Beckwith-Wiedemann Syndrome (2024)

Continuing Education Activity

Beckwith-Wiedemann syndrome is the most common congenital syndrome associated with overgrowth and childhood cancer predisposition.Thisgenetic imprinting disorderhas various clinical manifestations. Early recognition of the condition is critical for monitoring and treating complications.

This activity is designed to enhance healthcare professionals' competence in evaluating and managing patients with Beckwith-Wiedemann syndrome. Thiscourse is designed to improve the learners' skills when working with an interprofessional team.

Objectives:

Identify features indicative of Beckwith-Wiedemann syndrome during prenatal or postnatal evaluations.
Screen high-risk individuals or newborns displaying signs of Beckwith-Wiedemann syndrome using appropriate genetic and clinical tests.
Assess patients with Beckwith-Wiedemann syndrome for potential complications, monitoring growth patterns and tumor risk.
Coordinate with the interprofessional team onlong-term care plans, interventions, and follow-ups for patients affected by Beckwith-Wiedemann syndrome, promoting optimal health outcomes.

Access free multiple choice questions on this topic.

Introduction

Beckwith-Wiedemann syndrome (BWS) is the most common congenital overgrowth syndrome. Specifically, the condition is a human imprinting disorder caused by genetic and epigenetic changes affectingmolecular regulation on chromosome 11p15.

The most notable BWS features are hemihypertrophy, macrosomia, macroglossia, and abdominal wall defects. Patients also have an increased risk of childhood cancers. However,BWSpresents various signs and symptoms,making the diagnosis challenging. Early recognition in the prenatal or neonatal periods is critical for monitoring and timely treatment of complications.[1][2]BWSis namedafter the American pediatric pathologist John Bruce Beckwith and the German pediatrician Hans-Rudolf Wiedemann, who independently described its manifestationsin 1963 and 1964, respectively.[3]

Etiology

The etiology of Beckwith-Wiedemann syndrome is complex. About 80 to 90% of patients have a known chromosome 11p15.5 anomaly affecting cell cycle progression and somatic growth control. The process starts with genetic imprinting, where only one gene copy is expressed, depending on the sex of the parent carrying the allele. Two imprinting control regions, IC1 and IC2, regulate gene expressioninchromosome 11p15.

Methylation, which silences gene expression, usually occurs in the paternal allele at IC1 and the maternal allele at IC2. In an individual with BWS, the molecular defects commonly described are the following:[4]

Loss of methylation at IC2 on the maternal allele in 50% to 60% of cases
Paternal uniparental isodisomy of chromosome 11p15 in 20% to 25% of cases
IC1 methylation on the maternal allele in 5 to 10% of cases
Autosomal dominant maternal point mutations in IC2-regulated CDKN1C in 5% of sporadic cases and 40% of familial cases
Chromosomal rearrangements, ie, duplications, translocations, deletions, or inversions, in fewer than 1% of cases
An unknown molecular defect in 10% to 15% of cases

The diversityof clinical presentations and the complexity of genetic and epigenetic BWS mechanisms make diagnosis challenging. Genetic testing and molecular analyses are often used to confirm the diagnosis and identify specific genetic abnormalities associated with the syndrome. However, the exact cause of BWS is unidentified in many cases.

Epidemiology

The incidence of BWS is estimatedto be1 in 10,000 to 13,700 live births, likely alow estimate due to the underdiagnosis of subtle phenotypes. The condition affects all ethnic groups and has a 1:1 sex ratio. A correlation exists between BWS and assisted reproductive techniques (ART), with ART increasing BWS risk tenfold.[5][6]

History and Physical

BWS is a complex multisystem disorderwith a varied clinical spectrum. History and physical findings differ byage and stage of life.

Prenatal period:Pregnancy complicationswhen fetuseshave BWS usuallybegin after 22 weeks of gestationand include gestational hypertension, preeclampsia, gestational diabetes mellitus, vagin*l bleeding, polyhydramnios, macrosomia, increased α-fetoprotein (AFP), and ultrasonographic findings of organomegaly. At delivery, neonatesmay present with prematurity, placentomegaly, or macrosomia-related complications, including cephalohematoma and brachial plexus injury. A positive family history helps diagnose BWS since approximately 15% of casesare attributed to familial transmission.

