AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Griscelli and Prunieras¹ initially described Griscelli syndrome (GS), or partial albinism with immunodeficiency, in 1978. Griscelli worked at Hospital Necker-Enfants Malades in Paris, France.

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. 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 GS 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 Murata⁵ noted that a myosin Va mutation in rats is an animal model for the human hereditary neurological disease, GS type 1.

Janka⁶ 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 GS type 2 (GS2), Chediak-Higashi syndrome type 1, and X-linked lymphoproliferative syndrome, in which HLH is a sporadic event.  Thus one way of classifying GS is with other diseases that are associated with hemophagocytic lymphohistiocytosis such as Chediak Higashi syndrome.⁷

Pathophysiology

GS 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 GS (GS3), whose expression is restricted to the characteristic hypopigmentation of GS, results from mutation in the gene that encodes melanophilin MLPH, the ortholog of the gene mutated in leaden mice.⁸ 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 GS 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 GS 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 GS and in dilute mice. Slac2-a/melanophilin (leaden gene in mice) links the function of myosin Va and GTP-Rab27A present in the melanosome.⁹

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.

Unlike Myosin Va, which is the gene product of RAB27A, 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. Specifically, RAB27A-deficient T cells had a normal granule content in perforin and granzymes A and B, but they showed defective granule release.

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 GS 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 al¹⁰ noted that GS2 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 GS2

Neeft et al¹⁰ 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 GS2 mutant Rab27aW73G strongly decreased linking to Munc13-4, whereas the FHL3 mutant (Munc13-4Delta608-611) failed to bind Rab27a.

Neeft et al¹⁰ 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 GS2 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 al¹¹ reported a genomic RAB27A deletion found in a 21-month-old Moroccan GS patient and provided evidence that the loss of functional Rab27a in melanocytes of this GS 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 GS.

The immunofluorescence and yeast 2-hybrid screening studies performed by Westbroek et al¹¹ 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 GS 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 al¹² noted that in GS, NK cytotoxicity mediated by CD16 is functional but not by NKp30.

Desnos et al¹³ 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 GS2.

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 al¹⁴ and Rath et al¹⁵ reported several cases from India. Regardless, the disease is rare in all countries. As of January 2003, about 60 cases have been reported worldwide.

Mortality/Morbidity

Without bone marrow transplantation, GS results in death. The mean patient age at the time of death is 5 years.

Race

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

Sex

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

Age

GS usually manifests in persons aged 4 months to 4 years. One review reported that the onset of GS 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.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

Often, the first manifestation of GS that is noted is silver hair. The differential diagnosis of the disease in a patient presenting with silvery hair includes primarily GS, Chediak-Higashi syndrome, and Elejalde syndrome. Not long after, the immunologic effects of GS caused by mutations in RAB27A are noted. The immunologic defects of GS 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 GS.^{16, 17}

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

• Severe neurologic manifestations in GS 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 organomegaly¹⁸
• • Bilateral basal ganglia involvement¹⁹
• • 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
• GS 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 GS caused by the RAB27A mutation are related to lymphocyte infiltration of the CNS. These problems are not as severe as those found in GS 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 al²⁰ reported on a 6-year-old girl with GS. 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.

Physical

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

• Skin manifestations of both GS 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.
• 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 GS. Partial ocular albinism has been observed in some patients with GS, but retinal degeneration has not been reported in this disorder.²¹
• Akcakus et al²² noted GS in an infant associated with asymmetric crying facies.
• Kharkar et al²³ described a phenotype of GS with circumscribed pigment loss.
• Rajadhyax et al¹⁸ noted obstructive hydrocephalus without hematological abnormalities or organomegaly in a patients with GS.

Causes

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

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

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

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

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

Imaging Studies

• Both CT and MRI are used to assess GS. Usually, findings are normal at birth. When the disease manifests, imaging findings are abnormal. Findings in the 2 variants (ie, MYO5A, RAB27A) of GS 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 GS 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 GS 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 GS 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 GS to be distinguished from Chediak-Higashi syndrome.
• The peripheral blood smear shows no giant cytoplasmic granules in leukocytes. These findings allow GS to be distinguished from Chediak-Higashi syndrome.
• Neurologic evaluations reveal cerebral lymphohistiocytic infiltration and erythrophagocytosis with nonspecific electroencephalographic patterns.²⁴
• Valente et al²⁵ and Smith et al²⁶ noted that polarized light microscopy of hair shafts aids in the differential diagnosis of Chediak-Higashi syndrome and GS.

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 GS include prominent, mature melanosomes in skin and hair follicle melanocytes.

GS 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.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

Medical treatment of patients with GS is difficult.

• 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 GS 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 GS caused by a mutation in RAB27A, various immunosuppressive regimens have been used to attenuate HS (accelerated phase).
• Mehdizadeh and Zamani²⁸ noted a 10-year-old boy with GS 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 GS. Even a low number of donor cells in the patient's bone marrow can be sufficient to control symptoms of GS 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 GS.

Activity

Because patients with GS 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 GS can have seizures that are difficult to control, they must be actively monitored.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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.

Drug Category: Immunosuppressants

These agents are 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.

Drug Category: Immunosuppressive antibodies

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

Drug Category: Antineoplastics

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

Drug Category: Antimetabolites

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.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

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

Further Outpatient Care

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

In/Out Patient Meds

• Patients with GS 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 GS.
• Prenatal diagnosis of GS 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 GS 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 GS, polymorphic markers linked to the GS 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 GS can have HS; infections; and neurologic, immunologic, and bleeding problems.
• Köse et al²⁹ noted the development of in situ melanoma after allogeneic bone marrow transplantation in a person with GS2.

Prognosis

• The prognosis for long-term survival of patients with GS is relatively poor. In the form caused by the RAB27A defect, GS is usually rapidly fatal within 1-4 years without treatment at onset of an accelerated phase.
• Without bone marrow transplantation, the prognosis for this condition is dismal. Some patients die after transplantation, and some patients have had lasting remissions.

Patient Education

• Parents must understand that their children need aggressive care and that they can have additional children who will have GS.
• Parents 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.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• The main medicolegal pitfalls involve failure to diagnose this condition and failure to take steps to treat it.
• In addition, parents must be informed that, although GS is a recessive condition, they can have additional children with this condition.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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Article Last Updated: Feb 1, 2008