу в статті приділено питанню поєднання синдрому Сотоса із розладами аутистичного спектра в дітей. У наш час ця проблема мало представлена как у зарубіжній, так і у вітчизняній літературі. При обстеженні пацієнтів із розладами аутистичного спектра або затримкою психомовленнєвого розвитку у спеціалістів повинна бути настороженість щодо генетичних синдромів, які можуть лежати в основі захворювання.
... An apparently balanced translocation t(3;6)( p21;p21) was found in a 6-year-old boy with mental retardation, postnatal overgrowth and facial dysmorphism. 28 Another report published in 1992 described a non-smoking female with Sotos-like syndrome (including excessive growth during childhood, accelerated osseous maturation, developmental delay, incoordination) who died of small cell lung cancer at the unusually young age of 22. 29 Tumour cells showed a loss of heterozygosity of markers at region 3p2l. ...
Background:
Overgrowth conditions are a heterogeneous group of disorders characterised by increased growth and variable features, including macrocephaly, distinctive facial appearance and various degrees of learning difficulties and intellectual disability. Among them, Sotos and Weaver syndromes are clinically well defined and due to heterozygous mutations in NSD1 and EZH2, respectively. NSD1 and EZH2 are both histone-modifying enzymes. These two epigenetic writers catalyse two specific post-translational modifications of histones: methylation of histone 3 lysine 36 (H3K36) and lysine 27 (H3K27). We postulated that mutations in writers of these two chromatin marks could cause overgrowth conditions, resembling Sotos or Weaver syndromes, in patients with no NSD1 or EZH2 abnormalities.
Methods:
We analysed the coding sequences of 14 H3K27 methylation-related genes and eight H3K36 methylation-related genes using a targeted next-generation sequencing approach in three Sotos, 11 'Sotos-like' and two Weaver syndrome patients.
Results:
We identified two heterozygous mutations in the SETD2 gene in two patients with 'Sotos-like' syndrome: one missense p.Leu1815Trp de novo mutation in a boy and one nonsense p.Gln274* mutation in an adopted girl. SETD2 is non-redundantly responsible for H3K36 trimethylation. The two probands shared similar clinical features, including postnatal overgrowth, macrocephaly, obesity, speech delay and advanced carpal ossification.
Conclusions:
Our results illustrate the power of targeted next-generation sequencing to identify rare disease-causing variants. We provide a compelling argument for Sotos and Sotos-like syndromes as epigenetic diseases caused by loss-of-function mutations of epigenetic writers of the H3K36 histone mark.
... Combining this new patient, 15 Spanish Overgrowth Registry patients and 11 literature cases [Halal, 1982;Cole et al., 1992;Koenekoop et al., 1995;Inoue et al., 2000;Yen et al., 2000;Cefle et al., 2002;Compton et al., 2004;Tatton-Brown et al., 2005;Martinez-Glez and Lapunzina, 2007;Zechner et al., 2009], there were a total of 27 adults who met clinical diagnostic criteria for Sotos syndrome. Twenty-one of 27 patients (78%) had NSD1 molecular confirmation (Table I). ...
... Three adults from the literature had cancer, including retinoblastoma (RB1 negative) [Martinez-Glez and Lapunzina, 2007], small cell carcinoma [Cole et al., 1992], and acute lymphoblastic leukemia [Fryer, personal communication]. Our patient had numerous nonmelanoma skin cancers and pre-cancers, with unclear age of onset, but in approximately the sixth decade. ...
Sotos syndrome is a well-described multiple anomaly syndrome characterized by overgrowth, distinctive craniofacial appearance, and variable learning disabilities. The diagnosis of Sotos syndrome relied solely on these clinical criteria until haploinsufficiency of the NSD1 gene was identified as causative. We describe a 63-year-old woman with classic features and a pathogenic NSD1 mutation, who we believe to be the oldest reported person with Sotos syndrome. She is notable for the diagnosis of Sotos syndrome late in life, mild cognitive limitation, and chronic kidney disease attributed to fibromuscular dysplasia for which she recently received a transplant. She has basal cell and squamous cell carcinoma for which her lifetime of sun exposure and fair cutaneous phototype are viewed as risk factors. We also reviewed previous literature reports (n = 11) for adults with Sotos syndrome, and studied patients ascertained in the Spanish Overgrowth Syndrome Registry (n = 15). Analysis was limited to 21/27 (78%) total patients who had molecular confirmation of Sotos syndrome (15 with a mutation, 6 with a microdeletion). With a mean age of 26 years, the most common features were learning disabilities (90%), scoliosis (52%), eye problems (43%), psychiatric issues (30%), and brain imaging anomalies (28%). Learning disabilities were more severe in patients with a microdeletion than in those with a point mutation. From this small study with heterogeneous ascertainment we suggest modest adjustments to the general healthcare monitoring of individuals with Sotos syndrome. Although this series includes neoplasia in four cases, this should not be interpreted as incidence. Age-appropriate cancer surveillance should be maintained.
