AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

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.

Pathophysiology

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.

Frequency

United States

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).

International

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.

Mortality/Morbidity

SLS is not lethal. Patients with SLS typically do not show a progressive neurodegenerative course. Most patients survive into adulthood.

Race

No apparent racial predilection exists. Consanguinity seems to be the most important factor.

Sex

No sexual predilection exists.

Age

Newborns usually manifest symptoms and signs of the disease (first ichthyosis, subsequently neurologic symptoms). The latter develop in patients aged 4-30 months.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

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.

Physical

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.
• Neurologic signs
• • 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.
• Ophthalmologic signs
• • 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.

Causes

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.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Little syndrome

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• 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 SLS.
• 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 SLS 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.

Imaging Studies

• Cranial CT findings are consistent with cortical atrophy (white brain hypodensity that varies from frontal patches to diffuse confluent involvement). The severity of the CT findings is correlated well with the severity of the neurologic symptoms.
• Brain MRI demonstrates white matter disease characterized by dysmyelination or delayed myelination.
• • Dysmyelination is defined as a breakdown of already formed (also delayed) myelin.
  • Delayed myelination is a delay of myelin deposition, demonstrable by follow-up MRI examinations. In such cases, normal myelin is demonstrable at a later point in development at sites where no mature myelin signal was noticed on earlier MRI. Without follow-up data, the term hypomyelination might be applied in such cases.
• Protein magnetic resonance (MR) spectroscopy findings include abnormal pick at 1.3 ppm, consistent with long-chain fatty alcohol accumulation, in the periventricular white matter (mostly around the posterior and frontal horns.

Other Tests

• Analysis of LTB4 and its metabolites in urine offers a new and noninvasive diagnostic examination for patients with SLS.
• Electroencephalography (EEG) demonstrates multifocal epileptic discharges (eg, spike and wave complexes, polyspikes, sharp waves of high voltage) occurring in the presence of disorganized background activity.

Histologic Findings

Skin biopsy samples demonstrate hyperkeratosis, focal parakeratosis, acanthosis, papillomatosis, and a sparse dermal lymphocytic inflammatory infiltrate. Ultrastructural examination reveals abnormal lamellar inclusions in the cytoplasm of spinous, granular, and horny cells; prominent Golgi apparatus; and an increased number of mitochondria. Sometimes, lipid droplets are seen in the horny layer. Postmortem brain histopathologic examination reveals a basic disorder of central myelination, usually a mild loss of gray matter, including basal ganglia, with a tendency toward accumulation of astrocytes and lipoid substances (eg, lipids, lipofuscinlike pigments).

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

Curative treatment regimens are currently not available; however, recent studies provide some data on leukotriene synthesis inhibitors as possible therapeutic agents for patients with SLS.

Surgical Care

Early physiotherapy and later soft-tissue surgery may be helpful in treating patients with SLS.

Consultations

SLS is a multisystem disease and requires the attention of many specialists, including the following:

• Dermatologist
• Neurologist
• Pediatrician
• Physiotherapist
• Ophthalmologist
• Orthopedist

Diet

Dietary restrictions for patients with SLS that focused on reducing intake of long-chain fatty acids were mostly ineffective; however, some authors maintain that a low-fat diet with a medium-chain fatty acid addition could lead to skin lesion improvement, especially when started early in infancy and with high compliance.

Activity

The clinical spectrum of patients with SLS varies from those who are wheelchair-bound to those who can walk.

• Spasticity is usually so severe that many patients are never able to walk.
• Later in development (around age 3-5 y), severe neurologic deterioration prevents patients with SLS from walking.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Treatment of SLS is palliative. Dermatologic therapy consists of retinoids, emollients, and keratolytic agents. However, recent findings give the first support to the concept that gene therapy may be a future treatment option. Recent work has shown that patients with expression of the FALDH protein and some residual enzyme activity could benefit from the hypolipemic drug benzafibrate, which is a pan-agonist of all PPAR-isoforms.

Drug Category: Retinoids

These drugs are used to reduce the increased epidermal turnover in patients with SLS.

Drug Category: Vitamin D-3 analogues

These agents are used to reduce increased epidermal turnover.

Drug Category: Keratolytics

These agents are used to soften the affected skin.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Outpatient Care

• A multidisciplinary approach is mandatory (see Consultations).
• Sauna treatments (90-100°C) and frequent bathing or showering are beneficial for patients with SLS.
• Orthopedic measures, such as hamstring release and (if kyphosis is present) thoracic braces, can enable patients with SLS to walk.

In/Out Patient Meds

• Skin emollients and keratolytic agents are necessary for skin care.

Prognosis

• 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 mental retardation 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 SLS.
• Special schooling is necessary.
• For excellent patient education resources, visit eMedicine's Arthritis Center. Also, see eMedicine's patient education article Sjögren Syndrome.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Neurologic features of SLS are essential for establishing the diagnosis; however, they show considerable variation.
• Skin biopsy is never essential for SLS diagnosis.
• Enzymatic confirmation of the diagnosis is important because only about 50% of patients with skin and neurologic signs resembling SLS really have FALDH deficiency.
• No correlation exists between the severity of neurologic symptoms and the ichthyosis in patients with SLS.
• A positive correlation exists between the mental retardation and the degree of spasticity in patients with SLS.
• Itchy ichthyosis, gradual lichenification, usually is the first symptom that focuses physician attention on the child who is affected.

Special Concerns

• Prenatal diagnosis is based on enzymatic detection of FAO activity obtained from fetal skin biopsy (at 19 weeks' gestation); amniocentesis; or earlier in cultured chorionic villi cells, by linkage analysis or mutation detection. FALDH activity could be detected in cultured chorionic villus fibroblasts (CVF) derived from control fetuses. In fetuses affected with SLS, its activity was found to be markedly deficient.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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Article Last Updated: Dec 11, 2006