ABSTRACT
We describe a case of Beckwith-Wiedemann syndrome (BWS) demonstrating pre- and post-natal intra-familial variability. Our first encounter with the family occurred in the 1990s following the birth of 3 affected offspring. The first two pregnancies presented with exomphalos and elevated second trimester maternal serum alpha-fetoprotein (msAFP, 3.43 and 4.01 MOM, respectively) as well as elevated maternal human chorionic gonadotrophin (mhCG, 4.33 and 8.8 MOM, respectively). The diagnosis of BWS was confirmed postnatally in both cases. The third ongoing pregnancy presented only with elevated mhCG (7.09 MOM) and no malformation. Nonetheless BWS was suspected. The diagnosis was confirmed postnatally with clinical manifestations including macroglossia and cleft palate. Two affected female siblings were also diagnosed with Mullerian agenesis in adulthood. Suspecting a common genetic etiology, sequencing of the CDKN1C gene revealed a maternally inherited, likely pathogenic variant (NM_000076.2: c.367_385del; p.(Ala123Serfs*143)) causative of BWS. Chromosomal microarray and whole exome sequencing did not reveal any other pathogenic variant that would explain the Mullerian agenesis. One of the affected females underwent successful preimplantation genetic testing (PGT) with a surrogate and gave birth to a healthy female. To the best of our knowledge, this is the first report of Mullerian agenesis as a possible rare expansion of the BWS phenotype. In addition, this case highlights the potential role of abnormal second trimester biochemical markers (msAFP, mHCG) as possible indicators of BWS, especially in familial cases.
Subject(s)
46, XX Disorders of Sex Development/genetics , Beckwith-Wiedemann Syndrome/genetics , Congenital Abnormalities/genetics , Fetus/abnormalities , Mullerian Ducts/abnormalities , Phenotype , 46, XX Disorders of Sex Development/blood , 46, XX Disorders of Sex Development/diagnostic imaging , 46, XX Disorders of Sex Development/pathology , Adult , Beckwith-Wiedemann Syndrome/blood , Beckwith-Wiedemann Syndrome/diagnostic imaging , Beckwith-Wiedemann Syndrome/pathology , Biomarkers/blood , Chorionic Gonadotropin/blood , Congenital Abnormalities/blood , Congenital Abnormalities/diagnostic imaging , Congenital Abnormalities/pathology , Cyclin-Dependent Kinase Inhibitor p57/genetics , Female , Fetus/diagnostic imaging , Humans , Infant, Newborn , Mullerian Ducts/diagnostic imaging , Mullerian Ducts/pathology , Pregnancy , Ultrasonography, Prenatal , alpha-Fetoproteins/analysisABSTRACT
BACKGROUND: Constitutional or somatic mosaic epimutations are increasingly recognized as a mechanism of gene dysregulation resulting in cancer susceptibility. Beckwith-Wiedemann syndrome is the cancer predisposition syndrome most commonly associated with epimutation and is extremely variable in its phenotypic presentation, which can include isolated tumors. Because to the authors' knowledge large-scale germline DNA sequencing studies have not included methylation analysis, the percentage of pediatric cancer predisposition that is due to epimutations is unknown. METHODS: Germline methylation testing at the 11p15.5 locus was performed in blood for 24 consecutive patients presenting with hepatoblastoma (3 patients) or Wilms tumor (21 patients). RESULTS: Six individuals with Wilms tumor and 1 patient with hepatoblastoma were found to have low-level gain of methylation at imprinting control 1, and a child with hepatoblastoma was found to have loss of methylation at imprinting control 2. The loss of methylation at imprinting control 2 was found to be maternally inherited, despite not being associated with any detectable genomic alteration. CONCLUSIONS: Overall, 33% of patients (8 of 24 patients) with Wilms tumor or hepatoblastoma were found to have an epigenetic susceptibility that was detectable in the blood. It is interesting to note that low-level gain of methylation at imprinting control 1 predominantly was detected in females with bilateral Wilms tumors. Further studies in larger cohorts are needed to determine the efficacy of testing all patients with Wilms tumor or hepatoblastoma for 11p15.5 epimutations in the blood as part of DNA analysis because this hallmark of predisposition will not be detected by sequencing-based approaches and detecting a cancer predisposition may modify treatment.
