Clinical genetics fellow, Harvard Medical School


Genetic diagnoses in fetuses prenatally diagnosed with esophageal atresia

Esophageal atresia (EA) is a major congenital malformation affecting 1 in 3500 livebirths. In about half the cases, other malformations exist as part of either a genetic syndrome or an association such as VACTERL (Vertebral defects, Anal atresia, Cardiac malformations, Tracheoesophageal fistula with Esophageal atresia, Renal dysplasia, and Limb anomalies). Advances in prenatal care have allowed for EA to be diagnosed prenatally, but the data are scarce on the genetic diagnoses, associated malformations, and postnatal outcome in these prenatally diagnosed cases. To address this knowledge gap, we reviewed the charts of all mothers who were referred to the Advanced Fetal Care Center at Boston Children’s Hospital with a diagnosis of possible EA in the fetus. We identified 49 cases of intrauterine EA. Prenatal genetic consult was performed in 8/49 (16%) of the cases and prenatal genetic testing was done in 27/49 (55%), including karyotype in 24/27 (89%), Fluorescent In Situ Hybridization (FISH) for specific chromosomes in 5/27 (19%), and chromosomal microarray in 6/27 (22%). Associated anomalies identified after birth included: airway/pulmonary (77%), cardiac (75%), spine (58%), genitourinary (42%), other gastrointestinal (38%), neurological (34%), limb (29%), and ophthalmic (27%) malformations. Three (6%) had isolated EA with or without tracheoesophageal fistula. Twenty-one (45%) of these cases were born prematurely before 37 weeks’ gestation. More than half of (21/37 (57%)) children did not have any documented developmental delay. Twenty-one out of 46 (45%) of the patients were evaluated by a clinical geneticist after birth, and genetic testing was done in 23/46 (50%) of patients postnatally, including some who have had prenatal testing. Postnatal genetic tests included karyotype in 9/46 (19%), chromosomal microarray in 13/46 (28%), and a variety of single genes in 6/46 (13%). Out of those patients seen by a geneticist prenatally, 59% were seen in follow up by a geneticist postnatally. Twenty-six of 46 patients (57%) were given a genetic diagnosis. VACTERL association was the most common clinical diagnosis (21/26 (80%)), followed by Down syndrome in 3/26 (11%), Feingold syndrome in one patient and CHARGE syndrome in one patient. This data will help clinical geneticist for counseling of parents with EA in their fetus and also shows that referral to genetics is crucial prenatally in such cases.


The case for universal prenatal genetic counseling.

Abstract: Recent scientific advances in human genetics and prenatal diagnostic technologies challenge the counseling infrastructure of most obstetric services. In just the past several years, the American College of Obstetricians and Gynecologists has published guidelines on fragile X, spinal muscular atrophy, and cystic fibrosis screening, and new technologies including microarray analysis, cell-free fetal DNA, and carrier gene panels have become available. Obstetrics is at a crossroads, which requires consideration of new ways of providing genetic counseling. Currently a two-tiered process is used. Specific tests such as first- or second-trimester screening for aneuploidy are offered to virtually all women by a clinician who provides counseling and who may offer additional tests to patients in particular ethnic groups and those with unique obstetric or family histories. Frequently only this latter group and those who "screen positive" on the universally offered tests are sent to a genetic counselor. This approach worked well when screening focused on a relatively small number of diagnoses, but that is no longer the case. We argue that obstetricians, who were able to maintain mastery over the content of counseling when aneuploidies and karyotype analysis were the essential diagnoses and diagnostic tools available, are rarely able to offer the same level of expertise regarding the chromosomal, genomic, and genetic diseases now diagnosable and the newest available diagnostic methodologies. Therefore, all women, not just those surpassing some poorly defined level of risk, deserve genetic counseling. Approaches for achieving this goal are discussed.

Pub.: 09 May '14, Pinned: 30 Jun '17

Elucidating Genetic Counseling Outcomes from the Perspective of Genetic Counselors.

