The medical profession refers to hyper-IgD syndrome – also known as HIDS – as a hereditary disease that is predominantly characterized by recurrent episodes of fever. For this reason, hyper-IgD syndrome also belongs to the so-called periodic fever syndromes. During the fever episodes, the affected persons complain, among other things, of diarrhea, abdominal pain, and also nausea and vomiting. There is no causative treatment; however, the prognosis – in terms of the patient’s life expectancy – is good.
What is hyper-IgD syndrome?
Hyper-IgD syndrome (or HIDS) is a hereditary disease. It is characterized by recurrent episodes of fever as well as gastrointestinal symptoms. Periodic illnesses, of which Hyper-IgD syndrome is one, have been known since the 19th century, but were not redefined and coined until 1948 by the physician Hobart A. Reimann. In 1984, hyper-IgD syndrome was mentioned for the first time. A Dutch research group described recurrent fever and also general inflammatory reactions as well as significantly elevated immunoglobulin-D as well as also immunoglobulin-A in siblings. Since 2001, about 160 diagnoses have been made; the majority of those affected live in France and the Netherlands. However, it is suspected that the number of unreported cases is higher.
Causes
Hyper-IgD syndrome develops due to a genetic information change – a so-called mutation. The mutation occurs on chromosome 12. The mode of inheritance of hyper-IgD syndrome is autosomal recessive. In about 80 percent of all cases, there is primarily a missense mutation in the gene region that subsequently codes for MVK (12q12, GeneID 4598 – enzyme mevalonate kinase). This mutation causes a slightly reduced stability of the enzyme activity. However, it is still unclear why the reduced mevalonate kinase activity subsequently triggers fever episodes. Due to the unclear cause, there is also no known therapy to combat the cause. Medical practitioners can therefore only provide symptomatic treatments that focus predominantly on the febrile episodes.
Symptoms, complaints, and signs
Hyper-IgD syndrome occurs during the first year of life. Recurrent episodes of fever are characteristic; the patient complains of very rapid onset of fever and chills. These fever episodes are triggered by minor injuries, vaccinations, stress or surgery. In many cases, patients also complain of abdominal pain, nausea and vomiting, and diarrhea. Sometimes the cervical lymph nodes may also swell. Other symptoms characteristic of hyper-IgD syndrome are: Headaches, joint inflammation as well as joint pain and rashes. The relapses themselves occur at intervals of between four and six weeks. The duration is between three and also seven days. However, the duration and frequency of the episodes can vary significantly depending on the patient. Especially in childhood, febrile episodes occur more frequently; in adulthood, the frequency as well as intensity decreases.
Diagnosis and course of the disease
If characteristic symptoms suggestive of hyper-IgD syndrome are present, a check of the immunoglobulin D concentration in the blood may provide an indication of whether hyper-IgD syndrome actually exists. If the concentration of immunoglobulin D is above 100 IU/ml, it can be assumed that hyper-IgD syndrome is present. Sometimes molecular genetic evidence of an existing mutation can also provide information as to whether a hyper-IgD syndrome is present or not. However, in order to confirm the diagnosis, the physician must exclude other diseases that show similar symptoms in advance. Hyper-Ig-D syndrome, in fact, also belongs to the periodic fever syndromes; familial Mediterranean fever (FMF) must also be ruled out in advance. Other diseases that have a similar course and must be ruled out before a diagnosis of hyper-IgD syndrome can be made include “tumor necrosis factor receptor-1-associated periodic syndrome” (also known as TRAPS), cyclic neutropenia, chronic infantile neurologic cutaneous articular syndrome (or CINCA syndrome), and Muckle-Wells syndrome. Also, diseases that fall under PFAPA syndrome (periodic fever, aphthae, adenitis syndrome or pharyngitis) are also included. Although treatment of hyper IgD syndrome is relatively difficult, there is nevertheless a good prognosis.There is no restriction of life expectancy, even if the syndrome is extremely severe. However, the joints can be attacked in the course of the relapses, so that joint destruction is possible. Amyloidosis, such as in familial Mediterranean fever, has been documented only in isolated cases. In a few cases, neurological abnormalities as well as limitations of mental abilities have also been documented. Epilepsy, coordination as well as balance disorders are also possible, but also occur only rarely.
Complications
Due to hyper IgD syndrome, the affected person suffers from severe episodes of fever that recur after a certain period of time. In this case, it is not possible to predict the exact time of the next fever episode. In addition to fever, the patient also suffers from abdominal pain and diarrhea. Furthermore, there is also nausea and vomiting. The quality of life is greatly reduced by the hyper-IgD syndrome and everyday life is made more difficult by the symptoms. As a rule, the patient’s ability to cope with stress is also reduced and the affected person appears fatigued and tired. The fever episodes can also have a negative effect on the psyche, leading to depression or other moods. Furthermore, there is pain in the head and joints. Not infrequently, the skin is affected by rashes and the lymph nodes swell. As a rule, it is mainly children who are affected by the frequent episodes of fever. Treatment of hyper-IgD syndrome is symptomatic, limiting the symptoms of the fever episode. This does not lead to further complications. In most cases, the incidence decreases with age. Life expectancy is likewise not reduced by hyper-IgD syndrome.
