Pediatric Hematology and Oncology, 24:525–529, 2007Copyright C© Informa Healthcare USA, Inc.ISSN: 0888-0018 print / 1521-0669 onlineDOI: 10.1080/08880010701533793

Case Report

GRISCELLI SYNDROME: A Case Report

Mahshid Mehdizadeh, MD � Department of Pediatric Hematology and Oncology,Shaheed Beheshti Medical University, Tehran, Iran

Gholamreza Zamani, MD � Department of Pediatric Neurology, Tehran Universityof Medical Sciences, Tehran, Iran

� A 10-year-old boy presented with partial albinism and typical clinical features of a macrophageactivation syndrome (hepatosplenomegaly, fever, and pancytopenia), suggesting the diagnosis ofGriscelli syndrome. The diagnosis was confirmed by light microscopic evaluation of hair that showedcharacteristic large aggregates of pigment granules irregularly distributed along the hair shaft.Immunosuppressive therapy controlled his macrophage activation syndrome successfully. Since earlydiagnosis is life saving and simple methods confirm the diagnosis, finding of partial albinism inchildren should alert clinicians to consider Griscelli syndrome.

Keywords albinism, Griscelli syndrome, immune deficiency

The Griscelli syndrome (GS) is an autosomal recessive disorder thatis characterized by partial albinism, hepatosplenomegaly, pancytopenia,hepatitis, immunologic abnormalities, and lymphohistiocytosis [1]. Thehemophagocytosis may be associated with a viral infection. Microscopicexamination of hair shaft can be used to confirm the diagnosis in whichmelanosomes accumulate in melanocytes, causing clumps of pigment inhair shafts [2]. Several mutations in MYO5A, RAB27A, and melanophilingenes have been found in affected patients. Bone marrow or peripheralblood stem cell transplantation has been utilized to treat hemophagocyticsyndrome and immune deficiency [3, 4].

CASE REPORT

An 8-year-old boy born of first-degree consanguineous parents wasreferred to our hospital for prolonged fever. The patient complaints were

Received 5 March 2007; accepted 15 June 2007.We express our gratitude to our pathologist, Mohammad Rakhshan, and also the patient and his

family for permitting us to publish this case report.Address correspondence to Mahshid Mehdizadeh, Pediatric Division, Loghman Hospital, Kamali

Street, Tehran, Iran. E-mail: mahshid mehdizadeh@yahoo.com

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fever (3 months off and on), abdominal distension (2 months), andjaundice (1 month). There was no history of any relative affected by similarclinical presentation. He had a past history of fever, splenomegaly, andleukopenia at ages 19 and 22 months old, which resolved spontaneously.He had a normal female sibling who was 2 years old.

On examination, the child had fair skin when compared with his parentsand sibling. He had silver gray scalp hairs and white eyelashes, eyebrows,and body hair (Figure 1). He was pale, cachectic, and ill looking. His oraltemperature was 40◦C, his blood pressure was 110/60 mm Hg, and hisrespiratory rate was 18/min. Insignificant lymph nodes were palpated inneck and auxiliary regions. His liver was palpated 2 cm below costal margin.His spleen was palpable 10 cm below the costal margin and was firm inconsistency. The skin, iris, and retina had normal pigmentation. All othersystems, especially the nervous system were within normal limits.

