Genetics of Sjogren-Larsson Syndrome Clinical Presentation

Updated: Dec 17, 2014
  • Author: William B Rizzo, MD; Chief Editor: Luis O Rohena, MD, FAAP, FACMG  more...
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Presentation

History

Sjögren-Larsson syndrome (SLS) is a genetic disease evident before birth. Neonates are often born several weeks premature. [19]

Ichthyosis is usually the first symptom to prompt patients or parents to seek medical attention. In most patients with Sjögren-Larsson syndrome, the ichthyosis is apparent at birth. A collodion membrane (a parchmentlike membrane covering the skin) is not commonly present at birth but has been observed in about 15% of patients with this disorder. About 30% of patients with Sjögren-Larsson syndrome first develop ichthyosis after the neonatal period, usually during the first year of life; however, some patients do not have cutaneous disease until later in life. In contrast to most other forms of ichthyosis, pruritus is a common complaint in Sjögren-Larsson syndrome.

Intellectual disability develops during the first 2 years of life and is revealed by delays in achieving normal developmental milestones.

Spastic diplegia or tetraplegia causes a delay in reaching motor milestones in infants with Sjögren-Larsson syndrome. Spasticity in the lower extremities often prevents patients from achieving independent ambulation. Patients with Sjögren-Larsson syndrome who can walk typically develop a spastic gait and require leg braces. Patients with Sjögren-Larsson syndrome are at risk for progressive leg contractures.

Affected siblings may vary in the severity of neurologic symptoms.

Speech is often delayed and is a complicating factor in judging the degree of intellectual disability. Receptive language skills typically exceed those of expressive language.

Seizures occur in about 40% of patients with Sjögren-Larsson syndrome.

Photophobia causes squinting in bright sunlight. Patients with decreased visual acuity may require corrective lenses.

Sjögren-Larsson syndrome is not neurodegenerative. Developmental skills, once gained, are usually maintained over time. However, if contractures progress, patients may loose the ability to ambulate.

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Physical

Ichthyosis is apparent upon physical examination in almost all patients with Sjögren-Larsson syndrome. [20, 7, 18] The ichthyosis has a generalized distribution and is usually prominent on the trunk, extremities, flexures, axilla, nape of the neck, and back. The face is usually spared. The palms and soles are affected in 60% of patients with Sjögren-Larsson syndrome. Scales can be fine and dandrufflike, dark, or even platelike, especially on the shins and lower extremities. In some patients with Sjögren-Larsson syndrome, hyperkeratosis with prominent skin markings is more obvious than scales. Severity of the ichthyosis may not be apparent if the patient bathes shortly before examination (because bathing rehydrates the skin). As a consequence, the severity of the ichthyosis should be judged late in the day if the patient bathed in the morning. Likewise, the ichthyosis may not be evident immediately after the application of moisturizing lotions.

Excoriations due to pruritus are often present on patients with Sjögren-Larsson syndrome.

Spasticity is almost always present by age 2 years. [21] Spastic diplegia is much more common than spastic tetraplegia in individuals with this disorder. Contractures of the lower extremities often develop. In infants with Sjögren-Larsson syndrome, hypertonia is the most common neurologic finding on physical examination. Variable hypotonia occasionally precedes hypertonia. After infancy, hyperreflexia in the lower extremities is almost always present.

Considerable variation may be seen in the motor abilities of affected siblings. [22]

Intellectual disability varies from profound to mild; most patients with Sjögren-Larsson syndrome have mild-to-moderate retardation, and rare patients have little cognitive impairment. [7] In infants with Sjögren-Larsson syndrome, intellectual disability is revealed by developmental delay, which usually becomes evident during the first year of life.

Speech problems beyond that expected from intellectual disability alone are typically observed in individuals with Sjögren-Larsson syndrome. [23] Pseudobulbar dysarthria is most common. Expressive speech is usually impaired more than receptive speech.

The severity of the spasticity and the degree of intellectual disability are correlated. However, severity of the ichthyosis is not related to the neurologic symptoms.

Ophthalmologic findings include glistening white dots that affect the retina and retinal pigmentary changes. [24] Glistening white dots in a perifoveal distribution are present in most patients with Sjögren-Larsson syndrome. These dots may be pathognomonic for those with Sjögren-Larsson syndrome, but they might not be apparent in young infants with the disorder. Photophobia is common in individuals with Sjögren-Larsson syndrome, and visual acuity is often decreased.

In contrast to other disorders with ichthyosis, hair and nail abnormalities are not seen in individuals with Sjögren-Larsson syndrome.

Short stature is common owing to a combination of growth delay and leg contractures.

Because the ichthyosis is usually present at birth and because neurologic symptoms appear later in the first 2 years of life, the differential diagnosis varies with age at presentation. During the neonatal period and early infancy, the differential diagnosis includes other forms of congenital ichthyosis, such as those listed in Differentials.

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Causes

Sjögren-Larsson syndrome is a genetic disease caused by mutations in the ALDH3A2 gene (previously known as ALDH10 and FALDH) located on subband 17p11.2. [6] The mutations result in deficient activity of the FALDH enzyme and a severe reduction in the ability of FALDH to catalyze the oxidation of aliphatic aldehydes to their corresponding acids.

Sjögren-Larsson syndrome is inherited as an autosomal recessive trait. Two copies of the SLS gene, one from each parent, must be inherited for a patient to be affected with the disease. With the rare exception of the occurrence of a new mutation, each parent of a patient with Sjögren-Larsson syndrome is a heterozygous carrier for an SLS gene.

Like other autosomal recessive traits, most families have no history of Sjögren-Larsson syndrome. The disease does not affect genetic carriers for Sjögren-Larsson syndrome. For parents of a child affected with Sjögren-Larsson syndrome, the recurrence risk for a subsequent pregnancy is 1 in 4, or 25%. This recurrence risk is independent of the number of children (affected or unaffected with Sjögren-Larsson syndrome) the couple has had.

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