The patient was a 21-year-old female with past history of stage 3 ACT diagnosed at 4.9 years. Her development was normal except for an incidental note per the family of longer and larger right upper and lower extremities throughout her life that had not been specifically investigated as far as the patient and her family were aware, but was associated with chronic left-leaning posture and asymmetric shoe size. She had been in her usual state of good health until the age 4 years when she complained of abdominal pain. She also had weight loss, increased headaches, decreased activity and energy, increased tiredness, and sweating. Given the persistence of symptoms, she was examined by a physician who palpated an abdominal mass and noted hypertension and slight androgen elevations. Magnetic resonance imaging showed a large abdominal mass in the right adrenal gland, with direct extension into the inferior vena cava and nearly completely filling of the right atrium. She underwent a partial sternotomy, and extraction of the caval portion of the adrenal tumor and resection of the right retroperitoneal tumor. The tumor weight was 550 g and measured 13.5 × 10.5 × 6.0 cm. The pathology confirmed ACC (low Ki-67 LI, rare mitotic figures and negative for inhibin-α). There were large areas of necrosis, and vascular invasion with tumor penetration through the capsule. Immunohistochemistry analysis was negative for p53 and positive for beta-catenin. She was treated with the combination of cisplatin, doxorubicin, etoposide, and mitotane. Features of right-sided lateral overgrowth, including right-sided tongue enlargement as well as increased right vs. left arm circumferences (51 cm vs 50 cm), calf circumferences (39 cm vs 37 cm), and a slight leg length discrepancy (88 cm vs 85 cm) were first noted during exams performed at St. Jude as part of a multidisciplinary rare endocrine tumor clinic when she was 18 years old, and led to additional testing subsequently confirming chromosome 11p15 UPD. She has been alive and tumor free for 17 years.\nMolecular findings: Blood DNA of this patient was analyzed by whole exome sequencing (WES). No reportable structural, single nucleotide variants, and indel or copy number changes were identified in APC, CDKN1C, MEN1, PRKAR1A, and TP53. Chromosome paternal 11p15 UPD was confirmed by MS-MLPA.
The patient was an 8.5-year-old female with presumptive diagnosis of BWS who presented to the local physician in 2003 with new onset of herculean habitus, clitoromegaly, pubic hair, acne, and apocrine odor. Abdominal computed tomography imaging revealed synchronous bilateral adrenal masses. There was no evidence of disease elsewhere. The patient underwent laparotomy with excision of the left adrenal gland and tumor enucleation of the right gland. The left tumor weighed 21.5 g and measured 5.5 × 1.5 × 0.7 cm, and right tumor measured 1.3 × 1.2 × 1.0 cm. Sections of both tumors showed similar cellular constituents. Tumors were composed of a uniform population of cells with ample acidophilic cytoplasm and moderate anisonucleosis that recapitulated the zona reticularis, consistent with the diagnosis of adrenocortical adenoma. The p53 staining was negative and Ki-67 labeling index (LI) was less than 2%. Inhibin-α was positive in a subset of cells. No chemotherapy was indicated. The patient remained asymptomatic until 2008, and then developed bilateral small breast nodules. The right breast mass measured 3.5 × 2.5 × 2.0 cm and the left inferior breast mass measured 3.0 × 2.0 × 2.0 cm and both were surgically removed. Histology of the first mass had features of tubular adenoma and that of the left mass of juvenile fibroadenoma. The patient remained clinically stable until the age of 18 years when she was taken off the protocol.\nMolecular findings: Blood and tumor DNA of this patient was examined by whole exome sequencing (WES) (). Results showed that the patient had a wild type sequence for TP53 in both germline and tumor DNA as well as wild type sequence for CTNNB1 and ATRX in the tumor (, ). Additional findings included the somatic p.E150K variant in the imprinted MKRN3 and the p.D155fs in the cytochrome P450 Family 17 Subfamily A Member 1, CYP17A1. Of note, the patient harbored a germline p.E257K variant in EGFR () and the p.M595T variant in the regulator of epigenetic gene silencing SIRT1. Both variants were present in the tumor in the heterozygous state (). The variant in EGFR was classified as likely benign in CLINVAR (variant ID 1123013) and the SIRT1 variant was not reported. Therefore, both variants have been reported in the Genome Aggregation Database (gnomAD) originated from unrelated individual sequences as part of population genetic studies supporting lack of biological significance for both variants in the context of adrenocortical tumors. WES analysis of blood-derived DNA did not detect 11p15 UPD. However, a pattern of homozygosity at chromosome 11p15 was verified by microsatellite markers analyses and confirmed by MS-MLPA consistent with paternal uniparental disomy (UPD) in the germline sample ().