Smith-Lemli-Opitz syndrome (SLOS, OMIM 270400) is an autosomal recessive disorder caused by mutations of 7-dehydrocholesterol reductase gene (DHCR7) (^1-4). DHCR7 deficiency impairs cholesterol production, resulting in accumulation of precursor sterols, 7-dehydrocholesterol (7DHC) (⁵). The estimated incidence of SLOS is 1 in 20,000-40,000 births in the Caucasian population (^6-8). On the other hand, the incidence is low in African and Asian populations (^9-11) and only one case has been reported in Korea thus far (¹²).

Patients with SLOS show a wide variability of congenital anomalies, including dysmorphic facies, microcephaly, cleft palate, syndactyly of toes 2 and 3, visceral malformations, congenital heart defects, and ambiguous genitalia (⁷). Failure to thrive, behavior problems, and mental retardation are hallmarks of the disorder. The spectrum of phenotype is variable, from early embryonal non-viability to patients with minimal physical abnormalities and normal intelligence or minimal intellectual impairment. Liver disease has been reported infrequently in SLOS (¹³). We found a case of SLOS who presented with neonatal cholestasis and identified a novel mutation of the DHCR7 gene.

Two missense variations were identified in the patient. One was a C to T transition at nucleotide 679 (c.679C>T) in exon 7, resulting in a Pro to Ser substitution at the 227th residue (Pro227Ser; Fig. 2A). The other was a G to A transition at nucleotide 907 (c.907G>A) in exon 8, resulting in a Gly to Arg substitution at the 303rd residue (Gly303Arg; Fig. 2A). Both variations were inherited from the patient's mother and father, respectively. While Gly303Arg has been reported in a Japanese patient with SLOS (¹⁵), Pro227Ser variation has not been reported previously and it alters conserved residue among different species (Fig. 2B).

The frequency of hepatic manifestation in SLOS was reported to be low, ranged from 2.5% to 16% (⁹, ¹³, ¹⁵). Although cholestatic liver disease and isolated hypertransaminasemia were reported in SLOS, there are few studies investigating the histological abnormalities of the liver. In the present study, histologic findings showed septal fibrosis, ductular proliferation, and ballooning degeneration of hepatocytes, which are consistent with those of Rossi et al. (¹³). Since bile acids are synthesized from cholesterol, cholestasis may be caused by impaired bile acid synthesis due to a severe deficiency of DHCR. Severe cholestasis in SLOS was reported to be associated with severe phenotypes, while isolated hypertransaminasemia was associated with milder phenotypes (¹⁶). Our patient presented with severe cholestasis and severe phenotype. Serum GGT levels were normal in our case in spite of severe cholestasis. Normal GGT with neonatal cholestasis is also shown in progressive familial intrahepatic cholestasis 1 and 2, ARC syndrome, and inborn errors of bile acid synthesis.

To date more than 120 mutations have been identified (¹⁷). The missense mutations account for 87% of the total mutations. Fifty percent of the missense mutations are located in one of the nine predicted transmembrane domains. The p.Gly303Arg mutation was previously reported in Japanese SLOS patients and it is located in the seventh transmembrane domain, which represent a highly conserved sterol-sensing domain (¹⁴). The p.Pro227Ser mutation is located in the second cytoplasmic loop, and previously described mutations in this loop are p.Gln224Lys and p. Arg228Trp (¹⁸). Three mutations including IVS-1G→C, p.Thr93Met, and p.Val326Leu account for 50% of the spectrum of mutations in Caucasian patients (¹⁹). On the other hand, p.Arg325Gln is the most common mutation in Japanese SLOS patients (¹⁴). The previously reported case of SLOS in Korea harbored compound heterozygous mutations including p.Arg352Trp and p.Lys376ArgfsX37 (¹²). DHCR7 mutation patterns in Asian patients are different from those observed among Caucasians.

The genotype-phenotype analysis showed that most homozygotes for frameshift and nonsense mutations had the severe phenotypes (²⁰). However, Yu et al. (¹⁷) showed that there was great variation in severity in patients that had the same type of mutations.

In summary, we found a case of SLOS with mutations of the DHCR7 gene and neonatal cholestasis. SLOS should be considered in the differential diagnosis of neonatal cholestasis, especially in patients with multiple congenital anomalies and low serum cholesterol levels.

This work was Supported by grant no 04-2007-0230 from SNUH Research Fund.