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SJOGREN—LARSSON SYNDROME: DISEASE THAT DIFFICULT TO DIAGNOSE OR RARE SYNDROME IN NEUROPEDIATRICS?

L.G. Kirilova, M.F. Denisova, N.V. Chernega, V.V. Lysytsa, O.O. Miroshnykov, T.P. Galinskaya, L.F. Slepova
SI «Institute of Pediatrics, Obstetrics and GYNECOLOGY NAMS of Ukraine»

This article contains critical review of modern literature devoted to rare disease in neuroichthyosis group — Sjogren— Larsson syndrome. Based on analysis of various literature sources, modern views on etiology, pathogenesis, clinical-diagnostically characteristic and therapeutic approaches to Sjogren—Larsson syndrome were generalized and systematically examined. The article presents the description of clinical case in clinics of SI «Institute of pediatrics, obstetrics and gynecology NMSA of Ukraine».
Key words: rare diseases, Sjogren—Larsson syndrome, neuroichthyosis, organic lesion of CNS.

Sjogren—Larsson syndrome (SLS) — a rare hereditary disorder that belongs to a group of so-called neuroichthyosis. Obligate feature of this group of diseases is the presence in symptomatic complex pathology of the skin in the form of ichthyosis and organic CNS lesions. For the first time disease with a similar combination of features described by Swedish researchers Torsten Sjogren and Tage Larsson in 1957 Observing family history of the syndrome in Swedish families, experts came to the conclusion concerning autosomal recessive nature of inheritance of the disease [1].

Later, patients with Sjogren—Larsson syndrome were identified in most countries. At present, we did not find any description of this disease in children in national periodical literature. Sjogren—Larsson syndrome is a rare disease. According to a study conducted in Sweden, its prevalence is 0.4–0.6 cases per 100,000 people. Extremely high incidence of Sjogren—Larsson syndrome observed in areas where consanguineous marriages are common, for example in the province of Vasterbotten and Norrbotten in northern Sweden. In these regions the incidence is 8.3 cases per 100,000 births, while the prevalence of heterozygotes is 2%, and the frequency of a gene in a population about 0.01%. Low incidence rate occurs worldwide and is less than 1 case per 100,000 births.

According to Swedish specialists Sjogren—Larsson syndrome affect 1 per 1000 patients with mental retardation and 1 child per 2500, which has a skin disease [2].

During the last two decades have been studied the basic pathogenetic mechanisms of Sjogren—Larsson syndrome. The disease is based on disorders in lipid metabolism. In 1996 he identified a mutation of the gene ALDH3A2, located on hromomsomi 17pll.2 and responsible for the synthesis of the enzyme fatty aldehyde dehydrogenase (FALDH) [3].

New Insights into the pathogenesis of Sjogren— Larsson syndrome associated with understanding importance of FALDH in the processes of lipid metabolism. FALDH is an essential component of the enzyme complex NAD-oxidoreductase that catalyzes the sequential oxidation of fatty alcohols, aldehydes and fatty acids [4].

Children with the syndrome of Sjogren—Larsson suffer from insufficient activity of FALDH and NAD-oxidoreductase, which leads to a distorted metabolism of fatty aldehydes and fatty alcohols. FALDH effect on fatty aldehydes obtained from metabolism of fatty alcohols, phytic acid (branched fatty acid) phytol (alcohol precursor phytic acid), glycerol-lipids and leukotriene B4. Abnormal metabolites of lipid metabolism accumulate in various tissues of the body and damage them [5].

In skin keratinocytes increase fatty alcohol stimulates synthesis of wax esters and alkyl-2-acyl-glycerol. Accumulation of fatty alcohols and related metabolic products violates transform intercellular membranes in
stratum corneumthat leads to increased permeability of skin to water. The skin trying to restore waterproof barrier, which results in hypertrophy of the stratum corneum, which is clinically manifested as ichthyosis [6].

FALDH also involved in the oxidation of fatty aldehydes — products of myelin phospholipids catabolism. In case of enzyme insufficiency accumulation of fatty aldehydes results in damaging of white substance of the central nervous system [7].

