Griscelli Syndrome 

Updated: Jan 14, 2020
Author: Saud A Alobaida, MBBS, FRCPC; Chief Editor: Dirk M Elston, MD 

Overview

Background

Griscelli syndrome (GS) 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. Three variants of Griscelli syndrome have been identified: Griscelli syndrome types 1-3. Griscelli syndrome type 2 is the most common type and has the most severe presentation, if left untreated.

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.

In Griscelli syndrome type 1, a defect in the myosin Va gene leads to the pigment dilution and neurological sequelae. Myosin Va plays a role in neurons, including development, axonal transport, dendritic spine structure, and synaptic plasticity.[2] Myosin Va has no role involving the secretion of α-granules and dense granules from lymphocytes or other platelet functional responses.[3] Griscelli syndrome type 1 is also thought to be the same entity or allelic to Elejalde syndrome, with ocular manifestations being prominent in Elejalde syndrome.[4] The exact role of myosin Va in Griscelli syndrome has yet to been defined further. Children with a defect in the MYO5A gene (Griscelli syndrome type 1) develop neurologic problems but no immunologic problems.[5]

Griscelli syndrome type 2 is caused by a defect in the RAB27A gene, which affects a melanosome-anchoring complex in melanocytes, affecting release of cytolytic granules from T cells and natural killer cells. Children with Griscelli syndrome type 2 develop an uncontrolled T-lymphocyte and macrophage activation syndrome known as hemophagocytic syndrome (HS) or hemophagocytic lymphohistiocytosis (HLH).[6, 7, 8] HS usually results in death unless the child receives bone marrow transplantation. In Griscelli syndrome type 2, hepatosplenomegaly, lymphohistiocytosis, and a combined T- 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. The same mutation can have varying phenotypes in different patients.[9, 10]

Griscelli syndrome type 3 manifests with the sole feature of partial albinism. Affected individuals present with pigment dilution and no systemic findings; the immune and nervous systems are intact.

When analyzing cases of Griscelli syndrome, the three variations of it must be parsed and the apposite variant diagnosed.[11]

This parsing is important as the three types of Griscelli syndrome have different courses. Griscelli syndrome type 1 manifests with primary dysfunction of the CNS. Griscelli syndrome type 2 patients commonly develop HLH, and Griscelli syndrome type 3 presents with skin dilution and no systemic findings. In particular, one report describes a Griscelli syndrome type 1 patient alive at age 21 years with motor retardation and severe mental retardation and two patients with Griscelli syndrome type 3, healthy at ages 21 and 24 years, manifesting merely with silvery grey eyebrows, eyelashes, and hair, as well as pigmentary dilution in the skin.[12]

Griscelli syndrome type 2 can be classified with other familial causes of HLH (FHLH) such as Chédiak-Higashi syndrome type 1 (CHS1), Griscelli syndrome type 2, and X-linked lymphoproliferative (XLP) syndrome.[13, 14] This finding has been reiterated in other case reports.[15]

Pathophysiology

Griscelli syndrome (GS) is caused by mutations in one of three genes: RAB27A, MYO5A, or MLPH. Two of these genes, RAB27A and MYO5A, are located at band 15q21. These two genetic defects result in both similar and distinct physical and pathologic findings. The third form of Griscelli syndrome, whose expression is restricted to the characteristic hypopigmentation, results from mutation in the gene that encodes melanophilin, MLPH, the ortholog of the gene mutated in leaden mice.[16] Defect of MLPH is located on band 2q37.3. It has also been shown that an identical phenotype to Griscelli syndrome type 3 results from the deletion of the MYO5A F-exon, an exon with a tissue-restricted expression pattern.[17]

Deficient melanocytes of any of these genes leads to accumulation of melanosomes near the microtubule organizing center and failure to transfer to keratinocytes. Current understanding suggests that RAB27A-MLPH-MYO5A form a tripartite complex facilitating intracellular melanosome transport.[18]

The first genetic defect identified in Griscelli syndrome was the gene that codes for myosin Va (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. There is heterogenicity in genotype-phenotype in Griscelli syndrome type 2, with presentation that overlaps with Griscelli syndrome type 1.[19]

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 type 1 and in dilute mice. The gene products of MYO5A and RAB27A are involved in the movement of melanosomes. Defects in either result in pigmentary dilution.