Abstract: Outcomes in the field of genetic counseling have not been well-defined or categorized, despite pressures to provide evidence-based measures in all areas of healthcare. This study describes a process to elucidate and categorize a wide-ranging set of outcomes as characterized by diverse groups of practicing genetic counselors. Semi-structured focus groups were conducted at the National Society of Genetic Counselors 2013 NSGC Annual Education Conference during an educational breakout session. A general inductive qualitative research approach was utilized to code focus group notes, categorize them into themes, and compare them across specialty groups. A total of 107 individuals participated in 14 focus groups, consisting of specialists in cancer (n = 20), general genetics (n = 40), prenatal genetics (n = 11), and "other" (n = 36). Of the twelve genetic counseling outcomes themes identified, the most common across focus groups included: 1) appropriateness of testing and accuracy of results interpretation; 2) psychosocial outcomes; 3) adherence to or receipt of appropriate medical management; and 4) patient and provider knowledge. Data assessed by specialty demonstrated similarities in outcomes themes, suggesting that a common set of genetic counseling outcomes would likely be appropriate to cover the majority of needs for the profession. Results can serve as a platform from which to build a more well-defined and comprehensive set of outcomes.

Pub.: 20 Jan '16, Pinned: 30 Jun '17

Attitudes Towards Prenatal Genetic Counseling, Prenatal Genetic Testing, and Termination of Pregnancy among Southeast and East Asian Women in the United States.

Abstract: Recognizing the heterogeneity of the Asian population with regards to acculturation, education, health awareness, and cultural values is vital for tailoring culturally sensitive and appropriate care. Prior studies show that cultural values influence perceptions of genetics within Asian populations. The reputation of the family unit factors into decisions such as pregnancy termination and disclosure of family medical history, and the nondirective model of American genetic counseling may conflict with the historical Asian model of paternalistic health care. Previous studies also provide conflicting evidence regarding correlations between education, acculturation, age, and awareness and perceptions of genetic testing. The aims of this study were to describe attitudes towards prenatal genetics among Southeast and East Asian women living in the United States for varying amounts of time and to explore sociocultural factors influencing those attitudes. Twenty-three Asian women who were members of Asian cultural organizations in the United States were interviewed via telephone about their attitudes towards prenatal genetic counseling, prenatal genetic testing, and termination of pregnancy. Responses were transcribed and coded for common themes using a thematic analysis approach. Four major themes emerged. In general, participants: (1) had diverse expectations for genetic counselors; (2) tended to weigh risks and benefits with regards to genetic testing decisions; (3) had mixed views on termination for lethal and non-lethal genetic conditions; and (4) identified cultural factors which influenced testing and termination such as lack of available resources, societal shame and stigma, and family pressure. These findings may allow prenatal genetic counselors to gain a richer, more nuanced understanding of their Asian patients and to offer culturally tailored prenatal genetic counseling.

Pub.: 03 Mar '17, Pinned: 30 Jun '17

Outcomes of primary gastric transposition for long-gap esophageal atresia in neonates.

Abstract: Gastric transposition is a relatively novel method of esophageal replacement. The purpose of this retrospective study was to assess the outcomes of long-gap esophageal atresia (LGEA) treated with esophageal replacement using primary gastric transposition in neonates.Between March 2008 and May 2015, 14 newborns with LGEA were treated in our hospital. They were all found to have gaps of over 3 cm at the time of the surgery and were diagnosed with LGEA. Primary gastric transposition was performed. They also underwent a gastric drainage procedure by pyloromyotomy. The nasogastric tube was removed if no anastomotic fistula was present and oral feeding was initiated. After initial recovery and discharge, the patients were evaluated with outpatient follow-ups or telephone follow-ups from 1 month after the surgery.The mean age of the neonates at the time of the surgery was 32 hours (range, 4-96 h). The mean birth weight was 2550 g (range, 2100-3500 g). There were 2 deaths in this series of patients due to respiratory failure or withdrawal of treatment by the parents, with a mortality rate of 14.3%. Seven of the neonates developed unilateral or bilateral severe pneumonia. Early anastomotic leak occurred in 3 cases and anastomotic strictures occurred in 4 cases. These 4 neonates were able to eat a fairly normal diet after esophageal balloon dilation. Gastroesophageal reflux occurred in 7 of 12 cases. Feeding multiple small meals and postural support for positioning and feeding were instructed for these 7 cases. Subsequently, the symptoms alleviated and they had no additional surgical therapy. None of the neonates had delayed gastric emptying or gastric retention.Primary gastric transposition may be a rewarding reconstructive option in the treatment of LGEA.

Pub.: 29 Jun '17, Pinned: 30 Jun '17

Expanding the phenotype of feingold syndrome-2.

