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.

Manejo anestésico perioperatorio de glosoplastia reductora en paciente con síndrome de Beckwith-Wiedemann / Perioperative anesthetic management of reductive glossoplasty in a patient with Beckwith-Wiedemann syndrome

Introducción: El síndrome de Beckwith-Wiedemann (SBW) es un trastorno de crecimiento congénito. El manejo perioperatorio puede ser a veces complicado. Sus principales manifestaciones clínicas son macroglosia, que puede causar dificultades en el manejo de la vía aérea, prematuridad, hemihipertrofia, onfalocele, tumores embrionarios y episodios de hipoglucemia neonatal. Objetivo: Nuestro objetivo principal es describir el manejo perioperatorio de pacientes pediátricos con SBW sometidos a glosectomía y sus posibles complicaciones anestésicas. Métodos: Reporte de caso y revisión del tema. Resultados: Describimos el caso de una paciente de 11meses diagnosticada con SBW que se sometió a cirugía reductora de macroglosia. Se realizó una evaluación preoperatoria exhaustiva con la consideración de las posibles complicaciones anestésicas derivadas tanto de la macroglosia como de la prematuridad, y los posibles episodios de hipoglucemia. El procedimiento se realizó bajo anestesia general, siguiendo los algoritmos de intubación difícil de la vía aérea, sin incidencias, y se realizó una extubación segura en el quirófano. Durante el postoperatorio la paciente permaneció estable, presentó buena dinámica respiratoria, SatO2>96% y buen control glucémico, comenzando la dieta oral a las 4h después de la cirugía. Fue dada de alta a planta 24h después de la intervención. Conclusión: El manejo exitoso de pacientes con SBW requiere un enfoque multimodal, con planificación preoperatoria completa y conocimiento sobre posibles complicaciones en relación tanto con las vías respiratorias como con las sistémicas.(AU)

Introduction: Postoperative management of patients with the congenital growth disorder Beckwith-Wiedemann syndrome (BWS) can be complicated. The main clinical manifestations of the syndrome are macroglossia — which may hamper airway management —, prematurity, hemihypertrophy, omphalocele, embryonal tumours and episodes of neonatal hypoglycaemia. Objective: Our main objective is to describe the perioperative management and potential anaesthetic complications in paediatric patients with BWS undergoing glossectomy. Methods: Case report and literature review. Results: We describe the case of an 11-month-old patient diagnosed with BWS who underwent reduction glossoplasty. We performed a comprehensive preoperative evaluation, taking into account potential anaesthetic complications derived from both macroglossia and prematurity, and the risk of hypoglycaemia. The procedure was performed under general anaesthesia. Intubation — performed according to difficult airway management algorithms — was uneventful and the patient was successfully extubated in the operating room. The patient remained stable during the postoperative period, with good respiratory dynamics, SatO2>96% and good glycaemic control. Oral intake was started 4hours after surgery, and she was discharged to the ward at 24hours. Conclusion: BWS patients require a multimodal approach that includes detailed preoperative planning and knowledge of potential airway-related and systemic complications.(AU)

Rare association of Beckwith-Wiedemann syndrome with Hirschsprung's disease in an infant with hypoglycemia.

Hypoglycaemic due to congenital hyperinsulinism in Beckwith-Wiedemann syndrome is commonly seen. It is usually transient and is managed by enteral feeds, high glucose-containing intravenous fluids and medications like diazoxide. We describe a case of an infant with genetically proven Beckwith-Wiedemann syndrome with prolonged hyperinsulinemic hypoglycaemia. Despite treatment with high glucose-containing intravenous fluids, diazoxide and octreotide, her hypoglycaemia persisted. In addition to this, she also developed features of intestinal obstruction, which further complicated the management of hypoglycaemia. She underwent a rectal biopsy for this, which was highly suggestive of Hirschprung's disease. Following surgery, her abdominal distension and feed intolerance were settled and sugar control was improved. We present a rare association of Hirschsprung's disease with Beckwith-Wiedemann syndrome. To the best of our knowledge, this association has not been previously reported and this added to the difficulty in managing hyperinsulinemic hypoglycaemia in our patient.

Oxidative Stress in Cancer-Prone Genetic Diseases in Pediatric Age: The Role of Mitochondrial Dysfunction.

