Ichthyosis, congenital

This is part of Rare diseases.

Diagnosis: Ichthyosis, congenital

Synonyms: Lamellar ichthyosis, Epidermolytic (bullous) ichthyosis

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Publication date: 2013-12-27
Version: 5.0

The disease

Ichthyosis is the collective name for a group of disorders consisting of more than 20 hereditary conditions, all characterized by significantly increased thickness of the cornified layer of the skin, and extensive scaling of the skin. This text describes four subgroups, all with neonatal onset:

  • lamellar ichthyosis
  • erythrodermic ichthyosis
  • pleomorphic ichthyosi
  • epidermolytic (bullous) ichthyosis

The first three subgroups belong to a heterogeneous group of disorders known as “autosomal recessive congenital ichthyosis” (ARCI). Ichthyosis vulgaris and X-linked ichthyosis are not dealt with here as they seldom give rise to major problems, usually do not present in neonates, and are far more common than the rare diseases described here. Ichthyosis may also occur in association with other disorders, such as Sjögren-Larsson syndrome, Refsum disease or Netherton syndrome. Separate information on these disorders is available in the Rare Disease Database of the Swedish Board of Health and Welfare.

Some descriptions of individuals who are likely to have been affected by ichthyosis date very far back. One of the first scientific descriptions was made in 1777 by French physician Anne-Charles Lorry, who gave an account of a man with a severe and very rare form of ichthyosis.

Occurrence

Congenital ichthyosis in Sweden occurs in approximately 1-2 individuals per 100,000 population, meaning that between 100 and 200 people in Sweden are affected. Every year 2-4 children are born with congenital ichthyosis, most of whom have the types lamellar ichthyosis (with thick scales) or erythrodermic ichthyosis (with finer scales and severely reddened skin). In most cases the condition is life-long, but pleomorphic ichthyosis is a form that improves spontaneously.

Epidermolytic ichthyosis (associated with blisters, sores and scales) is a very rare form, affecting only a few individuals per million population.

Cause

Congenital ichthyosis is caused by a mutation in one of the genes required for normal formation of the cornified layer in the outermost layer of the skin (the epidermis). Approximately 15 genes with mutations that underlie ichthyosis are currently known, but new mutations in other genes are continuously being identified. The genetic cause of congenital ichthyosis can currently be identified in approximately 80 per cent of all cases.

The fact that so many different genes may underlie similar skin symptoms is most likely a result of their interaction in a chain of cellular processes involved in the creation of the outermost skin barrier, which consists of special fats (lipids) and horny cells. A fault anywhere in the chain of production will lead to impaired barrier function and excessive water loss through the skin. This will trigger the skin’s automatic repair processes, including increased cell regeneration, thickening of the horny layer, and some degree of skin reddening (inflammation).

As the genetic defect is permanent, the repair process is kept up without the skin ever healing properly. Most likely the intrinsic repair attempts contribute to the ichthyosis symptoms, which may explain why the clinical features of the various types of ichthyosis partly overlap. Another explanation of overlapping symptoms is that different types of mutation in one and the same gene may result in ichthyosis with varying degrees of severity. Many other genetic factors also affect the severity of the skin symptoms. There may therefore be wide variations, even in siblings with exactly the same mutations.

Epidermolytic ichthyosis is caused by a different type of barrier defect than lamellar, erythrodermic or pleomorphic ichthyosis. The defect is located in one of the proteins keratin 1 or 10, which form the cellular skeleton of epidermal cells. The anomalous keratin molecules are erroneously built into the cellular skeleton, which becomes fragile. The result is cellular break-up (epidermolysis), which may lead to superficial blistering and infections developing in the broken skin. Moreover, excessive keratin accumulates in the newly regenerated horny cells that form as a consequence of the repair process, thickening the horny layer in some parts of the skin.

Figure. Enlarged cross section of skin. The upper boxes show characteristic epidermal abnormalities associated with two major ichthyosis forms.