Investigations revealed a hemoglobin level of 7.5 g/dL, a total leuko-cyte count of 1000/mm3, platelet count of 9000/mm3, and a correctedreticulocyte count of 0.5%. There were no giant cytoplasmic granules inleukocytes. Serum bilirubin was 2 mg/dL, direct bilirubin 0.2 mg/dL, SGOTwas 146 U/L, SGPT was 148 U/L, total proteins were 6.6 g/dL with albumin5.4 g/dL. Plasma fibrinogen level was 186 (NL: 220–550) mg/dL. Theserum triglyceride level was 506 mg/dL (NL: 45–170), cholesterol levelwas 283 mg/dL (NL: 150–220), and ferritin level was 295 ng/mL. HBsAgand antibodies for HIV and HCV were negative. FANA, direct Coombstest, latex, Wright, 2-mercaptoethanol, Coombs Wright, Vidal, and IFAtest for leishmania were negative. Anti-DNA was 0.25 IU/mL. CD56 andCD16 counts were 11.1/mL and 4.9/mL, respectively, in normal limits.His serum IgG and IgM were normal but IgE was elevated (1182 mg/dL).Urine amino acids chromatography and serum tyrosine were normal. BrainCT scan was normal, Bone marrow aspiration was done twice during theaccelerated phase of the disease for suspected hemophagocytosis. It didnot reveal hemophagocytosis. The first time it was normal, but it becamehypocellular later. Assessment of his hair shaft showed clumps of pigmentdue to accumulation of melanosomes in melanocytes, compatible withGriscelli syndrome.

The patient received packed red cell transfusion and 2 g/kg IVIGbesides wide-spectrum antibiotics. We also added amphotericin B andG-CSF (granulocyte colony-stimulating factor) because fever and severeneutropenia continued. Despite all medications, the patient’s conditiondeteriorated over the next days, so, based on the pathology of the hair ‘shaftand other laboratory findings consistent with class II histiocytosis, we startedsystemic corticosteroid (dexamethasone 0.6 mg/kg/day) and etoposide(100 mg/body square meter × 3 days) and stopped other drugs. His fever,pancytopenia, and splenomegaly improved after 2 weeks’ treatment andhe was discharged in good condition. Eight courses of etoposide, each

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taken every 3 weeks, were continued. Dexametasone was tapered after 1month and then cyclosporine (5 mg/kg) with low dose of corticosteroidcontinued. He had an episode of chicken pox the next year that was nottoo severe. He had also another milder episode of disease that resolvedwith oral prednisolone and cyclosporine. In this episode and his follow-up he didn’t have any neurologic complaint or sign. He was also consid-ered for bone marrow transplantation but we didn’t find a HLA-matcheddonor for him. After 2 years he is now well and receiving low doses ofprednisolone and cyclosporine, although mild cytopenia and splenomegalypersist.

DISCUSSION

Griscelli et al. [1] described 2 patients with partial albinism in 1978. Upto now, less than 100 cases have been reported in the literature [5]. Mostpatients were diagnosed between 4 months and 7 years of age [6] with meanage about 17 months. Many of reported cases have been from Turkish andMediterranean regions.

Several mutations have been found in affected patients: Mutationsin MYO5A, which encodes an unconventional myosin, were detected inaffected patients with neurologic symptoms and who lacked thehemophagocytic syndrome [7, 8]. This is referred to as type 1 Griscellisyndrome (GS1). Mutations in RAB27A, which encodes a GTP-bindingprotein of the Ras family, were identified in patients presenting primarilywith the hemophagocytic syndrome and abnormal T-cell and macrophageactivation [8]. This is called type 2 Griscelli syndrome (GS2). Mutations inthe gene that encodes for melanophilin were found to underlie a third formof the syndrome that is characterized by the partial albinism alone [9].

Griscelli syndrome is characterized by partial albinism, variable cellu-lar and humoral immunodeficiency, low natural killer cell activity, andneurologic symptoms that may be progressive, possibly due to cerebrallymphohistiocytic infiltration [2, 6]. The occurrence of “macrophage activa-tion syndrome” is like class II histiocytosis, consisting of hemophagocytosis,pancytopenia, elevation of serum triglyceride levels, hypofibrinogenemia,hyperferritinemia, and hypoproteinemia. Sometimes hemophagocytosiscannot be found early in accelerated phases. The hemophagocytosis may beassociated with a viral infection, especially EBV infection, but other bacterialand viral pathogens have also been incriminated. Patients are susceptible tofungal, viral, and bacterial infections.