Subject(s)
Beckwith-Wiedemann Syndrome/blood , DNA Methylation/genetics , Genomic Imprinting/genetics , Hepatoblastoma/blood , Wilms Tumor/blood , Adolescent , Adult , Beckwith-Wiedemann Syndrome/genetics , Beckwith-Wiedemann Syndrome/pathology , Child , Child, Preschool , Chromosomes, Human, Pair 11/genetics , Female , Genetic Predisposition to Disease , Germ-Line Mutation/genetics , Hepatoblastoma/genetics , Hepatoblastoma/pathology , Humans , Infant , Male , Neoplasm Proteins/genetics , Wilms Tumor/genetics , Wilms Tumor/pathology , Young AdultABSTRACT
OBJECTIVE: To establish reference ranges for serum α-fetoprotein (AFP) at various ages in patients with Beckwith-Wiedemann spectrum (BWSp), to better predict the risk for hepatoblastoma in this population. STUDY DESIGN: A retrospective analysis of AFP measurements collected from patients with BWSp was performed. Factors including sex, prematurity, molecular diagnosis of patients, and performing laboratory were evaluated for significant differences. In total, 1372 AFP values were collected from 147 patients and the predictive AFP values at various ages were calculated to establish reference ranges. Mixed-effects polynomial regression models were used to study various potential factors affecting log(AFP) values. RESULTS: Overall, predicted AFP values declined to normal range for age (<10 ng/mL) by 14 months old. Patient sex and performing laboratory were found not to influence values. A significant difference was demonstrated between premature and nonpremature patients, and separate reference values were established. Significant differences in the predicted AFP value were not broadly apparent between molecular subtypes; however, interpretation was limited due to the small sample size of some of these subtypes. CONCLUSIONS: Predictive AFP values were created for premature and nonpremature patients with BWSp to aid with interpretation and monitoring of the risk for hepatoblastoma. Further analysis is needed to determine whether AFP values differ within the less common molecular subtypes of patients with BWSsp.
Subject(s)
Beckwith-Wiedemann Syndrome/blood , alpha-Fetoproteins/analysis , Beckwith-Wiedemann Syndrome/complications , Child, Preschool , Female , Hepatoblastoma/epidemiology , Hepatoblastoma/etiology , Humans , Infant , Infant, Newborn , Liver Neoplasms/epidemiology , Liver Neoplasms/etiology , Male , Predictive Value of Tests , Reference Values , Retrospective Studies , Risk AssessmentSubject(s)
Beckwith-Wiedemann Syndrome/blood , Hepatoblastoma/blood , Liver Neoplasms/blood , alpha-Fetoproteins/metabolism , Beckwith-Wiedemann Syndrome/complications , Beckwith-Wiedemann Syndrome/genetics , Beckwith-Wiedemann Syndrome/physiopathology , Hepatoblastoma/complications , Hepatoblastoma/genetics , Hepatoblastoma/pathology , Humans , Liver Neoplasms/geneticsABSTRACT
Beckwith-Wiedemann syndrome (BWS) is one of the most common cancer predisposition disorders. As a result, BWS patients receive tumor screening as part of their clinical management. Until recently, this screening has been employed uniformly across all genetic and epigenetic causes of BWS, including the utilization of ultrasonography to detect abdominal tumors and alpha-fetoprotein (AFP) to detect hepatoblastoma. The advancements in our understanding of the genetics and epigenetics leading to BWS has evolved over time, and has led to the development of genotype/phenotype correlations. As tumor risk appears to correlate with genetic and epigenetic causes of BWS, several groups have proposed alterations to tumor screening protocols based on the etiology of BWS, with the elimination of AFP as a screening measure and the elimination of all screening measures in BWS patients with loss of methylation at the KCNQ1OT1:TSS-DMR 2 (IC2). There are many challenges to this suggestion, as IC2 patients may have additional factors that contribute to risk of hepatoblastoma including fetal growth patterns, relationship with assisted reproductive technologies, and the regulation of the IC2 locus. © 2017 Wiley Periodicals, Inc.
