OBJECTIVE: To explore the genetic basis for a couple with recurrent conceptions of fetus with abnormal longbones, and another couple with a history of omphalocele. METHODS: Genomic DNA was extracted from the peripheral blood samples from both couples. All exons and flanking regions were analyzed with next generation sequencing. Candidate variants were verified by Sanger sequencing. RESULTS: Couple one was found to be heterozygous for, a c.997+1G>T splice-site variant and a missence c.871G>A(p.Glu291Lys) variant of the ALPL gene. Both variants were predicted to be pathogenic and may result in reduced function or loss of alkaline phosphatase. For couple two, the wife was found to harbor a novel c.637_652 delins CCC variant of the CDKN1C gene. This deletion-insertion variant resulted in frame-shift and loss of function (p.Ala213Profs*55) of the CDKN1C protein. Maternally inherited CDKN1C LOF variant has been found to underlie Beckwith-Wiedemann syndrome (BWS), which may manifest as omphalocele. CONCLUSION Dispite the lack the direct proof from the lost fetuses, the variants of ALPL and CDKN1C genes can explain the recurrence of fetal malformations for both couples.
Beckwith-Wiedemann Syndrome ; Fetus ; Humans ; Mutation

Patients with Beckwith-Wiedemann syndrome (BWS) are predisposed to developing embryonal tumors, with hepatoblastoma being the most common type. Our patient showed hemihypertrophy, macroglossia, and paternal uniparental disomy in chromosome 11 and was diagnosed with BWS. When the patient was 9 months old, a 2.5×1.5 cm oval hypoechoic exophytic mass was detected in the inferior tip of his right liver. Preoperative imaging identified it as hepatoblastoma; however, histologic, immunohistochemistry, and electron microscopic findings were compatible with adrenal cortical neoplasm with uncertain malignant potential. The origin of the adrenal tissue seemed to be heterotopic. Here, we describe for the first time an adrenal cortical neoplasm with uncertain malignant potential arising in the heterotopic adrenal cortex located in the liver of a patient with BWS.
Adrenal Cortex ; Adrenal Gland Neoplasms ; Beckwith-Wiedemann Syndrome ; Chromosomes, Human, Pair 11 ; Hepatoblastoma ; Humans ; Immunohistochemistry ; Liver ; Macroglossia ; Uniparental Disomy

PURPOSE: Overgrowth syndromes are conditions that involve generalized or localized areas of excess growth. In this study, the clinical, molecular, and genetic characteristics of Korean patients with overgrowth syndrome were analyzed. MATERIALS AND METHODS: We recruited 13 patients who presented with overgrowth syndrome. All patients fulfilled inclusion criteria of overgrowth syndrome. Analysis of the clinical and molecular investigations of patients with overgrowth syndrome was performed retrospectively. RESULTS: Among the 13 patients with overgrowth syndrome, 9 patients (69.2%) were found to have molecular and genetic causes. Among the seven patients with Sotos syndrome (SS), two had a 5q35microdeletion that was confirmed by fluorescent in situ hybridization. In two patients with SS, intragenic mutations including a novel mutation, c.5993T>A (p.M1998L), were found by Sanger sequencing. One patient had one copy deletion of NDS1 gene which was confirmed by multiplex ligation-dependent probe amplification. Among five patients with Beckwith-Wiedemann syndrome, three had aberrant imprinting control regions; 2 hypermethylation of the differentially methylated region of H19, 1 hypomethylation of the differentially methylated region of Kv. In one patient displaying overlapping clinical features of SS, a de novo heterozygous deletion in the chromosomal region 7q22.1-22.3 was found by single nucleotide polymorphism-based microarray. CONCLUSION: Considering high detection rate of molecular and genetic abnormalities in this study, rigorous investigations of overgrowth syndrome may be an important tool for the early diagnosis and genetic counseling. A detailed molecular analysis of the rearranged regions may supply the clues for the identification of genes involved in growth regulation.
Beckwith-Wiedemann Syndrome ; Early Diagnosis ; Genetic Counseling ; Humans ; In Situ Hybridization, Fluorescence ; Multiplex Polymerase Chain Reaction ; Retrospective Studies ; Sotos Syndrome

OBJECTIVETo explore the genetic cause for two children with omphalocele.

METHODSThe patients were examined, and the medical history of their families was collected. Methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) was performed to detect potential mutation in the patients.

RESULTSLoss of methylation of imprinting center 2 (IC2) at the 11p15.5 region of the maternal chromosome was detected in both children.

CONCLUSIONThe two patients were diagnosed with Beckwith-Wiedemann syndrome by MS-MLPA. The loss of methylation of IC2 probably underlies the disease in both patients.

