Alternative titles; symbols
SNOMEDCT: 719257008; ORPHA: 46059;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 11q23.3-q24.1 | Lathosterolosis | 607330 | Autosomal recessive | 3 | SC5D | 602286 |
A number sign (#) is used with this entry because of evidence that lathosterolosis (LATHOS) is caused by homozygous or compound heterozygous mutation in the SC5D gene (602286), which encodes sterol C5-desaturase, on chromosome 11q23-q24.
Lathosterolosis (LATHOS) is an autosomal recessive disorder characterized by a recognizable pattern of multiple congenital anomalies involving axial and appendicular skeleton, liver, central nervous and urogenital systems, and lysosomal storage. It is caused by a defect of cholesterol biosynthesis due to sterol C5-desaturase deficiency (summary by Rossi et al., 2007).
Brunetti-Pierri et al. (2002) reported the clinical, biochemical, and molecular characterization of a patient with a previously undescribed defect of cholesterol biosynthesis. The female patient presented with a complex phenotype, including multiple congenital anomalies, mental retardation, and liver disease. Physical examination at birth revealed dysmorphic features, including severe microcephaly, receding forehead, anteverted nares, micrognathia, prominent upper lip, highly arched palate, postaxial hexadactyly of the left foot, and syndactyly between the second to fourth toes and between the fifth toe and the extra digit. External genitalia were normal. Severe psychomotor delay became increasingly evident with age. The clinical features somewhat resembled those of Smith-Lemli-Opitz syndrome (270400), which is caused by a defect in cholesterol biosynthesis.
Rossi et al. (2007) provided follow-up on the patient reported by Brunetti-Pierri et al. (2002) and described her affected sib. The sib was a fetus aborted at 22 weeks' gestation following a routine ultrasound that revealed multiple malformations. Postmortem findings included type II Arnold-Chiari malformation, microcephaly, postaxial polydactyly (hands and feet), bilateral clubfeet, and lumbosacral meningocele. A diagnosis of lathosterolosis was suspected on the basis of the pattern of limb and craniofacial anomalies. Molecular analysis in DNA samples obtained from stored pathologic specimens of the SC5D gene revealed the same mutations identified in her living sister (602286.0001-602286.0002), confirming the diagnosis. The sister had developed bilateral lens opacities at age 6, which subsequently evolved to a total cataract of the right eye, requiring surgery. She had severe cholestasis with liver fibrosis and persistently elevated serum levels of transaminases, gamma-glutamyltransferase, alkaline phosphatase, total and direct bilirubin, and ammonia. Portal hypertension was noted on abdominal Doppler ultrasound at 7 years of age. The girl had experienced 2 pathologic fractures, and DEXA scan at 7.5 years revealed severe generalized osteoporosis. Blood smears revealed anisopoikilocytosis, acanthocytes, schistocytes, large platelets, and vacuolated monocytes. Electron microscopy of cultured fibroblasts showed concentric lamellar inclusion bodies, similar to lysosomal vacuoles visible in fibroblasts from patients with Niemann-Pick type C disease (257220).
Parnes et al. (1990) described a patient who was hypotonic at birth with height, weight, and head circumference below the 3rd percentile. He had ptosis, microcorneae, and bilateral cataracts. He also had hypospadias, bilateral 2-3 toe syndactyly, and bilateral hexadactyly of his feet. At 2 months of age, he developed myoclonus and pathologic hyperreflexia. He developed progressive hepatosplenomegaly, corneal clouding, and gingival hypertrophy. He died of respiratory failure at 18 weeks of age. Liver biopsy studies showed focal vacuolated hepatocytes, swollen and vacuolated Kupffer cells, and foamy granular histiocytes. Krakowiak et al. (2003) reported further on this patient and determined by molecular analysis that he had lathosterolosis.
Ho et al. (2014) described a child with lathosterolosis who had central myotonia, microcephaly, and dysmorphic features, including bitemporal narrowing, a broad nasal tip, micrognathia, bilateral postaxial hexadactyly of his feet, and bilateral 2-3 toe syndactyly. Brain MRI at age 18 months was normal. He had global developmental delay without developmental regression. Abdominal MRI revealed mild hyperintensities in the right anterior lobe. Bilateral dot cataracts were detected at age 4 years. Plasma sterol analysis showed elevated lathosterol and its precursor, 8,9-cholestenol. Patient fibroblasts grown on lipid-depleted medium showed elevated concentrations of lathosterol and its precursor, 8,9-cholestenol. Fibroblast staining for filipin showed a 'variant' cholesterol storage pattern, and perinuclear cholesterol content was moderately elevated. He was treated with simvastatin which correlated to a reduction in his plasma lathosterol levels.
Anderson et al. (2019) described a boy who was diagnosed with lathosterolosis at age 10 years. He had microcephaly and dysmorphic features, including a high palate, mild ptosis, anteverted nares, a long philtrum, and clinodactyly of both feet. Bilateral cataracts were detected at age 5 years. He had autistic features and developmental delay, with a total IQ of 64 at age 11. The patient's plasma lathosterol and 8,9,-cholestenol were elevated.
Plasma and cells of the patient with lathosterolosis reported by Brunetti-Pierri et al. (2002) showed increased levels of lathosterol. Biosynthesis of cholesterol in the patient's fibroblasts was defective, showing a block in the conversion of lathosterol into 7-dehydrocholesterol. Activity of 3-beta-hydroxysteroid-delta-5-desaturase (SC5D), the enzyme involved in this reaction, was deficient in the patient's fibroblasts.
