Biochemical Abnormality Associated with Smith-Lemli-Opitz Syndrome in an Infant with Features of Rutledge Multiple Congenital Anomaly Syndrome Confirms that the Latter is a Variant of the Former
Restricted accessResearch articleFirst published online May, 2003
Biochemical Abnormality Associated with Smith-Lemli-Opitz Syndrome in an Infant with Features of Rutledge Multiple Congenital Anomaly Syndrome Confirms that the Latter is a Variant of the Former
We describe a female infant with morphologic features of Rutledge multiple-congenital-anomaly syndrome (RM-CAS) and biochemical features of Smith-Lemli-Opitz syndrome (SLOS). She had microcephaly with hypoplastic cerebral frontal lobes and cerebellum, agenesis of the splenium of corpus callosum, abnormal facies including hypertelorism with bilateral inner epicanthal folds, a broad nasal bridge with slightly anteverted nares and patent choanae, low set ears and complex conchal formation, high-arched palate and thick maxillary alveolar ridges, and micrognathia. Her chest was broad, genitalia were ambiguous, and uterus was bicornuate. Skeletal abnormalities included a hypoplastic appendicular skeleton, post-axial hexadactyly of the right hand and the left foot, syndactyly of bilateral 2nd–3rd toes and left 5th–6th toes, right talipes varus and left talipes valgus, and fused L5–S1 vertebrae. Congenital heart disease consisted of hypoplastic left heart, coronary sinus agenesis, ostium secundum and ostium primum defects, and a thickened septum primum. The lungs were hypolobated and the kidneys manifested oligopapillary hypoplasia. Total colonic Hirschsprung disease was noted microscopically. Analysis of liver tissue taken at postmortem examination revealed the ratio of 7-dehydrocholesterol and cholesterol to be 143 (expected, 0.28 ± 0.28). Although initially described as a distinct syndrome, RMCAS was merged with the severe form of SLOS, because of significantly overlapping features [Online Mendelian Inheritance in Man (OMIM) #268670]. The biochemical data showing an excess of 7-dehydrocholesterol and low cholesterol in the liver tissue of our case supports this viewpoint.
HondaA, TintGS, SalenG, BattaAK, ChenTS, SheferS.Defective conversion of 7-dehydrocholesterol to cholesterol in cultured skin fibroblasts from Smith-Lemli-Opitz syndrome homozygotes. J Lipid Res1995;36:1595–1601.
4.
SheferS, SalenG, BattaAK, Markedly inhibited 7-dehydrocholesterol-delta 7-reductase activity in liver microsomes from Smith-Lemli-Opitz homozygotes. J Clin Invest1995;96:1779–1785.
5.
WassifCA, MaslenC, Kachilele-LinjewileS, Mutations in the human sterol delta7-reductase gene at 11q12–13 cause Smith-Lemli-Opitz syndrome. Am J Hum Genet1998;63:55–62.
6.
FitzkyBU, Witsch-BaumgartnerM, ErdelM, Mutations in the Delta7-sterol reductase gene in patients with the Smith-Lemli-Opitz syndrome. Proc Natl Acad Sci USA1998;95:8181–8186.
7.
KrakowiakPA, NwokoroNA, WassifCA, Mutation analysis and description of sixteen RSH/Smith-Lemli-Opitz syndrome patients: polymerase chain reaction-based assays to simplify genotyping. Am J Med Genet2000;94:214–227.
8.
LofflerJ, TrojovskyA, CasatiB, KroiselPM, UtermannG.Homozygosity for the W151X stop mutation in the delta7-sterol reductase gene (DHCR7) causing a lethal form of Smith-Lemli-Opitz syndrome: retrospective molecular diagnosis. Am J Med Genet2000;95:174–177.
9.
NowaczykMJ, FarrellSA, SirkinWL, Smith-Lemli-Opitz (RHS) syndrome: holoprosencephaly and homozygous IVS8-1G→C genotype. Am J Med Genet2001;103:75–80.
10.
BelmontJW, HawkinsE, HejtmancikJF, GreenbergF.Two cases of severe lethal Smith-Lemli-Opitz syndrome. Am J Med Genet1987;26:65–67.
11.
CurryCJ, CareyJC, HollandJS, Smith-Lemli-Opitz syndrome—type II: multiple congenital anomalies with male pseudohermaphroditism and frequent early lethality. Am J Med Genet1987;26:45–57.
12.
RutledgeJC, FriedmanJM, HarrodMJ, A “new” lethal multiple congenital anomaly syndrome: joint contractures, cerebellar hypoplasia, renal hypoplasia, urogenital anomalies, tongue cysts, shortness of limbs, eye abnormalities, defects of the heart, gallbladder agenesis, and ear malformations. Am J Med Genet1984;19:255–264.
