Child ; Child, Preschool ; Humans ; Infant ; Smith-Lemli-Opitz Syndrome

Smith-Lemli-Opitz syndrome is characterized by unusual facies, microcephaly, mental and growth retardation, skeletal and genitourinary malformations. We present a 10-year old boy who visited us with chief complaints of urinary incontinence and azotemia. He was manifested facial abnormalities and other features of Smith-Lemli-Opitz syndrome including vesicoureteral reflux, chronic pyelonephritis, hypospadia and cryptorchidism. Chromosomal study showed 15 chromosome short arm deletion, karyotypically he was depicted 46, XY, del(15)(p12).
Arm ; Azotemia ; Child ; Cryptorchidism ; Facies ; Female ; Humans ; Hypospadias ; Male ; Microcephaly ; Pyelonephritis ; Smith-Lemli-Opitz Syndrome* ; Urinary Incontinence ; Vesico-Ureteral Reflux

OBJECTIVE: To analyze the clinical features and genetic variants of two patients from a pedigree affected with Smith-Lemli-Opitz syndrome and explore their genotype-phenotype correlation. METHODS: Clinical data and family history of the pedigree were collected. Whole exome sequencing was carried out to identify the potential variants. Suspected variants were verified by Sanger sequencing of the family members. RESULTS: The proband and her sister both presented with feeding difficulty, facial dysmorphism, seizures, and mental and speech retardation. The third child of this family presented with feeding difficulty, poor weight gain and severe malnutrition after birth. He had died of unknown cause at 6 months without genetic testing. The fourth child was a healthy boy. Genetic testing showed that both the proband and her sister have carried c.127G>T (p.Val43Phe) and c.820_825del (p.Asn274_Val275del) compound heterozygous variants of the DHCR7 gene (NM_001360.2), but the fourth child carried neither of the variants. The two variants were unreported in the literature and disease-related databases, and were not included in the 1000G and gnomAD databases. The c.820_825del variant may affect the sterol-sensitive region of the DHCR7 protein, which can lead to deletion of two amino acids at positions 247 and 275, causing truncation of the DHCR7 protein. It is speculated that this may affect the stability of protein's spatial conformation, thereby decrease the activity of the enzyme. The c.127G>T variant may affect the first transmembrane region of the protein, which is involved in the transmembrane transport of proteins. Multiple software predicted it to be harmful. Conservation analysis suggested that the three amino acids all locate in a highly conserved region of the protein. In consideration of the clinical phenotype, family history and result of genetic testing, we speculated that both patients had Smith-Lemli-Opitz syndrome due to variants of the DHCR7 gene. CONCLUSION This pedigree has enriched the phenotypic and genotypic data of Smith-Lemli-Opitz syndrome, which clarified the genetic etiology of the patients and provided a basis for genetic counseling of this pedigree.
China ; Female ; Genetic Testing ; Humans ; Male ; Mutation ; Oxidoreductases Acting on CH-CH Group Donors/genetics* ; Pedigree ; Smith-Lemli-Opitz Syndrome/genetics*

OBJECTIVE: To explore the clinical phenotype and pathogenic variants in a Chinese pedigree affected with Smith-Lemli-Opitz syndrome. METHODS: Peripheral blood samples were collected from five members, including two affected ones, from the pedigree for the extraction of genomic DNA. Whole exome sequencing was carried out, and candidate variants were verified by Sanger sequencing as well as reverse transcription sequencing at the RNA level. RESULTS: The proband and another affected child from the pedigree showed mental retardation, dyskinesia, microcephaly, micrognathia, anteverted nares, and 2/3 toe syndactyly. The proband also had hypospadia, single upper incisor, and lower serum cholesterol level. Both children were found to harbor a paternally derived c.278C>T (p.T93M) variant and a maternally derived c.907G>A (p.G303R) variant of the DHCR7 gene. Both were known pathogenic mutations. CONCLUSION The compound heterozygous mutations of c.278C>T (p.T93M) and c.907G>A (p.G303R) of the DHCR7 gene probably underlay the disease in this pedigree. Above finding has enabled early diagnosis and treatment of Smith-Lemli-Opitz syndrome.
Child ; Genetic Testing ; Humans ; Oxidoreductases Acting on CH-CH Group Donors/genetics* ; Pedigree ; Phenotype ; Smith-Lemli-Opitz Syndrome/genetics*

