Clinical characteristics.

Lathosterolosis is characterized by global developmental delays, intellectual disability, microcephaly, characteristic facial features (bitemporal narrowing, sloping forehead, epicanthal folds, ptosis, downslanting palpebral fissures, anteverted nares, broad nasal tip, long philtrum, high-arched palate, and micrognathia), cataracts, digit anomalies (postaxial polydactyly, toe syndactyly), and liver disease. The severity of liver disease can range from asymptomatic elevation of liver enzymes to cirrhosis and liver failure.

Diagnosis/testing.

The diagnosis of lathosterolosis is established in a proband by identification of elevated lathosterol on plasma sterol analysis and/or biallelic pathogenic variants in SC5D by molecular genetic testing.

Management.

Treatment of manifestations: Potential targeted therapies include simvastatin (the safety and/or efficacy of simvastatin has not been proven in lathosterolosis) and liver transplantation. Supportive care includes developmental and educational support; treatment of cataracts per ophthalmologist; treatment of digit anomalies per orthopedist; management of liver disease per hepatologist; treatment of genitourinary anomalies per nephrologist and/or urologist; social work support and care coordination as needed.

Surveillance: Assess developmental milestones at each visit throughout childhood; neuropsychological testing and quality of life assessments as needed; annual ophthalmology evaluation; liver enzymes at each visit; liver imaging including ultrasound and FibroScan^® every six months or per hepatologist; plasma sterol profile before initiating simvastatin and every one to two months while on therapy.

Agents/circumstances to avoid: Medications and chemicals that are hepatotoxic.

Evaluation of relatives at risk: It is appropriate to clarify the status of at-risk relatives of an affected individual to identify as early as possible those who would benefit from initiation of potential treatment, surveillance, and awareness of agents and circumstances to avoid.

Genetic counseling.

Lathosterolosis is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an SC5D pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the SC5D pathogenic variants have been identified in an affected family member, molecular genetic carrier testing for relatives at risk, prenatal testing, and preimplantation genetic testing are possible.

Suggestive Findings

Lathosterolosis should be suspected in individuals with the following clinical, laboratory, imaging, and family history findings.

Clinical findings

• Global developmental delays
• Intellectual disability
• Microcephaly
• Characteristic facial features, including bitemporal narrowing, sloping forehead, epicanthal folds, ptosis, downslanting palpebral fissures, anteverted nares, broad nasal tip, long philtrum, high-arched palate, and micrognathia (similar to individuals with Smith-Lemli-Opitz syndrome)
• Cataracts
• Digit anomalies (postaxial polydactyly, toe syndactyly)
• Liver disease

Laboratory findings

• Elevated liver enzymes (alanine aminotransferase, alkaline phosphatase, and gamma-glutamyl transferase)
• Elevated lathosterol level on plasma sterol analysis

Imaging findings. Liver fibrosis detected by liver FibroScan^®

Family history is consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Absence of a known family history does not preclude the diagnosis.

Establishing the Diagnosis

The diagnosis of lathosterolosis is established in a proband with suggestive findings by identification of elevated lathosterol on plasma sterol analysis and/or biallelic pathogenic (or likely pathogenic) variants in SC5D on molecular genetic testing (see Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include any likely pathogenic variants. (2) Identification of biallelic SC5D variants of uncertain significance (or of one known SC5D pathogenic variant and one SC5D variant of uncertain significance) does not establish or rule out the diagnosis.

Molecular genetic testing approaches can include gene-targeted testing (single-gene testing, multigene panel) or comprehensive genomic testing (exome sequencing, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those with a phenotype indistinguishable from many other inherited disorders with congenital malformations, developmental delay, and liver disease are more likely to be diagnosed using genomic testing (see Option 2).

Clinical Description

Lathosterolosis is an ultra-rare disorder of cholesterol biosynthesis. To date, seven affected individuals have been reported [Brunetti-Pierri et al 2002, Krakowiak et al 2003, Rossi et al 2007, Ho et al 2014, Anderson et al 2019, Prasun et al 2019, Yaplito-Lee et al 2020]. Hence, the full phenotypic spectrum is unknown at present. However, developmental delay, intellectual disability, microcephaly, facial dysmorphisms, cataracts, digit anomalies, and liver involvement appear to be consistent features of this condition (see Table 2). The following description of the phenotypic features associated with this condition is based on the published case reports.

