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Lysosomal storage disease as an etiology of nonimmune hydrops Alexis C. Gimovsky, MD; Paola Luzi, PhD; Vincenzo Berghella, MD
H
ydrops fetalis is a life-threatening fetal state that is defined by the pathologically increased fluid accumulation in fetal soft tissues and body cavities. Specifically, hydrops fetalis is diagnosed by the presence of 2 or more abnormal fluid collections in the fetus including ascites, pleural effusions, pericardial effusions, and skin edema.1 This condition is diagnosed by prenatal ultrasound. A subset of hydrops fetalis that is classified as nonimmune hydrops fetalis (NIH) is comprised of cases that are not caused by red blood cell alloimmunization. NIH accounts for almost 90% of cases of hydrops, 2 with an incidence of 1 in 1700-3000 pregnancies. 3,4 NIH is the end-stage manifestation of several disorders. The differential diagnosis is extensive (Table 1), and the success in identifying a cause depends on the extent of the workup.1 Table 2 represents an example of a basic pre- and postnatal workup for NIH.1 Although older studies report many cases as idiopathic,5-7 recent larger series and a recent systematic review report that a cause can be found in up to 85% of cases.8 Some of the most common causes of NIH are cardiac disorders (both structural malformations and arrhythmias), other structural malformations,
From the Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology (Drs Gimovsky and Berghella), Department of Neurology (Dr Luzi), Sidney Kimmel College of Medicine at Thomas Jefferson University, Philadelphia, PA. Received Aug. 21, 2014; revised Oct. 4, 2014; accepted Oct. 6, 2014. The authors report no conflict of interest. Corresponding author: Alexis Gimovsky, MD. [email protected] 0002-9378/$36.00 ª 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ajog.2014.10.007
We performed a systematic review of the literature to evaluate the incidence and types of lysosomal storage disorders (LSDs) in case series of nonimmune hydrops (NIH). PubMed and Ovid were reviewed for case series evaluating the workup of NIH diagnosed in utero or in the neonatal period in human subjects. Search terms were as follows: nonimmune hydrops, non immune hydrops, metabolic genetic disorders, and lysosomal storage disorders. The time period searched was 1979 through January 2014. Retrospective case series with at least 5 cases of fetal and/or neonatal NIH with its workup mentioned were identified. Idiopathic NIH was defined as NIH without an apparent cause after an initial workup. Exclusion criteria included studies published in languages other than English and review articles. The 3 authors screened all abstracts and manuscripts independently. Metaanalysis of Observational Studies in Epidemiology guidelines were followed. Fifty-four case series with 678 total cases of NIH were identified. The overall incidence of LSD was 5.2% (35 of 678) in all NIH cases that tested for any LSD and 17.4% (35 of 201) in idiopathic NIH cases. The 3 most common LSDs identified in cases of NIH, in order of decreasing incidence, were Mucopolysaccharidosis type VII, Gaucher’s disease, and GM1-gangliosidosis. LSDs occur in 5.2% of all NIH cases and in 17.4% of idiopathic NIH cases and so should be screened for in this clinical scenario. Additionally, if a comprehensive LSD workup is completed on idiopathic cases, 29.6% of those would be reclassified as LSD. LSD testing does not only allow diagnosis but also ensures better counseling, appropriate management, and planning for possible early intervention. Moreover, their detection may aid in a prenatal diagnosis in subsequent pregnancies. Key words: lysosomal storage disease, nonimmune hydrops, systematic review
chromosomal anomalies, infections, and hematological abnormalities.1
Materials and methods Lysosomal storage disorders (LSDs) have been reported to account for about 115% of the causes of NIH cases,4,9-11 yet in clinical practice, these LSDs are often not evaluated. Our objective was to evaluate, by review of the literature, the significance of LSDs as the underlying etiology of NIH and whether evaluating for LSDs would be clinically useful in the workup of NIH. Methods for review PubMed and Ovid were reviewed for case series evaluating the workup of NIH diagnosed in utero or in the neonatal period in human subjects. Search terms were as follows: nonimmune
hydrops, non immune hydrops, metabolic genetic disorders, and lysosomal storage disorders. The time period searched was 1979 through January 2014. Exclusion criteria were studies published in languages other than English, abstracts, unpublished studies, and review articles. Hand searching was also done using reference lists of obtained articles. The literature search was done by 2 investigators (A.C.G. and V.B.). Retrospective studies and case series with cases of NIH with its workup described were identified. We included manuscripts with at least 5 cases of NIH to minimize publication bias. The criteria for the diagnosis of NIH were recorded. Three reviewers (A.C.G., V.B., and P.L.) screened all abstracts and manuscripts independently. Articles were
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TABLE 1
List of most commonly reported causes of NIH Conditions associated with NIH
Approximate percentage of NIH associated with condition
Cardiovascular
30%
Fetal arrhythmias Structural Cardiac/thoracic mass High cardiac output failure Vascular disorders Extracardiac anomalies
20%
Thorax Urinary Gastrointestinal Skeletal dysplasias Chromosomal abnormalities
20%
45x (or mosaic 45X/46XX) trisomy 21, trisomy 18, trisomy 13, triploidy Infections
10%
Hematologic
5-10%
Red cells loss Underproduction Monochorionic twin pregnancy
5%
Metabolic/genetic syndromes
2-6%
NIH, nonimmune hydrops. Adapted, with permission, from Berghella et al.1 Gimovsky. Systematic review of LSD in NIH. Am J Obstet Gynecol 2015.
screened for comparability of cases, and large studies were reviewed for overlapping cases. References for included articles are provided in the Reference section, and references excluded from the article are available from the authors upon request. In each article reporting the workup of NIH, the details of the workup (eg, ultrasound, karyotype, etc) were recorded, including any metabolic tests, such as LSD. Pre- vs postnatal workups were recorded. If no diagnosis was identified as the probable cause for the NIH after the initial workup, the case was defined as idiopathic. Each case series with 5 or more cases of NIH was evaluated for testing for LSD. LSD was defined as a category of
metabolic disorders caused by defects in the lysosomal function, resulting in the accumulation of undegraded materials that triggers a cascade of pathological outcomes.12 The Methods section of each article was evaluated to see which LSDs were screened and how many of the cases of NIH received this LSD screening (Table 3). Only cases of LSD confirmed by enzymatic or genetic tests were included. Which LSDs were the most commonly tested for was evaluated. Our primary outcome was the incidence of any LSD in the studies of NIH in which LSDs were tested. The Metaanalysis of Observational Studies in Epidemiology guidelines were followed for systematic review of observational
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Results The Figure reports the data extraction. Of the 54 case series reporting a workup for NIH, 15 (27.8%) reported testing for LSD.9,10,14-26 In these 15 series, a diagnosis as probable etiology for NIH was detected in 512 of 678 cases (75.5%) (Tables 3 and 4). One study27 reported genetic diagnoses but did not define what was included in that category. Another series28 had 10 cases of LSDs, but not all were NIH and we were unable to find out which cases were associated with NIH and which ones were not correlated. In comparison, in the other 39 series without an LSD workup, a diagnosis was achieved in 2028 of 2464 cases (82.3%). In the 15 series of NIH in which the LSD workup was done, the diagnosis of NIH was often made using slightly different criteria (Table 3). The initial workup for NIH differed in each study, and for some studies the initial workup was not described. In the workup for LSD, most studies (10 of 15, 67%) did not mention specific tests that were ordered, whereas others (5 of 15, 33%) did provide the exact tests for which LSDs were tested (Table 3). It is unclear whether LSD testing was completed in all cases within the series. We cannot report on the average number of LSDs tested per study because many are not listed. The majority of studies in which LSDs were tested had their workup for NIH done both pre- and postnatally (53%). Three studies made the diagnosis prenatally, 5 studies made postnatal diagnoses, and 7 studies used a combination of both methods. Of the postnatally diagnosed cases, many were diagnosed only after delivery. Table 4 shows the results of positive LSDs that were diagnosed from the 15 studies that tested for LSDs. Of the 678 total NIH cases identified, 477 (70.3%) had a diagnosis other than LSD, 166 (24.5%) were idiopathic, and 35 (5.2%) were diagnosed with LSD
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TABLE 2
Example of basic pre- and postnatal workup of NIH Step 1: prenatal
Step 1: neonatala
Maternal work up
Blood
CBC (MCV in particular), hemoglobin electrophoresis, RPR, Kleinhaur-Betke, serology for parvovirus, CMV, toxoplasmosis, rubella
Urea, electrolytes, creatinine, protein, albumin, protein electrophoresis, liver function tests, bilirubin, osmolality, CBC, hemoglobin electrophoresis, serology for parvovirus, CMV, toxoplasmosis, rubella, karyotype, microarray Urine Albumineexclude congenital nephrotic syndrome
Fetal workup
Ascitic fluid/pleural fluid
Detailed anatomy ultrasound, including MCA PSV; fetal echocardiography, microarray
Protein, albumin, lipid analysis to check for chylous secretion, micro, virology, microarray Other Chest X-ray, electrocardiogram, ultrasound of heart, kidney, brain, autopsy Step 2: neonatala
Step 2: prenatal LSD testing
LSD testing
CBC, complete blood count; CMV, cytomegalovirus; G6PD, glucose-6-phosphate dehydrogenase deficiency; LSD, lysosomal storage disorders; MCA PSV, middle cerebral artery peak systolic velocity; MCV, mean corpuscular volume; RPR, rapid plasma reagin. a
Some tests may be omitted if already done prenatally. Adapted, with permission, from Berghella et al.1
Gimovsky. Systematic review of LSD in NIH. Am J Obstet Gynecol 2015.
