Acute lymphocytic leukaemia in a child with Beckwith–Wiedemann syndrome harbouring a CDKN1C mutation

Abadie, Caroline; Bertucci, François; Netchine, Irène; Sanlaville, Damien; Roque, Ashley; Rossignol, Sylvie; Coupier, Isabelle

doi:10.1016/j.ejmg.2010.08.006

Cited by 7 publications

(7 citation statements)

References 10 publications

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“…Tumors occurred in four patients, comprising one abdominal ganglioneuroblastoma (surgery at the age of 2 years and 7 months), one acute lymphocytic leukemia occurring in a 10‐year‐old boy [Abadie et al., ], one neuroblastoma in a 6‐month‐old boy, and one superficial spreading melanoma diagnosed at the age of 42 years.…”

Section: Resultsmentioning

confidence: 99%

“…Furthermore, adrenal tumors (neuroblastomas and adrenal carcinomas) have also been described in patients with ICR2 LOM or 11p15 paternal UPD, two conditions that lead to CDKN1C loss of expression, whereas no adrenal tumors have been reported in patients with an ICR1 GOM. Cases of ALL have been previously reported in BWS ([Abadie et al., ] and references within). We recently reported a large cohort of BWS patients with molecular defects of the 11p15 region [Brioude et al., ] with two cases of ALL (one case of CDKN1C mutation [reported here] and one case of 11p15 paternal UPD).…”

Section: Discussionmentioning

confidence: 99%

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Mutations of the ImprintedCDKN1CGene as a Cause of the Overgrowth Beckwith-Wiedemann Syndrome: Clinical Spectrum and Functional Characterization

et al. 2015

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Beckwith-Wiedemann syndrome (BWS) is an imprinting disorder associating macroglossia, abdominal wall defects, visceromegaly, and a high risk of childhood tumor. Molecular anomalies are mostly epigenetic; however, mutations of CDKN1C are implicated in 8% of cases, including both sporadic and familial forms. We aimed to describe the phenotype of BWS patients with CDKN1C mutations and develop a functional test for CDKN1C mutations. For each propositus, we sequenced the three exons and intron-exon boundaries of CDKN1C in patients presenting a BWS phenotype, including abdominal wall defects, without 11p15 methylation defects. We developed a functional test based on flow cytometry. We identified 37 mutations in 38 pedigrees (50 patients and seven fetuses). Analysis of parental samples when available showed that all mutations tested but one was inherited from the mother. The four missense mutations led to a less severe phenotype (lower frequency of exomphalos) than the other 33 mutations. The following four tumors occurred: one neuroblastoma, one ganglioneuroblastoma, one melanoma, and one acute lymphoid leukemia. Cases of BWS caused by CDKN1C mutations are not rare. CDKN1C sequencing should be performed for BWS patients presenting with abdominal wall defects or cleft palate without 11p15 methylation defects or body asymmetry, or in familial cases of BWS.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Mutations of the ImprintedCDKN1CGene as a Cause of the Overgrowth Beckwith-Wiedemann Syndrome: Clinical Spectrum and Functional Characterization

et al. 2015

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“…Only 2 of the 24 tumors occurring in patients with ICR1 GOM or 11p15 pUPD were extra-abdominal (1 case of orbital rhabdomyosarcoma and 1 of thoracic neuroblastoma), whereas 3 of the 11 tumors occurring in patients with ICR2 LOM or CDKN1C mutations were extra-abdominal. Regardless of molecular subtype, only 3 tumors occurred after the age of 10 years - a WT in a 12-year-old patient and 2 nonabdominal tumors (1 case of acute lymphoblastic leukemia in a 10-year-old patient [36] and a papillary thyroid carcinoma in an 11-year-old patient).…”

Section: Resultsmentioning

confidence: 99%

“…For patients with CDKN1C loss-of-function mutations, the prevalence of tumors was 8.8% (3/37). However, it is difficult to estimate tumor risk precisely in this subgroup of patients due to the following: (1) the small size of this population, (2) the small number of tumors occurring in this subgroup and (3) the tumors occurring in the patients of this subgroup may not be common in patients with BWS, such as the acute lymphoid leukemia detected in 1 of these patients [36]. …”

