Griscelli Syndrome 

Updated: Jan 19, 2016
Author: Noah S Scheinfeld, JD, MD, FAAD; Chief Editor: Dirk M Elston, MD 

Overview

Background

Griscelli and Prunieras[1] initially described Griscelli syndrome, or partial albinism with immunodeficiency, in 1978. Griscelli worked at Hospital Necker-Enfants Malades in Paris, France.

Griscelli syndrome is a rare autosomal recessive disorder that results in pigmentary dilution of the skin and the hair (silver hair), the presence of large clumps of pigment in hair shafts, and an accumulation of melanosomes in melanocytes. In one variant, hepatosplenomegaly, lymphohistiocytosis, and a combined T-cell and B-cell immunodeficiency are pronounced. The associated immunodeficiency often involves impaired natural killer cell activity, absent delayed-type hypersensitivity, and a poor cell proliferation response to antigenic challenge. Occasionally, impaired lymphocyte function and an inability to produce normal levels of immunoglobulins have also been described. In another variant, neurologic signs are most prominent.

Children with Griscelli syndrome caused by a defect in the RAB27A gene develop an uncontrolled T-lymphocyte and macrophage activation syndrome known as hemophagocytic syndrome (HS) or hemophagocytic lymphohistiocytosis (HLH).[2, 3, 4] HS usually results in death unless the child receives a bone marrow transplant. Children with a defect in the MYO5A gene develop neurologic problems but no immunologic problems.

Takagishi and Murata[5] noted that a myosin Va mutation in rats is an animal model for the human hereditary neurological disease, Griscelli syndrome type 1. The exact role of myosin Va in Griscelli syndrome has to been defined further as Harper et al (2013)[6] demonstrated no significant functional defects in α-granule, lysosomal secretion, dense granule, Ca(2+) signalling, integrin α(IIb)β(3) activation, or spreading on fibrinogen in response to the PAR4 agonist or collagen-related peptide or in dense and α-granules numbers expressed. Thus, Harper et al conclude that myosin Va possesses no evident nonredundant role involving either the secretion of α-granules and dense granules and neither in other platelet functional responses.[6]

When analyzing cases of Griscelli syndrome, the 3 variations of it must be parsed and the apposite variant diagnosed.[7] Griscelli syndrome type 1 manifests with primary dysfunction of central nervous system. Type 2 Griscelli syndrome commonly develops HLH. Type 3 Griscelli syndrome manifests with merely partial albinism. This parsing is important as the 3 types of Griscelli syndrome have different courses. In particular, one report describes a Griscelli syndrome type I patient alive at age 21 years without no problems except motor retardation and severe mental retardation and 2 patients with Griscelli syndrome type 3, healthy at ages 21 and 24 years, manifesting merely with eye brows, eyelashes, silvery gray hair, and pigmentary dilution.[8]

Janka[9] reported that HLH occurs in (1) 3 types of familial genetic forms in which HLH is the primary and only manifestation and (2) in association with the immune deficiencies Griscelli syndrome type 2, Chediak-Higashi syndrome type 1, and X-linked lymphoproliferative syndrome, in which HLH is a sporadic event. Thus, one way of classifying Griscelli syndrome is with other diseases that are associated with HLH, such as Chediak-Higashi syndrome.[10] This finding has been reiterated in other case reports.[11]

Pathophysiology

Griscelli syndrome is caused by mutations in 1 of 3 genes. Two of these genes are located at band 15q21: RAB27A and MYO5A. These 2 genetic defects result in both similar and distinct physical and pathologic findings. A third form of Griscelli syndrome, whose expression is restricted to the characteristic hypopigmentation of Griscelli syndrome, results from mutation in the gene that encodes melanophilin MLPH, the ortholog of the gene mutated in leaden mice.[12] It has also been shown that an identical phenotype can result from the deletion of the MYO5A F-exon, an exon with a tissue-restricted expression pattern.

The first genetic defect identified in Griscelli syndrome was the gene that codes for myosin V-MYO5A. Subsequently, a second gene, the guanosine triphosphate (GTP)-binding protein RAB27A whose gene product is a reticular activating system–associated protein (RAS-associated protein), on a nearby locus, was cloned. Mutations in RAB27A have been found in all the patients with Griscelli syndrome who were analyzed and who did not have the mutated MYO5A.

