See discussions, st ats, and author pr ofiles f or this public ation at : https:www .researchgate.ne tpublic ation228663339 [621104]

See discussions, st ats, and author pr ofiles f or this public ation at : https://www .researchgate.ne t/public ation/228663339
Male Pseudohermaphroditism Caused by an Inborn Error in Cholesterol
Biosynthesis: Smith-Lemli-Opitz Syndrome
Article · Januar y 2006
DOI: 10.4183/ aeb .2006.365
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MALE PSEUDOHERMAPHRODITISM CAUSED BY AN INBORN
ERROR IN CHOLESTEROL BIOSYNTHESIS: SMITH-LEMLI-
OPITZ SYNDROME
Corina Rãducanu-Lichiardopol 1,*, Cristina Busuioc 1, Manuela Bãcãnoiu 2, Elena
Coletã 2, Olimpia Stãicuș 2, C. Bãtãiosu 2, F Mixich 1, ătefania Tudorache 1,
Florentina Tãnase 1, Mihaela Vasile 2
1University of Medicine and Pharmacy Craiova, Romania,
2Emergency Hospital, Craiova, Romania
Smith-Lemli-Opitz syndrome is an autosomal recessive disorder caused by mutations
of 3?-hydroxysterol – ?7reductase gene ( DHCR7 ) which maps to 11q12-13 and was the first
discovered defect in cholesterol biosynthesis resulting in a congenital dysmorphology
syndrome.
We present the case of a 46,XY newborn with ambiguous genitalia and multiple
congenital anomalies (atrial septal defect, ventricular septal defect, syndactyly of the second
and third toe, cleft palate, webbed neck, small fontanels, mesomelia, simian palmar crease,
micrognathia, wide nasal bridge with anteverted nostrils, low set ears).
Hormonal assessment performed at twelve days revealed a decreased testosterone
level (0.03 ng/mL), a high estradiol level (448.8 pg/mL), normal LH (2.8UI/mL), DHEAS
(86.61ìg/dL), progesterone (1.34ng/mL) and 17 hydroxyprogesterone (1.08ng/mL) levels.
Cholesterol was low (44mg/dL) confirming the diagnostic of Smith-Lemli-Opitz syndrome.
Key words : Smith-Lemli-Opitz syndrome, ambiguous genitalia, cholesterol
deficiency, DHCR7.
INTRODUCTION
The Smith-Lemli-Opitz syndrome (SLOS), first described in 1964, is an
autosomal recessive inborn error of cholesterol synthesis caused by deficiency of
the microsomal enzyme 3 ?-hydroxysterol- ?7-reductase (DHCR 7) which catalizes
the conversion of 7-dehydro-cholesterol (7DHC) to cholesterol (1, 2). Cholesterol
biosynthesis from lanosterol is confined to the endoplasmic reticulum and
comprises oxidations, reductions and demethylations (Fig. 1). The high level of
7DHC in patients with SLOS without an increase of 7 dehydrodesmosterol proved
365Case Report
*Correspondence to: Corina Lichiardopol, M.D., Department of Endocrinology, University of
Medicine and Pharmacy, Emergency Hospital, 1 Tabaci Str., Craiova, Romania, tel.:
04.0251.502.130, e-mail: [anonimizat]
Acta Endocrinologica (Buc), vol. II, no. 3, p.365-376, 2006Tipar Cap coada.qxd 12/1/2006 6:46 PM Page 365

that in humans the Kandutsch-Russel pathway predominates (3), though in some
tissues (testes, breast, neuronal tissues) desmosterol seems to be the main precursor.
The enzymes, carrier proteins, and the regulation of intracellular trafficking of
cholesterol have not been completely elucidated (4).
Cholesterol is a major structural component of the cell membrane, a precursor
for the synthesis of steroid hormones and bile acids and a regulator of hedgehog
signaling during early embryonic development (5). SLOS phenotype ranges from
mild (minor malformations, learning disabilities, behavioural problems) to severe
(dysmorphic facies, limb, central nervous system, genital, cardiovascular, renal,
pulmonary, gastrointestinal malformations, mental retardation, failure to thrive and
even intrauterine death or during the newborn period).
The human DHCR7 gene, located 11q12-13 was cloned and mapped (6-8) in
1998 and since then more than 121 mutations have been identified (9), with
missense mutations accounting for the vast majority (87.5%; 105 mutations) and
less frequent null mutations (5 nonsense, three splice site and 8 nucleotide insertions
or deletions).Corina Raducanu-Lichiardopol et al.
366Figure 1. Cholesterol biosynthesis from the first sterol, lanosterol.
(1)- 3 ?hydroxysteroid delta 8, delta 7 isomerase.
(2)- lathosterol dehydrogenase.
(3)- 3 ?hydroxysteroid delta 7 reductase (DHCR 7) is inhibited by AY – 9944 and BM 15.766.
(4) – desmosterol reductase – inhibited by Triparanol.
Tipar Cap coada.qxd 12/1/2006 6:46 PM Page 366

