Case Report
Jacobsen Syndrome Detected by Noninvasive Prenatal Testing Jamie O. Lo, MD, Cori D. Feist, CGC, Jason Hashima, MD, and Brian L. Shaffer,
Teaching Points 1. Noninvasive prenatal testing should be considered when multiple fetal anomalies are present and invasive testing is declined. 2. Noninvasive prenatal testing always should be confirmed with diagnostic testing.
MD
BACKGROUND: Noninvasive prenatal testing has a high detection rate of common fetal chromosomal aneuploidies. However, detection of additional chromosome abnormalities has not been well described or validated. CASE: We report a case of Jacobsen syndrome, a congenital disorder involving deletion of chromosome 11q, detected by noninvasive prenatal testing at 14 weeks of gestation and confirmed on neonatal testing with array chromosomal genomic hybridization. CONCLUSION: Noninvasive prenatal testing should be considered when multiple fetal anomalies are present and invasive testing is declined. As the clinical application of noninvasive prenatal testing continues to evolve, additional submicroscopic chromosomal information may be clinically helpful and should be confirmed with diagnostic testing until larger studies help further define the screening characteristics of noninvasive prenatal testing. (Obstet Gynecol 2015;125:387–9) DOI: 10.1097/AOG.0000000000000528
N
oninvasive prenatal testing or noninvasive prenatal screening refers to aneuploidy screening tests using cell-free DNA in the maternal plasma with increased detection rates of trisomy 21 and other common chromosomal aneuploidies in high-risk pregnancies. Noninvasive prenatal testing has been studied and validated in singleton pregnancies at risk for trisomy 21 secondary to advanced maternal age, an
From the Department of Obstetrics and Gynecology, Division of Maternal Fetal Medicine, Oregon Health & Sciences University, and the Department of Perinatology, Kaiser Permanente, Portland, Oregon. Corresponding author: Jamie O. Lo, MD, 3181 SW Sam Jackson Park Road, Mail Code L458, Portland, OR 97239; e-mail: [email protected]. Financial Disclosure The authors did not report any potential conflicts of interest. © 2015 by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved. ISSN: 0029-7844/15
VOL. 125, NO. 2, FEBRUARY 2015
abnormal serum screen, personal or family history of aneuploidy, or abnormal ultrasound findings suggestive of trisomy 13, 18, or 21.1 The use of noninvasive prenatal testing for genetic screening has increased rapidly since introduction of the first clinical test in 2011. Currently, two commercially available noninvasive prenatal tests offer screening for several subchromosomal microdeletion syndromes, although no large studies on the sensitivity or other test characteristics are available for patient counseling. With attention to other chromosomal aberrations, noninvasive prenatal testing may be able to accurately detect additional copy number changes causing structural abnormalities recognized by routine ultrasound examination. We describe a case of prenatal suspicion of Jacobsen syndrome in a fetus with multiple congenital anomalies undergoing noninvasive prenatal testing. Jacobsen syndrome results from deletion of the terminal region of chromosome 11 and is associated with cognitive disabilities and a distinctive facial appearance. In addition, it can result in a variety of physical problems including heart defects and bleeding diathesis. Thus, advanced knowledge of this condition may be valuable for delivery planning of an affected fetus.
