Follow-up for a Preterm Infant with Beckwith-Wiedemann Syndrome.

Abstract

We are excited to introduce this new NeoReviews feature: Outcomes of NICU Graduates. In this article, authors describe the clinical course of a NICU graduate who is receiving care in a specialty clinic. After providing a brief overview of the NICU hospitalization, the authors review the infant’s post-discharge clinical course including recommended follow-up and treatments. The article concludes with a short summary of major take-home lessons from the case as well as a discussion of expected outcomes for the specific condition. We hope that neonatal clinicians will benefit from these case presentations by gaining insight into the outpatient management and long-term outcome of a wide range of NICU diagnoses. If you are interested in submitting a case, please contact neoreviewseditorial@aap.org.—Dr. Dara Brodsky, Editor in Chief, and Dr. Santina Zanelli, Associate Editor, Outcomes of NICU GraduatesIn this article, we describe a female child born preterm with a postnatal diagnosis of Beckwith-Wiedemann syndrome (BWS) who has been followed in our multidisciplinary infant follow-up program.The infant was born at 31 and 3/7 weeks’ gestation via vaginal delivery to a 30-year-old gravida 2, para 1 woman following spontaneous preterm labor. The pregnancy had been unremarkable, with a normal second-trimester fetal survey. The infant initially emerged vigorous with good tone and spontaneous respiratory effort, though soon after, she had apnea and bradycardia. She ultimately required intubation in the delivery room and was transferred to a level III NICU for further evaluation and management. Her Apgar scores were 6 and 7 at 1 and 5 minutes of age, respectively. Her birth parameters were notable for a length of 47 cm (∼90th percentile), head circumference of 27.5 cm (∼90th percentile), and weight of 2,108 g (∼50th percentile).She underwent extubation and was transitioned to continuous positive airway pressure by 24 hours of age and subsequently to room air by 4 days of age. She continued to have occasional apnea/bradycardia/desaturation spells both at rest and with feedings that were initially attributed to prematurity. She was started on nasogastric feedings that were advanced without difficulty and she transitioned to full oral feedings by about 1 month of age. Her head ultrasound scan at 7 days of age was normal and she passed her newborn hearing screen.She continued to have spells both with feedings and at rest despite reaching term postmenstrual age. At 6 weeks of age, the neonatology team had observed that her tongue was large and thought that her spells may have an obstructive component. She was seen by the genetics team for macroglossia, mild hypotonia, and unique facial features. She was clinically diagnosed with BWS, based on her features of macroglossia, forehead and glabellar nevus simplex, ear creases and pits, umbilical hernia, bilateral infraorbital creases, and generalized overgrowth (Fig 1A). Genetic testing to determine the underlying molecular etiology of the infant’s clinical diagnosis included a karyotype, chromosomal microarray and methylation analysis (via methylation-sensitive Multiplex Ligation-Dependent Probe Amplification, Mayo Clinic Laboratories, Rochester, MN), all of which were nondiagnostic.Due to the clinical diagnosis of BWS, tumor surveillance with serum α-fetoprotein (AFP) levels and abdominal ultrasonography was recommended. The initial serum AFP was elevated at 17,500 ng/mL (17,500 μg/L), but this was not unexpected for a former preterm infant with a diagnosis of BWS because both prematurity and BWS are associated with elevated AFP levels. (1)(2) Following this initial AFP, a sharp downtrend was observed (Fig 2). Initial liver ultrasonography showed multiple hypoechoic lesions (Fig 3), suspected to be hemangiomas (she was also noted to have a hemangioma on her posterior scalp), and a splenic cyst.The infant was transferred to our institution at 2 months of age for a sleep study that showed mixed sleep-disordered breathing with a prominent obstructive component that was well-controlled with bilevel positive airway pressure (BiPAP). A modified barium swallow study showed oropharyngeal dysphagia and aspiration when she was fed upright with a regular-flow nipple, but this did not occur when she was fed side-lying with a slow-flow nipple. She was discharged to a rehabilitation facility at 2.5 months of age and ultimately went home at 3 months of age to continue to use BiPAP during naps and overnight sleep.Our genetics team counseled the family extensively about the diagnosis of BWS based on her clinical features. The family was appropriately concerned about the potential