Overview: What every practitioner needs to know

Are you sure your patient has a disorder of sterol synthesis? What are the typical findings for this disease?

Smith-Lemli-Opitz syndrome

Because patients with SLOS can present with a range of clinical severity—from almost normal children with mild developmental delays to intrauterine lethality from multiple organ malformations—a high index of suspicion is crucial for diagnosis. The diagnostic biochemical abnormality will not be revealed on routine laboratory testing. If considered, the diagnosis can be easily confirmed by demonstrating increased levels of 7- and 8-dehydrocholesterol in plasma or tissues.

Smith-Lemli-Opitz syndrome (SLOS), the most common inborn error of the cholesterol biosynthetic pathway and is a highly variable, multiple-congenital-anomaly syndrome with an autosomal recessive inheritance pattern. The underlying metabolic defect is deficient activity of the enzyme 7-dehydrocholesterol reductase, which converts 7-dehydrocholesterol in to cholesterol. Recognition and definitive diagnosis of SLOS is important for disease management and family counseling.

Mevalonate kinase deficiency and hyperimmunoglobulin D syndrome

Mevalonate kinase (MVK) deficiency is a defect in the first committed step of the isoprenoid-sterol pathway, which is responsible for the biosynthesis of many essential compounds, including dolichols, coenzyme Q10, vitamin D, cholesterol, and a variety of isoprenoid and sterol intermediates with hormone-like activities. A severe deficiency of MVK causes classicmevalonic aciduria (MVA), whereas mutations leaving 3% to 6% residual MVK activity cause the hyperimmunoglobinemia D autoinflammatory syndrome (HIDS).

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Classic HIDS is characterized by episodic inflammatory crises lasting 4-7 days and recurring every 3-6 weeks. The periodic crises are characterized by abdominal pain, nausea, vomiting, diarrhea, hepatosplenomegaly, lymphadenopathy, joint pain, and morbilliform rashes. In addition to recurrent autoinflammatory crises similar to those of HIDS, patients with MVA typically have facial dysmorphism, moderate to severe intellectual disability, progressive ataxia from cerebellar atrophy, failure to thrive, and, in long-term survivors, progressive retinal dystrophy. The common neonatal presentation of MVA with hepatosplenomegaly and a “blueberry muffin” rash caused by extramedullary hematopoiesis often is mistaken for congenital infection.

The most common clinical features of SLOS follow:

Intellectual disability (95%)

Two-thirds toe syndactyly (97%)

Microcephaly (84%)

Posterior, midline cleft palate

Hypospadias (males)

The most commonly seen clinical features in MVA and HIDS follow:

MVA: cognitive and neurologic deficits and episodic autoinflammatory crises

HIDS: episodic fevers accompanied by vomiting, diarrhea, and diffuse lymphadenopathy

Additional clinical features in Smith-Lemli-Opitz syndrome

Individuals with SLOS have variable malformations in multiple body systems of diverse embryologic origins. Facial dysmorphisms include ptosis, anteverted nares, midline cleft palate, small chin, and bitemporal narrowing. Extremity anomalies can include postaxial polydactyly in the hands or feet, two-thirds Y-shaped toe syndactyly, and hypoplastic proximally placed thumbs.

Cardiovascular anomalies most frequently involve the endocardial cushion and include the atrioventricular canal, atrial septal defect, patent ductus arteriosus, and ventricular septal defect.

Genital anomalies in male patients range from first-degree hypospadias to complete external feminization, and more severely affected females can have hypoplastic labia majora. Renal anomalies are common and include renal hypoplasia and aplasia, ectopia, cortical cysts, and hydronephrosis secondary to ureteral malformations.

Structural brain anomalies include varying degrees of frontal lobe hypoplasia, agenesis or hypoplasia of the corpus callosum, cerebellar hypoplasia, and elements of the holoprosencephaly sequence (5%). Pulmonary hypoplasia and under-lobulation of the lung can be seen in severely affected patients. Gastrointestinal manifestations include feeding difficulties (often secondary to the Pierre-Robin sequence), pyloric stenosis, and varying degrees of intestinal dysmotility, including intestinal aganglionosis (Hirschsprung disease).