CASE A 26-year-old white woman, gravida 6 para 0140, presented at 11 weeks of gestation for a routine prenatal ultrasonogram, which revealed a fetal cystic hygroma measuring 5.8 mm. She declined diagnostic testing with chorionic villous sampling. Her prior pregnancy history was notable for an intrauterine fetal demise at 21 weeks of gestation complicated by multiple fetal anomalies including double-outlet right ventricle, ventricular septal defect, and pulmonary valve atresia as well as intrauterine growth restriction. Amniocentesis was performed at 19 weeks of gestation, and the karyotype and array comparative genomic hybridization were both normal female. That pregnancy ended in the delivery of a nonviable fetus at 21 weeks of gestation. Workup including infection testing was negative. Autopsy
OBSTETRICS & GYNECOLOGY
Copyright ª by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
387
was declined. Maternal and paternal blood karyotypes were normal female, 46,XX and normal male, 46,XY, respectively (500–560 bands). There was no family history of congenital heart disease, birth defects, or genetic disorders. Pathologic placental evaluation revealed fetal thrombotic vasculopathy; thus, daily baby aspirin and low molecular weight heparin were recommended in her subsequent pregnancy. At 16 weeks of gestation in the current pregnancy, an ultrasonogram demonstrated a single umbilical artery, persistent right umbilical vein, cardiomegaly, pericardial effusions, and ascites. Fetal echocardiogram at 20 weeks of gestation was significant for a double-outlet right ventricle with normally related great vessels. The patient declined all options for additional diagnostic testing but accepted noninvasive prenatal testing. Maternal blood was processed by a commercial laboratory. Noninvasive prenatal testing was negative for trisomy 21, 18, and 13. However, the genomic profile underlying the patient’s results demonstrated insufficient coverage at the chromosome 11q region, raising the concern for a possible deletion. These results were communicated verbally to the ordering physician but were not included in the final result report. The patient was counseled that a deletion of 11q was possible and again was offered diagnostic testing through amniocentesis for further investigation, which she declined. Follow-up fetal ultrasonogram at 22 weeks of gestation demonstrated large, hyperechoic kidneys without cysts, a small bladder, and normal amniotic fluid. Ultrasonogram at 25 weeks of gestation noted cardiomegaly and fetal hydrops with pericardial effusion and ascites with normal middle cerebral artery Doppler flow. Maternal serum studies for toxoplasmosis, cytomegalovirus, and parvovirus were negative. Follow-up ultrasound examination at 31 weeks of gestation was notable for resolving ascites. Betamethasone 12 mg was administered intramuscularly at 33 5/7 and 33 6/7 weeks of gestation in preparation for a potential preterm delivery. The concern for fetal 11q deletion was discussed on multiple occasions, including the possibility of Jacobsen syndrome given the congenital heart defect, renal abnormalities, and noninvasive prenatal testing results. The patient and neonatal care team were informed of the risk for thrombocytopenia seen in more than 90% of individuals with Jacobsen syndrome. Induction of labor at 39 weeks of gestation resulted in an uncomplicated vaginal delivery of a live female neonate, 3,174 g, with Apgar scores of 1, 6, and 8 at 1, 5, and 10 minutes, respectively. She was transferred to the neonatal intensive care unit requiring ventilator support. She was morphologically abnormal, with a “blueberry muffin” facial rash that was body-sparing, a large posterior fontanel, a sunken anterior fontanel, and excess nuchal skin (Fig. 1A). Abdominal ultrasonogram was consistent with splenomegaly, and a neonatal echocardiogram confirmed a doubleoutlet right ventricle with subaortic ventricular septal defect, moderately thickened mitral, tricuspid, and aortic valves, and a small pericardial effusion. Thrombocytopenia
388
Lo et al
Jacobsen Syndrome
was present and significant for platelets of 18 K/mm3, and platelets and fresh-frozen plasma were transfused. Umbilical cord blood was sent for array comparative genomic hybridization (Fig. 1B), which revealed a 16-Mb deletion at band region 11q23.3 to the q terminus. G-banded chromosome analysis (450-band resolution) confirmed this deletion and was consistent with the diagnosis of Jacobsen syndrome or 11q deletion syndrome.
DISCUSSION Jacobsen syndrome is a rare deletion syndrome caused by a copy number loss of the long arm of chromosome 11.2 The prevalence is approximately 1 in 100,000 births with a female:male ratio of 2:1. The most common clinical features include growth restriction, psychomotor retardation, and characteristic dysmorphic facial features such as skull deformities, hypertelorism, coloboma, down-slanting palpebral fissures, epicanthal folds, a broad nasal bridge, short nose, V-shaped mouth, and small, low-set ears. Affected individuals commonly have cardiac, renal, gastrointestinal, genital, skeletal, and central nervous system anomalies that may require neonatal surgery. In addition, abnormal platelet function, thrombocytopenia, and pancytopenia are often present at birth. The deletion size varies considerably and ranges from 7 to 20 Mb with the proximal breakpoint at 11q23.3 with the loss typically extending to the telomere. This deletion is de novo in 85% of cases and inherited in 15%, most commonly secondary to a familial balanced translocation or other chromosomal rearrangement. Jacobsen syndrome is diagnosed by clinical findings and confirmed by cytogenetic analysis. Approximately 20% of children die within the first 2 years of life, most often as a result of congenital heart disease.2 There are no existing reported instances of prenatal diagnosis of Jacobsen syndrome detected by noninvasive prenatal testing based on a PubMed search for “noninvasive prenatal testing,” “Jacobsen syndrome,” “prenatal diagnosis,” “pregnancy,” or “subchromosomal microdeletion syndromes” through June 20, 2014. At least two commercially available noninvasive prenatal testing tests have expanded their platforms to screen for several microdeletion syndromes. Although the laboratory processing our patient’s noninvasive prenatal testing results did not officially report their findings, the suspected noninvasive prenatal testing results influenced the care of our patient. The parents were counseled regarding the possibility of Jacobsen syndrome and offered additional testing. Invasive diagnostic testing was declined, but consent
