Hepatoblastoma Associated With Sotos Syndrome

A 6-year-old girl with Sotos syndrome 1 presented with a 2-day history of abdominal pain and fever. Physical examination revealed a macrocephalic child with a prominent forehead, hypertelorism, down-slanted palpebral fissures, and an elongated face. She was nonverbal and unable to follow commands. The liver margin was palpable 5 cm below the costovertebral angle. The rest of the examination findings were normal.

Her past medical history included left renal agenesis and atrial septal defect (ASD). She had been born at term, and her birth weight, length, and head circumference were in the 50th to the 75th percentile for age. After 10 months, these growth measurements had risen to greater than the 95th percentile for age.

At 12 months of age, chromosomal microarray analysis identified a microdeletion of 5q35 in the NSD1 (nuclear receptor-binding SET domain protein 1) gene, diagnostic of Sotos syndrome.

With the exception of a mildly elevated white blood cell count, all of her laboratory test results, including serum electrolyte tests, liver function tests, urinalysis, and urine culture, were unremarkable.

An abdominal computed tomography scan revealed a large, infiltrative intrahepatic mass with tumor thrombus in the portal vein (A and B). The serum α-fetoprotein (AFP) level was found to be greater than 20,000 ng/mL (reference value: < 11 ng/mL), and pathologic examination of a liver biopsy sample was consistent with epithelial hepatoblastoma.

CLINICAL FEATURES

Sotos syndrome is an overgrowth syndrome characterized by 3 cardinal features: a facial gestalt consisting of a broad forehead, sparse frontotemporal hair, malar flushing, pointed chin, and down-slanted palpebral fissures; intellectual disability, and macrocephaly.^1-3

Other associations include poor feeding in the newborn period, neonatal hypoglycemia, hypotonia, seizures, advanced bone age, joint hyperlaxity, as well as cardiac, genitourinary and brain abnormalities, and learning disabilities.^4-6 Affected children become significantly taller than their peers during the first 2 to 3 years of life, but their adult height usually is in the average range.³

ETIOLOGY

Sotos syndrome has been differentiated into Sotos syndrome 1 and 2, with the former referring to NSD1 haploinsufficiency, and the latter to mutations of 19p13 in the NFIX (nuclear factor I/X) gene.^2,4-8

Sotos syndrome 1 accounts for 60% to 90% of cases, the vast majority of which result from de novo mutations in NSD1.^2,8-10 The NSD1 gene is expressed in the brain, kidneys, skeletal muscle, spleen, thymus, and lungs, and it has a role in human growth and development.^11,12

The risk of malignancy in patients with Sotos syndrome is 2% to 3%.¹³ Among the most common malignancies in these individuals are Wilms tumor, neuroblastoma, sacrococcygeal teratoma, leukemia, and lymphoma.^3,4,8,14 Hepatocarcinoma and hepatoblastoma have been reported only once previously in patients with this syndrome.^4,15

RELATED DISORDERS

While hepatic malignancy rarely is associated with Sotos syndrome, it is commonly described among patients with Beckwith-Wiedemann syndrome (BWS), an overgrowth syndrome that has phenotypic and molecular overlap with Sotos syndrome.¹⁶ BWS is characterized by macrosomia, macroglossia, visceromegaly, neonatal hypoglycemia, and renal abnormalities. Associated malignancies include embryonal tumors, Wilms tumor, hepatoblastoma, neuroblastoma, and rhabdomyosarcoma.^3,16 Dysregulation of growth-regulatory genes in chromosome 11p15 is the major cause of BWS. Interestingly, genetic anomalies in 11p15 have been found in patients with Sotos syndrome, and mutations in NSD1 also have been described in patients with BWS.¹⁶ The mechanism underlying this overlap between NSD1 and 11p15 dysregulation in Sotos syndrome and BWS remains unknown.

TREATMENT

Treatment for Sotos syndrome is symptomatic. In our patient’s case, chemotherapy was initiated with cisplatin, 5-fluorouracil, and vincristine for hepatocarcinoma, but this regimen later was switched to carboplatin and doxorubicin when a slight rise in serum AFP concentration was detected. No severe toxicity was detected during the course of treatment, and a gradual decrease of serum AFP was observed (C).

DISCUSSION

As suggested by recent data, NSD1 dysregulation could lead to hepatic oncogenesis in Sotos syndrome.⁴ This is the second case report in the literature of hepatoblastoma associated with Sotos syndrome 1.

Owing in part to the low incidence of malignancy in Sotos syndrome, routine screening for tumor development in affected children is not currently performed. Because abdominal pain and fever could be the presenting symptoms of hepatic malignancy in these children, diagnostic imaging should be considered in the initial workup, especially in the setting of hepatomegaly. Given that hepatoblastoma generally carries a good prognosis, early detection and treatment can help reduce morbidity and mortality from associated complications.

References

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