Smith-Lemli-Opitz Syndrome: Phenotypic ExtremeWith Minimal Clinical Findings

Malgorzata J.M. Nowaczyk,1,2* Donald T. Whelan,1,2 and Robert E. Hill1

1Department of Pathology and Laboratory Medicine (Program in Human Genetics), Hamilton Health SciencesCorporation and McMaster University, Hamilton, Ontario, Canada

2Department of Pediatrics, Hamilton Health Sciences Corporation and McMaster University,Hamilton, Ontario, Canada

Smith-Lemli-Opitz syndrome (SLO) iscaused by inherited enzymatic deficiency of7-dehydrocholesterol-D7-reductase and re-sultant cholesterol deficiency. It comprisesa characteristic combination of facial fea-tures, malformations, and mental retarda-tion. We report on three related patients(two brothers and their first cousin) withmental retardation and minimal physicalsigns in whom the diagnosis of SLO was de-layed for a number of years. The presence ofa third-degree relative in the absence ofconsanguinity in this family supports theproposed high population carrier fre-quency. Our report suggests that cases ofmild SLO remain undiagnosed and un-treated, and that awareness of this commoncause of mental retardation is low. Am. J.Med. Genet. 78:419–423, 1998.© 1998 Wiley-Liss, Inc.

KEY WORDS: 7-dehydrocholesterol; choles-terol synthesis; mental retar-dation; behavioral problems;toe syndactyly; thumb hypo-plasia

INTRODUCTION

Smith-Lemli-Opitz syndrome (SLO; MIM 270400) isan autosomal recessive error of cholesterol synthesiswith protean manifestations [Smith et al., 1964; Tint etal., 1994]. The clinical spectrum extends from life-threatening congenital anomalies of the central ner-vous system, heart, and lungs; cystic kidney dysplasia;ambiguous genitalia; polydactyly; cleft palate; and highneonatal mortality to mental deficits accompanied byvariable degrees of cleft palate or cutaneous syndactyly

of second and third toes [Smith et al., 1964; Lowry andYong, 1980; Greens et al., 1984; Bialer et al., 1987;Curry et al., 1987; Tint et al., 1994; Cunniff et al.,1997]. Neonatal feeding difficulties, irritability, andfailure to thrive are common. The typical facial appear-ance may be quite subtle and difficult to appreciate.The patients may have a broad and high forehead, pto-sis, epicanthal folds, broad nasal bridge, short nosewith anteverted nares, and micrognathia. The ears areapparently low-set and small, and midline cleft palateis common. Polydactyly of feet and hands, club feet,and other anomalies of the hands and feet are alsocommon. The genital anomalies observed in males withSLO (hypospadias, undescended testes, and micrope-nis) have resulted in an overascertainment bias of boyswith this condition. Various central nervous systemand internal malformations have been observed in pa-tients with SLO, but none of these malformations arecharacteristic.

The inherited defect in SLO yields inactive 7-dehydrocholesterol-D7-reductase, the enzyme that ca-talyses the conversion of 7-dehydrocholesterol (7-DHC)to cholesterol [Shefer et al., 1995; Moebius et al., 1998].As a result of this defect, 7-DHC accumulates and ageneralized cholesterol deficiency develops in all bodytissues. SLO is readily diagnosed by demonstration ofelevated levels of 7-DHC in plasma. Treatment withdietary cholesterol replacement results in marked im-provement in weight gain and in amelioration of be-havioral problems [Irons et al., 1997].

We report on three related patients with SLO withsignificant intellectual impairments, behavior difficul-ties, and minimal physical manifestations who re-mained undiagnosed for a number of years because oftheir mild phenotype. It appears that SLO is relativelyunknown to the general and developmental pediatri-cians, and that patients with this condition remain un-diagnosed.

