CLINICOPATHOLOGICAL CASE REPORT Beckwith-Wiedemann Syndrome

Verónica Fabiola Morán-Barroso,1 Constanza García-Delgado,1 Mónica Villa-Guillen,2 Eduardo Bracho- Blanchet,3 and Mario Perezpeña-Diazconti4

Departamentos de Genética Médica,1 Neonatología,2 Cirugía3 y Patología,4 Hospital Infantil de México Federico Gómez, México, D.F., México

Clinical History Summary A-2007-22 We report the case of a 3-day-old infant male who was The patient was diagnosed with an abdominal wall seen because of midline abdominal wall defect. The birth defect. Physical examination revealed an active family history included a healthy 25-year-old mother and reactive but dehydrated newborn. Chest presented and a healthy 27-year-old unemployed father. There intercostal tension with dissociation of chest/abdomen. were three healthy sisters and a 4-year-old cousin Lung sounds were normal. Examination revealed with intestinal atresia that was treated surgically. systolic ejection heart murmur. Midline abdominal wall Nonpathological history included information that defect was observed with a 12 x 6-cm omphalocele. The the family members were natives and residents of membrane was complete and visceral contents were the Mexican state of Guerrero. The family belonged contained inside. Diluted isodine and sterile gauzes to a low socioeconomic status. The child had no were applied to the membrane. nourishment since birth. Perinatal history included that he was the fourth child of a mother who had Evolution irregular prenatal care without vitamins or folic acid. Echocardiogram revealed a small conductus arteriosus A midwife-assisted delivery was carried out at home and patent foramen ovale. The patient entered the during the 38th gestation week. The infant’s height and operating room with phase II assisted breathing because weight at birth were unknown, and there was no Apgar of breathing difficulty and low oxygen saturation:

evaluation. The patient was referred to a second-level 40% FiO2, 17 maximum inspiratory pressure (MIP), 4 care hospital weighing 3250 g. He was managed with positive end-expiratory pressure (PEEP), 1:4 inspiration: fasting, intravenous solutions, antibiotics (ampicillin, expiration ratio, and respiratory rate 40/min. Renal amikacin), and open nasogastric tube and was then ultrasound revealed bilateral hydronephrosis. referred to the Hospital Infantil de Mexico “Federico Gomez” (HIMFG). Laboratory tests showed the following results: 19.7 g/ dL hemoglobin, 58% hematocrit, 4453/mm3 leukocytes, 4% segmental, 25% lymphocytes, 7% bands, 20% monocytes, 165,000/mm3 platelets, 103 fl mean corpuscular volume (MCV), 35 pg mean corpuscular Correspondence to: Mario Perezpeña-Diazconti hemoglobin (MCH), 13 mg/dL urea, 0.5 mg/dL Departamento de Patología creatinine, 133 mEq/L Na, 4.6 mEq/L K, 103 mEq/L Hospital Infantil de México Federico Gómez México, D.F., México Cl, 7.9 mg/dL Ca, 5.2 mg/dL P, 18.7 mg/dL C-reactive E-mail: [email protected] protein (CRP); 7.31 pH, 80.5 PaO2, 42.8 PaCO2, 17.8 Received for publication: 2-10-2009 CO T, 21.3 HCO , -3.8 BE, 96.7% SaO , 1.1 lactate. Accepted for publication: 2-17-2009 2 3 2 46 Bol Med Hosp Infant Mex The patient presented tachycardia, cutis marmorata, and of presenting non-syndrome omphalocele in 60% of hydric overload with systolic arterial pressure between 67 patients in a study including 72 cases of omphalocele and 91 mmHg, along with lower limb edema. The patient and 3029 control subjects in the metropolitan Atlanta, was administered furosemide. Peritoneal fluid and fetid Georgia area between 1968 and 1980. In this clinical green secretions were observed during omphalocele case, abdominal wall defect was diagnosed during the surgery, observing delay in capillary filling, yellowish sixth month of pregnancy using ultrasound. This is the secretions from tracheal tube and bleeding. Crepitant gold standard for prenatal diagnosis; however, detection rales were heard during auscultation and two doses of rate ranges between 60 and 90% and is dependent on dobutamine were administered without response. Chest the equipment and on the operator. It is important to x-ray showed right basal infiltration. Tracheal aspirate emphasize that diagnosis can be confirmed only after culture contained Pseudomonas aeruginosa. The patient gestation weeks 12-13; prior to that time, intestinal presented ventricular extrasystole, bradycardia and herniation is considered physiological (physiological cardiopulmonary arrest. The patient did not respond to herniation is <7 mm diameter and should not be apparent resuscitation maneuvers. in fetuses with crown-rump length >44 cm).