One third of all cases of ARCI, i.e. lamellar, erythrodermic and pleomorphic ichthyosis, are caused by mutations in a gene known as TGM1, on chromosome 14 (14q11.2). TGM1 regulates the production of (codes for) the enzyme transglutaminase type 1, which is essential for the development of the cornified cell envelope in the horny layer and the anchorage of lipid molecules to the surface of the cell envelope. Many types of TGM1 mutations may result in enzyme deficiency in the skin, and thereby a defective skin barrier. ARCI can also be caused by deficiencies in various transport proteins and lipid-converting enzymes in the epidermis that are required for normal formation of the horny layer lipids. One of several causes is found in point mutations in one of the genes CGI-58, ALOX12B or ALOXE3, the latter two on chromosome 17 (17p13.1), and ABCA12 on chromosome 2 (2q34). Mutations that cause complete absence of ABCA12 protein in the skin underlie the most severe and rarest form of the disease, known as harlequin ichthyosis, which may be lethal in the neonatal period.

Other causes of ARCI include mutations in NIPAL4 (ichthyin) on chromosome 5 (5q33) and CYP4F22 on chromosome 19 (19p13.12).

Pleomorphic ichthyosis is characterised by severe ichthyosis present at birth, followed by spontaneous improvement during the first few weeks of life. Mild skin symptoms will persist throughout life. “Pleomorphic” refers to the fact that the clinical presentation changes over time, and there are several genetic variants. In prematurely born children (prematurity ichthyosis) the condition is caused by mutations in SLC27A4, a gene that plays a role in the skin’s lipid metabolism, especially during the foetal stage. There are also forms caused by pressure- and temperature-sensitive mutations in the genes TGM1, ALOX12B and ALOXE3. These mutations cause major functional disturbances in warm skin, for example in the foetal environment or under tight clothes, but only mild problems after delivery or in cold skin. Approximately 15 per cent of all children born with a sticky membrane (collodion baby) develop this variant of pleomorphic ichthyosis.

Figure. Clinical categorization of congenital ichthyosis (with the exception of epidermolytic ichthyosis and syndromes associated with ichthyosis) based on the severity of scaling and degree of skin reddening (erythema) in adults. The most common genes are given. The different forms partially overlap, both genetically and clinically.

Heredity

The inheritance pattern of lamellar, erythrodermic and pleomorphic ichthyosis is, as a rule, autosomal recessive, but rare autosomal dominant forms most likely exist.

An autosomal recessive inheritance pattern means that both parents are healthy carriers of a mutated gene. In each pregnancy there is a 25 per cent risk that the child will inherit double copies of the mutated gene (one from each parent), in which case the child will have the disease. In 50 per cent of cases the child inherits only one mutated gene (from one parent only) and like both parents, will be a healthy carrier of the mutated gene. In 25 per cent of cases the child will not have the disease and will not be a carrier of the mutated gene.

A person with an inherited autosomal recessive disease has two mutated genes. If this person has a child with a person who is not a carrier of the mutated gene, all the children will inherit the mutated gene but they will not have the disorder. If a person with an inherited autosomal recessive disease has children with a healthy carrier of the mutated gene (who has one mutated gene) there is a 50 per cent risk of the child having the disorder, and a 50 per cent risk of the child being a healthy carrier of the mutated gene.

Figure: Autosomal recessive inheritance

The pattern of inheritance in epidermolytic ichthyosis is autosomal dominant, but in most cases the disorder is caused by a new mutation. This means that the genetic mutation occurs in an individual for the first time and is not inherited from either parent. Consequently, parents with a child with a new mutation generally do not have an increased risk of having another child with the disorder. An exception is if one of the parents only has the mutation in some cells (mosaicism), in which case the skin symptoms may be limited to one or only a few patches. However, the new genetic mutation will be hereditary and an adult with this mutation risks passing on the mutated gene to his/her children.

An autosomal dominant pattern of inheritance means that one of the parents has the disease, and so has one normal gene and one mutated gene. Sons and daughters of this parent have a 50 per cent risk of inheriting the disease. Children who do not inherit the mutated gene do not have the disease and do not pass it down.

Figure: Autosomal dominant inheritance

Symptoms

All forms of ichthyosis affect the protective function of the skin (the skin barrier), making the skin dry, thick, scaly, and sometimes red, itchy and blistered.

ARCI: Lamellar, erythrodermic and pleomorphic ichthyosis

Lamellar ichthyosis (thick scales) and ichthyosiform erythroderma (finer scales but severely reddened skin) are collective names for a number of severe, lifelong forms of ichthyosis that are not associated with blistering. In pleomorphic ichthyosis the child is severely affected at birth, but the condition rapidly improves.