(Table 4). The incidence of LSD in the cases without an initial diagnosis was 17.4% (35 of 201, with 201 being the sum of 35 LSD cases and 166 idiopathic cases). When analyzing the 2 studies that had extensive workup for LSD,10,25 86 NIH cases were identified, of which 59 (68.6%) had an initial diagnosis, 19 (22.1%) were idiopathic, and 8 (9.3%) were LSDs. The incidence of LSDs in the cases without an initial diagnosis was 29.6% (8 of 27, with 27 being the sum of 8 LSD cases and 19 idiopathic cases). Table 5 lists in order of frequency the LSDs that were most commonly diagnosed in the 15 studies. The most common LSD identified in cases of NIH, in order of decreasing incidence, were mucopolysaccharidosis type VII, Gaucher’s disease, GM1gangliosidosis, sialidosis, mucopolysaccharidosis (type not specified), Niemann-Pick disease type C, galactosialidosis, infantile sialic acid storage disease, Niemann-Pick type A
disease, mucopolysaccharidosis type IVa and mucolipidosis II.
Comment Several interesting issues are revealed by this literature review of case series of NIH with special emphasis on details of the workup for LSD. First, most series reporting the workup for NIH (72.2%) did not test for LSDs. Nonetheless, the initial work-up, whether pre- or postnatal, for the etiology of NIH reveals a probable diagnosis in approximately 75-82% of the cases. The incidence of idiopathic NIH was 17.7% in none LSD-tested vs 24.5% in LSD-tested case series. It is noteworthy that the researchers who performed the most extensive evaluations had the higher idiopathic rate. The fact that cases that were not tested for LSDs had a higher incidence of a diagnosis is counterintuitive, but expected, because once a probable diagnosis is found, there is no need for further workup (eg, LSD testing).
Unfortunately, the details of the initial NIH workup are often not mentioned in these case series (Table 3). Common etiologies of NIH (Table 1)1 and examples of the initial basic workup for NIH (Table 2)1 have been reported, but every study should provide its own details of workup and probable causes. Because most studies have not evaluated for LSDs, it can be assumed that usually, when the initial assessment reveals the diagnosis, the workup for LSD is omitted. It is likely that clinicians send an initial NIH workup and only test for LSD if the initial workup fails to identify a probable diagnosis as etiology. Indeed, the LSD workup may not always be necessary (eg, in cases of NIH diagnosed before 20 weeks’ gestation because 78% of these have chromosome abnormalities).29 Second, in the 18-30% of cases in which the initial NIH workup did not reveal a probable etiology, testing for LSDs resulted in a diagnosis in 17.4% of cases (Table 4). This is probably an underestimation because not all LSDs
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TABLE 3
Case series of NIH reporting LSD testing Author/year (oldest to newest) Mahony et al, 1984
14
Location
Cases of NIH Criteria for diagnosis of NIH
NIH initial workup
List of metabolic diseases tested for
Prenatal vs postnatal workup Comments
United States
27
Generalized skin thickening. and/or 2 of the following: placental enlargement, pericardial effusion, pleural effusion, and ascites
Ultrasound, other workup not specified
Not specified
Prenatal
Im et al, 19849
Canada
20
By ultrasound: a double fetal abdominal or scalp contour and fetal ascites. Postmortem generalized edema, accumulation of fluid in fetal serous compartments, and edema throughout placenta
Ultrasound, other workup not specified
Not specified
Both
McFadden and Taylor, 198915
Canada
90
NIH listed as a diagnosis (from autopsy) or with criteria for the diagnosis of NIH
Autopsy
Not specified
Postnatal
McCoy et al, 199516
United States
82
Presence of excess fluid in 2 sites
Thoracentesis, paracentesis, autopsy, karyotype, detailed ultrasound
Not specified
Both
Rejjal et al, 199617
Saudi Arabia
17
Presence of 2 of the following features by prenatal ultrasound: generalized gross subcutaneous edema, ascites, pleural effusion, pericardial effusion, plus the absence of antibodies to red blood cell antigens
Ultrasound, maternal antibody screen, echocardiogram, CBC, chromosomal analysis, TORCH, and parvovirus B19 testing
Not specified
Both
Groener et al, 199918
The Netherlands
17
Excessive fluid accumulation within fetal extravascular compartments and body cavities in cases not caused by red cell alloimmunization
Fetal blood samples
GM1-gangliosidosis Gaucher’s disease Mucopolysaccharidosis IVa Mucopolysaccharidosis VII
Prenatal
Recep, 200119
Turkey
30
Edema with effusion in at least 1 body cavity and skin edema or serous effusion in >1 body space
Ultrasound, maternal type and screen, TORCH titers, parvovirus B19 testing, karyotype, autopsy, echocardiography, and metabolic testing
Investigation for metabolic syndromes in selected cases
Both
(continued)
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Gimovsky. Systematic review of LSD in NIH. Am J Obstet Gynecol 2015.
51% diagnosed before autopsy; karyotypes were available for 14/18 idiopathic cases
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TABLE 3
Case series of NIH reporting LSD testing (continued) Author/year (oldest to newest)
Location
Cases of NIH Criteria for diagnosis of NIH
NIH initial workup
List of metabolic diseases tested for
Prenatal vs postnatal workup Comments
Brazil
29
One or more clinical signs, such as anasarca, peripheral edema, ascites, pericardial and/or pleural effusions, anemia, congestive heart failure, and hypoalbuminemia
Autopsy, ultrasound, echocardiography, karyotype, infectious workup, CBC, maternal type, and screen
Not specified
Both
Burin et al, 200410
Brazil
33
Not specified
Specific enzymatic analysis for lysosomal storage disorders by amniocentesis, autopsy, karyotype, viral studies, TORCH titers, parvovirus testing, coxsackie testing, fetal echocardiography, hemoglobin electrophoresis CBC, maternal type and screen, detailed ultrasound
Gaucher’s disease GM1-gangliosidosis Mucopolysaccharidosis I Mucopolysaccharidosis II Mucopolysaccharidosis IVa Mucopolysaccharidosis VII Niemann-Pick A/B Mucolipidosis II Sialic acid storage disease Sialidosis
Both
Reference center for LSDs
Favre et al, 200421
France
79
Fetal ascites
Detailed ultrasound, fetal echocardiography, maternal type and screen, TORCH titers, parvovirus B19 testing, karyotype, amniocentesis for cytomegalovirus, parvovirus, toxoplasmosis, cystic fibrosis screening, autopsy
Not specified
Postnatal
This study looked at both fetal hydrops and isolated ascites
Rodriguez et al, 200522 United States
32
Generalized soft tissue edema and presence of fluid in at least 1 of the pericardial, pleural, and peritoneal cavities
Ultrasound, CBC, maternal type and screen, rapid plasma reagin, blood cultures, autopsy, infectious workup
Tested enzyme levels on autopsy
Postnatal
One of the idiopathic fetuses had “histologic features of a lysosomal storage disease . but specific enzymatic defect could not be proved”
Kooper et al, 200623
The Netherlands
75
Presence of excessive fluid in >1 body cavity
Not specified
GM1-gangliosidosis Gaucher’s disease Niemann-Pick A/B Mucopolysaccharidosis I Mucopolysaccharidosis VII Sialidosis
Postnatal
Four definite cases and 2 probable cases of LSDs. This is a study evaluating reference values of lysosomal enzymes in NIH.