Subject(s)
Beckwith-Wiedemann Syndrome/blood , Beckwith-Wiedemann Syndrome/complications , Biomarkers, Tumor , Hepatoblastoma/diagnosis , Hepatoblastoma/etiology , Liver Neoplasms/diagnosis , Liver Neoplasms/etiology , alpha-Fetoproteins , Beckwith-Wiedemann Syndrome/genetics , DNA Methylation , Early Detection of Cancer , Humans , Mass Screening , Potassium Channels, Voltage-Gated/genetics , UltrasonographyABSTRACT
Beckwith-Wiedemann syndrome (BWS) is a congenital overgrowth syndrome that is occasionally associated with hyperinsulinemic hypoglycemia (HH) in the neonatal period. Sotos syndrome (SS) and Kabuki syndrome (KS) are other malformation syndromes that may be complicated with HH, however, the detailed clinical characteristics of HH accompanied with these syndromes remain unclear. We herein conducted a nationwide questionnaire survey in Japan. We sent a primary questionnaire concerning the clinical experience for these syndromes to 347 perinatal care institutions. As a result, 222 departments or hospitals returned the questionnaires and the total numbers of BWS, SS, and KS patients were 113, 88, and 51, respectively. We sent a secondary questionnaire to 31 institutions where patients with these syndromes presented with HH during infancy. The secondary questionnaires were returned from the institutions and the numbers of patients were 16 for BWS, 9 for SS, and 3 for KS, respectively. Then, we compared the clinical characteristics of infants suffering from transient HH with and without these dysmorphic syndromes. As a result, BWS, SS, and KS patients showed significantly larger body size, lower Apgar scores, higher insulin levels at HH, and shorter durations of HH than non-dysmorphic infants with transient HH. We propose that a careful observation for the signs of HH, even if not specific to the syndromes, is important for the diagnosis of patients with BWS, SS, and KS in the postnatal period. © 2016 Wiley Periodicals, Inc.
Subject(s)
Abnormalities, Multiple/blood , Beckwith-Wiedemann Syndrome/blood , Face/abnormalities , Hematologic Diseases/blood , Hyperinsulinism/blood , Hypoglycemia/blood , Sotos Syndrome/blood , Vestibular Diseases/blood , Abnormalities, Multiple/diagnosis , Abnormalities, Multiple/epidemiology , Apgar Score , Beckwith-Wiedemann Syndrome/diagnosis , Beckwith-Wiedemann Syndrome/epidemiology , Female , Genetic Testing , Hematologic Diseases/diagnosis , Hematologic Diseases/epidemiology , Hematologic Tests , Humans , Infant, Newborn , Japan/epidemiology , Male , Phenotype , Population Surveillance , Pregnancy , Pregnancy Complications/epidemiology , Sotos Syndrome/diagnosis , Sotos Syndrome/epidemiology , Surveys and Questionnaires , Vestibular Diseases/diagnosis , Vestibular Diseases/epidemiologyABSTRACT
Determination of the soluble fms-like tyrosine kinase-1 to placental growth factor ratio (sFlt-1/PlGF) in the maternal serum is expected to aid in the monitoring and decision-making process of women at risk for placental dysfunction. We report two cases of placental mesenchymal dysplasia (PMD) with sFlt-1/PlGF correlation. The first case is a dichorionic twin pregnancy with one fetus affected by PMD and Beckwith-Wiedemann syndrome in which a high value of sFlt-1/PlGF was found, coinciding with acute maternal and fetal wellbeing decline at 31 weeks. The second case corresponds to a singleton pregnancy diagnosed of PMD with normal sFlt-1/PlGF and favorable outcome.
Subject(s)
Biomarkers/blood , Neovascularization, Physiologic , Placenta Diseases/blood , Adult , Beckwith-Wiedemann Syndrome/blood , Diseases in Twins/blood , Diseases in Twins/pathology , Female , Humans , Infant, Newborn , Male , Perinatal Death , Placenta Diseases/diagnosis , Placenta Growth Factor/blood , Pregnancy , Pregnancy, Twin , Vascular Endothelial Growth Factor Receptor-1/bloodABSTRACT
BACKGROUND: Almost half of the children with Beckwith-Wiedemann syndrome (BWS) will develop hyperinsulinaemic hypoglycaemia (HH). In the majority of BWS cases, HH will be transient; however, approximately in 5% of them, HH will be severe and often medically-unresponsive. Children with BWS due to paternal uniparental disomy (UPD) of chromosome 11p15 belong to this severe category and have traditionally required near-total pancreatectomy. The use of mTOR inhibitors had not been reported yet in this type of patients. CASE: A 1-month-old female with genetically confirmed BWS due to UPD of chromosome 11p15 was admitted for management of severe HH. Blood glucose concentrations were stabilised with high intravenous dextrose concentration, glucagon and octreotide infusions as she was proven to be diazoxide unresponsive. To avoid a subtotal pancreatectomy, an mTOR inhibitor - sirolimus - was introduced. The dose of sirolimus was optimised progressively and she was able to come off intravenous fluids and glucagon therapy. She has not presented any side effects and her growth is normal after 19 months of therapy. CONCLUSION: This is the first case reported of BWS due to UPD of chromosome 11p15 where sirolimus treatment has been effective in stabilising the blood glucose concentrations and avoiding a near-total pancreatectomy without major side effects detected.