Also in Sjogren—Larsson syndrome there is an accumulation of leukotrienes B4, which causes itching skin, inherent to this disease. In addition, patients with this pathology have low levels of certain poly-unsaturated fatty acids in the blood plasma, which also contributes to the development of cutaneous and neurological manifestations of the disease [8].

Macular degeneration of retina in this disease is associated with deficiency of macular pigment from carotenoids group — zeaxanthin. This helps to increase free radical photo-oxidation of retinal cells with the deposition in it pathological lipofuscin. Acting as sensitizers photo-oxidation lipofuscin granules can stimulate oxidation of lipids, cardiolipin liposomes, proteins, and damage biological membranes, causing apoptosis of retinal cells [9,10].

The method of choice for the diagnosis of retinitis pigmentosa in case of Sjogren—Larsson syndrome is the fundus auto-fluorescence (FAF) — a new imaging technique that allows to obtain topographic maps of the distribution of lipofuscin in the retinal pigment cells [11].

Most children with Sjogren—Larsson syndrome born prematurely. Often in such children exist congenital skin erythema. Early diagnosis of the disease is almost always delayed because at birth are usually present only cutaneous manifestations of the disease («Butter» skin or ichthyosis). In family history may be information about this disease in brothers or sisters of the child or cognate marriage of parents [12,13].

The basic triad of symptoms in SLS includes not bullous congenital ichthyosis-forming erythroderma, spastic dior tetraparesis and mental retardation, which eventually becomes the mental retardation of varying degrees. Additional symptoms include other dermatological signs (erythroderma, pruritus), retinal damage, seizures, disorders of teeth growth and skeletal abnormalities [14,15].

Skin lesion observed in the first months of life. Skin gradually becomes thicker and scaly, with increasing of hyperkeratosis. Sometimes there is peeling on the palms and soles. Later the skin becomes wrinkled, becoming brownish-yellow color. Hyperkeratosis progresses gradually, reaching the highest expression at the folds flexor surfaces of the extremities. Itchy skin is pathognomonic symptom, not typical for other types of ichthyosis [12,13].

Ichthyosis affects the entire surface of the body, especially expressed on the trunk, folds and dorsal surfaces of the limbs. It is characterized by dry skin, formation on its surface scales whitish or grayish color, which sometimes turn into brown plate tight to the touch.

Hair and nails are usually normal. With dermatoglyphics study may observed changes as «ape folds» and hyper-linearity of hands [12,14].

Symptoms of CNS lesions at SLS is nonspecific, but always causing severe delays motor and mental development. Rough underdevelopment usually becomes apparent around the age of one year. Spastic tetraparesis is clearly visible at the age of 2–3 years [15].

Mental retardation in patients ranges from moderate to severe (IQ <50 approximately 70% of patients), and combined with impairments of speech. Seizures occur in approximately 30–50% of patients [16].

On examination of the oral cavity in patients observed disorders of teeth development caused by enamel hypoplasia. Sometimes in children with SLS presents skeletal anomalies (small growth, kifo-scoliosis) [15]. On examination, eye fundus will be pathognomonic for SLS symptom shiny dots that represent abnormal inclusion of lipofuscin in the area of the macula. Other ophthalmic signs include conjunctivitis, blepharitis, corneal erosions point, angiopathy of retina and macular pigment deficiency [10,11].

MRI of the brain in patients showing signs of demyelination and gliosis, mainly in the periventricular and subcortical areas. The nature of changes in the CNS is similar in most patients, but differ in the degree of severity [17].

Recently abroad using the method of positron MR spectroscopy which allows to reveal neurometabolic abnormalities in form of increased signal intensity on lipid peak, mainly in the periventricular areas of the anterior and posterior horns of the lateral ventricles [17,18].

Treatment of Sjogren—Larsson syndrome at present is symptomatic. To improve the state of skin appoint a diet with a low content of long-chain fatty acids. Apply drugs from group of carotenoids that reduce hyperproliferation keratinocytes, and inhibitors of leukotrienes B4 synthesis that help to reduce itching [19,20].

