Lowry and Yong17 made the earliest estimate of the incidence of SLOS. They found an incidence in British Columbia between 1964 and 1971 of 1 in 40,000 births, indicating a carrier frequency of 1 percent. The incidence increased to 1 in 20,000 births when suspected but less definite cases were included. A similar study in New England found an incidence of 1 in 30,000 births. In contrast to these relatively high incidences based exclusively on clinical diagnosis, the incidence of SLOS diagnosed biochemically in similar populations appears to be lower. For example, between the two laboratories that performed approximately 90 percent of biochemical testing for SLOS in the United States between 1993 and 1998, approximately 40 new cases per year were diagnosed, or less than 1 in 60,000 births (Kelley and Tint, unpublished data). Similarly low estimates of 1 in 80,000 to 100,000 births in the Netherlands (Hennekam et al., unpublished data) and 1 in 60,000 newborns in the United Kingdom32 have been made. Even lower incidences were reported by Tsukahara et al.33 They found only 2 of 31 clinically diagnosed cases in Japan had abnormal 7DHC metabolism. The number of reported cases with African ancestry is also low.25,34 Although there remains some uncertainty about the absolute incidence of SLOS in some countries, there clearly are strikingly different incidences among various ethnic groups. Both heterozygote advantage and founder effect have been suggested to explain the much higher incidence of SLOS among those of European descent.
Most literature reports about SLOS describe only a single patient or a small number of patients. There are a few exceptions in which 10 or more cases are described, notably Opitz et al.,2 Cherstvoy et al.,9 Bene et al.,35 Curry et al.,12 Cunniff et al.,25 and Ryan et al.32 Furthermore, several excellent reviews in the older literature exist.10,15,36 A tabulation of the major clinical features of patients who were described with sufficient detail in the literature is provided in Table 249-2. A comparison of the most common characteristics of patients ascertained by clinical versus biochemical diagnosis shows remarkably similar frequencies of the physical anomalies. Only structural brain anomalies and anomalies of the genitalia are somewhat more common in the clinically diagnosed group, otherwise the percentages show a remarkable similarity.
Table 249-2: Finding in 167 Clinically Diagnosed Cases of Smith-Lemli-Opitz Syndrome Compared with 151 Biochemically Confirmed Cases |Favorite Table|Download (.pdf) Table 249-2: Finding in 167 Clinically Diagnosed Cases of Smith-Lemli-Opitz Syndrome Compared with 151 Biochemically Confirmed Cases
|Finding ||Clinically diagnosed (167) (%) ||Biochemically confirmed (151) (%) |
|Mental retardaton ||97 ||95 |
|Postnatal growth retardaton ||85 ||80 |
|Microcephaly ||80 ||83 |
|Structural brain anomalies ||60 ||36 |
|Ptosis ||69 ||68 |
|Cataract ||23 ||22 |
|Anteverted nares ||90 ||77 |
|Cleft palate* ||51 ||47 |
|Congenital heart defect ||50 ||54 |
|Abnormal lung lobation ||40 ||45 |
|Pyloric stenosis ||15 ||14 |
|Colonic aganglionosis ||12 ||17 |
|Renal anomalies ||40 ||43 |
|Genital anomalies ||74 ||64 |
|2-3 Toe syndactyly ||85 ||95 |
|Polydactyly† ||52 ||48 |
Prior to the recognition of the biochemical cause of SLOS, several authors suggested that there might be two forms of SLOS, which were distinguishable by the severity of physical anomalies and their clinical course.12,13,37 “Type I” was the original, classical syndrome, and “type II” was a more severe entity, usually lethal in the early months of life and associated with severe internal anomalies and markedly abnormal male genitalia. Curry et al.12 cautiously suggested that types I and II might differ genetically, whereas others thought support for a genetic difference to be weak.38 To address this question, Bialer et al.15 devised a scoring system to measure the clinical severity of SLOS and analyzed the distribution of anomalies. Upon scoring 122 reported patients from literature, they found a unimodal distribution of the scores for various