Saturday, 5 November 2011

Quiz

                                                                       
                                                                                  A



                                                                                  B


                                                                                  C


12-year old patient presented with this type of scaling [scales, large “plate-like” , very thick, dark brown and firmly adherent, have been over most of the skin surface including the face (A and B) and accentuated on lower extremities (C)] which started within the first month of life. Which congenital disorder of cornification is this?

Normally, cornification involves the construction of the cornified envelope from intracellular protein precursors including loricrin and involucrin. These are cross-linked to lipid ceramides in the granular layer by the action of transglutaminase 1. Kinetic studies in this disease revealed a near-normal transit time, and it is therefore classified as a retention disorder of cornification (retention hyperkeratosis with hypergranulosis). Mutations in the keratinocyte transglutaminase-1 gene on chromosome 14q11.1 interfere with the crosslinkage of loricrin and involucrin and the formation of the cornified cell envelope (retention hyperkeratosis). What are the other congenital disorders of cornification that show retention hyperkeratosis?


Short and long answers are provided below as comments. 

4 comments:

  1. Short answer:
    • Lamellar ichthyosis
    • ‎*Ichthyosis vulgaris: Retention hyperkeratosis (with HYPOgranulosis or absent granular layer)
    *Recessive X linked ichthyosis: Retention hyperkeratosis (with NORMAL granular layer or SLIGHT HYPERgranulosis)

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  2. Note that:

    1) -Bullous congenital ichthyosiform erythroderma shows: Hyperproliferative hyperkeratosis
    -Non-bullous congenital ichthyosiform erythroderma shows: Hyperproliferative hyperkeratosis

    2) Patients with epidermolytic verrucous epidermal naevi (epidermolytic and non-epidermolytic verrucous epidermal naevi must be distinguished histopathologically) are at risk of parenting a child with bullous congenital ichthyosiform erythroderma. Patients with non-epidermolytic epidermal naevi can be counselled that these are sporadic lesions and are not passed on as a generalized skin condition.

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  3. One might ask, what is the relation between having a male baby with recessive X linked ichthyosis and labour?



    After the first trimester, the placenta is the major source of oestrogens and actually because the majority of maternal oestrogens are derived from the foetal adrenals and are metabolized by the placenta, low levels can reflect foetal abnormalities or death. The foetal endocrine system is notable for extensive conjugation of steroids with sulphate. Consequently, the placenta relies on sulphatase activity to cleave sulphate conjugates in the foetal compartment. Placental sulphatase deficiency results in a low oestrogen state in pregnancy. A role for oestrogen in the process of labour is supported by the finding that pregnancies are often prolonged when oestrogen levels in maternal blood and urine are low, as in placental sulphatase deficiency. In this condition, low levels do not indicate severe foetal morbidity but the enzyme deficiency and there is close association between failure to initiate or progress labour and recessive X linked ichthyosis in the male offspring, because of the lack of oestrogen role here. Please note that the major precursor for prostaglandins is arachadonic acid, which is stored in glycerophospholipids. As gestation advances, the progressively increasing levels of oestrogen stimulate the storage of these glycerophospholipids containing arachadonic acid, in foetal membranes, and the onset of labour is related to the release of stored precursors of prostaglandins from the foetal membranes. Take home message: Placental steroid sulphatase deficiency leads to low maternal oestrogens and, in some pregnancies, to a failure of labour to initiate or to progress normally.

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  4. Long answer:
    • Lamellar ichthyosis and it presents equally in both sexes.

    Classification of lamellar ichthyosis:
    1) Classical lamellar ichthyosis, autosomal recessive: There are 3 types of classical lamellar ichthyosis with 3 different genes mutations.
    2) Bathing-suit ichthyosis: a peculiar phenotype (a rare variant) of lamellar ichthyosis (temperature-sensitive phenotype), autosomal recessive and it is characterized by scaling confined to the warmer areas of skin with partial resolution of scaling in the face and limbs. It is due to temperature-sensitive transglutaminase 1, which was demonstrated to have reduced activity with a rise in temperature from 25° to 37°C.
    3) Autosomal dominant lamellar ichthyosis



    • ‎*Ichthyosis vulgaris: Retention hyperkeratosis (with HYPOgranulosis or absent granular layer, filaggrin synthesis is defective). Filaggrin (from filament aggregating protein) is a 37-kD peptide which is a major component of the keratohyaline granule in the granular layer. Filaggrin binds to keratin filaments causing their aggregation and leading to flattening of the stratum corneum keratinocytes (corneocytes).