OBSTETRICS & GYNECOLOGY
Copyright ª by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Fig. 1. A. Neonate with petechiae and jaundice, diagnosed with Jacobsen syndrome. B. Postnatal cord blood karyotype; deletion is indicated by an arrow. Lo. Jacobsen Syndrome. Obstet Gynecol 2015
was obtained for neonatal cord blood collection for chromosome studies. Delivering providers were notified of the possibility of neonatal thrombocytopenia to consider in operative delivery planning. The laboratory performing the postnatal array was notified to expedite results for clinical decision-making. Medical specialties were prepared for possible neonatal complications associated with Jacobsen syndrome, including thrombocytopenia requiring serial transfusions of platelets and fresh-frozen plasma. Subchromosomal microdeletion syndromes are individually rare, and thus performing clinical studies to validate detection by noninvasive prenatal testing is not readily feasible given the sample size required. The benefit of this technology for the general population and in those without multiple congenital abnormalities is controversial because the detection and false-positive rates are not currently available. Counseling in such cases when a rare microdeletion
VOL. 125, NO. 2, FEBRUARY 2015
syndrome is suspected is therefore challenging. Our case demonstrates that noninvasive prenatal testing for microdeletion syndrome may be clinically useful when multiple fetal anomalies requiring coordinated specialty care are present and the patient declines invasive testing. As the clinical application of noninvasive prenatal testing continues to evolve, additional submicroscopic chromosomal information may be clinically helpful and should be confirmed with diagnostic testing until larger studies help further define the screening characteristics of noninvasive prenatal testing. REFERENCES 1. Noninvasive prenatal testing for fetal aneuploidy. Committee Opinion No. 545. American College of Obstetricians and Gynecologists. Obstet Gynecol 2012;120:1532–4. 2. Mattina T, Perrotta C, Grossfeld P. Jacobsen syndrome. Orphanet J Rare Dis 2009;4:9.
Lo et al
Jacobsen Syndrome
Copyright ª by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
389
Jacobsen Syndrome Detected by Noninvasive Prenatal Testing Jamie O. Lo, MD, Cori D. Feist, CGC, Jason Hashima, MD, and Brian L. Shaffer,
Teaching Points 1. Noninvasive prenatal testing should be considered when multiple fetal anomalies are present and invasive testing is declined. 2. Noninvasive prenatal testing always should be confirmed with diagnostic testing.
MD
BACKGROUND: Noninvasive prenatal testing has a high detection rate of common fetal chromosomal aneuploidies. However, detection of additional chromosome abnormalities has not been well described or validated. CASE: We report a case of Jacobsen syndrome, a congenital disorder involving deletion of chromosome 11q, detected by noninvasive prenatal testing at 14 weeks of gestation and confirmed on neonatal testing with array chromosomal genomic hybridization. CONCLUSION: Noninvasive prenatal testing should be considered when multiple fetal anomalies are present and invasive testing is declined. As the clinical application of noninvasive prenatal testing continues to evolve, additional submicroscopic chromosomal information may be clinically helpful and should be confirmed with diagnostic testing until larger studies help further define the screening characteristics of noninvasive prenatal testing. (Obstet Gynecol 2015;125:387–9) DOI: 10.1097/AOG.0000000000000528
N
oninvasive prenatal testing or noninvasive prenatal screening refers to aneuploidy screening tests using cell-free DNA in the maternal plasma with increased detection rates of trisomy 21 and other common chromosomal aneuploidies in high-risk pregnancies. Noninvasive prenatal testing has been studied and validated in singleton pregnancies at risk for trisomy 21 secondary to advanced maternal age, an
From the Department of Obstetrics and Gynecology, Division of Maternal Fetal Medicine, Oregon Health & Sciences University, and the Department of Perinatology, Kaiser Permanente, Portland, Oregon. Corresponding author: Jamie O. Lo, MD, 3181 SW Sam Jackson Park Road, Mail Code L458, Portland, OR 97239; e-mail: [email protected]. Financial Disclosure The authors did not report any potential conflicts of interest. © 2015 by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved. ISSN: 0029-7844/15
VOL. 125, NO. 2, FEBRUARY 2015
abnormal serum screen, personal or family history of aneuploidy, or abnormal ultrasound findings suggestive of trisomy 13, 18, or 21.1 The use of noninvasive prenatal testing for genetic screening has increased rapidly since introduction of the first clinical test in 2011. Currently, two commercially available noninvasive prenatal tests offer screening for several subchromosomal microdeletion syndromes, although no large studies on the sensitivity or other test characteristics are available for patient counseling. With attention to other chromosomal aberrations, noninvasive prenatal testing may be able to accurately detect additional copy number changes causing structural abnormalities recognized by routine ultrasound examination. We describe a case of prenatal suspicion of Jacobsen syndrome in a fetus with multiple congenital anomalies undergoing noninvasive prenatal testing. Jacobsen syndrome results from deletion of the terminal region of chromosome 11 and is associated with cognitive disabilities and a distinctive facial appearance. In addition, it can result in a variety of physical problems including heart defects and bleeding diathesis. Thus, advanced knowledge of this condition may be valuable for delivery planning of an affected fetus.