Abstract: Feingold syndrome-2 has been recently shown to be caused by germline heterozygous deletions of MIR17HG with 10 reported patients to date. Manifestations common to both Feingold syndrome-1 and Feingold syndrome-2 include microcephaly, short stature, and brachymesophalangy; but those with Feingold syndrome-2 lack gastrointestinal atresias. Here we describe a 14-year-old male patient who presented to our Cardiovascular Genetics Clinic with a history of a bicuspid aortic valve with aortic stenosis, short stature, hearing loss, and mild learning disabilities. Upon examination he was noted to have dysmorphic features and brachydactyly of his fingers and toes. His head circumference was 54.5 cm (25th-50th centile) and his height was 161.3 cm (31st centile) after growth hormone therapy. A skeletal survey noted numerous abnormalities prompting suspicion for Feingold syndrome. A comparative genomic hybridization microarray was completed and a ∼3.6 Mb interstitial heterozygous deletion at 13q31.3 including MIR17HG was found consistent with Feingold syndrome-2. Clinically, this patient has the characteristic digital anomalies and short stature often seen in Feingold syndrome-2 with less common features of a congenital heart defect and hearing loss. Although non-skeletal features have been occasionally reported in Feingold syndrome-1, only one other patient with a 13q31 microdeletion including MIR17HG has had non-skeletal manifestations. Additionally, our patient does not have microcephaly and, to our knowledge, is the first reported pediatric patient with Feingold syndrome-2 without this feature. This report illustrates significant phenotypic variability within the clinical presentation of Feingold syndrome-2 and highlights considerable overlap with Feingold syndrome-1. © 2015 Wiley Periodicals, Inc.

Pub.: 12 Sep '15, Pinned: 30 Jun '17

Long-Gap Esophageal Atresia Is a Unique Entity within the Esophageal Atresia Defect Spectrum.

Abstract: Long-gap esophageal atresia (LGEA) may have clinical and syndromic presentations different from those of esophageal atresia (EA) that affects shorter segments of the esophagus (non-LGEA). This may suggest unique underlying developmental mechanisms.We sought to characterize clinical differences between LGEA and non-LGEA by carefully phenotyping a cohort of EA patients, and furthermore to assess molecular genetic findings in a subset of them.This is a retrospective cohort study to systematically evaluate clinical and genetic findings in EA infants who presented at our institution over a period of 10 years (2005-2015).Two hundred twenty-nine EA patients were identified, 69 (30%) of whom had LGEA. Tracheoesophageal fistula was present in most non-LGEA patients (158 of 160) but in only 30% of LGEA patients. The VACTERL association was more commonly seen with non-LGEA compared to LGEA (70 vs. 25%; p < 0.001). Further, trisomy 21 was more common in LGEA than in non-LGEA. 25% of LGEA patients had an isolated EA diagnosis without other anomalies, compared to <1% for non-LGEA. Chromosomal microarray analysis showed copy number variations (CNV) in 4 of 39 non-LGEA patients and 0 of 3 LGEA patients. A review of the ClinGen database showed that none of those CNV have been previously described with EA.LGEA represents a unique type of EA. Compared to non-LGEA, it is more likely to be an isolated defect and associated with trisomy 21. Further, it is less commonly seen with VACTERL anomalies. Our findings suggest the involvement of unique pathways that may be distinct from those causing non-LGEA.

Pub.: 19 Oct '16, Pinned: 30 Jun '17

Oesophageal atresia and tracheo-oesophageal fistula

Abstract: Oesophageal atresia and tracheo-oesophageal fistula is a congenital structural abnormality that affects 1:4500 live infants. It is due to failure of the primitive foregut tube to separate correctly into the oesophagus and trachea. About 50% have associated abnormalities, of which the VACTERL (Vertebral, Anorectal, Cardiac, Tracheo-oEsophageal, Renal and Limb) association is the most common. Prematurity is common and all have some degree of tracheomalacia. Surgery of the common type can be performed through a fourth interspace thoracotomy or by thoracoscopy. It involves division of the distal tracheo-oesophageal fistula and anastomosing together the two ends of the oesophagus. The absence of a distal fistula reveals itself as a ‘gasless abdomen’ on plain radiology, and usually indicates a long gap between the blind oesophageal ends: this sometimes necessitates an oesophageal replacement if extensive oesophageal mobilization fails to achieve an end-to-end anastomosis of the oesophagus. Potential postoperative problems include anastomotic leak, anastomotic stricture, recurrence of the fistula, gastro-oesophageal reflux, oesophageal dysmotility, and food impaction. Survival is determined mainly by coexisting congenital abnormalities. The long-term risk of oesophageal malignancy is yet to be established. Isolated tracheo-oesophageal fistula (‘H fistula’) can occur without atresia, and often presents after feeding has commenced. It is divided through a cervical incision.

