Anders Vahlquist

The classification of inherited epidermolysis bullosa (EB): Report of the Third International Consensus Meeting on Diagnosis and Classification of EB

BACKGROUND Since publication in 2000 of the Second International Consensus Report on Diagnosis and Classification of Epidermolysis Bullosa, many advances have been made to our understanding of this group of diseases, both clinically and molecularly. At the same time, new epidermolysis bullosa (EB) subtypes have been described and similarities with some other diseases have been identified. OBJECTIVE We sought to arrive at a new consensus of the classification of EB subtypes. RESULTS We now present a revised classification system that takes into account the new advances, as well as encompassing other inherited diseases that should also be included within the EB spectrum, based on the presence of blistering and mechanical fragility. Current recommendations are made on the use of specific diagnostic tests, with updates on the findings known to occur within each of the major EB subtypes. Electronic links are also provided to informational and laboratory resources of particular benefit to clinicians and their patients. LIMITATIONS As more becomes known about this disease, future modifications may be needed. The classification system has been designed with sufficient flexibility for these modifications. CONCLUSION This revised classification system should assist clinicians in accurately diagnosing and subclassifying patients with EB.

Metabolism of the Vitamin A Transporting Protein Complex

Abstract. Biological turnover studies of the human vitamin A transporting protein complex and its individual components, prealbumin and retinol binding protein (RBP) have been performed in normal persons and in patients with severely impaired kidney function. The metabolic behaviour of prealbumin was very similar in the two groups of subjects studied, and it was concluded that prealbumin eatabolism can be dependent to only a minor extent on normally functioning kidney glomeruli.–RBP is present in several molecular forms in plasma. In normal conditions virtually all PRB is bound to prealbumin, but small amounts of RBP also occur in free form. The concentration of the free RBP is greatly increased in patients with grossly impaired glomerular filtration. The biological half‐life for free RBP was short in normal persons (about 4 hours) whereas in the patients this parameter was increased 10 to 15 fold. These findings suggest that most if not all free RBP in plasma is catabolized by the kidney. RBP complexed with prealbumin has a considerably longer half‐life than its free counterpart in normal persons but the absolute synthetic rate of the two components of RBP is similar. Thus it is proposed that most RBP is catabolized from the pool of the uneomplexed species.–From the data it can be calculated that as much as one third of the plasma vitamin A may be deposited in the kidney tubuli on degradation of RBP, since the mechanism for the renal eatabolism of this small protein seems to involve glomerular filtration followed by tubular reabsorption.

Mutations in the Fatty Acid Transport Protein 4 Gene Cause the Ichthyosis Prematurity Syndrome

Ichthyosis prematurity syndrome (IPS) is an autosomal-recessive disorder characterized by premature birth and neonatal asphyxia, followed by a lifelong nonscaly ichthyosis with atopic manifestations. Here we show that the gene encoding the fatty acid transport protein 4 (FATP4) is mutated in individuals with IPS. Fibroblasts derived from a patient with IPS show reduced activity of very long-chain fatty acids (VLCFA)-CoA synthetase and a specific reduction in the incorporation of VLCFA into cellular lipids. The human phenotype is consistent with Fatp4 deficiency in mice that is characterized by a severe skin phenotype, a defective permeability barrier function, and perturbed VLCFA metabolism. Our results further emphasize the importance of fatty acid metabolism for normal epidermal barrier function illustrated by deficiency of a member in the FATP family of proteins.

Cutaneous gene transfer for skin and systemic diseases.

This article is partially based on the findings presented at a symposium on Cutaneous Gene Therapy, held in Uppsala, September 2001, and abstracted in Acta Derm Venereol 81: 227–239.

Retinoid concentrations in skin, serum and adipose tissue of patients treated with etretinate*

Synthetic and natural retinoids were analysed in epidermis, dermis, subcutis and serum of twenty‐seven patients treated with etretinate (0·6–1·0 mg/kg/day) for 1–36 months. The concentrations of etretinate (including its major metabolite) in serum and normal‐appearing epidermis were 150–600 ng/ml and 50–350 ng/g, respectively. The serum and epidermal values were significantly correlated (P<0·05). The drug progressively accumulated in the subcutis attaining a maximum value of 15,500 ng/g. After the treatment, etretinate disappeared from the epidermis within i week. By contrast, the drug remained in the subcutis for several months after cessation of treatment. The epidermal composition of endogenous retinoids changed during etretinate therapy as reflected in an increased ratio of 3‐dehydroretinol to all‐trans retinol.

The Concentrations of Retinol-Binding Protein, Prealbumin, and Transferrin in the Sera of Newly Delivered Mothers and Children of Various Ages

Umbilical-cord blood from 50 full-term newborns and capillary or venous blood from 226 children varying in age from 6 weeks to 16 years was examined for content of retinol-binding protein (RBP), prealbumin, and transferrin. The mean levels of the three proteins in the newborns were 21 mug/ml, 128 mug/ml, and 1.65 mg/ml, respectively. The corresponding maternal levels were 39 mug/ml, and 3.2 mg/ml. Paired serum values of mothers and newborns showed a correlation for both RBP and prealbumin but not for transferrin. The low levels of RBP at birth (about 50 per cent of that of nonpregnant women) increased rapidly over the first 6 months to a maximum of 31 mug/ml but declined thereafter to a mean level of about 26 mug/ml, which was maintained until the age of puberty when adult values were gradually attained. In serum, the prealbumin levels showed a similar development, whereas the transferrin values reached constant adult levels as early as 2 years of age.

