Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive disorder caused by mutations in the DHCR7 gene that result in reduced cholesterol biosynthesis. The aim of the study was to examine the biochemical and clinical features of SLOS in the context of the emerging evidence of the importance of cholesterol in morphogenesis and steroidogenesis.
We retrospectively reviewed the records of 18 patients (including four fetuses) with confirmed SLOS and documented their clinical and biochemical features.
Seven patients had branchial arch abnormalities, including micrognathia, immune dysfunction and hypocalcemia. Thymic abnormalities were found in three fetuses. All four patients with a cholesterol level of ≤0.35 mmol/L died. They all had electrolyte abnormalities (hyperkalemia, hyponatremia, hypocalcemia), necrotizing enterocolitis, sepsis-like episodes and midline defects including the branchial and cardiac defects. Patients with cholesterol levels ≥1.7 mmol/L had milder features and were diagnosed at 9 months to 25 years of age. All 10 patients had intellectual disability. One patient was found to have a novel mutation, c.1220A>G (p.Asn407Ser).
We suggest that screening for adrenal insufficiency and for hypoparathyroidism, hypothyroidism and immunodeficiency, should be done routinely in infants diagnosed early with SLOS. Early diagnosis and intervention to correct these biochemical consequences may decrease mortality and improve long-term outcome in these patients.
The Smith-Lemli-Opitz syndrome (SLOS; OMIM 270400) was first described in 1964 by Smith et al.  as a constellation of neonatal manifestations with typical congenital malformations including central nervous system, facial and genital and toe malformations. A clinical severity score, suggested by Kelley and Hennekam , is used to estimate the severity of the clinical manifestations in patients with SLOS based on the established features of the disorder. This score is based on a previously published score, suggested by Bialer et al. .
The relationship between SLOS and low plasma cholesterol and high 7-dehydrocholesterol (7DHC) and 8-dehydrocholesterol (8DHC) levels was first reported by Tint et al. . Cholesterol is essential for maintaining the integrity of the lipid bilayer of cell membranes and has a critical role in cell signaling. It has been shown to have a pivotal role in modification of sonic hedgehog during embryogenesis , , . It has important roles in neurodevelopment, myelination and brain growth , , in bile acid and in mineralo- and glucocorticoid hormone synthesis , ,  (Figure 1). Thus, it has been speculated that the dysmorphic and clinical features of the disorder result from decreased cholesterol synthesis. In the period following this discovery, several authors reported an apparent quantitative causative relationship between low plasma cholesterol, high 7DHC and 8DHC levels and the severity of the clinical manifestations and longevity in patients with SLOS , , , . It was assumed that the malformations found in SLOS may result from decreased cholesterol, increased 7DHC or a combination of these two factors (reviewed in Porter ). However, the only established relationship appears to be between lower plasma cholesterol levels and early demise , , , and Yu et al.  suggested that other factors may be involved in the severity of the clinical manifestations. Nevertheless, from a clinical perspective, the observation of an apparent causative relationship between a defect in cholesterol metabolism and SLOS enabled the biochemical confirmation of the diagnosis in patients suspected clinically.
As the clinical consequences of cholesterol metabolism and deficiency are now better understood, the purpose of the current study was to re-examine the relationship between the clinical manifestations, longevity and consequences of cholesterol deficiency in a cohort of patients and post-mortem examinations of fetuses with SLOS.
Materials and methods
A list of all patients with a confirmed diagnosis of SLOS was retrieved from the Victorian Clinical Genetics Services database and VICIEM, an in-house clinical metabolic database, and a review of all their clinical and laboratory records was performed. Only patients with elevated 7DHC levels or confirmed bi-allelic mutations in the DHCR7 gene that are known to be associated with a diagnosis of SLOS were included. Ethical approval for this study was granted by the Human Research Ethics Committee (HREC Ref. No.: 34148).