Neurologic features. Hypotonia has been described in all individuals with lathosterolosis except one who had a milder phenotype [Yaplito-Lee et al 2020]. All individuals had global developmental delays. The severity of developmental delays / intellectual disability is most often moderate to severe. However, in one individual developmental delay was reported to be mild and accompanied by features of autism spectrum disorder [Anderson et al 2019]. Microcephaly has been reported in all affected individuals. Microcephaly appears to be prenatal in onset and progressive in nature.

Dysmorphic facial features. The most common facial features described in individuals with lathosterolosis are bitemporal narrowing, sloping forehead, epicanthal folds, ptosis, downslanting palpebral fissures, anteverted nares, broad nasal tip, long philtrum, high-arched palate, and micrognathia. Facial features are similar to individuals with Smith-Lemli-Optiz syndrome. Facial features may be subtle in individuals with a milder phenotype [Anderson et al 2019, Yaplito-Lee et al 2020]. The craniofacial phenotype may evolve over time [Rossi et al 2007].

Ocular manifestations. Cataracts have been reported in all individuals to date. They are often bilateral. They may be present at birth, but they usually appear in early childhood and progress with age [Parnes et al 1990, Cavallini et al 2009]. Cataracts are usually described as posterior and subcapsular. In one individual, cataracts were present as small dot opacities without vision impairment [Ho et al 2014]. In another individual, corneal clouding was reported [Parnes et al 1990].

Digit anomalies. Postaxial polydactyly and 2-3 toe syndactyly are the most common digit anomalies. Interdigital polydactyly and 2-4 toe syndactyly were reported in one individual [Rossi et al 2007]. Clinodactyly was the only observed digit anomaly in another individual reported to have a milder phenotype [Anderson et al 2019].

Liver disease is common in individuals with lathosterolosis. The severity is variable and ranges from asymptomatic elevation of liver enzymes to cirrhosis and liver failure [Prasun et al 2019]. Liver enzymes, including alanine aminotransferase (ALT), alkaline phosphatase (ALP), and gamma-glutamyl transferase (GGT), may be elevated. However, two individuals had normal liver enzymes. In these individuals, liver involvement was very subtle, manifesting as increased liver echogenicity on MRI suggestive of fibrosis in one individual [Ho et al 2014] and elevated prothrombin time in the second individual [Anderson et al 2019].

Intrahepatic cholestasis caused by abnormal bile acids lead to hepatocellular and biliary damage and subsequent progression to fibrosis, cirrhosis, portal hypertension, and liver failure. There are no characteristic biopsy findings; intrahepatic cholestasis, portal and lobular hepatitis, and portal, focal, and bridging fibrosis have been described [Rossi et al 2005, Prasun et al 2019].

Genitourinary anomalies. Horseshoe kidney was reported in two individuals [Brunetti-Pierri et al 2002, Yaplito-Lee et al 2020]. Penoscrotal hypospadias was present in one individual [Parnes et al 1990].

Hematologic findings. Macroplatelets, acanthocytosis, schistocytosis, and vacuolated monocytes have been reported on peripheral blood smear examination [Rossi et al 2007, Yaplito-Lee et al 2020].

Rarely, features of a storage disorder may be present. One individual with lathosterolosis was described with poor weight gain, global developmental delay, progressive hepatosplenomegaly, corneal clouding, gingival hypertrophy, and death at 18 weeks of life. Autopsy showed widespread storage of mucopolysaccharides [Parnes et al 1990]. In addition, lamellar bodies suggestive of intracellular storage defect have been described in the cultured skin fibroblasts of two individuals [Rossi et al 2007, Herman & Kratz 2012].

Other. The following have each been identified in a single affected individual [Parnes et al 1990, Brunetti-Pierri et al 2002, Krakowiak et al 2003, Rossi et al 2007, Ho et al 2014, Prasun et al 2019, Yaplito-Lee et al 2020]:

• Chiari malformation
• Hydrocephalus ex vacuo
• Cerebral calcifications
• Lumbosacral meningocele
• Butterfly vertebra
• Bilobed gallbladder
• Severe food aversion leading to growth failure
• Single umbilical artery

Prognosis. Life span in lathosterolosis is related to the severity of liver involvement; individuals with mild liver disease or lacking liver disease completely may or may not have reduced life span. The individuals with milder liver involvement were reported to be alive in the early second decade of life [Anderson et al 2019, Yaplito-Lee et al 2020]. Thus, in the absence of severe liver involvement, survival into adulthood is possible. Since many adults with disabilities have not undergone comprehensive genomic testing, it is likely that adults with this condition are underrecognized and underreported.

