title: Bilateral pheochromocytomas, hemihyperplasia, and subtle somatic mosaicism: the importance of detecting low-level uniparental disomy.
abstract: We report on a patient with early onset pediatric bilateral pheochromocytomas caused by mosaic chromosome 11p15 paternal uniparental isodisomy (UPD). Hemihyperplasia of the arm was diagnosed in a 4-month-old female and clinical methylation testing for 11p15 in the blood was normal, with a reported detection threshold for mosaicism of 20%. She was subsequently diagnosed at 18 months with bilateral pheochromocytomas. Single-nucleotide polymorphism (SNP) array analysis of pheochromocytoma tissue demonstrated mosaic deletions of 8p12pter, 21q21.1qter, 22q11.23qter; commonly seen in pheochromocytomas. In addition, mosaic 11p15.3pter homozygosity was noted. Molecular testing for other causes of pheochromocytomas was normal, suggesting that 11p15 homozygosity was the primary event. Subsequent SNP array analysis of skin fibroblasts from the hyperplastic side demonstrated 5% mosaic paternal UPD for 11p15. We have subsequently used SNP array analysis to identify four patients with subtle hemihyperplasia with low-level mosaic UPD that was not detected by methylation analysis. Given the increased sensitivity of SNP array analysis to detect UPD along with the increased incidence of tumorigenesis in these UPD patients, we suggest that it has high utility in the clinical work-up of hemihyperplasia. The present case also suggests that 11p15 paternal UPD may be an under-detected mechanism of sporadic pheochromocytoma in the pediatric population. Furthermore, a review of the literature suggests that patients with 11p15 paternal UPD may present after 8 years of age with pheochromocytoma and raises the possibility that ultrasound screening could be considered beyond 8 years of age in this subset of hemihyperplasia and Beckwith-Wiedemann syndrome patients.
authors.affiliation: Division of Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Kalish
authors.forename: Laura K
authors.initials: LK
authors.lastname: Conlin
authors.forename: Sogol
authors.initials: S
authors.lastname: Mostoufi-Moab
authors.forename: Alisha B
authors.initials: AB
authors.lastname: Wilkens
authors.forename: Surabhi
authors.initials: S
authors.lastname: Mulchandani
authors.forename: Kristin
authors.initials: K
authors.lastname: Zelley
authors.forename: Megan
authors.initials: M
authors.lastname: Kowalski
authors.forename: Tricia R
authors.initials: TR
authors.lastname: Bhatti
authors.forename: Pierre
authors.initials: P
authors.lastname: Russo
authors.forename: Peter
authors.initials: P
authors.lastname: Mattei
authors.forename: William G
authors.initials: WG
authors.lastname: Mackenzie
authors.forename: Virginia
authors.initials: V
authors.lastname: LiVolsi
authors.forename: Kim E
authors.initials: KE
authors.lastname: Nichols
authors.forename: Jaclyn A
authors.initials: JA
authors.lastname: Biegel
authors.forename: Nancy B
authors.initials: NB
authors.lastname: Spinner
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Deardorff
mesh_terms: D001506:Beckwith-Wiedemann Syndrome / Q000175:diagnosis / Q000235:genetics*; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics*; D005260:Female; D006801:Humans; D006965:Hyperplasia / Q000175:diagnosis / Q000235:genetics*; D007223:Infant; D009030:Mosaicism; D010673:Pheochromocytoma / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D024182:Uniparental Disomy / Q000235:genetics*