CLINICAL REPORTSPatient 1

This boy was referred to the genetic service at theage of 31 months for assessment of developmental de-lay. The referring neurologist thought that a genetic

*Correspondence to: M.J.M. Nowaczyk, McMaster UniversityMedical Centre, Room 3N16, 1200 Main Street West, Hamilton,Ontario, Canada L8S 4J9. E-mail: nowaczyk@exchange1.cmh.on.ca

Received 17 April 1998; Accepted 11 May 1998

American Journal of Medical Genetics 78:419–423 (1998)

© 1998 Wiley-Liss, Inc.

cause for the boy’s delays must be ruled out because hehad a similarly affected younger brother. His parentswere not consanguineous and were of English-Scottishancestry. He was born at 36 weeks gestation followingan uncomplicated pregnancy and delivery. His birthweight was 2,897 g (10th centile). Infancy was markedby feeding difficulties, vomiting, and poor weight gain.He had recurrent ear infections. He walked unaided at18 months, and at 30 months he still had no speech andwas not toilet-trained. At the time of assessment, hewas able to communicate with pointing and had a fewsigns; he was not able to use a fork or spoon. He reactedwith temper tantrums and screaming when presentedwith new or stressful situations. His general healthwas good. He had a normal male karyotype, 46,XY.Weight was 14 kg (10th–25th centile), length 97 cm(25th centile), and occipitofrontal circumference (OFC)49 cm (10th centile). He had bilateral epicanthal folds,anteverted nares, short nose, marked blepharoptosis,and mild micrognathia (Fig. 1). There was bilateral 5thfinger clinodactyly and abnormal palmar creases:bridged transverse creases and hypoplastic thenar emi-nence. He had minimal cutaneous 2nd and 3rd toe syn-dactyly (Fig. 3). The remainder of the general physicalfindings were normal; external genitalia were normal.Results of biochemical tests are listed in Table I.

Patient 2

The younger brother of patient 1 was born followingan uncomplicated pregnancy by spontaneous vaginalvertex delivery. Birth weight was 3,260 g (50th centile),and OFC was 46.8 cm (10th centile). He had bilateralclub feet. His course was complicated by feeding diffi-culties and vomiting for which he was investigated by apediatric gastroenterologist; he required nasogastrictube feeding for a period of time with minimal improve-ment in weight gain. He sat unsupported at 8 monthsand crawled at 13 months. He started to follow simplecommands at 18 months. At the time of examination at21 months he did not have an isolated pincer grasp, hewas not walking, and he was able to communicate bypointing and sounds. His facial appearance was strik-ingly similar to that of his brother’s (Fig. 2). His weight

TABLE I. Plasma Cholesterol and 7-DHC*

Patient 1 Patient 2 Patient 3

Cholesterol [mmol/L]RR: <5.2 mmol/L 2.33 2.3 2.3

7-DHC [mmol/L]RR: not detectable 134 183 48

*RR, reference range.

Fig. 1. (a, b) Patient 1. Blepharoptosis, epicanthal folds, micrognathia, short nose, anteverted nares, and apparently low-set ears are evident.

420 Nowaczyk et al.

was 9.8 kg (<3rd centile), length was 80.7 cm (10thcentile), and OFC was 47 cm (10th centile). He hadbilateral 5th finger clinodactyly, hypoplastic thenareminences, abnormal palmar creases, and minimal cu-taneous 2nd–3rd toe syndactyly. External genitaliawere normal male. Karyotype was normal 46,XY.

Patient 3

This girl is a paternal first cousin of patients 1 and 2(their fathers are brothers). Her parents are not con-sanguineous and her mother, who is of Irish back-ground, is not related to the mother of patients 1 and 2.She was born at 38 weeks gestation, and her birthweight was 1,820 g (3rd centile). Neonatal course wascomplicated by transient apneic and bradycardic epi-sodes. Her infancy was marked by feeding difficultiesand failure to thrive. At the time of assessment, shewas an 11-year-old girl with marked developmental de-lays and behavior abnormalities; she was able to readand write at the level of senior kindergarten. Her be-havior problems, diagnosed as attention deficit-hyperactivity syndrome, responded well to treatmentwith methylphenidate instituted at the age of 6 years.Multiple investigations throughout childhood failed tofind the etiology of her medical and behavioral prob-lems. Following the diagnosis of SLO in her cousins,