Gort et al, 201224
Spain
30
Excessive fluid accumulation in >1 fetal compartments and body cavities
LSDs were investigated in all, amniocentesis
Gaucher’s disease GM1-gangliosidosis Mucopolysaccharidosis VII
Prenatal
Reference center for LSDs
285
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(continued)
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Mascaretti et al, 200320
Gimovsky. Systematic review of LSD in NIH. Am J Obstet Gynecol 2015.
678 Total cases
Hasnani-Samnani et al, 201326
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CBC, complete blood count; LSD, lysosomal storage disorders; MCA, middle cerebral artery; NIH, nonimmune hydrops; TORCH, testing for toxoplasmosis, syphilis, rubella, cytomegalovirus, herpes.
Qatar
64
Signs suggesting NIH
CBC, thalassemia screening, Kleinhauer-Betke, TORCH titers, parvovirus B19 testing, karyotype, echocardiography, MCA Dopplers, detailed ultrasound
Metabolic investigation. was done for only a few cases and was negative
Both
Reference center for LSD Both GM1-Gangliosidosis Gaucher’s disease Mucopolysaccharidosis I Mucopolysaccharidosis II Mucopolysaccharidosis IVa Mucopolysaccharidosis VII Mucolipidosis II Niemann-Pick A/B Sialidosis Sialic acid storage disorders Detailed ultrasound, fetal echocardiography, karyotype, TORCH titers, CBC, hemoglobin electrophoresis, inborn errors of metabolism testing, autopsy All patients with NIH referred to their center 53 Brazil Moreno et al, 2013
NIH initial workup Location
Cases of NIH Criteria for diagnosis of NIH Author/year (oldest to newest)
Case series of NIH reporting LSD testing (continued)
TABLE 3
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25
List of metabolic diseases tested for
Prenatal vs postnatal workup Comments
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were tested for in these studies. In fact, it was impractical to estimate how many LSDs were tested for in each study because many of the studies did not list every disease or enzyme tested. For example, 3 studies listed Mucopolysaccharidosis as a diagnosis without specifying the type. We can only conjecture that this refers to types VII, I, and IVa because these are the only 3 mucopolysaccharidoses associated with NIH. However, we know that 14 LSDs have been associated with NIH.30 Two studies had a comprehensive evaluation of LSDs. In these studies, the laboratories used either amniotic fluid supernatant or amniocytes prenatally or plasma testing, leukocytes, or fibroblasts (in the postnatal period) to measure enzymatic activity. These laboratories tested 10 different diseases.10,25 Table 5 shows the enzymatic correlation to specific diseases. Importantly, these studies with a comprehensive evaluation of LSDs were done in national reference centers.10,25 If we look at the evidence from the 2 studies with comprehensive testing for LSDs and if we assume that LSDs were not initially tested for, then we can estimate that 29.6% of those cases that would have been classified as idiopathic would have had a diagnosis of LSD. Clearly, the more comprehensive the LSD workup is, the higher the chance of reaching a diagnosis. Interestingly, in these 2 studies with 8 cases of LSD, 4 of the pregnancies had a recurrence of NIH or a recurrence of findings suggestive of LSDs in previous pregnancies.10,25 Some LSDs previously associated with NIH were not detected in our literature review because these were described in isolated case reports and not in series with 5 or more cases of NIH. In the case series, which diminish ascertainment bias compared with case reports, the more common positive LSDs were Mucopolysaccharidosis type VII, Gaucher’s disease, and GM1gangliosidosis (Table 5). Third, given that a diagnosis of LSD was made in 17.4% of cases of the
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ajog.org idiopathic NIH cases overall in which the initial workup failed to identify a cause of hydrops and 24.6% of those idiopathic NIH cases in which a more comprehensive LSD workup was done, it seems that if the initial NIH workup is negative, comprehensive LSD testing should be ordered (Table 5). Therefore, we suggest a 2-step approach. First, common causes of NIH should be evaluated as suggested in Table 2. Subsequently, for cases that remain as idiopathic after the initial NIH workup, testing for LSDs should be done. Prenatal LSD testing allows not only the diagnosis but also allows the options for termination, better counseling, appropriate management, and planning for possible early intervention. Moreover, their detection may aid in prenatal diagnosis in subsequent pregnancies because the LSDs associated with NIH have an autosomal recessive mode of inheritance. Prenatal LSD diagnosis is performed by enzyme analysis of fetal cells obtained by chorionic villus sampling or amniocentesis. Table 5 lists the genetic disease and associated enzymatic deficiency tested for. These 14 diseases are the only known inborn errors of metabolism associated with NIH. Enzymatic diagnosis of all LSDs can be easily done in a specialized laboratory on a blood sample, amniocytes, or fibroblasts (Appendix). Knowledge of the DNA mutations in the proband or in the heterozygous parents allows the use of DNA mutation analysis for prenatal diagnosis. Mutation analysis is recommended because a confirmatory assay is more accurate for prenatal diagnosis in a future pregnancy and can aid preimplantation genetic diagnosis. The most obvious shortcoming of our study is the fact that a review such as ours can only be as good as the published series. There is certainly substantial ascertainment bias in the literature. To establish the true incidence of LSDs in NIH, all idiopathic cases after the basic disease workup should be tested for all LSDs that have been associated with NIH (Table 5). The only studies with an extensive
FIGURE
Flow diagram
This figure illustrates the flow diagram, indicating inclusion and exclusion of articles, and the article numbers. Gimovsky. Systematic review of LSD in NIH. Am J Obstet Gynecol 2015.
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TABLE 4
LSD cases reported in case series of NIH Total NIH cases
Author/year 14
Mahony et al, 1984
Total cases with known diagnosis (excluding LSD)
Total idiopathic cases
Total LSD cases
Specific LSD type (n)
27
22 (81.0%)
4 (15.0%)
1 (3.7%)
Mucopolysaccharidosis (1)
20
12 (60.0%)
5 (25/0%)
3 (15%)
Gaucher disease (3)
90
70 (77.8%)
16 (17.8%)
4 (4.4%)
Mucopolysaccharidosis (2), Gaucher disease (1), Sialidosis (1)
McCoy et al, 199516
82
62 (75.6%)
18 (22.0%)
2 (2.4%)
Gaucher disease (1), Niemann-Pick disease type C (1)
Rejjal et al, 199617
17
6 (35.3%)
9 (52.9%)
2 (11.8%)
GM1-gangliosidosis (1), mucopolysaccharidosis (1)
Groener et al, 199918
17
8 (47.1%)
8 (47.1%)
1 (5.9%)
Mucopolysaccharidosis VII (1)
30
27 (90.0%)
3 (10.0%)
0 (0%)
N/A
9
Im et al, 1984
McFadden and Taylor, 1989
15
19
Recep, 2001
Mascaretti et al, 2003
20
29
20 (69.0%)
8 (27.6%)
1 (3.4%)
GM1-gangliosidosis (1)
10
Burin et al, 2004
33
16 (48.5%)
12 (36.4%)
5 (15.1%)
Mucolipidosis (1), Niemann-Pick A disease (1), galactosialidosis (1), sialidosis (1), mucopolysaccharidosis IVa (1)
Favre et al, 200421
79
60 (75.9%)
12 (15.2%)
7 (8.8%)
Sialidosis (2), mucopolysaccharidosis VII (3), Niewman Pick C (2)
Rodriguez et al, 200522
32
30 (93.8%)
2 (6.3%)
0 (0%)
N/A
Kooper et al, 2006
75
71 (94.7%)
0 (0%)
4 (5.3%)
Galactosialidosis (1), GM1-gangliosidosis (1), mucopolysaccharidosis VII (2)
Gort et al, 201224
30
28 (93.3%)
2 (6.7%)
Mucopolysaccharidosis VII (1), Gaucher disease (1)
Moreno et al, 201325
53
43 (81.1%)
7 (13.2%)
3 (5.7%)
GM1-gangliosidosis (2), infantile sialic acid storage disease (1)
Hasnani-Samnani et al, 201326
64
37 (57.8%)
27 (42.2%)
0 (0%)
N/A
678
477 (70.3)
23
Total, n (%)
0 (0%)
166 (24.5)
35 (5.2)
LSD, lysosomal storage disorders; N/A, not available; NIH, nonimmune hydrops. Gimovsky. Systematic review of LSD in NIH. Am J Obstet Gynecol 2015.
