Centro Médico Profesional Rosancar. Barquisimeto, Estado Lara, Venezuela.

Case Report

A 35-year-old patient was sent to our unit at 33 weeks of pregnancy due to polyhydramnios. During our ultrasound examination we discovered following findings:

• Protruding fetal tongue (Images 1 and 2);

• Postaxial polydactyly (Image 3);

• Abnormal ear shape (Image 4);

• Nephromegaly (Image 5);

• Fetal macrosomia - abdominal circumference over 95th percentile (Image 6);

• Tricuspid regurgitation (Image 7);

• Polyhydramnios.

An amniodrainage was performed because of the polyhydramnios. Fetal lung maturation was supported by the usage of Betamethasone.  At 38 weeks of pregnancy a cesarean was performed because of fetal macrosomia. A female newborn weighing 5070 grams (Figure 8 and 9) was delivered and 6 hours later the baby developed seizures because a severe hypoglycemia and was taken to the intensive care unit. The further postnatal course was favorable and the baby was discharged 10 days later. The final diagnosis was Beckwith – Wiedemann Syndrome.

Image 1 and 2: Fetal profile with protruding tongue/

Image 3 and 4: Image 3 - postaxial polydactyly of the right hand; image 4 - abnormal ear shape of the fetus.

Image 5 and 6: Image 5 - nephromegaly; image 6 - transverse plane through the abdomen with abdominal perimeter above 95th percentile.

Image 7 and 8: Postnatal appearance of the baby (with polydactyly of the right hand, and detailed photo of the ear).

Discussion

Beckwith-Wiedemann syndrome is a disorder of growth characterized by macrosomia, macroglossia, visceromegaly, embryonal tumors (e.g., Wilms tumor, hepatoblastoma, neuroblastoma, rhabdomyosarcoma), omphalocele, neonatal hypoglycemia, ear creases/pits, adrenocortical cytomegaly, and renal abnormalities (e.g., medullary dysplasia, nephrocalcinosis, medullary sponge kidney, and nephromegaly). Infants with BWS have approximately 20% mortality rate, mainly caused by complications of prematurity. Macroglossia and macrosomia are generally present at birth but may have postnatal onset. Growth rate slows around seven to eight years of age. Hemihyperplasia may affect segmental regions of the body or selected organs and tissues

Clinical diagnosis

No consensual diagnostic criteria for Beckwith-Wiedemann syndrome exist, although it is generally accepted that a diagnosis requires the presence of at least three findings (two major and one minor).

Major findings associated with Beckwith-Wiedemann syndrome are following:

• Positive family history (one or more family members with a clinical diagnosis of Beckwith-Wiedemann syndrome  or a history or features suggestive of Beckwith-Wiedemann syndrome);

• Macrosomia (traditionally defined as height and weight >97th centile);

• Anterior linear ear lobe creases/posterior helical ear pits;

• Macroglossia;

• Omphalocele (also called exomphalos)/umbilical hernia;

• Visceromegaly involving one or more intra-abdominal organs including liver, spleen, kidneys, adrenal glands, and pancreas;

• Embryonal tumor (e. g. Wilms tumor, hepatoblastoma, neuroblastoma, rhabdomyosarcoma) in childhood;

• Hemihyperplasia (asymmetric overgrowth of one or more regions of the body);

• Adrenocortical cytomegaly;

• Renal abnormalities including structural abnormalities, nephromegaly, and nephrocalcinosis;

• Cleft palate (rare).

Minor findings associated with Beckwith-Wiedemann syndrome are:

• Polyhydramnios;

• Prematurity;

• Neonatal hypoglycemia;

• Facial nevus flammeus;

• Hemangioma.

Prenatal and perinatal features

Beckwith-Wiedemann syndrome is associated with perhaps as high as 50% incidence of polyhydramnios, premature birth, and fetal macrosomia [EIliot et al 1994]. Other common features include a long umbilical cord and an enlarged placenta, averaging almost twice the normal weight for gestational age [Weng, Moeschler et al 1995]. Infants with BWS have an approximately 20% mortality rate, mainly as a result of complications of prematurity associated with omphalocele, macroglossia, neonatal hypoglycemia, and, rarely, cardiomyopathy [Pettenati et al 1986].

Growth

Macroglossia and macrosomia are general/y present at birth, though postnatal onset of both features has also been observed [Chitayat, Rothchild et al 1990; Weksberg, personal observation]. Although most individuals with Beckwith-Wiedemann syndrome show rapid growth in early childhood, height typically remains at the upper range of normal. Growth rate usually appears to slow around seven to eight years of age. Hemihyperplasia, if present, can generally be noticed at birth, but may become more or less evident as the child grows. Hemihyperplasia may affect segmental regions of the body or selected organs and tissues. When several segments are involved, hemihyperplasia may be limited to one side of the body (ipsilateral) or involve opposite sides of the body (contralateral) [Viljoen et al 1984 , Hoyme et al 1998].

