Background The Smith-Lemli-Opitz syndrome (frequency, 1:20,000to 1:40,000) is defined by a constellation of severe birth defectsaffecting most organ systems. Abnormalities frequently includeprofound mental retardation, severe failure to thrive, and ahigh infant-mortality rate. The syndrome has heretofore beendiagnosed only from its clinical presentation.
Methods Using capillary-column gas chromatography-mass spectrometry,we measured the sterol composition of plasma, erythrocytes,lens, cultured fibroblasts, and feces from five children withthe syndrome (three girls and two boys).
Results Plasma cholesterol levels were abnormally low (8 to101 mg per deciliter [0.20 to 2.60 mmol per liter]) in everypatient, being well below the 5th percentile for age- and sex-matchedcontrols. Concentrations of the cholesterol precursor 7-dehydrocholesterol(cholest-5,7-dien-3-ol), which was not detectable in most ofour controls, were elevated (11 to 31 mg per deciliter) morethan 2000-fold above normal and were similar to the levels ofcholesterol in all tissues from all patients. An isomeric dehydrocholesterolwith a structure similar to that of 7-dehydrocholesterol wasalso detected.
Conclusions The combination of abnormally low plasma cholesterollevels and a high concentration of the cholesterol precursor7-dehydrocholesterol points to a major block in cholesterolbiosynthesis at the step in which the C-7(8) double bond of7-dehydrocholesterol is reduced, forming cholesterol. The blockmay be sufficient to deprive an embryo or fetus of cholesteroland prevent normal development, whereas the incorporation of7-dehydrocholesterol into all membranes may interfere with propermembrane function.
The Smith-Lemli-Opitz syndrome1 is an autosomal recessive disordercharacterized by microcephaly, poor growth, easily recognizeddysmorphic facies (anteverted nares, ptosis of eyelids, andmicrognathia), limb abnormalities (especially syndactyly ofthe toes, polydactyly, and a high frequency of digital whorlridges), genital disorders (cryptorchidism and hypospadias inaffected boys), endocrine malfunction, cataracts, heart andkidney malformations, and mental retardation1,2,3,4,5. Its prevalencehas been estimated to be 1 in 20,000,6 with a probable carrierfrequency of 1 to 2 percent,5 and it may be the second mostcommon autosomal recessive disorder in the North American whitepopulation, after cystic fibrosis6. The cause of the syndromehas not yet been identified, and there is no laboratory testeither to confirm the diagnosis or to detect heterozygous carriers2.
We describe a severe abnormality in cholesterol biosynthesisin five patients with the Smith-Lemli-Opitz syndrome. Extremelylow levels of cholesterol (cholest-5-en-3-ol) were associatedwith the accumulation of the cholesterol precursor 7-dehydrocholesterol(cholesta-5,7-dien-3-ol), as well as an isomeric dehydrocholesterol.The marked elevation of 7-dehydrocholesterol places the defectat a known step in the pathway of cholesterol biosynthesis andserves as a biochemical marker for the disease.
Case Reports
At birth, the five patients (all were white) had many of thefeatures and limb abnormalities typical of the Smith-Lemli-Opitzsyndrome, including microcephaly, a sloping forehead, prominentepicanthal folds, flat nasal bridge, upturned nares, and micrognathia.All were mentally retarded. The clinical courses of the threegirls were similar and were remarkable for the girls' severefailure to thrive, which necessitated placement of a gastrostomytube to maintain adequate nutrition. All three girls had a normalkaryotype (46,XX).
Patient 1
Patient 1, a girl, weighed 3000 g at birth; she was noted tohave a congenital cataract of the right eye, low-set posteriorlyrotated ears, postaxial polydactyly of both hands and the leftfoot, and syndactyly of the second and third toes of both feet.Neurologic examination revealed decreased muscle tone and anunusual cry. The cataract was surgically excised when she waseight months old. At one year of age her size and weight weretypical of those of an infant two to four months old, and herdevelopment was that of a four-month-old.
Patient 2
Patient 2, a girl 10 years of age (Figure 1), was born aftera 37-week gestation and weighed 2900 g. Other defects notedat birth were hypoplastic labia, dislocated hips, and valgusdeformities of the feet. Her weight at this writing is at the5th percentile for her age, her height at the 50th percentilefor a five-year-old, and her head circumference at the 50thpercentile for a two-year-old. Although she had hypotonia duringinfancy, she now has hypertonia with flexion contractures ofmultiple joints. She cannot speak, may injure herself severely,and may become aggressive. Her serum alanine aminotransferaselevel was slightly elevated (36 U per liter; normal, 10 to 25).