Smith-Lemli-Opitz syndrome (SLOS) is a rare autosomal recessive disorder caused by 7-dehydrocholesterol reductase deficiency. The characteristic clinical features are syndactyly of the second and third toes, facial dysmorphism, multiple malformations, and intellectual disability. Few cases of SLOS have been reported in Korea. We observed a male patient with SLOS who presented with typical facial features, undescended testes, microcephaly, bilateral syndactyly of the second and third toes, and cardiac defects, including patent ductus arteriosus and atrial septal defect. Mutation analysis of the DHCR7 gene identified compound heterozygous mutations of c.907G>A (p.Gly303Arg) and c.1055G>A (p.Arg352Gln). In a review of the literature, c.1054C>T (p.Arg352Trp) was the most common mutation reported in Far East Asian countries. This report describes the clinical features, biochemical data, molecular characteristics, and clinical outcome of a Korean patient with SLOS.
Asian Continental Ancestry Group ; Cryptorchidism ; Ductus Arteriosus, Patent ; Far East ; Heart Septal Defects, Atrial ; Humans ; Intellectual Disability ; Korea ; Male ; Microcephaly ; Smith-Lemli-Opitz Syndrome* ; Syndactyly ; Toes

During the last 6.5 years 49 patients with inter sex were managed at the Department of Urology, Seoul National University Hospital. The median age was 8.8 years (from 2 months to 37 years). The patients consist of 15 female pseudohermaphroditism (adrenogenital syndrome), 4 true hermaphroditism, 21 male pseudohermaphroditism, 3 mixed gonadal dysgenesis, 3 Turner`s syndrome and 3 miscellaneous inter sex including Smith-Lemli-Opitz syndrome and Prader-Willi syndrome. Though early diagnosis and treatment are most important, only 10 patients (20%) were diagnosed before 2.5 years of age.
46, XX Disorders of Sex Development ; 46, XY Disorders of Sex Development ; Disorders of Sex Development* ; Early Diagnosis ; Gonadal Dysgenesis, Mixed ; Humans ; Ovotesticular Disorders of Sex Development ; Prader-Willi Syndrome ; Seoul ; Smith-Lemli-Opitz Syndrome ; Urology

Trisomy 9 mosaicism is a disease characterized not only by intrauterine growth retardation and mental retardation but also congenital heart defects, musculoskeletal, genitourinary and CNS anomalies, as well as craniofacial anomalies such as microcephaly, micrognathia, narrowed temples, prominent occiput, broad-based nose with bulbous tip, low set ears, deeply set eyes, short palpebral fissure and small mouth. This syndrome was first reported back in 1973 by Haslam and others, and has hardly ever been reported since. In Korea, a complete form of trisomy 9 syndrome was first reported in 1998 by Chun and others, but trisomy 9 mosaicism has not been reported yet. We recently experienced a case with a patient who was most likely suspected as diet therapy requiring Smith-Lemli-Opitz Syndrome(SLO), since the patient had unilateral ptosis, hypospadias, micrognathia, simian crease, and low set ears, which are the characteristics not yet reported as trisomy 9 mosaicism, but most similar to Smith-Lemli-Opitz syndrome. Also, the patient did not show the typical characteristics of trisomy 9 mosaicism such as broad nose or enophthalmosis. However, further evaluation was taken in order to make the correct diagnosis, and the serum cholesterol level of the patient was shown to be normal, which implied normal cholesterol metabolism, but the chromosomal studies of the patient confirmed the karyotype of 47,XY,+9/46,XY, which proved that the patient has trisomy 9 mosaicism.
Cholesterol ; Diagnosis ; Diet Therapy ; Ear ; Female ; Fetal Growth Retardation ; Heart Defects, Congenital ; Humans ; Hypospadias ; Intellectual Disability ; Karyotype ; Korea ; Male ; Metabolism ; Microcephaly ; Mosaicism* ; Mouth ; Nose ; Smith-Lemli-Opitz Syndrome* ; Trisomy*

Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive malformation syndrome caused by a defect in cholesterol biosynthesis. The incidence is very low in Asians and only one case has been reported in Korea thus far. Recently, we found an infant with neonatal cholestasis. He had microcephaly, ambiguous genitalia, cleft palate, syndactyly of toes, patent ductus arteriosus and hypertrophic pyloric stenosis. The serum cholesterol was decreased and serum 7-dehydrocholesterol was markedly elevated. Genetic analysis of the DHCR7 gene identified a novel missense mutation (Pro227Ser) as well as a known mutation (Gly303Arg) previously identified in a Japanese patient with SLOS. Although rare in Korea, SLOS should be considered in the differential diagnosis of neonatal cholestasis, especially in patients with multiple congenital anomalies and low serum cholesterol levels.
Amino Acid Substitution ; Base Sequence ; Cholestasis/*diagnosis ; Ductus Arteriosus, Patent/diagnosis ; Electroencephalography ; Humans ; Infant, Newborn ; Liver/pathology/ultrasonography ; Male ; *Mutation, Missense ; Oxidoreductases Acting on CH-CH Group Donors/*genetics ; Phenotype ; Smith-Lemli-Opitz Syndrome/diagnosis/*genetics

Smith-Lemli-Opitz syndrome (SLOS) is a rare, autosomal recessive disease caused by an inborn error in cholesterol synthesis. Patients with this disease suffer from multiple malformations due to reduced activity of 7-dehydrocholesterol reductase (DHCR7), which increases 7-dehydrocholesterol (7DHC) and 8-dehydrocholesterol (8DHC) concentrations and decreases cholesterol concentration in body fluids and tissue. The SLOS phenotypic spectrum ranges from a mild disorder with behavioral and learning problems to a lethal disease characterized by multiple malformations. Here, we describe a newborn male with ambiguous genitalia who was diagnosed to have type II SLOS during the neonatal period. A clinical examination revealed low levels of unconjugated estriol in the maternal serum, and a variety of fetal ultrasound anomalies, including prenatal growth retardation. After birth, the infant was diagnosed to have congenital heart disease (Tetralogy of Fallot with severe pulmonary artery stenosis), cleft lip and palate, micrognathia, postaxial polydactyly, ambiguous genitalia, and cataracts. Clinical investigation revealed extremely low plasma cholesterol levels and the presence of mutation (homozygote of p.Arg352Gln) in the DHCR7 gene. The patient underwent palliative heart surgery (to widen the pulmonary artery) and received intravenous lipid supplementation. Cholesterol levels increased slightly, but not to normal values. The patient died from cardiopulmonary failure and sepsis 72 days after birth. This report provides the first description of a Korean patient with SLOS confirmed by verification of DHCR7 gene mutation and illustrates the need for early recognition and appropriate diagnosis of this disease.
Body Fluids ; Cataract ; Cholestadienols ; Cholesterol ; Cleft Lip ; Dehydrocholesterols ; Disorders of Sex Development ; Estriol ; Heart Diseases ; Humans ; Infant ; Infant, Newborn ; Learning ; Male ; Oxidoreductases ; Oxidoreductases Acting on CH-CH Group Donors ; Palate ; Parturition ; Plasma ; Polydactyly ; Pulmonary Artery ; Reference Values ; Sepsis ; Smith-Lemli-Opitz Syndrome ; Thoracic Surgery