Clinical manifestations, longevity, features recorded in autopsy reports, cholesterol and 7DHC levels and mutations in the DHCR7 gene were noted and a clinical severity score reported by Kelley and Hennekam  was calculated as described by Nowaczyk and Irons .
Cholesterol and 7DHC levels were assayed in plasma by gas chromatography-mass spectrometry as previously described  with minor modification. Where blood/plasma samples were not available (three fetuses), 7DHC levels and neutral sterols (two fetal samples and one fetal sample, respectively) were measured from cultured fibroblasts or in tissues of one fetus according to Sharp et al. .
Qualitative urinary bile acid and steroid screening
Urine steroids were detected by tandem mass spectrometry as previously described . Results were qualitatively scored as standards of abnormal SLOS steroids are not commercially available.
Sanger sequencing was used to screen for mutations in exon 9 on the DHCR7 gene, followed by sequence analysis of the remaining coding exons and associated intron/exon boundaries. In silico prediction software tools Polyphen-2  and Mutation Taster  were then used to predict the pathogenicity of previously unreported variants.
A total of 18 patients with SLOS met the inclusion criteria, including four fetuses and 14 patients. Autopsy reports were available for three fetuses and one patient (Table 1). Clinical features are summarized in Table 2 and biochemical data, mutations and severity scores of the patients are summarized in Table 3. It should be noted that some data were derived from summary and referral letters to our center; hence, some of the data were limited in some cases (particularly the exact electrolyte concentrations in blood).
|Fetus 2, male||Fetus 3, male||Fetus 4, male||Patient 4, male|
|Head and neck||Broad nose, shallow external nares|
Low set ears
|Flat nose, broad alveolar ridges|
Large low set ears
|Flattened broad nose bridge|
Low set, posteriorly angulated ears
Posterior cleft of soft palate
Fused posterior fontanelle
Small anterior fontanelle
|Broad nose, flat nasal bridge slightly anteverted nares|
Secondary cleft palate; the tongue is hypoplastic with a tongue-tie bitemporal narrowing
Small fontanelles; sutures immobile and fixed
Hypertelorism and epicanthal folds
Low set ears, normally rotated
|Chest||Hypoplastic, unilobed lungs|
|Severe bilateral pulmonary hypoplasia; unilobed lungs|
High ventricular septal defect
Patent ductus arteriosus; thymus mildly involuted; cortico-medullary junction blurred
|Widely spaced nipples|
Unilobed left lung
|Patchy areas of pneumonia|
Hypoplastic thymus in normal location; moderate thymocyte depletion
|Urinary system||Hypoplastic kidneys||Bilateral renal and ureters agenesis|
|Hypoplastic left kidney||Normal kidneys|
|Genitalia||Hypospadias, bifid scrotum||Hypospadias|
|Severe hypospadias, micropenis, hypoplastic scrotum, right intra-abdominal gonad; left in inguinal canal|
Microscopy: poorly differentiated testicular tissue
|Phenotypically female; testes within the abdominal cavity Mullerian duct derivatives absent|
Very small vaginal vault present
Testis: normal tubules formation with occasional Sertoli cells and interstitial Leydig cells
|Hands and feet||Bilateral equinovalgus foot deformity, bilateral 2–3 toe syndactyly|
Left 4–5 toe fusion
Postaxial polydactyly of hands
|Bilateral equinovarus foot deformity: rocker bottom heels|
Postaxial polydactyly of feet
|Postaxial polydactyly of both hands|
Bilateral partial 2–3 toe syndactyly
|Clinodactyly and postaxial polydactyly|
Bilateral simian creases
Fusion of the soft tissues between the second and third digits bilaterally