for medical complications such as intra-abdominal tumors. They were also worried about issues related to the macroglossia, which they were reassured should improve over time and for which follow-up was arranged with surgical subspecialists in the event that a surgical intervention was needed.The infant is now 20 months old (Fig 1C) with a corrected age of 18 months and has been followed in our multidisciplinary infant follow-up program by genetics, physical therapy, and pediatric psychology in addition to other subspecialists including pulmonology (for history of sleep-disordered breathing) and plastic and oral surgery (for history of macroglossia). Her home BiPAP was discontinued at 5 months of age after a normal sleep study. Her AFP levels continue to trend downward and are now in the normal range, and subsequent ultrasonography over the first 18 months of age demonstrated resolution of all but 1 of the hepatic lesions. The most recent ultrasound scan at 18 months of age showed resolution of the final liver lesion with a stable splenic cyst. Her growth curve continues to demonstrate overgrowth (Fig 4).The plastic and oral surgery team monitored the child’s macroglossia, which was thought to become less clinically and cosmetically significant over time without intervention (Figs 1B and 1C); therefore, their plan is to continue to observe until 2 to 3 years of age before considering a tongue debulking procedure. She had a slight delay in oral motor skills for which she was followed by the outpatient feeding and swallowing team with no further clinical concerns for aspiration. After her last visit to this clinic at 18 months of age, she was noted to be doing wonderfully with her oral feeding skills and was discharged from their clinic with follow-up on an as-needed basis only.Developmentally, she continues to make excellent progress. She is a bright and determined child with a loving and nurturing attachment to her parents. Neuropsychological testing using the Bayley Scales of Infant and Toddler Development, 4th edition (Pearson, London, England) at 20 months of age (18 months’ corrected age) demonstrated gross and fine motor skills that are age-appropriate, cognitive skills that are also within the normal range, and a receptive and expressive language delay of 6 to 7 months (accounting for prematurity). She had some atypical self-stimulatory behaviors and social interactions noted during the most recent evaluation that deserve further monitoring. It is unclear whether the language delay is related to mechanical challenges associated with her macroglossia, or overall, whether the developmental assessments reflect a predominant influence of the preterm delivery versus BWS, or likely both. She continues to receive early intervention services for developmental support, and increased frequency of speech therapy has been recommended.The search for the genetic cause of the child’s BWS has yet to be successful. Additional testing has included CDKN1C sequencing (Genetic Diagnostic Laboratory, University of Pennsylvania, Philadelphia, PA), a genome-wide methylation study (EpiSign, Greenwood Genetics, Greenwood, SC), and MLPA with pyrosequencing (Greenwood Genetics). All of these results were nondiagnostic with no epigenetic pattern classic for BWS. Due to a potential for mosaicism, should she undergo the tongue debulking procedure, the excised tissue sample may be sent for genetic testing.BWS is an overgrowth disorder with a varied presenting phenotype that is attributed to disorders of genomic imprinting of the 11p15 chromosomal region. Interestingly, children with BWS are often born preterm. (3) BWS can be diagnosed clinically using major and minor findings associated with this condition: Major findings: Macrosomia, macroglossia, linear/transverse ear lobe creases and/or posterior pits, lateralized overgrowth or hemihyperplasia, cleft palate, omphalocele or umbilical hernia, cardiomyopathy, embryonal tumors such as Wilms tumor or hepatoblastoma, visceromegaly (enlargement of the intra-abdominal organs), adrenal cortex cytomegaly, renal abnormalities, placental mesenchymal dysplasia, and positive family historyMinor features: Prematurity, hypoglycemia, nevus simplex or hemangiomas, infraorbital creases, cardiac abnormalities, diastasis recti, and advanced bone ageUsing these criteria, a clinical diagnosis of BWS can be established in an individual who meets either (a) 3 major or (b) 2 major and at least 1 minor criteria. (4) This infant’s macroglossia, umbilical hernia, ear creases, and pits meet the major criteria (3 major), and her history of preterm delivery, nevus simplex and hemangiomas, and infraorbital creases are minor criteria (3 minor). With 3 major and 3 minor findings