Oxidative stress is a distinctive sign in several genetic disorders characterized by cancer predisposition, such as Ataxia-Telangiectasia, Fanconi Anemia, Down syndrome, progeroid syndromes, Beckwith-Wiedemann syndrome, and Costello syndrome. Recent literature unveiled new molecular mechanisms linking oxidative stress to the pathogenesis of these conditions, with particular regard to mitochondrial dysfunction. Since mitochondria are one of the major sites of ROS production as well as one of the major targets of their action, this dysfunction is thought to be the cause of the prooxidant status. Deeper insight of the pathogenesis of the syndromes raises the possibility to identify new possible therapeutic targets. In particular, the use of mitochondrial-targeted agents seems to be an appropriate clinical strategy in order to improve the quality of life and the life span of the patients.

Late Presentation of Fulminant Necrotizing Enterocolitis in a Child with Hyperinsulinism on Octreotide Therapy.

Congenital hyperinsulinism (HI) is the most common cause of persistent hypoglycemia in infants and children. In cases of diazoxide-unresponsive HI, alternative medical and surgical approaches may be required to reduce the risk of hypoglycemia. Octreotide, a somatostatin analog, often has a role in the management of these children, but a dose-dependent reduction in splanchnic blood flow is a recognized complication. Necrotizing enterocolitis (NEC) has been reported within the first few weeks of initiating predominantly high doses of octreotide. We describe the case of an infant with Beckwith-Wiedemann syndrome and diazoxide-unresponsive HI, who had persistent hypoglycemia after two pancreatectomy surgeries. She developed NEC 2 months after beginning octreotide therapy at a relatively low dose of 8 µg/kg/day. This complication has occurred later, and at a lower dose, than has previously been described. We review the case and identify the known and suspected multifactorial risk factors for NEC that may contribute to the development of this complication in patients with HI.

Severe Hyperinsulinaemic Hypoglycaemia in Beckwith-Wiedemann Syndrome due to Paternal Uniparental Disomy of 11p15.5 Managed with Sirolimus Therapy.

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.

Congenital hyperinsulinism in an infant with paternal uniparental disomy on chromosome 11p15: few clinical features suggestive of Beckwith-Wiedemann syndrome.

Beckwith-Wiedemann syndrome (BWS) is the most common congenital overgrowth syndrome involving tumor predisposition. BWS is caused by various epigenetic or genetic alterations that disrupt the imprinted genes on chromosome 11p15.5 and the clinical findings of BWS are highly variable. Hyperinsulinemic hypoglycemia is reported in about half of all babies with BWS. We identified an infant with diazoxide-unresponsive congenital hyperinsulinism (HI) without any apparent clinical features suggestive of BWS, but diagnosed BWS by molecular testing. The patient developed severe hyperinsulinemic hypoglycemia within a few hours after birth, with macrosomia and mild hydronephrosis. We excluded mutations in the K(ATP) channel genes on chromosome 11p15.1, but found a rare homozygous single nucleotide polymorphism (SNP) of ABCC8. Parental SNP pattern suggested paternal uniparetal disomy in this region. By microsatellite marker analysis on chromosome 11p15, we could diagnose BWS due to the mosaic of paternal uniparental disomy. Our case suggests that some HI of unknown genetic etiology could involve undiagnosed BWS with no apparent clinical features, which might be diagnosed only by molecular testing.

Beckwith-Wiedemann syndrome: potassium ascorbate with ribose therapy in a syndrome with high neoplastic risk.

BACKGROUND: Beckwith-Wiedemann Syndrome (BWS) is a genomic imprinting disorder characterized by overgrowth and increased risk of malignancy. We studied the oxidative stress (OS) pattern of our patients with BWS and administered, for the first time, potassium ascorbate with ribose (PAR) once a day as long-term therapy in order to correct the effects induced by free radicals. PATIENTS AND METHODS: We describe the clinical features of three patients examined every three months in our clinic. OS was ascertained by measuring a panel of OS biomarkers: non-protein-binding iron, total hydroperoxides, advanced oxidation protein products, isoprostanes, carbonyl groups and thiols. After the presence of OS was established, treatment with PAR was started at the dosage of 300 mg of Potassium Bicarbonate and 150 mg of Ascorbic Acid in aqueous solution and changes occurring in OS biomarkers were followed dosing every three months. RESULTS: Our patients showed higher levels of OS biomarkers than controls at the time of diagnosis. There was a reduction in OS biomarker values for all three patients with treatment. No primary or secondary neoplastic disease was observed in 9 months of follow-up. CONCLUSION: This is the first report showing OS occurring in BWS. No drug until this report has been published showing efficacy against OS in any cancer. Given the limited number of patients, care must be taken to mitigate enthusiasm. We are collecting data for a large number of BWS patients to confirm these preliminary results.

