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Sotos syndrome is an autosomal dominant genetic disorder caused by mutations in the NSD1 gene. In this study, we report a case of Sotos syndrome in a preterm infant. The main clinical manifestations were severe bronchopulmonary dysplasia, congenital heart disease, difficulty feeding, and characteristic facial appearance. The gene mutation was located at 177251854 on chromosome 5, and identified as a shear mutation, c.4765+1 G > A, which is a new mutation. The patient recovered well after symptomatic treatment. To the best of our knowledge, this is the first case of a preterm infant in whom a novel c.4765+1 G > A mutation in the NSD1 gene was identified. When premature infants present with abnormally severe bronchopulmonary dysplasia, feeding difficulties, and other congenital anomalies, Sotos syndrome should be considered. [ABSTRACT FROM AUTHOR]

Simple Summary: Epigenetic events, which comprise post-translational modifications of histone tails or DNA methylation, control gene expression by altering chromatin structure without change in the DNA sequence. Histone tails modifications are driven by specific cellular enzymes such as histone methyltransferases or histone acetylases, which play a key role in regulating diverse biological processes. Their alteration may have consequences on growth and tumorigenesis. Epigenetic regulations, that comprise histone modifications and DNA methylation, are essential to processes as diverse as development and cancer. Among the histone post-translational modifications, lysine methylation represents one of the most important dynamic marks. Here, we focused on methyltransferases of the nuclear binding SET domain 1 (NSD) family, that catalyze the mono- and di-methylation of histone H3 lysine 36. We review the loss of function mutations of NSD1 in humans that are the main cause of SOTOS syndrome, a disease associated with an increased risk of developing cancer. We then report the role of NSD1 in triggering tumor suppressive or promoter functions according to the tissue context and we discuss the role of NSD1 in melanoma. Finally, we examine the ongoing efforts to target NSD1 signaling in cancers. [ABSTRACT FROM AUTHOR]

