Acrodermatitis enteropathica is an autosomal recessive genetic disease, the main link in the pathogenesis of which is a violation of zinc absorption in the small intestine. This pathology is characterized by manifestations associated with zinc deficiency – damage to the gastrointestinal tract, the formation of rashes, pustules and vesicles on the skin, alopecia, decreased immunity, weight loss. Diagnosis is made by examining the concentration of zinc ions in blood plasma, the rate of absorption of radioactive Zn-65, zinc excretion through the urinary system. Treatment is taking increased doses of compounds of this trace element (for example, zinc oxide).
E83.2 Acrodermatitis enteropathica
Acrodermatitis enteropathica (Brandt syndrome, Dalbolt-Kloss disease) it was studied between 1935 and 1942. The dermatologist Brandt was the first to draw attention to the unusual form of skin lesions of the distal extremities (acrodermatitis) in the 30s. In 1942, Swedish doctors Dalbolt and Kloss identified enteropathy concomitant with acrodermatitis – a lesion of the gastrointestinal tract. Since then, according to all international classifications, including ICD-10, Brandt’s disease or Dalbolt-Kloss syndrome has been called “acrodermatitis enteropathica”. In the future, the development of genetics helped to explain the main manifestations of the syndrome.
The manifestation of the disease occurs in early childhood – at the age of one and a half weeks to 1-2 years. Cases of acrodermatitis enteropathica have also been described in older children (3-4 years and even 10-15 years). Like many autosomal recessive pathologies, it has an increased risk of occurrence in closely related marriages, on average in the population, the Dalbolt-Kloss syndrome occurs with a frequency of 1-9:1000000.
The point mutation occurs in the SLC39A4 gene, localized on the large arm of the 8th chromosome and consisting of 12 exon sites. Expression of this gene occurs in the cells of the pancreas, small and large intestine, duodenum. As a result of the mutation, the structure of the Zip4 protein (Zip4 transporter, zinc transporter protein), known as the zinc binding factor, is disrupted, so the bioavailability of zinc drops sharply – from 25-32% normally to 2-3% in acrodermatitis enteropathica. All clinical manifestations of Dalbolt-Kloss syndrome are caused by zinc deficiency in the body.
In acrodermatitis enteropathica, a genetic defect causes the insufficiency of a special zinc-binding factor, which is produced by the pancreas. Breast milk contains a sufficient amount of this factor, therefore, with proper breastfeeding, acrodermatitis enteropathica does not manifest itself for some time. The first signs of the disease occur when the baby is weaned and transferred to artificial feeding, often when introducing complementary foods into the diet.
Zinc is a part of many digestive enzymes, therefore, if its bioavailability is violated, the work of more than two hundred catalyzing proteins is disrupted. The defective zinc-binding factor produced by the pancreas may be compensated for some time by its intake from mother’s milk. With the refusal of natural feeding after 7-10 days, the first signs of acrodermatitis enteropathica appear, which, in the absence of specific treatment, become more pronounced.
The resulting hypocyncemia leads to a violation of tryptophan metabolism, metabolism and synthesis of other amino acids and some fats, as a result of which the cells are oversaturated with triglycerides. There is a drop in the level of immunoglobulins, especially classes A and M, disrupted by the interaction between the cellular and humoral immune response. Skin manifestations in acrodermatitis enteropathica are caused by a change in the ratio between oleic and linolenic acids, which play an important role in the activity of the epidermis. When studying the biopsy of the small intestine, a decrease in the activity of oligopeptidases and succinate dehydrogenase is revealed.
Manifestations of acrodermatitis enteropathica occur when the intake of exogenous zinc-binding factor with breast milk decreases. Depending on the nature of the child’s diet, symptoms may appear in the first weeks or months of life, in exceptional cases – in 3-5 years or in adolescence. First, the gastrointestinal tract is affected: the nature of the stool changes, it becomes frequent and watery, with an unpleasant odor, undigested food residues are determined in it. Flatulence develops, intestinal colic, which leads to anxiety of the child, feeding becomes difficult. Weight gain decreases, hypotrophy often occurs.