Range of severity of Smith-Lemli-Opitz syndrome

There is a wide range of clinical severity in SLOS, ranging from a severe fetal or neonatal lethal form (previously designated SLOS type II) to milder forms characterized by intellectual disability and mild dysmorphisms The severity of clinical findings correlates best with the level of 7-dehydrocholesterol as a fraction of total sterols, but the most severely affected infants who die in the newborn period typically have cholesterol levels less than 10 mg/dL.

What other disease/condition shares some of these symptoms?

Several multiple congenital malformation syndromes can have features of SLOS, including Noonan syndrome, Zellweger syndrome, and Pallister-Hall syndrome, among others. They can be differentiated from SLOS by their lack of two-third toe syndactyly, and normal plasma levels of 7-dehydrocholesterol. In addition, much rarer defects of the cholesterol biosynthetic pathway can have features similar to those of SLOS. Lathosterolosis, a deficiency of lathosterol 5-desaturase reported in only two sibships, has clinical features quite similar to those of SLOS.

More severely affected heterozygote females with X-linked Conradi-Hünermann syndrome (CDPX2) caused by a deficiency of sterol isomerase can have some of the physical features of SLOS (postaxial polydactyly, cleft palate, facial dysmorphism), but there is usually normal intelligence. Both lathosterolosis and CDPX2 can be securely differentiated from SLOS by identification of diagnostically increased levels of the intermediate sterols, lathosterol (lathosterolosis) and 8(9)-cholestenol (CDPX2), in plasma or tissues.

Although recurrent fevers occur in many systemic disorders, such as juvenile rheumatoid arthritis, malignancy, chronic infections, and PFAPA syndrome (periodic fever, aphthous stomatitis, pharyngitis, adenitis), MVA and other genetic causes of periodic fevers, such as familial Mediterranean fever and Hibernian fever, can be distinguished from nongenetic fever syndromes by their distinctive periodicities and symptom complexes.

What caused this disease to develop at this time?

These are genetic diseases inherited in an autosomal recessive manner, with nearly 100% penetrance. HIDS is occasionally manifested biochemically but without fevers. Both parents are asymptomatic carriers of the enzyme deficiency.

Fever episodes in MVA/HIDS are mostly spontaneous, observing predictable periodicities, but additional crises can be triggered by vaccination, injury, emotional stress, or infection.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

SLOS can be diagnosed by quantification of cholesterol intermediates, usually by gas chromatography/mass spectrometry (GC/MS). Individuals with SLOS will have increased levels of 7- and 8-dehydrocholesterol in any blood or tissue source. Because 10%-20% of patients with SLOS will have a normal serum cholesterol level, the diagnosis of SLOS can be excluded or made biochemically only by chromatographic separation and quantification of intermediate sterols in a specialized laboratory.

Of note, low-level false-positive sterol testing for SLOS can be caused by a wide variety of neuroleptic and antidepressant medications.

SLOS can also be diagnosed by molecular analysis of the
DHCR7 gene, although with few exceptions, the characteristic sterol abnormalities alone are sufficient to confirm a suspected diagnosis.

The biochemical signature of MVA and HIDS is an increased urine level of mevalonic acid. Although the 100-50,000–fold increased levels of mevalonic acid in MVA can be detected by routine urine organic acid analysis, the lower, 5-100–fold increased levels of mevalonic acid characteristic of HIDS requires detection by isotope-dilution GC/MS analysis. Most patients with HIDS will also have increased levels of IgD and/or IgA. Diagnosis is confirmed by mutation analysis of the MVK gene.

Would imaging studies be helpful? If so, which ones?

Imaging studies such as echocardiography and renal ultrasonography are useful in defining the extent of visceral abnormalities and critical for anticipatory treatment in SLOS.

