Sjogren-Larsson syndrome: A rare neurocutaneous disorder.

Sjogren-Larsson syndrome is an autosomal recessive disorder characterized by defective activity of fatty aldehyde dehydrogenase. It presents as a triad of congenital ichthyosis, spastic diplegia, and mental retardation. The pathology behind this syndrome is the failure of degradation of fatty aldehydes. This case is presented for its rarity.

Introduction

Sjogren-Larsson syndrome (SLS)/ichthyosis oligophrenia syndrome is a rare autosomal recessive disorder with neurocutaneous manifestations. It is associated with a defective activity of the enzyme fatty alcohol: NAD+ oxidoreductase.[1] It presents as a triad of congenital ichthyosis, spastic diplegia, and mental retardation. Excessive fatty aldehydes in SLS patients form adducts with myelin and accumulate in stratum corneum and granular cells resulting in various manifestations of SLS. Alterations in the fundus, speech defects, short stature, kyphosis of the thoracic vertebral column, and seizures of varying frequency are described as secondary symptoms.

Case Report

A 6-year-old male child, first born of third-degree consanguineous parents, presented with scaly lesions on skin over both upper and lower limbs since day 5 of life, global developmental delay and stiffness of all limbs. The child was delivered by cesarean section. He was admitted in neonatal intensive care unit for neonatal jaundice. He had recurrent episodes of generalized tonic clonic seizures since the age of 1½ years with a total of 8 episodes so far (last episode at the age of 4 years).

On examination, diffuse large brown colored diamond shaped adherent scales were present over the skin of all limbs implicating generalized ichthyosis with relative sparing of face [Figure 1]. Seborrheic dermatitis of scalp was present. Diffuse hyperpigmented macules were present over the flexural areas and abdominal skin. Kyphoscoliosis of trunk was present [Figure 2]. On assessment of higher cortical functions, he had global developmental delay. He is not able to stand till date. He is able to speak only monosyllables and obeys simple commands. Central nervous system motor examination showed spasticity, reduced power (3/5 in lower limbs and 4/5 in upper limbs), exaggerated deep tendon reflexes of all four limbs, and bilateral plantar extensor. Cranial nerve examination was normal. There was no sensory deficit or cerebellar signs. Eye examination revealed ectropion, mildly congested conjunctiva, and small opacity in the cornea at 8 o’clock position. Fundus examination revealed glistening spots in the foveal and parafoveal region. The triad of congenital ichthyosis, mental retardation and spastic diplegia arouses the suspicion of SLS.

Figure 1

Brown color diamond shaped adherent scales on the upper limb and peeling of skin on the lower limb

Figure 2

Case photograph of Sjogren-Larsson syndrome

Investigations

Magnetic resonance imaging (MRI) brain indicated bilateral periventricular hyperintensities in parietooccipital region [Figure 3]. On MR spectroscopy, elevated lipid peak was noted. Electroencephalogram revealed no epileptiform activity [Figure 4]. Histopathology of skin lesions revealed hyperkeratosis, normal dermis with irregular acanthosis indicating lamellar ichthyosis.

Figure 3

Coronal T1-weighted image of magnetic resonance imaging of brain showing bilateral periventricular hyperintensities

Figure 4

Magnetic resonance spectroscopy of hyperintense lesions showing abnormally elevated lipid peak

Fatty aldehyde dehydrogenase (FALDH) enzyme activity in skin fibroblasts and sequence analysis of FALDH gene is confirmatory (could not be done due to financial constraint). The child was prescribed emollients for symptomatic relief. Physiotherapy was advised to relieve spasticity.

Discussion

SLS is an autosomal recessively inherited inborn error of lipid metabolism. The incidence of the disease is <1 in 100,000.[2] The disease is caused by mutations in ALDH3A2 gene on chromosome 17p11.2 that encodes fatty alcohol: NAD+ oxidoreductase complex. About 72 mutations in ALDH3A2 gene have been identified in SLS patients with missense mutations constituting the highest percentage.[3] Among the two components (Fatty alcohol dehydrogenase and FALDH) of the enzyme, there is reduced activity of FALDH component leading to impaired oxidation of free toxic aldehyde.[1] FALDH is a Class 3 microsomal enzyme which catalyzes the NAD-dependent oxidation of aliphatic aldehydes derived from the metabolism of fatty alcohols, phytanic acid, ether glycerophospholipids, and leukotriene B4.[4] FALDH also protects the cells against oxidative stress induced lipid peroxidation.[5] These accumulated highly reactive aldehyde substrates are diverted into the production of other metabolites causing various symptoms.

The disorder presents as ichthyosis soon after birth and rarely as collodion baby. Ichthyosis is generalized with sparing of face. Pruritus is usually present. Periumbilical hyperkeratosis with radiating furrows[6] with palmoplantar keratoderma may be present. Most common differential diagnosis of congenital ichthyosis include harlequin ichthyosis, X-linked ichthyosis, and Netherton syndrome. However, the clinical triad of the syndrome eliminates the possibilities of other ichthyosiform erythrodermas. The cutaneous manifestations are the result of abnormal lipid accumulation in stratum corneum and granular cells. This leads to leaky dysfunctional water barrier and hyperkeratosis.[78] Pruritus results from elevated levels of leukotriene B4.[9] Zileuton, 5-lipoxygenase inhibitor relieves this symptom. Prematurity is common due to the inefficient degradation of Leukotriene B4.

Speech defects, delayed motor milestones, spastic diplegia or quadriplegia, and mental retardation are the neurological findings.[10] Excessive fatty aldehydes in SLS patients form adducts with phosphatidylethanolamine and myelin, thereby resulting in defects in myelination. MRI generally shows periventricular hyperintensities, and MR spectroscopy reveals elevated lipid peaks indicating defect in fatty acid metabolism. Retinal glistening with white dots in the perimacular region of the retina on fundus examination is pathognomic of the disease.[11]

Histopathological features of skin biopsy include hyperkeratosis and acanthosis consistent with lamellar ichthyosis. Confirmatory tests include FALDH enzyme assay in cultured skin fibroblasts and leukocytes and sequence analysis of ALDH3A2 gene on the locus 17p11.2.[12]

Management is mainly supportive and involves multidisciplinary approach. Topical emollients, keratolytics, and oral retinoids provide symptomatic relief. Low-fat diet early in infancy may improve clinical outcome.[13]

Any case of congenital ichthyosis with spastic paresis and mental retardation should be evaluated for SLS.

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Conflicts of interest

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