(but not complete) screening for LSDs in idiopathic NIH cases were represented by Moreno et al25 and Burin et al.10 The studies that describe the most extensive methodology were studies done at referral centers for LSDs.10,25 This makes intuitive sense because patients were sent to these referral centers specifically to look for LSDs. Although we did not consider the study by Kooper et al23 a comprehensive evaluation, this study was also performed at a reference
center, specifically looking for reference values of lysosomal enzymes in NIH; thus, the diagnosis might not have been the main objective. Additionally, we excluded manuscripts with fewer than 5 cases of NIH, but this was done to minimize publication bias. Studies were excluded if they were reported in a non-English language. Our objective was to evaluate the significance of LSDs as an etiology of NIH, so other inborn errors of metabolisms were not included in our study.
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There are 3 prior reviews of NIH case series in the literature. Bellini et al8 compiled a very thorough review of cases and classifications of the etiologies of NIH but did not delve into the workup. The review by Machin4 from 1989 had the most extensive list of cases of any prior study on NIH (1414 cases) but was limited because almost half of the cases studied were case reports. Jauniaux et al31 in 1990 wrote a large review paper of 600 cases of NIH, but his study was also limited by the fact that all of the LSD cases
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TABLE 5
Most commonly diagnosed LSD in cases of NIH LSD
Enzyme defect
Number of cases, %
Mucopolysaccharidosis type VII
Beta-glucuronidase
7 (20.0)
Gaucher’s disease
Glucocerebrosidase
6 (17.1)
GM1-gangliosidosis
Beta-galactosidase
5 (14.3)
Sialidosis
Sialidase
4 (11.4)
Mucopolysaccharidosis type not specified
Not applicable
4 (11.4)
Niemann-Pick disease type C
NPC1, NPC2
3 (8.5)
Galactosialidosis
Protective protein cathepsin A
2 (5.7)
Infantile sialic acid storage disease
Transport protein
1 (2.9)
Niemann-Pick A disease
Sphingomyelinase
1 (2.9)
Mucopolysaccharidosis type Iva
N-acetylgalactosamine-6-sulfatase
1 (2.9)
Mucolipidosis II
UDP-N-Ac-glucosaminyl phosphotransferase
1 (2.9)
Mucopolysaccharidosis I
A-iduronidase
0 (0)
Infantile sialic acid storage disease
Transport protein
0 (0)
Wolman disease
Acid lipase
0 (0)
Farber disease
Acid ceramidase
0 (0)
Multiple sulfatase deficiency
Sulfatase modifier protein
0 (0)
Total
35
LSD, lysosomal storage disorders; NIH, nonimmune hydrops. Gimovsky. Systematic review of LSD in NIH. Am J Obstet Gynecol 2015.
came from case reports. Therefore, our study is the only comprehensive literature case series review of the workup of NIH for LSD, starting from more than 2000 NIH reports. -
REFERENCES 1. Gomez R, Kusanovic J, Medina L. Non immune hydrops. In: Berghella V, ed. Maternalfetal evidence based guidelines, 2nd ed. London, UK: Informa Healthcare; 2012:382. 2. Sohan K, Carroll SG, De La Fuente S, Soothill P, Kyle P. Analysis of outcome in hydrops fetalis in relation to gestational age at diagnosis, cause and treatment. Acta Obstet Gynecol Scand 2001;80:726. 3. Heinonen S, Ryynänen M, Kirkinen P. Etiology and outcome of second trimester non-immunologic fetal hydrops. Acta Obstet Gynecol Scand 2000;79:15-8. 4. Machin GA. Hydrops revisited: literature review of 1,414 cases published in the 1980s. Am J Med Genet 1989;34:366-90. 5. Wy CA, Sajous CH, Loberiza F, Weiss MG. Outcome of infants with a diagnosis of hydrops fetalis in the 1990s. Am J Perinatol 1999;16: 561-7.
6. Larroche JC, Aubry MC, Narcy F. Intrauterine brain damage in nonimmune hydrops fetalis. Biol Neonate 1992;61:273-80. 7. Laneri GG, Classen DL, Scher MS. Brain lesions of fetal onset in encephalopathic infants with nonimmune hydrops fetalis. Pediatr Neurol 1994;11:18-22. 8. Bellini C, Hennekam RC, Fulcheri E, et al. Etiology of nonimmune hydrops fetalis: a systematic review. Am J Med Genet A 2009;149A: 844-51. 9. Im SS, Rizos N, Joutsi P, Shime J, Benzie RJ. Nonimmunologic hydrops fetalis. Am J Obstet Gynecol 1984;148:566-9. 10. Burin MG, Scholz AP, Gus R, et al. Investigation of lysosomal storage diseases in nonimmune hydrops fetalis. Prenat Diagn 2004;24: 653-7. 11. Bellini C, Hennekam RC. Non-immune hydrops fetalis: a short review of etiology and pathophysiology. Am J Med Genet A 2012;158A:597-605. 12. Wenger DA, Luzi P, Rafi MA. Lysosomal storage diseases: heterogeneous group of disorders. BioImpacts 2013;3:145-7. 13. Stroup DF, Berlin JA, Morton SC, et al. Metaanalysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) Group. JAMA 2000;283:2008-12.
14. Mahony BS, Filly RA, Callen PW, Chinn DH, Golbus MS. Severe nonimmune hydrops fetalis: sonographic evaluation. Radiology 1984;151: 757-61. 15. McFadden DE, Taylor GP. Cardiac abnormalities and nonimmune hydrops fetalis: a coincidental, not causal, relationship. Pediatr Pathol 1989;9:11-7. 16. McCoy MC, Katz VL, Gould N, Kuller JA. Non-immune hydrops after 20 weeks’ gestation: review of 10 years’ experience with suggestions for management. Obstet Gynecol 1995;85: 578-82. 17. Rejjal AR, Rahbeeni Z, al-Zahrani AF. Prognostic factors and prenatal management in non immune hydrops fetalis are still a dilemma. J Perinat Med 1996;24:461-6. 18. Groener JE, de Graaf FL, Poorthuis BJ, Kanhai HH. Prenatal diagnosis of lysosomal storage diseases using fetal blood. Prenat Diagn 1999;19:930-3. 19. Recep H. Non-immune hydrops fetalis in the first trimester: a review of 30 cases. Clin Exp Obstet Gynecol 2001;28:187-90. 20. Mascaretti RS, Falcao MC, Silva AM, Vaz FA, Leone CR. Characterization of newborns with nonimmune hydrops fetalis admitted to a neonatal intensive care unit. Rev Hosp Clin Fac Med Sao Paulo 2003;58: 125-32.
