Accessible Published by De Gruyter February 19, 2018

Smith-Lemli-Opitz syndrome: clinical and biochemical correlates

Sarah E. Donoghue, James J. Pitt, Avihu Boneh and Susan M. White



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. [1] 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 [2], 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. [3].

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. [4]. 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 [5], [6], [7]. It has important roles in neurodevelopment, myelination and brain growth [6], [8], in bile acid and in mineralo- and glucocorticoid hormone synthesis [6], [7], [9] (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 [6], [10], [11], [12]. 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 [13]). However, the only established relationship appears to be between lower plasma cholesterol levels and early demise [10], [11], [12], and Yu et al. [11] 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.

Figure 1: Cholesterol – bile acid, glucocorticoid and hormone derivatives.

Figure 1:

Cholesterol – bile acid, glucocorticoid and hormone derivatives.

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).

Patient characteristics

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 [2] was calculated as described by Nowaczyk and Irons [6].

Cholesterol measurement

Cholesterol and 7DHC levels were assayed in plasma by gas chromatography-mass spectrometry as previously described [14] 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. [15].

Qualitative urinary bile acid and steroid screening

Urine steroids were detected by tandem mass spectrometry as previously described [16]. Results were qualitatively scored as standards of abnormal SLOS steroids are not commercially available.

Mutation analysis

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 [17] and Mutation Taster [18] 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).

Table 1:

Post-mortem findings in SLOS.

Fetus 2, maleFetus 3, maleFetus 4, malePatient 4, male
Head and neckBroad nose, shallow external nares


Low set ears

Long philtrum


Mild hydrocephaly

Short neck
Flat nose, broad alveolar ridges


Large low set ears

Short neck
Flattened broad nose bridge


Low set, posteriorly angulated ears

Posterior cleft of soft palate


Fused posterior fontanelle

Small anterior fontanelle

Short neck
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
ChestHypoplastic, unilobed lungs

Thymic involution
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

Normal heart

Normal thymus

Patchy areas of pneumonia

Hypoplastic thymus in normal location; moderate thymocyte depletion
Urinary systemHypoplastic kidneysBilateral renal and ureters agenesis

Hypoplastic bladder
Hypoplastic left kidneyNormal kidneys
GenitaliaHypospadias, bifid scrotumHypospadias

Bifid scrotum
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 feetBilateral 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
EndocrineAdrenal glands – fetal cortexAdrenal glands normal

Thyroid normal
Adrenal glands normal

Thyroid normal
Hypoplastic adrenal glands bilaterally

No normal adrenal gland seen microscopically

Thyroid gland: occasional follicles of varying sizes with colloid production
OtherShortening of limbsHydrops fetalisPyloric stenosis

Affected small bowel: necrosis and soughing of villi, with crypt remnant present

Pneumatosis intestinalis
Table 2:

Main dysmorphic and clinical features in patients with SLOS.

No. of patientsFeatureaNo. of patientsComment
Head and neck (n=14)Broad nasal bridge7
Anteverted nares5
Low set ears6
Micrognathia7Cholesterol <1.0 in 6
Cleft palate7 (+1 submucous)Cholesterol <1.0 in 7
Bifid uvula3Cholesterol <1.0 in all
Cataracts4Cholesterol <1.0 in all
Ptosis3Cholesterol <1.0 in all
Short neck2Cholesterol <1.0 in all
Small fontanelle2Cholesterol <1.0 in all
Bitemporal narrowing2Cholesterol <1.0 in all
Limbs (n=14)2–3 toe syndactyly13
Bilateral talipes5Cholesterol <0.5 in all
Single palmar crease4
Short limbs3Cholesterol <1.0 in all; all deceased
Genitalia (n=6)Hypospadias3
Undescended testes4
Urinary system (n=6)Renal impairment4Cholesterol <1.0 in all
Heart (n=5), total cholesterol <1.0 in allCommon atrium2Both deceased
Hypoplastic ventricle2(left 1; right 1 deceased)
Atrioventricular defect2(common AV valve 1; deceased)
Electrolyte abnormalities (n=5)Hyperkalemia5Cholesterol <1.0 in all; four deceased
Hyponatremia4Cholesterol <1.0 in all; three deceased
Hypocalcemia3Cholesterol <1.0 in all; all deceased
Endocrine (n=?)Hypothyroidism2
Gastrointestinal (n=7)Necrotizing enterocolitis4Cholesterol <1.0 in all; all deceased
Immune (n=4), total cholesterol <1.0 in allSepsis-like episodes3Cholesterol <1.0 in all; all deceased
Recurrent infections2
SkeletalScoliosis2Cholesterol <1.0 in both
Delayed ossification2Cholesterol <1.0 in both; both deceased
Intellectual disabilityIntellectual disability10

  1. aFeatures noted only once not shown.