13.
BergerR, SmitGP, SchierbeekH, BijsterveldK, le CoultreR.Mevalonic aciduria: an inborn error of cholesterol biosynthesis?Clin Chim Acta1985;152:219–222.
14.
HoffmannG, GibsonKM, BrandtIK, BaderPI, WappnerRS, SweetmanL.Mevalonic aciduria—an inborn error of cholesterol and nonsterol isoprene biosynthesis. N Engl J Med1986;314:1610–1614.
15.
HoffmannGF, CharpentierC, MayatepekE, Clinical and biochemical phenotype in 11 patients with mevalonic aciduria. Pediatrics1993;91:915–921.
16.
GibsonKM, HoffmannGF, SweetmanL, BuckinghamB.Mevalonate kinase deficiency in a dizygotic twin with mild mevalonic aciduria. J Inherit Metab Dis1997;20:391–394.
17.
FrenkelJ, HoutenSM, WaterhamHR, Mevalonate kinase deficiency and Dutch type periodic fever. Clin Exp Rheumatol2000;18:525–532.
18.
ClaytonP, MillsK, KeelingJ, FitzPatrickD.Desmosterolosis: a new inborn error of cholesterol biosynthesis. Lancet1996;348:404.
19.
FitzPatrickDR, KeelingJW, EvansMJ, Clinical phenotype of desmosterolosis. Am J Med Genet1998;75:145–152.
20.
WaterhamHR, KosterJ, RomeijnGJ, Mutations in the 3beta-hydroxysterol Delta24-reductase gene cause desmosterolosis, an autosomal recessive disorder of cholesterol biosynthesis. Am J Hum Genet2001;69:685–694.
21.
ChitayatD, GruberH, MullenBJ, Hydrops-ectopic calcification–moth-eaten skeletal dysplasia (Greenberg dysplasia): prenatal diagnosis and further delineation of a rare genetic disorder. Am J Med Genet1993;47:272–277.
22.
GreenbergCR, RimoinDL, GruberHE, DeSaDJ, ReedM, LachmanRS. A new autosomal recessive lethal chondrodystrophy with congenital hydrops. Am J Med Genet1988;29:623–632.
23.
HornLC, FaberR, MeinerA, PiskazeckU, SprangerJ.Greenberg dysplasia: first reported case with additional non-skeletal malformations and without consanguinity. Prenat Diagn2000;20:1008–1011.
24.
BravermanN, LinP, MoebiusFF, Mutations in the gene encoding 3 beta-hydroxysteroid-delta 8, delta 7-isomerase cause X-linked dominant Conradi-Hunermann syndrome. Nat Genet1999;22:291–294.
25.
DerryJM, GormallyE, MeansGD, Mutations in a delta 8-delta 7 sterol isomerase in the tattered mouse and X-linked dominant chondrodysplasia punctata. Nat Genet1999;22:286–290.
26.
HappleR.X-linked dominant chondrodysplasia punctata. Review of literature and report of a case. Hum Genet1979;53:65–73.
27.
HasC, Bruckner-TudermanL, MullerD, The Conradi-Hunermann-Happle syndrome (CDPX2) and emopamil binding protein: novel mutations, and somatic and gonadal mosaicism. Hum Mol Genet2000;9:1951–1955.
28.
HasC, SeedorfU, KannenbergF, Gas chromatography-mass spectrometry and molecular genetic studies in families with the Conradi-Hunermann-Happle syndrome. J Invest Dermatol2002;118:851–858.
29.
KelleyRI, WilcoxWG, SmithM, KratzLE, MoserA, RimoinDS. Abnormal sterol metabolism in patients with Conradi-Hunermann-Happle syndrome and sporadic lethal chondrodysplasia punctata. Am J Med Genet1999;83:213–219.
30.
GrangeDK, KratzLE, BravermanNE, KelleyRI. CHILD syndrome caused by deficiency of 3beta-hydroxysteroid-delta8, delta7-isomerase. Am J Med Genet2000;90:328–335.
31.
HappleR, KochH, LenzW.The CHILD syndrome. Congenital hemidysplasia with ichthyosiform erythroderma and limb defects. Eur J Pediatr1980;134:27–33.
32.
HappleR, EffendyI, MegahedM, OrlowSJ, KusterW.CHILD syndrome in a boy. Am J Med Genet1996;62:192–194.
33.
KonigA, HappleR, BornholdtD, EngelH, GrzeschikKH. Mutations in the NSDHL gene, encoding a 3beta-hydroxysteroid dehydrogenase, cause CHILD syndrome. Am J Med Genet2000;90:339–346.
34.
Brunetti-PierriN, CorsoG, RossiM, Lathosterolosis, a novel multiple-malformation/mental retardation syndrome due to deficiency of 3beta-hydroxysteroid-delta5-desaturase. Am J Hum Genet2002;71:952–958.