Myosin Va (or Myosin 5a) is a member of the unconventional class myosin V family, and a mutation in the myosin Va gene causes pigment granule transport defects in the human form of Griscelli syndrome and in dilute mice. Slac2-a/melanophilin (leaden gene in mice) links the function of myosin Va and GTP-Rab27A present in the melanosome.[13]

The gene products of MYO5A and RAB27A are involved in the movement of melanosomes. Defects in each result in pigmentary dilution. In some body and cellular sites, MYO5A and RAB27A are expressed differently. MYO5A is expressed in the brain, whereas RAB27A is not. Defects in MYO5A cause neurologic pathology, whereas defects in RAB27A do not cause neurologic defects. Current understanding suggests that RAB27A-MLPH-MYO5A form a tripartite complex facilitating intracellular melanosome transport.[14]

Unlike Myosin Va, which is the gene product of MYO5A, the GTP-binding protein, which is the gene product of RAB27A (ie, Rab27a), appears to be involved in the control of the immune system because all patients with the RAB27A mutation develop HS, but none with the MYO5A mutation do. In addition, Rab27A-deficient T cells exhibit reduced cytotoxicity and cytolytic granule exocytosis, whereas MYO5A-defective T cells do not.

Rab27A appears to be a key effector of cytotoxic granule exocytosis, a pathway essential for immune homeostasis. Rab27a, a small GTPase, interfaces with multiple effectors, including Slp2-a and Myrip, all parts of the melanosome transport system. RAB27A -deficient T cells have demonstrated a normal granule content in perforin and granzymes A and B, but they showed defective granule release. RAB27B is another protein produced in cells and RAB27B and RAB27A are functionally redundant.[14] A novel missense mutation (G43S) in the switch I region of Rab27A causing Griscelli syndrome has been noted.[15]

The onset of HS (accelerated phase) seems to be associated with a viral infection (eg, Epstein-Barr virus, hepatitis A virus, herpes virus 6) or sometimes a bacterial infection. When a remission is obtained, recurrent, accelerated phases with increasing severity are seen. Patients with a RAB27A mutation also have neurologic problems related to HS and a lymphohistiocytic infiltration of the CNS. These CNS problems wax and wane. The CNS problems in patients with Griscelli syndrome with mutations in MYO5A, do not wax and wane.

As stated above, another gene termed leaden (ln) in mice and MLPH in humans located at band 2q37 produces melanophilin, which is involved in melanosome movement and the interaction of the gene products of RAB27A and MYO5A.

In 2005, Neeft et al[16] noted that Griscelli syndrome type 2 is caused by the absence of functional Rab27a; the manner in which Rab27a controls secretion of lytic granule contents remains elusive.

Mutations in Munc13-4 cause familial hemophagocytic lymphohistiocytosis subtype 3 (FHL3), a syndrome that resembles Griscelli syndrome type 2

Neeft et al[16] have shown that Munc13-4 intimately interacts with Rab27a. Rab27a and Munc13-4 are intensely expressed in cytolytic T lymphocytes and mast cells. Rab27a and Munc13-4 co-localize on secretory lysosomes. The region comprising the Munc13 homology domains is needed to facilitate the localization of Munc13-4 to secretory lysosomes. They found that the Griscelli syndrome type 2 mutant Rab27aW73G strongly decreased linking to Munc13-4, whereas the FHL3 mutant (Munc13-4Delta608-611) failed to bind Rab27a.

Neeft et al[16] also showed that overexpression of Munc13-4 enhances degranulation of secretory lysosomes in mast cells. This finding demonstrates that Munc13-4 plays a positive regulatory role in secretory lysosome fusion. They went on to suggest that the secretion defects observed in Griscelli syndrome type 2 and FHL3 have a common origin and proposed that the therab27a/Munc13-4 complex is an essential regulator of secretory granule fusion with the plasma membrane in hematopoietic cells. Mutations in either Rab27a or Munc13-4 prevented the formation of this complex and abolished secretion.

