Rutledge multiple congenital anomaly syndrome is a severe neonatal and lethal ‘type II’ disorder of Smith-Lemli-Opitz syndrome (SLOS). This autosomal recessive disorder is caused by homozygous or compound heterozygous mutations in delta-7-dehydrocholesterol reductase; located on chromosome 11q12-q13. In 1984 J.C.Rutledge first described multiple congenital malformations including joint contractures, polydactyly, craniofacial deformations, cardiac and respiratory anomalies, cerebellar hypoplasia, sex reversal and early lethality. Prenatal diagnosis by ultrasonography and analysis of cholesterol level by amniocentesis is possible.
We report a case of a premature female newborn sent to our department with multiple malformations including hypotrophy, ventricular septal defect, facial stigmatization, skeletal dysplasia, clubfoot, hexadactyly, syndactyly, hypoplastic kidney and lungs. Several blood samples were taken for classic cytogenetic examination, molecular and biochemical analyses. Biochemical analysis proved a high level of 7-dehydrocholesterol (123,2μmol/l; ref. up to 0,85μmol/l) and a low level of cholesterol (0,039mmol/l; ref. range 1,9 – 2,6mmol/l) which is significant for Smith-Lemli-Opitz syndrome. A multiplex ligation-dependent probe amplification (MLPA) method was used to rule out possible microdeletion or microduplication syndromes and came out as negative. Molecular methods such as PCR-RFLP (polymerase chain reaction – restriction fragment length polymorfism) revealed the most frequent mutation W151X (one allele) in exone 6. Mutation of DHCR7 gene leads to a premature termination codone and therefore a dysfunctional protein. Additional sequencing of exone 3 – 9 revealed another mutation IVS8-1G>C in introne 8 which affects mRNA splicing and leads to a dysfunctional protein as well. Cytogenetic methods (G- and C-banding) were used to confirm a sex reversal karyotype 46,XY supported by molecular analysis of Y-specific sequences with no other structural or numerical abnormalities. This phenotypically female baby, who died at the age of 2 days, was a confirmed compound heterozygote (W151X/IVS8-1G>C) in the DHCR7 gene with the manifestation of the Smith-Lemli-Opitz syndrome type II. As with any genetic disorder, genetic counseling for the parents is a very important part of this work and a necessary component for their future offspring.
Key words: Rutledge syndrome, Smith-Lemli-Opitz syndrome, delta-7-dehydrocholesterol reductase, DHCR7