If you are able to confirm that the patient has disorders of sterol synthesis, what treatment should be initiated?

Early life in children with SLOS usually is complicated by poor feeding and failure to thrive secondary to oromotor dysfunction and intestinal dysmotility, which is routinely managed with nasogastric or gastrostomy feedings. However, even with proper nutritional intervention, children with SLOS typically are constitutionally small and grow well below the third centile.

Cardiac and renal anomalies should be treated according to standard care.

Dietary cholesterol supplementation is commonly given to children with SLOS. This can be accomplished with high-cholesterol foods such as egg yolks in older infants and children or with pure cholesterol suspensions at any age. SLOS is a disease whose defects are embryologic, and as such, structural deficiencies of the brain are not amenable to treatment. Moreover, cholesterol does not cross the blood-brain barrier, and therefore the brain remains cholesterol depleted despite oral cholesterol supplementation.

Improved behavior and reduced self-injury have been reported in some cases, however, presumably by effects on adrenal steroid synthesis. Cholesterol supplementation has also been found to improve nutrition and growth, decrease infections, improve photosensitivity, and speed wound healing, especially in patients who are more severely affected biochemically.

Cholesterol in the form of LDL cholesterol can be provided with frozen plasma during medical crises when blood cholesterol can be come severely depleted. A dose of 10 mL/kg frozen plasma provides about 50% of the daily cholesterol requirement. Because stress-related, symptomatic mineralocorticoid deficiency has also been reported in children with SLOS and more severe degrees of cholesterol deficiency, stress-dose steroids are often provided for severely affected children with SLOS who are seriously ill or undergoing surgery.

In MVA, treatment is largely supportive, and management of progressive hepatosplenomegaly in some can be challenging. In HIDS, acute treatment with corticosteroids for severe attacks or chronic treatment with inhibitors of tumor necrosis factor-alpha production, such as montelukast and etanercept, can greatly limit the significant morbidity of frequent debilitating febrile attacks. Although a small study showed some benefit of simvastatin treatment in adult patients with HIDS , severe worsening of symptoms was seen when lovastatin was studied in patients with MVA.

What are the possible outcomes of disorders of sterol synthesis?

Outcome in individual cases of SLOS is largely determined by the severity of malformations (i.e., cardiac and renal) and the quality of supportive care. Approximately one quarter of patients with SLOS, will die in the first 2 years, and most of those within the first 2 months. There are no other available estimates of life expectancy in longer surviving children with SLOS, but many clinically stable adults, some in their 50s and 60s, are known.

With some exceptions, intellectual disability is in the moderate to severe range, and independent living is very rare among adults with SLOS. In general, children with SLOS have better receptive than expressive language, are sociable, and can be quite adept mechanically for their degree of intellectual disability. Some children with SLOS meet DSM-IV criteria for autism spectrum disorder and often show reduction in autism scores with cholesterol treatment.

Most patients with classic MVA have a poor outcome or early mortality. Among individuals with the HIDS form of MVK deficiency, the frequency of febrile attacks typically decreases by the adult years, and most lead otherwise normal lives. However, a few adult with HIDS have acquired ataxia secondary to progressive cerebellar atrophy. Renal amyloidosis, which is common in several other autoinflammatory diseases, is rare in HIDS.

What causes this disease and how frequent is it?

SLOS is a panethnic genetic defect in cholesterol synthesis, with an estimated incidence of 1/40,000-1/80,000 births in Western countries.

Carrier rates have been estimated to be 1% in populations of central and northern European origin, but birth incidence is much lower than predicted by the carrier rate because of high prenatal lethality of severely affected embryos. Carrier parents have a 25% chance with each pregnancy of conceiving a child with SLOS, a 50% chance with each pregnancy of having a child who is an asymptomatic carrier, and a 25% chance of having a child who is neither affected nor a carrier.