Genotype-Phenotype Correlations

No genotype-phenotype correlations have been identified.

Prevalence

Lathosterolosis is extremely rare; only seven individuals have been reported thus far. However, it is possible that individuals with milder manifestations have not been identified.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with lathosterolosis, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

There is no proven effective treatment or cure for lathosterolosis.

Potential targeted therapies

• Simvastatin inhibits the enzyme hydroxy methylglutaryl-coenzyme A (HMG-CoA) reductase, which converts HMG-CoA to mevalonate, an early and rate-limiting step in cholesterol biosynthesis. It has been used to treat at least three individuals with lathosterolosis [Ho et al 2014, Prasun et al 2019, Yaplito-Lee et al 2020]. A marked reduction in plasma lathosterol level was seen in all three individuals. In addition, reduction in plasma liver enzyme levels and reduced liver fibrosis was noted in one individual [Yaplito-Lee et al 2020], while in another, improvement in development was attributed to simvastatin [Ho et al 2014]. A dose of 0.2 mg/kg/day to 1 mg/kg/day was recommended. Safety and efficacy of simvastatin in individuals with lathosterolosis in large controlled clinical trials has not been established.
• Liver transplantation. One individual with lathosterolosis underwent liver transplantation at age seven years due to end-stage liver disease, which resulted in complete normalization of plasma lathosterol level and liver function tests. In addition, it led to arrest of cognitive decline [Calvo et al 2014]. A second individual with liver cirrhosis and liver failure underwent liver transplant at age 13 years, leading to normalization of liver function tests and plasma lathosterol level. Her aggressive behavior, quality of life, and need for hospitalization during intercurrent illnesses have significantly improved. However, the follow-up duration is too short to determine neurologic outcome in this individual [P Prasun, personal observation].

Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Table 5).

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 6 are recommended.

Agents/Circumstances to Avoid

Avoid medications and chemicals that are hepatotoxic.

Evaluation of Relatives at Risk

It is appropriate to clarify the status of at-risk relatives of an affected individual to identify as early as possible those who would benefit from initiation of potential treatment, surveillance, and awareness of agents and circumstances to avoid. Evaluations can include:

• Molecular genetic testing if the pathogenic variants in the family are known;
• Plasma comprehensive sterol profile if the pathogenic variants in the family are not known.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

Lathosterolosis is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

• The parents of an affected child are presumed to be heterozygous for an SC5D pathogenic variant.
• If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an SC5D pathogenic variant and to allow reliable recurrence risk assessment.
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017]. If the proband appears to have homozygous pathogenic variants (i.e., the same two pathogenic variants), additional possibilities to consider include:
  • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity.
  • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

• If both parents are known to be heterozygous for an SC5D pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband. To date, individuals with lathosterolosis are not known to reproduce.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of an SC5D pathogenic variant.

Carrier Detection

Molecular genetic carrier testing for at-risk relatives requires prior identification of the SC5D pathogenic variants in the family.

Note: The utility of plasma lathosterol level for carrier detection is unknown but is unlikely to be a sensitive or specific test.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers.

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see Huang et al [2022].

Prenatal Testing and Preimplantation Genetic Testing

Molecular genetic testing, Once the SC5D pathogenic variants have been identified in an affected family member, molecular genetic prenatal and preimplantation genetic testing are possible.

Note: The utility of amniotic fluid sterol profile in prenatal diagnosis is unknown. Lathosterol may be normally abundant in the amniotic fluid [Chevy et al 2005].

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

Lathosterolosis is a disorder of cholesterol biosynthesis. It is due to deficiency of the enzyme lathosterol oxidase (sterol-C5-desaturase), encoded by SC5D, which catalyzes conversion of lathosterol to 7-dehydrocholesterol, the second-to-last step in cholesterol biosynthesis. The molecular pathogenesis is unknown but considered to be either mediated by accumulation of lathosterol and/or decreased cholesterol [Cooper et al 2003]. An abnormal sterol profile may lead to a bile acid synthesis defect, causing cholestasis, and abnormal hedgehog signaling, leading to limb defects.

