ARTICLE
Sjögren and Larsson first described this disorder in 1956 and 1957,
respectively. They reported 28 cases coming from Vasterbotten and Norrbotten
provinces in Sweden [1]. Consanguinity was established in 8 of 13 families
in which both parents were known [1]. They concluded that all Swedish cases
could be determined by a single mutation that occurred in one heterozygote
gene about 600 years ago [2]. In those provinces the incidence of the syndrome
had been estimated as 2.7 per 100,000 births [1, 3]. (The overall incidence
in Sweden was 0.4 per 100,000 births). The incidence worldwide is estimated
to be 0.4/100,000 [1, 3].
Sjögren-Larsson syndrome (SLS) is an autosomal recessive disorder
characterized by congenital ichthyosis, mental retardation, spastic paraplegia
or tetraplegia, speech defects and epileptic type convulsions [4, 5].
Ophthalmological abnormalities are said to occur in about 30 percent of
affected individuals and include glistening white dots located in foveal
and parafoveal regions, blepharites, conjunctivitis, and punctate corneal
erosions [4, 6]. Other features of the syndrome reported in some patients
are dental and/or osseous dysplasia and hypertelorism [7]. Icthyosis is
usually present at birth, though neurologic symptoms become apparent during
the first or second year of life [4-7].
Patients have been found to have impaired fatty alcohol oxidation due
to deficient activity of the fatty aldehyde dehydrogenase (FALDH) component
of the complex enzyme fatty alcohol nicotinamide adenine dinucleotide
oxidoreductase (FAO), which is necessary for the oxidation of fatty alcohol
to fatty acids. In most patients, plasma levels of fatty alcohols (hexadecanol
and octadecanol) are increased. In addition the serum levels of certain
polyunsaturated fatty acids decrease, especially the delta-6 desaturation
products of linoleic acid [8-10]. This defect in fatty alcohol
metabolism in the skin and the central nervous system (CNS) is believed
to be responsible for the clinical manifestations [8-10].
The SLS is caused by a mutation in the ALDH3A2 gene which encodes FALDH
activity. It is located in 17p11.2, close to the neurofibromatosis-1 gene
and consists of 10 exons and 9 introns and 31 kilobases [4, 11]. The DNA
for FALDH encodes a protein of 485 amino acids. This protein has a hydrophobic
carboxylterminal amino acid sequence that is necessary for microsomal
membrane anchoring. Molecular studies revealed at least eight different
mutations in the FALDH3A2 gene in SLS [5, 11].
We followed three cases of SLS. They are siblings and their parents
are consanguineous. A laboratory study was done with measurement of FALDH
activity in fibroblast skin in two cases. Furthermore a dietary therapy
was introduced in an attempt to improve dermatological and neurologic
manifestation.
Cases report
Patient 1
A 5-year-old girl presented at birth erythematous and thickened skin
without other associated abnormalities. At 10 months of age she was hospitalized
because of spasticity associated with delayed psychomotor development.
Currently she has a marked dark brown and lichenified hyperkeratosis most
prominent on the elbows and knees (Fig.
1). Pruritus was the major problem for the mother. Neurologic examination
showed a pyramidal syndrome that was more obvious in her lower limbs,
diffuse hyperreflexia and pseudobulbar syndrome. She understood simple
orders but she was mute. A severe diffuse leukodystrophy was evident on
the magnetic resonance imaging (MRI). Ophthalmologic examination was normal.
A biopsy specimen of the abdominal skin revealed orthokeratotic hyperkeratosis,
slight papillomatosis and acanthosis. The granular cell layer was conspicuous,
but thin in some areas. (Fig.
2).
Patient 2
The 3-year old sister of patient 1 was born with diffuse redness of
the skin, which gradually faded. During childhood, the skin became dry,
with generalized itching and yellow-brown hyperkeratosis. There was a
lichenified appearance of the skin of the abdomen and flexural areas.
The central face was spared. Ophthalmologic examination was normal. She
had a very ataxic gait and walked only when supported. Pyramidal hypertonia
was present. Intelligence was delayed for her age and she was unable to
speak full sentences. Leukodystrophy was evident on MR. A skin biopsy
specimen of the abdomen showed hyperkeratosis, acanthosis, papillomatosis
and a stratum granulosum was present.
Patient 3
This male child, brother of patients 1 and 2, was born with diffuse
erythema and scaling of the skin (Fig.
