Sotos Syndrome Research Articles

COVID-19 pneumonia in a child with Sotos syndrome.

COVID-19 pneumonia in a child with Sotos syndrome.

Genetic heterogeneity of disorders with overgrowth and intellectual disability: Experience from a center in North India.

Overgrowth, defined as height and/or OFC ≥ +2SD, characterizes a subset of patients with syndromic intellectual disability (ID). Many of the disorders with overgrowth and ID (OGID) are rare and the full phenotypic and genotypic spectra have not been unraveled. This study was undertaken to characterize the phenotypic and genotypic profile of patients with OGID. Patients with OGID were ascertained from the cohort of patients who underwent cytogenetic microarray (CMA) and/or exome sequencing (ES) at our center over a period of 6 years. Thirty-one subjects (six females) formed the study group with ages between 3.5months and 13 years. CMA identified pathogenic deletions in two patients. In another 11 patients, a disease causing variant was detected by ES. The spectrum of disorders encompassed aberrations in genes involved in the two main pathways associated with OGID. These were genes involved in epigenetic regulation like NSD1, NFIX, FOXP1, and those in the PI3K-AKT pathway like PTEN, AKT3, TSC2, PPP2R5D. Five novel pathogenic variants were added by this study. NSD1-related Sotos syndrome was the most common disorder, seen in five patients. A causative variant was identified in 61.5% of patients who underwent only ES compared to the low yield of 11.1% in the CMA group. The molecular etiology could be confirmed in 13 subjects with OGID giving a diagnostic yield of 42%. The major burden was formed by autosomal dominant monogenic disorders. Hence, ES maybe a better first-tier genomic test rather than CMA in OGID.

Characterization of sleep habits of children with Sotos syndrome.

Sotos syndrome (SS) is a genetic disorder characterized by accelerated growth in childhood, developmental deficits, and characteristic craniofacial features. While clinicians and parents have reported unusual sleep habits, only one study by Rutter and Cole in 1991 mentioned sleep complaints (Rutter and Cole, Developmental Medicine and Child Neurology, 1991, 33, 898-902). This study aimed to characterize the sleep habits of individuals with SS. We performed a cross-sectional study of individuals with a definite, probable, or possible diagnosis of Sotos syndrome. Participants were asked to complete the Children's Sleep Habits Questionnaire (CHSQ). We compared our data to historical data available from the literature. Subjects with SS showed more sleep disturbance than typically developing individuals (TD), although their sleep onset was less likely to be delayed and their sleep duration was longer. Participants with SS also showed different sleep patterns compared to children with other forms of intellectual and developmental disabilities (IDD). Individuals with SS exhibited early bed and rise times, frequently used transitional objects, displayed repetitive motion at sleep onset, and did not show a decrease in sleep duration with age. The majority of participants fell asleep at the same time each night, in their own bed, and within 20 min, and rarely showed signs of sleepwalking or night terrors. These results improve our understanding of sleep habits of individuals with SS and may be used to guide treatment and provide normalization for children with SS.

Drosophila NSD deletion induces developmental anomalies similar to those seen in Sotos syndrome 1 patients.

Haploinsufficiency of the human nuclear receptor binding suppressor of variegation 3-9, enhancer of zeste, and trithorax (SET) domain 1 (NSD1) gene causes a developmental disorder called Sotos syndrome 1 (SOTOS1), which is associated with overgrowth and macrocephaly. NSD family proteins encoding histone H3 lysine 36 (H3K36) methyltransferases are conserved in many species, and Drosophila has a single NSD homolog gene, NSD. To gain insight into the biological functions of NSD1 deficiency in the developmental anomalies seen in SOTOS1 patients using an NSD-deleted Drosophila mutant. We deleted Drosophila NSD using CRISPR/Cas9-mediated targeted gene knock-out, and analyzed pleiotropic phenotypes of the homozygous mutant of NSD (NSD-/-) at various developmental stages to understand the roles of NSD in Drosophila. The site-specific NSD deletion was confirmed in the mutant. The H3K36 di-methylation levels were dramatically decreased in the NSD-/- fly. Compared with the control, the NSD-/- fly displayed an increase in the body size of larvae, similar to the childhood overgrowth phenotype of SOTOS1 patients. Although the NSD mutant flies survived to adulthood, their fecundity was dramatically decreased. Furthermore, the NSD-/- fly showed neurological dysfunctions, such as lower memory performance and motor defects, and a diminished extracellular signal-regulated kinase (ERK) activity. The NSD-deleted Drosophila phenotype resembles many of the phenotypes of SOTOS1 patients, such as learning disability, deregulated ERK signaling, and overgrowth; thus, this mutant fly is a relevant model organism to study various SOTOS1 phenotypes.