Talipes calcaneovalgus, left > right
|Endocrine||Adrenal glands – fetal cortex||Adrenal glands normal|
|Adrenal glands normal|
|Hypoplastic adrenal glands bilaterally|
No normal adrenal gland seen microscopically
Thyroid gland: occasional follicles of varying sizes with colloid production
|Other||Shortening of limbs||Hydrops fetalis||Pyloric stenosis|
Affected small bowel: necrosis and soughing of villi, with crypt remnant present
|No. of patients||Featurea||No. of patients||Comment|
|Head and neck (n=14)||Broad nasal bridge||7|
|Low set ears||6|
|Micrognathia||7||Cholesterol <1.0 in 6|
|Cleft palate||7 (+1 submucous)||Cholesterol <1.0 in 7|
|Bifid uvula||3||Cholesterol <1.0 in all|
|Cataracts||4||Cholesterol <1.0 in all|
|Ptosis||3||Cholesterol <1.0 in all|
|Short neck||2||Cholesterol <1.0 in all|
|Small fontanelle||2||Cholesterol <1.0 in all|
|Bitemporal narrowing||2||Cholesterol <1.0 in all|
|Limbs (n=14)||2–3 toe syndactyly||13|
|Bilateral talipes||5||Cholesterol <0.5 in all|
|Single palmar crease||4|
|Short limbs||3||Cholesterol <1.0 in all; all deceased|
|Urinary system (n=6)||Renal impairment||4||Cholesterol <1.0 in all|
|Heart (n=5), total cholesterol <1.0 in all||Common atrium||2||Both deceased|
|Hypoplastic ventricle||2||(left 1; right 1 deceased)|
|Atrioventricular defect||2||(common AV valve 1; deceased)|
|Electrolyte abnormalities (n=5)||Hyperkalemia||5||Cholesterol <1.0 in all; four deceased|
|Hyponatremia||4||Cholesterol <1.0 in all; three deceased|
|Hypocalcemia||3||Cholesterol <1.0 in all; all deceased|
|Gastrointestinal (n=7)||Necrotizing enterocolitis||4||Cholesterol <1.0 in all; all deceased|
|Immune (n=4), total cholesterol <1.0 in all||Sepsis-like episodes||3||Cholesterol <1.0 in all; all deceased|
|Skeletal||Scoliosis||2||Cholesterol <1.0 in both|
|Delayed ossification||2||Cholesterol <1.0 in both; both deceased|
|Intellectual disability||Intellectual disability||10|
aFeatures noted only once not shown.
|Patient||Karyotype||Genotype||Age at diagnosis||Severity score||Cholesterol||7DHCc, normal range||Gestation/longevity|
|Fetus 1||–||c.964-1G>C c.1210C>T||12.6%a||56.4%, 8-DHC 28%||12/40 weeks|
|Fetus 2||XY||23.7b||18/40 weeks|
|Fetus 3||XY||17b||20/40 weeks|
|Fetus 4||XY||0.3||208||35/40 weeks|
|Patient 1||XX||c.964-1G>C c.964-1G>C||Day 1||45||0.3||843||10 days|
|Patient 2||XX||Day 1||30||0.1 (2.3–5.4)||297 (<10)||21 days|
|Patient 3||XX||Day 3||50||1.1||>100||33 days|
|Patient 4||XY||Day 2||50||0.35||456||93 days|
|Patient 5||XX||Day 14||20||0.5 (>3.1)||930||Lost to follow-up; last review at 20 years|
|Patient 6||XY||6 months||25||0.5 (2.3–5.4)||526 (<20)||Lost to follow-up; last review 12 years/8 months|
|Patient 7||XY||–||7 months||55||0.9||587||Alive at 4 years/2 months|
|Patient 8||XY||–||Day 1||30||1.0 (2.3–5.4)||622 (<10)||Alive at 13 years/2 months|
|Patient 9||XX||–||7 years/2 months||10||1.7 (2.3–5.4)||209 (<10)||Alive at 17 years|
|Patient 10||XY||–||15 years/1 months||15||2.0 (2.3–5.4)||228 (<10)||Lost to follow-up; last review at 15 years/1 months|
|Patient 11||XY||–||9 months||5||2.2||390||Alive at 16 years|
|Patient 12||XY||–||12 years/8 months||20||2.5 (2.3–5.4)||210 (<10)||Lost to follow-up; last review at 12 years/8 months|
|Patient 13||XX||c.1228G>C c.1220A>G||24 years||15||3.2 (2.3–5.5)||603 (<20)||Lost to follow-up; last contact at 42 years|
|Patient 14||XX||–||1 years/1 months||5||4.4 (2.3–5.4)||306 (<10)||Alive at 4 years/7 months|
aPercentage of fetal tissue neutral sterols assessed in fibroblasts. bnmol/mg protein, measured in fibroblasts (normal <0.85 nmol/mg protein). cLevels at diagnosis.
