Women’s Health Alliance, Department of Ultrasound, 300 20^th Avenue North, Nashville, TN 37203-2131

Abstracts

Until the identification of a defect in the cholesterol metabolism as the cause of the Smith-Lemli-Opitz syndrome (SLO), the diagnosis was based on the detection of multisystemic anomalies. However, the recognition of ultrasonographic features present in this condition allows suspecting the diagnosis and prognosis. We present a case of SLO syndrome in which multiple anomalies were detected by ultrasound. An aneuploidy was suspected but the karyotype was normal. The diagnosis was made only postnatally by clinical findings and recognition of the abnormal cholesterol metabolism.

Introduction

Smith-Lemli-Opitz syndrome (SLO) is a common autosomal recessive disorder, described in 1964, by Smith et. al[1], characterized by multiple anomalies including typical facial appearance, mental and growth retardation, syndactyly of the second and third toes, genital and other internal organs abnormalities. Depending on the severity of the malformations, the prognosis can range from mild intellectual impairment to lethal. The diagnosis was based on clinical features found after birth or in autopsy until 1993, when Irons described the reduced plasma cholesterol levels and elevated levels of cholesterol precursor 7-dehydrocholesterol (7-DHC) in association with SLO. The confirmation of these biochemical findings by many other researchers proved that cholesterol and its precursors plasma levels could be reliable markers for the prenatal diagnosis. Currently, the cholesterol analysis can be made prenatally using amniotic fluid[3],[4,[5], [6], or in the first trimester, by chorionic villus sampling[7], [8]. The introduction of biochemical testing for SLO has improved the prenatal detection of this syndrome. However, the recognition of ultrasonographic features suggestive of SLO is necessary to raise the suspicion, especially in patients that are not aware of their carrier condition and are having their first affected pregnancy. The ultrasonographic examination also evaluates the severity of the anomalies, and thus assists in predicting the outcome.

We present a case of SLO syndrome in which multiple anomalies were detected by ultrasound. An aneuploidy was suspected but the karyotype was normal. The diagnosis was made only postnatally by clinical findings and recognition of the abnormal cholesterol metabolism.

Case report

A 21-year-old Caucasian, G₃P₂, was referred at 8 months gestation for ultrasound evaluation of the limbs, suspected to be short. That was the first child of the couple, but both partners had healthy children in previous marriages. Her past and prenatal histories were unremarkable except for smoking one pack per day.

Real-time ultrasound revealed a single live gestation at 35 weeks, with multiple anomalies including micromelia (all limbs below the 5^th percentile), clubfeet, simian crease and clinodactyly, hypoplastic middle phalanx of the 5^th digit at the left hand, hypoplastic kidneys, oligohydramnios, colpocephalus, and incomplete endocardial cushion defect. Genetic amniocentesis was performed revealing a normal male karyotype.

Fig. 1: Longitudinal view of the short upper extremity. Note the extra soft tissue due to a too small skeletal frame.

Fig. 2: The humerus measures 38 mm, which is equivalent to 23 weeks (gestational age of 35 weeks)

 Fig. 3: The femur measures 26 weeks for a gestational age of 35 weeks. The graph demonstrates how low this is.

Fig. 4: View of one open hand showing the single palmar crease.

Fig. 5: View of the other open hand showing the single palmar crease. Note the overlapping of the fingers in the second image.

Fig. 6: Section of the fingers demonstrating the overlapping of the 5^th digits over the 4^th.

Fig. 7: Longitudinal view of the hypoplastic kidney, measuring 23 and 29mm. The normal length expected for this gestational age is around 40mm^[9].

Fig. 8: Cross section of the head showing the colpocephaly (enlarged occipital horn).

Fig. 9: "Round head" with a cephalic index at 84% (upper limit of normal) (Biparietal diameter: 78mm, Occipitofrontal diameter: 93 mm)

Fig. 10: Downturned mouth angles (fish mouth)

Fig. 11: "4-chamber-view†of the heart that demonstrates a large atrioventricular septal defect.

At 39 weeks' gestation, the patient delivered vaginally a hypotonic baby, with multiple anomalies including low set malformed ears, bilateral cataracts, hypertelorism, micrognatia, short-webbed neck, polydactyly of the right hand and syndactyly of the 4^th and 5^th digits on the left hand, shortened limbs, bilateral simian crease, clubfeet and equinovarus deformity. Internal organs anomalies such as partial agenesis of the corpus callosum, hepatomegaly, hypoplastic kidneys, severe hypospadia and endocardial cushion defect were also identified.

This constellation of multi-systemic anomalies, associated with normal karyotype was suggestive of SLO. Biochemical analysis revealed extremely low levels of cholesterol and elevated levels of 7-dehydrocholesterol, confirming a defect in cholesterol biosynthesis. Due to the severity of the anomalies, in particular the cardiac defects, the newborn developed congestive heart failure and died on the third day of life.