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Systematic Reviews 21. Favre R, Dreux S, Dommergues M, et al. Nonimmune fetal ascites: a series of 79 cases. Am J Obstet Gynecol 2004;190: 407-12. 22. Rodriguez MM, Chaves F, Romaguera RL, Ferrer PL, de la Guardia C, Bruce JH. Value of autopsy in nonimmune hydrops fetalis: series of 51 stillborn fetuses. Pediatr Dev Pathol 2002;5:365-74. 23. Kooper AJ, Janssens PM, de Groot AN, et al. Lysosomal storage diseases in non-immune hydrops fetalis pregnancies. Clin Chim Acta 2006;371:176-82. 24. Gort L, Granell MR, Fernandez G, Carreto P, Sanchez A, Coll MJ. Fast protocol for the diagnosis of lysosomal diseases in nonimmune hydrops fetalis. Prenat Diagn 2012;32: 1139-42. 25. Moreno CA, Kanazawa T, Barini R, et al. Non-immune hydrops fetalis: A prospective study of 53 cases. Am J Med Genet A 2013;161A:3078-86. 26. Hasnani-Samnani Z, Mahmoud MI, Farid I, Al Naggar E, Ahmed B. Non-immune hydrops: Qatar experience. J Matern Fetal Neonatal Med 2013;26:449-53. 27. Haverkamp F, Noeker M, Gerresheim G, Fahnenstich H. Good prognosis for psychomo-
ajog.org tor development in survivors with nonimmune hydrops fetalis. BJOG 2000;107:282-4. 28. Piraud M, Froissart R, Mandon G, Bernard A, Maire I. Amniotic fluid for screening of lysosomal storage diseases presenting in utero (mainly as non-immune hydrops fetalis). Clin Chim Acta 1996;248:143-55. 29. Iskaros J, Jauniaux E, Rodeck C. Outcome of nonimmune hydrops fetalis diagnosed during the first half of pregnancy. Obstet Gynecol 1997;90:321-5. 30. Whybra C, Mengel E, Russo A, et al. Lysosomal storage disorder in non-immunological hydrops fetalis (NIHF): more common than assumed? Report of four cases with transient NIHF and a review of the literature. Orphanet J Rare Dis 2012;7:86. 31. Jauniaux E, Van Maldergem L, De Munter C, Moscoso G, Gillerot Y. Nonimmune hydrops fetalis associated with genetic abnormalities. Obstet Gynecol 1990;75(3 Pt 2): 568-72.
Appendix Generally, requirements for testing include the following: amniocytes (cultured form 25 mL of amniotic fluid; no
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additional fluid needed if sending for karyotype/microarray), skin fibroblasts (cultured from skin biopsy), or 5-8 mL of whole blood for screening tests or 4-6 mL of whole blood for a single disease test. These samples may be sent to reference laboratories such as the Lysosomal Disease Testing Laboratory at Sidney Kimmel College of Medicine at Thomas Jefferson University, Philadelphia, PA; Emory University School of Medicine, Emory Molecular Genetics Laboratory, Atlanta, GA; Greenwood Genetic Center Diagnostic Laboratories, Baylor Research Institute, Institute of Metabolic Disease, Dallas, TX; Mayo Clinic-Minnesota, Molecular Genetics Laboratory, Rochester, MN. Turnaround time is generally 7-14 days for enzymatic testing and several weeks for DNA testing. Cost varies from $300 to $4500, depending on enzymatic vs DNA testing and insurance coverage.
ajog.org
Lysosomal storage disease as an etiology of nonimmune hydrops Alexis C. Gimovsky, MD; Paola Luzi, PhD; Vincenzo Berghella, MD
H
ydrops fetalis is a life-threatening fetal state that is defined by the pathologically increased fluid accumulation in fetal soft tissues and body cavities. Specifically, hydrops fetalis is diagnosed by the presence of 2 or more abnormal fluid collections in the fetus including ascites, pleural effusions, pericardial effusions, and skin edema.1 This condition is diagnosed by prenatal ultrasound. A subset of hydrops fetalis that is classified as nonimmune hydrops fetalis (NIH) is comprised of cases that are not caused by red blood cell alloimmunization. NIH accounts for almost 90% of cases of hydrops, 2 with an incidence of 1 in 1700-3000 pregnancies. 3,4 NIH is the end-stage manifestation of several disorders. The differential diagnosis is extensive (Table 1), and the success in identifying a cause depends on the extent of the workup.1 Table 2 represents an example of a basic pre- and postnatal workup for NIH.1 Although older studies report many cases as idiopathic,5-7 recent larger series and a recent systematic review report that a cause can be found in up to 85% of cases.8 Some of the most common causes of NIH are cardiac disorders (both structural malformations and arrhythmias), other structural malformations,
From the Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology (Drs Gimovsky and Berghella), Department of Neurology (Dr Luzi), Sidney Kimmel College of Medicine at Thomas Jefferson University, Philadelphia, PA. Received Aug. 21, 2014; revised Oct. 4, 2014; accepted Oct. 6, 2014. The authors report no conflict of interest. Corresponding author: Alexis Gimovsky, MD. [email protected] 0002-9378/$36.00 ª 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ajog.2014.10.007
We performed a systematic review of the literature to evaluate the incidence and types of lysosomal storage disorders (LSDs) in case series of nonimmune hydrops (NIH). PubMed and Ovid were reviewed for case series evaluating the workup of NIH diagnosed in utero or in the neonatal period in human subjects. Search terms were as follows: nonimmune hydrops, non immune hydrops, metabolic genetic disorders, and lysosomal storage disorders. The time period searched was 1979 through January 2014. Retrospective case series with at least 5 cases of fetal and/or neonatal NIH with its workup mentioned were identified. Idiopathic NIH was defined as NIH without an apparent cause after an initial workup. Exclusion criteria included studies published in languages other than English and review articles. The 3 authors screened all abstracts and manuscripts independently. Metaanalysis of Observational Studies in Epidemiology guidelines were followed. Fifty-four case series with 678 total cases of NIH were identified. The overall incidence of LSD was 5.2% (35 of 678) in all NIH cases that tested for any LSD and 17.4% (35 of 201) in idiopathic NIH cases. The 3 most common LSDs identified in cases of NIH, in order of decreasing incidence, were Mucopolysaccharidosis type VII, Gaucher’s disease, and GM1-gangliosidosis. LSDs occur in 5.2% of all NIH cases and in 17.4% of idiopathic NIH cases and so should be screened for in this clinical scenario. Additionally, if a comprehensive LSD workup is completed on idiopathic cases, 29.6% of those would be reclassified as LSD. LSD testing does not only allow diagnosis but also ensures better counseling, appropriate management, and planning for possible early intervention. Moreover, their detection may aid in a prenatal diagnosis in subsequent pregnancies. Key words: lysosomal storage disease, nonimmune hydrops, systematic review
chromosomal anomalies, infections, and hematological abnormalities.1
Materials and methods Lysosomal storage disorders (LSDs) have been reported to account for about 115% of the causes of NIH cases,4,9-11 yet in clinical practice, these LSDs are often not evaluated. Our objective was to evaluate, by review of the literature, the significance of LSDs as the underlying etiology of NIH and whether evaluating for LSDs would be clinically useful in the workup of NIH. Methods for review PubMed and Ovid were reviewed for case series evaluating the workup of NIH diagnosed in utero or in the neonatal period in human subjects. Search terms were as follows: nonimmune
hydrops, non immune hydrops, metabolic genetic disorders, and lysosomal storage disorders. The time period searched was 1979 through January 2014. Exclusion criteria were studies published in languages other than English, abstracts, unpublished studies, and review articles. Hand searching was also done using reference lists of obtained articles. The literature search was done by 2 investigators (A.C.G. and V.B.). Retrospective studies and case series with cases of NIH with its workup described were identified. We included manuscripts with at least 5 cases of NIH to minimize publication bias. The criteria for the diagnosis of NIH were recorded. Three reviewers (A.C.G., V.B., and P.L.) screened all abstracts and manuscripts independently. Articles were
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ajog.org studies.13 This study was exempt from institutional review board approval.
