Novel Autopsy Findings in Premature Infant With Beckwith-Wiedemann Syndrome Uniparental Disomy: Multifocal Developmental Dysplastic Chrondromatous Lesions and Cortical Neuronal Heterotopias.

BACKGROUND: Beckwith-Wiedemann syndrome (BWS) is an overgrowth disorder that exhibits etiologic genomic imprinting characterized by molecular heterogeneity and phenotypic variability. Associations with localized developmental dysplastic chondromatous lesions and cortical neuronal heterotopias have not previously been described. CASE PRESENTATION: A 33-week gestational age female had an omphalocele and intractable hypoglycemia at birth. The placenta demonstrated placental mesenchymal dysplasia. Detection of hypermethylation of IC1 and hypomethylation of IC2 confirmed Beckwith-Wiedemann syndrome, most likely due to uniparental disomy. Additional findings included right mid-tibial and right 5-8th developmental dysplastic chondromatous lesions, absent corpus callosum and numerous right-sided cortical neuronal heterotopias, right hemihypertrophy, multiple cystic hepatic mesenchymal hamartomas and hepatic infantile hemangiomas, nisidioblastosis and cystic pancreatic lesions. The infant died with multi-organ failure and anasarca at 7 weeks of life. CONCLUSION: Beckwith-Wiedemann syndrome anomalies may include multifocal developmental dysplastic chondromatous lesions and cerebral neuronal heterotopias, lateralized, and corpus callosum aplasia.

Beckwith-Wiedemann syndrome mimicking the classical form of congenital adrenal hyperplasia in newborn screening.

Beckwith-Wiedemann syndrome (BWS) is a common genetic congenital disease characterized by somatic overgrowth and its broad clinical spectrum includes pre- and post-natal macrosomia, macroglossia, visceromegaly, increased risk of neonatal hypoglycemia, and development of embryonic tumors. BWS occurs due to genetic/epigenetic changes involving growth-regulating genes, located on region 11p15, with an important genotype-phenotype correlation. Congenital adrenal hyperplasia (CAH) comprises a spectrum of autosomal recessive diseases presenting a variety of clinical manifestations due to a deficiency in one of the enzymes involved in cortisol secretion. Early diagnosis based on newborn screening prevents the adrenal crisis and early infant death. However, high 17-hydroxyprogesterone (17-OHP) levels can occur in newborns or premature infants without CAH, in situations of stress due to maternal or neonatal factors. Here, we report new cases of false-positive diagnosis of 21-hydroxylase deficiency during newborn screening - two girls and one boy with BWS. Methylation-specific multiplex ligation-dependent probe amplification revealed a gain of methylation in the H19 differentially methylated region. Notably, all three cases showed a complete normalization of biochemical changes, highlighting the transient nature of these hormonal findings that imitate the classical form of CAH. This report sheds light on a new cause of false-positive 21-hydroxylase deficiency diagnosis during newborn screening: Beckwith-Wiedemann syndrome.

Beckwith-Wiedemann syndrome with multiple hepatic and cutaneous hemangiomas in a female patient of Albanian origin: Diagnostic and therapeutic considerations.

We describe a 2-month-old female infant with macroglossia, macrosomia, omphalocele, neonatal hypoglycemia, earlobe creases, low nasal bridge, midface retrusion, syndromic facies and multiple cutaneous and hepatic hemangiomas (HH). Genetic evaluation confirmed the diagnosis of Beckwith-Wiedemann Syndrome (BWS) with mosaic uniparental disomy 11 as the underlying genetic mechanism suggested by partial hypermethylation of H19/IGF2:IG-DMR and partial hypomethylation of KCNQ1OT1:TSS-DMR on chromosome 11p15.5. Pediatric endocrinology and cardiology assessments were normal. No malignant liver or renal tumors were detected during the follow-up period. Treatment with propranolol was started for the multiple HH, according to international recommendations. At 3-, 6-, and 9-month follow up, a gradual decrease in the size of the hemangiomas and AFP levels was observed, without side effects. This is the fifth case in the literature combining HH and BWS, and among these, the third case with this specific genetic defect suggesting a possible association between HH and BWS caused by 11 paternal uniparental disomy [upd(11)pat]. The case also highlights that if treatment is warranted, then oral propranolol can be used for the management of infantile HH in BWS patients similarly to non-BWS patients.