As illustrations of Sjogren—Larsson syndrome present medical history of the child, which was examined in children's hospitals SI «Institute of Pediatrics, Obstetrics and GYNECOLOGY NAMS of Ukraine». Boy N., 6 years, entered the department in a severe state, caused distinct cachexia with signs of chronic enterocolitis (weight 5000 g). On examination, attracted attention an unusual habitus of the child: the presence of numerous stigmas disembriogenesis (deformation ears, gothic palate, micro-ophthalmia, deformation of teeth), hyperkeratosis and xerodermia almost the entire surface of the skin (ichthyosis), spastic tetraparesis with expressive delay psycho-linguistic development. The child hardly reacted to others not tracked for a toy was marked frequent restless crying and pained expression on his face. Motor development also did not meet the age: boy did not sitting alone, not turned on its side, at the knee joints were formed flexion contracture.

The child was almost completely devoid of subcutaneous fat layer. The skin was dry, wrinkled, with sagging folds. On the trunk hyperpigmented skin, lamellar, on the scalp — gneiss. Body temperature during examination 37,5°C. In lungs vesicular breath, wheezing absent. Heart sounds rhythmic auditioned systolic noise at the apex. Excrements 3 times a day, in small quantities, liquid, yellow color with asour odor. Diuresis decreased, urinate 3 times a day.
 
From history we know that boy was born from the 1st pregnancy. Until 20 weeks of pregnancy ran across without complications. At 20 weeks mother was admitted to hospital relatively to anemia during treatment whose suddenly developed fever and appeared lymphadenopathy. At 34 weeks of pregnancy with an ultrasound diagnosis of fetal retardation in the development and oligohydramnios. Births by caesarean section at 38 weeks gestation. Birth weight 1300 g, height 38 cm were recorded signs of congenital ichthyosis, mainly on the flexor surfaces of the extremities and neck. After birth 1 month was on stationary treatment for congenital sepsis, delayed intra-uterine development of hypoxic-ischemic encephalopathy.

From maternity hospital was discharged with body weight 2050 g. In the first year of life observed delay in development of motor and mental functions. After in the second year appeared vomiting, unstable excrements, delayed of physical development, the child ceased to gain weight. The next 3 years boy was repeatedly admitted to hospital in serious condition, concerning acute enterocolitis, which ran with exsicosis on the background hypotrophy. Hereditary history is not burdened, parents healthy without family relations between them. In general blood analysis found hypochromic anemia, leukocytosis with a shift to the left. In the biochemical blood analysis increased levels of transaminases, urea and hypocalcaemia.

Ultrasound of the abdomen showed signs of ascites, liver enlargement. On ECG recorded sinus tachycardia (heart rate 150 beats / min.), disturbance of repolarization. On echocardiography — ultrasound signs of incomplete closure of the oval window. On examination, of ophthalmologist with slit lamp was diagnosed atypical retinitis pigmentosa.

Considering typical symptoms that include congenital ichthyosis, spastic tetraplehiyu, mental retardation, retinal damage and numerous micro abnormalities (including dental row), we diagnosed rare neurometabolic disease — Sjogren—Larsson syndrome.

During examination in children's clinics baby was on bottle-fed through a probe «Alfaro» and «FrezubinEnergy». Has intravenous infusion therapy, were appointed subalin, halstena, rehydron. However treatment was not performed in full volume because of parents refus for further stay in hospital and a desire to continue treatment on an outpatient basis. Thus Sjogren—Larsson syndrome, although they are fairly rare disease, however, in our opinion, not a harddiagnosed. Classic manifestations of the disease are obvious «argumentum ad oculos» for an experienced clinician (once to see a patient to remember it forever).