Metabolic abnormalities

Neonatal hypoglycemia is well documented [Engstrom et al 1988]; if undetected or untreated, it poses a significant risk for developmental sequelae. Most cases of hypoglycemia are mild and transient [EIliott & Maher 1994]; however, in more severe cases hypoglycemia can persist. Other less common endocrine/metabolic/hematologic findings include hypothyroidism, hyperlipidemia, hypercholesterolemia, and polycythemia. Hypercalciuria can be found in children with BWS even in the absence of renal abnormalities as detected on ultrasound examination (22% in Beckwith-Wiedemann syndrome as compared to 7-10% in the general population). [Goldman et al 2003] This may reflect an underlying primary structural abnormality in the kidneys

Structural anomalies

Anterior abdominal wall defects, including omphalocele [Weng, Moeschler et al 1995; Pettenati et al 1986], umbilical hernia, and diastasis recti, are common. Much of the information regarding cardiovascular problems in Beckwith-Wiedemann syndrome is anecdotal. Cardiomegaly is sometimes detected in infancy but typically resolves without treatment [Elliot & Maher 1994, Pettenati et al 1986]. Cardiomyopathy has been reported. Renal anomalies can include medullary dysplasia, duplicated collecting system, nephrocalcinosis, medullary sponge kidney, cystic changes, and nephromegaly [Choyke et al 1998 , Borer et al 1999].

Neoplasia

Children with Beckwith-Wiedemann syndrome have an increased risk of mortality associated with neoplasia, particularly Wilms tumor and hepatoblastoma, but also neuroblastoma, adrenocortical carcinoma, and rhabdomyosarcoma. Also seen are a wide variety of other tumors, both malignant and benign [Sotelo-Avila et al 1980 , Wiedemann 1983]. The estimated risk for tumor development in children with Beckwith-Wiedemann syndrome is 7.5%. This increased risk for neoplasia seems to be concentrated in the first eight years of life.

Development

Development is usually normal in children with Beckwith-Wiedemann syndrome unless there is a chromosome abnormality [Waziri et al 1983 , Slavotinek et al 1997] or a history of hypoxia or significant, untreated hypoglycemia.

Adulthood

After childhood, complications for individuals with Beckwith-Wiedemann syndrome are infrequent and prognosis is favorable.

Prevalence

The reported incidence of approximately one in 13,700 [Thorburn et al 1970] is probably an underestimate given the existence of milder, undiagnosed cases. BWS has been reported in a wide variety of ethnic populations with an equal incidence in males and females [Pettenati et al 1986].

Testing

Cytogenetic testing

Chromosome analysis at a band level of at least 550 in 20 metaphases reveals a cytogenetically detectable translocation or inversion of a maternal chromosome 11 or a cytogenetically detectable duplication of a paternal chromosome 11 involving band 11p15 in 1 % or fewer of individuals with BWS [Slavotinek et al 1997 , Li et al 1998].

Molecular genetic testing

FISH

FISH studies can be used to clarify the position of the chromosome 11 translocation or inversion and to confirm duplications of chromosome 11. Only 12% of individuals with Beckwith-Wiedemann syndrome have chromosomal abnormalities detectable by FISH.

Uniparental disomy studies

Approximately 10-20% of individuals fulfilling diagnostic criteria for BWS have paternal uniparental disomy for the Beckwith-Wiedemann syndrome critical region. Most demonstrate segmental paternal uniparental disomy for 11p15, suggesting that the underlying mechanism is a post-zygotic somatic recombination event resulting in mosaicsm. Therefore, uniparental disomy may not be detected because of a low level of mosaicsm in the tissue sampled. Testing of other tissues (e. g. skin fibroblasts, tumor biopsy) should be considered.

Methylation studies

• KCNQ10Tl methylation (DMR2). Up to 60% of individuals fulfilling diagnostic criteria for Beckwith-Wiedemann syndrome have detectable KCNQ10Tl methylatiol1 abnormalities.
• H19 methylation (DMR1). Between 2% and 7% of individuals fulfilling diagnostic criteria for Beckwith-Wiedemann syndrome have gain of methylation at H19. Note: (1) Individuals with UPD can be distinguished from individuals with abnormal methylation of either KCNQ10T1 or H19 because those with UPD have methylation abnormalities at both KCNQ10T1 and H19. (2) Interpretation of methylation data should take into account results of karyotype analysis because karyotypic abnormalities are associated with abnormal methylation status.
• Heritable microdeletion. Although most methylation defects at DMR1 and DMR2 are sporadic, a few families have been reported with microdeletion of DMR1 (Sparago et al 2004 , Prawitt et al 2005 ; three pedigrees) and of DMR2 (Niemetz et al 2004 ; one pedigree).

Mutation scanning

The majority of COKNl C mutations found in Beckwith-Wiedemann syndrome are located in exons 1 and 2 [Hatada et al 1996 , Hatada et al 1997 , Lee et al 1997 , O"Keefe et al 1997 , Lam et al 1999 , Algar et al 2000 , Li et al 2001]. Clinical testing for exon 1 and 2 mutations is available; testing for mutations in other exons and rare intronic splitting mutations [Lew et al 2004] may be done on a research basis.

