Griscelli syndrome is an autosomal recessive inherited pigmentary disorder of the skin and hair, of which three different manifestations, type 1 to type 3, are known. Each type of the inherited disorder is caused by mutations at different genes and is associated to varying degrees with concomitant spleen and liver enlargement, decreased neutrophil granulocyte counts, and decreased platelet counts in the blood.
What is Griscelli syndrome?
Griscelli syndrome represents a special form of albinism that, in addition to reduced pigmentation (hypomelanosis) of the skin and hair, is accompanied by other serious health problems such as a simultaneously abnormally enlarged liver and spleen (hepatosplenomegaly), a decreased number of neutrophilic granulocytes (neutropenia), and a decreased number of platelets (thrombocytopenia). Three different manifestations are referred to as type I, type II, and type III and are caused by different genetic defects. Griscelli syndrome must be differentiated from Chediak-Higashi syndrome, which is accompanied by similar symptoms and, like Griscelli syndrome, is inherited in an autosomal recessive manner. This means that the gene defects are not sex-specific and that the disease only occurs when both sets of parents have the same causative gene defects. The symptoms of the hereditary disease were first described in 1978 by Paris pediatrician Claude Griscelli. The disease can be classified as rare, with a frequency of one case per million births.
Causes
All three manifestations of Griscelli syndrome are caused by genetic defects. Acquisition of the disease by infection or exposure to harmful substances is not possible. Type I of the disease is caused by mutations in the MYO5A gene, which encodes the motor protein myosin VA. Mutations in the RAB27A gene are responsible for the type II manifestation of Griscelli syndrome. The membrane protein encoded by the RAB27A gene belongs to the superfamily of GTPases. Type III of the hereditary disease is due to certain mutations of the MLPH gene, which also, like the myosin gene, encodes a transport protein related to the intracellular and transmembrane transport of melanin. While the locus of the MYO5A and RAB27A genes are both located on chromosome 15 in the same region on the long arm (q), the MPLH gene is part of chromosome 2 and is located at position 2q37.3.
Symptoms, complaints, and signs
The three manifestations of Griscelli syndrome show sometimes different symptoms and signs. Common to all manifestations is the unusually pale and hypopigmented skin and early gray hairs that appear in childhood. More serious than the lack of pigmentation are the impaired brain functions associated with type 1 of the disease. These are manifested by slowed development and visual disturbances, as well as generally weak muscle tone. Symptomatic of the Griscelli syndrome type 2 course are concomitant immunological abnormalities. There is usually uncontrolled activation of T lymphocytes and macrophages. Lymph nodes and the CNS are invaded by the activated immune cells. A hemophagocytotic syndrome may develop, manifested by unrestrained phagocytosis of erythrocytes. Type 2 of the hereditary disease is usually not accompanied by neurodevelopmental disorders. However, CNS disorders may develop as a consequence of excessive hemophagocytosis. Only type 3 of Griscelli syndrome is not accompanied by serious – sometimes life-threatening – neurologic or immunologic symptoms.
Diagnosis and course
Suspicion of disease in one of the three manifestations of Griscelli syndrome is raised by the appearance of the newborn’s skin, which shows signs of albinism and hypomelanosis, respectively. Such signs may give reason to search for cases of albinism in the families of both sets of parents. There is no laboratory possibility that provides clear evidence of whether and which type of Griscelli syndrome is present. The only certain possibility of a diagnosis is a molecular genetic DNA analysis.Because the triggering genetic defects of the disease are known, an analysis of the three possible genes in question can be carried out specifically. If it is known that family members were affected by the disease in the past, prenatal genetic testing via a tissue sample of the chorionic villi is also possible. The course of Griscelli syndrome type 1 has an unfavorable prognosis due to the massive neuronal developmental abnormalities. In type 2 of the disease, although neuronal development is normal, the derailment of the immune system – if untreated – also leads to a very unfavorable prognosis. Only type 3 of Griscelli syndrome will allow for a normal life expectancy because there are no particular neurologic or immunologic abnormalities.
Complications
Due to Griscelli syndrome, pigmentary disorders occur on the entire body of the patient. Hair is also affected by the disorder, resulting in an unusual appearance. This can possibly lead to teasing or bullying in children, as a result of which those affected not infrequently suffer from psychological complaints. There is also an enlargement of the spleen and liver. These enlargements cause pain and can also displace or squeeze other internal organs. The affected person appears very pale and has little resilience. The hair is also dyed gray as a result of Griscelli syndrome, even in childhood. It is not uncommon for patients to suffer from visual disturbances and muscle weakness. The immune system is also weakened, so that inflammations and infections occur more often. The patient’s everyday life is made more difficult by the disease. Unfortunately, it is not possible to treat Griscelli syndrome. Only symptomatic therapy is possible in some cases and can limit the symptoms of the syndrome. However, it cannot be predicted whether there will be a positive course of the disease.
