Sotos syndrome is an autosomal dominant condition characterized by overgrowth with advanced bone age, macrodolicocephaly, motor developmental delays and learning difficulties, and characteristic facial features caused by heterozygous pathogenetic variants in the NSD1 gene located on chromosome 5q35. The prevalence of heart defects (HDs) in individuals with Sotos syndrome is estimated to be around 15-40%. Septal defects and patent ductus arteriosus are the most commonly diagnosed malformations, but complex defects have also been reported. The aim of our study was to analyze the prevalence of HD, the anatomic types, and the genetic characteristics of 45 patients with Sotos syndrome carrying pathogenetic variants of NSD1 or a 5q35 deletion encompassing NSD1, who were followed at Bambino Gesù Children\'s Hospital in Rome. Thirty-nine of the forty-five patients (86.7%) had a mutation in NSD1, while six of the forty-five (13.3%) had a deletion. Most of the patients (62.2%, 28/45) were male, with a mean age of 14 ± 7 years (range 0.2-37 years). A total of 27/45 (60.0%) of the patients had heart defects, isolated or combined with other defects, including septal defects (12 patients), aortic anomalies (9 patients), mitral valve and/or tricuspid valve dysplasia/insufficiency (1 patient), patent ductus arteriosus (3 patients), left ventricular non-compaction/hypertrabeculated left ventricle (LV) (4 patients), aortic coarctation (1 patient), aortopulmonary window (1 patient), and pulmonary valve anomalies (3 patients). The prevalences of HD in the two subgroups (deletion versus intragenic mutation) were similar (66.7% (4/6) in the deletion group versus 58.91% (23/39) in the intragenic variant group). Our results showed a higher prevalence of HD in patients with Sotos syndrome in comparison to that described in the literature, with similar distributions of patients with mutated and deleted genes. An accurate and detailed echocardiogram should be performed in patients with Sotos syndrome at diagnosis, and a specific cardiological follow-up program is needed.

Sotos syndrome (SS) is an overgrowth disease characterized by distinctive facial features, advanced bone age, macrocephaly, and developmental delay is associated with alterations in the NSD1 gene. Here, we report a case of a 4-year-old female child with SS caused by NSD1 gene nonsense mutation.
Whole-exome sequencing (WES) was applied for probands and her parents. Sanger sequencing was used to confirm the mutation. We performed the literature review using PubMed and found 12 articles and 14 patients who presented with SS.
The patient showed typical facial features of SS, hand deformities, and seizure. WES revealed de novo heterozygous variant: NSD1 (NM_022455.5), c.6095G > A, p.TRP2032*. We also reviewed the phenotype spectrum of 14 patients with SS, who exhibited a variety of clinical phenotypes, including developmental delay, seizures, scoliosis, hearing loss, cardiac and urinary system abnormalities, and so on.
The lack of correlation between mutation sites or types and phenotypes was summarized by literature reviewing. The NSD1 protein contains 14 functional domains and this nonsense mutation was located in SET domain. Early appearance of the termination codon leads to protein truncation. Haploinsufficiency of the NSD1 gene causes the overgrowth disorders.

Pediatric high-grade gliomas represent a heterogeneous group of tumors with a wide variety of molecular features. We performed whole exome sequencing and methylation profiling on matched primary and recurrent tumors from four pediatric patients with hemispheric high-grade gliomas. Genetic analysis showed the presence of some variants shared between primary and recurrent tumors, along with other variants exclusive of primary or recurrent tumors. NSD1 variants, all novel and not previously reported, were present at high frequency in our series (100%) and were all shared between the samples, independently of primary or recurrence. For every variant, in silico prediction tools estimated a high probability of altering protein function. The novel NSD1 variant (c.5924T > A; p.Leu1975His) was present in one in four cases at recurrence, and in two in four cases at primary. The novel NSD1 variant (c.5993T > A; p.Met1998Lys) was present in one in four cases both at primary and recurrence, and in one in four cases only at primary. The presence of NSD1 mutations only at recurrence may suggest that they can be sub-clonal, while the presence in both primary and recurrence implies that they can also represent early and stable events. Furthermore, their presence only in primary, but not in recurrent tumors, suggest that NSD1 mutations may also be influenced by treatment.

OBJECTIVE: Sotos syndrome 1 (SOTOS1; MIM:117550) is rare genetic disorder characterized by excessive physical growth before and after birth, distinctive facial features, a large and elongated head, and intellectual disability (Sotos et al., 1964; Tatton-Brown et al., 1993). This systematic review aims to determine otolaryngologic conditions and complications of SOTOS1 based on existing literature through a review of current and past case reports and studies regarding SOTOS1.
METHODS: A systematic review of all published literature (1964-2020) describing otolaryngologic conditions and/or complications of patients with SOTOS1. Twenty journal articles met inclusion criteria. These articles included 160 patients diagnosed with SOTOS1.
RESULTS: Of the 160 individuals with SOTOS1 included in this review, 22 (14%) were reported to have otologic conditions. 4 (3%) individuals were reported to have conditions involving the thyroid and parathyroid glands. 2 (1%) individuals were reported to have head & neck tumors. 39 (24%) individuals were reported to have congenital malformations or abnormalities of the head & neck. 47 (29%) individuals were reported to have feeding difficulties. 16% of individuals were reported to have other otolaryngologic conditions.
CONCLUSIONS: Our review found multiple otolaryngologic conditions present in patients with SOTOS1, including hearing loss, otitis, hyperthyroidism, hypothyroidism, head & neck tumors, congenital malformations (high arched palate, cleft lip and palate, macroglossia), feeding difficulties, respiratory difficulties, and speech disorders. Additional studies should be conducted to further assess these associations.