In 2004, Westbroek et al[17] reported a genomic RAB27A deletion found in a 21-month-old Moroccan Griscelli syndrome patient and provided evidence that the loss of functional Rab27a in melanocytes of this Griscelli syndrome patient was partially compensated by the up-regulation of Rab27b, a homologue of Rab27a. They used real-time quantitative polymerase chain reaction and Western blot analysis to show that Rab27b mRNA and protein were expressed at low levels in normal human melanocytes. In contradistinction, a significantly up-regulated expression of these genes occurred in melanocytes derived from this boy with Griscelli syndrome.

The immunofluorescence and yeast 2-hybrid screening studies performed by Westbroek et al[17] revealed that Rab27b can form a tripartite complex on the melanosome membrane with melanophilin, a Rab27a effector, and protein products of myosin Va transcripts that contain exon F. Their data suggest the presence of up-regulated Rab27b in melanocytes of Griscelli syndrome patients. Rab27b appears capable of partially assuming the role of Rab27a. This observation explains the observation that the patient in this study reportedly had evenly pigmented skin and was able to tan.

Gazit et al[18] noted that in Griscelli syndrome, NK cytotoxicity mediated by CD16 is functional but not by NKp30.

Desnos et al[19] noted that in neurons, myosin Va manages the targeting of IP3 (inositol 1,4,5-trisphosphate)–sensitive Ca2+ stores to dendritic spines. Myosin Va also controls the transport of mRNAs in persons with Griscelli syndrome type 2.

Vincent et al reported that severe Griscelli syndrome type 2 can result from a novel 47.5-kb deletion in RAB27A.[20]

A MYO-5A exon-F deletion in Griscelli syndrome type 3–like phenotype was noted in 2014.[21]

Patients with Griscelli syndrome and normal pigmentation denote RAB27A mutations, which selectively disrupt MUNC13-4 binding.[22]

Epidemiology

Frequency

United States

Fewer than 10 cases have been reported in the United States.

International

Most reported cases are from Turkish and Mediterranean populations; however, in 2004, Manglani et al[23] and Rath et al[24] reported several cases from India. Regardless, the disease is rare in all countries. As of January 2003, about 60 cases have been reported worldwide.

A report from India noted 7 patients with hemophagocytic lymphohistiocytosis, of which only 1 had Griscelli syndrome.[25]  A group of type 2 Griscelli syndrome patients was reported in 2015 in India.[26]  A report from France noted a 6-year-old child who presented with classic symptoms of Griscelli syndrome type 2, including hemophagocytic syndrome and severe sepsis.[27]

Race

Griscelli syndrome is a rare disease in all populations. Most cases reported are from Turkish and Mediterranean populations.

Sex

Griscelli syndrome is not a sex-linked condition; thus, males and females are affected equally.

Age

Griscelli syndrome usually manifests in persons aged 4 months to 4 years. One review reported that the onset of Griscelli syndrome ranged from 1 month to 8 years, with a mean patient age of 17.5 months. Children with mutations in MYO5A seem to manifest with symptoms earlier than those with mutations in RAB27A. In most patients, diagnosis occurs between the ages of 4 months to 7 years, with the youngest occurring at 1 month.[28]

 

Presentation

History

Often, the first manifestation of Griscelli syndrome that is noted is silver hair. The differential diagnosis of the disease in a patient presenting with silvery hair includes primarily Griscelli syndrome, Chediak-Higashi syndrome, and Elejalde syndrome. Not long after, the immunologic effects of Griscelli syndrome caused by mutations in RAB27A are noted. The immunologic defects of Griscelli syndrome resemble those of HLH syndrome and the X-linked lymphoproliferative syndrome. Although Hermansky-Pudlak disease is a form of albinism, it does not present with silver hair or immunologic findings like Griscelli syndrome.[29, 30]

Some patients can remain in good health, with only limited syndomes into their 20s.[31]

The neurologic effects of Griscelli syndrome caused by defects in MYO5A usually manifest early in life and even close to birth.

