IPEX

Introduction

IPEX (immune dysfunction, polyendocrinopathy, enteropathy, X-linked) syndrome is a very unique syndrome which was described first by Powel and colleagues in 1982 [1]. It is inherited and thus the child acquires the disease from his parents. Its most common manifestation is diabetes mellitus, the early onset type accompanied by severe diarrhea which is very watery, failure to thrive and dermatitis [2]. It can present with other variable clinical symptoms which may vary from one person to another. Most of the affected children die early with mean survival duration of two years. It is inherited as an X-linked disorder and thus is expressed exclusively in males. The females may act as a carrier but it does not manifest clinically in them [3].

Etiology

The cause of the disease is a defect in the genetic material of an individual. It results from inheritance of the defective genes from the parents of the child. It is a disease which manifests in males only while females act as carriers [2, 4 &5]. This is because the disease is X-linked and thus for it to occur, both of the X-chromosomes in the females have to be affected. However, in males, there is only one X-chromosome which is paired to a Y-chromosome [6]. When the X-chromosome is defective, there is an extra pair of chromosomal material resembling the X-chromosome genetic material and thus there will be manifestation of the symptoms [7].

The gene which is responsible for the disorder has been identified as FOXP3 (forkhead box protein) gene [8]. This gene undergoes mutation producing the defective gene and thus results in immune dysfunction, polyendocrinopathy, enteropathy, X-linked syndrome [9]. Targeting of this gene in the laboratory has been a major interest of researches with some scholars suggesting that the knocking of this gene can be very useful in the management of patients who have undergone a bone marrow transplant. The FOXP3 is a gene which encodes for a protein called Scurfin. The features of the disease are as a result of the deregulation of the immune system of the affected individual [6]. The mutation of the FOXP3 lead to a change in the stability of messenger RNA of Scurfin making it vulnerable to change [10].

Immunology

Immune dysfunction, polyendocrinopathy, enteropathy, X-linked syndrome is one of the autoimmune diseases which are monogenic like autoimmune lymphoproliferative syndrome and Wiskott-Aldrich syndrome [11]. The gene is located at position Xp11.23-Xq13.3. This region has also been said to be associated closely with WASP gene which is responsible for Wiskott-Andrich syndrome. The FOXP3 gene belongs to a family of genes which are responsible for the normal development of the immune system and the thymus in a normal individual [12]. It is also responsible for normal responses to infections by the immunity system in an individual [13].

FOXP3 gene is linked closely to the development of CD4+ CD25+ regulatory T cells which play the role of immune suppression. They form in the thymus of a normal individual and represent a small percentage of the total human CD4+ T-cells (about five to ten percent) [14]. The responsibility of these cells is the reduction in the responses to infectious agents in a healthy individual [15]. They act by counteracting the effect of the rest of activated immune cells. In the absence of the FOXP3 gene or presence of a dysfunctional gene leads to failure of development of the specific T cells. The absence of the suppressor T-cells will lead to problems in the immune suppression of the affected individual [16].

The disease presents with elevated levels of Ig E (immunoglobulin E) and IgA (immunoglobulin A). they also show eosinophilia in the complete blood count. However, this presentation is not universal and some of the patients may present with normal of low levels of the above immune factors [17]. The activity of the neutrophils is usually normal although their numbers may be reduced. The compliment system is less affected and the patients seem to have normal levels of compliment factors and they do not appear to be defective [18]. In the younger patients, the levels of immunoglobulin G and immunoglobulin M are normal but in the older patients, these levels may be reduced [19]. The reduction of the immunoglobulin G and M in the older patients may be as a result of the protein losing enteropathy. Thrombocytopenia, tubular nephropathy, lymphadenopathy, alopecia and hypothyroidism are also seen. Dermatitis also is evident in such patients [12].

Pathophysiology

The defect in the immune system of the individuals is responsible for most of the clinical features of the disease [20]. The suppressor T-cells which are produced in the patients suffering from the syndrome are either defective or they are not produced at all. The suppressor CD4 cells are needed for the depression of the immune system when activated [21]. This helps the body in the avoidance of an excessive reaction to an antigen perceived to be external. Thus, they prevent autoimmune reactions. However, when the gene is defective, the patient will not have any suppressor cells and thus the body will react very aggressively leading to the destruction of the host cells.

The dermatitis in these patients is as a result of autoimmune reaction. The body attacks the cells of the skin leading to their destruction and thus dermatitis. The suppressor CD4+ cells should have controlled the host immunity cells so that they do not attack normal host cells [16]. Their absence or defect leads to dis-inhibit ion of the immune system and thus left free to attack its own cells. In the skin,. It leads to dermatitis. In the small intestines, the antibodies attack the villi destroying them. This is because of the deficiency of the suppressor T-cells which would have otherwise protected the mucosal cells of the small intestines from destruction by the host immune system. The destruction of the villi leads to decrease in the absorptive surface area of the food contents in the small intestines. This results in decrease in the amount of nutrients absolved and thus leading to an increase in the concentration of the nutrients in the lumen of the small intestines. The increased number of nutrient will exert an osmotic pressure which will pull water molecules from the blood capillaries to the lumen, increasing the intraluminal fluid and later expelled as diarrhea.