anomalies, which was interpreted as evidence for a continuum of severity in SLOS and against a genetic distinction between SLOS types I and II. A similar continuum of severity was found by Cunniff et al.25 and Ryan et al.32 in their series of biochemically confirmed cases. Both the original scoring system of Bialer et al. and a revised scoring system wherein malformation in embryologically separate organ systems are weighted equally (Kelley and Hennekam, unpublished) show strong correlations with various biochemical parameters. Subsequent molecular genetic studies confirmed that the differences in severity between SLOS types I and II are explained by the severity of the responsible mutations (see “Enzymology and Molecular Genetics” below). However, this does not preclude the existence of genetic heterogeneity in SLOS, as suggested by the cases of Anderson et al.39
Differential Diagnosis of Smith-Lemli-Opitz Syndrome
Many papers describe patients with a clinical phenotype resembling SLOS, especially before the era of biochemical diagnosis. In the German literature, the designations Ullrich-Feichtiger syndrome40 or Typus Rostockiensis,41 a multiple congenital anomalies syndrome with facial anomalies, polydactyly, and hypospadias, probably describe severe forms of SLOS.42 Among clinical diagnoses that have been proven or suspected to include cases of SLOS are the acrodysgenital syndrome,37,43,44 Gardner-Silengo-Wachtel syndrome (MIM 231060),45,46 and holoprosencephaly-polydactyly (pseudotrisomy 13) syndrome (MIM 264480).47 However, the predominance in the Gardner-Silengo-Wachtel syndrome of conotruncal malformations and in holoprosencephaly-polydactyly syndrome of gonadal dysgenesis, both uncommon abnormalities in SLOS, suggests that some of these biochemically unconfirmed patients do not have SLOS. Among diagnoses that have been incorrectly assigned to patients with SLOS are Noonan syndrome (MIM 163950), Zellweger syndrome (MIM 214100), alpha-thalassemia-mental retardation syndrome (MIM 301040), and Opitz syndrome (MIM 145410, 300000). Other disorders that resemble SLOS, but less so, are Meckel syndrome (MIM 249000), hydrolethalus syndrome (MIM 236680), Pallister-Hall syndrome (MIM 146510), and orofaciodigital syndrome type VI (MIM 277170).12,13,42,48,49
The “SLOS-face” is highly characteristic of the syndrome and easily recognized in most patients.32,50 The most salient features are microcephaly, bitemporal narrowing, ptosis, a short nasal root, anteverted nares, and a small chin (Fig. 249-1A, Fig. 249-1B). Two other almost universal characteristics are congenital microcephaly and ptosis, often asymmetric or unilateral. Although a prominent metopic ridge can often be palpated, true craniosynostosis is uncommon.2 Other less frequent anomalies include hypertelorism, epicanthal folds, congenital, and occasionally postnatal, cataracts, strabismus,11,51-53 glaucoma,2,12 optic atrophy,2,12,52 and microphthalmia.5,25 The nasal bridge can be flat or high, often with a striking capillary hemangioma extending across the glabella. The degree of anteversion of the nares decreases with age but remains distinct in some adults.32,54
Smith-Lemli-Opitz syndrome. Upper left: 3 year old with cleft palate and (lower left) characteristic Y-shaped syndactyly of toes 2 and 3. Upper right: 3-year-old boy and his 8-month-old sister with near normal cholestrol levels, mildly increased 7-dehydrocholesterol levels (20–40 μg/ml), and unusually mild physical characteristics of Smith-Lemli-Opitz syndrome. Note the low-set ears and mild ptosis evident in the 3-year-old boy. Lower right: 12 year old with typical facial characteristics of classical Smith-Lemli-Opitz syndrome.
Smith-Lemli-Opitz syndrome. Severely affected 46,XY patients with ambiguous genitalia (upper right), low cholesterol level of 15.3 mg/dl, and a 7-dehydrocholesterol level of 138 μg/ml). Note the complete postaxial (ulnar side) polydactyly of the hand and the striking polysyndactyly of the foot with a greatly shortened first metatarsal. The view of the face illustrates the low-set ear, severe micrognathia, and hypotonia.