Five mutations (IVS8-1G, T93M, W151X, V326L and R404C) account for
50-60% of the mutant alleles. Phenotypic heterogeneity is generated by factors that
involve maternal cholesterol transfer to the developing foetus (recently maternal
apo E2 genotype was associated with a more severe SLOS phenotype – 10), the
amount of cholesterol that can accumulate in the central nervous system before the
blood- brain barrier is formed , the potential accumulation of toxic precursors, the
intervention of other enzymes that may be able to reduce the double bond at C7-8
of sterol precursors and, perhaps, yet unidentified genetic and epigenetic factors (9).
The incidence of SLOS ranges from 1/10000 to 1/60000 of live births (9), but
it could be higher considering foetal loss and mild, undiagnosed cases. Screening
for mutant DHCR7 alleles suggested a carrier frequency of 3-4% in Caucasian
populations thus, there could be 1 in 1590 to 1 in 13500 fertilized eggs with this
syndrome (11). SLOS appears to be most frequent in Central European populations
and is rare in Asian, African American, African and South American populations.
Both heterozygote advantage (increased vitamin D levels in heterozygotes provided
an advantage, since rickets was common in the European Paleolithic population)
and founder effect may explain this difference (4). Nevertheless, in SLOS patients,
despite the high 7-DHC concentrations, vitamin D metabolites are not significantly
increased, perhaps due to reduced sunlight exposure as a consequence of
photosensitivity, and/or an unknown metabolic mechanism that protects them from
vitamin D intoxication (12).
Severely affected patients are homozygotes or compound heterozygotes for
mutations with no or markedly reduced enzymatic activity, while milder phenotype
(usually compound heterozygotes) is associated with residual DHCR 7 activity and
most patients with very mild phenotypes are compound heterozygotes for unique or
common missense mutations (13).
Two murine genetic models have been generated in order to elucidate the
pathogenesis and to evaluate therapeutic attempts.
Smith-Lemli-Opitz syndrome was the first identified dysmorphic syndrome
generated by an error in postsqualen cholesterol biosynthesis and led to the
discovery of other similar syndromes such as desmosterolosis, lathosterolosis,
CHILD syndrome, CDPX2 (X-linked dominant chondrodysplasia punctata),
HEM/Greenberg skeletal dysplasia (hydrops-ectopic calcification – moth eaten
dysplasia) pointing out the major developmental role of cholesterol.
CASE REPORT
We present the case of an intersex infant, delivered at 37 weeks gestational age
by caesarean section due to fetal distress, after an apparently uneventful pregnancy.
He was the first child of a 40 year old couple, who had three other healthy sons
(one- the mother and two-the father) from previous marriages.Smith-Lemli-Opitz syndrome
367Tipar Cap coada.qxd 12/1/2006 6:46 PM Page 367