Subject(s)
Beckwith-Wiedemann Syndrome , Chromosomes, Human, Pair 11/genetics , Congenital Hyperinsulinism , Sirolimus/administration & dosage , Uniparental Disomy , Beckwith-Wiedemann Syndrome/blood , Beckwith-Wiedemann Syndrome/drug therapy , Beckwith-Wiedemann Syndrome/genetics , Congenital Hyperinsulinism/blood , Congenital Hyperinsulinism/drug therapy , Congenital Hyperinsulinism/genetics , Female , Humans , Infant , Uniparental Disomy/drug effects , Uniparental Disomy/geneticsABSTRACT
A preterm baby girl, born at 34â weeks gestation, with features of Beckwith-Wiedemann syndrome was noted to have a relatively large umbilical stump. No fetal abnormalities had been detected on anatomy scan at 28â weeks and only mild polyhydramnios and macrosomia were noted on a 32-week ultrasound scan. Although there was no obvious omphalocoele, clinical assessment of the umbilical cord revealed an abdominal wall defect through which bowel would protrude into the umbilicus when the infant was crying. In keeping with an abdominal wall defect α-fetoprotein was found to be elevated. Surgical consultation advised conservative management. Subsequently, detachment of the umbilical cord occurred 1â week postdischarge and a large umbilical hernia persists. Genetic analysis confirmed a diagnosis of Beckwith-Wiedemann syndrome.
Subject(s)
Beckwith-Wiedemann Syndrome/diagnosis , Hernia, Umbilical/diagnosis , Beckwith-Wiedemann Syndrome/blood , Crying , Female , Hernia, Umbilical/blood , Humans , Infant, Newborn , Infant, Premature , alpha-Fetoproteins/metabolismABSTRACT
Beckwith-Wiedemann syndrome (BWS) is the most common overgrowth disorder in infants. This article reviews a case of a premature infant with an atypical presentation of Beckwith-Wiedemann that was diagnosed at one month of age. It also addresses notable aspects of the etiology, diagnosis, and management of infants with BWS.
Subject(s)
Beckwith-Wiedemann Syndrome , Hypoglycemia , Beckwith-Wiedemann Syndrome/blood , Beckwith-Wiedemann Syndrome/complications , Beckwith-Wiedemann Syndrome/diagnosis , Beckwith-Wiedemann Syndrome/physiopathology , Beckwith-Wiedemann Syndrome/therapy , Blood Glucose/analysis , Diagnosis, Differential , Disease Management , Female , Humans , Hypoglycemia/blood , Hypoglycemia/diagnosis , Hypoglycemia/therapy , Infant, Newborn , Infant, Postmature , Insulin/blood , Symptom Assessment/methods , Twins, DizygoticABSTRACT
BACKGROUND: Beckwith-Wiedemann syndrome (BWS) and hemihyperplasia (HH) are overgrowth conditions with predisposition to hepatoblastoma for which early diagnosis patients undergo cancer screening based on determination of the tumor marker α-fetoprotein (αFP). Repeated blood draws are a burden for patients with consequent compliance issues and poor adherence to surveillance protocol. We sought to analyze feasibility and reliability of αFP dosage using an analytical micromethod based on blood dried on filter paper (DBS). METHODS: Overall 143 coupled αFP determinations on plasma and DBS collected simultaneously were performed, of which 31 were in patients with hepatoblastoma predisposition syndromes and 112 were in controls. The plasma αFP dosage method was adapted to DBS adsorbed on paper matrix for newborn screening. RESULTS: There was strong correlation between plasmatic and DBS αFP (r2 = 0.999, P < 0.001). Cohen's k coefficient for correlation was 0.96 for diagnostic cut-off of 10 U/ml (P < 0.001), commonly employed in clinical practice. The measurements on plasma and DBS were highly overlapping and consistent. CONCLUSION: The DBS method allowed to dose αFP reliably and consistently for the concentrations commonly employed in clinical settings for the screening of hepatoblastoma, opening new scenarios about conducting cancer screening in overgrowth syndromes.