In all three forms the degree of skin symptoms vary from fine light scaling to large, often dark-coloured thick scales covering the whole body. The skin is often extremely dry and sometimes develops superficial cracks. The skin may redden (erythroderma), hair and nails tend to be affected, and there may be extensive scaling and thickening of the skin on the palms of the hands and soles of the feet. The symptoms vary greatly in severity and impact on daily life.

At birth, infants with ARCI are usually encased in a glue-like membrane (“collodion baby”). This membrane cracks and is shed in a matter of days or weeks. The severity of the permanent skin condition can usually be determined during the first few months of life. In most collodion babies, the condition eventually develops into lamellar or erythrodermic ichthyosis. Some of these children have the “self-healing collodion baby syndrome”, which belongs to the group of pleomorphic ichthyosis.

In both children and adults the eyelids may be turned outwards and do not always close properly (ectropion). As a result these individuals often sleep with their eyes slightly open, which causes itching, infections, and runny eyes.

Skin flakes accumulating in the auditory canals may affect hearing.

In severe lamellar ichthyosis the hair may also be affected. Sometimes the hair only grows in patches or is completely missing. It is common to have a high hairline and poor hair growth.

More than 80 per cent of individuals with lamellar ichthyosis have trouble maintaining an even body temperature, as the ability to perspire is reduced. This causes overheating, fatigue, irritability and liability to develop headaches during physical exertion, or when the outdoor temperature is high. It is also common to be excessively sensitive to cold. Many individuals with severe ichthyosis find that the condition of their skin becomes worse in extreme heat and cold.

Children with severe ichthyosis may fail to thrive during the first year of life. Weight gain may be slower than expected or even absent for long periods of time, especially in surviving children with harlequin ichthyosis. In harlequin ichthyosis the taut layer of thick skin leads to abnormalities such as shortened fingers and toes, protruding mouth and eyes, and outer ears that fuse with the scalp.

Epidermolytic ichthyosis

Epidermolytic ichthyosis, also known as bullous ichthyosis, is very rare. In epidermolytic ichthyosis the newborn child has blisters and superficial sores all over the body. The blisters heal but tend to flare up at intervals, often in conjunction with skin infections.

During infancy the skin thickens and spiny scales appear. Later, the skin becomes excessively thick and scaly, especially on knees and elbows and in flexural creases. In such spots, the skin is very brittle, and may be difficult to keep soft and clean. Thick scales tend to collect in the folds of the skin, which may restrict movement and give rise to an unpleasant odour.

Depending on which keratin gene is mutated, the horny layer on the palms of the hands and soles of the feet may also be abnormally thick (keratodermia).

Diagnosis

The diagnosis is established primarily through clinical examination by an experienced dermatologist, in combination with family medical history. Examination of skin samples using light microscopy may be of value, especially in epidermolytic ichthyosis, but special examinations are usually required (electron microscopy, immune staining and DNA analysis) to establish an accurate diagnosis.

DNA-based diagnostics is becoming increasingly common. At the time of diagnosis the family should be offered genetic counselling. Carrier and prenatal diagnostics, as well as pre-implantation genetic diagnostics (PGD) in association with IVF (in vitro fertilization), are available in families where the mutation is known.

Newborn children with epidermolytic ichthyosis often have blisters and rashes that can be misdiagnosed as epidermolysis bullosa. There is separate information material about epidermolysis bullosa in the Rare Disease Database of the Swedish Board of Health and Welfare.

Treatment/interventions

There is currently no cure for congenital ichthyosis and efforts are directed at relieving symptoms. Ichthyosis requires continuous daily treatment of the skin, which may be both time-consuming and cosmetically displeasing. There are oral medications that have a beneficial effect, but since there is a risk of undesirable side effects they are only prescribed in severe cases.

Newborn children with severe ichthyosis need to be cared for at a neonatal ward. The hospital dermatologist should be contacted as soon as possible to make the diagnosis and inform parents and staff. An ophthalmologist should also be contacted at an early stage. After delivery the child is often cared for in an incubator, and is then placed in a cot as soon as the general state of health allows for it.

It is important that the parents are encouraged to look at and touch their child even if the baby’s appearance deviates from what they expected. Breast- or bottle-feeding the child while holding it should be encouraged.

