The otolaryngologic manifestations of Sotos syndrome 1: A systematic review.

OBJECTIVES: 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.

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

STUDY DESIGN: A retrospective comparative study. OBJECTIVE: 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. SUMMARY OF BACKGROUND DATA: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Overgrowth syndromes - clinical and molecular aspects and tumour risk.

Overgrowth syndromes are a heterogeneous group of rare disorders characterized by generalized or segmental excessive growth commonly associated with additional features, such as visceromegaly, macrocephaly and a large range of various symptoms. These syndromes are caused by either genetic or epigenetic anomalies affecting factors involved in cell proliferation and/or the regulation of epigenetic markers. Some of these conditions are associated with neurological anomalies, such as cognitive impairment or autism. Overgrowth syndromes are frequently associated with an increased risk of cancer (embryonic tumours during infancy or carcinomas during adulthood), but with a highly variable prevalence. Given this risk, syndrome-specific tumour screening protocols have recently been established for some of these conditions. Certain specific clinical traits make it possible to discriminate between different syndromes and orient molecular explorations to determine which molecular tests to conduct, despite the syndromes having overlapping clinical features. Recent advances in molecular techniques using next-generation sequencing approaches have increased the number of patients with an identified molecular defect (especially patients with segmental overgrowth). This Review discusses the clinical and molecular diagnosis, tumour risk and recommendations for tumour screening for the most prevalent generalized and segmental overgrowth syndromes.

Parent-Reported Communication Abilities of Children with Sotos Syndrome: Evidence from the Children's Communication Checklist-2.

Sotos syndrome is a congenital overgrowth syndrome associated with intellectual disability. This study investigated communicative abilities of children with Sotos syndrome (n = 31), using the Children's Communication Checklist, second edition. A cross-syndrome approach was used to establish the specificity of these abilities. Children with Williams syndrome (n = 34) were used as a comparison group. In both groups, the majority of participants had communicative impairment. Children with Sotos syndrome had an uneven pragmatic language profile and greater impairment with social relations, compared with restricted interests. Overall, children with Sotos syndrome had difficulties with both language structure and pragmatic language and a specific profile of relative difficulty with using nonverbal communication, using context-appropriate language and understanding peer relationships.

Recommendations for Cancer Surveillance in Individuals with RASopathies and Other Rare Genetic Conditions with Increased Cancer Risk.

In October 2016, the American Association for Cancer Research held a meeting of international childhood cancer predisposition syndrome experts to evaluate the current knowledge of these syndromes and to propose consensus surveillance recommendations. Herein, we summarize clinical and genetic aspects of RASopathies and Sotos, Weaver, Rubinstein-Taybi, Schinzel-Giedion, and NKX2-1 syndromes as well as specific metabolic disorders known to be associated with increased childhood cancer risk. In addition, the expert panel reviewed whether sufficient data exist to make a recommendation that all patients with these disorders be offered cancer surveillance. For all syndromes, the panel recommends increased awareness and prompt assessment of clinical symptoms. Patients with Costello syndrome have the highest cancer risk, and cancer surveillance should be considered. Regular physical examinations and complete blood counts can be performed in infants with Noonan syndrome if specific PTPN11 or KRAS mutations are present, and in patients with CBL syndrome. Also, the high brain tumor risk in patients with L-2 hydroxyglutaric aciduria may warrant regular screening with brain MRIs. For most syndromes, surveillance may be needed for nonmalignant health problems. Clin Cancer Res; 23(12); e83-e90. ©2017 AACRSee all articles in the online-only CCR Pediatric Oncology Series.

Hyperinsulinemic hypoglycemia in Beckwith-Wiedemann, Sotos, and Kabuki syndromes: A nationwide survey in Japan.

Beckwith-Wiedemann syndrome (BWS) is a congenital overgrowth syndrome that is occasionally associated with hyperinsulinemic hypoglycemia (HH) in the neonatal period. Sotos syndrome (SS) and Kabuki syndrome (KS) are other malformation syndromes that may be complicated with HH, however, the detailed clinical characteristics of HH accompanied with these syndromes remain unclear. We herein conducted a nationwide questionnaire survey in Japan. We sent a primary questionnaire concerning the clinical experience for these syndromes to 347 perinatal care institutions. As a result, 222 departments or hospitals returned the questionnaires and the total numbers of BWS, SS, and KS patients were 113, 88, and 51, respectively. We sent a secondary questionnaire to 31 institutions where patients with these syndromes presented with HH during infancy. The secondary questionnaires were returned from the institutions and the numbers of patients were 16 for BWS, 9 for SS, and 3 for KS, respectively. Then, we compared the clinical characteristics of infants suffering from transient HH with and without these dysmorphic syndromes. As a result, BWS, SS, and KS patients showed significantly larger body size, lower Apgar scores, higher insulin levels at HH, and shorter durations of HH than non-dysmorphic infants with transient HH. We propose that a careful observation for the signs of HH, even if not specific to the syndromes, is important for the diagnosis of patients with BWS, SS, and KS in the postnatal period. © 2016 Wiley Periodicals, Inc.

The otolaryngologic manifestations of Sotos syndrome.

OBJECTIVE: Soto's syndrome is a genetic disorder caused by mutations in the NSD1 gene. It is characterized by excessive growth in early life. It features craniofacial abnormalities, developmental delay, hypotonia and advanced bone age. A review of the current literature reveals only chronic otitis media and conductive hearing loss as otolaryngologic manifestations of Soto's syndrome. Our objective was to determine if there are additional manifestations relevant to the otolaryngologist. METHODS: We performed a retrospective case series in which the Department of Defense electronic medical record was searched for ICD 9 code 253.0 (acromegaly/gigantism). Records were reviewed for genetic testing indicative of Soto's syndrome. These records were further analyzed for evidence of otolaryngologic problems. RESULTS: Seventeen patients were identified with five having confirmed NSD1 mutations consistent with Soto's syndrome. Of these, 4/5 had otolaryngologic problems such as conductive hearing loss, aspiration, laryngomalacia, obstructive sleep apnea and sensorineural hearing loss. CONCLUSIONS: Currently there is no description in the literature of these additional manifestations of Soto's syndrome. We present this case series to support the idea that an otolaryngologist should be involved in the multidisciplinary care required for these patients.

Adults with Sotos syndrome: review of 21 adults with molecularly confirmed NSD1 alterations, including a detailed case report of the oldest person.

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.