Seizures in Sotos syndrome: Phenotyping in 49 patients.

We aimed to describe the phenotypic spectrum of seizures in Sotos syndrome, a genetic condition involving overgrowth, macrocephaly, dysmorphic features, and learning disability, in which 60%‐90% have NSD1 pathogenic variants. Patients were recruited from clinics and referral from support groups. Those with seizures and a clinical diagnosis of Sotos syndrome were included. Phenotyping data were collected via structured clinical interview and chart review. Forty‐nine patients were included. Twenty had NSD1 testing results available; of these, 15 (75%) had NSD1 pathogenic variants. Seizure onset age ranged from 3 months to 12 years. Staring spells (absence or focal impaired awareness seizure) were the most frequently reported semiology (33/49; 67%), followed by febrile seizures (25/49; 51%) and afebrile bilateral tonic‐clonic seizures (25/49; 51%). Most patients (33/49; 67%) had multiple seizure types. The majority (33/49; 67%) had seizures controlled on a single antiseizure medication or no medication. Nine (18%) had drug‐resistant epilepsy. Epilepsy syndromes included febrile seizures plus, Lennox‐Gastaut syndrome, childhood absence epilepsy, and generalized tonic‐clonic seizures alone. The seizure phenotype in Sotos syndrome most commonly involves staring spells, afebrile tonic‐clonic seizures or febrile convulsions; however, other seizure types may occur. Seizures are typically well‐controlled with medication, but drug‐resistant epilepsy occurs in a minority.

EP283 - Metastatic neuroblastoma at young age in Sotos syndrome - consideration of routine tumor screening

eP283 - Metastatic neuroblastoma at young age in Sotos syndrome - consideration of routine tumor screening

EP248 - The diagnostic utility of methylation episignature analysis in the diagnosis of Sotos syndrome

eP248 - The diagnostic utility of methylation episignature analysis in the diagnosis of Sotos syndrome

Γλωσσικά και γνωστικά ελλείμματα στο σύνδρομο Sotos: μια μελέτη περίπτωσης

Sotos syndrome is a genetic disorder of mental retardation characterized by specific facial characteristics, overgrowth in childhood, cognitive impairment and speech and language difficulties. In this paper, we report on a single case study of a female adolescent, TK, aged 15;9 diagnosed with Sotos syndrome. The main goal was to investigate her phonological short-term memory abilities as well as her visuospatial memory abilities and language abilities. We employed the following tests: (a) Raven’s Progressive Matrices and Vocabulary Scales (Greek edition) (Raven et al., 2003/2004), (b) Renfrew Word Finding Vocabulary Test – Greek edition (Vogindroukas et al., 2009), (c) Peabody Picture Vocabulary Test –Special Edition (Greek edition) (Simos et al., 2012), (d) Action Picture Test – Greek edition (Vogindroukas et al., 2011), and (e) Bezevegis et al.’s (2008) memory test. The most profound deficiencies were observed in expressive vocabulary and pragmatic/communicative skills, while difficulties were also found in verbal short-term memory. Deficiencies were also observed in verbal and non-verbal IQ in agreement with previous findings (Cole & Hughes, 1994. de Boer et al., 2004. Finegan et al., 1994). TK’s performance on visuospatial sketchpad was slightly better compared to the results obtained through the other tests. We discuss the clinical implications of our findings.

