Blue diaper syndrome is an inborn error of metabolism with tryptophan malabsorption as the leading symptom. The lack of absorption by the intestines results in conversion and excretion by the kidneys, causing the urine to turn blue. Treatment is equivalent to intravenous tryptophan supplementation.
What is blue diaper syndrome?
Blue diaper syndrome is also known as tryptophan malabsorption syndrome. This is an extremely rare metabolic disorder that is one of the inborn errors of metabolism. Patients suffer from malabsorption of tryptophan. Tryptophan is an amino acid that blue diaper syndrome patients can no longer absorb through the intestinal wall into the bloodstream. Tryptophan remains in the intestine, where it is excreted by the kidneys after conversion processes. In contact with air, the substance turns blue. This is where the name blue diaper syndrome comes from. All other symptoms of the symptom complex symptoms are also due to tryptophan malabsorption and the deficiency of the substance in the blood. Blue diaper syndrome is sometimes also referred to as familial hypercalcemia with the accompanying symptoms of nephrocalcinosis, hyperphosphaturia, and indicanuria, which is caused by an absorption disorder for tryptophan.
Causes
Blue diaper syndrome is extremely rare and, because of its rarity, has not been conclusively studied. Nonetheless, hereditary correlations are now known. The exact mode of inheritance of the disease is still unclear. An autosomal recessive and an X-linked recessive mode of inheritance are under discussion. The molecular biological cause of the syndrome is also still unknown. However, there are many speculations as to the cause, all of which presuppose a genetic mutation. For example, mutations of the L-type amino acid transporter 2 may be responsible for the disease. The genes coding for this are SLC7A8 and LAT2, which are located on chromosome 14 in gene locus q11.2. Equally conceivable causes would be mutations of the T-type amino acid transporter 1 on gene SLC16A10 and gene TAT1. These genes are located on chromosome 6 in gene locus q21-q22. Whether external factors such as toxin exposure play a role in the development of blue diaper syndrome is unknown.
Symptoms, complaints, and signs
Blue diaper syndrome is associated with all the symptoms of acquired tryptophan malabsorption. In addition to the lack of tryptophan in the blood, patients suffer from severe hypercalcemia associated with nephrocalcinosis. Calcium salts are thus deposited in the kidney tissue of those affected, which can later lead to renal insufficiency if left untreated. In addition, the patients’ excretion of hydrogen ions is higher than in healthy people. Patients also excrete large amounts of phosphorus through the kidneys, which can lead to hyperphosphaturia. However, the most characteristic symptom of the disease is the blue coloration of the diapers. Since the intestine does not absorb tryptophan, intestinal bacteria convert the amino acid to indole and its compounds. These compounds are absorbed by the intestinal mucosa and move on to the liver, where they are converted to indican. The indican is excreted renally through the urine and is responsible for the blue discoloration of diapers.
Diagnosis
The first suspected diagnosis of blue diaper syndrome occurs to the physician by eye diagnosis or anamnesis as soon as the blue discoloration of the diapers is mentioned. Since acquired tryptophan malabsorption is also associated with the symptoms of blue diaper syndrome and no molecular genetic analysis is available for the hereditary form of such a metabolic disorder, a corresponding tentative diagnosis can only be confirmed with difficulty. Thus, although blood tests may demonstrate a deficiency of the amino acid and hypercalcemia, in the final analysis there can be no question of a definite diagnosis until the gene responsible is identified. However, if multiple cases of blue diaper syndrome are observed in a family, the diagnosis may well be considered confirmed.
Complications
Because blue diaper syndrome is a congenital malabsorption of the amino acid tryptophan, it must be administered promptly to affected children when the condition is identified. However, the patients’ intestines cannot absorb the amino acid, so direct administration into the blood is recommended.This form of therapy is unavoidable because tryptophan is an important component of countless processes in the human body and is involved, among other things, in the formation of the tissue hormone serotonin. If tryptophan malabsorption remains untreated, there is a serious risk of hypercalcemia and renal insufficiency resulting from the associated nephrocalcinosis. This can then necessitate dialysis or even a donor organ, which considerably reduces the quality of life of the young patients. Many of those affected also have damage to their eyes, which is why complications can also arise in the area of defective vision. Because it is still not clear what the real cause of blue diaper syndrome is, there is no way to prevent the dangerous metabolic disorder. Therefore, it is imperative that parents contact the pediatrician immediately upon finding the first blue diapers in order to spare the child worse consequences.
When should you go to the doctor?