HIDS and MVA are autosomal recessive diseases caused by deficiencies in MVK, which is responsible for converting mevalonate to mevalonate phosphate. A specific gene mutation,
V377I, having approximately 6% residual activity, in combination with a more severe mutation in the other allele, is the most common genetic cause of HIDS, whereas patients with MVA most often are compound heterozygotes for two severe MVK mutations. MVA is rare, with fewer than 50 patients reported, whereas HIDS appears to be several times more common than MVA, with the highest prevalence of the V377I mutation among those of Central and Northern European heritage.

How do these pathogens/genes/exposures cause the disease?

Deficient levels of cholesterol in embryonic and fetal life are thought to lead to abnormal signaling by sonic hedgehog and other hedgehog proteins. This causes abnormal cell proliferation, migration, and apoptosis in the embryonic period and, when severe, limited growth during the fetal period.

MVK deficiency causes a deficiency of the distal isoprenoid metabolite geranylgeranyl pyrophosphate, which is an important posttranslational regulator of RAS proteins and the evolution of inflammatory cytokines. Hysteresis in the process of protein turnover and/or isoprenylation is presumed to underlie the cyclic nature of the fevers in HIDS.

Other clinical manifestations that might help with diagnosis and management.

Behavioral abnormalities can be major management problems in children with SLOS. These abnormalities include hyperactivity, sleep disturbances, self-injurious behaviors, autism spectrum disorders, and tactile hypersensitivities.

How can disorders of sterol synthesis be prevented?

Because the abnormal sterol chemistry of SLOS reduces fetal production of estriol, SLOS can be detected prenatally by finding an isolated low maternal estriol level by routine second trimester pregnancy screening. Although fetal death and steroid sulfatase deficiency are more common causes of a low maternal estriol level, SLOS should nonetheless be considered.

Definitive prenatal diagnosis in cases of positive pregnancy screening, family history of SLOS, or suspicious ultrasonographic findings is possible by sterol analysis of chorionic villi or amniotic fluid. Prenatal testing can also be carried out on maternal urine after 16 weeks’ gestation by measuring 7-dehydro species of several fetus-derived steroids.

Prenatal diagnosis of MVA can be done by stable isotope dilution GM/MS for mevalonate, by measurement of MVK activity in cultured amniocytes or in chorionic villi, or by mutation analysis of the MVK gene in fetal cell material.

What is the evidence?

Buhaescu, I, Izzedine, H. “Mevalonate pathway: a review of clinical and therapeutical implications”. Clin Biochem. vol. 40. 2007. pp. 575-84.

Haas, D, Hoffman, G. “Mevalonate kinase deficiencies: from mevalonic aciduria to hyperimmunoglobinemia D syndrome”. Orphanet J Rare Dis. vol. 1. 2006. pp. 13

Kelley, R, Hennekam, R. “The Smith Lemli Opitz syndrome”. J Med Genet. vol. 37. 2000. pp. 321-35.

Kelley, R, Herman, G. “Inborn errors of sterol siosynthesis”. Annu Rev Genomics Hum Genet. vol. 2. 2001. pp. 299-341.

Merkens, L, Wassif, C, Healy, K. “Smith-Lemli-Opitz syndrome and inborn errors of cholesterol synthesis: Summary of the 2007 SLOS/RHS Foundation Scientific Conference sponsored by the National Institutes of Health”. Genet Med. vol. 11. 2009. pp. 359-64.

Porter, F. “Human malformation syndromes due to inborn errors of cholesterol synthesis”. Curr Opin Pediatr. vol. 15. 2003. pp. 607-13.

Porter, F. “Smith-Lemli-Opitz syndrome: pathogenesis, diagnosis, and management”. Eur J Hum Genet. vol. 16. 2008. pp. 535-41.

Simon, A, Drewe, E, van der Meer. “Simvastatin treatment for inflammatory attacks of the hyperimmunoglobulinemia D and periodic fever syndrome”. Clin Pharmacol Ther. vol. 75. 2004. pp. 476-83.

Ongoing controversies regarding etiology, diagnosis, treatment

Effects of simvastatin on the reduction of 7-dehydrocholesterol are currently being studied.