Preneoplastic liver colonization by 11p15.5 altered mosaic cells in young children with hepatoblastoma.

Pediatric liver tumors are very rare tumors with the most common diagnosis being hepatoblastoma. While hepatoblastomas are predominantly sporadic, around 15% of cases develop as part of predisposition syndromes such as Beckwith-Wiedemann (11p15.5 locus altered). Here, we identify mosaic genetic alterations of 11p15.5 locus in the liver of hepatoblastoma patients without a clinical diagnosis of Beckwith-Wiedemann syndrome. We do not retrieve these alterations in children with other types of pediatric liver tumors. We show that mosaic 11p15.5 alterations in liver FFPE sections of hepatoblastoma patients display IGF2 overexpression and H19 downregulation together with an alteration of the liver zonation. Moreover, mosaic livers' microenvironment is enriched in extracellular matrix and angiogenesis. Spatial transcriptomics and single-nucleus RNAseq analyses identify a 60-gene signature in 11p15.5 altered hepatocytes. These data provide insights for 11p15.5 mosaicism detection and its functional consequences during the early steps of carcinogenesis.

Beckwith-Wiedemann Syndrome in Newborn of Mother with HELLP Syndrome/Preeclampsia: An Analysis of Literature and Case Report with Fetal Growth Restriction and Absence of CDKN1C Typical Pathogenic Genetic Variation.

Beckwith-Wiedemann Syndrome (BWS) is an imprinting disorder, which manifests by overgrowth and predisposition to embryonal tumors. The evidence on the relationship between maternal complications such as HELLP (hemolysis, elevated liver enzymes, and low platelet count) and preeclampsia and the development of BWS in offspring is scarce. A comprehensive clinical evaluation, with genetic testing focused on screening for mutations in the CDKN1C gene, which is commonly associated with BWS, was conducted in a newborn diagnosed with BWS born to a mother with a history of preeclampsia and HELLP syndrome. The case study revealed typical clinical manifestations of BWS in the newborn, including hemihyperplasia, macroglossia, midfacial hypoplasia, omphalocele, and hypoglycemia. Surprisingly, the infant also exhibited fetal growth restriction, a finding less commonly observed in BWS cases. Genetic analysis, however, showed no mutations in the CDKN1C gene, which contrasts with the majority of BWS cases. This case report highlights the complex nature of BWS and its potential association with maternal complications such as preeclampsia and HELLP syndrome. The atypical presence of fetal growth restriction in the newborn and the absence of CDKN1C gene mutations have not been reported to date in BWS.

Beckwith-Wiedemann syndrome and twinning: case report and brief review of literature.

BACKGROUND: Beckwith-Wiedemann syndrome (BWS, OMIM #130,650) is a pediatric overgrowth disorder involving a predisposition to tumor development. Although the clinical management of affected patients is well established, it is less clear how to handle with the cases of siblings of affected patients, since the prevalence of the condition in twins (1:1000) is ten times higher than in singletones (1:10000). CASE PRESENTATION: We report the case of a premature twin patient who during her follow-up develops a clinical phenotype compatible with BWS, genetically confirmed in blood. However, the methylation alteration characteristic of the condition was also found in the almost phenotypically normal sibling, making it challening her management. CONCLUSION: Through our case report we highlight how the diagnosis of BWS can be made without any prenatal suspicion and we propose a review of the literature on how to manage siblings of affected patients in twinning situation.

Concurrent Hepatoblastoma and Wilms Tumor Leading to Diagnosis of Beckwith-Wiedemann Syndrome.

Beckwith-Wiedemann syndrome (BWS) is an epigenetic overgrowth disorder and cancer predisposition syndrome caused by imprinting defects of chromosome 11p15.5-11p15.4. BWS should be considered in children with atypical presentations of embryonal tumors regardless of clinical phenotype. Risk of malignancy correlates with specific molecular subgroups of BWS making molecular subclassification important for appropriate cancer screening. We report the first case of concurrent embryonal tumors in a phenotypically normal child, leading to the diagnosis of BWS with paternal uniparental disomy and describe the molecular classification of BWS as it relates to malignancy risk, along with approach to management.

Lateralized overgrowth as a guiding sign of abdominal neoplasms for pediatric orthopedic surgeons.