The ears often appear low set and posteriorly rotated, but are otherwise unremarkable. Congenital sensorineural hearing deficits may affect as many as 10 percent of patients, but many more severely affected children are not tested. The philtrum is long, as can be expected in shortening of the nose. Cleft lip has been reported in SLOS;13,55,56 however, in patients with abnormal cholesterol metabolism, only the “midline” type of cleft associated with the holoprosencephaly sequence is present.57 In some patients, the mouth is large, which, combined with frequent micrognathia, gives a distinctive appearance.54 More severe micrognathia, including the classic Pierre Robin sequence, is not rare in SLOS. The neck can appear short, and excessive skin folds or nuchal edema are common, especially prenatally.58
The oral anomalies of SLOS are diagnostically important. The palate usually is highly arched, often with a midline cleft of the uvula, soft palate, or hard palate. In addition, the alveolar ridges typically are abnormally broad and conspicuously ridged. The tongue can be small with redundant sublingual tissue12 or sublingual cysts13,37 in the more severely affected children; rarely, the tongue is bifid.32 Crowding and widely spaced incisors are not uncommon, and oligodontia and polydontia,51 enamel hypoplasia,10 and premature tooth eruption59 have been reported. Pharyngeal abnormalities have included a small larynx13 and small vocal cords with a subglottic shelf of excess fibrocartilaginous tissue.12
The structural brain abnormalities of SLOS have been reviewed by Garcia et al.,60 Cherstvoy et al.,61 and Marion et al.62 In addition to microcephaly, which is almost universal in SLOS, common abnormalities include enlarged ventricles,2,12 hypoplasia or aplasia of the corpus callosum, and hypoplastic frontal lobes.9,12,32 Cerebellar hypoplasia, sometimes with severe hypoplasia or aplasia of the vermis, is also not uncommon.51,62,63 Various forms of the holoprosencephaly sequence occur in approximately 5 percent of patients.5,13,19,57 On histologic examination of the brain, the most important findings are disturbed cerebral neuronal migration, dysplasia of the medial olivary nuclei, and ectopic Purkinje cells.9,51 Several authors54 reported maturational abnormalities of the white matter, but these are not common. Although seizures are not uncommonly reported in the SLOS literature, they are uncommon in biochemically proven cases of SLOS, and may not be significantly more frequent than expected.2,32,64
The skeletal anomalies have been reviewed in detail.10,15,25,32,61 Bilateral or unilateral postaxial polydactyly can be present in the hands, or, less commonly, the feet, or both. However, preaxial polydactyly has not been reported in a biochemically proven case. The thumb is generally short and proximally placed and the first metacarpals and thenar eminences are typically hypoplastic.2,65 Other unusual digital abnormalities include ectrodactyly, monodactyly, and oligodactyly; radial agenesis; brachydactyly; absent middle phalanx of the second finger; radial or ulnar deviation of fingers; clinodactyly; camptodactyly; and syndactylies (between fingers 3 and 4 or 4 and 5).2,10,12,56,66,67 Rhizomelic and mesomelic limb shortness and, more rarely, “chondrodysplasia punctata” occur in SLOS, but a true chondrodystrophy is not found.12,13,16,32,61 Dermatoglyphics in SLOS are distinctive in having increased number of whorls on the fingertips.2,10 One of the most consistently present anomalies of SLOS is the distinctive Y-shaped cutaneous syndactyly of the second and third toe, which has been reported in up to 99 percent of biochemically proven cases.25,32 Postaxial polydactyly of the feet is common in severe SLOS, and sometimes takes the form of polysyndactyly with a “windswept” foot deformity. Other lower-limb abnormalities include club foot, varus or valgus foot deformities, short first toes, and hip dislocations.9,12,32,37 Occasionally, reported skeletal abnormalities include dense base of the skull,37 scoliosis,17,64 kyphosis,17,68 ovoid vertebrae,69 cervical ribs, thin ribs,43,69 and missing ribs.68 Although epiphyseal stippling (chondrodysplasia punctata) has been reported in a few cases,1,38,69 such stippling has been found in only one biochemically confirmed case.70