3). Now he is 10 months old, his skin is thick but without hyperkeratosis.
His neurologic and psychomotor development is normal so far.
Laboratory studies
FALDH activity in fibroblasts found in skin biopsies of cases 2 and
3 was measured by Dr. W. Rizzo (Department of Pediatrics, Medical College
of Virginia, Richmond, USA). These studies revealed reduced FALDH activity.
Patient 2 showed 175 pmol/min/mg and patient 3 showed 103 pmol/min/mg
protein enzymatic activity while normal controls were 8,860 ± 1,624
(n = 22) (Table I).
Treatment
Considering that the biochemical defect in SLS consists mainly in increased
fatty alcohol production, possibly associated with fatty acid deficiency,
we proposed the following dietary therapy: reduced fatty intake to 30%
of total caloric intake. To correct delta 6 desaturation products deficiency
of linoleic acid, we supplemented the diet with canola oil given orally
and used as emollient, plus high unsatured fatty acids using Milupan milk
(percentage of fatty acid content: docosahexaenoic acid - 0.3% and
arachidonic acid - 0.4%). The baby was breastfed up to 6 months of
age and received two daily doses of cholestyramine (2 grams), a bile acid-binding
resin. At present foods are cooked only in medium-chain triglyceride oil
(TCM). Topical keratolytic agents and moisturizing creams are used to
improve the ichthyosis.
Results
After therapy was introduced, the children have been followed for 12
months. In patients 1 and 2 skin symptoms of ichthyosis improved greatly.
Pruritus was markedly decreased in all patients. But there was only slight
clinical neurologic improvement in patient 2 and no improvement at all
in patient 1. Patient 3 has not presented pronounced ichthyosis like his
sisters up to now and his neuropsychomotor development is normal. We hope
that with the early diet prescription, practised from his first month
of life, this child will have a better neurologic prognosis and improved
cutaneous ichthyosis.
Discussion
Since the original description in 1957, over 200 cases of SLS have been
reported all the world [1]. Based on our observation we would like to
emphasize the importance of cutaneous clinical features to make the diagnosis
of SLS in the first six months of life, before the onset of neurologic
symptoms. Generalized ichthyosis is usually present at birth and brings
the patient to medical attention [4, 5]. A true collodion-like membrane
is rarely seen. In the neonatal period the affected infants exhibit varying
degrees of erythroderma, which tends to gradually fade with age [12].
The typical skin changes become evident during the first months of life
and fully developed ichthyosis is usually present by one year. There is
a generalized hyperkeratosis more pronounced on the lateral sides of the
trunk, neck, flexural areas and lower abdomen, with marked pruritus [8,
12]. Thickened areas may be yellow to brown in color and have a lichenified
appearance with accentuated skin markings [11, 13]. The central
face is spared, and ectropion is rarely present [4, 13]. There is no loss
of eyelashes or eyebrows. The nails and scalp are normal [14]. The palms
and soles may be involved, but usually only to a slight degree. The ability
to sweat is generally normal [5]. Clinical distinction from other autosomal-recessive
ichthyosis phenotypes (e.g. lamellar ichthyosis or congenital ichthyosis
erythroderma) may be difficult until the CNS or ocular manifestations
of the syndrome are expressed [4, 5, 12].
Histologically, orthokeratotic hyperkeratosis, acanthosis and papillomatosis
can be observed in the epidermis. The horny layer shows a basket-weave
appearance. The granular cell layer may be slightly thickened or not.
The subepidermal blood vessels are somewhat dilated, accompanied by a
little infiltration of round cells. On the other hand, uninvolved skin
is almost normal [15, 16].
Neurologic symptoms include severe mental retardation, abnormal reflexes,
muscular hypertonia and leg paresis. Spasticity becomes apparent between
4 and 30 months of age. The symptoms progress slowly and usually stabilize.
Mental retardation is often severe and parallels the extent of spasticity.
Computerized tomography (CT) scan does not show any suggestive features,
but severe leukodystrophy is evident on MR scans. This has been confirmed
in neuropathological studies, which demonstrate loss of myelinated axons
in the central cerebral white matter, corticospinal and vestibulospinal
tracts [14, 17]. Loss of neurons in the cortex and basal ganglia has also
been described. Speech deficits are frequently observed and are related
to the spastic disorder [14, 17, 18]. Seizures are not infrequent. Short
stature is not primary but results from neurologic impairment [4,
14, 17].