TABLE 1
List of most commonly reported causes of NIH Conditions associated with NIH
Approximate percentage of NIH associated with condition
Cardiovascular
30%
Fetal arrhythmias Structural Cardiac/thoracic mass High cardiac output failure Vascular disorders Extracardiac anomalies
20%
Thorax Urinary Gastrointestinal Skeletal dysplasias Chromosomal abnormalities
20%
45x (or mosaic 45X/46XX) trisomy 21, trisomy 18, trisomy 13, triploidy Infections
10%
Hematologic
5-10%
Red cells loss Underproduction Monochorionic twin pregnancy
5%
Metabolic/genetic syndromes
2-6%
NIH, nonimmune hydrops. Adapted, with permission, from Berghella et al.1 Gimovsky. Systematic review of LSD in NIH. Am J Obstet Gynecol 2015.
screened for comparability of cases, and large studies were reviewed for overlapping cases. References for included articles are provided in the Reference section, and references excluded from the article are available from the authors upon request. In each article reporting the workup of NIH, the details of the workup (eg, ultrasound, karyotype, etc) were recorded, including any metabolic tests, such as LSD. Pre- vs postnatal workups were recorded. If no diagnosis was identified as the probable cause for the NIH after the initial workup, the case was defined as idiopathic. Each case series with 5 or more cases of NIH was evaluated for testing for LSD. LSD was defined as a category of
metabolic disorders caused by defects in the lysosomal function, resulting in the accumulation of undegraded materials that triggers a cascade of pathological outcomes.12 The Methods section of each article was evaluated to see which LSDs were screened and how many of the cases of NIH received this LSD screening (Table 3). Only cases of LSD confirmed by enzymatic or genetic tests were included. Which LSDs were the most commonly tested for was evaluated. Our primary outcome was the incidence of any LSD in the studies of NIH in which LSDs were tested. The Metaanalysis of Observational Studies in Epidemiology guidelines were followed for systematic review of observational
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Results The Figure reports the data extraction. Of the 54 case series reporting a workup for NIH, 15 (27.8%) reported testing for LSD.9,10,14-26 In these 15 series, a diagnosis as probable etiology for NIH was detected in 512 of 678 cases (75.5%) (Tables 3 and 4). One study27 reported genetic diagnoses but did not define what was included in that category. Another series28 had 10 cases of LSDs, but not all were NIH and we were unable to find out which cases were associated with NIH and which ones were not correlated. In comparison, in the other 39 series without an LSD workup, a diagnosis was achieved in 2028 of 2464 cases (82.3%). In the 15 series of NIH in which the LSD workup was done, the diagnosis of NIH was often made using slightly different criteria (Table 3). The initial workup for NIH differed in each study, and for some studies the initial workup was not described. In the workup for LSD, most studies (10 of 15, 67%) did not mention specific tests that were ordered, whereas others (5 of 15, 33%) did provide the exact tests for which LSDs were tested (Table 3). It is unclear whether LSD testing was completed in all cases within the series. We cannot report on the average number of LSDs tested per study because many are not listed. The majority of studies in which LSDs were tested had their workup for NIH done both pre- and postnatally (53%). Three studies made the diagnosis prenatally, 5 studies made postnatal diagnoses, and 7 studies used a combination of both methods. Of the postnatally diagnosed cases, many were diagnosed only after delivery. Table 4 shows the results of positive LSDs that were diagnosed from the 15 studies that tested for LSDs. Of the 678 total NIH cases identified, 477 (70.3%) had a diagnosis other than LSD, 166 (24.5%) were idiopathic, and 35 (5.2%) were diagnosed with LSD
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TABLE 2
Example of basic pre- and postnatal workup of NIH Step 1: prenatal
Step 1: neonatala
Maternal work up
Blood
CBC (MCV in particular), hemoglobin electrophoresis, RPR, Kleinhaur-Betke, serology for parvovirus, CMV, toxoplasmosis, rubella
Urea, electrolytes, creatinine, protein, albumin, protein electrophoresis, liver function tests, bilirubin, osmolality, CBC, hemoglobin electrophoresis, serology for parvovirus, CMV, toxoplasmosis, rubella, karyotype, microarray Urine Albumineexclude congenital nephrotic syndrome
Fetal workup
Ascitic fluid/pleural fluid
Detailed anatomy ultrasound, including MCA PSV; fetal echocardiography, microarray
Protein, albumin, lipid analysis to check for chylous secretion, micro, virology, microarray Other Chest X-ray, electrocardiogram, ultrasound of heart, kidney, brain, autopsy Step 2: neonatala
Step 2: prenatal LSD testing
LSD testing
CBC, complete blood count; CMV, cytomegalovirus; G6PD, glucose-6-phosphate dehydrogenase deficiency; LSD, lysosomal storage disorders; MCA PSV, middle cerebral artery peak systolic velocity; MCV, mean corpuscular volume; RPR, rapid plasma reagin. a
Some tests may be omitted if already done prenatally. Adapted, with permission, from Berghella et al.1
Gimovsky. Systematic review of LSD in NIH. Am J Obstet Gynecol 2015.
(Table 4). The incidence of LSD in the cases without an initial diagnosis was 17.4% (35 of 201, with 201 being the sum of 35 LSD cases and 166 idiopathic cases). When analyzing the 2 studies that had extensive workup for LSD,10,25 86 NIH cases were identified, of which 59 (68.6%) had an initial diagnosis, 19 (22.1%) were idiopathic, and 8 (9.3%) were LSDs. The incidence of LSDs in the cases without an initial diagnosis was 29.6% (8 of 27, with 27 being the sum of 8 LSD cases and 19 idiopathic cases). Table 5 lists in order of frequency the LSDs that were most commonly diagnosed in the 15 studies. The most common LSD identified in cases of NIH, in order of decreasing incidence, were mucopolysaccharidosis type VII, Gaucher’s disease, GM1gangliosidosis, sialidosis, mucopolysaccharidosis (type not specified), Niemann-Pick disease type C, galactosialidosis, infantile sialic acid storage disease, Niemann-Pick type A
disease, mucopolysaccharidosis type IVa and mucolipidosis II.
Comment Several interesting issues are revealed by this literature review of case series of NIH with special emphasis on details of the workup for LSD. First, most series reporting the workup for NIH (72.2%) did not test for LSDs. Nonetheless, the initial work-up, whether pre- or postnatal, for the etiology of NIH reveals a probable diagnosis in approximately 75-82% of the cases. The incidence of idiopathic NIH was 17.7% in none LSD-tested vs 24.5% in LSD-tested case series. It is noteworthy that the researchers who performed the most extensive evaluations had the higher idiopathic rate. The fact that cases that were not tested for LSDs had a higher incidence of a diagnosis is counterintuitive, but expected, because once a probable diagnosis is found, there is no need for further workup (eg, LSD testing).
Unfortunately, the details of the initial NIH workup are often not mentioned in these case series (Table 3). Common etiologies of NIH (Table 1)1 and examples of the initial basic workup for NIH (Table 2)1 have been reported, but every study should provide its own details of workup and probable causes. Because most studies have not evaluated for LSDs, it can be assumed that usually, when the initial assessment reveals the diagnosis, the workup for LSD is omitted. It is likely that clinicians send an initial NIH workup and only test for LSD if the initial workup fails to identify a probable diagnosis as etiology. Indeed, the LSD workup may not always be necessary (eg, in cases of NIH diagnosed before 20 weeks’ gestation because 78% of these have chromosome abnormalities).29 Second, in the 18-30% of cases in which the initial NIH workup did not reveal a probable etiology, testing for LSDs resulted in a diagnosis in 17.4% of cases (Table 4). This is probably an underestimation because not all LSDs
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TABLE 3
Case series of NIH reporting LSD testing Author/year (oldest to newest) Mahony et al, 1984
14
Location
Cases of NIH Criteria for diagnosis of NIH
NIH initial workup
List of metabolic diseases tested for
Prenatal vs postnatal workup Comments
United States
27
Generalized skin thickening. and/or 2 of the following: placental enlargement, pericardial effusion, pleural effusion, and ascites
Ultrasound, other workup not specified
Not specified
Prenatal
Im et al, 19849
Canada
20
By ultrasound: a double fetal abdominal or scalp contour and fetal ascites. Postmortem generalized edema, accumulation of fluid in fetal serous compartments, and edema throughout placenta
Ultrasound, other workup not specified
Not specified
Both
McFadden and Taylor, 198915
Canada
90
NIH listed as a diagnosis (from autopsy) or with criteria for the diagnosis of NIH
Autopsy
Not specified
Postnatal
McCoy et al, 199516
United States
82
Presence of excess fluid in 2 sites
Thoracentesis, paracentesis, autopsy, karyotype, detailed ultrasound
Not specified
Both
Rejjal et al, 199617
Saudi Arabia
17
Presence of 2 of the following features by prenatal ultrasound: generalized gross subcutaneous edema, ascites, pleural effusion, pericardial effusion, plus the absence of antibodies to red blood cell antigens
Ultrasound, maternal antibody screen, echocardiogram, CBC, chromosomal analysis, TORCH, and parvovirus B19 testing
Not specified
Both
Groener et al, 199918
The Netherlands
17
Excessive fluid accumulation within fetal extravascular compartments and body cavities in cases not caused by red cell alloimmunization
Fetal blood samples
GM1-gangliosidosis Gaucher’s disease Mucopolysaccharidosis IVa Mucopolysaccharidosis VII
Prenatal
Recep, 200119
Turkey
30
Edema with effusion in at least 1 body cavity and skin edema or serous effusion in >1 body space
Ultrasound, maternal type and screen, TORCH titers, parvovirus B19 testing, karyotype, autopsy, echocardiography, and metabolic testing
Investigation for metabolic syndromes in selected cases
Both
(continued)
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Gimovsky. Systematic review of LSD in NIH. Am J Obstet Gynecol 2015.