associated with BWS, she meets the criteria for a clinical diagnosis of BWS.More recently, to recognize the variable clinical presentations and molecular etiologies of BWS, the term “BWS spectrum” (BWSp) has been adopted. (1) A recent international consensus group (1) has abandoned the terminology of major and minor associated findings and introduced “cardinal” and “suggestive” features of BWSp as well as a scoring system to diagnose clinical BWSp. Cardinal features include macroglossia, lateralized overgrowth (hemihyperplasia), omphalocele, multifocal Wilms tumor or nephroblastomatosis, hyperinsulinism, and other features seen on clinical pathologic examination such as placental mesenchymal dysplasia and adrenal cortex cytomegaly. Suggestive features, or features that also occur frequently in those without a BWSp diagnosis, include polyhydramnios or placentomegaly, increased birthweight for gestational age (>2 standard deviations above the mean), transient hypoglycemia, facial nevus simplex, ear creases or pits, umbilical hernias or diastasis recti, nephromegaly or hepatomegaly, and embryonal tumors. In this scoring system, 2 points are given for each cardinal feature and 1 point per suggestive feature. A score of greater than or equal to 4 points is consistent with a clinical diagnosis of BWSp. (1) The infant in this case has 1 cardinal feature (macroglossia) and 3 suggestive features (nevus simplex, ear creases and pits, and umbilical hernia) scoring a total of 5 points. In her initial genetic evaluation, a possible right leg length discrepancy was noted, which would lead to a score of 7, though this finding has not persisted.On a molecular level, BWSp is associated with various abnormalities in chromosome region 11p15 that affect imprinted genes. Methylation abnormalities make up the most common subgroup, with loss of methylation (LOM) at the maternal IC2 allele (IC2 LOM) found in 50% of individuals with BWSp and gain of methylation (GOM) at the material IC1 allele (IC1 GOM) in 5% to 10% of cases with BWSp. (5) Other underlying molecular etiologies include paternal uniparental isodisomy (pUPD) of 11p15.5 in 20% of cases, pathogenic sequence variants in the CDKN1C gene in 40% of familial and 5% of sporadic cases, and other chromosomal abnormalities affecting 11p15 in less than 5% of cases. (6) Determining the molecular etiology of BWSp can better predict the familial recurrence risk, the risk of tumor development, and health surveillance needs. (1) In pursuing a molecular diagnosis of BWSp, various genetic tests can be used, including methylation analysis (often via MLPA), chromosomal microarray analysis, karyotype analysis, and single gene testing of CDKN1C. (2) It is recommended that the first line of molecular testing should include methylation analysis, because methylation abnormalities are present in approximately 80% of individuals with BWSp. (7) Methylation testing would indicate the presence or absence of the IC2 LOM and IC1 GOM subtypes. Chromosomal microarray analysis can detect microdeletions, microduplications, and pUPD subtype, and a karyotype can test for inversions or translocations of the 11p15 region. Single gene testing including sequencing and deletion/duplication analysis of the CDKN1C gene in the 11p15 region is recommended, particularly in familial cases of BWSp. (4)In the present case, as noted earlier, the first line of genetic testing (ie, methylation analysis, chromosomal microarray analysis, and karyotype analysis) and the second round of genetic testing (ie, CDKN1C sequencing and further epigenetic testing) were nondiagnostic. Thus, despite extensive genetic testing, the molecular etiology of the child’s BWSp remains unknown. This patient is not alone, as about 20% of patients with a clinical BWSp diagnosis do not have a molecular diagnosis. (6) One explanation is related to potential mosaicism, where the pathogenic variant is present in some cells of the body—such as those affected by overgrowth—but not others. In most sporadic cases of BWSp, the underlying molecular defect is mosaic at a low enough level where it may not be detected in the peripheral blood genetic testing. (8)Many individuals with BWSp present in the NICU or newborn nursery, particularly as hypoglycemia related to hyperinsulinism (not seen in our case) and preterm delivery (as seen in our case) are common features. Following the recognition of this diagnosis, an AFP measurement and abdominal ultrasonography are recommended to assess for intra-abdominal malignancy. Evaluation for issues related to macroglossia such as poor feeding or sleep-disordered breathing should be pursued depending on the clinical presentation. Intubation may be challenging depending on the