Beckwith-Wiedemann Syndrome ; genetics ; Chromosomes, Human, Pair 11 ; DNA Methylation ; Female ; Genomic Imprinting ; Humans ; Infant ; Infant, Newborn ; Male ; Multiplex Polymerase Chain Reaction

Airway obstruction in pediatric patients always poses a challenge for anesthesiologists. Beckwith-Wiedemann syndrome causes various abnormalities such as macroglossia and omphalocele. Patients with these abnormalities often need corrective surgeries. Management of difficult airway caused by conditions such as macroglossia in patients with this syndrome could be challenging. We encountered a case of difficult airway in an infant with Beckwith-Wiedemann syndrome. It was predicted that macroglossia might cause difficult ventilation, intubation, and extubation. Preoperative assessment and preparations for difficult airway should be considered.
Airway Management* ; Airway Obstruction ; Anesthesia, General ; Beckwith-Wiedemann Syndrome* ; Hernia, Umbilical ; Humans ; Infant ; Intubation ; Macroglossia ; Ventilation

Overgrowth syndromes comprise a diverse group of conditions with unique clinical, behavioral and molecular genetic features. While considerable overlap in presentation sometimes exists, advances in identification of the precise etiology of specific overgrowth disorders continue to improve clinicians' ability to make an accurate diagnosis. Among them, this paper introduces two classic genetic overgrowth syndromes: Sotos syndrome and Beckwith-Wiedemann syndrome. Historically, the diagnosis was based entirely on clinical findings. However, it is now understood that Sotos syndrome is caused by a variety of molecular genetic alterations resulting in haploinsufficiency of the NSD1 gene at chromosome 5q35 and that Beckwith-Wiedemann syndrome is caused by heterogeneous abnormalities in the imprinting of a number of growth regulatory genes within chromosome 11p15 in the majority of cases. Interestingly, the 11p15 imprinting region is also associated with Russell-Silver syndrome which is a typical growth retardation syndrome. Opposite epigenetic alterations in 11p15 result in opposite clinical features shown in Beckwith-Wiedemann syndrome and Russell-Silver syndrome. Although the exact functions of the causing genes have not yet been completely understood, these overgrowth syndromes can be good models to clarify the complex basis of human growth and help to develop better-directed therapies in the future.
Beckwith-Wiedemann Syndrome* ; Epigenomics ; Genes, Regulator ; Genomic Imprinting ; Haploinsufficiency ; Humans ; Molecular Biology ; Silver-Russell Syndrome ; Sotos Syndrome*

Beckwith-Wiedemann Syndrome (BWS) is a rare congenital overgrowth disorder due to alterations in specific genes in chromosome 11p15. It has a variable clinical picture. Infants may exhibit a combination of the following characteristics: macroglossia, macrosomia, abdominal wall defects, ear creases or posterior helical pits, hypoglycemia, polyhydramnios and prematurity. Presented is a case of a 24-year-old gravida 3 para 2 (2002) who manifested with preterm labor and polyhydramnios. She delivered a preterm live baby girl who was diagnosed to have Beckwith-Wiedemann syndrome. The rarity of this condition, as well as the significant maternal and perinatal complications associated with it, is discussed in this paper.

Human ; Female ; Adult ; Infant Newborn ; Pregnancy ; Congenital Macroglossia ; Macroglossia ; Beckwith-wiedemann Syndrome ; Polyhydramnios ; Abdominal Wall ; Fetal Macrosomia ; Hypertrophy ; Chromosomes ; Hypoglycemia

Beckwith-Wiedemann Syndrome ; diagnosis ; drug therapy ; Humans ; Infant ; Male

PURPOSE: Beckwith-Wiedemann syndrome (BWS) is an overgrowth malformation syndrome caused by a methylation abnormality at chromosome 11p15, consisting of two imprinting centers, BWSIC1 (IGF2, H19) and BWSIC2 (LIT1, KvDMR). This study evaluated the applicability of a methylation-specific (MS) PCR RFLP method for the genetic diagnosis of BWS. MATERIALS AND METHODS: A total of 12 patients were recruited based on clinical findings. Karyotyping was performed using peripheral blood leukocytes, and genomic DNA was treated with bisulfate and amplified using methylation-specific primers. RFLP was conducted with restriction enzymes in differentially methylated regions of LIT1, H19, and IGF2. RESULTS: The 12 BWS patients had normal karyotypes. Abnormal methylation patterns in the BWSIC2 (LIT1) region were identified in seven patients (58.3%) using the MS-PCR RFLP method. CONCLUSIONS: The MS-PCR RFLP method is a simple, economical genetic test. It detected genetic abnormalities in 50-60% of BWS patients, suggesting that it can be used as a screening test. A more precise method is required, however, to enhance the detection rate of genetic abnormalities, especially in BWSIC1 region.
Beckwith-Wiedemann Syndrome ; DNA ; Genetic Testing ; Humans ; Karyotype ; Karyotyping ; Leukocytes ; Mass Screening ; Methylation ; Polymerase Chain Reaction ; Polymorphism, Restriction Fragment Length

Placental mesenchymal dysplasia (PMD) is a rare placental disorder that may coexist with a normal fetus but is frequently associated with fetal growth restriction, fetal demise, prematurity, and Beckwith-Wiedemann syndrome, as well as with various fetal anatomical and vascular anomalies. In this case, ultrasonography performed at 14 weeks of gestation revealed multiple, variable sized cysts in the placenta along with a morphologically normal fetus. Serial sonographic examinations found that the fetus became small for gestational age and had a dysplastic right kidney. After delivery at 33 weeks of gestation, histopathologic examination of the placenta showed enlarged, hydropic stem villi with cavity formation and absence of trophoblastic proliferation and pseudoinclusions, all of which were consistent with PMD. Neonatal abdominal ultrasonography showed multiple cysts in the right kidney consistent with a multicystic dysplastic condition. This appears to be the first case of PMD associated with fetal multicystic dysplastic kidney.
Beckwith-Wiedemann Syndrome ; Fetal Development ; Fetus ; Gestational Age ; Kidney ; Multicystic Dysplastic Kidney ; Placenta ; Pregnancy ; Trophoblasts