Discussion Ultrasound is useful in order to detect associated Dr. Monica Villa Guillen (Neonatal Intensive Care anomalies, which can be more than one and occur Unit) in >70% of cases. Chromosomal abnormalities are The patient presented omphalocele, which is present in 40-60% of cases; for instance, trisomy 8, 13 multifactorial in most cases with a 1% relapse rate. and 21, Turner’s syndrome, Klinefelter’s syndrome and However, as an isolated defect it is frequently associated triploidy. Ideally, amniocentesis should be carried out with a hereditary pattern that may be autosomal in each patient where omphalocele is found. dominant, recessive or X-linked where relapse rates are higher. It is interesting that there was another case of Other alterations include cardiac (16-47%), genitourinary digestive tube malformation within the same family. (40%), musculoskeletal (10-30%) and neurological or associated syndromes such as Beckwith-Wiedemann The patient was the fourth child whose mother had (5-10%), omphalocele, macroglossia, visceromegalies irregular prenatal control (the mother visited the and hypoglycemia. doctor only three times) without vitamins or folic acid administration. The Official Mexican Norm established These cases should be referred to and managed at a in 2003 a daily dosage of 400-µg folic acid to be tertiary care hospital from birth; however, this patient administered to women 3 months prior to conception was born at home through vaginal delivery despite and up to 12 weeks after conception in order to prevent prenatal diagnosis. In general, there is insufficient congenital defects. At the present time, tortilla (a basic evidence to support Caesarean delivery. However, it is component of the Mexican diet) fortification with folic recommended in cases of giant omphaloceles (as in this acid is in progress as part of the National Disability case) where such a large defect can complicate delivery Prevention Network program. The relationship and cause perinatal asphyxia. There are no data in the between folic acid deficiency and neural tube defects patient’s clinical history to support these theories; other such as myelomeningocele and anencephaly is clear. adverse events were three transfers within 48 h (from Still unclear is its association with cleft lip and palate, local hospital to general hospital in Chilpancingo, cardiopathies and urinary tract defects. Mills et al.1 in a Guerrero and finally to Hospital Infantil Mexico study including 25 cases of omphalocele and 59 control Federico Gomez in Mexico City). We know that the subjects without congenital defects found that a single patient was managed with fasting and antibiotics but nucleotide polymorphism from methyltetrahydrofolate management of the abdominal defect was not specified. reductase, which contains a change from cytokine to This is important because even though omphalocele thymine at position 667, increased the risk by three times was not 100% exposed (because of a protective sac), to present omphalocele. This variant reduces enzymatic it was important to cover it. There are special sterile activity, which suggests a mechanism where folic acid bags used in gastroschisis and omphalocele that reduce may prevent this problem. Botto et al.2 reported that the imperceptible losses, which are very frequent in these use of multivitamins during pregnancy reduced the risk cases. On the other hand, these bags prevent infections 47 Vol. 67, September-October 2009 and allow continuous monitoring of the defect. Another On the day of the patient’s death it was reported as 0.6 option is to protect the defect with humid sterile gauze; g, although we do not have values from previous days. however, this leaves residuals, absorbs liquid and may Monocytosis should be highlighted, which the patient lesion the defect. presented throughout his hospital stay. It is important to remember its causes and even if it can be explained When the patient arrived at our hospital, diagnosis of by abdominal inflammation, we should consider giant omphalocele was corroborated (diameter >5 cm). other entities such as syphilis (VDRL was not carried This defect was 12 cm in diameter with complete sac out), Listeria monocytogenes infection, respiratory and viscera inside without specifying which organs; infections from atypical microorganisms (Chlamydia, however, these large defects usually contain the Mycoplasma), etc; and chronic infectious and intestines, liver and other organs. inflammatory processes in general.

