A Case of Sotos Syndrome With Right Shoulder Disarticulation Due to a High-Grade Malignant Peripheral Nerve Sheath Tumor in the Right Arm and Shoulder

Abstract

Sotos syndrome is an autosomal dominant genetic disorder that causes an overgrowth of the body characterized by distinctive craniofacial features, excessive growth, and neurodevelopmental delay. We present a 49-year-old man diagnosed with Sotos syndrome and with a previous history of lymphoma in remission who developed a high-grade malignant peripheral nerve sheath tumor (MPNST) affecting the right upper extremity. Due to the tumor recurrence of a high-grade malignant peripheral nerve sheath tumor (MPNST) in the right arm and shoulder, the patient underwent a right shoulder disarticulation. This aggressive clinical course was further complicated by a pathological fracture, persistent local neoplastic disease, and the eventual development of pulmonary lesions radiographically highly suggestive of metastatic disease, though tissue biopsy was not performed. The patient originally refused amputation despite advice for early definitive surgical therapy, which caused the condition to worsen. Palliative radiation therapy, multi-agent chemotherapy, and supportive care for pain and psychological distress were part of the subsequent management. This case underscores the aggressive clinical course and the importance of early diagnosis, prompt surgical intervention, multidisciplinary care, and effective patient counseling.

Introduction

Sotos syndrome is a rare genetic disorder that was first described in 1964. Sotos syndrome has been previously referred to as cerebral gigantism [1]. This term is now outdated and no longer used. It follows an autosomal dominant pattern of inheritance. Both men and women are equally affected. It occurs in all ethnic groups around the globe. This condition is reported to occur in about one in 14,000 live births. Sotos syndrome is characterized by a distinctive facial appearance, overgrowth, and varying degrees of macrocrania with an elongated skull shape (dolichocephaly). The facial phenotype is uniquely recognizable, typically presenting with a prominent high forehead (frontal bossing), down-slanting palpebral fissures, malar flushing, and a long, pointed chin that gives the face an inverted triangular appearance. Because the condition affects the development of the nervous system, affected children have learning disabilities or delayed mental and developmental abilities. Frequent behavioral problems include autism spectrum disorder, attention-deficit/hyperactivity disorder (ADHD), different types of phobias, obsessions and compulsions, tantrums, and impulsive behaviors [2].

It is most frequently linked to mutations in the nuclear receptor-binding SET domain protein 1 (NSD1)geneand has an autosomal dominant inheritance pattern. All ethnic groups are affected, with an estimated incidence of one in 14,000 live births [3].

Sotos syndrome has been linked to a higher risk of malignancies, especially in childhood, including solid tumors and hematological malignancies, in addition to its distinctive phenotypic characteristics. The spectrum of reported neoplasms is wide, and early detection is crucial for prompt management even if the overall cancer risk is still quite low [4,5].

Malignant peripheral nerve sheath tumors (MPNSTs) that arise from peripheral nerves or their sheaths are aggressive soft tissue sarcomas and are linked to a poor prognosis due to high rates of metastases and recurrence. They are quite uncommon in Sotos syndrome, although they are most frequently associated with neurofibromatosis type 1 [6,7].

High-grade sarcomas such as MPNST need to be treated with a multidisciplinary strategy that includes radiation, chemotherapy, and surgical resection. Prognostic outcomes are adversely affected when definitive surgical management is delayed, an impact that is further compounded by advanced stage or the presence of distant metastases [8,9].

The emergence of a high-grade malignant peripheral nerve sheath tumor in an adult patient with Sotos syndrome is highlighted in this case, highlighting the difficulties in managing the condition, the significance of prompt intervention, and the requirement for thorough multidisciplinary care.