Herman (2003) reviewed the cholesterol biosynthetic pathway and 6 disorders involving enzyme defects in post-squalene cholesterol biosynthesis: Smith-Lemli-Opitz syndrome, desmosterolosis (602398), X-linked dominant chondrodysplasia punctata (CDPX2; 302960), CHILD syndrome (308050), lathosterolosis, and hydrops-ectopic calcification-moth-eaten skeletal dysplasia (HEM; 215140).
The transmission pattern of LATHOS in the family reported by Brunetti-Pierri et al. (2002) was consistent with autosomal recessive inheritance.
In a female patient with lathosterolosis, Brunetti-Pierri et al. (2002) identified compound heterozygosity for missense mutations in the SC5D gene (R29Q, 602286.0001; G211D, 602286.0002). Rossi et al. (2007) reported that an aborted female fetus sib with multiple malformations found on routine ultrasound was also compound heterozygous for the mutations. Each parent was heterozygous for one of the mutations and an unaffected brother was heterozygous for the R29Q mutation.
In an male infant with lathosterolosis, originally reported by Parnes et al. (1990), Krakowiak et al. (2003) identified a homozygous missense mutation in the SC5D gene (Y46S; 602286.0003). The parents were heterozygous for the mutation.
In a child with lathosterolosis, Ho et al. (2014) identified compound heterozygosity for 2 missense mutations in the SC5D gene (D210E, 602286.0004 and K148E, 602286.0005). Each parent was heterozygous for one of the mutations.
In a 10-year-old boy with lathosterolosis, Anderson et al. (2019) identified compound heterozygous mutations in the SC5D gene: the previously identified D210E mutation and a novel missense mutation (P160R; 602286.0006) Each parent was heterozygous for one of the mutations. The mutations were identified by next-generation sequencing of a panel of genes associated with congenital or childhood cataracts.
Krakowiak et al. (2003) disrupted the mouse lathosterol 5-desaturase gene (Sc5d). Sc5d -/- pups were stillborn, had elevated lathosterol and decreased cholesterol levels, craniofacial defects including cleft palate and micrognathia, and limb patterning defects. Many of the malformations found in Sc5d -/- mice were consistent with impaired hedgehog signaling and appeared to be a result of decreased cholesterol rather than increased lathosterol.
Anderson, R., Rust, S., Ashworth, J., Clayton-Smith, J., Taylor, R. L., Clayton, P. T., Morris, A. A. M. Lathosterolosis: a relatively mild case with cataracts and learning difficulties. JIMD Rep. 44: 79-84, 2019. [PubMed: 30097991] [Full Text: https://doi.org/10.1007/8904_2018_127]
Brunetti-Pierri, N., Corso, G., Rossi, M., Ferrari, P., Balli, F., Rivasi, F., Annunziata, I., Ballabio, A., Russo, A. D., Andria, G., Parenti, G. Lathosterolosis, a novel multiple-malformation/mental retardation syndrome due to deficiency of 3-beta-hydroxysteroid-delta(5)-desaturase. Am. J. Hum. Genet. 71: 952-958, 2002. Note: Erratum: Am. J. Hum. Genet. 73: 445 only, 2003. [PubMed: 12189593] [Full Text: https://doi.org/10.1086/342668]
Herman, G. E. Disorders of cholesterol biosynthesis: prototypic metabolic malformation syndromes. Hum. Molec. Genet. 12(R1): R75-R88, 2003. [PubMed: 12668600] [Full Text: https://doi.org/10.1093/hmg/ddg072]
Ho, A. C. C., Fung, C. W., Siu, T. S., Ma, O. C. K., Lam, C. W., Tam, S., Wong, V. C. N. Lathosterolosis: a disorder of cholesterol biosynthesis resembling Smith-Lemli-Opitz syndrome. JIMD Rep. 12: 129-134, 2014. [PubMed: 24142275] [Full Text: https://doi.org/10.1007/8904_2013_255]
Krakowiak, P. A., Wassif, C. A., Kratz, L., Cozma, D., Kovarova, M., Harris, G., Grinberg, A., Yang, Y., Hunter, A. G. W., Tsokos, M., Kelley, R. I., Porter, F. D. Lathosterolosis: an inborn error of human and murine cholesterol synthesis due to lathosterol 5-desaturase deficiency. Hum. Molec. Genet. 12: 1631-1641, 2003. [PubMed: 12812989] [Full Text: https://doi.org/10.1093/hmg/ddg172]
Parnes, S., Hunter, A. G., Jimenez, C., Carpenter, B. F., MacDonald, I. Apparent Smith-Lemli-Opitz syndrome in a child with a previously undescribed form of mucolipidosis not involving the neurons. Am. J. Med. Genet. 35: 397-405, 1990. [PubMed: 2309789] [Full Text: https://doi.org/10.1002/ajmg.1320350317]
Rossi, M., D'Armiento, M., Parisi, I., Ferrari, P., Hall, C. M., Cervasio, M., Rivasi, F., Balli, F., Vecchione, R., Corso, G., Andria, G., Parenti, G. Clinical phenotype of lathosterolosis. Am. J. Med. Genet. 143A: 2371-2381, 2007. [PubMed: 17853487] [Full Text: https://doi.org/10.1002/ajmg.a.31929]