Dermatological manifestations of costello syndrome

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Ramachandran Muthiah

Morning Star Hospital, India

: J Regen Med

Abstract

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Costello syndrome is a rare genetic disorder, characterized by distinctive facial features, short stature, flexible joints, loose folds of extra skin and structural malformations of the heart present at birth such as valvular pulmonic stenosis and abnormal thickening of the muscular walls of the ventricles (ventriculomegaly). Itis a rare rasopathy resulting from germline mutations of the protooncogene hras and discovered by dr. Jack costello, a new zealand paediatrician in 1977. In contrast to somatic oncogenic mutations in neoplasia, the costello syndrome changes are typically introduced in the paternal germline. Sequence analysis of hras exon 2 (the first coding exon) detects missense mutations in 80–90% of individuals tested costello syndrome is a severe developmental disorder characterised by postnatal growth retardation with delayed skeletal maturation, psychomotor retardation, cutis laxa, and acanthosis nigricans. Hras is highly expressed in epidermal cells, but not in immune cells and increases the expression of ilc2, il33 in the epidermis. Ras/mapk activation causes a) dermal connective tissue abnormalities such as cutis laxa, deep palmar plantar creases b) hyperproliferative skin diseases such as palmoplantar keratoderma, cutaneous papilloma, acanthosis nigricans c)inflammatory skin abnormalities such as sensitive skin, eczema, pruritis. Cutis laxa is caused by impaired assembly of elastin fibres, owing to a functional deficiency of the 67 kda elastin binding protein. This protein is inactivated by an abnormal binding to excessive mucopolysaccharides, which accumulate in cultured fibroblasts of patients with costello syndrome. Fgfr3 dominant germline mutations can cause different types of chondrodysplasia and acanthosis nigricans. Among these, the variant of crouzon syndrome and saddan are associated with acanthosis nigricans and hyperpigmentation which are also found in patients with costello syndrome. An intracellular accumulation of chondroitin non-sulphate, as a cause of functional deficiency of the 67 kda elastin binding protein, has been described in fibroblasts of patients with costello syndrome. This gives support to the previous hypothesis of a defect in lysosomal degradation. coarse facial features ( full lips, large mouth, sparse or curly hair, full cheeks, full nasal tip are characteristic. Cs mutation inhibit myoblast differentiation, inherent dysregulation of skeletal myogenesis, abnormal myofiber size variability as type2 fiber predominance and the achilles tendon becomes very tight. Most subjects had a hyperteloric (56%) and telencanthic (83%) appearance. Ras/mapk signaling causes epidermal homeostasis. Skin dermis in cs shows markedly reduced elastic fibers that are thin, short and fragmented. Excess il-33 can activate erk signaling, resulting in reduced claudin-1 expression and skin barrier dysfunction. Distinctive phenotypic findings in p.gly 13 cys are dolichocilia (extremely long eyelashes), loose anagen hair, papillomata, streaky areas of skin hypo and hyperpigmentation. Hras tandem base substitution (c.35_36gc>aa; p.g12e). Resulting p.g12e nonsense change, which may cause impaired elastogenesis in dermis, and exhibits tendency to frontal balding. Patients frequently suffer from increased heat intolerance, itchy skin, sweating and characteristic odor. Multiple nevi are infrequent in cs multiple papillomas are pathognomonic for cs as these do not occur in other cfcs. The most common location of the papillomas is the alar rim of the nose and other locations are eyelids, ears, the neck, arms, fingers and perianal region. Keratosis pilaris is significantly less common in cs than in cfcs. However, palmoplantar keratoderma, acanthosis nigricans and nail abnormalities (thin, pliable, upturned) with fast growth are very common. Also, calcified epitheliomas, dermoid cysts, mammary fibroadenosis, and syringomas have been reported. Malignant acanthosis nigricans- velvety, brown, papillomatous plaques on the neck, axilla and groin can occur. Therapeutically, mek inhibitors play a role in cs dermatological phenotypes. Pd 032590 ameliorate the skin abnormalities observed in rasopathies with significant improvement and dermatitis score. In hras, marked reduction of epidermal thickness, mast cell numbers, p-erk positive epidermal cells and recover the expression level of claudin-1, m rna levels of il1β, il4, il33, st2, and klk14 were significantly lower in the skin of pd0325901-treated hrasg12s/+ U0126, an another mek inhibitor in human keratinocytes, restore the reduced expression levels of claudin-1, filaggrin and increase erk activation through excess il-33. Acitretin is an oral retinoid (vitamin-a derivative), used to treat palmoplantar keratoderma in costello syndrome in dose of 0.3 mg/kg body weight Palmoplantar keratoderma is also managed with topical tazarotene and urea cream. For papilloma, snip excision, cryotherapy, cautery and imiquimod cream are useful. Par therapy (potassium ascorbate with ribose) combines the antioxidant action of vitamin c with the stabilizing intracellular effects of potassium and ribose acts as catalyst, strengthening the action of potassium ascorbate with clear improvement of skin and appendage lesions and better evolution of psychomotor development in costello syndrome.

Biography

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