Adult experiences in Beckwith-Wiedemann syndrome.

Beckwith-Wiedemann syndrome (BWS) is an overgrowth and epigenetic disorder caused by changes on chromosome 11p15. The primary features requiring management in childhood include macroglossia, omphalocele, lateralized overgrowth, hyperinsulinism, and embryonal tumors. Management guidelines have not been developed for adults with BWS and there have been few studies to assess the clinical needs of these patients. Furthermore, there have been few studies on the psychosocial implications of BWS in children or adults. Here, we present a descriptive summary of data gathered from two separate adult BWS cohorts. The first, a patient-based survey cohort, includes self-reported health information and recollections about BWS experiences, while the second provides results of a medical record-based assessment from patients in an overgrowth registry. Results highlight the clinical features and medical issues affecting two large independent cohorts of adults with BWS while noting similarities. Open-ended questions asked of the survey cohort yielded themes to guide future qualitative studies. Finally, the study demonstrated the reliability of patient-reported data and the utility of international partnerships in this context.

Macroglossia in a pig diagnosed as Becker muscular dystrophy due to dystrophin pseudoexon insertion derived from intron 26.

We report a case of Becker muscular dystrophy in a 6-month-old, mixed-breed, castrated male pig detected with macroglossia at a meat inspection center. The pig presented a severely enlarged tongue extending outside its mouth. The tongue was firm and pale with discolored muscles. Histologically, there was severe fibrosis, fatty replacement, and myofiber necrosis, degeneration, and regeneration. Immunofluorescence showed focal and severely weak labeling for dystrophin at the sarcolemma of myocytes in the tongue. Analysis of dystrophin mRNA showed a 62 base pair insertion between exons 26 and 27. The insertion was derived from intron 26. Based on these findings, we diagnosed the case as Becker muscular dystrophy-the first known muscular dystrophy case induced by pseudoexon insertion in animals.

Genome-wide DNA methylation and transcription analysis in tongue and biceps femoris muscles of cloned pigs with macroglossia.

Cloned animals are prone to abnormal phenotypes such as enlarged tongue, fetal oversize, and progeria. In the present study, whole-genome bisulfite sequencing and mRNA sequencing were performed on tongue and biceps femoris muscles of cloned piglets with and without macroglossia, in an attempt to elucidate the epigenetic causes of the macroglossia phenotype. We identified 14 958 and 18 752 differentially methylated regions in the tongue and biceps femoris muscles, respectively, of macroglossia piglets and these correspond to 4574 and 4772 differentially methylated genes compared with the control group (piglets without macroglossia). Larger methylation difference was found in tongue muscle than in biceps femoris muscle. In total, 114 genes in tongue and 72 genes in biceps femoris muscles were found to be differentially expressed between the two groups. Of these differentially expressed genes in tongue muscle, 31 were also differentially methylated genes, among which DIO3 and ZIC1 were imprinting or predicted imprinting genes. These two and another six overlapping genes (ALDH1A2, MKX, MAB21L2, CA3, RANBP3L, and MYL10) are crucial factors involved in embryonic development or tissue and organ development. GO enrichment analysis suggested possible alteration of these processes. Our study provides novel molecular insights into the formation of macroglossia in cloned pigs.

A novel mutation in CDKN1C in sibs with Beckwith-Wiedemann syndrome and cleft palate, sensorineural hearing loss, and supernumerary flexion creases.

We report on two daughters and a son of a Thai family who were affected with BWS. Their clinical findings consist of cleft palate, omphalocele, anterior ear creases, indented lesions on the posterior rim of the helix, macroglossia, posterior crossbite, and anterior open bite. The younger daughter and son had newly recognized findings of the BWS including sensorineural hearing loss and supernumerary flexion creases of the fingers. A novel mutation in CDKN1C (c.579delT; p.A193AfsX46) was found in all affected individuals and their mother. This mutation is located in the central highly polymorphic hexanucleotide repeat encoding a proline-alanine series of repeats (PAPA-domain). This domain is involved in MAP kinase phosphorylation. This is for the first time that sensorineural hearing loss and supernumerary flexion creases of the fingers are associated with mutation in CDKN1C.

