Chromosome 11 segmental paternal isodisomy in amniocytes from two fetuses with omphalocoele: new highlights on phenotype-genotype correlations in Beckwith-Wiedemann syndrome

Grati, Francesca Romana; Turolla, Licia; D’Ajello, Patrizia; Ruggeri, Anna; Miozzo, Monica; Bracalente, Gabriella; Baldo, Demetrio; Laurino, Licia; Boldorini, Renzo; Frate, Elisabetta; Surico, N; Larizza, Lidia; Maggi, Federico; Simoni, Giuseppe

doi:10.1136/jmg.2006.046854

Cited by 18 publications

(9 citation statements)

References 30 publications

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“…Loss of heterozygosity at 11p15 in the adenoma was ruled out because MLPA analysis did not detect any copy number variations. Previous studies on BWS fetuses have shown that in several organs, the proportion of abnormal cells is positively correlated with the risk of hyperplasia [16,17]. Therefore, we hypothesize that the high rate of abnormal cells in the pituitary increased the risk of adenomatous transformation.…”

Section: Discussionmentioning

confidence: 88%

Hypercortisolism due to a Pituitary Adenoma Associated with Beckwith-Wiedemann Syndrome

Brioude¹,

Nicolas

Marey

et al. 2016

Horm Res Paediatr

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Background: Beckwith-Wiedemann syndrome (BWS) is an overgrowth syndrome with an increased risk of cancer. Most BWS patients show a molecular defect in the 11p15 region that contains imprinted genes. BWS has been associated with malignant neoplasms during infancy. Descriptions of benign tumors, especially in adult patients, are rarer. Methods/Results: We report the case of a BWS patient with pituitary adenoma caused by loss of methylation (LOM) at ICR2 (locus CDKN1C/KCNQ1OT1). The patient was referred to an endocrinology unit for suspicion of Cushing's disease due to a history of macroglossia and hemihyperplasia. Biological tests led to the diagnosis of ACTH-dependent hypercortisolism. MRI showed a microadenoma of the pituitary gland, confirming the diagnosis of Cushing's disease. DNA methylation analysis revealed LOM at ICR2 that was in a mosaic state in the patient's leukocytes, but was present in nearly all cells of the pituitary adenoma. The epigenetic defect was associated with a somatic USP8 mutation in the adenoma. Conclusion: Pituitary adenoma rarely occurs in patients with BWS. However, BWS should be considered in cases of pituitary adenoma with minor and/or major signs of BWS. The association between ICR2 LOM and USP8 mutation in the adenoma is questionable.

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Section: Discussionmentioning

confidence: 88%

Hypercortisolism due to a Pituitary Adenoma Associated with Beckwith-Wiedemann Syndrome

Brioude¹,

Nicolas

Marey

et al. 2016

Horm Res Paediatr

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“…23 Grati et al reported new genotype-phenotype correlation paternal uniparental disomy 11 (pUPD11) and complete Beckwith-Wiedermann syndrome, and also suggested a molecular analysis to be performed in all cases with fetal omphalocele. 24 The etiological considerations for gastroschisis have focused on vascular problems caused by smoking 25 and teenage pregnancy. 26 Torfs et al tested DNA for polymorphisms of 32 genes representing the enzymes involved in angiogenesis, blood vessel integrity, infl ammation, wound repair, and dermal or epidermal strength in 57 cases of gastroschisis and 506 controls.…”

Section: Abdominal Wall Defectmentioning

confidence: 99%

Current progress in neonatal surgery

Taguchi

2008

Surg Today

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Neonatal surgery is the most specialized and sophisticated field of pediatric surgery. I herein review esophageal atresia, abdominal wall defects, gastrointestinal perforation, and congenital diaphragmatic hernia (CDH) as representative types of neonatal surgery. The clinical results of esophageal atresia have been considered to reflect the level of medicine of an individual country. Owing to an early diagnosis, improved operative techniques, and better perioperative management, the mortality rate has now become almost 0%. In addition, a minimally invasive thoracotomy is considered to improve long-term quality of life. The overall mortality rate of neonatal surgical disease has markedly decreased and is now less than 10%. However, abdominal wall defects, gastrointestinal perforation, and CDH still show a high mortality rate. A high incidence of chromosomal anomalies results in a poor outcome for abdominal wall defect. A gastrointestinal perforation in an infant complicated with an extremely how birth weight shows a high mortality rate. In CDH, pulmonary hypoplasia as well as pulmonary hypertension often causes an acute respiratory and circulatory deterioration after birth. Neither intensive care for pulmonary hypertension, including ECMO, nor fetal intervention has yet achieved a satisfactory outcome. Permissive hypercapnea and a delayed operation aiming at circulatory stabilization have resulted in a good survival rate. However, CDH survivors may be at risk for long-term morbidities. The method to induce pulmonary development is considered to be mandatory to achieve a good quality of life for severe CDH.

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“…Mosaic paternal UPD of 11p15.5 has been identified in ϳ20% of patients with Beckwith-Wiedemann syndrome (BWS) (11). BWS is a congenital overgrowth syndrome that results from the dysregulation of imprinted genes at 11p15.5.…”

Section: Molecular Genetic Analysismentioning

confidence: 99%

An ABCC8 Gene Mutation and Mosaic Uniparental Isodisomy Resulting in Atypical Diffuse Congenital Hyperinsulinism

et al. 2008

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OBJECTIVE-Congenital hyperinsulinism (CHI) may be due to diffuse or focal pancreatic disease. The diffuse form is associated with an increase in the size of ␤-cell nuclei throughout the whole of the pancreas and most commonly results from recessive ATP-sensitive K ϩ channel (K ATP channel) mutations. Focal lesions are the consequence of somatic uniparental disomy for a paternally inherited K ATP channel mutation with enlargement of the ␤-cell nuclei confined to the focal lesion. Some "atypical" cases defy classification and show pancreatic ␤-cell nuclear enlargement confined to discrete regions of the pancreas. We investigated an atypical case with normal morphology within the tail of the pancreas but occasional enlarged endocrine nuclei in parts of the body and head. RESEARCH DESIGN AND METHODS-The KCNJ11 andABCC8 genes encoding the K ATP channel subunits and microsatellite markers on chromosome 11 were analyzed in DNA samples from the patient and her parents.RESULTS-A mosaic ABCC8 nonsense mutation (Q54X) was identified in the proband. The paternally inherited mutation was present at 90% in lymphocytes and 50% in normal pancreatic sections but between 64 and 74% in abnormal sections. Microsatellite analysis showed mosaic interstitial paternal uniparental isodisomy (UPD) for chromosome 11p15.1.CONCLUSIONS-We report a novel genetic mechanism to explain atypical histological diffuse forms of CHI due to mosaic UPD in patients with dominantly inherited ABCC8 (or KCNJ11) gene mutations.

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Chromosome 11 segmental paternal isodisomy in amniocytes from two fetuses with omphalocoele: new highlights on phenotype-genotype correlations in Beckwith-Wiedemann syndrome

Cited by 18 publications

References 30 publications

Hypercortisolism due to a Pituitary Adenoma Associated with Beckwith-Wiedemann Syndrome

Hypercortisolism due to a Pituitary Adenoma Associated with Beckwith-Wiedemann Syndrome

Current progress in neonatal surgery

An ABCC8 Gene Mutation and Mosaic Uniparental Isodisomy Resulting in Atypical Diffuse Congenital Hyperinsulinism

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