51% diagnosed before autopsy; karyotypes were available for 14/18 idiopathic cases
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TABLE 3
Case series of NIH reporting LSD testing (continued) Author/year (oldest to newest)
Location
Cases of NIH Criteria for diagnosis of NIH
NIH initial workup
List of metabolic diseases tested for
Prenatal vs postnatal workup Comments
Brazil
29
One or more clinical signs, such as anasarca, peripheral edema, ascites, pericardial and/or pleural effusions, anemia, congestive heart failure, and hypoalbuminemia
Autopsy, ultrasound, echocardiography, karyotype, infectious workup, CBC, maternal type, and screen
Not specified
Both
Burin et al, 200410
Brazil
33
Not specified
Specific enzymatic analysis for lysosomal storage disorders by amniocentesis, autopsy, karyotype, viral studies, TORCH titers, parvovirus testing, coxsackie testing, fetal echocardiography, hemoglobin electrophoresis CBC, maternal type and screen, detailed ultrasound
Gaucher’s disease GM1-gangliosidosis Mucopolysaccharidosis I Mucopolysaccharidosis II Mucopolysaccharidosis IVa Mucopolysaccharidosis VII Niemann-Pick A/B Mucolipidosis II Sialic acid storage disease Sialidosis
Both
Reference center for LSDs
Favre et al, 200421
France
79
Fetal ascites
Detailed ultrasound, fetal echocardiography, maternal type and screen, TORCH titers, parvovirus B19 testing, karyotype, amniocentesis for cytomegalovirus, parvovirus, toxoplasmosis, cystic fibrosis screening, autopsy
Not specified
Postnatal
This study looked at both fetal hydrops and isolated ascites
Rodriguez et al, 200522 United States
32
Generalized soft tissue edema and presence of fluid in at least 1 of the pericardial, pleural, and peritoneal cavities
Ultrasound, CBC, maternal type and screen, rapid plasma reagin, blood cultures, autopsy, infectious workup
Tested enzyme levels on autopsy
Postnatal
One of the idiopathic fetuses had “histologic features of a lysosomal storage disease . but specific enzymatic defect could not be proved”
Kooper et al, 200623
The Netherlands
75
Presence of excessive fluid in >1 body cavity
Not specified
GM1-gangliosidosis Gaucher’s disease Niemann-Pick A/B Mucopolysaccharidosis I Mucopolysaccharidosis VII Sialidosis
Postnatal
Four definite cases and 2 probable cases of LSDs. This is a study evaluating reference values of lysosomal enzymes in NIH.
Gort et al, 201224
Spain
30
Excessive fluid accumulation in >1 fetal compartments and body cavities
LSDs were investigated in all, amniocentesis
Gaucher’s disease GM1-gangliosidosis Mucopolysaccharidosis VII
Prenatal
Reference center for LSDs
285
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(continued)
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678 Total cases
Hasnani-Samnani et al, 201326
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CBC, complete blood count; LSD, lysosomal storage disorders; MCA, middle cerebral artery; NIH, nonimmune hydrops; TORCH, testing for toxoplasmosis, syphilis, rubella, cytomegalovirus, herpes.
Qatar
64
Signs suggesting NIH
CBC, thalassemia screening, Kleinhauer-Betke, TORCH titers, parvovirus B19 testing, karyotype, echocardiography, MCA Dopplers, detailed ultrasound
Metabolic investigation. was done for only a few cases and was negative
Both
Reference center for LSD Both GM1-Gangliosidosis Gaucher’s disease Mucopolysaccharidosis I Mucopolysaccharidosis II Mucopolysaccharidosis IVa Mucopolysaccharidosis VII Mucolipidosis II Niemann-Pick A/B Sialidosis Sialic acid storage disorders Detailed ultrasound, fetal echocardiography, karyotype, TORCH titers, CBC, hemoglobin electrophoresis, inborn errors of metabolism testing, autopsy All patients with NIH referred to their center 53 Brazil Moreno et al, 2013
NIH initial workup Location
Cases of NIH Criteria for diagnosis of NIH Author/year (oldest to newest)
Case series of NIH reporting LSD testing (continued)
TABLE 3
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25
List of metabolic diseases tested for
Prenatal vs postnatal workup Comments
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were tested for in these studies. In fact, it was impractical to estimate how many LSDs were tested for in each study because many of the studies did not list every disease or enzyme tested. For example, 3 studies listed Mucopolysaccharidosis as a diagnosis without specifying the type. We can only conjecture that this refers to types VII, I, and IVa because these are the only 3 mucopolysaccharidoses associated with NIH. However, we know that 14 LSDs have been associated with NIH.30 Two studies had a comprehensive evaluation of LSDs. In these studies, the laboratories used either amniotic fluid supernatant or amniocytes prenatally or plasma testing, leukocytes, or fibroblasts (in the postnatal period) to measure enzymatic activity. These laboratories tested 10 different diseases.10,25 Table 5 shows the enzymatic correlation to specific diseases. Importantly, these studies with a comprehensive evaluation of LSDs were done in national reference centers.10,25 If we look at the evidence from the 2 studies with comprehensive testing for LSDs and if we assume that LSDs were not initially tested for, then we can estimate that 29.6% of those cases that would have been classified as idiopathic would have had a diagnosis of LSD. Clearly, the more comprehensive the LSD workup is, the higher the chance of reaching a diagnosis. Interestingly, in these 2 studies with 8 cases of LSD, 4 of the pregnancies had a recurrence of NIH or a recurrence of findings suggestive of LSDs in previous pregnancies.10,25 Some LSDs previously associated with NIH were not detected in our literature review because these were described in isolated case reports and not in series with 5 or more cases of NIH. In the case series, which diminish ascertainment bias compared with case reports, the more common positive LSDs were Mucopolysaccharidosis type VII, Gaucher’s disease, and GM1gangliosidosis (Table 5). Third, given that a diagnosis of LSD was made in 17.4% of cases of the
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ajog.org idiopathic NIH cases overall in which the initial workup failed to identify a cause of hydrops and 24.6% of those idiopathic NIH cases in which a more comprehensive LSD workup was done, it seems that if the initial NIH workup is negative, comprehensive LSD testing should be ordered (Table 5). Therefore, we suggest a 2-step approach. First, common causes of NIH should be evaluated as suggested in Table 2. Subsequently, for cases that remain as idiopathic after the initial NIH workup, testing for LSDs should be done. Prenatal LSD testing allows not only the diagnosis but also allows the options for termination, better counseling, appropriate management, and planning for possible early intervention. Moreover, their detection may aid in prenatal diagnosis in subsequent pregnancies because the LSDs associated with NIH have an autosomal recessive mode of inheritance. Prenatal LSD diagnosis is performed by enzyme analysis of fetal cells obtained by chorionic villus sampling or amniocentesis. Table 5 lists the genetic disease and associated enzymatic deficiency tested for. These 14 diseases are the only known inborn errors of metabolism associated with NIH. Enzymatic diagnosis of all LSDs can be easily done in a specialized laboratory on a blood sample, amniocytes, or fibroblasts (Appendix). Knowledge of the DNA mutations in the proband or in the heterozygous parents allows the use of DNA mutation analysis for prenatal diagnosis. Mutation analysis is recommended because a confirmatory assay is more accurate for prenatal diagnosis in a future pregnancy and can aid preimplantation genetic diagnosis. The most obvious shortcoming of our study is the fact that a review such as ours can only be as good as the published series. There is certainly substantial ascertainment bias in the literature. To establish the true incidence of LSDs in NIH, all idiopathic cases after the basic disease workup should be tested for all LSDs that have been associated with NIH (Table 5). The only studies with an extensive
FIGURE
Flow diagram
This figure illustrates the flow diagram, indicating inclusion and exclusion of articles, and the article numbers. Gimovsky. Systematic review of LSD in NIH. Am J Obstet Gynecol 2015.