References
  1. Sjogren T., Larsson T. Oligophrenia in combination with congenital ichthyosis and spastic disorders. Acta Psych Neurol Scand. 1957; 32 (113): 1—113
  2. Jagell S., Gustavson K.H., Holmgren G. Sjogren—Larsson syndrome in Sweden: a clinical, genetic and epidemiological study. Clin Genet. 1981; 19: 233—256.
  3. Rizzo W., Buehler B. Genetics of Sjogren—Larsson Syndrome [Electronic resource]. Assess mode : http://emedicine.medscape.com/article/949023_overview. — Title from the screen.
  4. De Laurenzi V., Rogers G.R., Hamrock D.J. [et al.] Sjogren— Larsson syndrome is caused by mutations in the fatty aldehyde dehydrogenase gene. Nat Genet. 1996; 12(1): 52—7.
  5. Rizzo W.B,. Carney G. Sjogren—Larsson syndrome: diversity of mutations and polymorphisms in the fatty aldehyde dehydroge_ nase gene (ALDH3A2). Hum Mutat. 2005; 26 (1): 1—10.
  6. Rizzo W.B., S'aulis D., Jennings M.A. [et al.] Ichthyosis in Sjogren— Larsson syndrome reflects defective barrier function due to abnormal lamellar body structure and secretion. Arch. Dermatol. Res. 2010; 5.
  7. Rizzo W.B. Sjogren—Larsson syndrome: molecular genetics and biochemical pathogenesis of fatty aldehyde dehydrogenase defi_ciency. Mol. Genet. Metab. 2007; 90 (1): 1—9.
  8. Willemsen M.A., Rotteveel J.J., de Jong J.G. [et al.] Defective metabolism of leukotriene B4 in the Sjogren—Larsson syndrome. J. Neurol Sci. 2001; 183 (1): 61—7.
  9. Ostrovsky M.А. Molekulyarnye mehanizmy povrejdayushchego deystviya sveta na struktury glaza i sistemy zashchity ot takogo povrejdeniya. Uspehi biologicheskoy khimii. 2005; 45: 173—204.
  10. Van der Veen R.L., Fuijkschot J. [et al.] Patients with Sjogren— Larsson syndrome lack macular pigment. Ophthalmology. 2010; 117: 966—71.
  11. Willemsen M.A., Cruysberg J.R., Rotteveel J.J. [et al.] Juvenile macular dystrophy associated with deficient activity of fatty aldehyde dehydrogenase in Sjogren—Larsson syndrome. Am. J. Ophthalmol. 2000; 130 (6): 782—9.
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  13. Jagell S., Liden S. Ichthyosis in the Sjogren—Larsson syndrome. Clin. Genet. 1982; 21 (4): 243—52.
  14. Zalewska A., James W. Dermatologic Manifestations of Sjogren—Larsson Syndrome [Electronic resource] — Assess mode : http://emedicine.medscape.com/article/1114823—treatment#showall. — Title from the screen.
  15. Vel'tishchev Yu.E., Tyomin P.A. Nasledstvennye bolezny nervnoy systemy. — М.: Meditcina, 1998: 496.
  16. Jagell S., Heijbel J. Sjogren—Larsson syndrome: physical and neurological features. A survey of 35 patients. Helv. Paediatr. Acta. 1982; 37: 519—530.
  17. Fuijkschot J., Maassen B., Gorter J. W. [et al.] Speech-language performance in Sjogren—Larsson syndrome. Dev Neurorehabil. 2009; 12 (2): 106—12.
  18. Willemsena A., van der Graafb M. [et al.] MR Imaging and Proton MR Spectroscopic Studies in Sjogren—Larsson Syndrome: Characterization of the Leukoencephalopathy. AJNR. 2004; 25: 649—657.
  19. Toshiyuki Mano. Proton MR Spectroscopy of Sjogren—Larsson's Syndrome. AJNR. 1999; 20: 1671—1673.
  20. Lacour M., Mehta-Nikhar B., Atherton D.J., Harper J.I. An appraisal of acitretin therapy in children with inherited disorders of keratinization. Br. J. Dermatol. 1996; 134 (6): 1023—9.
  21. Willemsen M.A., Lutt M.A., Steijlen P.M. [et al.] Clinical and biochemical effects of zileuton in patients with the Sjogren— Larsson syndrome. Eur. J. Pediatr. 2001; 160 (12): 711—7.

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