1 Introduction

Sotos syndrome is a rare congenital overgrowth condition first described in 1964 by Juan Sotos (Tatton-Brown and Rahman 2007). The condition is caused by pathogenic variants in the nuclear receptor-binding set domain protein 1 (NSD1) gene on chromosome 5q35 and has a prevalence of 1 in 14,000 live births (Baujat and Cormier-Daire 2007; Tatton-Brown and Rahman 2004). Sotos syndrome is characterized by a variety of clinical features, most notably overgrowth, mild intellectual disability, and a distinctive facial appearance (broad, prominent forehead, sparse frontotemporal hair, down-slanting palpebral fissures, malar flushing, bitemporal narrowing, and a long chin) (Tatton-Brown and Rahman 2007). A broad spectrum of childhood cancers has been reported in patients with Sotos syndrome, the most frequently of which include sacrococcygeal teratomas, acute lymphocytic leukemia, and neuroblastomas (Al-Mulla et al. 2004; Grand et al. 2019; Hersh et al. 1992; Jin et al. 2002; Kaya et al. 2022; Kulkarni et al. 2013; Leonard et al. 2000; Lourdes et al. 2023; Nagai et al. 2003; Tatton-Brown et al. 2005; Yule 1999). Routine cancer screenings, however, are typically not recommended as none of these cancer types appear to have a frequency above 1% (Kalish et al. 2024). Patients with Sotos syndrome also often present with advanced bone age, cardiac anomalies, cranial MRI/CT anomalies, renal anomalies, scoliosis, seizures, joint hyperlaxity, and neonatal complications such as jaundice and hypotonia (Tatton-Brown et al. 2005; Tatton-Brown and Rahman 2007).

In addition to these physical features, there has been a broad cognitive and behavioral spectrum reported among patients with Sotos syndrome. Attention deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) are among two of the most common neurodevelopmental conditions associated with Sotos syndrome (Finegan et al. 1994; Lane et al. 2017). In addition, caregivers have reported increased incidence of tantrums and outbursts as common behavioral manifestations of the condition (Compton et al. 2004; Mauceri et al. 2000). Symptoms of anxiety have also been sporadically reported in this patient population (Rutter and Cole 1991; Sarimski 2003; Siracusano et al. 2023). Outside of these behavioral phenotypes, intellectual disability and developmental delay have previously been reported (Lane et al. 2019; Nagai et al. 2003; Tatton-Brown et al. 2005). A recent study by Siracusano et al. (2023) showed a genotype–phenotype correlation between patients with microdeletions in 5q35 and greater impairment in cognitive functioning compared to patients with intragenic mutations. Nevertheless, the neuropsychological and behavioral profile of Sotos syndrome still remains poorly defined.

Our study presents a single-center cohort of 25 patients with molecularly confirmed Sotos syndrome, 18 of which have not been previously reported in the literature. The behavioral phenotypes found in this novel cohort and the detailed stories of two of the older patients within the cohort were investigated to delineate the complex behavioral spectrum found in patients with Sotos syndrome. With these data and our experience from our multidisciplinary overgrowth clinic, we provide guidance for managing the behavioral manifestations of Sotos syndrome and highlight the importance of a multidisciplinary approach to care for patients with this complex overgrowth condition.

2 Materials and Methods

We collected data from 25 patients with molecularly confirmed Sotos syndrome, all of whom were either evaluated or had records reviewed at the Children's Hospital of Philadelphia. Charts were reviewed and data abstraction was performed under IRB13-010658 and IRB19-016459. Patients under the age of 3 years were excluded from frequency calculations for the following categories: attention deficit/hyperactivity disorder, autism spectrum disorder, anxiety disorder, and medication for neuropsychological condition. This decision was based on our experience that patients with underlying neuropsychological conditions are typically only diagnosed in our clinic after the age of 3. Informed consent, where applicable, was obtained from all participants or families in this study according to the relevant IRB protocol.

3 Results

There were 25 pathogenic variants of NSD1 identified in this cohort of 25 patients, of which 12 were male and 13 were female. The genotypes and phenotypes of each of the patients in the cohort are reported in Table 1. A characteristic facial appearance (100%), developmental delay (92%), and macrosomia (88%) were the most common features in the cohort. All patients in the cohort presented with a broad and prominent forehead, and 87.5% had a dolichocephalic head shape. In addition, 91.3% had sparse frontotemporal hair and 86.4% had down-slanting palpebral fissures (Table 2). Each of the patients in the cohort had at least two of the features that made up the characteristic facial appearance of Sotos syndrome. Figure 1 highlights some of the facial characteristics of patients in our cohort.