OBJECTIVES: This study aims to increase the awareness of the association between lateralized overgrowth (LO) and abdominal tumor among the pediatric orthopedic community and to evaluate its incidence in our center. PATIENTS AND METHODS: Between January 1997 and December 2021, a total of 166 patients with Wilms tumors and hepatoblastomas were retrospectively analyzed. Data including age, sex, initial clinical signs (hematuria, abdominal mass with or without general discomfort), type of asymmetric regional body overgrowth (isolated or in relation with any syndrome), and tumor stage at diagnosis were recorded. In addition, age at which asymmetric regional body overgrowth was described and age at the time of tumor diagnosis were noted. RESULTS: Of a total of 166 patients, 133 were diagnosed with Wilms tumors (nephroblastomas) and 33 were diagnosed with hepatoblastomas. In 94% of the cases, the initial clinical signs were an abdominal mass and/or hematuria. Overall, five (3%) patients presented with LO. Four patients with Wilms tumor presented it at the initial clinical examinations. In three of these cases (2.3%), we found it isolated and, in the remaining patient (0.75%), it was associated with Beckwith-Wiedemann spectrum. Only one patient affected from hepatoblastoma (3%) presented with an isolated LO at the time of tumor diagnosis. CONCLUSION: Our study results show an incidence of LO in relation to intra-abdominal tumors of 3%. The latest updates recommend genetic testing to identify subgroups with a higher risk for tumor development that are more likely to benefit from tumor protocol surveillance.

[Preterm with Macroglossia and Persistent Hypoglycemia - Beckwith-Wiedemann Syndrome]. / Frühgeborenes mit Makroglossie und persistierender Hypoglykämie ­ Beckwith-Wiedemann-Syndrom.

Beckwith-Wiedemann syndrome (BWS) is a genetic disease with phenotypic variability and the following signs: macroglossia, asymmetry, lateralised overgrowth, overgrowth of the internal organs, abdominal wall defects, neonatal hypoglycemia and increased risk of embryonic tumours. The prevalence is reported as being between 1 in 10,000 and 1 in 21,000 live births. The disease is caused by molecular changes in gene clusters on the short arm of chromosome 11 region P15.5. We present the case of a female, born preterm at 32 0/7 weeks. A UPD(11)pat-mutation was diagnosed postnatally. The particular feature of her case was an early tongue reduction surgery which was necessary because of drinking and breathing difficulties. Long-lasting hypoglycemia was difficult to treat.

Familial Beckwith-Wiedemann syndrome in a multigenerational family: Forty years of careful phenotyping.

Beckwith-Wiedemann Spectrum (BWSp) is an overgrowth and cancer predisposition disorder characterized by a wide spectrum of phenotypic manifestations including macroglossia, abdominal wall defects, neonatal hypoglycemia, and predisposition to embryonal tumors. In 1981, Best and Hoekstra reported four patients with BWSp in a single family which suggested autosomal dominant inheritance, but standard clinical testing for BWSp was not available during this time. Meticulous phenotyping of this family has occurred over the past 40 years of follow-up with additional family members being identified and samples collected for genetic testing. Genetic testing revealed a pathogenic mutation in CDKN1C, consistent with the most common cause of familial BWSp. CDKN1C mutations account for just 5% of sporadic cases of BWSp. Here, we report the variable presentation of BWSp across the individuals affected by the CDKN1C mutation and other extended family members spanning multiple generations, all examined by the same physician. Additional phenotypes thought to be atypical in patients with BWSp were reported which included cardiac abnormalities. The incidence of tumors was documented in extended family members and included rhabdomyosarcoma, astrocytoma, and thyroid carcinoma, which have previously been reported in patients with BWSp. These observations suggest that in addition to the inheritance of the CDKN1C variant, there are modifying factors in this family driving the phenotypic spectrum observed. Alternative theories are suggested to explain the etiology of clinical variability including diffused mosaicism, anticipation, and the presence of additional variants tracking in the family. This study highlights the necessity of long-term follow-up in patients with BWSp and consideration of individual familial characteristics in the context of phenotype and/or (epi)genotype associations.

