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ORIGINAL RESEARCH |
From the Regional Perinatal Screening Program and Departments of Genetics and Perinatology, Kaiser Permanente Medical Center, Oakland, California.
Address reprint requests to: Edgar J. Schoen, MD, Department of Genetics, Kaiser Permanente Medical Center, 280 West MacArthur Boulevard, Oakland, CA 94611-5693; E-mail: edgar.schoen{at}kp.org.
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ABSTRACT |
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 ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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METHODS: We studied serum unconjugated E3 levels in 120,071 gravidas having California Expanded Alpha-Feto-protein prenatal screening at 15–20 weeks’ gestation during a 5-year period.
RESULTS: Of the 120,071 women, 323 (0.27%) had low unconjugated E3 levels (less than or equal to 0.2 ng/mL, or 0.15 multiples of the median). Excluding women who were screened too early or who had indeterminate screening results, 103 (0.08%) women with unexplained low unconjugated E3 level remained; of these 103 women, 33 had negative screening results and 68 had positive screening results, and two were tested too late for interpretation. Intrauterine fetal death occurred in 39 (57%) of the 68 women with low unconjugated E3 and positive screening results and occurred in two (6%) of the 33 women with low unconjugated E3 levels and negative screening results, a significant difference (P < .001). Two cases of Smith–Lemli–Opitz syndrome were identified and the patients did not survive the neonatal period; one was a therapeutic abortion for severe oligohydramnios, and the other died at age 48 hours. Low unconjugated E3 level also predicted presence of steroid sulfatase deficiency, a much more common X-linked skin disorder characterized by ichthyosis.
CONCLUSION: Low maternal serum unconjugated E3 diagnosed more cases of steroid sulfatase deficiency and undetected intrauterine fetal death than Smith–Lemli–Opitz syndrome (1:60,000 prevalence), although the clinical importance of having this information prenatally is uncertain.
Smith–Lemli–Opitz syndrome is an inborn error of cholesterol metabolism that results from failure to convert 7-dehydrocholesterol to cholesterol.1–5 The prevalence of Smith–Lemli–Opitz has been reported at between one in 10,000 and one in 60,000 births, and the condition is often fatal early in life.6,7 Phenotypic manifestations of Smith–Lemli–Opitz include growth failure; moderate-to-severe mental retardation; microcephaly; distinctive facial features; and syndactyly, polydactyly, or both.8–12 Male Smith–Lemli–Opitz patients may have genital abnormalities, including ambiguous genitalia. Cholesterol is the precursor for steroid hormone biosynthesis, and prenatal unconjugated estriol (E3) levels are low in maternal serum and urine (Canick JA, Abuelo DN, Bradley LA, Tint GS. Maternal serum marker levels in two pregnancies affected with Smith–Lemli–Opitz syndrome [letter]. Prenat Diagn 1997;17:187–9[Medline]).13–15
Data have shown that low second-trimester maternal unconjugated E3 levels can be used to predict Smith–Lemli–Opitz, but choosing the proper cutoff level is difficult (Bradley LA, Palomaki GE, Knight GJ, Haddow JE, Opitz JM, Irons M, et al. Levels of unconjugated estriol and other maternal serum markers in pregnancies with Smith–Lemli–Opitz (RSH) syndrome fetuses [letter]. Am J Med Genet 1999;82:355–8[Medline]). According to analysis of the data of Bradley et al by Shackleton (personal communication, C. H. Shackleton, 1999), an unconjugated E3 value of less than 0.70 multiples of the median is sufficient to diagnose all cases of Smith–Lemli–Opitz but yields an unacceptably large number of false-positive results ( Bradley LA et al. Am J Med Genet 1999;82:355–8). Using an unconjugated E3 level of less than 0.15 multiples of the median results in a lower rate of false-positive results, but can lead to missed diagnoses of Smith–Lemli–Opitz ( Bradley LA et al. Am J Med Genet 1999;82:355–8; personal communication, C. H. Shackleton, 1999).
To assess the clinical value of using maternal serum unconjugated E3 level of less than 0.2 ng/mL or 0.15 multiples of the median to screen for Smith–Lemli–Opitz, we looked at outcomes of pregnancy in women with this level of unconjugated E3 level in a large health maintenance organization, Kaiser Permanente of Northern California.
Because low unconjugated E3 levels have also been associated with fetal death, anencephaly, congenital adrenal hypoplasia, and steroid sulfatase deficiency (an X-linked skin disorder characterized by ichthyosis),16–18 we also analyzed our results for these conditions.