Myosin Va is an important protein in intracellular vesicle transport. This is important for fast axonal transport in nerve cells. This may explain the neurological complications seen in Griscelli syndrome type 1. Myosin Va plays a role in neurons, including development, axonal transport, dendritic spine structure, and synaptic plasticity.[6] An enzyme spermine synthetase has been noted to interact with myosin Va GTD by means of yeast two hybrid screen. Mutation in MYO5A results in reduced activity of spermine synthase; this enzyme is reduced in the X-linked disorder Snyder-Robinson mental retardation syndrome.[20]

Desnos et al 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.[21]

In certain sites in the body, 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. A possible overcompensation by other proteins in different organs might explain the different phenotypes.

In Griscelli syndrome type 2, 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 does. 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.[18] A novel missense mutation (G43S) in the switch I region of Rab27A causing Griscelli syndrome has been noted.[22]

In 2005, Neeft et al[23] 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.

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 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.

Mutations in Munc13-4 cause familial hemophagocytic lymphohistiocytosis subtype 3 (FHL3), a syndrome that resembles Griscelli syndrome type 2. Neeft et al 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. 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.[23]

In 2004, Westbroek et al[24] 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[24] 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[25] noted that in a Griscelli syndrome type 2 patient, CD16-mediated killing was intact and therefore RAB27A-independent, whereas NKp30-mediated killing was impaired and is therefore RAB27A-dependent. They demonstrated signaling pathways of these two receptors and phosphorylation of Vav1 after CD16 activation but not after NKp30 engagement. This shows the functional dichotomy in the killing mediated by these human NK-activating receptors.[25]

Vincent et al reported that severe Griscelli syndrome type 2 can result from a novel 47.5-kb deletion in RAB27A.[26]

The gene termed MLPH in humans, leaden (ln) in mice, is located at band 2q37 and produces a protein melanophilin. Melanophilin is involved in melanosome movement and the interaction of the gene products of RAB27A and MYO5A to form the tripartite complex (RAB27A-MLPH-MYO5A). MLPH function in organelle motility appears to be limited to skin melanocytes.[18] Slac2-a/melanophilin (leaden gene in mice) links the function of myosin Va and GTP-Rab27A present in the melanosome.[16]

A MYO-5A exon-F deletion in Griscelli syndrome type 3–like phenotype was noted in 2014.[27]

Patients with Griscelli syndrome and normal pigmentation denote RAB27A mutations, which selectively disrupt MUNC13-4 binding.[28]

Etiology

Griscelli syndrome (GS) is a genetic disorder related to mutations in MYO5A in Griscelli syndrome type 1, RAB27A in Griscelli syndrome type 2, and MLPH in Griscelli syndrome type 3. The condition is inherited as an autosomal recessive disorder. Each parent carries one defected gene. History of consanguinity is common. Mutations in any of the three genes, MYO5A, RAB27A, or MLPH, impair the normal transport of melanosomes within melanocytes.

Epidemiology

United States

Around 10 cases of Griscelli syndrome (GS) have been reported in the United States.

International

There are 150 cases of Griscelli syndrome reported to date. Most reported cases are from Turkish and Mediterranean populations. Several cases have been reported from India,[29, 30, 31, 32] as well as one from France,[33] the site of Griscelli’s initial observation. In 2004, Manglani et al and Rath et al reported several cases from India. Regardless, the disease is rare in all countries.

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 and 7 years, with the youngest occurring at 1 month.[34] Late-onset Griscelli syndrome type 2 has been described, reported in a 24-year-old female with CNS involvement and HS.[35]

Prognosis

The prognosis for long-term survival of patients with Griscelli syndrome (GS) type 2 is relatively poor. It is usually rapidly fatal within 1-4 years without aggressive treatment and bone marrow transplantation at onset of an accelerated phase. Some patients have died after transplantation, but others have had lasting remissions. The mean patient age at the time of death is 5 years.

The presence of cutaneous granulomas aids in detection of Griscelli syndrome, and it portends a poor prognosis with systemic involvement.[36]

The prognosis for Griscelli syndrome type 1 and 3 is better, although with long-term neurological sequela and disabilities in the former.

Patient Education

Parents must understand that their children need aggressive care and that they can have additional children with Griscelli syndrome (GS); there is a 25% chance for the disease to be passed to future children.

In Griscelli syndrome type 2, counselling is needed about the urgent need for a bone marrow transplantation and the complications associated with the procedure. Without bone marrow transplantation, the prognosis is dismal.

Type 1 and 3 Griscelli syndrome have no specific treatments. Symptomatic and supportive therapies are provided.