The genitalia in male SLOS patients range from normal to apparent complete sex reversal.12,13,14,15,59,71 Classically, hypospadias varies from coronal to perineoscrotal hypospadias, although the latter is uncommon except in the biochemically most severely affected cases. Cryptorchidism is common, but even with severely malformed genitalia, the testes often are easily palpated in the scrotum, which is sometimes bifid. Müllerian duct derivatives usually are absent in 46,XY males, as expected, but blind-ending vaginas, rudimentary or bicornuate uteri, and persistent cloacae have been described.12,13,15,37,72,73 The gonads vary from normal testes to ovotestes to normal ovaries. In females, the external genitalia may appear normal or there may be distinct hypoplasia of the labia majora and minora. There are also single reports of premature thelarche and high serum-prolactin levels in a 15-month-old girl with SLOS74 and a malignant germ-cell tumor with a contralateral streak gonad in another female.75 Menstrual function is often irregular but otherwise normal in most SLOS adolescent females and adults, except for somewhat later menarche. One adolescent girl with SLOS and borderline intelligence gave birth to an apparently normal daughter.17
Robinson et al.,7 Johnson,10 and, most extensively, Lin et al.76 have reviewed the cardiac anomalies of SLOS. Almost half of SLOS patients have a congenital heart defect; if only biochemically confirmed patients are considered, however, this percentage is somewhat lower.25,32,76 There is a strong predominance of endocardial cushion defects and the hypoplastic left heart sequence, whereas conotruncal defects are uncommon. The five most prevalent defects found in a study of 95 biochemically confirmed cases of SLOS were: atrioventricular canal (25 percent), secundum atrial septal defect (20 percent), patent ductus arteriosus (18 percent), and membranous ventricular septal defect (10 percent).76 Although Lin et al. hypothesized that the abnormal development of the extracellular matrix may be the cause of both the cardiac defects and the absence of ganglion cells in the bowel wall (Hirschsprung disease), abnormal development of the neural crest, which contributes substantially to the endocardial cushions, could explain both the cardiac defects and abnormal intestinal ganglion cells. In addition to structural heart defects, there is a substantially increased frequency of pulmonary hypertension in the newborn period and persistent systemic hypertension postnatally, but limited largely to patients with especially low cholesterol levels and possibly related to the abnormal steroid metabolism of these patients.64,68,77
Renal and Adrenal Anomalies
Approximately one-fourth of patients with biochemically confirmed SLOS have renal anomalies,13,32 most commonly renal hypoplasia or aplasia,10,12,13,32,55,78 renal cortical cysts,9,12,32 hydronephrosis,9,32,59,79 renal ectopia,1,9,37 ureteral duplication,37,59 or persistent fetal lobation.15,32,37 A number of cases with the oligohydramnios sequence caused by bilateral aplasia or other renal causes of severely diminished urinary output have been described.12,13,78 The bladder and ureters may be hypoplastic, probably secondary to renal hypoplasia or aplasia.
Both adrenal hyperplasia12,19 and adrenal hypoplasia13 have been reported in SLOS, but growth and shape of the adrenals appear to be normal in most patients.13 Histologic studies of hyperplastic SLOS adrenal glands19 typically show deficient cortical lipid, which, in normal fetal adrenals, contains much cholesterol. Postnatal studies of adrenal function in children with SLOS have shown either normal function80 or, in several biochemically severely affected children, decreased steroid synthesis.81
Abnormal pulmonary lobation and pulmonary hypoplasia are common in the more severely affected cases of SLOS and are common causes of death in such patients.9,12,13,37,72 As expected, pulmonary hypoplasia is also common in SLOS patients with the oligohydramnios sequence secondary to renal aplasia.12,13 Anomalies of the laryngeal and tracheal cartilages are common even among patients with mild forms of SLOS. Serious complications have resulted from difficulties with emergent or elective intubation because of marked tracheal narrowing and other abnormalities of the laryngeal and tracheal structures63 (Kelley, unpublished observations).
Pyloric stenosis is a prominent clinical problem noted in the original description of SLOS and in many subsequent case reports.1,2,32,82 Pyloric stenosis in SLOS has the usual characteristics of pyloric stenosis in otherwise normal children, but vomiting and other feeding problems commonly persist after surgical repair, in part due to apparent abnormalities of intestinal motility. In the more severe cases, intestinal aganglionosis occurs, either as short segment disease or as extensive involvement of the upper and lower intestinal tract.12,70,83,84 Even among SLOS patients lacking histologic evidence of intestinal aganglionosis, intestinal dysmotility is common, especially in the first year. However, whereas pyloric stenosis historically has been reported in up to 25 percent of SLOS patients, it is now uncommon in SLOS patients treated with supplementary cholesterol starting shortly after birth.