Sotos syndrome is characterised by the presence of excessive growth during childhood, advanced bone age, macrocephaly, characteristic facial appearance and non-progressive learning difficulties [1]. It affects males and females in equal numbers. Its incidence is one in 14,000 live births. It was first described in 1964 by Dr. J.F. Sotos [2]. Until the early 2000s, diagnosis of Sotos syndrome was based upon the presence of characteristic clinical features as listed above [3]. It was subsequently discovered that mutations and deletions of the NSD1 (nuclear receptor-binding SET domain) gene - localised on chromosome 5q35.3, which codes for a histone methyltransferase implicated in transcriptional regulation - is responsible for more than 75 % of cases of Sotos syndrome [4]. In Europe and the USA, NSD1 mutations cause 60-80 % of cases of Sotos syndrome, whereby microdeletions of NSD1 cause approximately 10 % of cases. In contrast: in Japan, NSD1 microdeletions are the primary cause of Sotos syndrome in over 50 % of cases [4]. The function of the NSD1 gene has not yet been fully described. The gene codes for a histone methyltransferase, which acts as a transcriptional intermediary factor capable of both negatively and positively influencing transcription. NSD1 has been described as a "corepressor of genes that promote growth" [5]. While it remains unclear exactly how the malfunction of NSD1 leads to the features of Sotos syndrome, it is thought that mutations and microdeletions involving NSD1 disrupts the activity of genes involved in normal growth and development [4]. While over 95 % of cases are sporadic in aetiology, autosomal dominant inheritance has also been described in several cases [4]. As other genetic abnormalities were identified in patients with Sotos syndrome, patients with abnormalities of the NSD1 gene were later termed 'Sotos syndrome 1'. Heterozygous mutations in the NFIX (nuclear factor I, X type) on chromosome 19p13.3 were identified in a cohort of children with the Sotos syndrome phenotype. They were labelled 'Sotos syndrome 2' [6]. Furthermore, in 2015, a loss-of-function, frameshift mutation in the APC2 (adenomatous polyposis coli 2) gene was identified in two siblings with features of Sotos syndrome but without NSD1 mutations [7]. They exhibited intellectual disability, abnormal brain structure and typical facial features but no other features such as bone or heart abnormalities. The APC2 gene is a downstream regulator of the NSD1 gene and its expression is downregulated by abnormalities of the NSD1 gene, potentially explaining the resulting neurological manifestations [7]. This genotype-phenotype combination is now known as 'Sotos syndrome 3'. In Sotos syndrome, childhood growth is particularly advanced in the first year of life, after which it stabilises, before normalising in puberty. Height measurements are consistently above the 97th percentile in years 2-6, while final height is usually in the high normal range [4]. Craniofacial features are distinctive. The forehead tends to be overly prominent in infancy, while in adolescences an elongated face with a prominent chin is seen. Hypertelorism and down slanting palpebral fissures are common, as are receding hairline, prominent jaw, high arched palate, anteverted nostrils and long ears. Occipitofrontal circumference remains between the 98th and 99.6th percentile throughout life [8]. Most patients have a non-progressive neurological dysfunction, although the degree of learning disability appears to be extremely variable. Delay in motor development and expressive language is common [4]. Other manifestations of Sotos syndrome are variable. Delayed attainment of milestones of development is to be expected. Developmental delay is present in 80-85 % of the patients, for example excessive drooling; central nervous system abnormalities: enlarged ventricles, increased subarachnoid spaces that may require treatment, agenesis or hypoplasia of the corpus callosum, agenesis of the septum pellucidum, hypoplasia and atrophy of the cerebellar vermis, large cisterna magna and abnormalities of the Sylvian fissure. Among musculoskeletal abnormalities, hypotonia is the most frequent (84 %), pectus excavatum or carinatum has also been reported. Ophthalmologic manifestations are frequent: strabismus, nystagmus, retinal and optic nerve anomalies [9]. Hypothyroidism, hyperthyroidism, hypoparathyroidism and thyrotoxicosis has been reported [9,10]. There is an increased incidence of different tumours at a young age [9,11], non-progressive hypotonia [12]. About 14 % of patients present with auditory-related conditions [10] such as hearing loss, EMO, recurrent ear infections, cholesteatoma, and degenerative changes of the eardrum. About 24 % of individuals have congenital malformations or abnormalities of the head and neck [10], including high arched palate, auricular dysplasia, macroglossia, cleft lip and palate, and alveolar cleft. Feeding difficulties have also been reported [10]. It can be due to the hypotonia that may result in weakness in the muscles of swallowing and subsequent feeding difficulties or the associated congenital malformations of the head and neck. About 16 % of individuals were reported to have other conditions, including speech disorder, respiratory difficulties, laryngomalacia, severe OSA, gastroesophageal reflux disease, and parotitis [109]. Scoliosis and kyphoscoliosis are present in approximately 30 % of patients. Early detection of scoliosis is important to facilitate early intervention with back braces and/or surgery [8]. There is no reported or published data on pulmonary function capacity with the subset of patients with scoliosis compared to Sotos syndrome patients without scoliosis. Congenitally dislocated hips, genu vara/valga and propensity to fractures with minimal trauma have been described [8]. Childhood seizures are common in 50 %, frequently febrile in nature [4]. Behaviour abnormalities include social inhibition and attention deficit [13]. An increased occurrence of congenital heart disease is seen, the most common defects being patent ductus arteriosus and septal defects [8]. Renal anomalies (bifid, duplex, cystic or absent kidneys; vesicoureteral reflux; pelviureteric junction obstruction) and genital anomalies (hypospadias; cryptorchidism) are present in 15 % of children with NSD1 abnormalities [14]. Recurrent upper respiration tract infections and otitis media are also common, and constipation also often requires treatment [4]. [ABSTRACT FROM AUTHOR]

The article presents the discussion on anaesthesia recommendations for Sotos syndrome. Topics include mutations and microdeletions involving NSD1 disrupting the activity of genes involved in normal growth and development; and APC2 gene being a downstream regulator of the NSD1 gene and the expression downregulated by abnormalities of the NSD1 gene.