The main aim of the study was to assess the practical clinical value of using prenatal unconjugated E3 levels alone in the diagnosis of Smith–Lemli–Opitz syndrome as well as other conditions associated with low prenatal unconjugated E3 levels, particularly intrauterine fetal demise and steroid sulfatase deficiency.
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MATERIALS AND METHODS |
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Expanded AFP screening test results, analyzed by the State of California Department of Health Services Genetic Disease Branch, as legally required, were reported as positive under any one of the three following conditions: high AFP levels (neural tube defects); low levels of all three analytes (trisomy 18); or a combination of low levels of AFP and unconjugated E3 and high levels of hCG (Down syndrome). Women with positive screening results for any of these conditions were offered genetic counseling, amniocentesis, and detailed ultra-sonography. Moreover, as recommended by the current Kaiser Permanente obstetric standard of care, ultra-sonography was done in most women during the second trimester to evaluate fetal anatomy and to confirm gestational age. Low unconjugated E3 level in this study was defined as less than 0.2 ng/mL or less than 0.15 multiples of the median because this value was the lowest measurable by the methods used by the State of California. Data were excluded for women who were screened too early in gestation or for whom results of screening were indeterminate.
Outcome of pregnancies was tracked using Kaiser Permanente databases; in questionable cases, medical records were reviewed. To assess whether evaluation of low unconjugated E3 alone would have missed cases of Smith–Lemli–Opitz, we reviewed records maintained in the Kaiser Permanente Interregional Genetics System, a database that lists all genetic referrals received by Kaiser Permanente providers since 1990. Most cases of developmental delay and congenital anomalies are referred to our regional genetics departments, are examined by a geneticist, and are entered into this database, so our use of this database minimized the chances of missing a case of Smith–Lemli–Opitz syndrome. The medical records of neonates who were clinically normal at birth and whose mothers had low serum unconjugated E3 levels prenatally were reviewed for symptoms or diagnoses consistent with steroid sulfatase deficiency.
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RESULTS |
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). Use of ultra-sonography dating showed that 216 (67%) of the women were at a gestational date too early for screening (dating error); in four cases, test results were inadequate or inconsistent with pregnancy.
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Outcome of the 33 pregnancies in women with low unconjugated E3 levels and negative expanded AFP screening results included one infant with Smith–Lemli–Opitz, who died in the immediate neonatal period (age 2 days); one male infant born alive with multiple congenital anomalies and negative results of Smith–Lemli–Opitz testing; one therapeutic abortion of a fetus with trisomy 13 with multiple anomalies seen ultrasono-graphically; one stillborn infant with stigmata of trisomy 18 but no confirmatory chromosome analysis of this condition; and two cases of intrauterine fetal death (one fetus at 18 weeks and one fetus at 22 weeks) (Table 1). The other 27 infants born to women with low unconjugated E3 levels and negative results of expanded AFP screening were clinically normal at birth. Of these 27 normal live births, 24 were boys; six of the boys later had ichthyosis diagnosed by a dermatologist, and nine of the boys had other chronic skin disorders, including "eczema," "seborrheic dermatitis," and "leathery skin."
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The two women for whom the results were too late for interpretation had a normal outcome of pregnancy—one female and one male infant, neither of whom had skin abnormalities.
No additional cases of Smith–Lemli–Opitz were found in the Kaiser Permanente Interregional Genetics system.
Thus, of the total of 103 women with unexplained low unconjugated E3 levels, 48 had "normal newborns," of whom 43 were male; medical chart review showed that 12 of these 43 male infants were diagnosed with ichthyosis, and 16 others had a chronic form of skin disease. In addition, there were two Smith–Lemli–Opitz cases: one infant who died soon after birth and a fetus with Smith–Lemli–Opitz, diagnosed after therapeutic abortion for severe oligohydramnios.
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DISCUSSION |
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A previous report of screening results in Smith–Lemli–Opitz-affected pregnancy showed unconjugated E3 levels ranging from undetectable to 0.65 multiples of the median with a median of 0.23 multiples of the median ( Bradley LA et al. Am J Med Genet 1999;82:355–8). These cases also had slightly low median AFP (0.72 multiples of the median) and hCG (0.80 multiples of the median) levels. Using a cutoff value of 0.65 multiples of the median for unconjugated E3 levels to detect all cases of Smith–Lemli–Opitz would result in an unacceptably high number of false-positive test results. In an attempt to avoid this high false-positive rate, an algorithm using levels of all three analytes (unconjugated E3, hCG, and AFP) was developed on the basis of 30 Smith–Lemli–Opitz cases.19 This algorithm is currently being used in the expanded AFP screening program by the California Genetic Disease Branch. One of our two Smith–Lemli–Opitz cases would have been missed using this algorithm because the woman had normal hCG (1.04 multiples of the median) and low AFP (0.40 multiples of the median) levels. The estimate of the expected positive rate using the algorithm was three in 1000 women screened (0.33%) with an expected 60% detection rate for Smith–Lemli–Opitz.19 Using our low fixed unconjugated E3 cutoff value, we had a similar positive rate (0.27%) with 100% detection of Smith–Lemli–Opitz, but this was based on only two cases. Nevertheless, we are concerned about the use of a more complex algorithm and will be very interested in validation of the use of this algorithm versus single analyte analysis in large screening programs.