Sotos syndrome is characterized by overgrowth, macrocephaly, distinctive facial features, and learning disabilities and is associated with alterations in the nuclear receptor binding SET domain protein 1 (NSD1) gene. Due to the advanced bone age, the eventual adult height is usually at the upper limit of normal. In this case report, a 6-year and 10-month old boy who presented with Sotos syndrome was described. He also had increased testicular volumes with advanced bone age. The stimulated levels of gonadotropins revealed central precocious puberty and brain magnetic resonance imaging (MRI) showed a pineal cyst. A heterozygous duplication variant [NM_022455.4:c.4560dup; p.(His1521Thrfs*9)] in the NSD1 was identified. Triptorelin acetate treatment was started. The aim was to report the novel duplication variant in the NSD-1 in a patient with Sotos syndrome accompanied by a pineal cyst and central precocious puberty, and also to discuss the rationale for treating precocious puberty.

BACKGROUND: Berlin Heart EXCOR® pediatric ventricular assist device is a mechanical circulatory support device currently used in pediatric patients. Sotos syndrome is a well-described multiple anomaly syndrome characterized by overgrowth, distinctive craniofacial appearance, cardiac abnormalities, and variable learning disabilities.
METHODS: We describe a 7-year-old female Caucasian child with classic Sotos syndrome features subjected to implantation of Berlin Heart EXCOR® pediatric biventricular assist device mechanical support. A heart transplant was carried out after a support time of 459 days. After 5 years of follow-up, our patient is clinically stable and the performance of the transplanted heart is excellent.
CONCLUSIONS: This case confirms that Berlin Heart EXCOR® pediatric ventricular assist device can provide satisfactory and safe circulatory support for children with end-stage heart diseases, even in those with Sotos syndrome. The syndrome is not a contraindication to implantation, since the complications are the same as those observed in patients without the syndrome and the prognosis is not affected by the disease.

Sotos syndrome is a rare congenital syndrome caused by deletions or mutations in the NSD1 gene (chromosome 5q35) which results in overgrowth. A wide range of manifestations may result in unexpected and/or early death, including congenital cardiac malformations and tumours, epilepsy, intra-tumoural haemorrhage or embolism and bleeding diatheses. A case of lethal pulmonary fat embolism complicating revision of a left total hip replacement following spontaneous fracture is reported in a 39-year-old man with Sotos syndrome. This case demonstrates that orthopaedic problems later in life may be added to potential causes of premature death in this syndrome.

Sotos Syndrome (SS) is a genetic disease with an autosomal dominant pattern caused by haplo-insufficiency of NSD1 gene secondary to point mutations or microdeletion of the 5q35 locus where the gene is located. It is a rare syndrome, occurring in 7 out of every 100,000 births. The objective of this report is to present the case of a 4 year-old patient with a global developmental delay, as well as specific physical findings suggesting a syndrome of genetic origin.
METHODS: Female patient, 4 years of age, thinning hair, triangular facie, long palpebral fissure, arched palate, prominent jaw, winged scapula and clinodactilia of the fifth finger both hands. The molecular test comparative genomic hybridisation test by microarray was subsequently performed, with the result showing 5q35.2 q35.3 region microdeletion of 2,082 MB, including the NSD1 gene.
CONCLUSIONS: Finally, this article also proposes the performing of comparative genomic hybridisation as the first diagnostic option in cases where clinical findings are suggestive of SS.

We report a case of Japanese girl with a rare disorder of Weaver syndrome, which was characterized by overgrowth with advanced and disharmonic bone age, craniofacial abnormalities, developmental delay, metaphyseal flaring of the long bones and camptodactyly. The patient was delivered at 38 weeks of gestation with a length of 54.2 cm (+ 2.6 SD), a weight of 3805 g (+ 2.5 SD) and an occipitofrontal circumference (OFC) of 35.0 cm (+ 1.1 SD). She manifested hypertonia and flexion contractures in the first few years. She also had submucosal soft cleft palate and difficulty in swallowing and breathing in early infancy. When she was 5 years and 7 months old, her height and weight were 133.3 cm (+ 5.5 SD) and 32.0 kg (+ 5.1 SD), respectively. We could not detect any endocrinological abnormalities for the cause of overgrowth. According to clinical features, Weaver syndrome was suspected and genetical analysis was performed. Fluorescence in situ hybridization (FISH) and direct sequencing analysis showed neither deletion nor point mutation of the nuclear receptor SET-domain-containing protein 1 (NSD1) gene on 5q35, which is responsible for Sotos syndrome. Therefore, we made a diagnosis of Weaver syndrome for this patient and discussed the differential diagnosis in terms of overgrowth syndrome.