Family history was not significant, and no prenatal tests were performed, with
the exception of sonographic evaluation just before birth, that detected intrauterine
growth retardation and severe oligohydramnios.
Clinical examination showed growth parameters below the 5th centile for
gestational age (weight was 2250 g, length 43 cm, head circumference 31 cm). The
Apgar score at 1 minute was 7 with hypotonia, apnoea and cyanosis, and at five
minutes it was 9.
Craniofacial features included small fontanels, micrognathia, wide nasal
bridge, anteverted nostrils, cleft palate and low set ears (Fig. 2). Other findings
were: webbed neck, mesomelia, simian palmar crease, syndactyly of the second and
third toes (Fig. 3) and ambiguous genitalia – a 2 cm long penoclitoridian organ with
ventral opening of the urethra, fused labia minora and nonpalpable gonads (Fig. 4).
Karyotype was normal, 46,XY.
Ultrasound evaluation showed the absence of mullerian derivatives, detected no
gonads and no kidney anomalies. Chest X ray showed cardiac enlargement (Fig. 5).
Echocardiogram (Fig. 6) revealed a 2.3 mm atrial septal defect and a 3.7 mm
ventricular septal defect; reexamination after 1 month showed that only the
ventricular septal defect persisted.
At 3 days of age haemoglobin was normal (14.6g/dl), sodium was 149mmol/L,
kalium was 6.6mmol/L and calcium 1.4mmol/L. At six days of age anemia was
present (haemoglobin 10.6g/dL) and persisted thereafter. At 12 days of age
cholesterol level was determined, showing a decreased value of 44mg/dL (normalCorina Raducanu-Lichiardopol et al.
368Figure 2. Craniofacial aspect.
Figure 3. Syndactyly of the second and third toes.
Tipar Cap coada.qxd 12/1/2006 6:46 PM Page 368

newborn range is 50-80mg/dL) confirming the diagnosis of Smith-Lemli-Opitz
syndrome and hormonal assessment was performed (by ELISA method with the
exception of LH and E2 for which ECLIA method was used) showing a decreased
testosterone level 0.03ng/mL, high E2 448.8pg/mL, normal LH 2.8mUi/mL,
DHEAS 86.61 ?/dL, progesterone 1.34 ng/mL and 17 hydroxyprogesterone
1.08ng/ml. Unfortunately, the size of the blood sample was too small, so cortisol
and ACTH were not determined. DHCR7 genotyping was not available, nor the
7DHC assay. Modified clinical severity score (4) was 8.
The child had feeding difficulties requiring nasal gastric gavage in the neonatal
period and afterwards, he was hospitalized in a pediatric clinic for recurrent
vomiting and failure to thrive. He died at the age of three months.
DISCUSSION
The pathogenesis of Smith-Lemli-Opitz syndrome is complex and comprises
the deficiency of cholesterol and accumulation of its precursors 7DHC and its
isomer 8-DHC.
Interference of cholesterol with the hedgehog embryonic pathway (required
for somatic segmentation) as a negative regulator downstream of Smothened (Smo)
provides an explanation for the malformations that characterize SLOS (14), but the
developmental role of cholesterol may extend beyond morphogenic pathways since
it was proved that its role, for example, in normal synaptogenesis is independent of
the Shh (sonic hedgehog) pathway (15).
Dhcr 7 -/-mice die in the neonatal period; a study performed on hindbrain
regions, on gestational day 14, identified altered expression of genes associated
with cholesterol homeostasis, cell cycle control and apoptosis, neurodifferentiation,
transcription and translation, cellular transport, axonal guidance, neuronal
cytoskeleton; 91 genes were upregulated and 98 downregulated compared withSmith-Lemli-Opitz syndrome
369Figure 4. External genitalia.
Figure 5. Chest X ray.Tipar Cap coada.qxd 12/1/2006 6:46 PM Page 369