The patient presented breathing difficulty and, upon Echocardiogram revealed the presence of ductus exploration, heart murmur, tachycardia and isonatremic arteriosus. Electrocardiogram was normal except dehydration were noted. Breathing difficulty may have for QTc, which was elongated at 0.36 when it should had an infectious origin with or secondary to pulmonary not be >0.24. This finding is probably explained by hypoplasia. These abnormalities have been associated hypocalcemia. with abdominal wall defect with a poor prognosis. Chest x-ray was reported as normal and we ruled out Transfontanellar ultrasound revealed collapsed pneumonia and hypoplasia at that time. Hemoglobin (18 ventricles, which are usually found in patients with g/dL) was normal on the second day of life; however, brain edema. In this case, it may have been associated it was at the upper limits. This may be explained by with perinatal asphyxia or hypoalbuminemia. Renal dehydration. The patient had a low leukocyte level ultrasound revealed normal morphology and dimensions for his age (minimum 9000/mm3), 50% bandemia, I/T with bilateral hydronephrosis. Genitourinary ratio 0.7, monocytosis, platelets within normal lower anomalies associated with omphalocele include limits, hypocalcemia and hyperbilirubinemia. Blood obstruction of ureteropelvic junction, which may gas analysis showed mild metabolic acidosis with have caused hydronephrosis or possibly an increase hyperlactatemia. The patient also presented infection in intra-abdominal pressure, compressing kidneys and data that may have been nosocomial or acquired before obstructing urinary flow. arriving at the hospital. The patient probably should have received a different antibiotic schema to improve The patient’s condition was severe on the third day of life. platelet count as an important part of sepsis control in He required intubation during the first hospitalization newborns. day because of breathing difficulty and respiratory acidosis. Complete blood count revealed leukocytes Dehydration was assumed as 10% and isonatremic from <5000/mm3 and PCR = 18.7. The literature contains management with solutions (1:1) with a solute deficit >160 references of PCR in newborns, but only two calculation of 28 mOsm/kg where sodium deficit was studies were randomized and controlled. Despite the >50%. Dehydration was mild without weight loss. One abundant literature, a standardized practice for the use of the lower limbs presented edema. There was mild of PCR for evaluation of neonatal sepsis has not been acidosis and slightly altered urea (16, which should be established. PCR may increase in several noninfectious 13 during the first week of life) and could have been clinical situations. Ishibachi et al. found that between managed with solutions at 150 mL/kg (2:1) with sodium 24 and 48 h after vaginal childbirth, PCR levels can be contribution 7 mEq/L (basal requirements = 80 mL/kg >10 mg/L. Because PCR is a reactant or a nonspecific plus 50% for imperceptible losses, 10 mL/kg = 90 mL/ acute phase molecule, inflammatory and tissue damage kg + 50 mL/kg because of dehydration). can increase it, as in the case of our patient. Benitz et al.,3 in a retrospective study (Stanford University, Hypoalbuminemia (1.5 g) was noticeable, which is California) reported that serial PCR measurements had frequent in these patients and should be followed-up a negative predictive value of 99% for sepsis. Two PCR because lower values indicate albumin administration concentrations <10 mg/dL obtained each 24 h, 8-48 h in order to avoid fluid escape to third space at all levels. after clinical profile presentation, indicated sepsis was 48 Bol Med Hosp Infant Mex not very probable. >103 colony-forming units (CFU/mL) if obtained by Unfortunately, there is not a unique and definitive bronchoscope, either from bronchoalveolar wash or neonatal marker for sepsis; therefore, an evaluation of through brushing. Samples can also be obtained without all elements available should be carried out to establish using a bronchoscope. Also, ≥5% of cells should contain a diagnosis. The patient did not have a favorable intracellular bacteria when examined directly under evolution, from either clinical data or from laboratory microscope (gram stain). Pseudomonas should not be test results. Two days after hospitalization, respiratory ruled out as the infectious agent, but clearly tracheal acidosis persisted with leukopenia and reduced platelet or bronchial aspirates are not appropriate diagnostic count. The next day the patient presented tachycardia