CASE A 26-year-old white woman, gravida 6 para 0140, presented at 11 weeks of gestation for a routine prenatal ultrasonogram, which revealed a fetal cystic hygroma measuring 5.8 mm. She declined diagnostic testing with chorionic villous sampling. Her prior pregnancy history was notable for an intrauterine fetal demise at 21 weeks of gestation complicated by multiple fetal anomalies including double-outlet right ventricle, ventricular septal defect, and pulmonary valve atresia as well as intrauterine growth restriction. Amniocentesis was performed at 19 weeks of gestation, and the karyotype and array comparative genomic hybridization were both normal female. That pregnancy ended in the delivery of a nonviable fetus at 21 weeks of gestation. Workup including infection testing was negative. Autopsy
OBSTETRICS & GYNECOLOGY
Copyright ª by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
387
was declined. Maternal and paternal blood karyotypes were normal female, 46,XX and normal male, 46,XY, respectively (500–560 bands). There was no family history of congenital heart disease, birth defects, or genetic disorders. Pathologic placental evaluation revealed fetal thrombotic vasculopathy; thus, daily baby aspirin and low molecular weight heparin were recommended in her subsequent pregnancy. At 16 weeks of gestation in the current pregnancy, an ultrasonogram demonstrated a single umbilical artery, persistent right umbilical vein, cardiomegaly, pericardial effusions, and ascites. Fetal echocardiogram at 20 weeks of gestation was significant for a double-outlet right ventricle with normally related great vessels. The patient declined all options for additional diagnostic testing but accepted noninvasive prenatal testing. Maternal blood was processed by a commercial laboratory. Noninvasive prenatal testing was negative for trisomy 21, 18, and 13. However, the genomic profile underlying the patient’s results demonstrated insufficient coverage at the chromosome 11q region, raising the concern for a possible deletion. These results were communicated verbally to the ordering physician but were not included in the final result report. The patient was counseled that a deletion of 11q was possible and again was offered diagnostic testing through amniocentesis for further investigation, which she declined. Follow-up fetal ultrasonogram at 22 weeks of gestation demonstrated large, hyperechoic kidneys without cysts, a small bladder, and normal amniotic fluid. Ultrasonogram at 25 weeks of gestation noted cardiomegaly and fetal hydrops with pericardial effusion and ascites with normal middle cerebral artery Doppler flow. Maternal serum studies for toxoplasmosis, cytomegalovirus, and parvovirus were negative. Follow-up ultrasound examination at 31 weeks of gestation was notable for resolving ascites. Betamethasone 12 mg was administered intramuscularly at 33 5/7 and 33 6/7 weeks of gestation in preparation for a potential preterm delivery. The concern for fetal 11q deletion was discussed on multiple occasions, including the possibility of Jacobsen syndrome given the congenital heart defect, renal abnormalities, and noninvasive prenatal testing results. The patient and neonatal care team were informed of the risk for thrombocytopenia seen in more than 90% of individuals with Jacobsen syndrome. Induction of labor at 39 weeks of gestation resulted in an uncomplicated vaginal delivery of a live female neonate, 3,174 g, with Apgar scores of 1, 6, and 8 at 1, 5, and 10 minutes, respectively. She was transferred to the neonatal intensive care unit requiring ventilator support. She was morphologically abnormal, with a “blueberry muffin” facial rash that was body-sparing, a large posterior fontanel, a sunken anterior fontanel, and excess nuchal skin (Fig. 1A). Abdominal ultrasonogram was consistent with splenomegaly, and a neonatal echocardiogram confirmed a doubleoutlet right ventricle with subaortic ventricular septal defect, moderately thickened mitral, tricuspid, and aortic valves, and a small pericardial effusion. Thrombocytopenia
388
Lo et al
Jacobsen Syndrome
was present and significant for platelets of 18 K/mm3, and platelets and fresh-frozen plasma were transfused. Umbilical cord blood was sent for array comparative genomic hybridization (Fig. 1B), which revealed a 16-Mb deletion at band region 11q23.3 to the q terminus. G-banded chromosome analysis (450-band resolution) confirmed this deletion and was consistent with the diagnosis of Jacobsen syndrome or 11q deletion syndrome.