Mechanism of disease causation. Loss of function

Author Notes

Dr Pankaj Prasun is actively involved in clinical research regarding individuals with lathosterolosis and would be happy to communicate with persons who have any questions regarding diagnosis of lathosterolosis or other considerations.

Revision History

• 7 December 2023 (sw) Review posted live
• 12 January 2023 (pp) Original submission

Literature Cited

• Anderson R, Rust S, Ashworth J, Clayton-Smith J, Taylor RL, Clayton PT, Morris AAM. Lathosterolosis: a relatively mild case with cataracts and learning difficulties. JIMD Rep. 2019;44:79-84. [PMC free article: PMC6323057] [PubMed: 30097991]
• Besnard T, Sloboda N, Goldenberg A, Küry S, Cogné B, Breheret F, Trochu E, Conrad S, Vincent M, Deb W, Balguerie X, Barbarot S, Baujat G, Ben-Omran T, Bursztejn AC, Carmignac V, Datta AN, Delignières A, Faivre L, Gardie B, Guéant JL, Kuentz P, Lenglet M, Nassogne MC, Ramaekers V, Schnur RE, Si Y, Torti E, Thevenon J, Vabres P, Van Maldergem L, Wand D, Wiedemann A, Cariou B, Redon R, Lamazière A, Bézieau S, Feillet F, Isidor B. Biallelic pathogenic variants in the lanosterol synthase gene LSS involved in the cholesterol biosynthesis cause alopecia with intellectual disability, a rare recessive neuroectodermal syndrome. Genet Med. 2019;21:2025-2035. [PubMed: 30723320]
• Brunetti-Pierri N, Corso G, Rossi M, Ferrari P, Balli F, Rivasi F, Annunziata I, Ballabio A, Russo AD, Andria G, Parenti G. Lathosterolosis, a novel multiple-malformation/mental retardation syndrome due to deficiency of 3beta-hydroxysteroid-delta5-desaturase. Am J Hum Genet. 2002;71:952-8. [PMC free article: PMC378549] [PubMed: 12189593]
• Calvo PL, Brunati A, Spada M, Romagnoli R, Corso G, Parenti G, Rossi M, Baldi M, Carbonaro G, David E, Pucci A, Amoroso A, Salizzoni M. Liver transplantation in defects of cholesterol biosynthesis: the case of lathosterolosis. Am J Transplant. 2014;14:960-5. [PubMed: 24621408]
• Cavallini GM, Masini C, Chiesi C, Campi L, Rivasi F, Ferrari P. Cataract development in a young patient with lathosterolosis: a clinicopathologic case report. Eur J Ophthalmol. 2009;19:139-42. [PubMed: 19123163]
• Chevy F, Humbert L, Wolf C. Sterol profiling of amniotic fluid: a routine method for the detection of distal cholesterol synthesis deficit. Prenat Diagn. 2005;25:1000-6. [PubMed: 16231320]
• Cooper MK, Wassif CA, Krakowiak PA, Taipale J, Gong R, Kelley RI, Porter FD, Beachy PA. A defective response to Hedgehog signaling in disorders of cholesterol biosynthesis. Nat Genet. 2003;33:508-13. [PubMed: 12652302]
• Herman GE, Kratz L. Disorders of sterol synthesis: beyond Smith-Lemli-Opitz syndrome. Am J Med Genet C Semin Med Genet. 2012;160C:301-21. [PubMed: 23042573]
• Ho AC, Fung CW, Siu TS, Ma OC, Lam CW, Tam S, Wong VC. Lathosterolosis: a disorder of cholesterol biosynthesis resembling Smith-Lemli-Opitz syndrome. JIMD Rep. 2014;12:129-34. [PMC free article: PMC3897790] [PubMed: 24142275]
• Huang SJ, Amendola LM, Sternen DL. Variation among DNA banking consent forms: points for clinicians to bank on. J Community Genet. 2022;13:389-97. [PMC free article: PMC9314484] [PubMed: 35834113]