A small number of SLOS patients have had the unusual finding of dysplasia or aplasia of the gallbladder12,32 or gallstones in infancy or later childhood.12,64 More common, however, is transient or, more rarely, lethal cholestatic liver disease.12,32,85,86 Histologically, iron pigment in liver cells is increased.72,86 Although lipidosis is not commonly associated with SLOS, diffuse lipid storage was reported by Parnes et al.,87 and Porter et al.88 recently described impaired intracellular trafficking of LDL in SLOS fibroblasts.
Pancreatic islet cell hyperplasia has been reported frequently in severe SLOS.9,12,19,37,72 The histology in these cases features nesidioblastosis and reduced quantities of somatostatin.19,89 Other abdominal malformations that are less frequently reported include intestinal malrotations,9,12,32 absence of the diaphragm or diaphragmatic hernia,9,55 polysplenia and asplenia,9 anal stenosis or atresia,9,13,71 and Meckel's diverticulum.2,7
Other Anomalies and Clinical Problems
Involuted86 and hypoplastic thymus84 and absent parathyroids12 have been found. Among the more common dermatologic and hair abnormalities are hypopigmented hair,2,90 mild to extreme skin photosensitivity in more than half of patients,32 hyperhidrosis of the palms,91 marked cutis marmorata,84 and eczema.32 Widely spaced nipples are mentioned repeatedly. There are two reports of excessive muscle rigidity after halothane anesthesia, but diagnostically elevated creatine kinase levels were not documented.92,93
The neonatal period and infancy are almost invariably associated with feeding problems including weak or abnormal suck, swallowing difficulties, vomiting, and lack of interest in feeding. Oral tactile defensiveness and failure of progression to textured foods in later months is also characteristic of the SLOS infant. As a result, more than 50 percent of patients require nasogastric tube feedings, often progressing to gastrostomy feeding for several years. As expected, patients with a cleft palate and a small mandible (Pierre Robin sequence) have the most severe feeding problems. Although gastroesophageal reflux is a common problem in patients with SLOS, such reflux is often caused by a failure to recognize that the children have congenitally small stomachs and primary intestinal dysmotility. Pyloric stenosis also is much more common in SLOS cases when compared to incidence in the general population.76,82 Lin et al.76 found pyloric stenosis in 7 percent of biochemically confirmed cases and in 11 percent of literature cases, but both figures may be underestimates.
Severe hypotonia is essentially universal in SLOS during infancy. Although the hypotonia is partly central in origin, congenital muscle hypoplasia also contributes. However, during the second year, muscle mass and tone improve and muscle strength and tone are typically normal in older children with SLOS. In later childhood, increased muscle tone is common and can lead to joint and skeletal problems in nonambulatory children. Such hypertonia appears to be extrapyramidal rather than spastic.
Failure to thrive is almost universally diagnosed in children with SLOS, but the diagnosis is incorrect more often than not. Infants with SLOS are small for gestational age and most continue to grow below the third percentile despite adequate caloric intake, indicating a fundamental, genetic hypotrophy as the basis of the growth retardation. Weight gain can be poor in the first 2 years because of feeding and GI motility problems, but most children with SLOS have normal linear and weight growth velocities in later years. Similarly, head circumference is proportionally the smallest measurement at birth and usually increases proportionally with other measurements postnatally. Although almost all SLOS children are small for their age, a formal study of the natural history of growth in SLOS has not been undertaken. Whereas most measurements for classical SLOS fall between −1 and −5 standard deviations (SD), measurements as low as −8 to −10 SD occur in more severely affected patients. With a few exceptions at the extremes, final adult height and head circumference are between 2 and 5 SD below normal.12,13,32,94 In several published series, final height in adults was between 143 and 170 cm.32,54,95 However, these figures are for patients with classic type I SLOS. Size at birth and growth of patients with more severe biochemical abnormalities, more of whom now survive with cholesterol treatment, are substantially less than in classic SLOS.