Neonatal period:Neonates with BWSmay have macrosomia, whole-body hemihyplasia, limb-length discrepancy, distinctive facial features, abdominal wall defects (omphalocele, umbilical hernia, or diastasis recti), organomegaly, (liver, kidneys, spleen, pancreas, thymus, heart, and adrenal glands),renal malformationsand hydronephrosis, cardiac anomalies (patent ductus arteriosus, patent foramen ovale, and congenital long QT syndrome), and hypotonia. Typical dysmorphic facies include macroglossia, prominent eyes, infraorbital creases, midfacial hypoplasia, prognathism, anterior earlobe creases, posterior helical pits, and nevus flammeusof the glabella. Cleft palate, supernumerary nipples, polydactyly, and cryptorchidism are less common. Neonatal BWSmay also present with hypoglycemia fromislet cell hyperplasia and hyperinsulinism.[7]

Infancy, childhood, and adolescence:Typical facial features are usuallyoutgrown in later childhood (see Image. Photos of Patients With BWS). Height and weightoften remainnearthe 90th percentile, while the head circumference grows closer to the mean. Development isgenerally unaffected unless a specificchromosome 11p15.5 duplication exists or a history of perinatal complications is present. Nephrocalcinosis, nephrolithiasis, renal cysts, and recurrent urinary tract infectionsmay developfrom infancy to adolescence. Predisposition to embryonal tumors is the most fearedoutcome of BWS,so long-term monitoring is recommended. The most common malignancies are Wilms tumor and hepatoblastoma,but neuroblastoma, adrenocortical carcinoma, and rhabdomyosarcoma can also occur. Tumor risk is about 5-10%, and the incidence is greatest in the first7 years of life.[8]

Adulthood:Adult height is usually in theaverage range, although some studies report an increased mean adult height in the BWS population. The limb-length discrepancy can persist or worsen,predisposing to scoliosis. Fertility issues have been reported in malesdue to primary testicular dysfunction or cryptorchidism. Data on the female populationare insufficient.[9]

Not all individuals with BWS have every characteristic feature, and the severity and combination of symptoms vary widely.

Evaluation

The diagnosis of BWS is based on clinical criteria and confirmed by molecular or cytogenetic testing. However, given the heterogeneous presentation of this disorder, no consensus exists. Most experts agree that these criteria should not replace clinical judgment. Negative diagnostic testingdoes not necessarily rule out a BWS clinical diagnosis.

Clinical Diagnosis

There are several published diagnostic criteria for BWS.[10][11][12][13][14][15]Recent reviews consider it acceptable tobase the clinical diagnosis on major and minor findings. Three major findings or2 major and1 or more minor findings support a diagnosis of BWS.

Major Findings

Abdominal wall defect, including omphalocele or umbilical hernia
Macroglossia
Neonatal macrosomia (birth weightgreater than 90th percentile)
Postnatal overgrowth (height/lengthgreater than 90th percentile)
Embryonal tumors(Wilms tumor, hepatoblastoma, adrenal tumors, neuroblastoma)
Outer ear malformations (anterior ear creases, posterior helical pits)
Visceromegaly
Cytomegaly of the adrenal fetal cortex
Hemihypertrophy
Anomalies of the kidney and ureter(eg, medullary dysplasia, nephrocalcinosis, medullary sponge kidney, and nephromegaly)
Positive family history of BWS
Cleft palate

Minor Findings

Treatment / Management

A qualified healthcare providershould coordinatespecialty care for each patient. Once a diagnosis of BWS is made or suspected, anticipatory medical management is required,including a comprehensive planof supportive medical and surgical care when necessary. Treatment should be individualized, given the high heterogenicity and variety of clinical features.[17][18]

Prenatal Management

Expect fetal or maternal complications in suspected or confirmed cases.Such complications include preeclampsia, congenital anomalies, macrosomia-related injuries, and postnatal hypoglycemia. Ideally, delivery shouldoccur in an institution with a neonatal intensive care unit (NICU).

Neonatal Hypoglycemia

Glucose monitoring should be performedduring the first 48 hours of life. Newborns with hypoglycemia should be treated according to standard guidelines. Fasting blood glucose, insulin, and ketone tests are recommended before nursery discharge if hypoglycemia is not detected after 48 hours. Severe persistent hyperinsulinism warrants further investigation.

Growth Anomalies

Growth should be regularly monitored, with growth charts modified for BWS patients. Interventions for possibleovergrowthmay be considered. Lateralized overgrowth should bemeasured at leastyearly.A leg-length discrepancywarrants apediatric orthopedic surgery referral.In contrast,arm-length asymmetry may simply be monitored.Thissymptom does not warrant surgical intervention unless it presents with severe functional limitations.

Macroglossia

Feeding problems require the involvement of infant feeding specialists and dietitians. For suspected airway obstruction, thorough evaluation includes sleep studies and pulmonary andotorhinolaryngology consultations. Tongue-reduction surgery is indicatedfor macroglossia-related complications, such as feeding difficulties, persistent drooling, speech difficulties, dental malocclusion, and appearance-related psychosocial problems. Surgery is usually performed after age1 or earlier in cases of severe airway obstruction.