Pub.: 11 Nov '16, Pinned: 30 Jun '17

Current knowledge on esophageal atresia.

Abstract: Esophageal atresia (EA) with or without tracheoesophageal fistula (TEF) is the most common congenital anomaly of the esophagus. The improvement of survival observed over the previous two decades is multifactorial and largely attributable to advances in neonatal intensive care, neonatal anesthesia, ventilatory and nutritional support, antibiotics, early surgical intervention, surgical materials and techniques. Indeed, mortality is currently limited to those cases with coexisting severe life-threatening anomalies. The diagnosis of EA is most commonly made during the first 24 h of life but may occur either antenatally or may be delayed. The primary surgical correction for EA and TEF is the best option in the absence of severe malformations. There is no ideal replacement for the esophagus and the optimal surgical treatment for patients with long-gap EA is still controversial. The primary complications during the postoperative period are leak and stenosis of the anastomosis, gastro-esophageal reflux, esophageal dysmotility, fistula recurrence, respiratory disorders and deformities of the thoracic wall. Data regarding long-term outcomes and follow-ups are limited for patients following EA/TEF repair. The determination of the risk factors for the complicated evolution following EA/TEF repair may positively impact long-term prognoses. Much remains to be studied regarding this condition. This manuscript provides a literature review of the current knowledge regarding EA.

Pub.: 02 Aug '12, Pinned: 30 Jun '17

Mother's Lived Experience During Repair of Long-Gap Esophageal Atresia: A Phenomenological Inquiry.

Abstract: Infants born with long-gap esophageal atresia (LGEA) pose unique physiologic risks in the newborn period. Anatomic and physiologic anomalies require an extended hospitalization with procedural analgesia and sedation that impact the mother's experience of birth, maternal response, and nurturing of her infant.The aim of this study was to understand the meaning of experiences that mothers of infants born with LGEA encounter in the neonatal intensive care unit while their infant undergoes esophageal repair.A hermeneutical phenomenological design was used to guide this inquiry. Three mothers were interviewed on 3 separate occasions. The conversations were audio-recorded and transcribed verbatim. The findings were analyzed using fundamental existential lifeworld themes.The essence that conceptualized the study was "making connections: day-by-day." Themes that emerged are (a) the many phases; (b) the long and winding road; (c) a new me, my purpose; and (d) our new community.Nurses' knowledge and understanding of maternal experiences of having an infant with LGEA will enable for increased physical closeness, optimizing time spent together to learn their infant's unique personality. Creating partnerships with mothers can enhance our understanding of their perspectives, concerns, needs, and guide interventions.Further exploration of family dynamics including fathers, siblings, and contextual factors may illuminate interventions to enhance relationships and communication that may influence developmental outcomes for families of infants with LGEA.

Pub.: 02 Jun '17, Pinned: 30 Jun '17

Associated anomalies in cases with esophageal atresia.

Abstract: Esophageal atresia (EA) is a common type of congenital anomaly. The etiology of esophageal atresia is unclear and its pathogenesis is controversial. Infants with esophageal atresia often have other non-EA associated congenital anomalies. The purpose of this investigation was to assess the prevalence and the types of these associated anomalies in a defined population. The associated anomalies in cases with EA were collected in all livebirths, stillbirths, and terminations of pregnancy during 29 years in 387,067 consecutive births in the area covered by our population-based registry of congenital malformations. Of the 116 cases with esophageal atresia, representing a prevalence of 2.99 per 10,000, 54 (46.6%) had associated anomalies. There were 9 (7.8%) cases with chromosomal abnormalities including 6 trisomies 18, and 20 (17.2%) nonchromosomal recognized dysmorphic conditions including 12 cases with VACTERL association and 2 cases with CHARGE syndrome. Twenty five (21.6%) of the cases had multiple congenital anomalies (MCA). Anomalies in the cardiovascular, the digestive, the urogenital, the musculoskeletal, and the central nervous systems were the most common other anomalies. The anomalies associated with esophageal atresia could be classified into a recognizable malformation syndrome or pattern in 29 out of 54 cases (53.7%). This study included special strengths: each affected child was examined by a geneticist, all elective terminations were ascertained, and the surveillance for anomalies was continued until 2 years of age. In conclusion the overall prevalence of associated anomalies, which was close to one in two cases, emphasizes the need for a thorough investigation of cases with EA. A routine screening for other anomalies may be considered in infants and in fetuses with EA.

Pub.: 04 Jun '17, Pinned: 29 Jun '17