Skin manifestations of acrodermatitis enteropathica begin with an erythematous rash, which is localized around the eyes, mouth, and anus. Then the rash spreads to the buttocks, inguinal-femoral folds, genitals. A frequent sign is the development of symmetrical rashes on the elbow and knee bends, the trunk. The erythematous nature of the rash is gradually replaced by the appearance of pustular and vesico-bullous elements, which then transform into serous crusts – the latter can acquire a purulent character due to the addition of a secondary infection. The final development of rashes are ulcers and erosions of a bluish-red color.
In addition to the epidermis, skin appendages and mucous membranes are also affected in acrodermatitis enteropathica. A characteristic symptom is alopecia, often of a total nature, with loss of eyelashes and eyebrows. Pathological changes also affect the nails – paronychia, subarticular hyperkeratosis develop, in some cases there is complete rejection of the nails. On the mucous membranes there are inflammations of a candidal nature – stomatitis, balanoposthitis, glossitis, conjunctivitis. In the corners of the mouth, long-term non-healing jams are formed. Due to a decrease in the activity of immunity caused by acrodermatitis enteropathica, a secondary infection quickly joins all skin and mucous membrane lesions, which aggravates the course of the disease and complicates diagnosis.
In the absence of specific treatment, the general condition of the child continues to deteriorate. Fever, general exhaustion, insomnia and lethargy, increased tearfulness are added to these symptoms. As a result of diarrhea, dehydration and water-salt imbalance sometimes occur. Eventually, severe dystrophy develops, which can cause death in acrodermatitis enteropathica.
Acrodermatitis enteropathica is diagnosed based on the study of symptoms and special laboratory tests:
- In the biochemical analysis of blood, there is a decrease in the level of zinc ions in plasma and a decrease in the activity of alkaline phosphatase, one of the zinc–dependent enzymes. The number of beta-lipoproteins decreases, the concentration of immunoglobulins A and M, cholesterol levels, and residual blood nitrogen increases. A general blood test shows an increase in ESR, often there is hypochromic anemia.
- The excretion of zinc in the urine is studied, in exceptional cases, the rate of absorption of this trace element is studied using its radioactive isotope – zinc-65.
- During a biopsy of the small intestine, villi atrophy is noticeable, there are inclusions in Paneta cells, the activity of enzymes, including saccharidases, is reduced.
- The diagnosis of this condition requires the mandatory participation of a geneticist, sequencing of the coding sequence of the SLC39A4 gene and identification of mutations in it.
Differential diagnosis is carried out with secondary zinc deficiency caused by malabsorption syndrome, inflammatory lesions of the small intestine, atrophy of its mucous membrane. Very often, skin rashes that appear are mistakenly associated with eczema, pyoderma, candidiasis – this can lead to improper treatment and even to the death of a child.
The aim of therapy for acrodermatitis enteropathica is to replenish zinc deficiency in the blood and tissues. For this purpose, publicly available drugs are used – zinc oxide or acetate. Already a week after the start of treatment, there is a significant improvement in the general condition – the work of the gastrointestinal tract is normalized, skin manifestations gradually fade away. The restoration of the skin appendages takes a little longer, but after 10-15 days the growth of hair and nails begins.
In the treatment of acrodermatitis enteropathica in infants, it is very important to keep them naturally fed to obtain the necessary zinc binding factor. In the absence of milk from the mother, you can use donor breast milk. In the future, you need to continue taking zinc-containing drugs for many years and at the same time regularly monitor the level of zinc in blood plasma.
The use of iodochlorohydroxyquinoline derivatives (enterosediv and others), previously widely used in the therapy of acrodermatitis enteropathica, is currently prohibited. This is due to a large number of side effects, including damage to peripheral nerves and the retina of the eye.
Symptomatic treatment is carried out by taking vitamins A, E, C and group B, digestive enzymes of the pancreas, antifungal agents, probiotics, gamma globulin. When secondary skin infections are added, antibiotics are prescribed. Externally, solutions of aniline dyes, clotrimazole, triderm, anti-inflammatory agents are used.
Prognosis and prevention
With timely detection of the disease and the beginning of specific therapy, the prognosis is usually favorable. It is important to constantly replenish zinc deficiency in order to maintain the normal level of activity of the immune system, the condition of the skin and gastrointestinal tract. In case of violation of the treatment regimen, enteropathic actodermatitis may have a recurrent course, including in an adult. Prevention is limited only to preventing the fall of zinc levels in tissues below the critical value, which is ensured by regular intake of its preparations and periodic biochemical blood tests.