Abdominal Wall Defects

There are no specific recommendations for individuals with BWS compared to others with these conditions. The management of abdominal wall defects in BWS is tailored to the individual's specific circ*mstances. Surgical interventionmay be considered based on the individual's overall health status, the size of the defect, and the presence of associated complications. Surgical repair is often delayed until the child is medically stable and strong enough to tolerate the procedure.

Cardiac Anomalies

A baseline clinical cardiovascular examinationshould be performedas soon as a BWS clinical diagnosis is made. The patient may be referredto a pediatric echocardiologist for suspected abnormalities. Annualfollow-upand electrocardiograms are recommended for patients with a known IC2 molecular aberration.

Renal Complications

Clinical and ultrasonographic evaluation for nephrological anomaliesshould be madeat diagnosis andduringthe transition to adult medical care. Nephrology and urology referrals are necessary if anomalies are detected. Nephrocalcinosis and renal stones should be monitoredconcurrently with abdominal surveillance for tumors.

Embryonal Tumors

BWS is a recognized cancer predisposition syndrome. The estimated tumor riskis 5% to 10% in the1st decade of life, with the highest incidence during the first2 years. Different tumor screening protocols have been proposed with the common goals of early detection, reduced morbidity, and increased survival.

The tumor surveillance protocol usedin the United States includes abdominal ultrasound and serumα-fetoprotein at diagnosis, then every3 months until age4 years. Ultrasound screening should continue every3 to4 months until age 7 or8 years. Abdominal ultrasound identifies the most commonly associated tumors, including Wilms tumor, hepatoblastoma, neuroblastoma, rhabdomyosarcoma, and adrenal carcinoma. Serum α-fetoproteinlevels are used for monitoring hepatoblastoma. However, this practice is controversial since infants with BWS often have higher α-fetoprotein levels, obscuring interpretation. Additionally, repeated blood collection by venipuncture can be traumatic to young patients.

Althoughsome molecular defects havea greater predispositionfor certain types of cancer, most institutions apply the same protocol to all BWS patients regardless of the molecular subtype. Studiessuggest that genetically guided stratified tumor screening may be useful for further management.

Neurological Manifestations

Cognitive development is usually normal. However,monitoring by a pediatrician is recommended, especially for patients with chromosomal anomalies or a history ofperinatal complications, eg, prematurity, birth trauma, and neonatal hypoglycemia.

Late-Onset Complications

A comprehensive evaluation at age 16to 18 years is recommended to detect any complications that require follow-up by adult healthcare services. Genetic counseling should be offered for family planning.Continuous education and guidance for both individuals with BWS and their families are essential.

Psychological and Counseling Aspects

Anindividualized care plan for BWS includes psychological services, specialist counseling, and family support.Promoting self-esteem and confidence is essential for individuals with this condition. Encouraging the patients' strengths, supporting their achievements, and emphasizing their value beyond their condition can help foster a positive self-image. Families shouldreceive contact information for BWS support groups at diagnosis.

Differential Diagnosis

Other overgrowth syndromes include the following:

Isolated hemihyperplasia
Sotos syndrome
Simpson-Golabi-Behmel syndrome
Costello syndrome
Perlman syndrome
Weaver syndrome
NF1-microdeletion syndrome
Proteus syndrome

The diagnosis is made after a comprehensive clinical assessment, including family history, physical findings,and confirmation withgeneticor molecular analysis when necessary. A particular consideration in the differential diagnosis of BWSis isolated hemihyperplasia sincethese conditions oftenshare similar epigenetic chromosome 11p15 alterations.Hemihypertrophyis a feature of both conditions.

The following disordersalso have symptoms similar to BWS:

Trisomy 8 mosaicism
Congenital hypothyroidism
Mucopolysaccharidoses, eg, Hurler, Hunter, and Maroteaux–Lamy syndromes
Gangliosidoses
Pompe disease

Neonatal macrosomia, macroglossia, and hypoglycemia should prompt a comprehensive evaluation for other diagnoses, such as maternal diabetes mellitus.Other causes of developmental delaymust be considered in children with developmental delaybut withoutchromosomal abnormalitiesor a history of prematurity, birth trauma, or neonatal hypoglycemia.[19]

Prognosis

The prognosis varies depending on the symptoms' severity, molecular subtype, timeof diagnosis, and occurrence of BWS-related tumors. Most patients with BWS have an average life expectancy. Adults with BWSmay have less pronounced growth or facial abnormalities.Early diagnosis, anticipatory guidance, tumor screening, and timely management of complications will contribute to healthy outcomes.