Of the four fetuses, three were male. The remaining fetus was miscarried at 12 weeks and did not have a karyotype performed. All three fetuses had typical facial features, short necks, abnormalities in lobation of the lungs, post-axial polydactyly, genitourinary abnormalities and hypospadias (Table 1). Of note, two fetuses had evidence of ‘involution’ and one had ‘hypoplasia’ of the thymus on histology. Mild thymocyte depletion was reported in one. In one fetus, there was poor differentiation of the testes on microscopy, poor development of the seminiferous tubules and fewer Leydig cells than expected for gestational age. In another fetus, the adrenal cortex appeared immature for gestational age.
Of the 14 patients who were diagnosed after birth (Table 2), four died at 10–93 days of age, four are still reviewed in the clinic (age range 4 years 2 months–17 years) and six have been lost to follow-up (last clinic review at age 20 years; contact with one patient aged 42 years).
A summary of clinical and laboratory manifestations in the 14 patients is provided in Table 2: syndactyly of the 2nd and 3rd toes was the most common finding in our study (two of three fetuses and 13 of 14 patients). Abnormalities in branchial arch development were common in our series with seven of 14 patients with micrognathia, eight of 14 patients presenting with a cleft palate and three of 14 patients presenting with a bifid uvula. Hypocalcemia was reported in three of the 14 patients and hypothyroidism was reported in two of the 14 patients. Immune problems were found in three of the deceased patients having sepsis-like episodes and two patients with recurrent infections. In six of the seven male patients, there was a spectrum of genital abnormalities ranging from ambiguous genitalia, hypospadias or varying degrees of undescended testes. Cardiac abnormalities were noted in five of the 14 patients and abnormalities in vision were found in seven of the 14 patients, with cataracts in four of these patients (congenital cataract in three, no further information about the fourth).
All 10 patients who remained alive after age 3 months had intellectual disability, as assessed through formal neuropsychological testing: two had mild, three had moderate and one had severe intellectual disability. Two additional children had not had any formal cognitive testing at the time of the study, but were reported to have delayed motor and speech development. Information about the degree of intellectual impairment in the remaining two was not available.
Characteristics of deceased patients
All four patients who died were born at term. All had electrolyte abnormalities (hyperkalemia, hyponatremia; one requiring sodium supplementation, hypocalcemia), necrotizing enterocolitis, sepsis-like episodes and midline defects including the branchial and cardiac defects. Three of these infants had positive blood cultures peri-mortem: two with Staphylococcus epidermidis and one with group B streptococcus.
Electrolyte abnormalities suggestive of adrenal insufficiency (hyperkalemia and hyponatremia) were noted in four (or five) patients but specific tests to assess adrenal function were recorded in only one patient who was found to have adrenal insufficiency and was treated with corticosteroids. At autopsy his adrenal glands were found to be hypoplastic bilaterally (Table 1).
Cholesterol, 7DHC, other sterols, bile acids and steroids
All patients with a cholesterol level of ≤0.35 mmol/L died (Table 3). Patients with cholesterol levels ≥1.7 mmol/L had milder features and were diagnosed at 9 months to 25 years of age. Patients with cholesterol levels between these levels had a variable clinical course (Table 3). All patients had 7DHC levels ≥209 μmol/L with corresponding increases in 8DHC (not shown).