Figure 1. Patient 2, a 10-Year-Old Girl with Facies Typical of the Smith-Lemli-Opitz Syndrome.
Patient 3
Patient 3, a girl three years old, was born at term weighing3300 g. A small congenital cataract of the right eye, cleftpalate, camptodactyly, and valgus foot deformities were noted.When 35 months old, she had the motor skills of an 8-month-oldand the cognitive skills of a 10-to-12-month-old. She has severehypotonia, although her muscle tone has improved somewhat overtime. Her serum aspartate aminotransferase level was moderatelyelevated at 47 U per liter (normal, 10 to 35), and her serumalanine aminotransferase was 50 U per liter.
Patient 4
In Patient 4, a 13-year-old boy, the syndrome was diagnosedat birth on the basis of dysmorphic facial features, valgusfoot deformities, and perinatal hypotonia. His karyotype wasnormal (46,XY); unlike many boys with the disorder1,2,3,4 hehad normal genitalia. Placement of a gastrostomy tube was notrequired in spite of early severe failure to thrive. He is profoundlyretarded (IQ of 32 on Stanford-Binet testing) but can speakand walk.
Patient 5
Patient 5, a 10-year-old boy, had somewhat dysmorphic facialfeatures and an increased number of large whorls on his fingertips.He is less severely affected than the other four patients, isonly moderately retarded, and is communicative and ambulatory.
Patient 3 has consumed a cholesterol-rich diet of ground lambalmost since birth, whereas Patients 4 and 5 eat regular tablefood. In contrast, Patients 1 and 2 are fed infant formulasthat contain plant sterols but little cholesterol.
Methods
Sterol and Bile Acid Analysis
We identified and measured neutral sterols in plasma and erythrocytesobtained from fasting blood samples from the five patients,the parents of Patients 1 and 2, and the mother of Patient 3.Also, for Patient 1 only, we assayed neutral sterols in culturedfibroblasts and in a small section of lens obtained at surgery.The ratio of free to esterified sterols was determined in plasmafrom Patients 2 and 5. Neutral sterols and bile acids were measuredin feces obtained from Patients 1, 2, and 3. All measurementswere carried out in duplicate.
Control values for plasma cholesterol in children were obtainedfrom published tables,7 and control (median) values for plasma7-dehydrocholesterol from measurements in healthy adults describedby Axelson8. We also assayed plasma from six unaffected childrenand erythrocytes9,10,11 from four unaffected men for the presenceof dehydrocholesterols.
As a control procedure, sterols were assayed in cultured fibroblastsfrom two women and a 14-year-old boy with sitosterolemia9,10and two healthy men.
Neutral sterols in plasma and tissues and neutral sterols andbile acids in feces were identified and measured by capillary-columngas chromatography and capillary-column gas chromatography-massspectrometry as described previously9,10,11,12. The unesterifiedplasma sterol fraction was determined by extracting 0.5 ml ofplasma and analyzing the sample without alkaline hydrolysis10.
The relative response of the gas-chromatography column and detectorwas measured by injecting known quantities of 7-dehydrocholesteroland cholesterol. The effect of alkaline hydrolysis and solventextraction was determined by spiking 0.5 ml of control plasmawith 1.0 mg of 7-dehydrocholesterol9,10,11,12. No extraneouscompounds were detected, and the recovery of 7-dehydrocholesterolwas essentially complete.
The identification of 7-dehydrocholesterol and cholesterol wasverified by matching the retention times of the trimethylsilylether derivatives of the natural compounds extracted from patients'tissues with the retention times of the derivatives of authenticcompounds (Aldrich Chemical, Milwaukee). Sterols were injectedinto a 25-m high-polarity capillary column (polyethylene glycol-Carbowax[CP-Wax 57CB]) and a 25-m low-polarity capillary column (dimethylpolysiloxane [CP-Sil 5CB]) (Chrompack, Raritan, N.J.) installedin gas chromatographs (Model 5890, Hewlett-Packard, Palo Alto,Calif.)9,10,11,12. The identities of the sterols were furtherconfirmed by analysis of the mobilities on argentation thin-layerchromatography plates13,14 and the mass spectra10,11,12 (Hewlett-PackardModel 5988 mass spectrometer) of the natural and authentic compounds.