Complications

The following are some of the complicationsobserved in patients with BWS:

Perinatal: gestational hypertension, preeclampsia, gestational diabetes mellitus, vagin*l bleeding, polyhydramnios, prematurity, andmacrosomia-related complications, such as cephalohematomaand brachial plexus injury
Neonatal: prematurity, macroglossia-related breathing and feeding difficulties, hypoglycemia, and, rarely, cardiomyopathy
Childhood to adulthood: macroglossia-related speech or feeding difficulties, genetic or perinatally acquired cognitive impairment, embryonal tumorslike Wilms tumor and hepatoblastoma, nephrocalcinosis, nephrolithiasis, renal cysts, recurrent urinary tract infections, scoliosis from leg-length discrepancy, male infertility, andcoping issues

Early detection, appropriate surveillance, and timely intervention are crucial in managing complications and improving outcomes for individuals with BWS.

Deterrence and Patient Education

Preventing complications associated with BWS primarilyentails early detection, regular monitoring, and proactive management. While it's not always possible to prevent complications,the following measures can help minimize risks and optimize the care of individuals with BWS:

Regular medical follow-ups and monitoring
Tumor surveillance and screening
Hypoglycemia management
Early intervention for macroglossia
Orthopedic and musculoskeletal assessments
Psychological support

Patients and their families should be offered counseling, education, support, and guidance as soon as a diagnosis of BWS is suspected. Clinicianscanshare contact information forBWS support groups andresources,such as the National Organization for Rare Disorders (NORD) and the Beckwith-Wiedemann Children’s Foundation International, as part of the holistic approach to managing patients.

Pearls and Other Issues

The following are the most important points to remember in BWS management:

BWS is a heterogeneous syndrome affecting multiple organ systems. Classic features may or may not benoted at birth.
The etiology of BWS is complex. Most cases arise from sporadic molecular alterations on chromosome 11p15.
The index of suspicion should be high when evaluatingpatients with possible BWS. Genetic testingmust be performed to confirm the diagnosis.
Anticipatory guidanceabout BWS complications, particularly tumors,iscrucial incaring foraffected patients, given the high risk of developing malignancies early in life.
Prompt diagnosis and a holistic, multidisciplinary management approachresult in betteroutcomes.

Each person with BWS is unique, and their care plan should be individualized based on their specific needs, health status, and any associated complications they may experience.

Enhancing Healthcare Team Outcomes

Interprofessional teammanagement helps enhance outcomes for patients with BWS. The following are the members of the interprofessional team:[16]

Primary care physician or pediatrician works closely with patients and their families to coordinate care, consults,and appropriate follow-up.Comprehensive periodic evaluations and a smooth transition to adult healthcare services for teens are tasks the primary care providercan arrange.
The pediatric or medical geneticist has expertise in diagnosing and managing BWS. This provider also oversees the overall management plan.
A radiologist interprets imaging tests and helps in diagnosis and treatment planning.
Nursing staff identifies infant feeding difficulties, administers medications to hospitalized patients, helps coordinate care, and reinforces patient education.
An otorhinolaryngologist manages cleft palate and macroglossia-related airway issues.
The pediatric surgeon treats abdominal wall defects surgicallywhen warranted.
An oncologist specializes in tumor surveillance and management. These cliniciansplay a critical role indetectingandmanaging tumors associated with BWS.
An endocrinologist monitors and manages hormonal issues, such as hypoglycemia, that may arise in individuals with BWS.
Orthopedic specialists assess and manage musculoskeletal problems, such as limb asymmetry and other overgrowth-related orthopedic complicationsin patients with BWS.
A genetic counselor provides information, guidance, and support to affected individuals and families regardingBWS' genetic basisand inheritance patterns. This provider alsoemphasizes the importance of genetic testing.
A speech and language therapist helps address macroglossia-related speech and communication difficulties.
A physical therapist assists in managing musculoskeletal issues and developing strategies to enhance mobility and function.
Dietitians and feeding specialists helpmanage specific macroglossia-related feeding problems.

A mental health professional (psychologist or psychiatrist) offers psychological support to help patients with BWS cope withemotional stressors.

A social worker or care coordinator assists with coordinating appointments, accessing resources, and supporting families navigating healthcare systems.

Collaboration and communication among theseprofessionals are essential to developing and implementing a comprehensive, personalized care plan for patients with BWS.

Review Questions

Figure

Patients With BWS. Photos of 6 patients with Beckwith-Wiedemann syndrome due to (A) IC2 loss of methylation (IC2 LOM), (B) IC1 gain of methylation (IC1 GOM), (C) chromosomal rearrangements (deletions, duplications), (D) paternal uniparental isodisomy (more...)

References

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: Disclosure: Paulo Borjas Mendoza declares no relevant financial relationships with ineligible companies.
: Disclosure: Sharon Daley declares no relevant financial relationships with ineligible companies.
: Disclosure: Magda Mendez declares no relevant financial relationships with ineligible companies.