Growth hormone treatment for short stature associated with duplication of the NSD1 Sotos syndrome gene

SummaryNSD1 deletions are associated with the Sotos syndrome, a syndrome of overgrowth in childhood without evidence of endocrine disturbance. Duplications involving the NSD1 gene have been reported to be associated with a ‘reverse Sotos syndrome’ phenotype, characterised by short stature, microcephaly, dysmorphic features and developmental delay. A 2-year-old girl with short stature, dysmorphic features and developmental delay was found to have duplication of 5q32.2–5q32.3, which includes the NSD1 gene. Growth hormone stimulation testing was normal. Growth hormone therapy was initiated at 5 years of age due to severe short stature and growth failure, with height 3.35 standard deviations (SDS) below the median. Growth velocity increased markedly, by +4.91 SDS in the first year of treatment. At the time of last follow-up at 9 years and 11 months, she had achieved a height within 1 SDS of the median. This is the first report of growth hormone therapy for the short stature associated with duplication of the NSD1 gene, showing that despite normal pituitary function, exogenous growth hormone can dramatically improve linear growth.Learning pointsSotos syndrome is a disorder of childhood overgrowth caused by NSD1 deletions.Duplications involving NSD1 cause a ‘reverse Sotos syndrome’ phenotype characterised by short stature and microcephaly.The contrasting phenotypes of NSD1 deletions and duplications suggest a dose effect.Stimulated growth hormone secretion is normal in children with NSD1 deletions and duplications.Growth hormone therapy can be very effective in children with NSD1 duplications, comparable to the response seen in severe growth hormone deficiency.

Impaired Regulation of Histone Methylation and Acetylation Underlies Specific Neurodevelopmental Disorders.

Epigenetic processes are critical for governing the complex spatiotemporal patterns of gene expression in neurodevelopment. One such mechanism is the dynamic network of post-translational histone modifications that facilitate recruitment of transcription factors or even directly alter chromatin structure to modulate gene expression. This is a tightly regulated system, and mutations affecting the function of a single histone-modifying enzyme can shift the normal epigenetic balance and cause detrimental developmental consequences. In this review, we will examine select neurodevelopmental conditions that arise from mutations in genes encoding enzymes that regulate histone methylation and acetylation. The methylation-related conditions discussed include Wiedemann-Steiner, Kabuki, and Sotos syndromes, and the acetylation-related conditions include Rubinstein-Taybi, KAT6A, genitopatellar/Say-Barber-Biesecker-Young-Simpson, and brachydactyly mental retardation syndromes. In particular, we will discuss the clinical/phenotypic and genetic basis of these conditions and the model systems that have been developed to better elucidate cellular and systemic pathological mechanisms.

A Rare Pathogenic Frameshift Mutation in NSD1 Gene Related to Sotos Syndrome in a Turkish Patient

A Rare Pathogenic Frameshift Mutation in NSD1 Gene Related to Sotos Syndrome in a Turkish Patient

Pilot Implementation of the Curriculum "Promoting Learning Through Active Interaction (PLAI)" in a Child with Sotos Syndrome

The present study focused on the implementation of the PLAI Program in a boy with Sotos syndrome, aged 10 years. The aim was to describe the results regarding the communication skills of the child after the pilot implementation of the specific Curriculum. Video observation and analysis were used to assess the child's communication skills, both before and after the implementation of the program. The PLAI program, which was implemented for about 4 months, focused on improving the child's communication skills, included similar activities and was based mainly on the strategy of routine and sensory cues. The results from the implementation of the individualized educational program were quite satisfactory, as a significant improvement in the communication skills of the specific child was found. The contribution of the Curriculum "Promoting Learning Through Active Interaction" is very important for the education of students with severe-multiple disabilities.

The Association of Scoliosis and NSD1 Gene Deletion in Sotos Syndrome Patients.

