J Med Genet 2000;37:321–335 321 Review article J Med Genet: first published as 10.1136/jmg.37.5.321 on 1 May 2000. Downloaded from The Smith-Lemli-Opitz syndrome Richard I Kelley, Raoul C M Hennekam Abstract genitalia. In all informative families, segregation The Smith-Lemli-Opitz syndrome (SLOS) of either form of SLOS was consistent with is one of the archetypical multiple congeni- autosomal recessive inheritance.212The genetic tal malformation syndromes. The recent cause of the disorder was not suspected for many discovery of the biochemical cause of years, although by the mid 1980s a number of SLOS and the subsequent redefinition of abnormalities of steroid metabolism in SLOS SLOS as an inborn error of cholesterol had been reported, including enlarged, lipid metabolism have led to important new depleted adrenal glands17 and aberrant patterns treatment possibilities for aVected pa- of steroid sulphates in plasma and urine.12 17 18 tients. Moreover, the recent recognition of Nevertheless the primary defect remained un- the important role of cholesterol in verte- known until Natowicz and Evans19 found that a brate embryogenesis, especially with re- patient with SLOS had essentially undetectable gard to the hedgehog embryonic signalling levels of normal urinary bile acids. An analysis of pathway and its eVects on the expression of that patient’s plasma sterols led to the homeobox genes, has provided an explana- discovery20 that the patient had a more than tion for the abnormal morphogenesis in 1000-fold increase in the level of the syndrome. The well known role of chol- 7-dehydrocholesterol (cholesta-5,7-dien-3beta- esterol in the formation of steroid hor- ol; 7DHC), suggesting a deficiency of mones has also provided a possible 7-dehydrocholesterol reductase (DHCR7), the explanation for the abnormal behavioural final step in the Kandutsch-Russell cholesterol characteristics of SLOS. biosynthetic pathway.21 The same sterol pattern (J Med Genet 2000;37:321–335) has subsequently been found in most patients with either type of SLOS, as well as in patients http://jmg.bmj.com/ Keywords: Smith-Lemli-Opitz syndrome; cholesterol with variant syndromes that could not be metabolism; 7-dehydrocholesterol reductase; clinical history; management assigned the diagnosis of SLOS on clinical grounds alone.22 23 Although initial evidence suggested that the human gene for SLOS was History located at 7q32.1, the human DHCR7 gene was The Smith-Lemli-Opitz syndrome was first later cloned and localised to chromosome described in 1964 by the late David Smith, the 11q12-13 by Moebius et al.24 Shortly afterwards, on September 30, 2021 by guest. Protected copyright. Belgian paediatrician Luc Lemli, and John three groups independently reported apparently 1 Opitz in a report of three patients who had in disabling mutations of DHCR7 in patients with common a distinctive facial appearance, micro- SLOS.24–26 cephaly, broad alveolar ridges, hypospadias, a characteristic dermatoglyphic pattern, severe feeding disorder, and global developmental Table 1 Findings in 167 clinically diagnosed cases of The Johns Hopkins Smith-Lemli-Opitz syndrome compared with 164 University, Kennedy delay. A more complete delineation of SLOS biochemically confirmed cases Krieger Institute, 707 was presented in 1969 as the “RSH syndrome”, North Broadway, a non-descriptive acronym of the first letters of Clinically Biochemically Baltimore, Maryland 2 diagnosed confirmed the original patients’ surnames. The description Finding (%) (%) 21205, USA of many new cases of SLOS over the next 20 R I Kelley years expanded the known characteristics of the Mental retardation 97 95 Postnatal growth retardation 85 82 Institute for Human syndrome, especially in the recognition of multi- Microcephaly 80 84 2–11 Genetics and ple internal anomalies (table 1). Many Structural brain anomalies 60 37 Department of aVected children died in the first year from fail- Ptosis 69 70 Cataract 23 22 Paediatrics, Academic ure to thrive and infections, but many others Anteverted nares 90 78 Medical Centre, survived to adulthood. Somewhat later, several Cleft palate* 51 47 University of authors described patients with a lethal syn- Congenital heart defect 50 54 Amsterdam, Abnormal lung lobation 40 45 Meibergreef 15, 1105 drome that resembled SLOS, and which they Pyloric stenosis 15 14 12–16 AZ Amsterdam, designated “type II SLOS”. These children Colonic aganglionosis 12 16 Renal anomalies 40 43 The Netherlands had many of the anomalies found in SLOS, but Genital anomalies 74 65 R C M Hennekam died in the newborn period from internal 2/3 toe syndactyly 85 97 malformations. Moreover, most 46,XY “males” Polydactyly† 52 48 Correspondence to: Dr Hennekam, with so called type II SLOS had severe *Includes cleft soft palate, submucous cleft, and cleft uvula. [email protected] hypogenitalism or female appearing external †Includes postaxial polydactyly of hand(s)/foot. 322 Kelley, Hennekam Clinical overview lar genetic studies confirmed that the diVer- GENERAL ences in severity between types I and