Tissue Culture
Fibroblasts from Patient 1 and five controls were grown in 75-cm2flasks containing 10 ml of Dulbecco's minimum essential mediumsupplemented with 10 percent fetal-calf serum (GIBCO, GrandIsland, N.Y.). After the cultures reached confluence (3 x 106to 4 x 106 cells after about one week), one half to one thirdof each culture was reseeded in new flasks and regrown. Beforeassay, cholesterol biosynthesis was stimulated by incubatingthe cells for 48 hours in delipidated growth medium. Assayswere carried out in duplicate.
Results
Plasma, Erythrocyte, and Lens Sterols
The pattern of plasma sterols in the five patients on capillary-columngas chromatography was highly distinctive and very unusual (Figure 2).The patients' cholesterol concentrations were abnormallyreduced, to below the 5th percentile, as compared with concentrationsin controls (Table 1), and two or three additional sterols wereeasily detected (peaks II, III, and IV, Figure 2). The massspectra of peaks II and IV suggested that they were C27 diunsaturated3-hydroxy sterols. We unequivocally identified the most abundantof these compounds (peak IV) as the cholesterol precursor 7-dehydrocholesterol(Figure 3). Plasma levels of 7-dehydrocholesterol in all fivepatients were higher than 10 mg per deciliter, a concentrationat least 2000-fold greater than the median reported in controls(Table 1). Erythrocytes obtained from all the patients (Table 1)also contained high concentrations of 7-dehydrocholesterol,the isomeric dehydrocholesterol II, and sterol III. In contrast,when we analyzed plasma sterols in a group of six young childrenwithout the Smith-Lemli-Opitz syndrome, we were not able todetect peaks corresponding to dehydrocholesterols on gas chromatography.
Figure 2. Gas Chromatograms of the Trimethylsilyl Ether Derivatives of Plasma Neutral Sterols in Patient 1 and a Control (a Five-Year-Old Boy).
The compounds denoted by peaks I and IV were positively identified as cholesterol and 7-dehydrocholesterol, respectively. Peaks II and III denote isomeric dehydrocholesterols. Chomatography was performed isothermally at 225 °C on a 25-m CP-Sil 57CB capillary column with an internal diameter of 0.32 mm, with helium as the carrier gas with a flow rate of 1 ml per minute.
Figure 3. Mass Spectra of the Trimethylsilyl Ether Derivatives of Authentic 7-Dehydrocholesterol (Upper Panel) and 7-Dehydrocholesterol from the Plasma of Patient 1 (Lower Panel).
The three aberrant sterols were esterified efficiently. In Patients2 and 5, 87 and 87 percent, respectively, of cholesterol, 68and 63 percent of 7-dehydrocholesterol, 83 and 83 percent ofdehydrocholesterol II, and 69 and 67 percent of sterol III weredetermined to be sterol esters.
Lens sterols in Patient 1 consisted of cholesterol, 7-dehydrocholesterol,dehydrocholesterol II, and sterol III in the proportion 1.00:1.33:1.33:1.10.Thus, the three unusual sterols accounted for 79 percent ofthe total.
The fasting cholesterol concentrations of the patients' parentswere either normal (180, 188, and 210 mg per deciliter [4.65,4.85, and 5.45 mmol per liter] in the mother and father of Patient1 and the mother of Patient 2, respectively) or moderately elevated(260 and 266 mg per deciliter [6.70 and 6.90 mmol per liter]in the father of Patient 2 and the mother of Patient 3, respectively).We did identify two or three unusual sterols in trace amounts(0.1 to 0.2 percent of total sterols) in the chromatograms ofthree of the parents, but because of their low concentrationswe could not analyze these compounds using the methods describedabove.
Fecal Neutral Sterols and Bile Acids
The results of the analysis of fecal neutral sterols and bileacids in the three girls with the Smith-Lemli-Opitz syndromeare shown in Table 2. 7-Dehydrocholesterol and isomeric dehydrocholesterolswere found in all three patients. Although the excretion ofcholesterol and bile acid was highest in Patient 3, whose dietwas rich in cholesterol, the output of dehydrocholesterols wasalso considerable. We also analyzed the formula given to Patient1 (Pregestimil, Mead-Johnson); it contained plant sterols anda trace of cholesterol, but no cholesterol precursors. Hence,cholesterol and the dehydrocholesterols were being secretedinto bile by the liver.