As the child grows older teachers as well as classmates and others who meet the child should be informed about the cause of the skin disorder. The appearance of the child’s skin may cause peers to avoid games that involve holding hands or other kinds of touching. It should be emphasised that the disease is not communicable. To prevent isolation and other social problems, age-appropriate information about the cause and treatment of the disease is important. Professional psychological and social support are important both for individuals with ichthyosis and for those close to them.

If the thickened skin layers restrict movement, daily movement training is needed. Exercise instructions are provided by a physiotherapist.

Children who fail to thrive need contact with a dietician, who can help plan meals and recommend supplements if necessary.

Individuals with ichthyosis should take daily baths or showers and keep their skin well moisturised using creams with a keratolytic effect that should be applied at least once a day. Keratolytics re-hydrate the skin and soften the horny outer layer of the skin. This eases the scaling process, softens the skin, and alleviates any tendencies to cracking. Common moisturising agents are carbamide (urea), propylene glycol and certain alpha hydroxy acids (AHAs), including lactic acid and glycolic acid. Topical salicylic acid may be used on small skin areas. Medications in cream form (such as retinoids) are sometimes used.

Long baths at least once a week are a vital part of the treatment regime. Oil, salt or carbamide should be added to the bathwater to soften the skin. The scales can then be removed using a pumice stone, scrubbing glove or a wet washcloth.

Regular foot care is recommended, for example to alleviate problems with cracks in calloused feet.

Oral vitamin A drugs (synthetic retinoids) are sometimes used. These have a normalising effect on the cornification process, but treatment results vary among the different types of ichthyoses. In epidermolytic ichthyosis oral retinoids are only effective in individuals with a particular type of mutation, while others seem to get worse, with increased blistering. Pregnant women must never be treated with drugs containing vitamin A as retinoids cause severe birth defects. If a pregnancy is planned, treatment involving drugs containing vitamin A should be discontinued at least one year, and preferably two years before the pregnancy, as retinoids may be retained in the body for a long period of time. The liver, the skeleton, and blood lipids may also be affected by long-term treatment.

In the choice of career, it is advisable for individuals with ichthyosis to avoid occupations that require being in very dirty, hot, or extremely cold environments.

Lamellar, erythrodermic and pleomorphic ichthyosis

Newborn children with ichthyosis need to be treated 6-8 times a day with a cream consisting of equal parts of paraffin and petroleum jelly. Medical staff should regularly check that the skin is not infected, since infected skin cracks may lead to blood poisoning (sepsis).

The thick, glue-like membrane with which many of these children are born cracks and is shed within the first few weeks. The membrane may be shed earlier if the child is given frequent baths as soon as the umbilicus is sufficiently healed. Common tap water can be used.

Newborns who lack the collodion membrane are sometimes born with an intense redness of the skin. As the skin barrier is thin and damaged these children lose a great deal of heat and moisture through the skin and the fluid balance needs to be carefully monitored. Ointments used to lubricate the skin must also be chosen with care, since foreign substances can easily penetrate the thin skin barrier.

If the eyes cannot be closed properly (ectropion), regular contact with an ophthalmologist is required. Eye drops or lubricants (tear substitutes) need to be used daily to prevent dehydration and permanent damage to the cornea. In older children and adults with severe problems, eyelid plastic surgery may be helpful, although the effect is rarely permanent.

In cases of hearing impairment or other discomfort, an ENT physician may remove accumulated skin scales from the auditory canals.

Scales on the scalp may be removed with a fine-toothed comb after the scalp has been treated with ointment for a few hours. Scalp treatment can sometimes be carried out overnight, with plastic film and a cap over the scalp.

Most individuals with congenital ichthyosis are sensitive to heat. Air conditioning in the car, a spray bottle of water, a plastic bag of ice cubes, or a wet towel from a cooler bag are helpful aids in hot weather. It is important to inform preschool and school personnel that the child needs extra attention when playing or participating in games or sports.

Epidermolytic ichthyosis

Newborn children with epidermolytic ichthyosis have very fragile skin and the outermost skin layer (the epidermis) easily peels off. To minimise skin damage the child should not be monitored with taped electrodes, or other adherent materials. Non-adherent dressings should be applied to sores and blisters.