When should you see a doctor?
Griscelli syndrome always requires treatment by a physician. There is no self-healing in this syndrome, and usually there is also a permanent worsening of symptoms. A doctor should be consulted if the child suffers from severely slowed development. Visual disturbances or weak muscle tone may also indicate Griscelli syndrome. In this case, especially the parents and relatives must pay attention to the symptoms of the syndrome and consult a doctor. There are also neurological and motor disorders that indicate the disease. Furthermore, a visit to a doctor is advisable if the child shows gray hair at an early age or if the skin is affected by unusual pigmentation. Griscelli syndrome can be diagnosed by a pediatrician or general practitioner. A dermatologist should also be visited if pigmentation disorders are present. Since many patients and their parents and relatives also suffer from psychological symptoms in Griscelli syndrome, a visit to a psychologist is equally advisable.
Treatment and therapy
Because Griscelli syndrome is caused by gene mutations that interfere quasi-systemically with the metabolism of each individual cell of certain tissues, no therapy exists (yet) to cure the disease. Any treatment options for type 1 of the disease are limited to treatment of the symptoms. If the dreaded hemophagocytotic syndrome develops in type 2, it can only be overcome and cured by a matching bone marrow donation. No other therapeutic options are available.
Prospect and prognosis
The prognosis of Griscelli syndrome depends largely on the form of the disease. Three types are distinguished, each showing a different evolution. In type I, the prognosis is unfavorable because of significant neuronal disturbances. These show up individually during the development and growth process, are considered irreparable for the most part, and have a strong impact on the patient’s quality of life. Symptomatic therapy is given, to improve well-being, since the causes cannot be corrected due to the conditions. In type II, severe cases can lead to a fatal course of the disease. The prognosis of this type is unfavorable due to immunodeficiency in affected patients, which may ultimately lead to premature death. If this type is not medically managed, the disease presents with a steady progression with no prospect of relief.In some cases, bone marrow donation can provide relief. In type III patients, there are no neuronal disorders, nor is the immune system damaged. Therefore, this form of the disease shows the best prognosis in direct comparison. Life expectancy is not reduced and the quality of life is comparatively good. Nevertheless, secondary diseases or mental disorders may occur, which contribute significantly to a worsening of the overall prognosis.
Prevention
Direct preventive measures that could prevent Griscelli syndrome are nonexistent because the disease is exclusively genetic in origin. If cases of the syndrome are known to run in the family of one or both parents, genetic counseling can take place to provide clarity about the statistical probability of the disease occurring if the desire to have children is realized. In principle, genetic analysis can also take place during pregnancy with all the ethical problems and consequences that may derive from this.
Follow-up
In Griscelli syndrome, no special aftercare options are available to the affected person. The focus is on medical treatment of this disease to prevent further complications and discomfort. As a rule, it is not possible to cure the disease oneself. Whether Griscelli syndrome leads to a reduced life expectancy of the affected person cannot be predicted in general. Since this is a hereditary disease, genetic counseling should always be performed if the patient wishes to have children. In this way, the occurrence of the syndrome in the descendants can possibly be avoided. The treatment of Griscelli syndrome is purely symptomatic, so that a causal treatment is not possible. Only bone marrow transplantation can completely alleviate the symptoms. The affected person is therefore heavily dependent on the support of other people in his or her daily life. In particular, the help and support of friends and family has a very positive effect on the further course of the disease. In some cases, contact with other people affected by Griscelli syndrome can also be useful, as this leads to an exchange of information that can make everyday life easier.
What you can do yourself
Griscelli syndrome cannot be prevented. However, if the patient wishes to have a child, genetic analysis or counseling can be done to possibly prevent the syndrome in the child. Unfortunately, there are also no particular self-help options available to the patient for this condition. The slowed development of the patient can in many cases be compensated by special support and therapy, so that complications in adulthood are minimized. Visual disturbances can be limited with the help of visual aids. However, the affected person should always wear the visual aids, as vision may continue to deteriorate. Since patients suffer from weak muscle tone, strenuous activities should be avoided. Due to the skin complaints, long stays in the sun with direct irradiation are not advisable. The affected person should always cover the skin with clothing or protect it with sunscreen. Furthermore, support from parents or friends can have a positive effect on the disease and alleviate depression or other moods. Contact with other patients suffering from Griscelli syndrome also helps. Treatment by a psychologist is always advisable when support from family and friends is no longer sufficient. Children should also be educated about the symptoms and about the further course of the disease.
