Practice Essentials
Sjögren-Larsson syndrome (SLS) is a rare autosomal recessive neurocutaneous disorder characterized by intellectual disability, diplegia or tetraplegia, and congenital ichthyosis. The ichthyosis (usually evident at birth) may be seen in some patients after the first year of life. [1, 2]
Signs and symptoms
Also see Presentation.
Most Sjögren-Larsson syndrome (SLS) patients are born preterm and have erythema at birth. [3] The diagnosis of Sjögren-Larsson syndrome is almost always delayed because only cutaneous symptoms (eg, scaling, hyperkeratosis) are usually present at birth.
A family history of siblings affected by Sjögren-Larsson syndrome or a consanguineous marriage of the parents is sometimes present.
Pruritus is a prominent feature that is not found in other types of ichthyosis.
Photophobia is a common complaint.
The skin gradually becomes thickened and scaly in the first year of life. Desquamation of the palms and the soles is observed in some cases. Later, a wrinkled brownish yellow hyperkeratosis gradually develops, with a predilection on the main flexor folds of the extremities. Ichthyosis is seen at birth and worsens with time.
The key triad of symptoms for Sjögren-Larsson syndrome (SLS) includes nonbullous congenital ichthyosiform erythroderma, spastic diplegia or quadriplegia, and intellectual disability. An additional group of signs comprises other dermatologic symptoms, ophthalmologic signs, speech defects, epilepsy, dental problems, and skeletal abnormalities.
Diagnostics
See Workup for a full discussion.
Sjögren-Larsson syndrome (SLS) is diagnosed by demonstrating the enzyme deficiency or by mutation analysis of the FALDH gene. To date, more than 70 different FALDH gene mutations have been found in patients with Sjögren-Larsson syndrome.
FALDH or FAO activity is measured in cultured skin fibroblasts or leukocytes. Median FALDH activity in healthy control subjects is estimated to be 8540 ±1158 pmol/min/mg of protein. Normal control values of FAO activity are estimated to be 75 ±13 pmol/min/mg of protein. Patients who are affected usually have less than 10% of the normal mean FALDH activity in cultured skin fibroblasts, and obligate Sjögren-Larsson syndrome heterozygotes demonstrate reduced enzyme activity to about 50% of the normal value. FALDH activity is also deficient in cultured keratinocytes, peripheral blood leukocytes, and other tissues of patients who are affected.
An accumulation of fatty alcohols (hexadecanol and octadecanol) occurs in plasma. In contrast, free fatty aldehyde levels are not elevated.
Routine laboratory investigations of plasma, urine, and cerebrospinal fluid do not reveal any consistent diagnostic abnormalities.
Management
See Treatment and Medication for a full discussion.
Curative Sjögren-Larsson syndrome (SLS) treatment regimens are currently not available; however, studies provide some data on leukotriene synthesis inhibitors as possible therapeutic agents for patients with Sjögren-Larsson syndrome. [4]
Early physiotherapy and later soft-tissue surgery may be helpful in treating patients with Sjögren-Larsson syndrome.
Pathophysiology
Sjögren-Larsson syndrome (SLS) is due to deficient activity of fatty aldehyde dehydrogenase (FALDH), an enzyme required to oxidize fatty alcohol to fatty acid. This syndrome is a result of mutations in the gene that codes for fatty aldehyde dehydrogenase. [5, 6, 7, 8, 9] It catalyzes the oxidation of medium- and long-chain fatty aldehydes to their corresponding carboxylic acids.
The gene encoding FALDH is called the ALDH3A2 gene (or ALDH10) and has been mapped to the Sjögren-Larsson syndrome locus on band 17p11.2. FALDH is involved in the last step of the conversion of 22-hydroxy-C22:0 into the dicarboxylic acid of C22:0 (C22:0-DCA). [10, 11]
Novel ALDH3A2 mutations causing diverse clinical phenotypes have been described. [12]
Current results show a large variety of mutant alleles carrying different mutations (>72), including amino acid substitutions, small and large contiguous gene deletions, insertions, and splicing errors in this gene. Most mutations are private, but many common mutations reflect founder effects, consanguinity, or recurrent mutationalevents. [13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23]
Beyond mutations, the neurologic and other phenotypic characteristics may result from unidentified epigenetic/environmental factors, gene modifiers, or other mechanisms. [5]
Accumulation of long-chain fatty alcohols and modification of macromolecules by an excess of fatty aldehydes are thought to be the pathophysiologic mechanisms causing the manifestations of Sjögren-Larsson syndrome. This accumulation may lead to alteration of the epidermal water barrier and increased transepidermal water loss, subsequently leading to ichthyosis. Permeability barrier abnormality localizes to the stratum corneum interstices and presents as abnormalities in lamellar body formation and secretion.
Etiology
Sjögren-Larsson syndrome (SLS) is caused by a heterogenous group of mutations in the ALDH3A2 gene, which encodes FALDH and is located on band 17p11.2. The ALDH10 gene consists of 11 exons and is widely expressed in tissues. A variant ALDH3A2 gene coded for FALDH and products regulating pathogenic melanogenesis may account for associated hyperpigmentation with this syndrome. [24]
Sjögren-Larsson syndrome is due to a genetic block in the oxidation of fatty alcohol to fatty acid because of deficient activity of FALDH, a component of the fatty alcohol:NAD oxidoreductase enzyme complex (FAO).
FALDH catalyzes the oxidation of medium- and long-chain (aliphatic) fatty aldehydes derived from fatty alcohols.
Epidemiology
Frequency
United States
Detailed epidemiologic studies have not been conducted; however, in regions where the population is inbred, Sjögren-Larsson syndrome is much more common (eg, in the Haliwas of Halifax County and Warren County in North Carolina).
International
An unusually high incidence of patients with Sjögren-Larsson syndrome is observed in areas where consanguineous marriages are noted (eg, Vasterbotten County and Norrbotten County in Sweden, where a mutation was introduced around the 13th century).
The prevalence of patients with Sjögren-Larsson syndrome in northern Sweden is 8.3 cases per 100,000 births, whereas the prevalence of heterozygotes is 2% and the gene frequency is 0.01%. The overall incidence in Sweden is estimated to be around 0.6 cases per 100,000 births. A lower incidence (< 1 case per 100,000 births) has been observed worldwide.
Sjögren-Larsson syndrome is estimated to be observed in 1 in every 1000 patients with intellectual disability and in 1 in every 2500 pediatric dermatologic patients.
Race-, sex-, and age-related information
No apparent racial predilection exists. Consanguinity seems to be the most important factor.
No sexual predilection exists.
Newborns usually manifest symptoms and signs of Sjögren-Larsson syndrome (first ichthyosis, subsequently neurologic symptoms). The latter develop in patients aged 4-30 months. [25, 26]
Prognosis
Sjögren-Larsson syndrome is not lethal. Patients with Sjögren-Larsson syndrome typically do not show a progressive neurodegenerative course. Most patients survive into adulthood.
After neurologic symptoms appear (age 1-2 y), the developmental milestones are progressively delayed. The initial ability to walk a short distance alone is lost, which is caused by progressive spasticity. No progression of the neurologic findings or intellectual disability occurs after puberty. Symptoms tend to appear earlier in patients who will be more severely affected in the future.
Patient Education
Active involvement of a third party (eg, parents, family) is mandatory for the continuous special care of patients with Sjögren-Larsson syndrome. Special schooling is necessary.