Aspects of the metabolism of retinol-binding protein and retinol.

Publisher Summary This chapter presents different aspects of the metabolism of retinol-binding protein (RBP) and retinol. RBP is not significantly decreased until the liver reserves of the vitamin are virtually abolished. The diminished concentration of RBP in plasma in manifest vitamin A deficiency reflects the impaired transport of retinol to the various tissues. The catabolism of RBP is probably greatly dependent on renal function, since a small fraction of free RBP exists in plasma although most is bound to prealbumin. The biological half-life of RBP was increased by about 50% in protein deficiency while the rate of synthesis was diminished to one-third of the normal value. The cellular accumulation of retinol is a temperature-dependent process. Incubations of the cells in the absence of oxygen or in the presence of metabolic inhibitors like sodium azide and EDTA did not change their ability to extract retinol from RBP. It is seen that the labeled RBP component exhibited a slower electrophoretic mobility than genuine RBP, which could complex with prealbumin. The low pH was chosen to minimize charge differences due to variable content of amide groups in the two forms of RBP.

Congenital ichthyosis: an overview of current and emerging therapies.

Congenital ichthyosis is a collective name for a group of monogenetic disorders of cornification, sometimes associated with systemic symptoms. There may be an abnormal quality or quantity of scale produced, abnormal thickness of stratum corneum or abnormal keratinocyte kinetics, often associated with skin inflammation. Pruritus, skin fragility, ectropion and anhidrosis are sometimes associated with the rare types of ichthyosis. Three important mechanisms are involved in the action of topical agents used in the treatment of ichthyosis: hydration, lubrication and keratolysis. The latter effect can also be achieved with systemic retinoids. For ichthyosis with an increased tendency towards skin infections, antimicrobials are another group of widely used agents. Considering that patients with ichthyosis are potential mega-users of topical therapy, with an estimated lifetime consumption of approximately one tonne cream per capita, surprisingly few controlled trials of the various treatments have been performed. Moreover, nearly all therapeutic principles were established long before the recent increase in knowledge about the aetiology and pathophysiology of ichthyosis. This calls for new ideas and intensified efforts to develop future ichthyosis therapies.

Improved topical treatment of lamellar ichthyosis: a double-blind study of four different cream formulations

Lamellar ichthyosis (LI) is characterized by generalized scaling of the skin and is often resistant to ordinary emollients. Recently, Locobase® fatty cream containing a mixture of 5% lactic acid and 20% propylene glycol (LPL) was found to be markedly effective in a pilot study. To consolidate this finding, a double‐blind study comparing LPL with the corresponding mixture in Essex® (Diprobase®) cream (LPE) and Locobase® fatty cream containing either 5% urea or 20% propylene glycol was conducted in 20 patients with LI. Before and after applying the creams twice daily on each of the four extremities for 4 weeks, the following investigations were performed: scoring of xerosis, scaling and erythema, measurements of skin hydration (capacitance) and transepidermal water loss (TEWL), and moulding of the skin surface (replicas). Xerosis was reduced by all four creams, but significantly more so by LPL (P < 0·001) and LPE (P < 0·01). Scaling was only reduced by LPL (P < 0·001) and LPE (P < 0·01), which also caused a slight increase in the erythema score (P < 0·05 for both). The patients’ weekly evaluation of symptoms showed that LPL produced the most rapid effect: the response rate after 4 weeks was 63%. Skin hydration and TEWL were both significantly increased by LPL and LPE, whereas skin roughness was reduced most by LPL. Fourteen patients preferred LPL over the other cream formulations. Ten patients continued using LPL for up to 8 weeks with good results and no side‐effects other than occasional irritation in the skin folds. LPL is a major advance in the topical treatment of LI that suits most patients. Some patients, however, seem to prefer the more hydrophilic LPE formulation. Both formulations effectively reduce hyperkeratosis and xerosis, but may cause slight irritation and adversely affect the epidermal barrier function.

Long-term safety of retinoid therapy*

The concern about long-term toxicity of oral synthetic retinoids has developed because many patients, especially those with genodermatoses, require lifelong therapy. Several organ systems are at risk, especially the hepatic, skeletal, and cardiovascular systems. Although acute hepatotoxicity is a rare side effect of etretinate and acitretin therapy, prospective studies have not demonstrated chronic liver toxicity. The frequency of bone changes induced by retinoids is difficult to estimate, because this adverse effect is usually asymptomatic and requires x-ray or scintigraphic examination for detection. Atherosclerosis develops in many patients who receive long-term retinoid therapy, but the extent to which the process is aggravated by drug-induced hyperlipidemia is not known. Many patients have now been treated with either etretinate or isotretinoin continuously for as many as 15 years and have not developed any signs of severe chronic toxicity. However, continued intense surveillance is recommended for patients expected to require lifelong therapy.