Subject(s)
Beckwith-Wiedemann Syndrome/diagnosis , Dried Blood Spot Testing , Early Detection of Cancer/methods , Hepatoblastoma/diagnosis , Hyperplasia/diagnosis , Liver Neoplasms/diagnosis , alpha-Fetoproteins/analysis , Adolescent , Beckwith-Wiedemann Syndrome/blood , Beckwith-Wiedemann Syndrome/genetics , Case-Control Studies , Child , Child, Preschool , Feasibility Studies , Female , Genetic Predisposition to Disease , Hepatoblastoma/blood , Hepatoblastoma/genetics , Humans , Hyperplasia/blood , Hyperplasia/genetics , Infant , Liver Neoplasms/blood , Liver Neoplasms/genetics , Male , Predictive Value of Tests , Reproducibility of ResultsABSTRACT
The Beckwith-Wiedemann syndrome is caused by disturbed imprinting of genes at 11p15.5. Routine diagnostic testing for Beckwith-Wiedemann syndrome (BWS) includes methylation analysis of the imprinting centers ICR1 and ICR2 in DNA extracted from lymphocytes. In approximately 15% of BWS patients the diagnosis cannot be molecularly confirmed. In this study we determined the methylation status in resected tongue tissue of 11 BWS patients and compared this to the genetic defects found by routine diagnostic screening of blood lymphocytes. In all three patients with normal methylation levels in blood, aberrant methylation patterns were found in tongue tissue. In two patients a UPD was detected and the third case had hypermethylation of ICR1. This result shows that tissue specific mosaic (epi)genetic changes, not present in blood, is the underlying defect in at least a subset of BWS patients without a molecular diagnosis after standard genetic testing.
Subject(s)
Beckwith-Wiedemann Syndrome/genetics , DNA Methylation , Genomic Imprinting , Tongue/metabolism , Beckwith-Wiedemann Syndrome/blood , Female , Humans , Infant , Male , Uniparental DisomyABSTRACT
UNLABELLED: We report on a girl with an unusual Beckwith-Wiedemann syndrome (BWS) and hemihypertrophy, who developed an adrenocortical carcinoma with atypical clinical behaviour. At 4 y of age the girls was admitted to hospital with cushingoid features, virilization, increased excretion of steroids and low serum ACTH. A right-sided adrenocortical carcinoma was removed. At age 12.5 y the cushingoid features reappeared together with a tumour in the left thigh. A CT scan of the thorax and abdomen revealed pulmonary metastasis only. Corticosteroid excretion was increased and serum ACTH level suppressed. The femoral and the pulmonary metastases were removed and histology showed adrenocortical carcinoma. Excretion of corticosteroids subsequently normalized. Meningeal and pulmonary metastases with similar histologies appeared one year later with normal hormone values. Twenty-two months after the recurrence the girl died of an intracranial metastasis. Southern blot analysis of the LITI transcript in the KvLQT1 gene in the BWS region on chromosome 11p15 revealed hypomethylation of the maternal allele. CONCLUSION: Adrenocortical carcinoma in childhood may recur years after onset and at rare sites and hormonal levels may be an insufficient indicator of small metastases.
Subject(s)
Adrenal Cortex Neoplasms/genetics , Adrenal Cortex Neoplasms/pathology , Adrenocortical Carcinoma/genetics , Adrenocortical Carcinoma/secondary , Beckwith-Wiedemann Syndrome/complications , Beckwith-Wiedemann Syndrome/genetics , Endocrine System/metabolism , Lung Neoplasms/genetics , Lung Neoplasms/secondary , Meningeal Neoplasms/genetics , Meningeal Neoplasms/secondary , Muscle Neoplasms/genetics , Muscle Neoplasms/secondary , Neoplasm Recurrence, Local/genetics , Neoplasm Recurrence, Local/pathology , Adrenal Cortex Neoplasms/blood , Adrenocortical Carcinoma/blood , Beckwith-Wiedemann Syndrome/blood , Child , Child, Preschool , Female , Humans , Lung Neoplasms/blood , Meningeal Neoplasms/blood , Muscle Neoplasms/blood , Muscle, Skeletal/pathology , Neoplasm Recurrence, Local/blood , Thigh/pathology , Time FactorsABSTRACT
We conducted a retrospective study that compared serial alpha-fetoprotein (AFP) concentrations obtained from 22 children with Beckwith-Wiedemann syndrome (BWS) with levels established for healthy children. The AFP concentration is greater in patients with BWS and declines during the postnatal period at a significantly slower rate than what is reported in healthy children. AFP levels obtained in the course of routine tumor screening in children with BWS should be interpreted with a normal curve established specifically for BWS rather than with previously published data for healthy infants and children.