methods. with cutis marmorata and was administered cefotaxime. On the fourth day the patient required an increase of The patient required amines due to 30,000/mm3 assisted ventilation, and dicloxacillin was administered platelets, 30% bands, hyperlactatemia and coagulation (because of a suspected pneumonia). On the fifth day problems. Finally, he presented ventricular extrasystole, the patient presented peritonitis and shock, receiving bradycardia and did not respond to resuscitation carbapenem. Possibly from the first day, the patient maneuvers. Final clinical diagnoses are included in needed a more aggressive antimicrobial management Table 1. because the infection was not controlled. There is the possibility also of the addition of a nosocomial disease. Dr. Santos It is possible that an untimely detected peritonitis and The initial antibiotic schema was not appropriate. deficient antibiotic coverage determined the patient’s Presence of monocytes is suggestive, but not diagnostic, death. of L. monocytogenes; however, ampicillin was not considered at any time, which was appropriate under Nosocomial infections are a serious problem in neonatal those circumstances. On the day before the patient’s intensive care units. The use of catheters, parenteral death, he was administered imipenem. Monocyte levels feeding, ventilators and broad-spectrum antibiotics remained very high, and L. monocytogenes treatment has created an appropriate environment for bacterial should have been completed. contamination, and newborns are especially vulnerable. From 2002 to 2006, the nosocomial infection rate was Dr. Bracho 49/100 discharges from the Neonatal Intensive Care From previous comments on antibiotic schemas, it Unit (NICU) (one out of every two patients presented a is appropriate to listen to the comments of Dr. Rene nosocomial infection). If we take into consideration the Farfan (Department of Infectology). epidemiology of our hospital, resistance patterns and hosts, we should consider gram-negative bacteria that Dr. Farfan represent 70% of nosocomial infections during surgery When initiating an empiric therapeutic schema, (chiefly Klebsiella and Pseudomonas). Gram-positive risk factors for every patient should be considered. bacteria represent 20% of infections (coagulase- Although ampicillin/amikacin is a first-line treatment negative 96% methicillin-resistant Staphylococcus) schema for neonatal sepsis, other risk factors should be and the remaining Candida albicans. A seriously ill considered such as omphalocele, unexpected childbirth, host with abdominal wall defect requires an imipenem/ premature rupture of membranes and transfer between vancomycin schema to cover even anaerobic bacteria hospitals. Monocytosis plays an important role. A more associated with peritoneal infection. Dicloxacillin appropriate treatment for this patient would have been should not be administered to these newborns. a third-generation cephalosporin with ampicillin to cover most of the usual bacteria. Changing an antibiotic On April 4, shock persisted along with pneumonia. schema depends on the patient’s clinical evolution and Bronchial aspirate culture was positive for Pseudomonas; Table 1. Final clinical diagnoses however, this result is suspicious for diagnosis of • Giant omphalocele pneumonia associated with ventilator because the • Bilateral hydronephrosis culture may be contaminated or at an early colonization • Nosocomial sepsis • Ventilator-associated pneumonia phase. According to CDC criteria (October 2004), • Purulent peritonitis an airway culture should be quantitative with values • Shock (cause of death) 49 Vol. 67, September-October 2009 risk factors. prenatal ultrasound did not reveal hydronephrosis, this suggests it was possibly not full-blown and postnatal Dr. Bracho ultrasound does not report dilated calyces or thinning I requested Dr. Anselmo Dominguez Chicas (Urology of the kidney cortex. Possibly it was due to a dilatation Department) to offer his comments on non-prenatal from fetal folds or a fetal kidney that does not imply hydronephrosis. any pathology. Finally, hydronephrosis that occurs in patients with gastroschisis/omphalocele presents after Dr. Dominguez silo is applied and tightened or after it closes, which Postnatal hydronephrosis study is related with probable increases intra-abdominal pressure. Otherwise it is not diagnoses. We are interested in obstructive types, very frequent. which will possibly require surgery, e.g., pyeloureteral, ureterovesical and posterior urethra valve obstructions Pathological