This case report serves several primary clinical objectives. It comprehends the complex diagnostic and therapeutic challenges encountered when managing aggressive soft tissue sarcomas complicated by pathological fractures and treatment delays. Additionally, it evaluates the efficacy of a multimodal palliative regimen involving chemotherapy, radiation, and supportive care for advanced metastatic disease. Ultimately, the report emphasizes the vital role of early tumor surveillance and structured multidisciplinary counseling to improve patient compliance and clinical outcomes.

Case presentation

This case illustrates a 49-year-old man with Sotos syndrome (Figure 1) who presented to the emergency department with profuse hemorrhage and severe acute pain localized to his right shoulder disarticulation site. The patient’s oncological history was notable for a recurrent osteosarcoma of the right humerus diagnosed six months prior, which was initially identified via radiography (Figure 2) and necessitated the subsequent disarticulation; he was also undergoing clinical surveillance for concurrent lung nodules. In addition to Sotos syndrome and its associated musculoskeletal and neurodevelopmental manifestations, including stable scoliosis, chronic ataxia, an unsteady gait, and peripheral neuropathy, the patient’s history was further complicated by a chronic pain syndrome. His remaining comorbidities included atrial fibrillation, hypothyroidism, and recurrent gout. Upon presentation, immediate hemostatic stabilization and surgical evaluation of the bleeding surgical site were initiated.

Figure 1. Characteristic Craniofacial Features of Sotos Syndrome in an Adult Patient.

The figure illustrates a frontal view showing classic progeroid features, including alopecia, prominent ears, a sculpted nose, and micrognathia with associated dental crowding.

Figure 2. Right Humerus Osteosarcoma.

An anteroposterior (AP) radiograph of the right shoulder demonstrating highly aggressive bone destruction and periosteal reaction in the proximal humerus.

Imaging revealed multiple soft tissue masses of the right humerus, a pathological fracture of the mid diaphysis with evidence of bone tumor extending into the soft tissues of the mid arm, and new lung nodules concerning metastasis. Despite persistent recommendations for definitive surgery, including disarticulation/amputation, the patient had refused further surgical management for over six months. On admission, he was alert but with cognitive impairment, and physical examination revealed an enlarged right upper extremity stump with edema, bleeding, and decreased range of motion. He had a prior history of leukopenia and neutropenia during an admission for pneumonia. Positron emission tomography (PET) scan performed on 8/9/2022, compared to a PET scan dated 5/13/2022, showed an interval decrease in extent and fluorodeoxyglucose (FDG) activity avidity of the destructive proximal right humerus lesion with new pathological fracture, scattered heterogeneous ossification, and increased extent of associated low attenuation centrally. There was also new heterogeneous FDG activity in the right, mid, and lower lungs corresponding to nodular ground glass opacities/consolidations that were either increased or not significantly changed from CT on 6/23/2022, probably of infectious or inflammatory nature, new small pelvic ascites, and nonspecific mild diffuse bone marrow hypometabolism without CT correlate. X-ray confirmed an acute displaced pathological fracture of the right humerus. His past medical history included hypertension (HTN), hyperlipidemia (HLD), atrial fibrillation (A-Fib) with pericardial effusion status post (s/p) window in 2016, lymphoma in remission s/p chemo in 2016, and sarcoma/osteosarcoma diagnosed after biopsy.

After the recurrence of the tumor in the stump with uncontrolled pain, the patient eventually consented to aggressive management. Treatment included palliative radiation to the right shoulder, aggressive chemotherapy, and supportive care, including Neulasta administered by the oncologist, pain control with oxycodone and morphine, and psychiatric support for anxiety and depression, as the sarcoma had already metastasized on the PET scan. Radiation consult recommended palliative radiation therapy to the right shoulder to address pain and bleeding. Despite these measures, the patient experienced increased depression and anxiety related to the apparent spread of cancer to his lymph nodes and chest. The resident noted that he remained alert but exhibited cognitive impairment when communicating. Throughout the course of treatment, definitive surgery was consistently recommended for local control but was initially refused, and palliative measures were later used as an alternative. The patient’s condition was further complicated by a pathological fracture of the right humerus and the persistent refusal of the disarticulation of the right arm.