Later in life the main symptom is thick, moist scaling, and the skin easily blisters in response to forceful exfoliation. Bacterial infections may lead to increased blistering and should be treated with antibiotics. If there is a problem with recurring skin infections, prophylactic antiseptics or antibiotics may be necessary.

Practical advice

The home should be easy to keep clean and have no wall-to-wall carpeting. It is important to have a good vacuum cleaner that picks up skin flakes that may accumulate on the floor. If possible, the bathroom should be equipped with a bathtub and there should be room enough to apply moisturisers. A large cupboard is practical for storage of various ointments.

Washing machines should contain as few rubber gaskets as possible, as the ointments erode them. Water use and laundry detergent consumption will be extremely high.

Clothing should be cotton rather than synthetics. Wear and tear is considerable, particularly on underwear and socks, but also on sheets and towels.

National and regional resources in Sweden

Diagnostics is usually carried out at a county hospital dermatology clinic. Severe cases may be referred to the Dermatology Clinic at Uppsala University Hospital, which is a national centre of expertise for certain types of inherited skin diseases (genodermatoses). As soon as the diagnosis is established, the medical treatment is managed by dermatologists and paediatricians.

Resource personnel

Senior physician Marie Virtanen, MD, PhD, Dermatology Clinic, Uppsala University Hospital, SE-751 85 Uppsala, Sweden. Tel: +46 18 611 00 00, fax: +46 18 611 26 80, email: marie.virtanen@akademiska.se.

Senior physician Maritta Hellström Pigg, MD, PhD, Department of Clinical Genetics, The Rudbeck Laboratory, Uppsala University Children’s Hospital, SE-751 85 Uppsala, Sweden. Tel: +46 18 611 30 00, fax: +46 18 611 59 47, email: maritta.hellstrom.pigg@akademiska.se.

Associate professor Agneta Gånemo, registered nurse, Dermatology Clinic, Skåne University Hospital, SE-205 02 Malmö, Sweden. Tel: +46 40 33 18 44, email: agneta.ganemo@skane.se.

Courses, exchanges of experience, recreation

The Ichthyosis Association arranges a weekend seminar for people with ichthyosis and their families, usually on an annual basis. The programme includes lectures and provides opportunities to exchange experiences. It is also the annual meeting of the association. Regional meetings are arranged two or three times every year. For further information, contact the Ichthyosis Association (see under “Organizations for the disabled/patient associations”).

Ågrenska is a national competence centre for rare diseases and its families’ programme arranges stays for children and young people with rare diseases and their families. Ågrenska is open to families from the whole of Sweden and focuses particularly on the needs of children and young people with rare diseases. Every year a number of adults with rare diseases also visits Ågrenska. Information is available from Ågrenska, Box 2058, SE-436 02 Hovås, Sweden. Tel: +46 31 750 91 00, fax: +46 31 91 19 79, email: agrenska@agrenska.se, www.agrenska.se.

Organizations for the disabled/patient associations etc.

The Ichthyosis Association is a national association for those with ichthyosis, syndromes which include ichthyosis, and related skin diseases. The association is active both on a regional and national level. The Ichthyosis Association is divided into twelve regions, ten of them with a governing committee. The two regions without a governing committee have a contact person. Information about these regions is available on the website of the association. The Ichthyosis Association publishes a newsletter for members three times a year.
The Ichthyosis Association, Sturegatan 4C, Box 1386, SE-172 27 Sundbyberg, Sweden. Tel: +46 8 546 404 51, www.iktyos.se.

Rare Diseases Sweden, Box 1386, SE-172 27 Sundbyberg, Sweden. Tel: +46 8 764 49 99, email: info@sallsyntadiagnoser.se, www.sallsyntadiagnoser.se. Rare Diseases Sweden is a national association promoting the interests of people with rare diseases.

Courses, exchanges of experience for personnel

During the Ågrenska Family Program weeks, training days are organized for personnel working with the children and young people who are participating. Information is available from Ågrenska, Box 2058, SE-436 02 Hovås, Sweden. Tel: +46 31 750 91 00, fax: +46 31 91 19 79, email: agrenska@agrenska.se, www.agrenska.se.