During both infancy and childhood, children with SLOS appear to have an increased rate of infections. Although many of the infections are otitis media, skin infections and pneumonias also seem to occur more often. However, despite the frequency of reflux in children with SLOS, aspiration pneumonia is surprisingly uncommon, most likely because the children's exaggerated gag reflux provides excellent airway protection. Except for a single report of abnormal monocyte oxidative metabolism,96 no specific primary immune disturbances have been described in SLOS. However, death from sudden, overwhelming infection is not rare in SLOS, suggesting a fundamental abnormality in immune defenses or, possibly, adrenal function.81 Apart from the high frequency of milk and soya protein allergy68 and possibly an increased frequency of reactive airway disease, other allergies, or immunologic diseases such as eczema, thyroiditis, or arthritis, do not seem to be common in SLOS.
With few exceptions, global psychomotor retardation is characteristic of SLOS. Although, historically, most patients have been described as severely mentally retarded (IQ 20 to 40), such apparently poor development in part reflected difficulties in testing. The average SLOS child is very sociable, has much better receptive than expressive language, and may be surprisingly mechanically adept for their degree of retardation. Because of their poor expressive language, routine developmental testing, unless performed by an expert, often underestimates the cognitive abilities of SLOS children. Gross motor development is typically more severely delayed than fine motor development, but children with SLOS usually learn to walk between 2 and 4 years of age. With the availability of biochemical testing and the recognition of many more mildly affected SLOS children, the known developmental spectrum has widened significantly. Approximately 10 percent of children with biochemically diagnosed SLOS have development in the mildly retarded range (IQ 50 to 70). A few patients with normal or borderline normal development have been described,17,32 and it is likely that the number of patients with borderline and normal intelligence will increase, largely because biochemical testing now allows the identification of heretofore undiagnosable patients with minimal disease.
Excessive sleeping and poor responsiveness are common in the first few months of life. However, hours of shrill screeching or inconsolable screaming, especially at night and early in the morning, are major behavioral characteristics of SLOS later in infancy.10,32 Other patients appear hypersensitive to all visual and auditory stimuli and must be kept in quiet, dark rooms. Ryan et al.32 drew attention to the strikingly diminished amount of sleep in early childhood, which they found in 70 percent of their patients, some of whom slept only 2 or 3 hours at night. Although this abnormal sleeping pattern may gradually improve with age, adult SLOS patients with similar sleep problems are known. Many patients, even those with very mild clinical disease, may show self-injurious and aggressive behaviors. Most characteristic above the age of 3 years are forceful hyperarching, with or without head banging, and arm and hand biting. Aggressiveness, manifested most often as abrupt striking out, is seen when the children are frustrated. Marked tactile hypersensitivity of the hands and feet is also seen in more than 50 percent of patients. Common behavioral abnormalities that fall within the spectrum of autism include hand-flapping, abnormal obsessions, rigidity and insistence on routine, and poor visual contact. Despite these many behavioral problems, most parents describe their children as loving, affectionate, and happy.2,32
Prenatal Losses and Postnatal Life Expectancy.
Although some investigators have suggested that there is an increased rate of spontaneous abortion in families with SLOS, Ryan et al.,32 in the only systematic study of prenatal losses, found 39 propositi, 51 healthy sibs, 16 spontaneous abortions, and 7 elective terminations among 43 sibships with 113 known conceptions. Although these data do not support the hypothesis10,18 that there is a substantially increased rate of spontaneous abortions in SLOS families, such may still obtain in families with more severely affected children, because severe cardiac or renal abnormalities have been known to lead to mid-trimester intrauterine demise of SLOS fetuses. The low 17 percent segregation ratio found in one large series10 could also be explained by the inclusion of a proportion of genetically different disorders because the diagnoses were made clinically.
Although there are no recent figures for life expectancy in SLOS, Johnson10 found that 27 percent of cases in her series died before 2 years of age. However, an analysis of the causes of death was not provided. As ascertainment of SLOS, even in the era of biochemical diagnosis, has been incomplete, the exact percentage of cases with early lethality remains uncertain. Clearly, however, life expectancy in SLOS is determined largely by the severity of the internal malformations and the quality of general supportive care and not by an intrinsic degenerative process.