Beckwith-Wiedemann syndrome with long QT caused by a deletion involving KCNQ1 but not KCNQ1OT1:TSS-DMR.

Beckwith-Wiedemann syndrome (BWS) is an imprinting disorder with characteristic features, such as overgrowth, macroglossia, and exomphalos. Hypomethylation of the KCNQ1OT1:TSS-differentially methylated region (DMR) on the 11p15.5 imprinted region is the most common etiology of BWS. KCNQ1 on 11p15.5 is expressed from the maternally inherited allele in most tissues, but is biparentally expressed in the heart, and maternal KCNQ1 transcription is required to establish the maternal DNA imprint in the KCNQ1OT1:TSS-DMR. Loss of function variants in KCNQ1 result in long QT syndrome type 1 (LQT1). To date, eight patients with BWS due to KCNQ1 splice variants or structural abnormalities involving KCNQ1 but not the KCNQ1OT1:TSS-DMR have been reported (KCNQ1-BWS), and four of them had LQT1. We report a Japanese boy with BWS and LQT1 presenting with extreme hypomethylation of the KCNQ1OT1:TSS-DMR caused by a de novo 215-kb deletion including KCNQ1 but not the KCNQ1OT1:TSS-DMR on the maternal allele. He was born by emergency cesarean section due to suspicion of placental abruption at 30 weeks of gestation. His birth weight and length were +1.6 SD and +1.0 SD, respectively. His placental weight was +3.9 SD, and histological examination of his placenta was consistent with mesenchymal dysplasia. He had BWS clinical features, including macroglossia, ear creases and pits, body asymmetry, and rectus abdominis muscle dehiscence, and BWS was therefore diagnosed. LQT1 was first noticed at three months in a preoperative examination for lingual frenectomy. The summarized data of our patient and the previously reported eight patients in KCNQ1-BWS showed more frequent and earlier preterm births and smaller sized birth weight in KCNQ1-BWS cases than those with BWS caused by epimutation of the KCNQ1OT1:TSS-DMR. In addition, in five of nine patients with KCNQ1-BWS, LQT1 was detected, and two of them were identified at school age. In our patient and in another single case with LQT1, the LQT1 was not detected early despite neonatal ECG monitoring. For BWS patients with extreme hypomethylation of the KCNQ1OT1:TSS-DMR, searching for CNVs involving KCNQ1 and mutation screening for KCNQ1 should be considered together with periodic ECG monitoring. (338/500 words).

Partial paternal uniparental disomy of chromosome 6 in monozygotic twins with transient neonatal diabetes mellitus and macroglossia.

Transient neonatal diabetes mellitus (TNDM) usually develops within the first few weeks of life and resolves at a median age of 3 months. In most of the cases, TNDM is caused by the over-expression of a paternally expressed imprinted PLAGL1 locus on chromosome 6q24. The most frequent manifestation other than TNDM is intrauterine growth retardation (IUGR), and in some cases macroglossia. We investigated monozygotic twins who had macroglossia without IUGR. Both of the twins developed insulin-dependent hyperglycemia within the first week of life, which subsequently resolved. DNA profiling with polymerase chain reaction amplification was performed for polymorphic microsatellite markers of chromosome 6. The six informative markers, located between 6p24 and 6q15, showed normal biparental inheritance. However, the six distal informative markers, located between 6q23.2 and the 6q telomeric region, showed the absence of a maternal allele and the presence of a single paternal allele. The monosomy of the 6q telomeric region was not confirmed by chromosome banding showing 46, XX. These findings provide further evidence that partial paternal uniparental disomy of chromosome 6 (pUPD6) causes TNDM. The phenotypes other than diabetes observed in patients with partial pUPD6 may differ from those observed in patients with complete pUPD6.