Urine steroid screening, which is done as part of urine bile acid screening, was performed for patients 1, 3, 9 and 14. Patients 1, 3 and 9 had increases in abnormal steroids characteristic of SLOS , namely 5,7-pregnadientriol sulfate, 5,7-pregnadientetrol sulfate and 5,7-pregnadien-diol-20-one sulfate which are derived from secondary metabolism of 7DHC utilizing established steroid biochemical pathways. Patient 14 had normal levels of these steroids. There were normal urine levels of physiological bile acids (taurocholic, taurochenodeoxycholic, glycocholic and glycochenodeoxycholic). It is possible that the SLOS group had statistically lower values than the controls but this cannot be confidently ascertained given that the levels measured were near the limit of detection.
One fetus was heterozygous for the c.964-1G>C (IVS8-1G>C) mutation and for the 1210C>T (p.Arg404Cys) mutation. One patient was homozygous for the c.964-1G>C mutation. One patient was heterozygous for the c.1228G>C (p.G410R) mutation and for the c.1220A>G (p.Asn407Ser), a novel mutation that is predicted to be deleterious by Mutation Taster  and Polyphen-2  programs.
The clinical features of SLOS represent two major consequences of cholesterol deficiency: (1) its effect on hedgehog modification and signaling during fetal life, leading to abnormal development of the branchial system and central nervous system , , and (2) its effect on the synthesis of steroid hormones and in particular, that of dihydrotestosterone. Indeed, the clinical severity score adapted by Kelley and Hennekam  focuses on the phenotypic consequences of the disruption of cholesterol-dependent processes during early development. Whilst dysmorphic features have been widely described, other manifestations have been described mainly in single case reports. Our observations in patients and post-mortem analyses suggest a relatively high prevalence of apparent adrenal insufficiency, abnormalities in calcium regulation and, possibly, thymic dysfunction in the more severely affected patients. However, the actual prevalence of these abnormalities is not known because of the retrospective nature of this study.
The small number of patients in our series precludes a proper statistical analysis to correlate between plasma cholesterol levels and outcome, yet a plasma cholesterol concentration of ≤0.35 mmol/L was associated with early death, in line with the findings of Tint et al. . These authors found an association between early death and a cholesterol level of <0.4 mmol/L. By contrast, Olah et al.  reported neonates with higher cholesterol levels of up to 0.93 mmol/L dying in the newborn period. However, caution must be exercised when correlating between plasma cholesterol levels and clinical outcome because the routine method used in most laboratories for determining cholesterol concentration measures, in fact, a sum of several sterols, including 7DHC . More specific techniques, such as gas chromatography-mass spectrometry, are required to accurately measure cholesterol in SLOS patients. Moreover, although most cholesterol is endogenously produced in the fetus, it has been suggested that maternal cholesterol transport in utero and cholesterol absorption and utilization post-natally affect the clinical severity of SLOS .
Abnormal urinary steroids have previously been identified in SLOS  and proposed as a rapid screening technique . We observed increases in these steroids in three out of four patients. Interestingly, the patient with normal steroids (patient 14) had the lowest severity score. Thus, while urine steroid screening may be helpful to rapidly identify severe SLOS patients, plasma 7DHC is still the preferred means of diagnosing suspected cases.
Almost all male patients in our series presented with varying degrees of failure of normal descent of the testes and undervirilization suggesting dihydrotestosterone deficiency in utero. These manifestations in the male fetuses and patients have been widely reported previously. Quelin et al.  did not find any abnormalities in testicular differentiation on microscopy. By contrast, one affected fetus in our series was noted to have poor differentiation of the testes, poor development of the seminiferous tubules and fewer Leydig cells than expected on microscopy. This fetus had a significantly low cholesterol of 0.3 mmol/L. The consequences of failure of hormone formation in females are not well understood. Some females have been reported to have structural abnormalities of their reproductive system and external genitalia , , . The three females in our series underwent puberty at an appropriate age, consistent with previous reports , .