Section: Discussionmentioning

confidence: 99%

Beckwith-Wiedemann Syndrome: Growth Pattern and Tumor Risk according to Molecular Mechanism, and Guidelines for Tumor Surveillance

Brioude¹,

Lacoste

Netchine³

et al. 2013

Horm Res Paediatr

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142

216

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Background: Beckwith-Wiedemann syndrome (BWS) is an overgrowth syndrome associated with an increased risk of pediatric tumors. The underlying molecular abnormalities may be genetic (CDKN1C mutations or 11p15 paternal uniparental isodisomy, pUPD) or epigenetic (imprinting center region 1, ICR1, gain of methylation, ICR1 GOM, or ICR2 loss of methylation, ICR2 LOM). Aim: We aimed to describe a cohort of 407 BWS patients with molecular defects of the 11p15 domain followed prospectively after molecular diagnosis. Results: Birth weight and length were significantly higher in patients with ICR1 GOM than in the other groups. ICR2 LOM and CDKN1C mutations were associated with a higher prevalence of exomphalos. Mean adult height (regardless of molecular subtype, n = 35) was 1.8 ± 1.2 SDS, with 18 patients having a final height above +2 SDS. The prevalence of tumors was 8.6% in the whole population; 28.6 and 17.3% of the patients with ICR1 GOM (all Wilms tumors) and 11p15 pUPD, respectively, developed a tumor during infancy. Conversely, the prevalence of tumors in patients with ICR2 LOM and CDKN1C mutations were 3.1 and 8.8%, respectively, with no Wilms tumors. Conclusion: Based on these results for a large cohort, we formulated guidelines for the follow-up of these patients according to the molecular subtype of BWS.

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“…For example, Beckwith–Weidemann syndrome (BWS) is an overgrowth disorder which carries an estimated risk of malignancy of approximately 7.5%. The most common tumor types in BWS are Wilms tumor and hepatoblastoma, but leukemia has been reported as well (Abadie et al, ; Tan & Amor, ). Malignancy in BWS is most associated with aberrant methylation at the H19 DMR (differentially methylated region) and uniparental disomy that results in loss of inhibition IGF2 and consequent overexpression.…”

Section: Introductionmentioning

confidence: 96%

Acute leukemia in a patient with 15q overgrowth syndrome

Bodle

Gupta

Cherry

et al. 2019

American J of Med Genetics Pt A

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Overgrowth syndromes are rare genetic conditions which present as global or segmental hyperplasia and are sometimes associated with increased risk of malignancy. Trisomy of the terminal portion of 15q which includes the IGFR1 gene, produces a rare overgrowth phenotype that has been termed 15q overgrowth syndrome (15q OGS). Upregulation of IGF1R has long been implicated in oncogenesis of multiple cancer types, including acute leukemias, and has been shown to render cells more susceptible to other transforming events. To date, too few cases of 15q OGS have been reported to identify any cancer predisposition. We present a case of a 34‐year‐old female with intellectual disability, macrocephaly, and subtle dysmorphic features who was diagnosed with mixed phenotype acute leukemia (lymphoid and myeloid). Prior to initiation of therapy she was referred to medical genetics for further evaluation and was identified as having a chromosomal translocation resulting in a partial trisomy of chromosome 15q, consistent with 15q OGS. A review of the literature for cases of malignancy in individuals with increased copy number of 15q revealed only one other reported patient. Given the small number of reported individuals, we cannot rule out an increased risk of cancer associated with this chromosomal overgrowth syndrome. Although concerns have been raised regarding treatment feasibility in the setting of chromosomal disorders, the reported patient underwent successful treatment with allogeneic hematopoietic stem‐cell transplant.

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Acute lymphocytic leukaemia in a child with Beckwith–Wiedemann syndrome harbouring a CDKN1C mutation

Cited by 7 publications

References 10 publications

Mutations of the ImprintedCDKN1CGene as a Cause of the Overgrowth Beckwith-Wiedemann Syndrome: Clinical Spectrum and Functional Characterization

Mutations of the ImprintedCDKN1CGene as a Cause of the Overgrowth Beckwith-Wiedemann Syndrome: Clinical Spectrum and Functional Characterization

Beckwith-Wiedemann Syndrome: Growth Pattern and Tumor Risk according to Molecular Mechanism, and Guidelines for Tumor Surveillance

Acute leukemia in a patient with 15q overgrowth syndrome

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