Griscelli syndrome should be considered in infants with silvery-grayhair, hepatosplenomegaly, and immune deficiency. Dermatologic findingsmay be limited to hair, but skin and retinal pigmentation are occasion-ally affected. Microscopic examination of hair reveals uneven clusters

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528 M. Mehdizadeh and G. Zamani

of aggregated melanin pigment and accumulated phagocytosis [6]. Thedifferential diagnosis includes Chediak-Higashi syndrome (CHS), otherhemophagocytic syndromes, and Elejalde syndrome. CHS differs from GSby the presence of abnormal giant cytoplasmic granules in leucocytes,smaller, more evenly distributed pigment clumps in hair shafts, and moreconsistent defective granulocyte activity [6]. Elejalde syndrome, like GS, hasthe presence of spotty hair pigmentation, but incomplete melanization ofmelanosomes in skin, and no immune deficiency.

Many patients die in childhood, and the cause is usually secondary to se-vere neurological sequelae or recurrent infection. In familial hemophago-cytic lymphohistiocytosis, X-linked lymphoproliferative syndrome, and virus-associated hemophagocytic syndrome patients develop an accelerated phaseidentical to the one observed in Griscelli syndrome but they do not havepartial albinism. Bone marrow transplant and peripheral blood stem celltransplant have been utilized to treat this condition, if hemophagocyticsyndrome and immunodeficiency are present [9]. In patients who do nothave an HLA-matched donor immunosuppressive therapy may have somebenefits.

Our patient was somehow different because usually the course of theuntreated disease is fatal but he tolerated two phases of disease exacerba-tions at young ages and the third exacerbation of disease was controlledby immunosuppressive therapy. Most of reported Griscelli syndrome caseshave been in very young children. Only few cases older than 10 years oldhave been reported [10], but our patient is now 10 years old so this suggeststhat this syndrome may have some different gene expressions.

CONCLUSION

The finding of silver-gray hairs in childhood period should alert clin-icians to consider Griscelli syndrome, since an early diagnosis may be lifesaving.

REFERENCES

[1] Griscelli C, Durandy A, Guy-Grand D, Daguillard F, Herzog C, Prunieras M. A syndrome associatingpartial albinism and immunodeficiency. Am J Med. 1978;65:691–702.

[2] Dufourcq-Lagelouse R, Pastural E, Barrat FJ, et al. Genetic basis of hemophagocytic lymphohistio-cytosis syndrome (Review). Int J Mol Med. 1999;4:127–133.

[3] Schuster F, Stachel DK, Schmid I, et al. Griscelli syndrome: report of the first peripheral bloodstem cell transplant and the role of mutations in the RAB27A gene as an indication for BMT. BoneMarrow Transplant. 2001;28:409–412.

[4] de Saint Basile G. Griscelli syndrome. Orphanet Encyclopedia. May 2003.[5] Mamta M, Kaitav A, Bageshree S. Griscelli syndrome: a case report. Indian Pediatr. 2004;41:734–737.[6] Mancini AJ, Chan LS, Paller AS. Partial albinism with immunodeficiency: Griscelli syndrome:

report of a case and review of literature. J Am Acad Dermatol. 1998;38:295–330.

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[7] Pastural E, Ersoy F, Yalman N. Two genes are responsible for Griscelli syndrome at the same 15q21locus. Genomics. 2000;63:299–306.

[8] Menasche G, Pastural E, Feldmann J, et al. Mutations in RAB27A cause Griscelli syndromeassociated with haemophagocytic syndrome. Nat Genet. 2000;25:173–176.

[9] Arico M, Zecca M, Santoro N, et al. Successful treatment of Griscelli syndrome with unrelateddonor allogenic hematopoietic stem cell transplantation. Bone Marrow Transplant. 2002;29:995–998.

[10] Aksu G, Kutukculer N, Genel F, Vergin C, Omowaire B. Griscelli syndrome without hemophago-cytosis in an eleven-year-old girl: expanding the phenotypic spectrum of Rab27A mutations inhumans. Am J Med Genet A. 2003;116:329–333.

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