If a blue coloration of the diapers is noticed, the affected child should be taken to the pediatrician immediately. The medical professional can then determine blue diaper syndrome by eye and confirm the diagnosis with a blood test and medical history. Immediate treatment is then required in any case. It is therefore recommended to consult a physician already at the first suspicion of the disease. Typical symptoms that must be clarified immediately are, in addition to the blue color of the diapers, unusually frequent urination and sometimes also pain when urinating. Occasionally, other complaints also occur and the affected child shows, for example, typical fever symptoms or appears fatigued. Therefore, the pediatrician should be consulted with any symptoms that deviate from the norm. If there are already cases of the disease in a family, the child and especially the stool should be examined immediately after birth, if possible. An appropriate medical history will allow a reliable diagnosis and facilitate the targeted treatment of blue diaper syndrome.
Treatment and therapy
Causal therapy is not available for patients with blue diaper syndrome until the causative gene is identified and gene therapy approaches have reached the clinical stage. Therefore, the disease is treated more or less symptomatically. Supplementation of the amino acid tryptophan may play a major role in such treatment. Since the disease does not allow tryptophan uptake in the intestine, the amino acid must be administered by another route. Direct administration into the blood is an option in this case. Supplementation of the amino acid reduces all symptoms of the metabolic disorder. In extremely severe cases, hypercalcemia must be treated separately. Serum calcium can be lowered, for example, by increasing excretion, as can be achieved with a loop diuretic and glucocorticoids. Symptoms such as nephrocalcinosis can again be treated exclusively by eliminating hypercalcemia. If nephrocalcinosis has already led to renal insufficiency, this insufficiency requires separate treatment. Treatment options range from dialysis to transplantation, depending on the severity of the insufficiency. However, blue diaper syndrome is usually detected early enough to successfully prevent renal insufficiency by permanently lowering calcium levels. By supplementing tryptophan, hypercalcemia ideally will not occur in the future.
Outlook and prognosis
The outlook for a cure is not given for blue diaper syndrome. The syndrome is a genetic predisposition that cannot be cured with existing medical and scientific options. For legal reasons, it is not allowed to interfere with the genetics of the person, which makes the prospects of recovery impossible. There are also no alternative healing methods or self-healing processes of the organism that contribute to the improvement of health. Without medical care for the consequences of blue diaper syndrome, the patient is at risk of serious complications. In severe cases, untreated patients experience organ failure of the kidney. This can lead to a sudden fatal course of the disease.The patient needs a donor kidney as soon as possible in order to improve his quality of life and maintain his well-being. With the use of regular drug treatment, the survival of the sufferer is assured. Although there is no cure, the patient with the syndrome can manage his life independently. Overexertion and unnecessary stress should be avoided, as should the consumption of alcohol or other harmful substances. If life is adapted to the needs of the organism and the lifestyle is made as healthy and sustainable as possible, the patient’s general health improves immensely.
Prevention
Blue diaper syndrome has not yet been conclusively researched. Neither the exact cause, nor the possible influencing factors have undoubtedly been brought to identification. Without knowing the influencing factors, the complex of symptoms cannot be prevented. The poor research situation of the syndrome is mainly due to its low prevalence. Because of this low prevalence, the research situation is unlikely to change much in the near future.
Follow-up
In this extremely rare metabolic disorder, medical follow-up is essential because of the potential consequences of the disease. The beneficial effects of the strict diet under which affected children are placed must be monitored regularly. However, an unsuitable diet with too much calcium and the amino acid tryptophan can lead to kidney damage. Intravenous administration of tryptophan is preferable to dietary tryptophan. The injection is usually administered under medical supervision or by medically trained nursing staff. To keep blue diaper syndrome under control, therapies with antibiotics may be necessary if intestinal infections or bacterial infestations in the digestive system occur. If renal damage has already occurred in affected individuals, follow-up care must provide monitoring of the resulting hypercalcemia and prescribed loop diuretics and glucocorticoids. Follow-up in blue diaper syndrome is complicated by the fact that tryptophan malabsorption has been poorly studied. The metabolic disorder is one of the very rare diseases. What is certain so far is heritability. Since there may be a gene mutation as the cause of blue diaper syndrome, gene therapy may be able to achieve better treatment results in a few years. Whether medical follow-up will still be necessary then or whether blue diaper syndrome can be treated prenatally remains to be seen.
What you can do yourself
Parents of children who have blue diaper syndrome need only ensure that the child is taking the necessary medications regularly and is not showing any noticeable symptoms or discomfort. If treatment is given early, the development of renal insufficiency can be reliably prevented. In general, affected children do not experience any other symptoms or complaints that need to be treated apart from the blue coloration of the urine. In individual cases, however, symptoms of the gastrointestinal tract or even serious kidney problems may develop. Parents should keep a close eye on their child and alert the pediatrician immediately if they notice any noticeable symptoms. Despite its comparatively good prognosis, the disease can have an impact on the mental state of parents, who often suffer from severe anxiety. A conscious confrontation with blue diaper syndrome and its causes gives relatives a new perspective on the disease and makes it easier to deal with. Attending a support group or talking to other parents whose children suffer from the metabolic disorder can also help. Parents should address their questions and concerns to the responsible physician and consult a therapist through him or her.