Table 3:

Karyotype, genotype, severity scores, cholesterol metabolites and longevity

PatientKaryotypeGenotypeAge at diagnosisSeverity scoreCholesterol7DHCc, normal rangeGestation/longevity
Fetus 1c.964-1G>C c.1210C>T12.6%a56.4%, 8-DHC 28%12/40 weeks
Fetus 2XY23.7b18/40 weeks
Fetus 3XY17b20/40 weeks
Fetus 4XY0.320835/40 weeks
Patient 1XXc.964-1G>C c.964-1G>CDay 1450.384310 days
Patient 2XXDay 1300.1 (2.3–5.4)297 (<10)21 days
Patient 3XXDay 3501.1>10033 days
Patient 4XYDay 2500.3545693 days
Patient 5XXDay 14200.5 (>3.1)930Lost to follow-up; last review at 20 years
Patient 6XY6 months250.5 (2.3–5.4)526 (<20)Lost to follow-up; last review 12 years/8 months
Patient 7XY7 months550.9587Alive at 4 years/2 months
Patient 8XYDay 1301.0 (2.3–5.4)622 (<10)Alive at 13 years/2 months
Patient 9XX7 years/2 months101.7 (2.3–5.4)209 (<10)Alive at 17 years
Patient 10XY15 years/1 months152.0 (2.3–5.4)228 (<10)Lost to follow-up; last review at 15 years/1 months
Patient 11XY9 months52.2390Alive at 16 years
Patient 12XY12 years/8 months202.5 (2.3–5.4)210 (<10)Lost to follow-up; last review at 12 years/8 months
Patient 13XXc.1228G>C c.1220A>G24 years153.2 (2.3–5.5)603 (<20)Lost to follow-up; last contact at 42 years
Patient 14XX1 years/1 months54.4 (2.3–5.4)306 (<10)Alive at 4 years/7 months

  1. 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 [16], 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 [18] and Polyphen-2 [17] 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 [5], [7], 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 [2] 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. [10]. These authors found an association between early death and a cholesterol level of <0.4 mmol/L. By contrast, Olah et al. [12] 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 [13]. 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 [7].

Abnormal urinary steroids have previously been identified in SLOS [19] and proposed as a rapid screening technique [16]. 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. [20] 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 [20], [21], [22]. The three females in our series underwent puberty at an appropriate age, consistent with previous reports [2], [22].

Large adrenal glands had been found in autopsies of 4/19 patients [23] and adrenal insufficiency has been reported in the neonatal period in patients with SLOS [21], [24], [25], [26]. 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 [25]. 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 [27]. 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 [28] and recurrent viral infections and fatal viral infections have been reported [29]. This may be due to defective monocyte oxidative metabolism, which has also been reported in a child with SLOS [30]. Decreased tissue concentration of cholesterol in the thymus [31] and abnormalities of thymus development have previously been reported in SLOS [32]. 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 [23]. 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) [33], [34], the c.1210C>T (p.Arg404Cys) mutation [35] and the 1228G>C (p.Gly410Arg) mutation [36]. 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 [37]. 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.

Corresponding author: Avihu Boneh, MD, PhD, FRACP, Department of Metabolic Medicine, Royal Children’s Hospital, Flemington Road, Parkville, Victoria 3052, Australia, Fax: +61-3-93456740


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.

  1. Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.

  2. Research funding: None declared.

  3. Employment or leadership: None declared.

  4. Honorarium: None declared.

  5. 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.