Despite the eventual agreement to aggressive multimodal therapy, the intervention was undertaken at a late stage with extensive local and metastatic disease burden. The patient succumbed to complications of metastatic cancer, highlighting that a delay in definitive surgical management of sarcomas can limit treatment efficacy and worsen prognosis, even with subsequent aggressive measures. This case underscores the challenges in managing advanced sarcoma in the setting of comorbid Sotos syndrome and cognitive impairment and the importance of early definitive intervention when feasible.

Discussion

In more than 90% of the patients, Sotos syndrome has been associated with a nuclear receptor-binding SET domain protein 1 (NSD1) gene mutation. NSD1 gene is responsible for maintaining normal body growth. When a mutation affects the NSD1 gene, it cannot regulate the body’s growth, causing children diagnosed with Sotos syndrome to be taller than their peers. Other reported gene mutations include the nuclear factor I, X type (NFIX) gene and the APC2 gene [2].

Neonates with Sotos syndrome may have jaundice (65%), hypotonia (75%), and poor feeding (70%). These complications tend to resolve spontaneously, but in a small minority, intervention may be required. Mothers are also reported to have suffered from preeclampsia during pregnancy (15%). Characteristic facial features include a prominent high-bossed forehead, receded hairline in 90% of cases, flushed cheeks, high arched palate, downward slant of the outer corners of the eyes (antimongoloid slant of the palpebral fissures), hypotonia, increased arm span, talipes equinovarus, umbilical hernia, vertebral anomalies, 2/3 toe syndactyly, and tall stature. The growth velocity is exceptionally high in the first 3-4 years of life. Later, it precedes the average rate but is still in the high percentile [2].

The diagnosis of Sotos syndrome is primarily established based on characteristic clinical presentations, which remain the foundational basis for identification. To achieve a definitive diagnosis, clinical findings are typically supported or confirmed by molecular genetic testing. DNA studies using fluorescence in situ hybridization (FISH) analysis provide a simple and reliable method to detect partial NSD1 gene deletions. Additionally, genome sequencing can be utilized to identify point mutations, while G-banding karyotyping combined with FISH is effective for identifying cryptic chromosomal translocations [10].

The management of Sotos syndrome requires collaboration among multiple specialties, including pediatricians, pediatric endocrinologists, geneticists, neurologists, surgeons, speech-language pathologists, ophthalmologists, orthopedists, physiotherapists, oncologists, and other healthcare professionals. Treatment is based on individual signs and symptoms, tailored to the needs of each patient [11].

Patients with Sotos syndrome may experience complications such as difficulty feeding, low muscle tone, heart defects, genitourinary symptoms, recurrent upper airway respiratory tract disease, conductive hearing loss, and congenital hypothyroidism [12]. Premature teeth eruption, scoliosis, skeletal problems, and strabismus are also expected. Recurrent epilepsy is a widespread manifestation and should be considered during the preoperative evaluation of epileptic surgery, particularly in MRI-negative straightforward cases. Genetic testing is recommended in patients with overgrowth and developmental delay presenting with recurrent seizures [13]. These patients are also prone to developing tumors such as sacrococcygeal teratoma, neuroblastoma, acute lymphoblastic leukemia (ALL), and presacral ganglioma. In some cases, seizures, pectus deformity, and cardiac and renal organ anomalies may be observed. Over the last decades, congenital hyperinsulinemic hypoglycemia (CHI) has been increasingly reported in association with Sotos syndrome [14].

The condition often has no life-threatening side effects, and patients usually have an average life expectancy. Sotos syndrome is a lifelong condition that has no cure, although a few case reports of severe complications such as ST-segment elevation myocardial infarction (STEMI) and chronic subdural hematoma have been described [15]. Echocardiography and kidney ultrasound are recommended at diagnosis, followed by yearly follow-up [16].