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TABLE 4
LSD cases reported in case series of NIH Total NIH cases
Author/year 14
Mahony et al, 1984
Total cases with known diagnosis (excluding LSD)
Total idiopathic cases
Total LSD cases
Specific LSD type (n)
27
22 (81.0%)
4 (15.0%)
1 (3.7%)
Mucopolysaccharidosis (1)
20
12 (60.0%)
5 (25/0%)
3 (15%)
Gaucher disease (3)
90
70 (77.8%)
16 (17.8%)
4 (4.4%)
Mucopolysaccharidosis (2), Gaucher disease (1), Sialidosis (1)
McCoy et al, 199516
82
62 (75.6%)
18 (22.0%)
2 (2.4%)
Gaucher disease (1), Niemann-Pick disease type C (1)
Rejjal et al, 199617
17
6 (35.3%)
9 (52.9%)
2 (11.8%)
GM1-gangliosidosis (1), mucopolysaccharidosis (1)
Groener et al, 199918
17
8 (47.1%)
8 (47.1%)
1 (5.9%)
Mucopolysaccharidosis VII (1)
30
27 (90.0%)
3 (10.0%)
0 (0%)
N/A
9
Im et al, 1984
McFadden and Taylor, 1989
15
19
Recep, 2001
Mascaretti et al, 2003
20
29
20 (69.0%)
8 (27.6%)
1 (3.4%)
GM1-gangliosidosis (1)
10
Burin et al, 2004
33
16 (48.5%)
12 (36.4%)
5 (15.1%)
Mucolipidosis (1), Niemann-Pick A disease (1), galactosialidosis (1), sialidosis (1), mucopolysaccharidosis IVa (1)
Favre et al, 200421
79
60 (75.9%)
12 (15.2%)
7 (8.8%)
Sialidosis (2), mucopolysaccharidosis VII (3), Niewman Pick C (2)
Rodriguez et al, 200522
32
30 (93.8%)
2 (6.3%)
0 (0%)
N/A
Kooper et al, 2006
75
71 (94.7%)
0 (0%)
4 (5.3%)
Galactosialidosis (1), GM1-gangliosidosis (1), mucopolysaccharidosis VII (2)
Gort et al, 201224
30
28 (93.3%)
2 (6.7%)
Mucopolysaccharidosis VII (1), Gaucher disease (1)
Moreno et al, 201325
53
43 (81.1%)
7 (13.2%)
3 (5.7%)
GM1-gangliosidosis (2), infantile sialic acid storage disease (1)
Hasnani-Samnani et al, 201326
64
37 (57.8%)
27 (42.2%)
0 (0%)
N/A
678
477 (70.3)
23
Total, n (%)
0 (0%)
166 (24.5)
35 (5.2)
LSD, lysosomal storage disorders; N/A, not available; NIH, nonimmune hydrops. Gimovsky. Systematic review of LSD in NIH. Am J Obstet Gynecol 2015.
(but not complete) screening for LSDs in idiopathic NIH cases were represented by Moreno et al25 and Burin et al.10 The studies that describe the most extensive methodology were studies done at referral centers for LSDs.10,25 This makes intuitive sense because patients were sent to these referral centers specifically to look for LSDs. Although we did not consider the study by Kooper et al23 a comprehensive evaluation, this study was also performed at a reference
center, specifically looking for reference values of lysosomal enzymes in NIH; thus, the diagnosis might not have been the main objective. Additionally, we excluded manuscripts with fewer than 5 cases of NIH, but this was done to minimize publication bias. Studies were excluded if they were reported in a non-English language. Our objective was to evaluate the significance of LSDs as an etiology of NIH, so other inborn errors of metabolisms were not included in our study.
288 American Journal of Obstetrics & Gynecology MARCH 2015
There are 3 prior reviews of NIH case series in the literature. Bellini et al8 compiled a very thorough review of cases and classifications of the etiologies of NIH but did not delve into the workup. The review by Machin4 from 1989 had the most extensive list of cases of any prior study on NIH (1414 cases) but was limited because almost half of the cases studied were case reports. Jauniaux et al31 in 1990 wrote a large review paper of 600 cases of NIH, but his study was also limited by the fact that all of the LSD cases
Systematic Reviews
ajog.org
TABLE 5
Most commonly diagnosed LSD in cases of NIH LSD
Enzyme defect
Number of cases, %
Mucopolysaccharidosis type VII
Beta-glucuronidase
7 (20.0)
Gaucher’s disease
Glucocerebrosidase
6 (17.1)
GM1-gangliosidosis
Beta-galactosidase
5 (14.3)
Sialidosis
Sialidase
4 (11.4)
Mucopolysaccharidosis type not specified
Not applicable
4 (11.4)
Niemann-Pick disease type C
NPC1, NPC2
3 (8.5)
Galactosialidosis
Protective protein cathepsin A
2 (5.7)
Infantile sialic acid storage disease
Transport protein
1 (2.9)
Niemann-Pick A disease
Sphingomyelinase
1 (2.9)
Mucopolysaccharidosis type Iva
N-acetylgalactosamine-6-sulfatase
1 (2.9)
Mucolipidosis II
UDP-N-Ac-glucosaminyl phosphotransferase
1 (2.9)
Mucopolysaccharidosis I
A-iduronidase
0 (0)
Infantile sialic acid storage disease
Transport protein
0 (0)
Wolman disease
Acid lipase
0 (0)
Farber disease
Acid ceramidase
0 (0)
Multiple sulfatase deficiency
Sulfatase modifier protein
0 (0)
Total
35
LSD, lysosomal storage disorders; NIH, nonimmune hydrops. Gimovsky. Systematic review of LSD in NIH. Am J Obstet Gynecol 2015.
came from case reports. Therefore, our study is the only comprehensive literature case series review of the workup of NIH for LSD, starting from more than 2000 NIH reports. -
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Appendix Generally, requirements for testing include the following: amniocytes (cultured form 25 mL of amniotic fluid; no
290 American Journal of Obstetrics & Gynecology MARCH 2015
additional fluid needed if sending for karyotype/microarray), skin fibroblasts (cultured from skin biopsy), or 5-8 mL of whole blood for screening tests or 4-6 mL of whole blood for a single disease test. These samples may be sent to reference laboratories such as the Lysosomal Disease Testing Laboratory at Sidney Kimmel College of Medicine at Thomas Jefferson University, Philadelphia, PA; Emory University School of Medicine, Emory Molecular Genetics Laboratory, Atlanta, GA; Greenwood Genetic Center Diagnostic Laboratories, Baylor Research Institute, Institute of Metabolic Disease, Dallas, TX; Mayo Clinic-Minnesota, Molecular Genetics Laboratory, Rochester, MN. Turnaround time is generally 7-14 days for enzymatic testing and several weeks for DNA testing. Cost varies from $300 to $4500, depending on enzymatic vs DNA testing and insurance coverage.