Abordagem interdisciplinar no tratamento da macroglossia na síndrome de Beckwith-Wiedemann: relato de caso / Interdisciplinary approach in the treatment of macroglossia in Beckwith-Wiedemann syndrome: case report

RESUMO O objetivo deste estudo foi relatar a abordagem interdisciplinar no manejo da macroglossia em um caso de paciente com síndrome de Beckwith-Wiedemann, no período de dez anos. O acompanhamento iniciou pela equipe de Cirurgia Bucomaxilofacial, seguido da Fonoaudiologia, em função de dificuldades alimentares. Após avaliação clínica e instrumental, aos 8 meses de idade, iniciou-se a intervenção fonoaudiológica com foco na disfagia orofaríngea e na terapia miofuncional orofacial. Foi verificado, com 1 ano e 11 meses, ausência de sinais de alteração de deglutição em fase faríngea e melhora na postura de lábios e língua. Aos 3 anos, foram iniciados estímulos para retirada dos hábitos orais e o treino da função mastigatória. O tratamento ortodôntico para correção de mordida aberta anterior e mordida cruzada posterior unilateral iniciou-se aos 6 anos. Aos 7 anos e 5 meses de idade, constatou-se estabilidade do modo respiratório nasal e adequação da postura de repouso de lábios e língua. Aos 9 anos, em função de recidiva das alterações oclusais, optou-se pela redução cirúrgica da língua seguida de terapia miofuncional orofacial, retomada aos 9 anos e 3 meses. O resultado foi a correção da postura da língua na deglutição e a adequação da fala. A associação dos tratamentos, envolvendo Fonoaudiologia, Ortodontia e Cirurgia Bucomaxilofacial foi considerada efetiva no manejo da macroglossia, resultando na adequação e equilíbrio das funções orofaciais.

ABSTRACT This study aims to report the interdisciplinary management of macroglossia in a Beckwith-Wiedemann syndrome patient during ten years. Clinical follow-up started by the Oral and Maxillofacial Surgery team, followed by Speech Therapy due to feeding difficulties. After clinical and instrumental evaluation, at 8 months old, the speech therapy intervention was indicated, focusing on oropharyngeal dysphagia and orofacial myofunctional therapy. At 1 year and 11 months, no signs of swallowing alteration in the pharyngeal phase and improvement in the posture of the lips and tongue were found. At the age of 3, stimulation to remove oral habits and train masticatory function were initiated. Orthodontic treatment to correct anterior open bite and unilateral posterior crossbite started at age 6. At 7 years and 5 months, there was stability in the nasal breathing mode and adequacy of resting posture of lips and tongue. At the age of 9, due to relapse of the occlusal alterations, surgical reduction of the tongue was indicated, followed by orofacial myofunctional therapy, restarted at the age of 9 years and 3 months. The result was the correction of the posture of the tongue during swallowing and speech adequacy. The association of treatments involving Speech Therapy, Orthodontics and Oral and Maxillofacial Surgery was considered effective in the management of the macroglossia. It resulted in the adequacy and equilibrium of orofacial functions.

First step towards a consensus strategy for multi-locus diagnostic testing of imprinting disorders.

BACKGROUND: Imprinting disorders, which affect growth, development, metabolism and neoplasia risk, are caused by genetic or epigenetic changes to genes that are expressed from only one parental allele. Disease may result from changes in coding sequences, copy number changes, uniparental disomy or imprinting defects. Some imprinting disorders are clinically heterogeneous, some are associated with more than one imprinted locus, and some patients have alterations affecting multiple loci. Most imprinting disorders are diagnosed by stepwise analysis of gene dosage and methylation of single loci, but some laboratories assay a panel of loci associated with different imprinting disorders. We looked into the experience of several laboratories using single-locus and/or multi-locus diagnostic testing to explore how different testing strategies affect diagnostic outcomes and whether multi-locus testing has the potential to increase the diagnostic efficiency or reveal unforeseen diagnoses. RESULTS: We collected data from 11 laboratories in seven countries, involving 16,364 individuals and eight imprinting disorders. Among the 4721 individuals tested for the growth restriction disorder Silver-Russell syndrome, 731 had changes on chromosomes 7 and 11 classically associated with the disorder, but 115 had unexpected diagnoses that involved atypical molecular changes, imprinted loci on chromosomes other than 7 or 11 or multi-locus imprinting disorder. In a similar way, the molecular changes detected in Beckwith-Wiedemann syndrome and other imprinting disorders depended on the testing strategies employed by the different laboratories. CONCLUSIONS: Based on our findings, we discuss how multi-locus testing might optimise diagnosis for patients with classical and less familiar clinical imprinting disorders. Additionally, our compiled data reflect the daily life experiences of diagnostic laboratories, with a lower diagnostic yield than in clinically well-characterised cohorts, and illustrate the need for systematising clinical and molecular data.