35.
KelleyRI, KratzLE, GlaserRL, NetzloffML, WolfLM, JabsEW. Abnormal sterol metabolism in a patient with Antley-Bixler syndrome and ambiguous genitalia. Am J Med Genet2002;110:95–102.
36.
NowaczykMJ, WayeJS. The Smith-Lemli-Opitz syndrome: a novel metabolic way of understanding developmental biology, embryogenesis, and dysmorphology. Clin Genet2001;59:375–386.
37.
CunniffC, KratzLE, MoserA, NatowiczMR, KelleyRI. Clinical and biochemical spectrum of patients with RSH/Smith-Lemli-Opitz syndrome and abnormal cholesterol metabolism. Am J Med Genet1997;68:263–269.
38.
RyanAK, BartlettK, ClaytonP, Smith-Lemli-Opitz syndrome: a variable clinical and biochemical phenotype. J Med Genet1998;35:558–565.
39.
NowaczykMJ, WhelanDT, HillRE. Smith-Lemli-Opitz syndrome: phenotypic extreme with minimal clinical findings. Am J Med Genet1998;78:419–423.
40.
BialerMG, PenchaszadehVB, KahnE, LibesR, KrigsmanG, LesserML. Female external genitalia and mullerian duct derivatives in a 46,XY infant with the Smith-Lemli-Opitz syndrome. Am J Med Genet1987;28:723–731.
41.
KelleyRI, HennekamRC. The Smith-Lemli-Opitz syndrome. J Med Genet2000;37:321–335.
42.
DonnaiD, YoungID, OwenWG, ClarkSA, MillerPF, KnoxWF. The lethal multiple congenital anomaly syndrome of polydactyly, sex reversal, renal hypoplasia, and unilobular lungs. J Med Genet1986;23:64–71.
43.
KratzLE, KelleyRI. Prenatal diagnosis of the RSH/Smith-Lemli-Opitz syndrome. Am J Med Genet1999;82:376–381.
44.
WayeJS, NakamuraLM, EngB, Smith-Lemli-Opitz syndrome: carrier frequency and spectrum of DHCR7 mutations in Canada. J Med Genet2002;39:E31.
45.
Witsch-BaumgartnerM, FitzkyBU, OgorelkovaM, Mutational spectrum in the Delta7-sterol reductase gene and genotype-phenotype correlation in 84 patients with Smith-Lemli-Opitz syndrome. Am J Hum Genet2000;66:402–412.
46.
YuH, LeeMH, StarckL, Spectrum of Delta(7)-dehydrocholesterol reductase mutations in patients with the Smith-Lemli-Opitz (RSH) syndrome. Hum Mol Genet2000;9:1385–1391.
47.
PorterJA, YoungKE, BeachyPA. Cholesterol modification of hedgehog signaling proteins in animal development. Science1996;274:255–259.
48.
PorterJA, von KesslerDP, EkkerSC, The product of hedgehog autoproteolytic cleavage active in local and long-range signalling. Nature1995;374:363–366.
49.
MarigoV, DaveyRA, ZuoY, CunninghamJM, TabinCJ. Biochemical evidence that patched is the hedgehog receptor. Nature1996;384:176–179.
50.
StoneDM, HynesM, ArmaniniM, The tumour-suppressor gene patched encodes a candidate receptor for Sonic hedgehog. Nature1996;384:129–134.
51.
HolmerL, PezhmanA, WormanHJ. The human lamin B receptor/sterol reductase multigene family. Genomics1998;54:469–476.
52.
SilveS, DupuyPH, FerraraP, LoisonG.Human lamin B receptor exhibits sterol C14-reductase activity in Saccharomyces cerevisiae. Biochim Biophys Acta1998;1392:233–244.
53.
EliasER, IronsMB, HurleyAD, TintGS, SalenG.Clinical effects of cholesterol supplementation in six patients with the Smith-Lemli-Opitz syndrome (SLOS). Am J Med Genet1997;68:305–310.
54.
IronsM, EliasER, AbueloD, Treatment of Smith-Lemli-Opitz syndrome: results of a multicenter trial. Am J Med Genet1997;68:311–314.
55.
LinckLM, LinDS, FlavellD, ConnorWE, SteinerRD. Cholesterol supplementation with egg yolk increases plasma cholesterol and decreases plasma 7-dehydrocholesterol in Smith-Lemli-Opitz syndrome. Am J Med Genet2000;93:360–365.
56.
NwokoroNA, MulvihillJJ. Cholesterol and bile acid replacement therapy in children and adults with Smith-Lemli-Opitz (SLO/RSH) syndrome. Am J Med Genet1997;68:315–321.
