Sjögren-Larsson syndrome (SLS) is a rare autosomal recessive neurocutaneous disorder characterized by mental retardation, diplegia or tetraplegia, and congenital ichthyosis. The ichthyosis (usually evident at birth) may be seen in some patients after the first year of life.
SLS is due to deficient activity of fatty aldehyde dehydrogenase (FALDH), an enzyme required to oxidize fatty alcohol to fatty acid. 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 SLS locus on band 17p11.2. Current results show a large variety of mutant alleles carrying different mutations (>70), including amino acid substitutions, deletions, insertions, and splicing errors in this gene.
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 SLS. This accumulation may lead to alteration of the epidermal water barrier and increased transepidermal water loss, subsequently leading to ichthyosis.
Defective metabolism of leukotriene B4 (LTB4) is the first biochemical pathway demonstrated to be distorted in patients with SLS. Distorted inactivation of LTB4 might form one of the mediator pathways responsible for considerable pruritus in patients with SLS.
Detailed epidemiologic studies have not been conducted; however, in regions where the population is inbred, SLS is much more common (eg, in the Haliwas of Halifax and Warren Counties in North Carolina).
An unusually high incidence of patients with SLS is observed in areas where consanguineous marriages are noted (eg, Vasterbotten and Norrbotten County in Sweden, where a mutation was introduced around the 13th century).
The prevalence of patients with SLS 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.
SLS is estimated to be observed in 1 in every 1000 patients with mental retardation and in 1 in every 2500 pediatric dermatologic patients.
SLS is not lethal. Patients with SLS typically do not show a progressive neurodegenerative course. Most patients survive into adulthood.
No apparent racial predilection exists. Consanguinity seems to be the most important factor.
No sexual predilection exists.
Newborns usually manifest symptoms and signs of the disease (first ichthyosis, subsequently neurologic symptoms). The latter develop in patients aged 4-30 months.
Most patients are born preterm and have erythema at birth. The diagnosis of SLS is almost always delayed because only cutaneous symptoms (eg, scaling, hyperkeratosis) are usually present at birth.
A family history of siblings affected by SLS 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.
At first, the neurologic signs are nonspecific (eg, mental retardation, spasticity); however, severe neuromotor and mental developmental delay is usually obvious by the time the patient is aged 1-2 years. It gradually progresses to reach a plateau phase.
Neck posturing seems to be apparent by the time the patient is aged 3 years.
Involuntary jaw opening while eating is usually observed by the time the patient is aged 6 years.
Seizures usually develop later in childhood.
The key triad of symptoms for SLS includes nonbullous congenital ichthyosiform erythroderma, spastic diplegia or quadriplegia, and mental retardation. An additional group of signs comprises other dermatologic symptoms, ophthalmologic signs, speech defects, epilepsy, dental problems, and skeletal abnormalities.
Skin involvement (type of lesions)
Ichthyosis is generalized, with the trunk, the flexures, and the dorsal aspects of the hands and the feet most severely affected. It may present as fine, furfuraceous (dandrufflike) scaling; lamellar-type hyperkeratosis with thin scales; or nonscaly thickening in the stratum corneum.
A yellow discoloration may occur with extensive thickening of the skin and is mostly pronounced around the umbilicus and the main flexures.
The face is mostly spared.
Hair and nails are usually normal.
Dermatoglyphic alterations (eg, simian creases, palmar hyperlinearity) may be present.
Dental findings: Enamel hypoplasia may be present.
Skeletal findings: Skeletal abnormalities (eg, short stature, kyphoscoliosis) may be observed.
Spasticity may be apparent before age 3 years and is more severe in the lower limbs than in other parts of the body.
Mental retardation is moderate to severe and mostly progressive (intelligence quotient [IQ] <50 in about 70% of patients).
Seizures (epilepsy) occur in about 30-50% of patients with SLS.
Delayed or impaired speech may be present.
Hyperreflexia (tendon reflexes) is increased, and a positive bilateral Babinski reflex may occur.
Joint hyperextensibility may be observed.
Glistening dots on the macular region of the retina are pathognomonic for SLS.
Other ophthalmologic findings include subnormal visual acuity, conjunctivitis, blepharitis, and punctate erosions of the cornea.
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.
SLS 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.