Subject(s)
Beckwith-Wiedemann Syndrome/blood , alpha-Fetoproteins/analysis , Child, Preschool , Female , Humans , Infant , Infant, Newborn , Male , Retrospective StudiesABSTRACT
Beckwith-Wiedemann syndrome (BWS) comprises of a number of childhood abnormalities, often associated with one or more tumors. Thirty-eight patients were investigated to determine clinical and/or biological signs associated with a tumor presence. Our patients exhibited a higher incidence of tumor development (21%) than that previously reported, underlying the care with which such patients should be followed, when particular clinical features are observed: visceromegaly affecting three organs (liver, kidney, spleen), and also family history with sign of BWS such as macroglossia, omphalocele, hemihypertrophy, embryonic tumor), high body weight at birth (> or = +2 standard deviations and diastasis recti.
Subject(s)
Beckwith-Wiedemann Syndrome/genetics , Neoplasms/genetics , Beckwith-Wiedemann Syndrome/blood , Child, Preschool , Female , Humans , Infant , Insulin-Like Growth Factor I/metabolism , Insulin-Like Growth Factor II/metabolism , Male , Neoplasms/blood , Odds Ratio , Phenotype , RiskABSTRACT
Hypoglycaemia is a frequent finding during the neonatal period and may be due to insulin overproduction. Patients with Beckwith-Wiedemann syndrome have reduced numbers of somatostatin-producing cells and decreased extractable somatostatin. In this study the effect of long-acting somatostatin (SMS201-995) on the glucose and insulin levels in an infant with Beckwith-Wiedemann syndrome and hyperinsulinaemic non-ketotic hypoglycaemia is described. SMS201-995 lowered basal insulin levels while maintaining normal glucose and insulin homeostasis. During fasting however, both glucose levels declined rapidly whereas insulin levels did not. The absence of both ketosis and elevated levels of free fatty acids and lactate during hypoglycaemia, as observed in our patient, are important diagnostic clues since the insulin levels themselves may sometimes be only slightly elevated.
Subject(s)
Beckwith-Wiedemann Syndrome/blood , Hyperinsulinism/drug therapy , Hypoglycemia/drug therapy , Octreotide/therapeutic use , Beckwith-Wiedemann Syndrome/complications , Beckwith-Wiedemann Syndrome/drug therapy , Humans , Hydrocortisone/blood , Hyperinsulinism/etiology , Hypoglycemia/etiology , Infant, Newborn , Insulin/blood , MaleSubject(s)
Beckwith-Wiedemann Syndrome/blood , alpha-Fetoproteins/analysis , Female , Humans , Infant , Infant, NewbornABSTRACT
The endocrine cell content of the pancreas of two cases of Beckwith-Wiedemann syndrome with islet cell adenomatosis were studied. Insulin, glucagon, somatostatin and pancreatic polypeptide cells were evaluated qualitatively and quantitatively with the indirect immunofluorescence method and morphometry was used to establish the volume density of the four endocrine cell populations. This evaluation showed a marked increase of insulin and glucagon cells and a lesser augmentation of pancreatic polypeptide cells and somatostatin cells. However, the percent of somatostatin cells was decreased in comparison with controls. Qualitatively, the two pancreas were characterized by the lack of segregation of glucagon and pancreatic polypeptide cells to distinct parts of the gland, with each cell type being abundant in the pancreatic region in which they are normally very sparse. The marked increase of endocrine cells often took the form of giant islet-like structures formed by smaller subunits; however, despite this increase, the distribution of insulin cells respected the normal pattern, i.e. clusters of B cells surrounded by non-B cells. These findings indicate that besides the proliferation of pancreatic endocrine cells maintaining a normal topographical distribution of B versus non-B cells, the pancreas of patients with the Beckwith-Wiedemann syndrome may have undergone abnormal development with a consequent lack of segregation of glucagon and pancreatic polypeptide cells to different parts of the gland.