Sotos syndrome (SS) is characterized by overgrowth, distinctive facial appearance, and learning disability. It is caused by heterozygous mutations, including deletions of NSD1 located at chromosome 5q35. While advanced bone age can occur in some cases, precocious puberty (PP) has only been reported in three cases previously. Here, we reported a case of SS diagnosed in the infancy period with central PP. The discovery of potential factors that trigger puberty is one of the central mysteries of pubertal biology. Depot gonadotropinreleasing hormone analogs constitute the first-line therapy in central PP (CPP), which has proven to be both effective and safe. In our cases, leuprolide acetate at maximum dose was not successful in controlling pubertal progression, and cyproterone acetate (CPA) was added to therapy, with successful control of pubertal progression. In some specific syndromes with PP, such as SS, treatment can be challenging. CPA may be an asset for effective treatment. [ABSTRACT FROM AUTHOR]

Most histone methyltransferases (HMTase) harbor a predicted Su(var)3-9, Enhancer-of-zeste, Trithorax (SET) domain, which transfers a methyl group to a lysine residue in their substrates. Mutations of the SET domains were reported to cause intellectual disability syndromes such as Sotos, Weaver, or Kabuki syndromes. Sotos syndrome is an overgrowth syndrome with intellectual disability caused by haploinsufficiency of the nuclear receptor binding SET domain protein 1 (NSD1) gene, an HMTase at 5q35.2-35.3. Here, we analyzed NSD1 in 34 Brazilian Sotos patients and identified three novel and eight known mutations. Using protein modeling and bioinformatic approaches, we evaluated the effects of one novel (I2007F) and 21 previously reported missense mutations in the SET domain. For the I2007F mutation, we observed conformational change and loss of structural stability in Molecular Dynamics (MD) simulations which may lead to loss-of-function of the SET domain. For six mutations near the ligand-binding site we observed in simulations steric clashes with neighboring side chains near the substrate S-Adenosyl methionine (SAM) binding site, which may disrupt the enzymatic activity of NSD1. These results point to a structural mechanism underlying the pathology of the NSD1 missense mutations in the SET domain in Sotos syndrome. NSD1 mutations were identified in only 32% of the Brazilian Sotos patients in our study cohort suggesting other genes (including unknown disease genes) underlie the molecular etiology for the majority of these patients. Our studies also found NSD1 expression to be profound in human fetal brain and cerebellum, accounting for prenatal onset and hypoplasia of cerebellar vermis seen in Sotos syndrome. [ABSTRACT FROM AUTHOR]

Background: Overgrowth syndromes represent clinically and genetically heterogeneous conditions characterized by a wide spectrum of malformations, tall stature, intellectual disability and/or macrocephaly. Results: In a cohort of four clinically characterized patients with overgrowth syndrome without known causative gene mutation, we performed an Illumina SNP-array analysis to identify the pathogenic copy number variations. We identified two rare copy number variations harboring overgrowth syndrome related genes. Patient 1 was Malan syndrome with a 1.4 Mb 19p13.2-13.13 microdeletion including NFIX, and Patient 2 was identified as Sotos syndrome with a 1.6 Mb 5q35.2 microdeletion encompassing NSD1. Conclusions: We identified two patients associated with Manlan syndrome and Sotos syndrome respectively. We also discuss the use of the microarrays-based candidate gene strategy in Mendelian disease-gene identification. [ABSTRACT FROM AUTHOR]

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 criteria. Within this literature, data relating to cognition and/or behaviour in 247 individuals with a diagnosis of Sotos syndrome were reported. Ten papers reported group data on cognition and/or behaviour. The remaining papers employed a case study design. Results: Intelligence quotient (IQ) scores were reported in twenty five studies. Intellectual disability (IQ < 70) or borderline intellectual functioning (IQ 70–84) was present in the vast majority of individuals with Sotos syndrome. Seven studies reported performance on subscales of intelligence tests. Data from these studies indicate that verbal IQ scores are consistently higher than performance IQ scores. Fourteen papers provided data on behavioural features of individuals with Sotos syndrome. Key themes that emerged in the behavioural literature were overlap with ASD, ADHD, anxiety and high prevalence of aggression/tantrums. Conclusion: Although a range of studies have provided insight into cognition and behaviour in Sotos syndrome, specific profiles have not yet been fully specified. Recommendations for future research are provided. [ABSTRACT FROM AUTHOR]

A case study of a 2‑year‑old girl presented with developmental delay and epilepsy without gigantism, and seizures for 3 months of age of Soto's Syndrome. Topics include delay in attainment of language, and social milestones, as compared to gross and fine motor milestones; and magnetic resonance imaging of the brain was normal, and electroencephalogram showed frequent bilateral frontotemporal epileptiform discharges.