A retrospective comparative study. The aim of this study was to examine the NSD1 abnormalities in patients diagnosed with Sotos syndrome and its correlation with the presence, severity, and progression of associated scoliosis. Scoliosis has been reported in approximately 30% of patients diagnosed with Sotos syndrome, a genetic disorder characterized by a distinctive facial appearance, learning disability, and overgrowth. Sotos syndrome is mainly attributed to NSD1 haploinsufficiency, but with ethnical differences in genetic profile: NSD1 microdeletions are frequently identified in Japanese Sotos patients whereas intragenic mutations are more frequently found in non-Japanese patients. Although possible genotype-phenotype correlations have been proposed, the genotype of Sotos syndrome patients suffering from scoliosis has not been examined. The medical records and spinal radiographs of 63 consecutive Sotos syndrome patients at a single center were reviewed. Fluorescent in situ hybridization or microarray comparative genomic hybridization and DNA sequencing or multiplex ligation-dependent probe amplification were performed to detect 5q35 microdeletion involving the NSD1 gene and intragenic mutations of the NSD1 gene, respectively. The phenotypes of all cases and radiological assessments for the presence and progression of scoliosis were studied. NSD1 abnormalities were identified in 55 patients (87%): microdeletion in 34 patients (54%) and intragenic mutation in 22 patients (33%). Scoliosis was observed in 26 patients (41%), with a significantly higher ratio of microdeletions than mutations. The 10 patients with progressive scoliosis all had NSD1 microdeletions. Scoliosis was a common phenotypical trait in children with Sotos syndrome and its presence as well as progression were higher in cases with NSD1 microdeletions. Although all Sotos syndrome patients should be monitored for scoliosis, clinicians should be made aware that patients with NSD1 microdeletions have a higher probability of scoliosis development and progression that may require early intervention.Level of Evidence: 3.

Epilepsy with eyelid myoclonias and Sotos syndrome features in a patient with compound heterozygous missense variants in APC2 gene

Epilepsy with eyelid myoclonias and Sotos syndrome features in a patient with compound heterozygous missense variants in APC2 gene

DNA Methylation Profiling and Genomic Analysis in 20 Children with Short Stature Who Were Born Small for Gestational Age.

In a significant proportion of children born small for gestational age (SGA) with failure of catch-up growth, the etiology of short stature remains unclear after routine diagnostic workup. We wanted to investigate if extensive analysis of the (epi)genome can unravel the cause of growth failure in a significant portion of these children. Twenty SGA children treated with GH because of short stature were selected from the BELGROW database of the Belgian Society for Pediatric Endocrinology and Diabetology for exome sequencing, single-nucleotide polymorphism (SNP) array and genome-wide methylation analysis to identify the (epi)genetic cause. First-year response to GH was compared with the response of SGA patients in the KIGS database. We identified (likely) pathogenic variants in 4 children (from 3 families) using exome sequencing and found pathogenic copy number variants in 2 probands using SNP array. In a child harboring a NSD1-containing microduplication, we identified a DNA methylation signature that is opposite to the genome-wide DNA methylation signature of Sotos syndrome. Moreover, we observed multilocus imprinting disturbances in 2 children in whom no other genomic alteration could be identified. Five of 6 children with a genetic diagnosis had an "above average" response to GH. The study indicates that a more advanced approach with deep genotyping can unravel unexpected (epi)genomic alterations in SGA children with persistent growth failure. Most SGA children with a genetic diagnosis had a good response to GH treatment.

Some Audiologic Characteristics in Individuals with Sotos Syndrome

Some Audiologic Characteristics in Individuals with Sotos Syndrome

Tall stature in children and adolescents.

Tall stature is usually defined as a height beyond 97th percentile or more than 2 SD above the mean height for age and sex in a defined population. Familiar tall stature, also known as constitutional tall stature, is the most common cause of tall stature. Overnutrition, obesity, also usually causes overgrowth. Tall stature by itself is not a pathological condition, however, there are a number of disorders associated with tall stature. Some genetic disorders and syndromes may be associated with mental retardation and various complications. Therefore, recognition of tall stature and revealing the underlying pathogenic causes and making the diagnosis are important not to miss the serious conditions and to provide adequate medical care and genetic counseling. Pathological causes for tall statute include endocrine disorders, such as excessive growth hormone secretion, hyperthyroidism, precocious puberty and lipodystrophy, chromosome disorders, such as Trisomy X (47, XXX female), Klinefelter Syndrome (47, XXY), XYY syndrome (47, XYY male) and fragile X syndrome, and syndromes and metabolic disorders, such as Marfan Syndrome, Beckwith-Wiedemann Syndrome, Simpson-Golabi-Behmel Syndrome, Sotos Syndrome and homocystinuria. Children may require growth-reductive treatment if the predicted adult height would be excessive and unacceptable. Some hormonal, high doses of sex steroids, or surgical, bilateral percutaneous epiphysiodesis of the distal femur and proximal tibia and fibula, treatment is currently available to reduce adult height.

