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.

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.

Silver-Russell syndrome (SRS) is characterized by pre- and postnatal growth deficiency. It is most often caused by hypomethylation of the paternal imprinting center 1 of chromosome 11p15.5. In contrast, Sotos syndrome is an overgrowth syndrome that results either from pathogenic NSD1 gene variants or copy number variations affecting the NSD1 gene. Here, we report on a 6 month-old boy with severe short stature, relative macrocephaly, severe feeding difficulties with underweight, muscular hypotonia, motor delay, medullary nephrocalcinosis, bilateral sensorineural hearing impairment and facial dysmorphisms. SNP array revealed a 2.1 Mb de novo interstitial deletion of 5q35.2q35.3 encompassing the NSD1 gene. As Sotos syndrome could not satisfactorily explain his symptoms, diagnostic testing for SRS was initiated. It demonstrated hypomethylation of the imprinting center 1 of chromosome 11p15.5 confirming the clinically suspected SRS. We compared the symptoms of our patient with the typical clinical features of individuals with SRS and Sotos syndrome, respectively. To our knowledge, this is the first study reporting the very unusual coincidence of both Sotos syndrome and SRS in the same patient.

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.

Sotos syndrome is one of the overgrowth syndromes, and can present with intellectual disability, behavioral problems and tall stature. In some cases, seizures, pectus deformity, cardiac and renal anomalies may be identified. Here we report two Indian children with Sotos syndrome whose initial presentation was macrocephaly and behavioral problems, respectively. The pathogenic variants in NSD1 gene were confirmed by next generation sequencing. The gene variants in the two children, one male and one female; were NSD1: c.2362C>T and NSD1: c.5474dup, respectively, leading to premature termination of protein formation.

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 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.

Acromegaly is usually not a difficult condition to diagnose once the possibility of this disease has been raised. However, a few conditions present with some aspects of acromegaly or gigantism but without growth hormone (GH) excess. Such cases are described as \"pseudoacromegaly\" or \"acromegaloidism\". Here we describe a female patient investigated for GH excess at 10 years of age for tall stature since infancy (height and weight > +3 standard deviations) and typical acromegalic features, including large hands/feet, large jaw, tongue, hoarse deep voice, and headache. Results of radiography of the sella turcica and GH response at an oral glucose tolerance test and insulin-arginine- thyrotrophin-luteinizing hormone-releasing hormone test were normal. Ethinylestradiol and medroxyprogesterone were given for 2 years; this successfully stopped further height increase. Although the patient\'s growth rate plateaued, coarsening of the facial features and acral enlargement also led to investigations for suspicion of acromegaly at 23 and 36 years of age, both with negative results. On referral at the age of 49 years, she had weight gain, sweating, sleep apnea, headaches, joint pain, and enlarged tongue. Endocrine assessment again showing normal GH axis was followed by genetic testing with a macrocephaly/overgrowth syndrome panel. A denovo mutation in the NSD1 gene (c.6605G>C; p.Cys2202Ser) was demonstrated. Mutations affecting the same cysteine residue have been identified in patients with Sotos syndrome. In summary, Sotos syndrome and other overgrowth syndromes can mimic the clinical manifestations of acromegaly or gigantism. Genetic assessment could be helpful in these cases.

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.