... a One case of hepatoblastoma Lapunzina, personal observation; not published. Cases reported by Sugarman et al., 1977;Seyedabadi et al., 1981;Maldonado et al., 1984;Nance et al., 1990;Cole et al., 1992;Hersh et al., 1992;Lippert, 1993;Corsello et al., 1996;Fabry et al., 1997;Le Marec et al., 1999;Muraishi et al., 1999;Yule, 1999;Leonard, 2000;Jin et al., 2002;Al-Mulla et al., 2004. There are at least 9 cases of SGBS with neoplasia; all tumors were intra-abdominal (4 Wilms tumors, 2 hepatoblastomas, 1 adrenal neuroblastoma, 1 gonadoblastoma and 1 hepatocellular carcinoma. ...
Overgrowth syndromes (OGS) comprise a heterogeneous group of disorders in which the main characteristic is that either weight, height, or head circumference is 2-3 standard deviations (SD) above the mean for sex and age. A striking feature of OGS is the risk of neoplasms. Here, the relative frequency of specific tumors in each OGS, topographic location, and age of appearance is determined by reviewing published cases. In some OGS (Perlman, Beckwith-Wiedemann, and Simpson-Golabi-Behmel syndromes and hemihyperplasia) more than 94% of tumors appeared in the abdomen usually before 10 years of age, mainly embryonal in type. In Perlman syndrome, only Wilms tumor has been recorded, whereas in Sotos syndrome, lympho-hematologic tumors are most frequent. Based on literature review, a specific schedule protocol for tumor screening is suggested for each OGS. A schedule with different intervals and specific tests is proposed for a more rational cost/benefit program for these disorders.
... In addition to Wilms' tumor, which occurs in a number of conditions with excessive growth, rare tumors of the stomach and lungs in children have been described. 19,20 The study of Sotos syndrome may shed light in the process involved in neuronal proliferation and growth of the brain. It may also be possible to describe the process involved in the initiation and termination of the growth process. ...
Sotos syndrome belongs to a group of neuroproliferative diseases associated with macrocephaly and excessive growth. Children with this syndrome are said to have a higher incidence of develop- mental and neurobehavioral problems. Most of the growth and developmental aberrations normalize by adulthood. Some of the genetic mechanisms involved in its inheritance are now known. During childhood, these children require early intervention and be- havioral therapy. In this review, the neurological, behavioral, and genetic aspects of the disease are described, the differential diag- nosis is discussed, and a brief presentation of a child with Sotos syndrome is presented. In view of the neurobehavioral abnormali- ties and the higher risk of malignancies, it is important to make the
... The left testicular swelling did not transillumi-with Sotos syndrome, including hepatocarcinoma, Wilms' tumour, vaginal carcinoma and small cell lung nate and testicular ultrasonography revealed a left testicular tumour. His serum AFP, at 6758 ng/mL (normal carcinoma [2,3]. A review of the world literature revealed no reported case of testicular tumour in Sotos <7 ng/mL) was remarkably elevated. ...
Macrocephaly, defined as head circumference ≥ 2 SDs, is a cardinal feature of Sotos syndrome (SS) and generally persists in adulthood. Subdural fluid collection, typically associated with macrocephaly, is described in children due to anatomical conformation, and in adulthood due to brain atrophy and ex‐vacuo hydrocephalus. On the other hand, a true, symptomatic, chronic subdural hematoma (CSH) is a previously unreported complication of SS in adulthood. Here we describe the first SS patient presenting symptomatic CSH, leading to frequent hospitalizations for surgical evacuations that consistently recurred. Middle meningeal artery (MMA) embolization and epidural blood patch (EBP) allowed to resolve the CSH with complete resolution of clinical signs and symptoms. We hypothesize that appearance and recurrences of CSH may be related to pathological biomechanics of brain, cerebro‐spinal fluid and skull, secondary to anatomical features of SS. In this context, surgical evacuation may be less efficient than usual to cure CSH. Alternative treatment to avoid blood extravasation, as MMA embolization, or to cure concurrent causes of the pathology, as EBP, may be considered.
Septo-Optic Dysplasia (SOD) is a highly variable developmental abnormality of the midline structures of the brain, classically resulting in hypoplasia of the optic nerves, absence of the septum pellucidum and dysgenesis of the pituitary gland. The homeobox gene Hesx1 is a transcriptional repressor expressed at gastrulation within the anterior midline visceral endoderm, with subsequent expression in the prosencephalon and Rathke's pouch. Hesx1 null mutant mice manifest a phenotype similar to SOD in man and this led to the successful characterisation of a recessive HESX1 mutation within two familial cases (Dattani et al., 1998). However, the cohort sample size was too small to draw general conclusion about the role of HESX1 in SOD. This thesis investigated the role of HESX1 in SOD, particularly sporadic cases, and involved the collection of the largest cohort of SOD and SOD-like phenotypes to date (n=670). Mutation screening of HESX1 was carried out using both SSCP detection and d-HPLC heteroduplex detection. The mutation screen identified a number of heterozygous sequence variants of which two appear to be mutations (S170L and E149K). An S170L mutation was identified in a sporadic case of growth hormone deficiency and an ectopic posterior pituitary. This mutation had been previously described in a sib pair and functional analysis carried out (Thomas et al., 2001 and Brickman et al, 2002). An E149K variant was identified in a child demonstrating growth hormone deficiency, hypoplasia of the anterior pituitary and an ectopic posterior pituitary. The E149K variant lies at position 42 of the homeodomain, at the first position of the third helix. This change is highly conserved and has not been found in 140 control chromosomes. Functional studies were undertaken to investigate the function of this variant, including in-vitro DNA binding assays and in-vitro transfection studies.