Anatomy and vesicoureteral reflux level that might require Dr. Mario Perezpeña Diazconti (Pathology treatment. Department) Postmortem study revealed macroglossia, ear creases, As for hydronephrosis, we are basically interested in and bilateral pneumothorax. In the abdomen there was dilatation, the anteroposterior diameter of the renal intestinal malrotation and omphalocele (15 x 13 cm) with pelvis as well as the dilatation of calyces or renal complete sac (Figure 1). Intestinal loops were visible cortex thinning. Any of these data imply severity. If through the sac. Once the sac was removed, intestinal it is unilateral, an ultrasound is carried out to evaluate loops presented distension, yellowish-green purulent hydronephrosis and determine ureter dilatation. If there material in serosa and intestinal lumen showed a red- is dilatation, a cystogram should be carried out to rule violet flattened mucosa. Stomach contained dark-brown out reflux. If there is no dilatation, we may consider hematic material and mucous was red-wine colored uteropyelic obstruction, which is the most common (Figure 2). Colon contained fibrin and inflammation diagnosis. In this case a renal scan is scheduled during comprised of lymphocytes, plasma cells and foreign- the 3rd or 4th week of life in order to confirm diagnosis body giant cells. The mucous was congestive with based on a delayed elimination curve or a difference in focal ulceration. Abdominal wall presented fibrous relative renal function. connective tissue, coagulative necrosis and highly inflammatory polymorphous infiltrate. Adrenal glands Bilateral obstruction is considered an emergency. showed cortical cytomegaly (Figure 3). Pancreas Ultrasound is carried out as soon as possible, during presented islets of Langerhans and acinus hyperplasia the first or second day of life. If there is dilatation (Figure 4). Lungs showed intense damage with hyaline of the ureters, a cystogram is carried out to rule out membranes (Figure 5) and arteriole wall thickening as vesicoureteral reflux. If there is no dilatation, we may a reference of pulmonary vascular disease. consider perilateral obstruction, carrying out a renal scan during the second week of life to confirm diagnosis. At Results led to the diagnosis of Beckwith-Wiedemann the end of the week, serum creatinine can be determined. syndrome. Table 2 shows the final anatomic diagnoses. If creatinine decreases, renal function is preserved and Beckwith-Wiedemann syndrome is characterized by we can carry out the renal scan during the second or macroglossia, hypertrophy and abdominal wall defect, third week of life. If creatinine does not decrease, we omphalocele, umbilical hernia or rectal diastasis.4 Patients should evaluate using bilateral nephrostomy to insure may present hypoglycemia; therefore, prophylaxis kidney function. Surgical decisions are prompted by helps to prevents severe neurological consequences. results. If a unilateral obstruction is confirmed, surgery Patients present macrosomia and polyhydramnios.5,6 can be accomplished after 3 months of life. If there Facial alterations include nevus flammeus, midface is bilateral obstruction, it may be useful to carry out hypoplasia and ear creases or pits. Cranial alterations at least one procedure before 3 months of life, and it and macroglossia are prominent. Omphalocele and is particularly important to detect hypertension in the visceromegaly are common, although umbilical hernia newborn. If hypertension is confirmed, surgery must or rectal diastasis may be present. Intestinal malrotation, be carried out before the first month of life to insure hepatomegaly, splenomegaly and occasional control of hypertension. In our studied case, because cardiomegaly can be present. Pancreatomegaly is 50 Bol Med Hosp Infant Mex found during autopsy. Several hyperplasias have been up to 7.5% develop intra-abdominal neoplasias with reported: uterine, ovarian, testicular, phallic, bladder or higher frequency.6,7 The most common neoplasias clitoris. Intelligence levels are normal and when there are Wilms’ tumor, adrenal cortex carcinoma and is retardation, this is associated with 11p5 chromosomal hepatoblastoma. There is an increased frequency duplicity, uncontrolled hypoglycemia or complications of rhabdomyosarcoma and neuroblastoma. The due to prematurity. increased frequency of Wilms’ tumor is associated with hemihypertrophy, nephromegaly, nephrogenic remains For patients with Beckwith-Wiedemann syndrome, or nephroblastomatosis and uniparental disomy 11p5 and hypermethylation of H19.

