Bilateral Pheochromocytomas, Hemihyperplasia, and Subtle Somatic Mosaicism: The Importance of Detecting Low‐<scp>L</scp>evel Uniparental Disomy

Kalish, Jennifer M.; Conlin, Laura K.; Mostoufi‐Moab, Sogol; Wilkens, Alisha; Mulchandani, Surabhi; Zelley, Kristin; Kowalski, Megan; Russo, Pierre; Mattei, Peter; Mackenzie, William G.; LiVolsi, Virginia A.; Nichols, Kim E.; Biegel, Jaclyn A.; Spinner, Nancy B.; Deardorff, Matthew A.

doi:10.1002/ajmg.a.35831

Cited by 24 publications

(21 citation statements)

References 35 publications

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“…Overlooking UPD might be an important limitation in the identification of BWS cases that have a high risk of cancer 20 . Moreover, this approach allows UPD to be identified without the need to analyze the DNA of the parents, meaning the number of cases that can be tested is increased.…”

Section: Discussionmentioning

confidence: 99%

Quantitative DNA methylation analysis improves epigenotype-phenotype correlations in Beckwith-Wiedemann syndrome

et al. 2013

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Beckwith-Wiedemann syndrome (BWS) is a rare disorder characterized by overgrowth and predisposition to embryonal tumors. BWS is caused by various epigenetic and/or genetic alterations that dysregulate the imprinted genes on chromosome region 11p15.5. Molecular analysis is required to reinforce the clinical diagnosis of BWS and to identify BWS patients with cancer susceptibility. This is particularly crucial prenatally because most signs of BWS cannot be recognized in utero. We established a reliable molecular assay by pyrosequencing to quantitatively evaluate the methylation profiles of ICR1 and ICR2. We explored epigenotype-phenotype correlations in 19 patients that fulfilled the clinical diagnostic criteria for BWS, 22 patients with suspected BWS, and three fetuses with omphalocele. Abnormal methylation was observed in one prenatal case and 19 postnatal cases, including seven suspected BWS. Seven cases showed ICR1 hypermethylation, five cases showed ICR2 hypomethylation, and eight cases showed abnormal methylation of ICR1 and ICR2 indicating paternal uniparental disomy (UPD). More cases of ICR1 alterations and UPD were found than expected. This is likely due to the sensitivity of this approach, which can detect slight deviations in methylation from normal levels. There was a significant correlation (p < 0.001) between the percentage of ICR1 methylation and BWS features: severe hypermethylation (range: 75–86%) was associated with macroglossia, macrosomia, and visceromegaly, whereas mild hypermethylation (range: 55–59%) was associated with umbilical hernia and diastasis recti. Evaluation of ICR1 and ICR2 methylation by pyrosequencing in BWS can improve epigenotype-phenotype correlations, detection of methylation alterations in suspected cases, and identification of UPD.

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Section: Discussionmentioning

confidence: 99%

Quantitative DNA methylation analysis improves epigenotype-phenotype correlations in Beckwith-Wiedemann syndrome

et al. 2013

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“…This is also true in cases with very subtle 11p overgrowth features including one case of HI being the only presenting feature of 11p overgrowth and the patient developing a hepatoblastoma 16 17. Due to these additional clinical implications, UPD-11p overgrowth HI should be considered in cases with large focal pancreatic lesions with or without a KATP mutation, even in the absence of overt features of 11p overgrowth.…”

Section: Discussionmentioning

confidence: 99%

“…The genetic or epigenetic changes causing BWS typically occur during embryonal development in a subset of cells, leading to a mosaic mixture of normal and BWS cells and resulting in a mosaic spectrum of clinical features 16. The BWS locus on 11p15.5 includes two adjacent regions of imprinted genes, including IGF2, a growth-promoting protein, and two growth-inhibitory genes; the long non-coding RNA H19 and the cell cycle regulator p57/ CDKN1C (see figure 1).…”

Section: Introductionmentioning

confidence: 99%

“…11 Finally, 20% of BWS cases are caused by paternal uniparental isodisomy for chromosome 11p (pUPD11p), which leads to a combined loss of p57/ CDKN1C and KCNQ1 expression as well as biallelic IGF2 expression (figure 1). This same genetic change, pUPD11p, can lead to classic BWS, but can often lead to more subtle features including isolated hemihypertrophy of a limb or isolated overgrowth of an organ 16 17. The entire group of disorders caused by genetic or epigenetic alterations on chromosome 11 can be referred to as ‘11p overgrowth spectrum’ or ‘11p overgrowth’.…”

Section: Introductionmentioning

confidence: 99%

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Congenital hyperinsulinism in children with paternal 11p uniparental isodisomy and Beckwith–Wiedemann syndrome

et al. 2015

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Background Congenital hyperinsulinism (HI) can have monogenic or syndromic causes. Although HI has long been recognised to be common in children with Beckwith–Wiedemann syndrome (BWS), the underlying mechanism is not known. Methods We characterised the clinical features of children with both HI and BWS/11p overgrowth spectrum, evaluated the contribution of KATP channel mutations to the molecular pathogenesis of their HI and assessed molecular pathogenesis associated with features of BWS. Results We identified 28 children with HI and BWS/ 11p overgrowth from 1997 to 2014. Mosaic paternal uniparental isodisomy for chromosome 11p (pUPD11p) was noted in 26/28 cases. Most were refractory to diazoxide treatment and half required subtotal pancreatectomies. Patients displayed a wide range of clinical features from classical BWS to only mild hemihypertrophy (11p overgrowth spectrum). Four of the cases had a paternally transmitted KATP mutation and had a much more severe HI course than patients with pUPD11p alone. Conclusions We found that patients with pUPD11p–associated HI have a persistent and severe HI phenotype compared with transient hypoglycaemia of BWS/11p overgrowth patients caused by other aetiologies. Testing for pUPD11p should be considered in all patients with persistent congenital HI, especially for those without an identified HI gene mutation.

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“…It involves an 18-month-old girl, who at the age of 4 months presented with bilateral pheochromocytomas (17).…”

Section: Discussionmentioning

confidence: 99%

Recurrent benign adrenal pheochromocytomas associated with hemihypertrophy

Pikilidou

Yavropoulou

Katsounaros

2014

Endocrinology, Diabetes &Amp; Metabolism Case Reports

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SummaryWe report a case of a female with hemihypertrophy, who developed five recurrences of pheochromocytomas until the age of 35. Timely follow-up of the patient's blood pressure assisted in early diagnosis and treatment of recurrent tumors.Learning points Recurrent benign pheochromocytomas should raise suspicion of a genetic syndrome.A pheochromocytoma at a young age has a high propensity to recur and strict follow-up is mandatory.

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Bilateral Pheochromocytomas, Hemihyperplasia, and Subtle Somatic Mosaicism: The Importance of Detecting Low‐Level Uniparental Disomy

Cited by 24 publications

References 35 publications

Quantitative DNA methylation analysis improves epigenotype-phenotype correlations in Beckwith-Wiedemann syndrome

Quantitative DNA methylation analysis improves epigenotype-phenotype correlations in Beckwith-Wiedemann syndrome

Congenital hyperinsulinism in children with paternal 11p uniparental isodisomy and Beckwith–Wiedemann syndrome

Recurrent benign adrenal pheochromocytomas associated with hemihypertrophy

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