her parents requested a measurement of her plasma7-DHC (Table I). The elevated level of 7-DHC led to agenetic consultation and the diagnosis of SLO. Physicalexamination showed a normal-appearing girl with mi-nor anomalies features and mild micrognathia (Fig. 4),bilateral 5th finger clinodactyly, hypoplastic thenareminences and thumbs, abnormally bridged palmarcreases, and bilateral 2nd–3rd toe syndactyly notice-

Fig. 3. Patient 1. Minimal cutaneous 2nd–3rd toe syndactyly.

Fig. 2. (a, b) Patient 2. The facial abnormalities are more pronounced in this patient than in his older brother.

Mild Smith-Lemli-Opitz Syndrome 421

able only from the plantar aspect (Fig. 5). Her weightwas 22.7 kg (< 3rd centile), height was 123.5 cm (10thcentile), and OFC was 49.5 cm (3rd centile). Her threesisters are phenotypically and intellectually normal,and their 7-DHC and cholesterol levels are normal.

DISCUSSION

SLO is associated with various internal and externalmalformations, but none of these malformations is di-agnostic. The facial appearance of SLO may be subtleand difficult to appreciate. The characteristic abnor-mality of the feet is a variable degree of cutaneous 2nd–3rd toe syndactyly; however, this malformation can beinherited as an autosomal dominant trait and occurs

with the incidence of ∼0.5% [Castilla et al., 1980]. Thegenital anomalies observed in males with SLO (hypo-spadias, undescended testes, and micropenis) have re-sulted in an overascertainment bias of boys with thiscondition [Cunniff et al., 1997; Curry et al., 1987]. Theseverity of the physical presentation and mortality ofSLO correlates with the severity of the cholesterol de-ficiency [Tint et al., 1995]; however, numerous caseswith low normal cholesterol have been reported.

Following the discovery of the underlying metabolicdefect in SLO, a number of milder and ‘‘atypical’’ caseshas been reported [Kelley et al., 1994]. Our patients didnot have malformations other than minimal cutaneous2nd–3rd toe syndactyly. The facial anomalies werecharacteristic, albeit subtle, in the boys and evenmilder in the girl. All three had significant intellectualimpairment and behavioral difficulties. Their plasmacholesterol levels before institution of cholesteroltherapy were low normal. The similar mild phenotype

Fig. 4. (a, b) Patient 3. The facial changes are subtle; however, retro-gnathia and low-set ears are appreciable.

Fig. 5. Patient 3. The 2nd–3rd toe syndactyly demonstrated from dorsal(a) and plantar (b) aspects.

422 Nowaczyk et al.

in these three related patients may be attributable toother shared genetic loci that may ameliorate theirphenotype. However, these three patients are likelyrepresentative of patients at the mild extreme of SLOwho escape diagnosis because of lack of recognition.

SLO is an autosomal recessive condition. The virtualabsence of consanguineous matings in the parents ofpatients with SLO and frequent occurrence of affectedsecondary sibships in previously reported cases of SLOsuggest a high carrier frequency. The birth prevalencein the Caucasian population of North European ances-try has been estimated to be in the order of 1:20,000 to1:30,000 resulting in the estimated carrier rate of 1–2%[Holmes, 1994; Opitz, 1994]. However, the rate of di-agnosis in referral laboratories that provide the diag-nostic test is in the order of 1 in 50,000 births. Ourreport may partly explain this discrepancy, as it illus-trates that a number of mildly affected cases escapediagnosis for prolonged periods. Cases at the other ex-treme (severe neonatal) may escape detection becauseof death before definite diagnosis is made.