When should one go to the doctor?
In hyper-IgD syndrome, after the completion of the first year of life, such violent symptoms suddenly appear that a doctor’s consultation always becomes necessary. Since similar symptoms are also observed in other diseases, urgent diagnostic clarification of the complaints is necessary. Only then can an effective therapy be initiated. A visit to the doctor should be made, among other things, if the one-year-old child suddenly suffers from unexplained episodes of fever, which can also occur at longer intervals. The fever usually announces itself with the onset of chills. Above all, the doctor should also be consulted if a fever spurt occurs during special occasions such as vaccinations, stress or injuries. Even the accompanying symptoms of febrile episodes should be taken as a reason to seek medical attention. These symptoms include lymph node swelling, severe abdominal pain, vomiting and diarrhea. If the doctor diagnoses hyper-IgD syndrome, he or she will discuss the necessary therapy with the parents. This consists of administering the cholesterol-lowering drug simvastatin and the immunosuppressant etanercept. These drugs alleviate the symptoms and at the same time reduce the risk of rare complications such as joint contractures or adhesions in the abdominal cavity. Because the disease does not usually limit life expectancy and fever episodes become less frequent as the patient ages, ongoing medical care is not necessary.
Treatment and therapy
To date, there is no therapy or treatment that predominantly addresses or even treats the cause of hyper-IgD syndrome. For this reason, physicians focus primarily on symptomatic treatment of the recurrent episodes of fever. However, even those treatments prove to be extremely difficult. This is because they not only vary from patient to patient, but can also have different intensities depending on the episode. Classical antipyretic or anti-inflammatory drugs – such as non-steroidal anti-inflammatory drugs – are completely ineffective. Colchicine, steroids, and even thalidomide have also been found to be ineffective. However, physicians have recognized that simvastatin can help treat any fever episodes. Some time ago, positive developments in the “interleukin-1ra analogue anakinra” were also reported. Sometimes the “tumor necrosis factor-α antagonist etanercept” can also reduce fever days and relieve intensity. No other treatments are currently known.
Outlook and prognosis
Hyper-IgD syndrome offers a relatively positive prognosis.Although the disease is accompanied by severe symptoms such as gastrointestinal distress, skin rashes, damage to the joints and fever, in the long term these health problems can be greatly reduced or even completely eliminated by comprehensive drug treatment. Even if the joints are involved, the disease is not always associated with long-term symptoms, provided that early treatment is given. Only in isolated cases do permanent joint disorders occur, which permanently impair the quality of life and well-being and thus carry the risk of mental suffering. Amyloidosis, which can affect all organs and the endocrine system, also occurs in only a few patients. However, some patients experience neurological disorders that can affect mental abilities as well as coordination. In severe cases, epilepsy may develop. In most cases, patients can lead a pain-free life, but this is always associated with long-term drug treatment and physiotherapeutic measures. Sufferers also have to undergo repeated surgical interventions or suffer from side effects and interactions as a result of the constant administration of medication. Psychological complaints can also occur in chronically ill HIDS patients. Typical mental sequelae are inferiority complexes and depressive moods up to severe depression. Life expectancy is not reduced by hyper-IgD syndrome.
Prevention
Due to the fact that hyper-IgD syndrome is a hereditary disease, preventive measures are not known or possible.
Follow-up
Measures or options for follow-up care are usually very limited in hyper-IgD syndrome. Since it is also a hereditary disease, no complete cure can be achieved in this process. Affected persons are therefore dependent on lifelong therapy and treatment in order to permanently alleviate the symptoms. In order to avoid the inheritance of the hyper IgD syndrome to the descendants, genetic counseling should also take place if the patient wishes to have children. This is the only way to prevent inheriting the disease. Since the treatment of hyper-IgD syndrome is usually carried out by taking medication, those affected should make sure that they take it regularly and, above all, correctly. Possible interactions should also be taken into account. In case of questions or uncertainties, a physician should always be contacted first. Since the hyper-IgD syndrome can also promote tumors, those affected should have themselves examined regularly by a doctor. The support and care of friends and one’s own family is also very important and can alleviate the symptoms. Above all, psychological complaints or depression can be prevented. The life expectancy of affected persons may be reduced by the hyper IgD syndrome.
What you can do yourself
Since hyper-IgD syndrome unfortunately cannot be treated causally and thus causally, only the individual symptoms and complaints can be limited in the process. The fever episodes are thereby treated with the help of medication. Also a general bed rest and the protection of the own body can have thereby very positive effects on the course of the illness. Those affected should not carry out physical activities without further ado. Taking fever-reducing medication or painkillers can also have a negative effect on the stomach, so a doctor should be consulted. Furthermore, contact with other affected persons can be helpful in the case of hyper-IgD syndrome. This may make it easier to cope with everyday life. The help of friends and acquaintances can also significantly limit and alleviate the psychological symptoms of the syndrome. Unfortunately, those affected have to come to terms with the disease and must not forget that the fever episodes only occur over a short period of time. Furthermore, however, treatment is necessary for epileptic seizures. Above all, driving vehicles or operating heavy machinery should not be carried out in the presence of epilepsy.