Table 2. Fecal Neutral Sterols and Bile Acids in Three Girls with the Smith-Lemli-Opitz Syndrome.
More secondary bile acids (deoxycholic, lithocholic, and ursodeoxycholicacids) were detected in the feces of Patient 2 than in thoseof Patient 3; this is not unexpected, since a three-year-oldchild might be expected to have fewer intestinal bacteria. Itis interesting that the ratio of total bile acids to the totalamount of sterols II, III, and IV was 0 and 2 in Patients 1and 2, respectively, but exceeded 10 in Patient 3. An especiallynotable finding was the virtual absence of bile acids in thefeces of Patient 1.
Fibroblast Cultures
The biochemical defect was also readily detectable in culturesof skin fibroblasts from Patient 1. The ratio of 7-dehydrocholesterolto cholesterol was 15 percent, 18 percent, and 18 percent afterthe second, fourth, and sixth cell passages, respectively. However,neither isomeric dehydrocholesterol II nor sterol III couldbe detected. Because each passage represented the harvestingand replating of one half to one third of the cells, no morethan 1/64 of the original material remained after the sixthpassage. Therefore, these fibroblasts must have synthesizedmeasurable quantities of 7-dehydrocholesterol in vitro. No traceof 7-dehydrocholesterol or any other unusual sterol was foundin fibroblast cultures from any of the controls.
Discussion
These results demonstrate a major defect in cholesterol biosynthesisin five patients with the Smith-Lemli-Opitz syndrome, threegirls with normal karyotypes and two sexually unambiguous boys.The combination of abnormally low plasma cholesterol levelsand a markedly elevated concentration of the cholesterol precursor7-dehydrocholesterol suggests that cholesterol biosynthesisis blocked because of a defect in the reduction of the C-7 doublebond of 7-dehydrocholesterol (Figure 4, bottom right). Our observationthat 7-dehydrocholesterol could be found easily in all tissuesindicates that the defect is widespread and probably affectsevery organ. Although a six-month-old child with the syndromeand an abnormally low plasma cholesterol level of 63 mg perdeciliter (1.65 mmol per liter) has been described previously,4the presence of unusual sterols in patients with this diseasehas not yet been reported.
Cholesterol is synthesized from C-24(25) saturated and C-24(25) unsaturated intermediates (structures at left and right, respectively). The symbol X denotes the proposed block in cholesterol biosynthesis in the Smith-Lemli-Opitz syndrome -- defective reduction of the C-7 double bond of 7-dehydrocholesterol or of any other intermediate with a C-7 double bond.
Cholesterol is synthesized15,16 in mammalian tissues by a multistepprocess in which mevalonate is condensed to squalene and squaleneundergoes cyclization to lanosterol (4,4',14-methyl-5-cholest-8(9),24-diene-3-ol).Lanosterol must be demethylated, the C-8(9) double bond isomerizedto C-5(6), and the side chain reduced. Demethylation may bethe final step, in which case desmosterol (cholest-5,24-dien-3-ol)is the ultimate cholesterol precursor, or reduction at C-24(25)can occur early so that synthesis proceeds through the intermediates24,25-dihydrolanosterol (4,4',14-methyl-5-cholest-8(9)-en-3-ol),lathosterol (5-cholest-7-en-3-ol), and 7-dehydrocholesterol13,14,15,16,17,18(Figure 4). It is generally agreed, however,19,20,21,22,23,24,25that the two branches do not constitute separate and mutuallyexclusive pathways but share common enzymes, including 3-hydroxysterols7-reductase and 3-hydroxysterol s24-reductase. That is, theside-chain double bond can be reduced early, late, or sometimein between, but cholesterol biosynthesis must always includean intermediate with a C-7 double bond20,22,25. Therefore, ifthe enzyme 3-hydroxysterol s7-reductase is defective but allother enzymes are functional, one would expect to see reducedcholesterol biosynthesis coupled with an accumulation of 7-dehydrocholesterol.
Experimental compounds that block the action of 3-hydroxysterols7-reductase administered to rats elicit precisely this response21,22,23,24,26,27,28,29,30,31,32,33,34,35,36.Such studies have also demonstrated that in rats in neonatalor embryonic stages, inhibiting the reduction of 7-dehydrocholesterolto cholesterol can lead to severe tissue and organ abnormalitiesreminiscent of the Smith-Lemli-Opitz syndrome. These defectsinclude degeneration of neurologic tissue and reduced myelination,26,27,28,29,30,31,32decreased body29,31,33 and brain29 weight, pituitary agenesis,31nephrotic kidney disorders, increased fetal mortality and cryptorchidism,33,34clubfoot and cleft lip,33 maxillary and mandibular hypoplasia,and reduced head size31.