The Utility of Early Tongue Reduction Surgery for Macroglossia in Beckwith-Wiedemann Syndrome.

BACKGROUND: Macroglossia, a cardinal feature of the (epi)genetic disorder Beckwith-Wiedemann syndrome, is associated with obstructive sleep apnea, speech and/or feeding difficulties, and dental or jaw malalignment. These sequelae may be treated and/or prevented with tongue reduction surgery; the authors sought to determine whether certain Beckwith-Wiedemann syndrome patients may benefit from early surgical intervention before age 12 months. METHODS: The authors conducted a retrospective review of patients with Beckwith-Wiedemann syndrome who underwent tongue reduction from 2014 to 2019. The authors assessed primary outcomes of change in obstructive sleep apnea by polysomnography, respiratory support required, and feeding route before and after tongue reduction, and reviewed postoperative complications and the need for repeated tongue reduction. RESULTS: Of the 36 patients included, the median age at tongue reduction was 9.5 months (interquartile range, 3.8 to 22.8 months). For those with severe obstructive sleep apnea, there was a significant reduction in the obstructive apnea hypopnea index from 30.9 ± 21.8 per hour to 10.0 ± 18.3 per hour (p =0.019) and improvement in nadir oxyhemoglobin saturation from 72 ± 10 percent to 83 ± 6 percent (p =0.008). Although there was no significant change in overall supplemental feeding tube or respiratory support, there were specific patients who experienced clinically meaningful improvement. Of note, these positive outcomes applied equally to those who underwent surgery at a younger age (<12 months). To date, only one patient required a repeated tongue reduction. CONCLUSION: Based on improved polysomnographic findings and rarity of surgical complications or repeated surgery, the authors' data support the safety and efficacy of this early intervention when clinical indications are present and an experienced multidisciplinary team is available for consultation. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

The 11p15.5 chromosomal region: When did the instability occur?

The disturbances of the 11p15.5 chromosomal region are associated with Beckwith-Wiedemann syndrome, Russell-Silver syndrome, Wilms tumor, IMAGe syndrome, and idiopathic hemihyperplasia. The aim of this research was to examine the hypothesis that 11p15.5 initially became unstable in the European population about 200 years ago. The medical literature from 1557 onwards, especially treatises on teratology, body asymmetry, and books of normal and pathologic anatomy, was searched for any mentioning of lateral body asymmetry, macroglossia and other possible visually detectable symptoms associated with the above-mentioned syndromes. The results indicate that lateral body asymmetry was not described before the first half of the 19th century, it was mentioned in the 1820s, and the first description of a true case was published in 1850. All first cases of hemihyperplasia were reported in continental Europe. Historical data suggest that the 11p15.5 chromosomal region became unstable in the first half of the 19th century. Our preliminary hypothesis is that de novo mutation occurred in continental Europe. Additional genetic research is needed to investigate the development of 11p15.5 instability during this period.

Molecular basis of neonatal diabetes in Japanese patients.

CONTEXT: Neonatal diabetes mellitus (NDM) is classified clinically into a transient form (TNDM), in which insulin secretion recovers within several months, and a permanent form (PNDM), requiring lifelong medication. However, these conditions are genetically heterogeneous. OBJECTIVE: Our objective was to evaluate the contribution of the responsible gene and delineate their clinical characteristics. PATIENTS AND METHODS: The chromosome 6q24 abnormality and KCNJ11 and ABCC8 mutations were analyzed in 31 Japanese patients (16 with TNDM and 15 with PNDM). Moreover, FOXP3 and IPF1 mutations were analyzed in a patient with immune dysregulation, polyendocrinopathy, enteropathy X-linked syndrome and with pancreatic agenesis, respectively. RESULTS: A molecular basis for NDM was found in 23 patients: 6q24 in eleven, KCNJ11 in nine, ABCC8 in two, and FOXP3 in one. All the patients with the 6q24 abnormality and two patients with the KCNJ11 mutation proved to be TNDM. Five mutations were novel: two (p.A174G and p.R50G) [corrected] in KCNJ11, two (p.A90V and p.N1122D) in ABCC8, and one (p.P367L) in FOXP3. Comparing the 6q24 abnormality and KCNJ11 mutation, there were some significant clinical differences: the earlier onset of diabetes, the lower frequency of diabetic ketoacidosis at onset, and the higher proportion of the patients with macroglossia at initial presentation in the patients with 6q24 abnormality. In contrast, two patients with the KCNJ11 mutations manifested epilepsy and developmental delay. CONCLUSIONS: Both the 6q24 abnormality and KCNJ11 mutation are major causes of NDM in Japanese patients. Clinical differences between them could provide important insight into the decision of which gene to analyze in affected patients first.