DISCUSSION Jacobsen syndrome is a rare deletion syndrome caused by a copy number loss of the long arm of chromosome 11.2 The prevalence is approximately 1 in 100,000 births with a female:male ratio of 2:1. The most common clinical features include growth restriction, psychomotor retardation, and characteristic dysmorphic facial features such as skull deformities, hypertelorism, coloboma, down-slanting palpebral fissures, epicanthal folds, a broad nasal bridge, short nose, V-shaped mouth, and small, low-set ears. Affected individuals commonly have cardiac, renal, gastrointestinal, genital, skeletal, and central nervous system anomalies that may require neonatal surgery. In addition, abnormal platelet function, thrombocytopenia, and pancytopenia are often present at birth. The deletion size varies considerably and ranges from 7 to 20 Mb with the proximal breakpoint at 11q23.3 with the loss typically extending to the telomere. This deletion is de novo in 85% of cases and inherited in 15%, most commonly secondary to a familial balanced translocation or other chromosomal rearrangement. Jacobsen syndrome is diagnosed by clinical findings and confirmed by cytogenetic analysis. Approximately 20% of children die within the first 2 years of life, most often as a result of congenital heart disease.2 There are no existing reported instances of prenatal diagnosis of Jacobsen syndrome detected by noninvasive prenatal testing based on a PubMed search for “noninvasive prenatal testing,” “Jacobsen syndrome,” “prenatal diagnosis,” “pregnancy,” or “subchromosomal microdeletion syndromes” through June 20, 2014. At least two commercially available noninvasive prenatal testing tests have expanded their platforms to screen for several microdeletion syndromes. Although the laboratory processing our patient’s noninvasive prenatal testing results did not officially report their findings, the suspected noninvasive prenatal testing results influenced the care of our patient. The parents were counseled regarding the possibility of Jacobsen syndrome and offered additional testing. Invasive diagnostic testing was declined, but consent
OBSTETRICS & GYNECOLOGY
Copyright ª by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Fig. 1. A. Neonate with petechiae and jaundice, diagnosed with Jacobsen syndrome. B. Postnatal cord blood karyotype; deletion is indicated by an arrow. Lo. Jacobsen Syndrome. Obstet Gynecol 2015
was obtained for neonatal cord blood collection for chromosome studies. Delivering providers were notified of the possibility of neonatal thrombocytopenia to consider in operative delivery planning. The laboratory performing the postnatal array was notified to expedite results for clinical decision-making. Medical specialties were prepared for possible neonatal complications associated with Jacobsen syndrome, including thrombocytopenia requiring serial transfusions of platelets and fresh-frozen plasma. Subchromosomal microdeletion syndromes are individually rare, and thus performing clinical studies to validate detection by noninvasive prenatal testing is not readily feasible given the sample size required. The benefit of this technology for the general population and in those without multiple congenital abnormalities is controversial because the detection and false-positive rates are not currently available. Counseling in such cases when a rare microdeletion
VOL. 125, NO. 2, FEBRUARY 2015
syndrome is suspected is therefore challenging. Our case demonstrates that noninvasive prenatal testing for microdeletion syndrome may be clinically useful when multiple fetal anomalies requiring coordinated specialty care are present and the patient declines invasive testing. As the clinical application of noninvasive prenatal testing continues to evolve, additional submicroscopic chromosomal information may be clinically helpful and should be confirmed with diagnostic testing until larger studies help further define the screening characteristics of noninvasive prenatal testing. REFERENCES 1. Noninvasive prenatal testing for fetal aneuploidy. Committee Opinion No. 545. American College of Obstetricians and Gynecologists. Obstet Gynecol 2012;120:1532–4. 2. Mattina T, Perrotta C, Grossfeld P. Jacobsen syndrome. Orphanet J Rare Dis 2009;4:9.
Lo et al
Jacobsen Syndrome
Copyright ª by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
389