Sotos syndrome shares many symptoms with autism spectrum disorder, including intellectual disabilities, delayed motor skills and language development, delayed coordination, difficulty adjusting to social situations, attention difficulties, and patterns of repetitive behavior. The main difference is that Sotos syndrome also affects growth, whereas autism spectrum disorder does not [17].

There are also reports of Sotos syndrome coexisting with Silver-Russell syndrome (SRS). Single nucleotide polymorphism (SNP) array revealed a 2.1 Mb de novo interstitial deletion of 5q35.2q35.3 in the NSD1 gene. When Sotos syndrome could not explain all symptoms satisfactorily, diagnostic testing for SRS was initiated, which demonstrated the hypomethylation of the imprinting center 1 of chromosome 11p15.5, confirming the clinically suspected SRS [18]. Diagnosing Sotos syndrome can be challenging due to its unique manifestations and overlapping features with other conditions. Close differentials include Weaver-Smith syndrome, Beckwith-Wiedemann syndrome, Simpson dysmorphia syndrome, fragile X syndrome, Gorlin syndrome, and Malan syndrome [19]. Overgrowth conditions that may be confused with Sotos syndrome are summarized in Table 1, along with a comparison with Sotos features to help prepare for specific diagnosis [20].

Table 1. Overgrowth Syndromes With Clinical Features Overlapping Sotos Syndrome.

The table illustrates the differential diagnosis of overgrowth syndromes mimicking Sotos syndrome, categorized by genetic etiology, inheritance patterns, and distinct clinical phenotype variations [21-24].

Name of disease	Gene(s) involved	Inheritance pattern	Similarities	Differences
Weaver-Smith syndrome	EZH2	Autosomal dominant	Typical facial appearance, increased height velocity, microcephaly, scoliosis, and hypotonia at birth	Round face with hypertelorism, prognathism not seen, joint problems, and infants with a low-pitched cry
Beckwith-Wiedemann syndrome	Chromosome 11p15	Autosomal dominant	Weight and height of ≥2 SD	Macroglossia, visceromegaly, omphalocele, and increased risk of embryonal tumors, especially Wilms tumor.
Simpson-Golabi-Behmel syndrome type 1	GPC3 and GPC4	X-linked recessive	Prenatal and postnatal overgrowth and intellectual disability	Male predominance, polydactyly, supernumerary nipples, pectus excavatum, and rectus sheath diastasis
Fragile X syndrome	FMR-1	X-linked dominant	Macrocephaly, intellectual disability, dolicocephalic-shaped head, and prominent forehead and jaw	Male predominance; large ears in affected men, which is not seen in Sotos syndrome; macroorchidism post-puberty
Malan syndrome	NFIX	Autosomal dominant	Characteristic facial appearance, scoliosis, and intellectual disability	Eye problems are more common
Gorlin syndrome	PTCH and SUFU	Autosomal dominant	Characteristic facial features and head circumference of >98th percentile until 10-18 months	Jaw keratocysts, basal cell carcinoma usually occurring from the third decade, bifid ribs, and wedge-shaped vertebrae

Conclusions

This case highlights the aggressive biology and poor prognosis of high-grade sarcomas in adults with Sotos syndrome, emphasizing a critical need to shift focus from well-documented pediatric manifestations to adult malignancy risks. Advanced local and metastatic disease severely limited the efficacy of multimodal therapy, underscoring that definitive treatment delays drastically compromise survival. Optimizing outcomes in these complex patients requires early diagnostic vigilance, prompt surgical intervention, coordinated multidisciplinary care, and proactive patient counseling to prevent management delays. Future investigations must focus on establishing standardized, lifelong oncological surveillance protocols tailored for adult overgrowth syndromes. Additionally, collaborative registries and molecular studies are warranted to clarify the precise genetic mechanisms driving accelerated oncogenesis in this population.