    *Recessive X linked ichthyosis: Retention hyperkeratosis (with NORMAL granular layer or SLILGHT HYPERgranulosis). Typically, recessive X-linked ichthyosis affects males who inherit an X chromosome bearing a mutated steroid sulphatase gene from their asymptomatic carrier mother. The gene for steroid sulphatase is located at the distal end of the short arm of the X chromosome. The steroid sulphatase deficiency has been identified as the cause of both recessive X-linked ichthyosis and placental sulphatase deficiency. Placental steroid sulphatase deficiency is a risk factor in affected pregnancies, and knowledge of the carrier status could reduce perinatal risk for mother and baby (prolonged labour). The enzyme SUBSTRATE, cholesterol sulphate, is elevated in many tissues, including stratum corneum, but serum cholesterol levels are normal, reason? Because its main synthetic enzyme is hydroxymethylglutamyl-CoA reductase. Lipid analysis of normal epidermis shows a gradual decline in cholesterol sulphate (which stabilizes lipid bilayers) from 6% in the granular layer to 3% in the stratum corneum. In recessive X-linked ichthyosis, cholesterol sulphate accounts for 12–30% of stratum corneum lipids. This disturbs stratum corneum intercellular lipid bilayer disintegration and desquamation (normally epidermal cholesterol, NOT cholesterol sulphate, triggers it). So the elevated cholesterol sulphate level leads to retention ichthyosis while cholesterol prevents it (note that many cholesterol-lowering drugs have caused ichthyosis as a side effect). Steroid sulphatase is one of the two isomers of aryl sulphatase C, a membrane-bound microsomal enzyme, and is responsible for hydrolysing sulphate groups from cholesterol sulphate and certain other steroids. The sulphated forms of some steroid sex hormones, such as oestrone, are increased in patients with recessive X-linked ichthyosis. Thus, altered sex hormone profile may, in part, explain the abnormal testicular development in some recessive X-linked ichthyosis patients.

    *Lamellar ichthyosis: Retention hyperkeratosis (with HYPERgranulosis). Normally, cornification involves the construction of the cornified envelope from intracellular protein precursors including loricrin and involucrin. These are cross-linked to lipid ceramides in the granular layer by the action of transglutaminase 1. Kinetic studies in this disease revealed a near-normal transit time, and it is therefore classified as a retention disorder of cornification (retention hyperkeratosis with hypergranulosis). Mutations in the keratinocyte transglutaminase-1 gene on chromosome 14q11.1 interfere with the crosslinkage of loricrin and involucrin and the formation of the cornified cell envelope (retention hyperkeratosis).

    ReplyDelete

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Main Works of Reference List (The first eight are my top favourites)

  • British National Formulary
  • British National Formulary for Children
  • Guidelines (BAD - BASHH - BHIVA - Uroweb)
  • Oxford Handbook of Genitourinary Medicine, HIV, and Sexual Health
  • Oxford Handbook of Medical Dermatology
  • Rook's Textbook of Dermatology
  • Simple Skin Surgery
  • Weedon's Skin Pathology
  • A Concise Atlas of Dermatopathology (P Mckee)
  • Ackerman's Resolving Quandaries in Dermatology, Pathology and Dermatopathology
  • Andrews' Diseases of the Skin
  • Andrology (Nieschlag E FRCP, Behre M and Nieschlag S)
  • Bailey and Love's Short Practice of Surgery
  • Davidson's Essentials of Medicine
  • Davidson's Principles and Practice of Medicine
  • Fitzpatrick's Colour Atlas and Synopsis of Clinical Dermatology (Klaus Wolff FRCP and Richard Allen Johnson)
  • Fitzpatrick’s Dermatology in General Medicine
  • Ganong's Review of Medical Physiology
  • Gray's Anatomy
  • Hamilton Bailey's Demonstrations of Physical Signs in Clinical Surgery
  • Hutchison's Clinical Methods
  • Lever's Histopathology of the Skin
  • Lever's Histopathology of the Skin (Atlas and Synopsis)
  • Macleod's Clinical Examination
  • Martindale: The Complete Drug Reference
  • Oxford Handbook of Clinical Examination and Practical Skills
  • Oxford Textbook of Medicine
  • Practical Dermatopathology (R Rapini)
  • Sexually Transmitted Diseases (Holmes K et al)
  • Statistics in Clinical Practice (D Coggon FRCP)
  • Stockley's Drug Interactions
  • Treatment of Skin Disease: Comprehensive Therapeutic Strategies
  • Yen & Jaffe's Reproductive Endocrinology