Insulin depended diabetes mellitus results from destruction of the insulin producing cells of the endocrine pancreas called the Islets of Langerhans [13]. The destruction can be from infection or autoimmunity. In the s immune dysfunction, polyendocrinopathy, enteropathy, X-linked syndrome, there is decreased suppressor T-cells. This results in the attack of the endocrine pancreas which will lead to the destruction of these cells. These patients will not be able to metabolize their carbohydrates well and will have an increase in the sugars of the blood. This defect will be because of the decrease in the amount of insulin which is needed in the metabolism of glucose. When these patients are treated with insulin, they will recover well and they will need to be on insulin always because cannot be able to produce intrinsic insulin [14].

Children with immune dysfunction, polyendocrinopathy, enteropathy, X-linked syndrome will tend to develop failure to thrive. This is as a result of many factors. First, the villi and microvilli of the small intestines have been destroyed by the immune system. As a result, there is decreased absorption of nutrients for use by the body. The child will only absorb a limited amount of nutrients which will be insufficient for the proper growth and development of the child. Secondly, the defect in the immune system predisposes the child to a lot of infections. Infections will interfere with the acquisition of the nutrients by the child since the child will not be able to feed properly when sick [11]. They will also reduce the absorption of the nutrient and thus lead to more loss of the nutrients. Infections also lead to an increased catabolic state. In this state, the patient will have an increase in the metabolism of an individual. This will lead to an increase in the amount of nutrients and energy used at the expense of growth of the child [22].

Epidemiology

In the United States, the condition is very rare. There have not been estimates of the prevalence of the condition in the country [23]. However, it has been said that the incidence may be very high than the expected because most of the cases go unnoticed. There is also the element of under reporting. Few children with this condition will be brought to the hospital. in addition, when they get to the hospital, some of them are misdiagnosed [24]. The disease appears to affect the white and black races evenly with no predisposition of a certain race towards the disease. It is a disease which presents only in males although females can carry the recessive gene. The obligate female carries do not appear to have any symptoms of the disease but their children who are males can present with the disease [6].

It is a disease which presents in the first three to four months of life. Most children will die at the age of two years. The most common cause of death in these patients is sepsis and failure to thrive which are complications of immune dysfunction, polyendocrinopathy, enteropathy, X-linked syndrome [4]. However, for children who receive appropriate treatment do not die at that age. Other causes of death in these patients include the complication from interventional measures such as bone-marrow transplantation.

Clinical Presentation

History

Immune dysfunction, polyendocrinopathy, enteropathy, X-linked syndrome must be considered in young patients who are male and present to the hospital with severe diarrhea which is very watery and intractable [3]. This can be reinforced by history of failure to thrive of the child. Presence of other features of the syndrome such as dermatitis or insulin depended diabetes mellitus should raise the suspicion. These children will tend to present with infections which are usually on and off. It may be confused with malnutrition or child abuse since they present in an almost similar manner in children [25].

Failure to thrive is an important part of the history. The mother or the caretaker will report that the child has not been able to gain weight in the past few months although the child has been fed well. The caretaker will, express concern at the inability of the child to increase his weight but will state that he or she has been feeding the child adequately. This should raise the suspicion. The weight for age will be lower than the expected weight for age for that age group. The will report that the child appears wasted [26].

Diarrhea is a common presentation. Most of the patients will present to the hospital because of the diarrhea which seems to be resistant to the treatment modalities for diarrhea. The diarrhea will be very loose and will be very frequent. The caretaker may report that the diarrhea worsens when the child feeds. However, it may be present before the child is fed. However, it will not be affected by the food the child takes. Gluten free diet will not act as a relief from the diarrhea.

The patient will present with features of insulin dependent diabetes mellitus. The child will have increased glucose suggesting diabetes or glucose intolerance [27]. However, the administration of insulin will lead to the resolution of the symptoms. They will present with polyuria, mother or care taker may complain of wetting of beddings of the child or child urinating more frequently than the rest of the children. The child will also be feeding a lot compared to the rest of the children. They will also take a lot of water more frequently than the rest of the children. A investigation of the patient may reveal antinuclear antibodies. Diabetes mellitus will present after three to four months of life [17].

In the endocrine system, the patient will present with features of hypothyroidism or hyperthyroidism. They will have awareness of the heartbeat, heat and cold intolerance and wasting [10]. They may also be hyper alert or hypo alert. Some patients will also present with dermatitis which may be an eczematous rash or even diffuse erythematous rash. Alopecia universalis, pemphigoid nodularis and psoriasiform rashes may be the presentation of the dermatitis. Some of the patients, about thirty percent with immune dysfunction, polyendocrinopathy, enteropathy, X-linked syndrome will present with hematuria and proteinuria which will indicate a renal disease in the patient. A history of a positive coombs test or thrombocytopenia in the patient may be elicited although very rarely [28].