• Jónsson H, Sulem P, Kehr B, Kristmundsdottir S, Zink F, Hjartarson E, Hardarson MT, Hjorleifsson KE, Eggertsson HP, Gudjonsson SA, Ward LD, Arnadottir GA, Helgason EA, Helgason H, Gylfason A, Jonasdottir A, Jonasdottir A, Rafnar T, Frigge M, Stacey SN, Th Magnusson O, Thorsteinsdottir U, Masson G, Kong A, Halldorsson BV, Helgason A, Gudbjartsson DF, Stefansson K. Parental influence on human germline de novo mutations in 1,548 trios from Iceland. Nature. 2017;549:519-22. [PubMed: 28959963]
• Krakowiak PA, Wassif CA, Kratz L, Cozma D, Kovárová M, Harris G, Grinberg A, Yang Y, Hunter AG, Tsokos M, Kelley RI, Porter FD. Lathosterolosis: an inborn error of human and murine cholesterol synthesis due to lathosterol 5-desaturase deficiency. Hum Mol Genet. 2003;12:1631-41. [PubMed: 12812989]
• Parnes S, Hunter AG, Jimenez C, Carpenter BF, 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. 1990;35:397-405. [PubMed: 2309789]
• Platt FM, Wassif C, Colaco A, Dardis A, Lloyd-Evans E, Bembi B, Porter FD. Disorders of cholesterol metabolism and their unanticipated convergent mechanisms of disease. Annu Rev Genomics Hum Genet. 2014;15:173-94. [PMC free article: PMC6292211] [PubMed: 25184529]
• Prasun P, Ferguson E, Iverson A, Cork E, Dolinger M, Ward SC, Arnon R. Lathosterolosis: an extremely rare inherited condition associated with progressive liver disease. J Pediatr Gastroenterol Nutr. 2019;69:e142-5. [PubMed: 31259789]
• Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405-24. [PMC free article: PMC4544753] [PubMed: 25741868]
• Romano MT, Tafazzoli A, Mattern M, Sivalingam S, Wolf S, Rupp A, Thiele H, Altmüller J, Nürnberg P, Ellwanger J, Gambon R, Baumer A, Kohlschmidt N, Metze D, Holdenrieder S, Paus R, Lütjohann D, Frank J, Geyer M, Bertolini M, Kokordelis P, Betz RC. Bi-allelic mutations in LSS, encoding lanosterol synthase, cause autosomal-recessive hypotrichosis simplex. Am J Hum Genet. 2018;103:777-85. [PMC free article: PMC6218848] [PubMed: 30401459]
• Rossi M, D'Armiento M, Parisi I, Ferrari P, Hall CM, Cervasio M, Rivasi F, Balli F, Vecchione R, Corso G, Andria G, Parenti G. Clinical phenotype of lathosterolosis. Am J Med Genet A. 2007;143A:2371-81. [PubMed: 17853487]
• Rossi M, Vajro P, Iorio R, Battagliese A, Brunetti-Pierri N, Corso G, Di Rocco M, Ferrari P, Rivasi F, Vecchione R, Andria G, Parenti G. Characterization of liver involvement in defects of cholesterol biosynthesis: long-term follow-up and review. Am J Med Genet A. 2005;132A:144-51. [PubMed: 15580635]
• Ryan AK, Bartlett K, Clayton P, Eaton S, Mills L, Donnai D, Winter RM, Burn J. Smith-Lemli-Opitz syndrome: a variable clinical and biochemical phenotype. J Med Genet. 1998;35:558-65. [PMC free article: PMC1051366] [PubMed: 9678700]
• Stenson PD, Mort M, Ball EV, Chapman M, Evans K, Azevedo L, Hayden M, Heywood S, Millar DS, Phillips AD, Cooper DN. The Human Gene Mutation Database (HGMD®): optimizing its use in a clinical diagnostic or research setting. Hum Genet. 2020;139:1197-207. [PMC free article: PMC7497289] [PubMed: 32596782]
• Yaplito-Lee J, Pai G, Hardikar W, Hong KM, Pitt J, Marum J, Amor DJ. Successful treatment of lathosterolosis: a rare defect in cholesterol biosynthesis-A case report and review of literature. JIMD Rep. 2020;56:14-9. [PMC free article: PMC7653246] [PubMed: 33204591]