Additional high-prevalence features included advanced bone age (80%), cranial MRI/CT anomalies (89%), and neonatal complications such as hypotonia and jaundice (95%).

There were two cases of tumors found among the patients in our cohort, both of which were benign sacrococcygeal teratomas. CHOP1 was diagnosed with a sacrococcygeal teratoma at 2 weeks of age, which was subsequently removed by surgery at 3 weeks of age. CHOP5 was diagnosed with a fetal cystic sacrococcygeal teratoma prenatally and had a debulking procedure performed shortly after birth.

In the cohort, 84.6% of patients were diagnosed with either ADHD, ASD, or an anxiety disorder. Seven patients in the cohort had a diagnosis of ADHD and five had a diagnosis of ASD. In addition, seven patients were diagnosed with an anxiety disorder.

In our cohort, 68.2% of patients were seen by our Developmental Pediatrics team. As part of their treatment plans, all but two of the patients in our cohort received speech therapy, occupational therapy, and physical therapy for underlying developmental, motor, and speech delays. In addition, 80% of school-age patients in our cohort received an IEP and 38.5% of patients took medication for a neurodevelopmental condition.

4 Discussion

This study presents a large novel cohort of patients with Sotos syndrome, allowing for the further characterization of the incidence of common Sotos features—in particular the characteristic facial appearance, overgrowth, and developmental delay. Particular attention was given to the behavioral presentations of these patients, with a more extensive behavioral history provided for two of the older patients within the cohort.

5 Characteristic Facial Appearance

The characteristic facial appearance of Sotos syndrome, which includes a prominent forehead, dolichocephalic head shape, and anterior hairline, has long been used as a diagnostic tool for the condition (Castro et al. 2021; Dodge et al. 1983; Tatton-Brown et al. 1993). All 25 patients in our cohort presented with a dysmorphic facial appearance that is characteristic of Sotos syndrome. In all these cases, the characteristic appearance was noted before molecular testing was performed. The prevalence of characteristic facial features in our cohort highlights the importance of dysmorphic appearance in the diagnostic process. The facial gestalt associated with Sotos syndrome does tend to evolve over time as patients age (Figure 1). Most notably, the forehead is found to become less prominent, the pointed chin squarer, and jaw line less pronounced (Castro et al. 2021; Foster et al. 2019). This makes the facial findings of Sotos syndrome more difficult to identify with age, an important consideration when evaluating older patients for an overgrowth condition.

6 Tumors

There were two cases of benign sacrococcygeal teratomas found in our cohort, seen in CHOP1 and CHOP5. In both cases, the benign tumors were removed via surgery and no further complications were found. Sacrococcygeal teratomas have previously been reported in patients with Sotos syndrome along with other forms of cancer like acute lymphocytic leukemia and neuroblastomas (Al-Mulla et al. 2004; Grand et al. 2019; Hersh et al. 1992; Jin et al. 2002; Kaya et al. 2022; Kulkarni et al. 2013; Leonard et al. 2000; Lourdes et al. 2023; Nagai et al. 2003; Tatton-Brown et al. 2005; Yule 1999). However, none of these cancers appear to cross the 1% screening threshold recommended by the American Association for Cancer Research, and routine cancer screening is not currently recommended for patients with Sotos syndrome (Kalish et al. 2024). The presence of tumors like sacrococcygeal teratomas in this patient population nevertheless highlights the complexity of clinical presentations found in patients with Sotos syndrome and underscores the importance of multidisciplinary care for this patient population.

7 Behavioral Phenotypes

ADHD and ASD have been reported as two of the most common neurodevelopmental conditions associated with Sotos syndrome (Lane et al. 2017). There have been multiple case reports of individuals with comorbid Sotos syndrome and ASD (Morrow et al. 1990; Mouridsen and Hansen 2002; Trad et al. 1991). In addition, previous cohorts by Lane et al. (2016), Sheth et al. (2015), and Timonen-Soivio et al. (2016) have shown an increased incidence of ASD in individuals with Sotos syndrome. Sheth et al. (2015) reported characteristics of 38 patients with Sotos syndrome and found that 26 (68.42%) of the 38 patients met the clinical cut-off for ASD as assessed by the social communications questionnaire. Lane et al. (2016) found that 65 (83%) of the 78 patients in their cohort with Sotos syndrome met clinical cut-off for ASD according to the Social Responsiveness Autism Scale. In our cohort, 5 (38.5%) of 13 patients over the age of 3 were diagnosed with ASD, which supports the increased incidence of ASD in patients with Sotos syndrome. Many of the younger patients in our cohort were noted to display early signs of ASD as well, which may explain the lower incidence of ASD in our cohort compared to those previously reported in the literature.