Severe neurologic manifestations in Griscelli syndrome are associated with defects in the MYO5A gene. Severe neurologic symptoms are noticeable at birth without any sign of an accelerated phase. CNS disorder is stable and never regresses with time. The symptoms consist of the following:

  • Obstructive hydrocephalus without hematological abnormalities or organomegaly[32]

  • Bilateral basal ganglia involvement[33]

  • Hypotonia

  • Absence of coordinated voluntary movements

  • Bulbar poliomyelitis

  • Encephalopathy

  • Hemiparesis

  • Peripheral facial palsy

  • Spasticity

  • Seizures

  • Psychomotor retardation

  • Severe retarded psychomotor development similar to that observed in Elejalde syndrome

Griscelli syndrome caused by the RAB27A mutation can also cause neurologic manifestations in association with HS (accelerated phase). Neurologic problems may be the first sign of HS (accelerated phase). Neurologic manifestations occurring in patients with Griscelli syndrome caused by the RAB27A mutation are related to lymphocyte infiltration of the CNS. These problems are not as severe as those found in Griscelli syndrome caused by MYO5A mutations.

The symptoms include hyperreflexia, seizures, signs of intracranial hypertension (eg, vomiting, altered consciousness), regression of developmental milestones, hypertonia, nystagmus, and ataxia. Psychomotor development is normal at onset, and regression of CNS signs, at least in part, can be observed during remission, although some sequelae may be irreversible.

At birth, nonspecific findings can occur that include petechiae and hepatosplenomegaly.

A history of severe infections associated with the occurrence of acute phases of uncontrolled lymphocyte and macrophage activation, so-called HS (accelerated phase), can be present in patients with mutations in RAB27A. These infections are not present in patients with mutations in MYO5A.

In 2003, Dinakar et al[34] reported on a 6-year-old girl with Griscelli syndrome. The patient experienced perpetual infections, seizures, regression of milestones, silvery hair, and organomegaly. Her brain was affected with unusual features of a Dandy-Walker cyst, and her blood and bone marrow were also affected, manifesting hypergammaglobulinemia.

Al-Idrissi et al reported on a preterm neonate with Griscelli syndrome type 3 who presented with silvery-gray hair and eyelashes, respiratory distress, and intracerebral hemorrhage. The authors stressed the importance of early differentiation of type 3 from Griscelli syndrome type 2, which is associated with a curable (but life threatening) immune disorder.[35]

Physical

Mutations in both MYO5A and RAB27A cause pigmentary dilution and other internal organ abnormalities.

Skin manifestations of both Griscelli syndrome variants include granulomatous skin lesions, partial albinism, and generalized lymphadenopathy. The appearance of the hair has been variably described as silvery gray, silvery, grayish golden, or dusty. The skin is usually pale, but the albinism is not complete. Kharkar et al[36] described a phenotype of Griscelli syndrome with circumscribed pigment loss.

Liver manifestations include hepatosplenomegaly and jaundice as a result of hepatitis.

Patients can present with pallor as a result pancytopenia.

Neurologic impairments can occur as a result of CNS lymphohistiocytic infiltration with erythrophagocytosis. Upon physical examination, especially in children with mutations in MYO5A, hemiparesis, peripheral facial palsy, spasticity, seizures, psychomotor retardation, and severe retarded psychomotor development may be noted.

Ocular defects can occur in Griscelli syndrome. Partial ocular albinism has been observed in some patients with Griscelli syndrome, but retinal degeneration has not been reported in this disorder.[37]

Akcakus et al[38] noted Griscelli syndrome in an infant associated with asymmetric crying facies.

Rajadhyax et al[32] noted obstructive hydrocephalus without hematological abnormalities or organomegaly in a patients with Griscelli syndrome.

Causes

Griscelli syndrome is a genetic disorder related to mutations in MYO5A and RAB27A (see Pathophysiology).

 

DDx

Diagnostic Considerations

Also conisder the following:

  • HLH syndrome
  • Familial lymphohistiocytosis (MIM 603553)
  • X-linked lymphoproliferative syndrome (MIM 308240)
  • Partial albinism and immunodeficiency syndrome (MIM 604228)
  • Elejalde syndrome (MIM 256710)

Differential Diagnoses

 

Workup

Laboratory Studies

Characteristic laboratory features include pancytopenia, hypofibrinogenemia, hypertriglyceridemia, and hypoproteinemia. In Griscelli syndrome without delayed-type cutaneous hypersensitivity and impaired natural killer cell function manifests as the ever-present immunologic abnormalities.

Some patients with Griscelli syndrome have secondary hypogammaglobulinemia, impaired major histocompatibility complex–mediated cytotoxic effects, a decreased capacity of lymphocytes to trigger a mixed lymphocyte reaction, or various functional granulocytic abnormalities. One report noted low levels of immunoglobulin G2 in a patient with Griscelli syndrome.