Differential Diagnosis

Overgrowth

The following disorders should be included in the differential diagnosis:

• Simpson-Golabi-Behmel syndrome is an X-linked recessive condition that shares many features with Beckwith-Wiedemann syndrome (e.g., macrosomia, visceromegaly, macroglossia, and renal anomalies). It is distinguished by the presence of distinctive facial features, cleft lip, and skeletal abnormalities, including polydactyly. Developmental delay may be present. Although cases with tumors have been reported, the tumor risk and range of tumors remain to be defined. In 30% of individuals with Simpson-Golabi-Behmel syndrome, deletions of the glypican-3 (GPC3) gene are detected. This gene encodes an extracellular proteoglycan believed to function in the regulation of growth during development [Weksberg et al 1996 , Neri et al 1998].
• Perlman syndrome is a rare autosomal recessive condition with macrosomia and a high incidence of Wilms tumor. Facial features are distinctive; neonatal mortality is high and significant intellectual handicap is common. Perlman syndrome is thought to be genetically distinct from Beckwith-Wiedemann syndrome, though the gene causing Perlman syndrome has not yet been identified [Greenberg et al 1986 , Grundy et al 1992].
• Costello syndrome can be similar to Beckwith-Wiedemann syndrome in the neonatal period, when affected individuals present with macrosomia, coarse facial features, and cardiac defects. Over time, however, individuals with Costello syndrome exhibit failure to thrive, developmental delay, and other distinctive features including coarsening of the facial features [Van Eeghen et al 1999].
• Sotos syndrome is an autosomal dominant disorder characterized by a typical facial appearance, intellectual impairment, and overgrowth involving both height and head circumference. About 80-90% of individuals with Sotos syndrome have a demonstrable mutation or deletion of NSD1. Because of some clinical overlap between Sotos syndrome and Beckwith-Wiedemann syndrome, consideration should be given to testing NSDl in individuals with Beckwith-Wiedemann syndrome who do not have a 11p15 alteration and testing for chromosome 11p15 alterations in individuals with Sotos syndrome with no identified NSDl mutation [Baujat etaI2004].

Hemihyperplasia

Hemihyperplasia can occur as an isolated finding or may be associated with other syndromes such as Proteus syndrome, Klippel-Trenauny-Weber syndrome (KTW), and neurofibromatosis type 1 [Hoyme et al 1998]. Of note, a subgroup of individuals with apparently isolated hemihyperplasia may have Beckwith-Wiedemann syndrome with minimal clinical findings. Asymmetries, such as of the face or chest, should be evaluated carefully to exclude plagiocephaly and chest wall deformities. Children with isolated hemihyperplasia carry an increased tumor risk of 5.9% [Hoyme et al 1998] and should be offered tumor surveillance.

Postnatal management

• Adjustment of airway sufficiency in the presence of macroglossia;
• Assessment of feeding possibilities by a feeding specialist if macroglossia causes significant feeding difficulties;
• Adjustment of neonatal hypoglycemia; evaluation by a pediatric endocrinologist if hypoglycemia persists beyond the first few days;
• Abdominal ultrasound examination to assess of organomegaly, structural abnormality, and tumors; a baseline MRI or CT examination of the abdomen to screen for tumors [Clericuzio et al 1993, Beckwith 1998];
• A comprehensive cardiac evaluation including ECG and echocardiogram prior to any surgical procedures or when a cardiac abnormality is suspected on clinical evaluation

Treatment

• Prompt treatment of hypoglycemia by standard methods to reduce the risk of central nervous system complications. Because onset of hypoglycemia is occasionally delayed for several months, parents should be informed of the symptoms of hypoglycemia so that they can seek appropriate medical attention;
• Abdominal wall repair soon after birth in neonates with Beckwith-Wiedemann syndrome and omphalocele. Generally, this surgery is well tolerated [Elliott & Maher 1994];
• Anticipation of difficulties with endotracheal intubation that may result from macroglossia [Weng, Mortier et al 1995];
• Management of feeding difficulties secondary to macroglossia by use of specialized nipples such as the longer nipple used for babies with cleft palate or, rarely, short term use of nasogastric tube feedings;
• Follow-up of children with enlarged tongues by a craniofacial team including plastic surgeons, orthodontists, and speech pathologists familiar with the natural history of Beckwith-Wiedemann syndrome. Although tongue growth slows over time and jaw growth accelerates to accommodate the enlarged tongue, some children may benefit from tongue reduction surgery, typically performed between two and four years of age;
• Assessment of macroglossia-related speech difficulties by a speech pathologist, preferably one familiar with Beckwith-Wiedemann syndrome and its natural history;
• Consultation with an orthopedic surgeon if hemihyperplasia includes a significant difference in leg length.
• Referral to a craniofacial surgeon if facial hemihyperplasia is significant ;
• Treatment of neoplasias following standard pediatric oncology protocols;
• Standard interventions such as infant stimulation programs, occupational and physical therapy, and individualized education programs for children with developmental delay
• Referral of children with structural renal abnormalities or gastrointestinal tract abnormalities to the relevant specialists.

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