We also found that Smith–Lemli–Opitz was the least likely cause for a low unconjugated E3 level; intrauterine fetal death and steroid sulfatase deficiency were much more common. Of the 103 cases with low unconjugated E3, 41 (39%) had intrauterine fetal death, 39 of which occurred at or before the time of the expanded AFP blood test (ie, 20 weeks’ gestation or less). There was significantly higher prevalence (P < .001) of intrauterine fetal death for cases with both low unconjugated E3 and positive expanded AFP screening tests (57%) than for cases with low unconjugated E3 and negative expanded AFP screening tests (6%). Although alerting the patient and the practitioner to an intrauterine fetal death is important, this finding was not considered clinically useful because no intervention to improve outcome was possible at that point.
Some speculate that cases of Smith–Lemli–Opitz caused by severe mutations are underrepresented in live-born infants and are more likely to result in intrauterine fetal death and stillbirth.20,21 Both of our Smith–Lemli–Opitz cases resulted in perinatal loss and were diagnosed by pathologic examination (after therapeutic abortion for severe oligohydramnios) and examination at the genetics department at time of neonatal death. Presence of Smith–Lemli–Opitz cases among our early intrauterine fetal death cases seems unlikely because no suspicious anomalies were seen during ultrasound or pathologic examination. Further, we believe that no evidence of an increased number of first- and second-trimester pregnancy losses has been reported in couples carrying Smith–Lemli–Opitz mutations.20 Finally, on the basis of physiology, low unconjugated E3 values after fetal death from any cause can be expected.
Although both our case patients died early (one in utero and the other in the early neonatal period), milder cases of Smith–Lemli–Opitz can survive for many years, a situation analogous to that of Down syndrome, and can result in very high lifetime costs. These costs would be saved if the diagnosis were made during prenatal testing and if parents chose to abort the fetus. However, at Kaiser Permanente, where about 33,000 deliveries occur annually, about 30% of the parents of a fetus diagnosed prenatally with Down syndrome elect to continue the pregnancy.
The majority of normal infants born to women with low unconjugated E3 value were boys (43 of 48), and the records of 12 of these 43 boys indicated that they were later diagnosed by a dermatologist as having ichthyosis and that 16 others had multiple record entries indicating chronic skin disorders, such as eczema or seborrheic dermatitis.
Steroid sulfatase deficiency is caused by deletion of the steroid sulfatase gene on the short arm of the X chromosome and is known to cause low maternal unconjugated E3 values in affected pregnant women. If, as is reasonable, we assume that the 28 male infants with chronic skin rashes had steroid sulfatase deficiency, the minimum prevalence of this disorder is 1:4289—a prevalence more than ten times greater than we found for Smith–Lemli–Opitz and similar to previous estimates.16,22,23 Steroid sulfatase deficiency symptoms are generally limited to skin manifestations, which can be treated locally, so steroid sulfatase deficiency alone would probably not warrant prenatal screening. However, reports indicate that some children with steroid sulfatase deficiency may be at risk for other conditions, such as Kallmann syndrome, chondrodysplasia punctata, short stature, and mental retardation, as part of a contiguous gene disorder (Yates JR, McMahon R, Gelson W, Willatt LR, Raggatt PR, Carr C, et al. Steroid sulphatase deficiency: Genotype and phenotype in cases ascertained by maternal serum screening [abstract]. Am J Hum Genet 1999;65 Suppl 4:A23).24 The extent of the relation is not well quantified because not enough large, unbiased studies are available to determine true prevalence of contiguous gene disorder among patients with steroid sulfatase deficiency. Fluorescence in situ hybridization testing may be used to see if the steroid sulfatase deficiency gene deletion extends into the Kallmann syndrome or into the subtelomeric region, but currently no clinical test is available to look for small deletions distal to the steroid sulfatase deficiency gene, where mental retardation genes have been reported.24 This situation creates a problem in counseling parents prenatally when steroid sulfatase deficiency is detected.