1. Smith DW, Lemli L, Opitz JM. A newly recognized syndrome of multiple congenital anomalies. J Pediatr 1964;64:210–7. Search in Google Scholar

2. Kelley RI, Hennekam RC. The Smith-Lemli-Opitz syndrome. J Med Genet 2000;37:321–35. Search in Google Scholar

3. Bialer MG, Penchaszadeh VB, Kahn E, Libes R, Krigsman G, et al. Female external genitalia and mullerian duct derivatives in a 46,XY infant with the Smith-Lemli-Opitz syndrome. Am J Med Genet 1987;28:723–31. Search in Google Scholar

4. Tint GS, Irons M, Elias ER, Batta AK, Frieden R, et al. Defective cholesterol biosynthesis associated with the Smith-Lemli-Opitz syndrome. N Engl J Med 1994;330:107–13. Search in Google Scholar

5. Lewis PM, Dunn MP, McMahon JA, Logan M, Martin JF, et al. Cholesterol modification of sonic hedgehog is required for long-range signaling activity and effective modulation of signaling by Ptc1. Cell 2001;105:599–612. Search in Google Scholar

6. Nowaczyk MJ, Irons MB. Smith-Lemli-Opitz syndrome: phenotype, natural history, and epidemiology. Am J Med Genet C Semin Med Genet 2012;160C:250–62. Search in Google Scholar

7. Baardman ME, Kerstjens-Frederikse WS, Berger RM, Bakker MK, Hofstra RM, et al. The role of maternal-fetal cholesterol transport in early fetal life: current insights. Biol Reprod 2013;88:24. Search in Google Scholar

8. Hennekam RC. Congenital brain anomalies in distal cholesterol biosynthesis defects. J Inherit Metab Dis 2005;28:385–92. Search in Google Scholar

9. Bianconi SE, Cross JL, Wassif CA, Porter FD. Pathogenesis, epidemiology, diagnosis and clinical aspects of Smith-Lemli-Opitz syndrome. Expert Opin Orphan Drugs 2015;3:267–80. Search in Google Scholar

10. Tint GS, Salen G, Batta AK, Shefer S, Irons M, et al. Correlation of severity and outcome with plasma sterol levels in variants of the Smith-Lemli-Opitz syndrome. J Pediatr 1995;127:82–7. Search in Google Scholar

11. Yu H, Lee MH, Starck L, Elias ER, Irons M, et al. Spectrum of Delta(7)-dehydrocholesterol reductase mutations in patients with the Smith-Lemli-Opitz (RSH) syndrome. Hum Mol Genet 2000;9:1385–91. Search in Google Scholar

12. Olah AV, Szabo GP, Varga J, Balogh L, Csabi G, et al. Relation between biomarkers and clinical severity in patients with Smith-Lemli-Opitz syndrome. Eur J Pediatr 2013;172:623–30. Search in Google Scholar

13. Porter FD. Smith-Lemli-Opitz syndrome: pathogenesis, diagnosis and management. Eur J Hum Genet 2008;16:535–41. Search in Google Scholar

14. Kelley RI. Diagnosis of Smith-Lemli-Opitz syndrome by gas chromatography/mass spectrometry of 7-dehydrocholesterol in plasma, amniotic fluid and cultured skin fibroblasts. Clin Chim Acta 1995;236:45–58. Search in Google Scholar

15. Sharp P, Haan E, Fletcher JM, Khong TY, Carey WF. First-trimester diagnosis of Smith-Lemli-Opitz syndrome. Prenat Diagn 1997;17:355–61. Search in Google Scholar

16. Pitt JJ. High-throughput urine screening for Smith-Lemli-Opitz syndrome and cerebrotendinous xanthomatosis using negative electrospray tandem mass spectrometry. Clin Chim Acta 2007;380:81–8. Search in Google Scholar

17. Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, et al. A method and server for predicting damaging missense mutations. Nat Methods 2010;7:248–9. Search in Google Scholar

18. Schwarz JM, Rodelsperger C, Schuelke M, Seelow D. Mutation Taster evaluates disease-causing potential of sequence alterations. Nat Methods 2010;7:575–6. Search in Google Scholar

19. Shackleton C, Roitman E, Guo LW, Wilso WK, Porter FD. Identification of 7(8) and 8(9) unsaturated adrenal steroid metabolites produced by patients with 7-dehydrosterol-delta7-reductase deficiency (Smith-Lemli-Opitz syndrome). J Steroid Biochem Mol Biol 2002;82:225–32. Search in Google Scholar

20. Quelin C, Loget P, Verloes A, Bazin A, Bessieres B, et al. Phenotypic spectrum of fetal Smith-Lemli-Opitz syndrome. Eur J Med Genet 2012;55:81–90. Search in Google Scholar

21. Chemaitilly W, Goldenberg A, Baujat G, Thibaud E, Cormier-Daire V, et al. Adrenal insufficiency and abnormal genitalia in a 46XX female with Smith-Lemli-Opitz syndrome. Horm Res 2003;59:254–6. Search in Google Scholar