Beckwith-Wiedemann-like macroglossia and 18q23 haploinsufficiency.

Beckwith-Wiedemann syndrome (BWS) is an overgrowth condition with tumor proclivity linked to a genetic imbalance of a complex imprinted region in 11p15.5. A female child with features fitting in with the BWS diagnostic framework and an apparent loss of imprinting (LOI) of the IGF2 gene in 11p15.5 was also reported to have a de novo chromosome 18q segmental deletion (Patient 1), thus pointing at the location of a possible trans-activating regulator element for maintenance of IGF2 imprinting and providing one of the few examples of locus heterogeneity of BWS. A second child with de novo 18q23 deletion and features of macroglossia, naevus flammeus, bilateral inguinal hernia and transient neonatal hypoglycemia, thus also fitting in with the BWS diagnostic framework, is here fully reported (Patient 2). In this child, an analysis of the BWS1 locus precluded any paternal isodisomy and showed a normal imprinting pattern (mono-allelic expression of IGF2 and normal H19 and CDKN1OT1/LIT1 methylation index). In Patients 1 and 2, deletions were shown to overlap, defining a minimal region of haplo-insufficiency of 3.8-5.6 Mb in 18q23. We conclude that this region provides a candidate location for an original macroglossia condition with strong overlap with BWS, but without obvious upstream functional relationship with the BWS1 locus in 11p15.5. Because this minimal region of haplo-insufficiency falls into a common region of deletion in 18q- syndrome, we inferred that this macroglossia condition would follow a recessive pattern of inheritance.

13q31.1 microdeletion: A prenatal case report with macrocephaly and macroglossia.

We report on a female fetus with macrocephaly and macroglossia harbouring 13q31.1 microdeletion encompassing three genes: SPRY2, NDFIP2 and RBM26. NDFIP2 protein is involved in ubiquitination and in Ras/mitogen-activated protein kinase (MAPK) signaling pathways. SPRY2 protein is part of Sprout protein family and inhibits the Ras/MAPK pathways. Ras/MAPK pathway plays important role in complex cellular programs including cell differentiation and proliferation. Germline mutations in genes encoding protein involved in the MAPK cascade is responsible for a wide family of developmental disorders known as RASopathies. Some RASopathies, such as Costello syndrome, present a phenotype with (relative) macrocephaly as perinatal features. However, prenatal-onset macroglossia are generally absent in this syndrome but rather suggestive of the Beckwith-Wiedemann syndrome for which molecular testing were negative. Phenotype-genotype correlation with patients from DECIPHER defines NDFIP2 and SPRY2 as a possible candidate genes for a RASopathy potentially responsible for the clinical features in the fetus. Finally, this original case of 13q31.1 microdeletion underlines the importance of array-CGH in prenatal diagnosis with sonographic signs such as macroglossia and/or macrocephaly. In this case, genetic investigation should be not limited to the search of well-known genetic causes and other genomic microdeletions should be considered as alternative diagnoses for macroglossia.

Clinical variability in adult-onset acid maltase deficiency: report of affected sibs and review of the literature.