The structures of compounds II and III (Figure 2) are uncertain.However, Axelson has recently isolated trace quantities of twoisomeric dehydrocholesterols from plasma from adults, whichhe has identified as cholest-6,8(9)-dien-3-ol and cholest-5,8(9)-dien-3-ol8.Because we found that plasma 7-dehydrocholesterol, isomericdehydrocholesterol II, and sterol III are well esterified, theymust be good substrates for either hepatic acyl-coenzyme A:cholesterolO-acyltransferase or lecithin-cholesterol acyltransferase.
It is noteworthy that almost no bile acids were synthesizedby Patient 1. This deficiency is probably a direct consequenceof her limited ability to synthesize cholesterol. Cholesterol,in addition to being the obligate substrate for biosynthesisof bile acids, induces an increase in the activity of hepaticcholesterol 7-hydroxylase, the rate-controlling enzyme for bileacid biosynthesis, and the level of its messenger RNA36. Bileacids are essential for the intestinal absorption of lipids,so that a small bile acid pool would further reduce the supplyof cholesterol by hindering its absorption from food37.
Patient 3, who was nourished for her first three years by adiet high in cholesterol, had higher plasma cholesterol concentrationsthan any of the other patients (Table 1). This finding suggeststhat cholesterol feeding may be useful therapy. However, treatmentof the neurologic deficit in the Smith-Lemli-Opitz syndromewill be difficult unless a method can be devised that will delivercholesterol across the blood-brain barrier to the central nervoussystem.
It appears reasonably certain (Table 1) that the combinationof a grossly elevated plasma 7-dehydrocholesterol level anda reduced plasma cholesterol concentration4 is diagnostic ofthe Smith-Lemli-Opitz syndrome. In addition, because the defectseems to be expressed in most tissues, prenatal testing forthe disease may be possible by assaying amniotic fluid for 7-dehydrocholesterol.Also, it may be possible to identify obligate heterozygotesby a provocative test that stimulates cholesterol biosynthesis,such as the administration of a bile acid-binding resin38. However,it is important to note that routine methods of measuring plasmacholesterol, which use a colorimetric assay, probably detectall 3-hydroxy sterols as a single entity. Consequently, suchtests may yield spuriously high plasma cholesterol concentrations.At present, only a chromatographic assay is suitable for detectingand quantitating 7-dehydrocholesterol.
Supported in part by grants from the Department of VeteransAffairs Research Service (to Drs. Tint and Salen), by grants(DK-18707 and HL-17818) from the National Institutes of Health,and a grant from the Herman Goldman Foundation (to Dr. Salen).
We are indebted to Drs. Richard I. Kelley and John M. Opitzfor their many helpful discussions and continuing cooperationand to Bibiana Pcolinsky for her excellent technical assistance.Patient 5 has been cared for by Dr. Opitz.
Source Information
From the Departments of Medicine (GS.T., A.K.B., G.S.) and Pathology (T.S.C.), Veteran Affairs Medical Center, East Orange, N.J., and the University of Medicine and Dentistry-New Jersey Medical School, Newark; the Section of Clinical Genetics, Department of Pediatrics, New England Medical Center, Tufts University School of Medicine, Boston (M.I., E.R.E.); and Elliot Hospital, Manchester, N.H. (R.F.).
Address reprint requests to Dr. Tint at the Veterans Affairs Medical Center, 385 Tremont Ave., East Orange, NJ 07018-1095.
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Diagnosis of Smith-Lemli-Opitz Syndrome
McGaughran J., Donnai D., Clayton P., Mills K., Seedorf U., Walter M., Assmann G., Tint G. S., Salen G., Irons M.
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N Engl J Med 1994;
330:1685-1687, Jun 9, 1994.
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-ol), which was not detectable in most of our controls, were elevated (11 to 31 mg per deciliter) more than 2000-fold above normal and were similar to the levels of cholesterol in all tissues from all patients. An isomeric dehydrocholesterol with a structure similar to that of 7-dehydrocholesterol was also detected. 
-cholest-8(9),24-diene-3
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