Discussion

Historical Perspectives

Smith, Lemli and Opitz, who identified a syndrome of retardation, with multiple skeletal and urogenital anomalies, did the first description of the syndrome in 19641. After that, many other cases were reported, however, the variety of phenotype was always an important obstacle in making the diagnosis. In 1987, Curry proposed the division of the entity into two classes: type I (the classical syndrome described by Smith) and type II (the most severe cases)^[10]. In 1993, Irons and Tint described the abnormal cholesterol biosynthesis in association with SLO2.

Incidence

Some authors suggest that SLO is the second commonest autosomal recessive disorder in North American Caucasians, after cystic fibrosis^[11]. The prevalence of this syndrome has been estimated between 0.25:10,000 to 0.5:10,000^[12], but an incidence of 1:10,000 was mentioned in1997, in a population in Middle Bohemia^[13]. Further, with the identification of a metabolic defect a re-evaluation of these data has been suggested^[14].

Etiology-Pathogenesis

Dellaire observed in 1966, the autosomal recessive pattern of transmission[15]. In 1994, Wallace reported a case of balanced translocation in an affected patient and suggested that the gene locus might be at 7q32[16]. Caused by a defect in the cholesterol biosynthesis, SLO is the first known genetic syndrome with a metabolic etiology.

Figure I: Latter part of the cholesterol biosynthesis pathway. The symbol X represents the block that occurs in SLO. The blue circle highlight the defect

A deficient activity of the 7-dehydrocholesterol D⁷-reductase which catalyses the conversion of 7-dehydrocholesterol (7-DHC) to cholesterol and 7-dehydrocholesterol to desmosterol, causes the inhibition of cholesterol production and marked elevation [Table 1] of 7DHC and 8DHC cholesterol precursor[17] as well as its isomer 8-dehydrocholesterol (8-DHC)[18].

Table 1¹⁸

Cholesterol is an important component of cell membranes, bile acid, vitamin D, precursor of all steroid hormones, and also constitutes 23% of human myelin weight[19]. The low levels of cholesterol not only prevents normal structural and neurological development of the embryo and fetus, but derivatives of cholesterol will be reduced and processes that requires steroid hormones18 such as masculinization of genitalia will be deficient. Accumulation of 7-dehydrocholesterol may also interferes with a proper membrane function[20]. The severity of the insult depends on the severity of the metabolic deficiency.

Diagnosis

The detection of extremely reduced concentration of cholesterol and abnormal accumulation of 7-dehydrocholesterol in the plasma make the diagnosis in infants and adults. Elevated concentration of 7-dehydrocholesterol at amniotic fluid in the second trimester ^{3, 4, 5,}6 or at chorionic villus sample in the first trimester7^, 8, normally undetectable in both specimens, is a reliable marker for prenatal diagnosis of SLO. The techniques employed for biochemical analysis of cholesterol and 7-dehydrocholesterol are gas-liquid chromatography, gas chromatography-mass spectrometry or ultraviolet spectrometry[21]. Cases of SLO with normal cholesterol and abnormal 7DHC have been reported and thus, normal levels of cholesterol, isolated do not completely exclude the disorder. Estriol levels in maternal urine late in pregnancy may be reduced[22], as well as estriol levels in maternal circulation6^{, [23], [24]}. Half of the intrauterine fetal demise with SLO were found to have low or undetectable maternal serum estriol levels, raising the speculation that this finding might became a maternal serum screening for this syndrome18^{, [25]}. The gene for SLO has been mapped and mutations have been isolated, but only on experimental basis now.

Ultrasonographic findings during prenatal examination may raise the suspicion in patients that do not have familial or past histories of SLO and thus, are not aware of their condition of carriers. Ultrasonographic detection of multiple anomalies such as facial anomalies, polydactyly, syndactyly (more common between the 2^nd and 3^rd toes), single palmar crease, hypospadia and cryptorchidism in male, ambiguous genitalia, cardiac defects, lung malformations and many others in association with normal karyotype is suggestive of SLO. The detection of major anomalies is important to evaluate the severity of the disorder. Detection of increased nuchal translucency, or persisting nuchal edema with non-immune hydrops are other findings reported in fetuses with SLO8^{, [26]¸ [27].}

Differential diagnosis

The pattern of multi-systemic anomalies is characteristic of trisomies 21, 18 and 13, and thus, karyotype is recommended to exclude these disorders. Overlap of Smith-Lemli-Opitz syndrome with disorders such as Meckel syndrome has been reported, due to variability of phenotype in both conditions[28]. Presence of occipital encephalocele as well as dysplastic kidneys favors Meckel syndrome. Genital anomalies and syndactyly support SLO.

Associated anomalies

Although SLO presents more frequently features such as facial, limbs, and genital anomalies associated with growth and mental retardation, the wide phenotype variation is the most important aspect of this disorder. Anomalies from all the systems have been described, and the most common are mentioned in table II.

Table 2: Associated anomalies and peculiarities of Smith-Lemli-Opitz