Silver-Russell syndrome and Beckwith-Wiedemann syndrome phenotypes associated with 11p duplication in a single family.

Genomic imprinting is an epigenetic phenomenon resulting in differential expression of maternal and paternal alleles of a subset of genes. In the mouse, mutation of imprinted genes often results in contrasting phenotypes, depending on parental origin. The overgrowth-associated Beckwith-Wiedemann syndrome (BWS) and the growth restriction-associated Silver-Russell syndrome (SRS) have been linked with a variety of epigenetic and genetic defects affecting a cluster of imprinted genes at chromosome 11p15.5. Paternally derived and maternally derived 11p15.5 duplications represent infrequent findings in BWS and SRS, respectively. Here, we report a case in which a 6.5 Mb duplication of 11p15.4-pter resulted in SRS and BWS phenotypes in a child and her mother, respectively. Molecular analyses demonstrated that the duplication involved the maternal chromosome 11p15 in the child and the paternal chromosome 11p15 in the mother. This observation provides a direct demonstration that SRS and BWS represent specular images, both at the clinical and molecular levels.

Early presentation of right adrenal mass, hepatoblastoma and hepatic cavernous haemangioma in Beckwith-Wiedemann Syndrome.

Beckwith-Wiedemann Syndrome (BWS) is associated with early development of embryonal tumours usually in the first four years of life. We describe a patient who presented with a right adrenal cyst in the first month of life and hepatoblastoma in the third month of life. A cavernous haemangioma was subsequently found in the resected tumour.

Acute lymphocytic leukemia in a child with Beckwith-Wiedemann syndrome.

Beckwith-Wiedemann syndrome (BWS) is an overgrowth syndrome characterized by neonatal hypoglycemia, abdominal wall defects, macroglossia, organomegaly, ear pits and creases, hemihypertrophy, and increased birthweight. Children with BWS have an increased risk of malignancy. The authors present the case of a 3-year-old boy diagnosed with both BWS and acute lymphocytic leukemia (ALL). This case report will elaborate on the possibilities as to how BWS and ALL may be associated due to abnormal genomic imprinting and IGF dysregulation.

The effects of a somatostatin analogue on the metabolism of an infant with Beckwith-Wiedemann syndrome and hyperinsulinaemic hypoglycaemia.

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.

[Tall stature and its correction in girls]. / Vysokoroslost' i ee korrektsiia u devochek.

The paper presents a classification of tall stature and clinical and hormonal findings in 35 girls in the age range of 11 to 18 years with constitutional tall stature. They showed a normal decline in growth hormone (GH) concentrations in the second phase of pubertal maturation. Concentrations of GH clearly correlated with the menstrual status. They were low in regularly menstruating girls, higher in non-menstruating girls and highest in tall girls with irregular menstrual cycles. Estrogen therapy in 7 girls decelerated growth rates and promoted epiphyseal ossification. Regular menstrual cycles established after withdrawal of therapy in all patients.

Virilizing adrenal adenoma in an adult with the Beckwith-Wiedemann syndrome: paradoxical response to dexamethasone.

An adult woman with Beckwith-Wiedemann syndrome, hemihypertrophy and an androgen-secreting adrenal adenoma is described. She presented with a 7-year history of progressive virilization and was found to have high plasma levels of testosterone and dehydroepiandrosterone (DHEA) sulphate and elevated levels of urinary metabolites of testosterone and its precursors. Administration of dexamethasone was associated with progressive rises in plasma 17 alpha OH progesterone, 11 beta-desoxycortisol, DHEA sulphate, androstenedione and testosterone, together with increased urinary excretion of androsterone, 11 beta OH androsterone, etiocholanolone, DHEA, and 16 alpha OH DHEA. Hormone levels fell to normal following removal of the tumour.