In addition to ASD, ADHD has been previously linked to Sotos syndrome. Finegan et al. (1994) reported 27 patients with Sotos syndrome and found that 10 (37.0%) individuals met clinical characteristics of ADHD according to the Child Behavior Checklist. Varley and Crnic (1984) found that 3 (27.3%) of the 11 patients in their cohort met the clinical threshold of ADHD. In our cohort, 7 (53.8%) of 13 patients over the age of 3 had a diagnosis of ADHD, which adds to the evidence of a link between ADHD and Sotos syndrome.

Outside of ASD and ADHD, there appeared to be an increased rate of reported anxiety in our cohort. Thus far, there have been few reports of increased rates of anxiety in patients with Sotos syndrome. Sarimski (2003) conducted a study that showed significantly more separation anxiety in patients with Sotos syndrome compared to age and cognitive-matched controls according to the Children's Social Behavior Questionnaire. The study also found that the Sotos group had higher scores in insecure/anxious behavior as measured by the Nisonger Child Behavior Rating Form (Sarimski 2003). In our cohort, 7 (53.8%) of 13 patients over the age of 3 had reported increased anxiety, which supports Sarimski's findings. CHOP25, for example, developed a fear of dogs at the age of 8, which required extensive counseling and therapy to overcome. The prevalence of anxiety in patients with Sotos syndrome remains an area of future study.

In addition to neurodevelopmental and neuropsychiatric conditions, patients with Sotos syndrome have been reported to exhibit more tantrums and display more aggressive behavior (Compton et al. 2004; Mauceri et al. 2000). Both CHOP1 and CHOP25 were noted to have increased incidences of aggressive behaviors and temper tantrums by their caregivers and teachers. The presence of these aggressive behaviors in patients with Sotos syndrome remains an area of future study.

8 Multidisciplinary Care for Sotos Syndrome

The prevalence of ADHD, ASD, anxiety, and aggressive behaviors in patients with Sotos syndrome highlights the need for longitudinal multidisciplinary care for these patients.

As seen in our cohort, 68% of patients were seen by our DBP team during the course of their care. Nearly all our patients received speech therapy, occupational therapy, and/or physical therapy for underlying developmental, motor, and/or speech delays. In addition, 80% of patients in our cohort received an IEP in their school, highlighting the importance of careful coordination between providers, caregivers, teachers, and school administration. Outside of these physical interventions, nearly 40% of patients took medication for a neurodevelopmental condition, most often ADHD. Importantly, the combination of interventions needed for patients in our cohort changed over time. For example, ADHD in the cases of CHOP1 and CHOP25 was managed using a combination of stimulant medication and educational supports like IEPs and school aids. In both cases, the medication regimen and educational supports provided to patients evolved as the needs and concerns of the patients changed. Without regular follow-up and coordination between caregivers, providers, and school staff, such efforts to adapt interventions would not have been possible.

Based on our experience in our multidisciplinary overgrowth clinic and the data collected in this study, we recommend an initial DBP evaluation between the ages of 12 and 24 months for patients with Sotos syndrome. During this visit, we recommend careful attention be paid to signs of the most frequent behavioral and neurodevelopmental concerns for patients with Sotos syndrome, which include developmental delay, motor delay, speech delay, ASD, ADHD, anxiety, and aggressive behavior or tantrums. A list of common evaluation methods and interventions for these conditions are listed in Table 3. Depending on the results of this initial evaluation, we recommend annual, biannual, or quarterly follow-up with DBP and adjustment of interventions as concerns change over time (Figure 2).

9 Conclusion

In this study, we presented and phenotyped a novel cohort of patients with molecularly confirmed Sotos syndrome. The behavioral presentations of two of the older patients in the cohort were highlighted in detail. The prevalence of neurodevelopmental, neuropsychiatric, and behavioral challenges in this patient population underscores the importance of multidisciplinary care and coordination between providers, caregivers, and school administration. Using our cohort and experience with our multidisciplinary overgrowth clinic, we also provide guidance for managing the behavioral manifestations of Sotos syndrome and highlight the need for multidisciplinary care for this patient population. The longitudinal changes in the behavioral characteristics of patients with Sotos syndrome and complete phenotypic spectrum of this rare overgrowth condition remain areas of future study.

Author Contributions

Aravind Viswanathan: investigation; writing original draft and review. Andrew M. George: investigation; writing original draft and review. Evan R. Hathaway, Carlyn Glatts: investigation; writing review. Jennifer M. Kalish: conceptualization; supervision; investigation; writing review and editing.

Conflicts of Interest

The authors declare no conflicts of interest.