severity of macroglossia. Cardiac evaluation, including electrocardiography and echocardiography, may be performed if abnormalities are suggestive on examination to assess for a possible association with cardiomyopathy, however, a proportion of individuals with BWSp have cardiomegaly that resolves spontaneously. (4)Tumor surveillance is of utmost importance for patients with BWSp because of the increased risk of tumor development associated with this syndrome. Tumor surveillance can vary based on the molecular etiology of the BWSp, another motivation to determine the underlying etiology. The overall risk of developing a tumor is lowest in the IC2 LOM subtype (2.6%), CDKN1C subtype (6.9%), and in BWSp with no detectable molecular defect (6.7%) and highest in the pUPD subtype (16%) and the IC1 GOM subtype (28.1%). (1) Wilms tumor is most frequent in the IC1 GOM subtype as well as the subtype with negative molecular tests. Hepatoblastoma occurs mostly in the IC2 LOM and pUPD subtypes. In the CDKN1C subtype, neuroblastoma is the most common tumor. (9) This risk of malignancy decreases with age and in general, the associated tumors are treatable with favorable outcomes provided they are detected early. Abdominal ultrasonography every 3 to 4 months until age 8 years is the preferred method of tumor screening, with serum AFP levels added for increased sensitivity to detect hepatoblastoma; however, this recommendation has more recently been called into question. (4)(10)(11) Particularly, many families have difficulty with blood draws every 3 months for the first 4 years of age, and without evidence of substantial benefit over a detailed abdominal ultrasound scan, it is thought to be safe to perform surveillance with ultrasonography alone. In our case, the initial persistence of the liver lesion prompted continuing surveillance using AFP levels, though the lesions have spontaneously resolved as expected with the presumed diagnosis of hemangioma.Adults with BWSp are expected to have normal intelligence and a normal lifespan, though little research has been conducted on health outcomes in adulthood. An older study surveying 87 children with BWSp (mean age 9.7 years) and their parents noted higher scores than the general population on a social/behavioral questionnaire indicating a higher frequency of behavioral issues. Six children, or 6.8% of the cohort, had a diagnosis of autism spectrum disorder, higher than the general population. (12) Another study has shown developmental delay and mild intellectual disability in about 26% of 34 adults with BWSp, though this was usually referring to mild speech delay. For the rare cases with severe delays, co-occurring perinatal events such as severe hypoglycemia or hypoxic-ischemic encephalopathy also affected these outcomes. Most medical issues in adulthood reflect the evolution of BWSp features noted in infancy or the consequences of surgical intervention. (13) This highlights the need for preventive follow-up care and treatment of associated medical problems during childhood. Many features of BWSp such as macroglossia and lateralized overgrowth improve with age but can potentially cause lasting effects into adulthood such as speech and swallow difficulties or orthodontic abnormalities, scoliosis, or back pain related to lateralized overgrowth. (1)(13) One study, with substantial limitations such as a small sample size, showed an increased risk of tumor development in adults with BWSp, though it is more generally believed that there is not enough evidence to make this claim or change any tumor surveillance protocols. (13)Recognizing the clinical features of BWSp in the neonatal period is important, as tumor surveillance in these cases may be lifesaving. The overall prognosis for this condition is excellent, and the clinical and cosmetic impact of issues such as macroglossia and asymmetric overgrowth tends to wane over time. Developmental surveillance may aid in management due to the higher risk of developmental delays or other neuropsychological challenges associated with this condition, though further research into the associated neurodevelopmental outcomes is needed. In our case, the combination of preterm birth and clinical diagnosis of a genetic syndrome prompted referral to a specialized developmental follow-up program at our institution for infants with genetic conditions where developmental service needs have been identified.The authors thank the child’s family for their willingness and enthusiasm to participate in this report. They also thank the multidisciplinary team of the NICU Growth and Developmental Support Program (NICU GraDS) at Boston Children’s Hospital for their thoughtful and insightful care of this child and her family.