22. Ellingson MS, Wick MJ, White WM, Raymond KM, Saenger AK, et al. Pregnancy in an individual with mild Smith-Lemli-Opitz syndrome. Clin Genet 2014;85:495–7. Search in Google Scholar

23. Curry CJ, Carey JC, Holland JS, Chopra D, Fineman R, 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. Search in Google Scholar

24. Andersson HC, Frentz J, Martinez JE, Tuck-Muller CM, Bellizaire J. Adrenal insufficiency in Smith-Lemli-Opitz syndrome. Am J Med Genet 1999;82:382–4. Search in Google Scholar

25. Bianconi SE, Conley SK, Keil MF, Sinaii N, Rother KI, et al. Adrenal function in Smith-Lemli-Opitz syndrome. Am J Med Genet A 2011;155A:2732–8. Search in Google Scholar

26. McKeever PA, Young ID. Smith-Lemli-Opitz syndrome. II: a disorder of the fetal adrenals? J Med Genet 1990;27:465–6. Search in Google Scholar

27. Short SS, Papillon S, Berel D, Ford HR, Frykman PK, et al. Late onset of necrotizing enterocolitis in the full-term infant is associated with increased mortality: results from a two-center analysis. J Pediatr Surg 2014;49:950–3. Search in Google Scholar

28. Babovic-Vuksanovic D, Jacobson RM, Lindor NM, Weiler CR. Selective antibody immune deficiency in a patient with Smith-Lemli-Opitz syndrome. J Inherit Metab Dis 2005;28:181–6. Search in Google Scholar

29. Beby-Defaux A, Maille L, Chabot S, Nassimi A, Oriot D, et al. Fatal adenovirus type 7b infection in a child with Smith-Lemli-Opitz syndrome. J Med Virol 2001;65:66–9. Search in Google Scholar

30. Ostergaard GZ, Nielsen H, Friis B. Defective monocyte oxidative metabolism in a child with Smith-Lemli-Opitz syndrome. Eur J Pediatr 1992;151:291–4. Search in Google Scholar

31. Tint GS, Seller M, Hughes-Benzie R, Batta AK, Shefer S, et al. Markedly increased tissue concentrations of 7-dehydrocholesterol combined with low levels of cholesterol are characteristic of the Smith-Lemli-Opitz syndrome. J Lipid Res 1995;36:89–95. Search in Google Scholar

32. Ness GC, Lopez D, Borrego O, Gilbert-Barness E. Increased expression of low-density lipoprotein receptors in a Smith-Lemli-Opitz infant with elevated bilirubin levels. Am J Med Genet 1997;68:294–9. Search in Google Scholar

33. Jira PE, Wanders RJ, Smeitink JA, De Jong J, Wevers RA, et al. Novel mutations in the 7-dehydrocholesterol reductase gene of 13 patients with Smith-Lemli-Opitz syndrome. Ann Hum Genet 2001;65(Pt 3):229–36. Search in Google Scholar

34. Balogh I, Koczok K, Szabo GP, Torok O, Hadzsiev K, et al. Mutational spectrum of Smith-Lemli-Opitz syndrome patients in hungary. Mol Syndromol 2012;3:215–22. Search in Google Scholar

35. Fitzky BU, Witsch-Baumgartner M, Erdel M, Lee JN, Paik YK, et al. Mutations in the Delta7-sterol reductase gene in patients with the Smith-Lemli-Opitz syndrome. Proc Natl Acad Sci USA 1998;95:8181–6. Search in Google Scholar

36. Witsch-Baumgartner M, Schwentner I, Gruber M, Benlian P, Bertranpetit J, et al. Age and origin of major Smith-Lemli-Opitz syndrome (SLOS) mutations in European populations. J Med Genet 2008;45:200–9. Search in Google Scholar

37. De Brasi D, Esposito T, Rossi M, Parenti G, Sperandeo MP, et al. Smith-Lemli-Opitz syndrome: evidence of T93M as a common mutation of delta7-sterol reductase in Italy and report of three novel mutations. Eur J Hum Genet 1999;7:937–40. Search in Google Scholar

Received: 2017-11-29
Accepted: 2018-1-18
Published Online: 2018-2-19
Published in Print: 2018-3-28

©2018 Walter de Gruyter GmbH, Berlin/Boston