 

Presentation

History

Often, the first manifestation of Griscelli syndrome (GS) is silver hair. The differential diagnosis for silvery hair of the newborn includes Griscelli syndrome, Chédiak-Higashi syndrome (CHS), Elejalde syndrome, and oculocerebral hypopigmentation syndrome (OHS), Cross type.[37] Although Hermansky-Pudlak disease is a form of albinism, it does not present with silver hair or immunologic findings like Griscelli syndrome.[38, 39]

Some patients can remain in good health, with only limited symptoms into their 20s.[40]

Griscelli syndrome type 1

The neurologic effects of Griscelli syndrome type 1 usually manifest early in life and even at birth. Severe neurologic symptoms are noticeable without any sign of an hemophagocytic syndrome (HS), accelerated phase. CNS disorder is permanent and never regresses with time. The symptoms consist of the following:

  • Obstructive hydrocephalus without hematological abnormalities or organomegaly [41]
  • Bilateral basal ganglia involvement [42]
  • Hypotonia
  • Absence of coordinated voluntary movements
  • Bulbar poliomyelitis
  • Encephalopathy
  • Hemiparesis
  • Peripheral facial palsy
  • Spasticity
  • Seizures
  • Psychomotor retardation

Griscelli syndrome type 2

In Griscelli syndrome type 2, immunologic effects are noted shortly after the silvery hair. The immunologic defects of Griscelli syndrome type 2 resemble those of familial hemophagocytic lymphohistiocytosis (HLH) syndromes. Griscelli syndrome II can also cause neurologic manifestations in association with HS (accelerated phase). Neurologic problems may be the first sign of HS (accelerated phase). They are related to lymphocyte infiltration of the CNS. These problems are not as severe as those found in Griscelli syndrome type 1 and tend to fluctuate.

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 in Griscelli syndrome type 2, including 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), is seen in Griscelli syndrome type 2.

In 2003, Dinakar et al[43] reported on a 6-year-old girl with Griscelli syndrome type 2. 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.

Griscelli syndrome type 3

Patients with Griscelli syndrome type 3 present with silvery hair, but generally do not have other complications.

One report describes a preterm neonate with Griscelli syndrome type 3 who presented with silvery-gray hair and eyelashes, respiratory distress, and intracerebral hemorrhage. The child recovered the systemic symptoms and had no persistent neurological symptoms or HS.[44]

Physical Examination

Griscelli syndrome (GS) types 1 and 2 cause pigmentary dilution and other internal organ abnormalities.

Skin manifestations in all Griscelli syndrome variants include partial albinism. 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[45] described a phenotype of Griscelli syndrome with circumscribed pigment loss. Granulomatous skin lesions have been described in patients with Griscelli syndrome type 2, and this finding was thought to portend a poor prognosis.[36]

Liver manifestations include hepatosplenomegaly and jaundice as a result of hepatitis. In patients with Griscelli syndrome type 2, bone marrow involvement can present as pallor and petechia.

Griscelli syndrome type 1 presents with neurological findings including hemiparesis, peripheral facial palsy, spasticity, seizures, and psychomotor retardation. In Griscelli syndrome type 2, neurologic impairments can occur as a result of CNS lymphohistiocytic infiltration with erythrophagocytosis. Rajadhyax et al[41] noted obstructive hydrocephalus without hematological abnormalities or organomegaly in a patient with Griscelli syndrome type 2.

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.[46]

Asymmetric crying facies was a feature observed in a patient with Griscelli syndrome.[47]

Complications

In Griscelli syndrome (GS) type 1, severe neurological sequelae, including psychomotor retardation and visual complications, are permanent.[12]

Patients with Griscelli syndrome type 2 may have infections as well as neurologic, immunologic, and bleeding problems. A case of melanoma in situ was reported in a patient after allogeneic bone marrow transplantation in a person with Griscelli syndrome type 2.[48]

 

DDx

Diagnostic Considerations

Differential diagnosis includes conditions with hypopigmentation; these can be congenital or acquired conditions.

Differential Diagnoses

 

Workup

Laboratory Studies

Genetic analysis can be performed to detect mutations in MYO5A, RAB27A, and MLPH.

For Griscelli syndrome (GS) type 2, laboratory features include pancytopenia, hypofibrinogenemia, hypertriglyceridemia, and hypoproteinemia, which can be seen with hemophagocytic syndrome (HS). In some patients, 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 can be found. One report noted low levels of immunoglobulin G2 in a patient with Griscelli syndrome type 2.

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.

A prospective survey of degranulation assays for the rapid diagnosis of Griscelli syndrome type 2 and other familial hemophagocytic syndromes shows that such testing has promise.[49]

Imaging Studies

Both CT and MRI of the head can be used to assess Griscelli syndrome (GS). Usually, findings are normal at birth. When the disease manifests, imaging findings become abnormal. Findings differ in the two variants Griscelli syndrome type 1 and type 2.