II SLOS J Med Genet: first published as 10.1136/jmg.37.5.321 on 1 May 2000. Downloaded from Although most published reports of SLOS are explained by the severity of the mutations describe only a single patient or a small number responsible. However, these results do not pre- of patients, there are a few exceptions in which clude the existence of genetic heterogeneity in 10 or more cases are described.2 9 12 23 27–29 Fur- SLOS; recently two mildly aVected sibs were thermore, several excellent older reviews found to have probably a related but biochemi- exist.10 15 30 A tabulation of the major clinical cally diVerent disorder of sterol metabolism.33 features of patients described in suYcient detail is provided in table 1. A comparison of INCIDENCE the most common characteristics of patients The earliest estimate of the incidence of SLOS ascertained by clinical v biochemical diagnosis was made by Lowry and Yong,34 who found an shows similar frequencies of the physical incidence in British Columbia of 1/40 000 anomalies. Only structural brain anomalies and births and a carrier frequency of 1%. The inci- anomalies of the genitalia are somewhat more dence in that survey increased to 1/20 000 common in the clinically diagnosed group. births when suspected but less definite cases Before the recognition of the biochemical cause were included. The incidence in a completely of SLOS, several authors suggested division of ascertained newborn population in Middle Bohemia (Czech Republic) was estimated to be SLOS into the relatively less expressed type I 35 form and the more severe type II form.12 13 31 greater than 1 in 10 000. However, in contrast Curry et al12 cautiously suggested that type I to these relatively high incidences based exclu- and type II might diVer genetically, whereas sively on clinical diagnosis, the incidence of others thought the subdivision was not SLOS diagnosed biochemically in similar justified.32 To address this question, Bialer et populations appears to be much lower. For example, between 1995 and 1998, when al15 devised a scoring system to evaluate the knowledge of the biochemical defect was wide- clinical severity of SLOS. Upon scoring 122 spread, the two laboratories that perform at published cases, they found a unimodal least 80% of biochemical testing for SLOS in frequency distribution of the scores for various the United States identified only about 40 new anomalies, which was interpreted as evidence cases per year, or an estimated incidence of less for a continuum of severity in SLOS and than 1 in 60 000 births (Kelley and Tint, against a genetic distinction between types I unpublished data). Similarly, estimates of only and II SLOS. However, because length of sur- 1 in 60 000 newborns in the United vival was part of the original scoring in addition Kingdom,27 1 in 80 000-100 000 births in The to separate scores for individual visceral Netherlands (Waterham et al, unpublished anomalies, the original scoring system of Bialer 36 15 data), and an even lower incidence in Japan et al was overweighted for internal anomalies. have been reported. The number of cases with 23 37 38 39 40 Therefore, we (Kelley and Hennekam, unpub- African, Asian, or South American http://jmg.bmj.com/ lished data) modified the Bialer score, to ancestry is also low. Although there remains weight embryologically separate organ systems some uncertainty about the absolute incidence equally. The revised scoring system (table 2) of SLOS in some countries, there clearly are has been used in two series of biochemically strikingly diVerent incidences among various 23 27 confirmed cases and showed a continuum ethnic groups. Both heterozygote advantage of severity and strong correlations with various and founder eVect have been suggested to biochemical parameters. Subsequent molecu- explain the relatively higher incidence of SLOS on September 30, 2021 by guest. Protected copyright. Table 2 Adapted (from ref 15) severity score for anatomical abnormalities in among those of European descent. The per- Smith-Lemli-Opitz syndrome centage of patients born to consanguineous parents is relatively low for an autosomal reces- Organ Score Criteria sive entity,23 27 35 which suggests persistence in Brain 1 Seizures; qualitative MRI abnormality the population of multiple mutant alleles 2 Major CNS malformations; gyral defects through heterozygote advantage. Oral 1 Bifid uvula or submucous cleft 2 Cleft hard palate or median cleft lip Acral 0 Non-Y shaped minimal toe syndactyly CRANIOFACIAL CHARACTERISTICS 1 Y shaped 2/3 toe syndactyly; club foot; upper or lower In the following listing of cases with various polydactyly; other syndactyly 2 Any two of the above features, no indication is made of whether a Eye 2 Cataract; frank microphthalmia case was biochemically confirmed or not. In Heart 0 Functional defects general, cases published after 1994 will have 1 Single chamber or vessel defect 2 Complex cardiac malformation been biochemically confirmed, but in cases Kidney 0 Functional defect from earlier papers this remains unknown.