Research and development

Several research projects on ichthyosis are ongoing at Uppsala University:

  • Basic research on keratinisation mechanisms and treatment, including retinoid treatment, as well as molecular genetic characterisation of the congenital ichthyoses. Contact persons: Associate Professor Hans Törmä, PhD, The Skin Research Laboratory.
  • New treatments. Contact person: Marie Virtanen, MD, PhD.
  • Molecular genetic characterisation of congenital ichthyosis. Contact persons: Professor Niklas Dahl and Maritta Hellström Pigg, MD, PhD, Department of Clinical Genetics, The Rudbeck Laboratory.

Information material

Short summaries of all the database texts are available as leaflets, in Swedish only. They can be printed out or ordered by selecting the Swedish version, and then clicking on the leaflet icon which will appear under “Mer hos oss” in the column on the right-hand side.

Information from The Swedish Ichthyosis Association (see under “Organizations for the disabled/patient associations etc.”):

  • “Iktyos – en handbok för dig som vill veta mer” (in Swedish only, 2008). Gånemo, A.
  • “Att leva med iktyos” (in Swedish only). Information DVD about life with ichthyosis.

 The Ichthyosis Association also provides booklets and broschures that can be ordered free of charge. They can also be downloaded from their website: www.iktyos.nu.

Newsletter from Ågrenska on ichthysosis, nr. 342 (2009). Newsletters are edited summaries of lectures delivered at family and adult visits to Ågrenska. Can be ordered from Ågrenska, Box 2058, SE-436 02 Hovås, Sweden. Tel: +46 31 750 91 00, fax: +46 3191 19 79, email: agrenska@agrenska.se
The newsletter is also available at www.agrenska.se.

Literature

Fowler AJ, Moskowitz DG, Wong A, Cohen SP, Williams ML, Heyman MB. Nutritional status and gastrointestinal structure and function in children with ichthyosis and growth failure. J Pediatr Gastroenterol Nutr 2004; 38: 164-169.

Gånemo A, Lindholm C, Lindberg M, Sjödén PO, Vahlquist A. Quality of life in adults with congenital ichthyosis. J Adv Nurs 2003; 44: 412-419.

Gånemo A, Pigg M, Virtanen M, Kukk T, Raudsepp H, Rossman-Ringdahl I et al. Autosomal recessive congenital ichthyosis in Sweden and Estonia: clinical, genetic and ultrastructural findings in eighty-three patients. Acta Derm Venereol 2003; 83: 24-30.

Oji V, Tadini G, Akiyama M, Blanchet Bardon C, Bodemer C, Bourrat E et al. Revised nomenclature and classification of inherited ichthyoses: results of the First Ichthyosis Consensus Conference in Sorèze 2009. J Am Acad Dermatol 2010; 63: 607-641.

Vahlquist A, Gånemo A, Virtanen M. Congenital ichthyosis: an overview of current and emerging therapies. Acta Derm Venereol 2008; 88: 4-14.

Vahlquist A. Pleomorphic ichthyosis: proposed name for a heterogeneous group of congenital ichthyoses with phenotypic shifting and mild residual scaling. Acta Derm Venereol 2010; 90: 454-460.

Books

Vahlquist A. Hudsjukdomar. Genetiska sjukdomar. Ed: Nordenskjöld M. Liber 2011; 231-234.

Gånemo A. Iktyos - en handbok för dig som vill veta mer! Ängelholm 2008. ISBN 978-91-633-3327-9.

Database references

OMIM (Online Mendelian Inheritance in Man)
www.ncbi.nlm.nih.gov/omim 
Search: ichthyosis

GeneReviews (University of Washington)
www.genetests.org (select “GeneReviews”, then “Titles”)
search: ichthyosis

Document information

The Swedish Information Centre for Rare Diseases produced and edited this information material.

The medical expert who wrote the draft of this information material is Professor emeritus Anders Vahlquist, Uppsala University Hospital, Sweden.

The relevant organisations for the disabled/patient associations have been given the opportunity to comment on the content of the text.

An expert group on rare diseases, affiliated with the University of Gothenburg, approved the material prior to publication.

Publication date: 2013-12-27
Version: 5.0
Publication date of the Swedish version: 2012-12-06

For enquiries contact The Swedish Information Centre for Rare Diseases, The Sahlgrenska Academy at the University of Gothenburg, Box 422, SE-405 30 Gothenburg, Sweden. Tel: +46 31 786 55 90, email: ovanligadiagnoser@gu.se.

 

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