Hypoglycemia is present in up to 63% of cases, is transitory and responds to therapy. Spontaneous regression occurs at about 4 years of age. The patient may present polycythemia in up to 20% of cases, as well as hypocalcemia, hypercholesterolemia and hyperlipidemia. Hypercalciuria is present in up to 22%

Figure 1. Omphalocele with complete sac (13 × 15 cm) with underlying intestinal loops.

Figure 3. Histological sections from adrenal cortex showing extreme cytomegaly.

Figure 2. Hyperemic gastric mucosa with traces of dark- brown blood. Figure 4. Pancreas demonstrating islets of Langerhans with hyperplasia, affecting acinus and conduits. 51 Vol. 67, September-October 2009 of cases. received high-frequency ventilation from intubation and Cytomegaly in adrenal cortex with adrenal marrow not conventional ventilation because he also presented hyperplasia is characteristic of this syndrome. Pancreas pulmonary arterial hypertension. presents acinus, conduits and hyperplasia of islets of Langerhans. Leydig cell hyperplasia and ovarian Medical Genetics Discussion adenoma may also be present. Dr. Garcia-Delgado Dr. Adrian Chavez (Pediatric Intensive Care Unit) The patient had a cousin with a digestive tube The patient presented acute respiratory failure secondary malformation. We are unaware if the patient and to abdominal sepsis. Therefore, the critical analysis of cousin were maternally or paternally related. This is our procedure is as follows: this patient should have relevant to analyze clinical profiles of these children who, if diagnosed and opportunely treated, show good survival prognosis. Of Beckwith-Wiedemann cases, 2-3% present cytogenetic abnormalities involving the short arm of chromosome 11 in region 15, including duplications from paternal chromosome, inversions and maternal translocations. Only 15% of these patients have a family history and, in these cases, is inherited from the mother. Twenty percent of cases are spontaneous and there is uniparental disomy of chromosome 11, frequently associated with hemihypertrophy. Of spontaneous cases, 5-10% have an abnormal mutation pattern of H19 and IGF2 genes, which means that 80% of cases are spontaneous and 20% are inherited.5

Table 2. Final anatomic diagnoses Figure 5. Multifactorial hyaline membranes associated with sepsis, shock and disseminated intravascular Main diseases coagulation. • Beckwith-Wiedemann syndrome • Macroglossia • Omphalocele with complete sac • Adrenocortical cytomegaly • Intestinal malrotation • Hydronephrosis • Islets of Langerhans hyperplasia Concomitant Alterations • Multifactorial hyaline membrane disease • Rabinovitch’s pulmonary vascular disease level I • Bilateral pneumothorax • Acute peritonitis Anatomic shock and disseminated intravascular coagulation data • Fibrin thrombi in liver • Hemorrhagic gastritis • Acute involution of the thymus • Colliquative myocytolysis

Postmortem cultures • Hemoculture, cerebrospinal fluid, lungs, spleen and liver without bacteria Figure 6. Autopsy demonstrating changes of pulmonary • Small intestine with Pseudomonas aeruginosa vascular disease in arterioles. and Stenetrophomona maltophilia • Colon with P. aeruginosa and yeast

Cause of death • Sepsis • Disseminated intravascular coagulation 52 Bol Med Hosp Infant Mex In uniparental disomy, one pair of homologous maternal or paternal origins. The primary expression chromosomes is inherited from a single parent. If we control genes in the region include genes H19 (which carry out conventional chromosomal study, their number codes to a nontranslated RNA) and IGF2 (which codes is normal. Only the molecular level would reveal an to type-2 insulin-like growth factor) and gene KVLQT1 alteration. The clinical example of this nosologic entity and CDKN1C or LTI1, which codes a cyclin-dependent is alteration of chromosome 15 where, if the disomy kinase inhibitor. If it is altered, H19 gene can alter IGF2 is maternal, patients present Prader-Willi Syndrome expression producing overgrowth. It is interesting to (OMIM 176270) and if paternal they present Angelman remember that the Beckwith-Wiedemann syndrome Syndrome (OMIM 10583).6,7 counterpart is Silver-Russell Syndrome where H19 hypomethylation in maternal uniparental disomy will As for Beckwith-Wiedemann syndrome, it is important inversely affect IGF2 expression. This may explain to remember that it is associated with genomic imprinting the overgrowth observed in Beckwith-Wiedemann alterations; therefore, gene expression depends on syndrome; however, this is not the unique proposed parental origin. Genomic imprinting has been known molecular mechanism.9-15 since the 1980s and it is known that certain genomic regions are not functionally equivalent.8 Beckwith- In order to assist this family, we can carry out a complete Wiedemann syndrome-related genes, with loci on genetic assessment with conventional karyotyping the short arm of chromosome 11 (region 1, subregion for parents and also to perform molecular study from 5) present a differential expression when they have autopsy tissues.

References

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