wild-type mice. Brain pathology includes impaired cortical response to glutamate,
hypermorphic development of hindbrain serotonergic neurons, midline comissural
deficiencies and hyppocampal pathfinding errors (16).
Cholesterol is an essential component of the cell membranes, with major roles
in cell signaling and intracellular trafficking. Membranes are heterogeneous
structures with discrete domains. Lipid rafts are assemblies of cholesterol and
sphingolipids and caveolae are cholesterol rich domains containing the scaffolding
protein caveolin that compartmentalizes a multitude of signaling molecules. The
deficiency in cholesterol and accumulation of 7-DHC in the cell membrane leads to
its defective structure and function. Though 7-DHC differs from cholesterol only by
the presence of a double bond, its incorporation in the membrane induces significant
differences in lipid organization and dynamics, decreasing intermolecular packing of
phospholipid fatty acyl chains associated with a reciprocal increase in molecular
packing at the surface of the membrane. These structural changes are responsible for
an increased calcium permeability, decreased Na +/K+ATPase activity, decreased
folate uptake, decreased IP 1, IP2, IP3(inositol phosphates are important second
messengers involved in regulating the intracellular calcium level in response to
extracellular stimuli); similar changes occur in intracellular membranes as well (17).
In cholesterol deficient mouse models of SLOS and lathosterolosis there is a
significant decrease of the number of secretory granules in the pancreas, pituitary
and adrenals but the secretory function was restored with exogenous cholesterol.
Secretory granules are malformated because incorporation of sterol precursors in
their membrane results in decreased bending rigidity and intrinsic curvature (18).
Cholesterol serves as a precursor for steroid hormones, bile acids and
metabolic mediators such as oxysterols. Oyxsterols are sterol intermediates in
cholesterol synthesis that undergo 25R,26-hydroxylation and are present in
micromolar amounts in the plasma of patients with SLOS. 25r,26-7-DHC proved to
be a ligand for nuclear receptors (19).
Cell proliferation rates are markedly reduced in SLOS patients and in light–
exposed tissues (skin, retina) there is an increased apoptosis mediated by oxidative
stress (20).
Though much progress has been made, the pathophysiological mechanisms in
SLOS have not been fully elucidated. One difficulty could be represented by the
fact that most reports describe only a patient or a few number of cases, and another
that biochemical diagnosis was possible only after 1993 (1).
In the case of our patient, the association of ambiguous genitalia with the
particular facies, limb anomalies and cardiovascular anomalies raised the suspicion
of SLOS (a delineation of the anomalies described in SLOS is presented in Table
1). Karyotype analysis allowed the establishing of the genetic sex. Fortunately,
cholesterol level was low and confirmed the diagnosis (the 7-DHC level and
DHCR7 genotyping could not be determined) because it is known that
approximatively 10% of patients with SLOS have normal cholesterol values at any
age. Moreover, because 7DHC and 8DHC react as cholesterol in cholesterolCorina Raducanu-Lichiardopol et al.
370Tipar Cap coada.qxd 12/1/2006 6:46 PM Page 370

oxidase assay methods, cholesterol level appears as “normal”; it is advisable to
determine cholesterol, 7DHC and 8DHC by gas chromatography/mass
spectrometry and, in rare cases, where levels are normal or fall in the heterozygote
range, either DHCR7 genotyping or analysis of sterol biosynthesis in cultured cells
must be undertaken (4).
The very low level of testosterone can be explained by the low level of
cholesterol (an altered testis organogenesis due to impaired hedgehog signaling
would also be associated with a deficiency of antimullerian hormone and aSmith-Lemli-Opitz syndrome
371Craniofacial – microcephaly (84%), bitemporal narrowing, ptosis (70%), short
nasal root, anteverted nostrils (78%), micrognathia, epicanthus,
upward or downward slanting, hypertelorism, low set ears, cleft
lip, cleft palate (47%), large mouth, broad alveolar ridges, small
tongue.
Ocular – cataract (22%), strabismus, nystagmus; less common:
sclerocornea, heterochromia iridis, coloboma, glaucoma, retinal
pigmentation, optic atrophy, microphtalamia.
Central nervous system (37%) -enlarged ventricles, hypoplastic or absent corpus callosum,
hypoplastic frontal lobes, cerebellar hypoplasia, aplasia of the
vermis, holoprosencephaly (5%).
-histologic findings: altered neuronal migration, extensive gliosis,
dysplasia of the medial olivary nuclei, ectopic Purkinje cells.
Skeletal – postaxial polydactyly (48%), syndactyly of the second and third
toes (97%), short, proximally placed thumb, hypoplastic first
metacarpals and thenar eminences, rizomelic and mesomelic limb
shortness, radial agenesis, foot deformities, scoliosis, kyphosis.
Genital (65%) – ranges from normal to complete sex reversal in males;
hypospadias, undescended testes, bifid scrotum; mullerian duct
derivatives are usually absent.
Adrenal – hyperplasia or hypoplasia.
Cardiovascular (54%) – atrioventricular canal, atrial septal defect, patent ductus
arteriosus, ventricular septal defect, pulmonary hypertension.
Renal (25%) – renal hypoplasia or aplasia, cortical cysts, ectopia, ureteral
duplication, persistent fetal lobation.
Pulmonary (45%) – abnormal lobation, hypoplasia, laryngeal and tracheal anomalies.
Gastrointestinal – pyloric stenosis (4%), intestinal aganglionosis (16%), dysplasia
or aplasia of the gall bladder, hepatic fibrosis, progressive
colestasis (associated with early lethality), isolated
hypertransaminasemia, pancreatic islet cell hyperplasia (in severe
forms).
Mental and behavioral – psychomotor retardation (95%); hyperactivity, hypersensitivity,
selfinjurious and aggresive behavior, autism.
Other – poor growth (82%), photosensitivity, frequent infections, allergy.Table 1. Anomalies in Smith Lemli Opitz syndrome (4, 21-27)Tipar Cap coada.qxd 12/1/2006 6:46 PM Page 371