Physical Examination

The patient's general appearance is very important. The examiner will notice that the child is wasted and hyper alert. The child may be sweating profusely or clinically hypothermic. The child will have a poor weight gain, cachexia and small in size [29]. Other features of malnutrition may be elicited such as discoloration of the hair and prominent skull bones. Examination of the skin will reveal skin lesions such as psoriatic rash which will be a form of dermatitis.  Examination of the joints may reveal erythema, edema and reduced range of joint movement [30]. This will be features of arthritis although such presentation is rare [29]. On examination of lymph nodes may reveal enlarged lymph nodes which are none tender and not malted. The lymph nodes may also be mobile thus not fixed to the skin or the underlying tissues.

Examination of the cardiovascular system will reveal a pulse which is of high volume if the child has hyperthyroidism [31]. The auscultation will also reveal a murmur. The patient may also present with anemia because of the reduced absorption of iron and other nutrients [21]. Respiratory system may reveal fine crackles if the patient is suffering from any chest infection secondary to the defective immune system [32]. Central nervous system examination will reveal poor development of the child [33]. The child might have regressed milestones or delayed milestones. This will be because of the decreased nutrient availability in the patient's body [34]. Examination of the gastrointestinal system may show features of peritonitis or perforation. The child may also ascites because of the decreased albumin levels in the blood [35].

Laboratory Studies

Molecular testing for the immune dysfunction, polyendocrinopathy, enteropathy, X-linked syndrome is the gold standard as it will show the defective or the absent FOXP3 gene in the patients suffering from the disease [36]. However, only sixty percent of the patients presenting with features of immune dysfunction, polyendocrinopathy, enteropathy, X-linked syndrome will have a mutation or absent FOXP3 gene. The rest will not show such a mutation. This is because, in the rest of the patients, the disorder is in the regulatory sequences of FOXP3 gene [37].

Clinical suspicion is essential in the diagnosis of the syndrome. Although not definitive, the above clinical features will direct the physician towards the immune dysfunction, polyendocrinopathy, enteropathy, X-linked syndrome and thus further investigations [38]. This means that in the diagnosis of this syndrome, the physician should take a very good history and physical examination paying close attention to all systems so as to pick the disease and also its complications [39].

There are several other tests which may help in the making of the diagnosis or in the management of the patient [31]. These include the following: Serum glucose test may indicter hyperglycemia. This is because patients suffering from immune dysfunction, polyendocrinopathy, enteropathy, X-linked syndrome will tend to have insulin dependent diabetes mellitus as a result of destruction of the pancreatic endocrine part [34]. The complete blood count may show normal or low neutrophil count, a decreased lymphocyte count and decreased white blood cells. The hemoglobin concentration might be normal or low and the platelet count will be low or normal [40].

Urinalysis may show either microscopic or macroscopic hematuria. It may also show proteinuria which may be indicative of a kidney disease as part of the immune dysfunction, polyendocrinopathy, enteropathy, X-linked syndrome [41]. Liver function tests will be important in the determination of the presence of an autoimmune disease in the liver. Thyroid function tests will indicate if the levels of thyroid hormones are raised or reduced [40]. This is because in immune dysfunction, polyendocrinopathy, enteropathy, X-linked syndrome, there is a mixed picture of hyperthyroidism and hypothyroidism. Serum immunoglobulin E and immunoglobulin A are usually elevated in patients with immune dysfunction, polyendocrinopathy, enteropathy, X-linked syndrome and this can be picked by checking their levels in the blood [42]. Serum urea and creatinine will also be useful in the establishment of the presence of an autoimmune renal disease [43]. Deranged electrolytes may point towards renal involvement of the autoimmune disease in these children. Imaging modalities are not frequently used in the diagnosis and management of immune dysfunction, polyendocrinopathy, enteropathy, X-linked syndrome [44].

Treatment

The definitive treatment of immune dysfunction, polyendocrinopathy, enteropathy, X-linked syndrome is bone marrow transplantation [23]. However, there are other supportive treatment modalities which can manage the other conditions associated with immune dysfunction, polyendocrinopathy, enteropathy, X-linked syndrome, as follows:

Insulin replacement in patients with type 1 diabetes mellitus will be able to control the sugars and maintain them at the normal levels [45]. Hypothyroidism is treated with levothyroxine while hyperthyroidism is treated with ant thyroid medications or by the surgical removal of the thyroid gland. Enteropathy is treated by the use of drugs which are immunosuppressive such as steroids and cyclosporine [46]. Dermatitis can be treated with topical steroids, emollients or use of any other ant inflammatory medications. Autoimmune cytopenias can be treated with granulocyte colony stimulating factor and also the replacement of the specific blood components [47].

Patients with immune dysfunction, polyendocrinopathy, enteropathy, X-linked syndrome are predisposed to infections more than the rest of the people in the society [43]. The infections are a leading cause of death in patients with this syndrome and thus a good evaluation of the patient should be carried so as to rule out any infection [48]. If there is evidence of infection, antibiotics should be used in the treatment of that infection [49]. Broad spectrum prophylaxis can also be given to the patients who are asymptomatic. Surgical care is not however part of the primary care of the patient. In case of complications, various specialists can be consulted such as nephrologist, gastroenteritis and surgery so as to help in the management of the patient [50].