Sotos syndrome with a novel mutation in the NSD1 gene associated with congenital hypothyroidism

Childhood overgrowth syndromes are relatively rare. A generalized overgrowth syndrome should be suspected when tall stature and macrocephaly are present, after ruling out nutritional excess and endocrinopathies. Sotos syndrome is a well-described overgrowth syndrome due to haploinsufficiency of the NSD1 gene. We present a case of an infant with permanent congenital hypothyroidism, who had tall stature and macrocephaly by 7 months of age. He was noted to have typical facial features, mild gross motor and speech delay, and scoliosis by 13 months of age. Gene sequencing revealed a heterozygous novel c6076_6087del12: p.Asn2026_Thr2029del variant in exon 20 of the NSD1 gene, pathogenic for Sotos syndrome. Congenital hypothyroidism with Sotos syndrome has been infrequently reported and may expand the spectrum of disease characteristics. Early diagnosis of overgrowth syndromes is important for developmental follow up and multidisciplinary care coordination.

Common variation of the NSD1 gene is associated with susceptibility to Hirschsprung's disease in Chinese Han population.

Hirschsprung's disease (HSCR) is the most common congenital cause of intestinal obstruction in children. Sotos syndrome (SoS) is an overgrowth disorder with constipation and sometimes accompanied by HSCR. NSD1 gene mutation is the main cause of SoS. We aimed to investigate association of NSD1 common single nucleotide polymorphisms (SNPs) with HSCR susceptibility in Chinese Han population. We genotyped 15 SNPs encompassing NSD1 gene region in 420 HSCR patients and 1665 controls on Fludigm EP1 platform. Association analysis was performed between cases and controls. Rs244709 was the most associated SNP with HSCR susceptibility of the sample set (PAllelic = 9.69 × 10-5, OR = 1.37, 95% CI: 1.17-1.61). Gender stratification analysis revealed that NSD1 SNPs were associated with HSCR in males, but not in females. The nonsynonymous coding SNP rs28932178 in NSD1 exon 5 represented the most significant signal in males (PAllelic = 6.43 × 10-5, OR = 1.42, 95% CI: 1.20-1.69). The associated SNPs were expression quantitative trait loci (eQTLs) of nearby genes in multiple tissues. NSD1 expression levels were higher in aganglionic colon tissues than ganglionic tissues (P = 3.00 × 10-6). NSD1 variation conferred risk to HSCR in males, indicating SoS and HSCR may share common genetic factors. This is the first study to reveal that NSD1 variation conferred risk to Hirschsprung's disease susceptibility in males of Chinese Han population, indicating Sotos syndrome and Hirschsprung's disease may share some common genetic background. This study indicates more attention should be paid to the symptom of constipation in patients with Sotos syndrome. Our results raise questions about the role of NSD1 in the development of enteric nervous system and the pathogenesis of Hirschsprung's disease.

First report of tethered cord syndrome in a patient with Sotos syndrome

BackgroundSotos syndrome is caused by a gene deletion with an autosomal dominant pattern of inheritance. The Sotos syndrome was first described by Juan Sotos. Cole and Hughes identified the clinical characteristics of this syndrome. This syndrome is characterized by macrocephaly, frontal bossing, ocular hypertelorism, overgrowth, subdural hygroma, ventricular dilatation, agenesis of the corpus callosum. This syndrome is associated with mutations in NSD 1 (nuclear receptor SET domain-containing protein 1) gene, protein insufficiency, and a 5q35 microdeletion. Sotos syndrome is reported to occur in approximately 1/10,000–15,000 births.Case presentationWe present a patient with Sotos syndrome who is harboring a sacral lipoma and tethered cord syndrome and she had growth retardation, frontal bossing and hypertelorism. After a standard approach for tethered cord syndrome, the patient was discharged 3 days after without any additional neurodeficits.ConclusionIn the literature, sacral lipoma and tethered cord syndrome with Sotos syndrome have not been published yet.