consequent presence of mullerian derivatives, which proved to be absent on pelvic
ultrasound) and possibly by the lack of the neonatal LH surge because of the
persistence of high levels of placenta – derived estrogens with an inhibitory effect
on both GnRH pulse generator and pituitary gonadotropes.
Normally, in the neonate, estradiol reaches prepubertal values within the first
week. Probably, the very high estradiol level in this infant was the result of a
decreased placental steroids clearance due to fetal hepatopathy and/or prematurity.
It is unclear why progesterone, which is also a placental steroid, was in the
normal range, in the context of the high estradiol level. DHEAS and 17
hydroxyprogesterone were also in the normal range proving a normal adrenal
function, because both compounds are produced in the fetal adrenals (placenta lacks
17?hydroxylase, so cholesterol can be converted to progesterone only). A thorough
study concerning gonadal and adrenal function in SLOS patients is lacking.
Prenatal tests were not performed in this case, but prenatal diagnosis is
possible; triple screen test reveals a low estriol, mildly depressed chorionic
gonadotropin and ?-fetoprotein and the association with an abnormal fetal
ultrasound (intrauterine growth retardation, nuchal oedema, microcephaly, cleft
palate, 2-3 toe syndactyly, polydactyly, cardiovascular and renal anomalies,
ambiguous genitalia or a 46,XY karyotype in a phenotypically female fetus) is
suggestive for the diagnosis of SLOS. Determination of the 7DHC level in the
amniotic fluid establishes the positive diagnosis with a typically more than 500 fold
increase in affected pregnancies; chorionic villus genotyping for DHCR7 is rarely
needed (4, 28).
Recently, a non invasive biochemical test – steroid measurements in maternal
urine between 9 and 20 weeks of gestation with increased ratios of 7
dehydropregnantriol/pregnatriol (0.74) and 8 dehydroestriol/estriol (1.7) – proved
to be a reliable test for prenatal diagnosis of SLOS (29).Corina Raducanu-Lichiardopol et al.
372
Figure 6. Colour Doppler echocardiogram showing an atrial septal defect and a ventricular septal
defect.Tipar Cap coada.qxd 12/1/2006 6:46 PM Page 372

The main therapeutic approach consists of dietary cholesterol supplementation
which restores steroid hormone and bile acid deficiencies. Once bile salts are
present in sufficient amounts, intestinal absorbtion of cholesterol is restored. Though
total sterols, HDL and LDL increase (30) the presence of the blood brain barrier
prevents cholesterol delivery to the central nervous system; this inconvenience can
be overcome by two ways: direct cholesterol delivery to the CNS by low pressure
catheter infusion (9), and second, by the use of statins in patients with residual
DHCR7 activity, because statins are able to cross the blood brain barrier. At first
glance, the use of a statin in patients with cholesterol deficiency seems paradoxical,
but it was shown that inhibition of HMGCoA reductase decreases the level of
precursor sterols such as 7DHC and 8DHC thereby limiting exposure to potentially
toxic metabolites (9) and increases the expression of DHCR7 alleles with residual
enzymatic activity (31).
In the case of null mutations, mutant mRNA undergoes a rapid degradation by
the nonsense mediated decay (NMD) pathway. Aminoglycoside antibiotics, which
bind to ribosomes can induce translational read through of nonsense codons and
thus supress NMD (32). The next step will be the discovery of less toxic suppressors
of NMD to treat SLOS patients with null alleles.
CONCLUSION
SLOS syndrome was the first discovered syndrome in which a metabolic
disorder is the cause of multiple malformations and it revealed the unique role
cholesterol plays in human development, in an era in which cardiovascular
mortality focused therapeutic efforts on decreasing its level. New therapeutic
challenges emerge for the patients affected by cholesterolopathies which need an
increase in lipids level, including brain lipids.
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