We recommend that plasma 7-DHC be measured inall children with ‘‘idiopathic’’ mental retardation or de-velopmental delays especially if associated with cleftpalate of any degree (such as bifid uvula), microgna-thia, or 2nd–3rd toe syndactyly. Normal plasma cho-lesterol level does not rule out SLO and should not beused as a screening test.

ACKNOWLEDGMENTS

The authors thank Mrs. Melanie Flokstra for secre-tarial assistance, Mrs. Donna McCaughey for technicalassistance, and Mr. Tim Heshka, M.Sc., M. Sc., for re-view of the manuscript.

REFERENCESBialer MG, Penchaszadeh VB, Kahn E, Libes R, Krigsman G, Lesser ML

(1987): Female external genitalia and Mullerian duct derivatives in a

46,XY infant with the Smith-Lemli-Opitz syndrome. Am J Med Genet28:723–731.

Castilla EE, Paz JE, Orioli-Parreiras IM (1980): Syndactyly: Frequency ofspecific types. Am J Med Genet 5:357–364.

Curry CJR, Carey JC, Holland JS (1987): Smith-Lemli-Opitz syndrometype II: Multiple congenital anomalies with male pseudohermaphrodit-ism and frequent early lethality. Am J Med Genet 26:45–57.

Cunniff C, Kratz LE, Moser A, Natowicz MR, Kelley RI (1997): Clinical andbiochemical spectrum of patients with RSH/Smith-Lemli-Opitz syn-drome and abnormal cholesterol metabolism. Am J Med Genet 68:263–269.

Greens C, Picts W, Rosenfeld R (1984): Smith-Lemli-Opitz syndrome in two46,XY infants with female external genitalia. Clin Genet 25:366–372.

Holmes LB (1994): Prevalence of Smith-Lemli-Opitz syndrome. Am J MedGenet 50:334.

Irons MB, Elias ER, Abuelo D, Bull MJ, Greens CL, Johnson VP, KeppenL, Schanen C, Tint S, Salen G (1997): Treatment of Smith-Lemli-Opitzsyndrome: Results of a multicenter trial. Am J Med Genet 68:311–314.

Kelley RI, Moser A, Natowicz MR (1994): The clinical and biochemicalspectrum of 7-dehydrocholesterolemia: Smith-Lemli-Opitz syndromeand its variants. Am J Med Genet 50:335.

Lowry RB, Yong S-L (1980): Borderline normal intelligence in the Smith-Lemli-Opitz (RHS) syndrome. Am J Med Genet 5:137–143.

Moebius FF, Fitzky BU, Lee JN, Paik YK, Glossmann H (1998): Molecularcloning and expression of the human delta 7-sterol reductase. Proc NatlAcad Sci USA 95:1899–1902.

Opitz JM (1994): RSH-SLO (‘‘Smith-Lemli-Opitz’’) syndrome: Historical,genetic and developmental considerations. Am J Med Genet 50:344–346.

Shefer S, Salen G, Batta AK, Honda A, Tint GS, Irons M, Elias ER, ChenTC, Holick MF (1995): Markedly inhibited 7-dehydrocholesterol-delta(7)-reductase activity in liver microsomes from Smith-Lemli-Opitzhomozygotes. J Clin Invest 96:1779–1785.

Smith DW, Lemli L, Opitz JM (1964): A newly recognized syndrome ofmultiple congenital anomalies. J Pediatr 64:210–217.

Tint GS, Irons M, Elias ER (1994): Defective cholesterol biosynthesis as-sociated with the Smith-Lemli-Opitz syndrome. N Engl J Med 330:107–113.

Tint GS, Salen G, Batta AK, Shefer S, Irons M, Elias ER, Abuelo DN,Johnson VP, Lambert M, Lutz R, Schanen C, Morris CA, Hoganson G,Hughes-Benzie R (1995): Correlation of severity and outcome withplasma sterol levels in variants of the Smith-Lemli-Opitz syndrome. JPediatr 127:82–87.

Mild Smith-Lemli-Opitz Syndrome 423