In 1988, Rizzo et al. found that the oxidation of fatty alcohol
in patients is impaired for the deficiency of FALDH and FAO [9]. FALDH
is a complex enzyme which first catalyses fatty alcohol to fatty aldehyde
(fatty alcohol dehydrogenase, FALDH) and then fatty aldehyde to fatty
acid (FALDH) [19]. Subsequent studies confirmed these enzymatic deficiencies
in cultured skin fibroblasts and leukocytes and demonstrated fatty alcohol
accumulation (hexadecanol and octadecanol) in plasma [8, 10, 20]. Fatty
alcohol is a substrate for the biosynthesis of wax esters in the skin
and glycerol ether lipids in myelin [10, 20, 21]. This enzyme defect is
specific to SLS and is not seen in other forms of neurocutaneous diseases
[19].
Once SLS was considered to be due to an inborn error of metabolism,
several studies established a dietetic therapy for SLS patients, aiming
at the primary biochemical defect to block the exogenous admission of
toxic substances (long-chain fatty alcohol) [8, 22]. Unfortunately many
of these studies had only partial or no success at all. This may be attributed
to the heterogeneity of genetic mutation or to the fact that the diet
was recommended after the children had reached a certain age (the youngest
patient started it when he was 5 months old) [8, 22].
Recently Willemsen et al. [23] demonstrated the role of FALDH
in the leukotrienes metabolism through the degradation of leukotriene
B4 (LTB4). They are synthesized from arachidonic acid via the 5-lipoxygenase
pathway and are proinflammatory mediators. Elevated concentrations of
the highly active metabolites LTB4 could contribute to the pathogenesis
of SLS [23-25]. Analyses of urinary LTB4 metabolites offer a new and non
invasive diagnostic tool for SLS [23-25]. Moreover, the discovery of the
role of leukotriene B4 in SLS symptoms opened the way to the development
of a new therapeutic strategy, i.e., 5-lipoxygenase inhibition.
Willemsen et al. [24] treated one patient with zileuton,
a medicine previously used in asthma, that blocks the synthesis of LTB4
by inhibiting 5-lipoxygenase, with slight beneficial effects, such as
a decrease of pruritus. However, the pathophysiological significance of
LTB4 in SLS is not well established. Its concentration is also elevated
in patients with other neurological diseases, as meningitis and toxoplasmic
encephalitis [23].
Some patients were treated with acitretin; ichthyosis and pruritus were
markedly improved. Retinoids exert their effects on gene expression in
the nucleus via cellular retinoic acid receptors. Patients with ichthyosis
lamellar treated with acitretin had their clinical improvement associated
with an increase in the expression of involucrin, the major component
of the cornified envelope cell. Further studies at tissue level are needed
to improve therapeutic options [8, 26, 27].
In patients 1 and 2 cutaneous features were improved, especially the
pruritus that was the major problem for their mother. However, favorable
changes were observed in neurologic symptoms in patient 2 after one year
of dietary manipulation. At this moment, she seems to be more receptive
to environmental contact and exhibits an improved corporal posture. However
dietary treatment was started too late, at five years old for patient
1 and three years old for patient 2, when there was already a severe neurologic
impairment. We hope to have some therapeutic success with patient 3, as
he has had dietary counseling from birth. His neuropsychomotor development
is normal to date, as is his skin, which, although dry, does not present
obvious ichthyosis. It is necessary to remember that a high proportion
of the fatty alcohols in the human body is not ingested, but rather produced
by endogenous lipogenesis. Furthermore, the severity of neurologic symptoms
shows considerable variation [11]. Thus, the beneficial effect of the
dietary treatment cannot be assured even for the youngest patient.
Early diagnosis of SLS based on specific findings offers possibilities
of developing the earliest therapeutic approaches and the dietary therapy
proposed should be tested in more patients, before a negative conclusion
be assumed. The precise relationship between the FALDH defect and clinical
symptoms is not clear and little is known about the effects of fatty alcohol
accumulation in skin and CNS.
CONCLUSION
Acknowledgements
We thank Dr. W.B. Rizzo (Medical College of Virginia, USA) for performing
the assays for enzyme activities (Fatty Aldehyde Dehydrogenase- FALDH)
in our two patients.
Article accepted on 8/1/02
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