One of the boys whose mother had low unconjugated E3 was diagnosed postnatally (using fluorescence in situ hybridization) as having steroid sulfatase deficiency, and the child was later reported to have mild developmental delay; however, the significance of this finding is not known because we were unable to look for other gene deletions on the X chromosome. The contiguous gene disorder theory is of interest, but further evidence is required to establish the true prevalence of contiguous gene disorders in relation to steroid sulfatase deficiency.
Our results show that analyzing maternal serum for low (less than or equal to 0.2 ng/mL, or 0.15 multiples of the median) unconjugated E3 level diagnoses more than Smith–Lemli–Opitz. Although two cases of Smith–Lemli–Opitz were found among 120,071 pregnancies, low unconjugated E3 levels were more helpful for diagnosing steroid sulfatase deficiency and undetected fetal death. The clinical value of having this information prenatally is uncertain, although identifying steroid sulfatase deficiency during pregnancy could lead to early diagnosis of ichthyosis after birth and could avoid repeated office visits for unknown chronic skin disorders. Whether this finding warrants a prenatal screening program is problematic, particularly in view of the unknown relation between steroid sulfatase deficiency and other genetic conditions. We are concerned that current Smith–Lemli–Opitz screening programs using low maternal uncon-jugated E3 levels concentrate on this rare disorder and do not adequately consider conditions that are much more common.
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Footnotes |
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The authors thank the Genetic Disease Branch of the California Department of Health Services for their cooperation. The Medical Editing Department of the Kaiser Foundation Research Institute provided editorial assistance
Published in abstract form in Pediatric Research, 2000;47(4 Pt 2):A242.
doi:10.1016/S0029-7844(03)00370-3
Received October 28, 2002. Received in revised form January 30, 2003. Accepted February 13, 2003.
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REFERENCES |
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2. Tint GS, Irons M, Elias ER, Batta AK, Frieden R, Chen TS, et al. Defective cholesterol biosynthesis associated with the Smith-Lemli-Opitz syndrome. N Engl J Med 1994;330:107–13.
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4. Tint GS, Abuelo D, Till M, Cordier MP, Batta AK, Shefer S, et al. Fetal Smith-Lemli-Opitz syndrome can be detected accurately and reliably by measuring amniotic fluid dehydrocholesterols. Prenat Diagn 1998;18:651–8.[Medline]
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9. Curry CJ, Carey JC, Holland JS, Chopra D, Fineman R, Golabi M, et al. Smith-Lemli-Opitz syndrome-type II: Multiple congenital anomalies with male pseudohermaphroditism and frequent early lethality. Am J Med Genet 1987; 26:45–57.[Medline]
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13. Shackleton CH, Roitman E, Kratz LE, Kelley RI. Equine type estrogens produced by a pregnant woman carrying a Smith-Lemli-Opitz syndrome fetus. J Clin Endocrinol Metab 1999;84:1157–9.
14. Angle B, Tint GS, Yacoub OA, Clark AL. A typical case of Smith-Lemli-Opitz syndrome: Implications for diagnosis. Am J Med Genet 1998;80:322–6.[Medline]
15. Blitzer MG, Kelley RI, Schwartz MF. Abnormal maternal serum marker pattern associated with Smith-Lemli-Opitz (SLO) syndrome. Am J Hum Genet 1994;55:A277.
16. David M, Isreal N, Merksamer R, Bar-Nizan N, Borochowitz Z, Bar-el H, et al. Very low maternal serum unconjugated estriol and prenatal diagnosis of steroid sulfatase deficiency. Fetal Diagn Ther 1995;10:76–9.[Medline]
17. Schleifer RA, Bradley LA, Richards DS, Ponting NR. Pregnancy outcome for women with very low levels of maternal serum unconjugated estriol on second-trimester screening. Am J Ostet Gynecol 1995;173:1152–6.[Medline]
18. Bradley LA, Canick JA, Palomaki GE, Haddow JE. Undetectable maternal serum unconjugated estriol levels in the second trimester: Risk of perinatal complications associated with placental sulfatase deficiency. Am J Obstet Gynecol 1997;176:531–5.[Medline]
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21. Kelley RI, Herman GE. Inborn errors of sterol biosynthesis. Annu Rev Genomics Hum Genet 2001;2:299–341.[Medline]
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24. Paige DG, Emilion GG, Bouloux PM, Hatper JI. A clinical and genetic study of X-linked recessive ichthyosis and contiguous gene defects. Br J Dermatol 1994;131:662–9.
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