Evidence of hepatitis can be demonstrated by abnormal liver function results. Neonatal hyperbilirubinemia (peak total bilirubin 26.5 mg/dL at age 4 wk) has been reported.

Chromosome analysis can be performed to detect mutations in MYO5A and RAB27A.

A prospective survey of degranulation assays for the rapid diagnosis of Griscelli syndrome and other familial hemophagocytic syndromes shows that such testing has promise.[39]

Imaging Studies

Both CT and MRI are used to assess Griscelli syndrome. Usually, findings are normal at birth. When the disease manifests, imaging findings are abnormal. Findings in the 2 variants (ie, MYO5A,RAB27A) of Griscelli syndrome are different.

Isolated congenital cerebellar atrophy was observed in a patient with the MYO5A defect. No evidence of infiltration of lymphocytes is present in these patients. In Griscelli syndrome caused by RAB27A defects, CT scan can show areas of coarse calcification in the globi pallidi, left parietal white matter, and periventricular and left brachium pontis.

Patients with Griscelli syndrome can manifest hypodense signals in the genu and posterior limb of the internal capsule on the right side (which is compatible with inflammatory changes), as well as posterior aspects of both thalami, together with minimal generalized atrophy. CT scanning can also suggest cell infiltration of the brain. In both variants, MRI can reveal areas of increased T2 signal intensity and a focal area of abnormal enhancement in the subcortical white matter. At birth, findings from long-bone plain radiography have been reported to be normal.

When Griscelli syndrome manifests, abdominal ultrasonograms can show hepatosplenomegaly with intrahepatic cholestasis and absence of bile duct distension.

Other Tests

Transmission electron microscopy of the skin shows an accumulation of numerous normal-sized stage IV mature melanosomes in the cytoplasm of melanocytes, with virtual absence of such melanosomes in adjacent keratinocytes. These findings allow Griscelli syndrome to be distinguished from Chediak-Higashi syndrome.

The peripheral blood smear shows no giant cytoplasmic granules in leukocytes. These findings allow Griscelli syndrome to be distinguished from Chediak-Higashi syndrome.

Neurologic evaluations reveal cerebral lymphohistiocytic infiltration and erythrophagocytosis with nonspecific electroencephalographic patterns.[40]

Valente et al[41] and Smith et al[42] noted that polarized light microscopy of hair shafts aids in the differential diagnosis of Chediak-Higashi syndrome and Griscelli syndrome.

Procedures

Biopsy specimens of internal organs can reveal abnormalities. Liver biopsy specimens can show marked portal inflammation with focal hepatocellular necrosis.

Bone marrow aspiration samples can reveal slight hypocellularity with mild erythroid hyperplasia and hemophagocytosis.

Histologic Findings

The common histopathologic findings of Griscelli syndrome include prominent, mature melanosomes in skin and hair follicle melanocytes.

Griscelli syndrome demonstrates hyperpigmented basal melanocytes and sparse pigmentation of adjacent keratinocytes. This pathology of melanocytes and keratinocytes leads to large, clumped melanosomes in hair shafts, and, as a result, the hair has a silvery-gray sheen. These results can be highlighted in Fontana-Masson–stained sections. Light microscopy shows irregular, large aggregations of melanin pigment in hair.

Celik et al[43] investigated the light and scanning electron microscopic examination of hair in persons with Griscelli syndrome and found that the hair showed a normal cuticular pattern but nodular structures were present as abnormal findings.

Electron microscopic examination of the skin shows many mature melanosomes in melanocytes accompanied by few melanosomes in adjoining keratinocytes. Peripheral leukocytes lack giant granules.[28]

 

Treatment

Medical Care

Medical treatment of patients with Griscelli syndrome is difficult. The only real treatment for the hemophagocytic lymphohistiocytosis syndromes of which Griscelli syndrome is a part is stem cell transplantation. This has received evidence-based support in an Italian study of 61 patients with Griscelli syndrome) reported in 2009.[44] Similarly, a Swedish study with 5 patients with Griscelli syndrome type 2 responded to stem cell transplantation.[45]

For patients with defects in RAB27A, antibiotics and antiviral agents are used with mixed effects. Similarly, medications may not control the neurologic symptoms of the disease.