Large adrenal glands had been found in autopsies of 4/19 patients  and adrenal insufficiency has been reported in the neonatal period in patients with SLOS , , , . Despite baseline ACTH levels higher than the normal, the ACTH-adrenal axis was reported to function adequately in a group of patients treated with cholesterol . Nevertheless, the authors found a statistically significant linkage between disease severity and both ACTH and cortisol concentrations. In a series of term neonates with necrotizing enterocolitis, one baby was found to have SLOS . The authors also reported several neonates with endocrinopathies but it is not clear whether the neonate with SLOS was one of those. Taken together with our series of patients, these findings suggest that adrenal dysfunction may be more prevalent in the more severely affected infants than currently recognized and should be evaluated in every baby suspected of having SLOS.
Immune deficiency has been recognized in patients with SLOS  and recurrent viral infections and fatal viral infections have been reported . This may be due to defective monocyte oxidative metabolism, which has also been reported in a child with SLOS . Decreased tissue concentration of cholesterol in the thymus  and abnormalities of thymus development have previously been reported in SLOS . Our findings (Tables 1 and 2) corroborate this previous report and suggest that abnormalities of thymus development may contribute to the immunodeficiency reported in SLOS.
Several features of SLOS overlap with other syndromes, such as the 22q11.21 deletion syndrome with the DiGeorge/velocardiofacial syndrome clinical manifestations. One infant with SLOS with absent parathyroid glands has been reported . The observation of hypothyroidism, hypocalcemia and the developmental abnormalities of the thymus in some of our patients suggest that patients should be screened for problems that are associated with branchial arch abnormalities such as those found in the 22q11.21 deletion disorders. The significance and specificity of the three positive blood cultures in the deceased patients are not clear at this stage but given the thymic abnormalities noted in some infants, this suggests that evaluation of patients’ immune status in individuals with SLOS is indicated.
Finally, three of the mutations in our series of patients were already known to cause SLOS: the c.964-1G>C mutation (p. Ser397Leu) , , the c.1210C>T (p.Arg404Cys) mutation  and the 1228G>C (p.Gly410Arg) mutation . The c.1220A>G (p.Asn407Ser) mutation has previously been reported in heterozygous form in the Exome Aggregate Consortium in two out of 315,600 European individuals, but there have been no publications about pathogenicity. The corresponding 1219 position on the DHCR7 gene corresponds to a highly conserved nucleotide binding site and other mutations in this region have been reported as pathogenic . We believe that our patient may be the first biochemically confirmed patient reported with this change.
We conclude that accurate measurement of plasma cholesterol and 7DHC is essential for making a correct diagnosis of SLOS, but a direct correlation between cholesterol levels and the severity of symptoms cannot be firmly established. In our cohort, a plasma cholesterol level of <0.35 mmol/L was associated with a high severity score and with death within 3 months of age. We did not find any correlation between 7DHC level and morbidity or mortality.
Our findings suggest that screening for adrenal insufficiency and for hypoparathyroidism, hypothyroidism and immunodeficiency, should be done routinely in patients diagnosed early with SLOS and adequate treatment be provided. We suggest that early diagnosis and therapeutic intervention to correct these biochemical consequences may decrease mortality and improve long-term outcome in these patients, but this will need further, prospective studies.
Study data were collected and managed on VICIEM, an in-house clinical databank for IEM using REDCap electronic data capture tools, hosted at the Murdoch Childrens Research Institute, Melbourne, Australia and supported by the Australian Communities Foundation, the N.E. Renton Bequest. This work was supported by the Victorian Government’s Operational Infrastructure Support Program.
Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.
Research funding: None declared.
Employment or leadership: None declared.
Honorarium: None declared.
Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.
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