Acid maltase deficiency (AMD) is a rare cause of muscle disease in adult patients. The present report of 2 sibs and review of 36 previously reported cases illustrates the vast clinical variability in adult-onset AMD. This is 1 of only 3 reports to document tongue weakness and enlargement in an adult with AMD. The presenting signs and symptoms usually include progressive limb weakness, restrictive lung disease, or both. Consistent supportive abnormalities include a modest elevation in serum CK, a reduction in the forced vital capacity, and abnormal spontaneous activity (that is, myotonic discharges or fibrillations) in resting muscles during needle electromyography. The clinical spectrum is also extended to include distal limb weakness, scapular winging, asymmetric muscle weakness, and tongue involvement.

Familial occurrence of the Wiedemann-Beckwith syndrome and persistent fontanel.

We describe a family in which 3 sisters gave birth to 8 infants with the Wiedemann-Beckwith syndrome. The clinical manifestations in all the affected individuals included macroglossia, macrosomia and omphalocele, while their mothers all were entirely normal. Pedigree analysis suggests that familial occurrence of the Wiedemann-Beckwith syndrome may be due to delayed mutation.

Wiedemann-Beckwith syndrome: autosomal-dominant inheritance in a family.

We report four additional cases of Wiedemann-Beckwith syndrome (WBS): A mother, her brother, and two of her children (half-sibs). Theories of the genetic transmission of the WBS are reviewed. The trait in this family appears to be an autosomal-dominant with variable expressivity. A theory of delayed mutation of an unstable premutated gene is discussed and an interpretation and observations are offered which could alter slightly the expected pattern of inheritance. Eighty-eight other family members were screened for evidence of WBS and noteworthy findings are presented.

Autosomal dominant congenital macroglossia: further delineation of the syndrome.

We describe seven patients from two Mexican families with congenital macroglossia. Comparative analysis of these cases and the patients previously described in literature, allows to confirm the notion that this isolated primary macroglossia is a distinct dominant condition.

Autosomal dominant macroglossia: an addendum to the etiological classification.

There are multiple causes and classifications of macroglossia. We report a new observation of this entity in a mother and her daughter. Together with our previous report in two Mexican families with autosomal dominant transmission, we now expand the current classification with a new category: autosomal dominant macroglossia.

[EMG syndrome. Review apropo of 2 cases]. / Sindrome EMG. Revisión a propósito de dos casos.

Two cases of EMG syndrome are reported (exomphalos, macroglossia, gigantism). One of them died some hours after the birth. A review of clinical findings, pathogenesis and evolution is presented. Only 60 cases of this rare disease are reported in the world literature.

Genetic causes of macroglossia: diagnostic approach.

OBJECTIVE: Evaluate the contribution of standard diagnostic tests for macroglossia when clinical features are not suggestive of Beckwith-Wiedemann syndrome (BWS). METHODS: A retrospective analysis of data from clinical, laboratory, and imaging information from children with macroglossia seen at Cincinnati Children's Hospital Medical Center between 1997 and 2010 was performed. RESULTS: One hundred thirty-five children with macroglossia were identified. Macroglossia was the main reason for consultation in 84 children. Patients were classified on initial examination as isolated macroglossia (n = 24), provisional BWS (n = 36), and syndromic (n = 24). A final diagnosis was reached in 74 patients, and in 10 patients the reason for macroglossia remained undetermined. Among the elucidated cases, BWS was the most common cause of macroglossia (39/84). Six of the 24 patients in the isolated macroglossia group had an abnormal molecular test for BWS (P = .006). Thirteen diagnostic conditions were confirmed in this study, and 42% of the population had a specific diagnosis that was not BWS (35/84). CONCLUSIONS: These results can be used to improve our strategy in the evaluation of macroglossia. Distinction between isolated macroglossia and BWS may be difficult when only taking into account clinical features. These findings suggest that all patients with apparently isolated macroglossia have at least initial evaluation with abdominal ultrasounds and molecular studies for BWS before a final diagnosis is given. BWS was the most common cause of macroglossia even in the absence of additional clinical findings.