Further understanding of paternal uniparental disomy in Beckwith-Wiedemann syndrome.

INTRODUCTION: Paternal uniparental disomy of chromosome 11 (upd(11)pat) accounts for up to 20% of molecularly confirmed Beckwith-Wiedemann spectrum (BWSp) cases. It belongs to the BWSp subgroup with the second highest tumor risk, and therefore needs particular awareness in research, diagnostics and clinical management. AREAS COVERED: We overview the contribution of paternal (mosaic) uniparental disomy of chromosome 11 (UPD, upd(11)pat) and mosaic paternal uniparental diploidy in patients with Beckwith-Wiedemann features. The review comprises the current knowledge on their formation and their molecular and clinical consequences. Accordingly, the consequences for diagnostic testing and clinical monitoring are compiled. EXPERT OPINION: The necessity to diagnostically identify and thus discriminate genome-wide paternal uniparental disomy, and upd(11)pat becomes obvious, due to the differences in the clinical course, disease prognosis, and treatment. In particular, monitoring of tumor development by liquid biopsy might be a promising option in the future. From the research point of view, it should be addressed why 11p is prone to mitotic recombination and thus also provide to the role of upd(11) as second hit in tumorigenesis.

Hepatoblastoma in molecularly defined, congenital diseases.

Beckwith-Wiedemann spectrum, Simpson-Golabi-Behmel syndrome, familial adenomatous polyposis and trisomy 18 are the most common congenital conditions associated with an increased incidence of hepatoblastoma (HB). In patients with these genetic disorders, screening protocols for HB are proposed that include periodic abdominal ultrasound and measurement of alpha-fetoprotein levels. Surveillance in these children may contribute to the early detection of HB and possibly improve their chances of overall survival. Therefore, physicians must be aware of the high HB incidence in children with certain predisposing genetic diseases.

Prevalence of (Epi)genetic Predisposing Factors in a 5-Year Unselected National Wilms Tumor Cohort: A Comprehensive Clinical and Genomic Characterization.

PURPOSE: Wilms tumor (WT) is associated with (epi)genetic predisposing factors affecting a growing number of WT predisposing genes and loci, including those causing Beckwith-Wiedemann spectrum (BWSp) or WT1-related syndromes. To guide genetic counseling and testing, we need insight into the prevalence of WT predisposing (epi)genetic factors. PATIENTS AND METHODS: All children diagnosed with WT in the Netherlands between 2015 and 2020 were referred to a clinical geneticist. Phenotypic data, disease characteristics, and diagnostic test results were collected. If no genetic predisposition was identified by targeted diagnostic testing, germline (trio-)whole-exome sequencing and BWSp testing on normal kidney-derived DNA were offered. RESULTS: A total of 126 cases were analyzed of 128 identified patients. (Epi)genetic predisposing factors were present in 42 of 126 patients (33.3%) on the basis of a molecular diagnosis in blood-derived DNA (n = 26), normal kidney-derived DNA (n = 12), or solely a clinical diagnosis of BWSp (n = 4). Constitutional, heterozygous DIS3L2 variants were identified as a recurrent predisposing factor in five patients (4%), with a second somatic hit in 4 of 5 tumors. Twenty patients (16%) were diagnosed with BWSp while four additional patients without BWSp features harbored chromosome 11p15 methylation defects in normal kidney tissue. Remaining findings included WT1-related syndromes (n = 10), Fanconi anemia (n = 1), neurofibromatosis type 1 (n = 1), and a pathogenic REST variant (n = 1). In addition, (likely) pathogenic variants in adult-onset cancer predisposition genes (BRCA2, PMS2, CHEK2, and MUTYH) were identified in 5 of 56 (8.9%) patients with available whole-exome sequencing data. Several candidate WT predisposition genes were identified, which require further validation. CONCLUSION: (Epi)genetic WT predisposing factors, including mosaic aberrations and recurrent heterozygous DIS3L2 variants, were present in at least 33.3% of patients with WT. On the basis of these results, we encourage standard genetic testing after counseling by a clinical geneticist.

Prenatal presentation in two fetuses with features of Beckwith Wiedemann syndrome-An unexpected diagnosis of androgenetic chimera and its clinical implications.