The Nuclear Factor I-X ( NFIX ) is a member of the nuclear factor I (NFI) protein family and is deleted or mutated in a subset of patients with a peculiar overgrowth condition resembling Sotos Syndrome as well as in patients with Marshall-Smith syndrome. We identified three additional patients with this phenotype each carrying a different new mutation affecting the DNA-binding/dimerization domain of the NFIX protein. The present report further adds weight to the hypothesis that mutations in DNA-binding/dimerization domain are likely to cause haploinsufficiency of the NFIX protein and confirms that NFIX is the second gene that should be tested in individuals with overgrowth conditions resembling Sotos syndrome, previously tested negative for NSD1 mutations. We then propose to consider this overgrowth syndrome (namely Malan syndrome) and Marshall-Smith syndrome NFIX -related diseases. [ABSTRACT FROM AUTHOR]

De novo monoallelic variants in NFIX cause two distinct syndromes. Whole gene deletions, nonsense variants and missense variants affecting the DNA-binding domain have been seen in association with a Sotos-like phenotype that we propose is referred to as Malan syndrome. Frameshift and splice-site variants thought to avoid nonsense-mediated RNA decay have been seen in Marshall-Smith syndrome. We report six additional patients with Malan syndrome and de novo NFIX deletions or sequence variants and review the 20 patients now reported. The phenotype is characterised by moderate postnatal overgrowth and macrocephaly. Median height and head circumference in childhood are 2.0 and 2.3 standard deviations (SD) above the mean, respectively. There is overlap of the facial phenotype with NSD1-positive Sotos syndrome in some cases including a prominent forehead, high anterior hairline, downslanting palpebral fissures and prominent chin. Neonatal feeding difficulties and/or hypotonia have been reported in 30% of patients. Developmental delay/learning disability have been reported in all cases and are typically moderate. Ocular phenotypes are common, including strabismus (65%), nystagmus (25% ) and optic disc pallor/hypoplasia (25%). Other recurrent features include pectus excavatum (40%) and scoliosis (25%). Eight reported patients have a deletion also encompassing CACNA1A, haploinsufficiency of which causes episodic ataxia type 2 or familial hemiplegic migraine. One previous case had episodic ataxia and one case we report has had cyclical vomiting responsive to pizotifen. In individuals with this contiguous gene deletion syndrome, awareness of possible later neurological manifestations is important, although their penetrance is not yet clear. [ABSTRACT FROM AUTHOR]

Whole-exome sequencing (WES) is becoming a standard tool for detecting nucleotide changes, and determining whether WES data can be used for the detection of copy-number variations (CNVs) is of interest. To date, several algorithms have been developed for such analyses, although verification is needed to establish if they fit well for the appropriate purpose, depending on the characteristics of each algorithm. Here, we performed WES CNV analysis using the eXome Hidden Markov Model (XHMM). We validated its performance using 27 rare CNVs previously identified by microarray as positive controls, finding that the detection rate was 59%, or higher (89%) with three or more targets. XHMM can be effectively used, especially for the detection of >200 kb CNVs. XHMM may be useful for deletion breakpoint detection. Next, we applied XHMM to genetically unsolved patients, demonstrating successful identification of pathogenic CNVs: 1.5-1.9-Mb deletions involving NSD1 in patients with unknown overgrowth syndrome leading to the diagnosis of Sotos syndrome, and 6.4-Mb duplication involving MECP2 in affected brothers with late-onset spasm and progressive cerebral/cerebellar atrophy confirming the clinical suspect of MECP2 duplication syndrome. The possibility of an 'exome-first' approach for clinical genetic investigation may be considered to save the cost of multiple investigations. [ABSTRACT FROM AUTHOR]

Sotos syndrome is a rare sporadic genetic disorder characterized by pathognomonic facial features, motor developmental delay induced by hypotonia, learning difficulties, and cardiac and renal anomalies. This report describes the case of a 4-year-old child with Sotos syndrome who underwent a right hydrocelectomy under general anesthesia. We report our experience with airway management, choice of anesthetic drugs, and other anesthetic implications in Sotos syndrome. [ABSTRACT FROM AUTHOR]