In Griscelli syndrome related to MYO5A mutations, no specific treatment exists because the defect is in the brain rather than in the blood cells as in cases caused by the RAB27A mutation. The severe neurologic impairment and retarded psychomotor development do not improve with time.

Only bone marrow transplantation offers a possibility of extended survival. In preparation for transplantation, particularly in patients with Griscelli syndrome caused by a mutation in RAB27A, various immunosuppressive regimens have been used to attenuate hemophagocytic syndrome (HS) (accelerated phase).

Mehdizadeh and Zamani[46] noted a 10-year-old boy with Griscelli syndrome and macrophage activation syndrome, which was controlled with immunosuppressive therapy.

Surgical Care

Bone marrow transplantation is the most effective treatment of this condition. Bone marrow transplantation is the only possible cure for Griscelli syndrome.[47] Even a low number of donor cells in the patient's bone marrow can be sufficient to control symptoms of Griscelli syndrome in cases caused by mutations in RAB27A.

Consultations

The specialists who are most often initially consulted for treatment of this condition are geneticists, hematologists, dermatologists, neurologists, and pediatricians. Once a diagnosis is made, such specialists should consider the need for chemotherapy in patients and how to proceed with bone marrow transplantation.

Diet

No special diet is recommended for patients with Griscelli syndrome.

Activity

Because patients with Griscelli syndrome can have severe neurologic and immunologic problems, their activities are usually limited. For patients, avoiding interactions that expose them to infections is important. Because patients with Griscelli syndrome can have seizures that are difficult to control, they must be actively monitored.

 

Medication

Medication Summary

To suppress the accelerated phase (lymphohistiocytic infiltration of multiple organs, in particular the brain and the meninges) of disease, immunosuppressive therapy is used.

Chemotherapy (VP16) or, more recently, antithymocyte globulins (ATG) (10 mg/kg for 5 d) and cyclosporin A have achieved remissions, and the use of intrathecal methotrexate injections transiently help treat the neurocerebral involvement. However, chemotherapy is sometimes ineffective for the treatment of the primary disease and frequently fails to control relapses. Recurrent infections have been minimized with antibacterial and antiviral agents.

Other regimens that have resulted in the induction of remission have been obtained with the combination of high-dose systemic methylprednisolone and etoposide and intrathecal methotrexate, cytosine arabinoside, and prednisone, and with a regimen of ATGs, steroids, and cyclosporine, but these therapies are palliative rather than curative.

In one case, before a bone marrow transplant was performed, a child was given a preparative regimen consisting of busulfan, thiotepa, and fludarabine with good effect. In another case, when a patient experienced HS (accelerated phase) characterized by hemophagocytosis, the patient was treated with prednisolone, rabbit ATGs, and intrathecal methotrexate. Remission was maintained with cyclosporin A until HLA-compatible peripheral blood stem cell transplantation from the patient's mother was performed.

Immunosuppressants

Class Summary

To suppress the accelerated phase (lymphohistiocytic infiltration of multiple organs, in particular the brain and the meninges) of disease, immunosuppressive therapy is used.

These agents include cyclic polypeptides that suppress some humoral immunity and, to a greater extent, cell-mediated immune reactions, such as delayed hypersensitivity, allograft rejection, experimental allergic encephalomyelitis, and graft versus host disease, for a variety of organs. Prednisone is used to suppress T-cell and immune function.

Cyclosporine (Sandimmune, Neoral)

Cyclosporine is used with other immunosuppressive and chemotherapeutic agents to down-regulate the lymphohistiocytic infiltration that occurs in this disease.

Prednisone (Sterapred)

Prednisone is an immunosuppressant for the treatment of autoimmune disorders; it may decrease inflammation by reversing increased capillary permeability and suppressing PMN activity. Prednisone stabilizes lysosomal membranes and suppresses lymphocyte and antibody production.

Immunosuppressive Antibodies

Class Summary

This agent is used with other immunosuppressive and chemotherapeutic agents to down-regulate the lymphohistiocytic infiltration that occurs in this disease.