Beckwith Wiedemann Syndrome (BWS, OMIM 130650) is an imprinting disorder that may present antenatally with a constellation of sonographic features namely polyhydramnios, macrosomia, macroglossia, omphalocele, placental mesenchymal dysplasia, cardiomegaly, nephromegaly, fetal hydrops, and other rare anomalies. Paternal uniparental disomy in chromosome 11p15 imprinting region accounts for 20% of all BWS, and 8% among those were due to genome-wide paternal uniparental disomy (GWpUPD). GWpUPD is a rare condition and usually results in prenatal lethality. The 31 liveborns reported in the literature demonstrate female predominance in surviving GWpUPD. Here, we reported two prenatal cases which initially presented with features suggestive of BWS, which subsequently were confirmed to have GWpUPD. Further trio SNP genotyping analysis using SNP-based chromosomal microarray revealed androgenetic biparental chimera as the underlying cause. Finally, we highlighted the importance of recognizing GWpUPD as a possible cause in a fetus presenting with BWS phenotype, as it carried a different disease prognosis, tumor predisposition, manifestations of other imprinting disorders, and possibility in unmasking autosomal recessive disorders from the paternal alleles.

Glioblastoma in Beckwith-Wiedemann syndrome: first case report and review of potential pathomechanisms.

Beckwith-Wiedemann syndrome (BWS) is a rare congenital overgrowth syndrome associated with certain childhood tumours. We present the case of a 36-year-old lady with BWS who developed a left frontoinsular secondary glioblastoma. This is the first case report in the literature of glioblastoma associated with BWS. We explore similarities in the molecular pathomechanisms of BWS and glioblastoma.

Colon hypoganglionosis in Beckwith-Wiedemann syndrome: a new rare comorbidity?

We describe the case of a patient with a clinical and molecular diagnosis of Beckwith-Wiedemann Syndrome (BWS) and a clinical, radiologic and histologic diagnosis of colon isolated hypoganglionosis. BWS is a genetic multisystem disorder characterized by generalized and lateralized overgrowth, macroglossia, abdominal wall defects, neonatal hypoglycemia and predisposition to embryonal tumors (Brioude et al., Nat Rev Endocrinol 1998; 14:229-249). Hypoganglionosis of the colon is a condition that clinically resembles Hirschsprung's disease and it is part of a group of numerous and heterogeneous conditions that are defined 'Variants of Hirschsprung's disease' (Friedmacher and Puri, Pediatr Surg Int 2013; 29:855-872). To the best of our knowledge, the association of BWS with Hirschsprung's disease has been observed only in one patient, an infant with hypoglycemia (Shah et al., BMJ Case Rep 2020; 13:e235121). We suppose that dysganglionosis could be rare comorbidity of BWS. We suggest to put particular attention to patients affected by BWS who develop early severe constipation taking into account the possibility to study them at radiologic and histologic levels to show the possible evidence of Hirschsprung's disease variants.

Beckwith-Wiedemann syndrome: Clinical, histopathological and molecular study of two Tunisian patients and review of literature.

BACKGROUND: Beckwith-Wiedemann syndrome (BWS) is a rare overgrowth syndrome characterized by congenital malformations and predisposition to embryonic tumors. Loss of methylation of imprinting center 2 (IC2) is the most frequent alteration and rarely associated with tumors compared to paternal uniparental disomy of chromosome 11 (UPD(11)pat) and gain of methylation of imprinting center 1. METHODS: Our study aimed to describe the clinical, histopathological and genetic characteristics of two patients and establish genotype-phenotype correlations. The clinical diagnosis was based on the criteria defined by the international expert consensus of BWS. Molecular study of 11p15.5 methylation status was assessed using methylation-specific-multiplex ligation probe amplification (MS-MLPA). RESULTS: Patients were aged 12 months and 3 months and fulfilled the clinical score of BWS. MS-MLPA showed molecular alterations consisting of loss of methylation in IC2 (IC2-LOM) at the maternal allele for one patient and a mosaic UPD(11)pat for the second patient in whom follow-up at 6months revealed adrenocortical carcinoma (ACC) with low grade of malignancy. Molecular subtypes guide the follow-up and tumor surveillance, our major concern. CONCLUSION: We have to take into account the psychological impact of a possible tumor whatever the underlying mechanism is. Nevertheless, the tumor risk remains high for UPD(11)pat. Our study extended the phenotype of BWS with absence of macrosomia in Tunisian patients, contrasting with literature, and added a supplementary case of ACC in the tumor spectrum of BWS patients with UPD(11)pat.