Sotos syndrome or cerebral gigantism is a syndrome of accelerated overgrowth during childhood with characteristic facial features and learning disabilities. It includes behavioral disorders and neuropsychiatric signs such as attention deficits, social inhibition, psychomotor delay and clumsiness, tantrums and aggressiveness. We describe a case of 9 years old male individual with Sotos syndrome who exhibits oppositional behaviour, impulsiveness and aggressiveness. [ABSTRACT FROM AUTHOR]

Sotos syndrome is an overgrowth syndrome with characteristic facial dysmorphism, variable severity of learning disabilities and macrocephaly with overgrowth. Haploinsufficiency of the nuclear receptor SET domain-containing protein 1 (NSD1) gene located on 5q35 has been implicated as the cause of Sotos syndrome. This study was performed to investigate the mutation spectrum of NSD1 abnormalities and meaningful genotype−phenotype correlations in Korean patients with Sotos syndrome. Eighteen unrelated Korean patients with Sotos syndrome were enrolled for clinical and molecular analyses. Cytogenetic studies were performed to confirm 5q35 microdeletion, and NSD1 sequencing analysis was performed to identify intragenic mutations. NSD1 abnormalities were identified in 15 (83%) patients. Among them, eight patients (53%) had 5q35 microdeletions and the other seven patients (47%) had seven different NSD1 intragenic mutations including four novel mutations. The mutation spectrum of Korean patients with Sotos syndrome was similar to that of previous studies for Japanese patients. Height was significantly shorter and age of walking alone was significantly older in the microdeletion group compared with those in the intragenic mutation group. No significant differences were observed for other clinical characteristics between the microdeletion and intragenic mutation groups. Further studies with a larger number of patients will be necessary to draw conclusive genotype−phenotype correlations. [ABSTRACT FROM AUTHOR]

Low intelligence has been associated with poor health and mortality, but underlying mechanisms remain obscure. We hypothesized that low intelligence is associated with accelerated biological ageing as reflected by telomere length; we suggested potential mediation of this association by unhealthy behaviors and low socioeconomic position. The study was performed in a longitudinal population-based cohort study of 895 participants (46.8% males). Intelligence was measured with the Generalized Aptitude-Test Battery at mean age 52.8 years (33-79 years, SD = 11.3). Leukocyte telomere length was measured by PCR. Lifestyle and socioeconomic factors were assessed using written self-report measures. Linear regression analyses, adjusted for age, sex, and telomere length measured at the first assessment wave (T1), showed that low intelligence was associated with shorter leukocyte telomere length at approximately 2 years follow-up (beta = .081, t = 2.160, p = .031). Nearly 40% of this association was explained by an unhealthy lifestyle, while low socioeconomic position did not add any significant mediation. Low intelligence may be a risk factor for accelerated biological ageing, thereby providing an explanation for its association with poor health and mortality. [ABSTRACT FROM AUTHOR]

Sotos syndrome is one of the most common overgrowth diseases and it predisposes patients to cancer, generally in childhood. The prevalence of this genetic disorder is 1:10,000–1:50,000, and it is characterized by wide allelic heterogeneity, with more than 100 different known mutations in the nuclear receptor-binding SET domain containing protein 1 (NSD1) gene. Most of these alterations are deletions and common micro-deletions with haploinsufficiency. Singular variants are missense mutations. The present study reports a case of a 4-year-old boy with specific clinical features of Sotos syndrome and a particular complex skin hamartoma on the right femoral side, in addition to other minor findings, such as a "café-au-lait" spot on the right hemithorax and syndactyly of the second and third right toes. NSD1 gene analysis identified a de novo missense mutation, "c.[5867T>A]+[=]"; "p.[Leu1956Gln]+[=]", that was not previously described in the literature. This mutation was localized to the functional domain of the gene and was likely the cause of Sotos syndrome in our patient. We also compared aspects of our patient's condition with the clinical features of tuberous sclerosis (TSC), which is an autosomal neurocutaneous syndrome caused by mutations in the TSC1/TSC2 genes. These genes control cell growth and cell survival. This disorder is characterized by hamartomas in multiple organ systems, several coetaneous abnormalities, epilepsy, and increased risk of several types of tumors. [ABSTRACT FROM AUTHOR]