Antithymocyte globulin equine

ATG is usually used as an antirejection medication. The mechanisms of action of polyclonal ATGs are still poorly understood, and the selection of doses used in different clinical applications (eg, prevention or treatment of acute rejection in organ allografts, treatment of graft-vs-host disease, conditioning for allogeneic stem cell transplantation) remains empirical. Low T-cell counts are usually achieved in peripheral blood during ATG treatment, but the extent of T-cell depletion in lymphoid tissues is unknown. T-cell depletion is achieved rapidly and primarily in peripheral lymphoid tissues at high ATG dosage.

Antineoplastics

Class Summary

Antineoplastics are used with other immunosuppressive and chemotherapeutic agents to down-regulate the lymphohistiocytic infiltration that occurs in this disease.

Etoposide (VePesid, Toposar)

Etoposide inhibits topoisomerase II and causes DNA strand breakage, resulting in cell proliferation to arrest in late S or early G2 portion of the cell cycle.

Antimetabolites

Class Summary

Cytarabine is converted intracellularly to the active compound cytarabine-5'-triphosphate, which inhibits DNA polymerase. This inhibition, in turn, halts viral replication. Intrathecal methotrexate is an antimetabolite that inhibits dihydrofolate reductase, thereby hindering DNA synthesis and cell reproduction in malignant cells. Satisfactory response seen in 3-6 wk following administration. Adjust dose gradually to attain satisfactory response.

Cytarabine (Cytosar-U)

Cytarabine is used as part of an immunosuppressive regimen.

Intrathecal methotrexate (Folex PFS, Rheumatrex)

Intrathecal methotrexate is used with other immunosuppressive and chemotherapeutic agents to down-regulate the lymphohistiocytic infiltration that occurs in this disease. It is injected intrathecally to treat the neurologic complications. Patients are also given leucovorin to mitigate some effects of methotrexate.

 

Follow-up

Further Outpatient Care

Because patients can have seizures and HS, they must be carefully monitored by their caregivers.

Further Inpatient Care

Patients must be aggressively supported and monitored when experiencing hemophagocytic syndrome (HS). Care can require antibiotics and systemic support. Patients who have seizures must be monitored and positioned accordingly.

Inpatient & Outpatient Medications

Patients with Griscelli syndrome can be given antibiotics if they have HS. Seizures have not been reported to be controlled by anticonvulsants. Immunosuppressive medications are given in preparation for bone marrow transplants.

Deterrence/Prevention

Morphologic examination of peripheral blood or cultured amniotic and chorionic villi cells can help in prenatal diagnosis of Griscelli syndrome.

Prenatal diagnosis of Griscelli syndrome has been accomplished by examination of hair from a biopsy sample of fetal scalp obtained at 21 weeks of gestation. A fetus that had such a biopsy was aborted. These results were confirmed by a postabortion examination of the fetus revealing silvery hair and characteristic microscopic findings.

With cloning of the Griscelli syndrome genes, direct mutation-based carrier detection and prenatal diagnosis currently appears possible in families with defined MYO5A or RAB27A gene mutations. In addition, given the proximity of the 2 genes responsible for Griscelli syndrome, polymorphic markers linked to the Griscelli syndrome locus in the band 15q21 region can be used for identifying the presence of the gene even if the precise mutation has not yet been identified in a family.

Complications

Patients with Griscelli syndrome can have HS; infections; and neurologic, immunologic, and bleeding problems. Köse et al[48] noted the development of in situ melanoma after allogeneic bone marrow transplantation in a person with Griscelli syndrome type 2.

Prognosis

The prognosis for long-term survival of patients with Griscelli syndrome is relatively poor. In the form caused by the RAB27A defect, Griscelli syndrome is usually rapidly fatal within 1-4 years without treatment at onset of an accelerated phase.

The presence of cutaneous granulomas aids in detection of Griscelli syndrome, and it portends a poor prognosis with systemic involvement.[49]

Without bone marrow transplantation, the prognosis for this condition is dismal. Some patients die after transplantation, and some patients have had lasting remissions. The mean patient age at the time of death is 5 years.

Patient Education

Parents must understand that their children need aggressive care and that they can have additional children who will have Griscelli syndrome. Parents also must understand the need for a bone marrow transplant and the complications of the procedure. Parents must also understand the dismal prognosis of this condition without transplantation and the risks of bone marrow transplantation.