In Griscelli syndrome type 1, isolated congenital cerebellar atrophy was observed. No evidence of infiltration of lymphocytes is present in these patients.

In Griscelli syndrome type 2, CT scanning can show areas of coarse calcification in the globi pallidi, left parietal white matter, and periventricular and left brachium pontis. They can manifest as 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.

When HS manifests in Griscelli syndrome type 2, 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.

The peripheral blood smear shows no giant cytoplasmic granules in leukocytes. These findings allow Griscelli syndrome (GS) to be distinguished from Chédiak-Higashi syndrome (CHS).

Nonspecific electroencephalographic patterns can be seen in Griscelli syndrome type 2.[50]

Polarized light microscopy of the hair shafts aids in the differential diagnosis of CHS and Griscelli syndrome.[51, 52, 53]

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 (GS) 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 large, irregular aggregations of melanin pigment in hair. In contrast, CHS pigment aggregates are regular and resemble natural white hair.

Electron microscopic examination of the skin shows many mature melanosomes in melanocytes accompanied by few melanosomes in adjoining keratinocytes.[34]

 

Treatment

Medical Care

A multidisciplinary team should manage patients with Griscelli syndrome (GS) types 1 and 2.

Griscelli syndrome type 1

In Griscelli syndrome type 1, no specific treatment exists because the defect is in the brain rather than in the blood cells, as in Griscelli syndrome type 2. The severe neurologic impairment and retarded psychomotor development are permanent.

Griscelli Syndrome type 2

Bone marrow (or stem cell) transplantation is the only real treatment option for the hemophagocytic lymphohistiocytosis (HLH) syndromes in Griscelli syndrome type 2. This has received evidence-based support in an Italian study of 61 patients with Griscelli syndrome type 2, reported in 2009.[54] Similarly, a Swedish study with 5 patients with Griscelli syndrome type 2 responded to stem cell transplantation.[55, 56]

In preparation for transplantation, various immunosuppressive regimens have been used to attenuate hemophagocytic syndrome (HS) (accelerated phase).

Mehdizadeh and Zamani[57] noted a 10-year-old boy with Griscelli syndrome type 2 and macrophage activation syndrome, which was controlled with immunosuppressive therapy.

Care might require antimicrobial therapy. Patients who have seizures must be monitored and treated accordingly. Unfortunately, antibiotics and antiviral agents are used with mixed effects. Similarly, medications may not control the neurologic symptoms of the disease.

Surgical Care

Bone marrow transplantation is the most effective treatment for this condition. Bone marrow transplantation is the only possible cure for Griscelli syndrome (GS) type 2.[58] Even a low number of donor cells in the patient's bone marrow can be sufficient to control symptoms of Griscelli syndrome type 2.

Consultations

The specialists who are most involved in the care of Griscelli syndrome (GS) include geneticists, hematologists, dermatologists, neurologists, and pediatricians. Once a diagnosis is made in Griscelli syndrome type 2, specialists should consider the need for chemotherapy and proceed with bone marrow transplantation.

Diet

No special diet is recommended for patients with Griscelli syndrome (GS).

Activity

Because patients with Griscelli syndrome (GS) types 1 and 2 can have severe neurologic and immunologic problems, their activities are usually limited. For patients, avoiding interactions that expose them to infections is important. Because they can have seizures that are difficult to control, they must be actively monitored.

Patients with Griscelli syndrome type 3 have normal activity and no complications.

Prevention

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

Prenatal diagnosis of Griscelli syndrome has been accomplished by examination of hair from a biopsy sample of the 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 is possible in families. In addition, given the proximity of the two genes responsible for Griscelli syndrome types 1 and. 2, 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.

Long-Term Monitoring

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

 

Medication

Medication Summary

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

Chemotherapy (VP16) or, more recently, antithymocyte globulins (ATGs) (10 mg/kg for 5 d) and cyclosporin A, have achieved remissions, and the use of intrathecal methotrexate injections transiently helps 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 are 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 bone marrow transplantation 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 hemophagocytic syndrome (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. Patients with Griscelli syndrome (GS) type 2 can be given antibiotics if they have HS.

Seizures have not been reported to be controlled by anticonvulsants.

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 polymorphonuclear activity. Prednisone stabilizes lysosomal membranes and suppresses lymphocyte and antibody production.

Immunosuppressive Antibodies

Class Summary

These are 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 versus 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 3-6 weeks following administration. Adjust the dose gradually to attain a 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.