Partial albinism with immunodeficiency: Griscelli syndrome: Report of a case and review of the literature

Partial albinism with immunodeficiency: Griscelli syndrome: Report of a case and review of the literature Anthony J. Mancini, MD,a,b,c Lawrence S. Chan, MD,b and Amy S. Paller, MDa,b,c Chicago, Illinois Partial albinism with immunodeficiency (Griscelli syndrome) is an uncommon disorder characterized by pigmentary dilution and variable immunodeficiency. Features include a silvery-gray sheen to the hair, large clumped melanosomes in hair shafts, and prominent mature melanosomes in cutaneous melanocytes with sparse pigmentation of adjacent keratinocytes. Immunologic abnormalities most often include impaired natural killer cell activity, absent delayed-type hypersensitivity, and impaired responses to mitogens. Impaired helper T cell function and hypogammaglobulinemia have also been described. The syndrome can be differentiated from Chediak-Higashi syndrome by pathognomonic light and electron microscopic features in skin and hair, and absence of consistent granulocyte abnormalities, but similarly carries a poor prognosis without bone marrow transplantation. We describe a patient with Griscelli syndrome who presented with hepatosplenomegaly, hepatitis, pancytopenia, and silvery hair in the newborn period. (J Am Acad Dermatol 1998;38:295-300.)

Griscelli syndrome, or partial albinism with immunodeficiency, was initially described in 1978,1 and as of 1995, fewer than 40 cases had been reported.2 Most patients have had the disease diagnosed between 4 months and 7 years of age,1-10 with the youngest at 3 months of age.2,9 We describe a female infant who presented at birth with hepatitis, pancytopenia, and silvery hair. The diagnosis of Griscelli syndrome was suggested by the dermatology service at 6 weeks of age and confirmed by microscopic skin and hair examination. CASE REPORT A 39-week gestational age Hispanic girl was born to a 25-year-old gravida 2, para 1 mother by normal spontaneous vaginal delivery. Mild meconium staining of amniotic fluid was noted at birth, as were petechiae and

This article is made possible through an educational grant from Ortho Dermatological. From the Departments of Pediatricsa and Dermatology,b Northwestern University Medical School, and the Division of Dermatology,c Children’s Memorial Hospital. Reprint requests to: Anthony J. Mancini, MD, Division of Dermatology #107, Children’s Memorial Hospital, 2300 Children’s Plaza, Chicago, IL 60614. Copyright © 1998 by the American Academy of Dermatology, Inc. 0190-9622/98/$5.00 + 0 16/4/84853

hepatosplenomegaly. Neonatal hyperbilirubinemia (peak total bilirubin 26.5 mg/dL at 4 weeks of age), hepatitis, and pancytopenia developed, necessitating multiple platelet and packed red blood cell transfusions for the patient. Complete blood cell count at day 1 of life revealed a white blood cell count of 9,200 cells/mm3 (9,100 to 34,000), hemoglobin 13.4 g/dL (15 to 24), hematocrit 41.7% (44% to 77%), platelets of 25 × 109/L (130 to 450), and an absolute neutrophil count of 2,392. Laboratory evaluation on admission to Children’s Memorial Hospital at 6 weeks of age revealed a white blood cell count of 2800 cells/mm3 (5,000 to 19,500), hemoglobin 6.5 g/dL (15.8 to 18.9), hematocrit 19.2% (42% to 56%), and platelets of 58 × 109/L (150 to 450). Absolute neutrophil count was 196, and a reticulocyte count was 2.2%. Serum chemistry profile revealed a total bilirubin of 8.3 mg/dL (0.2 to 1.0), direct bilirubin 5.7 mg/dL (<0.3), alkaline phosphatase 317 U/L (52.5 to 190), aspartate aminotransferase 175 U/L (7 to 35), alanine aminotransferase 69 U/L (10 to 96), lactic dehydrogenase 352 U/L (140 to 275), g-glutamyl transpeptidase 237 U/L (8 to 55), cholesterol 118 mg/dL (65 to 175), triglycerides 115 mg/dL (32 to 99), total protein 5.2 g/dL (3.6 to 7.4), and albumin 3.1 g/dL (2.7 to 3.4). Prothrombin time and partial thromboplastin time were within normal limits. Elevated titers against parvovirus were consistent with presence of maternal antibody. Serologic tests for Epstein-Barr virus, rubella, cytomegalovirus, toxoplas-

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A

Fig. 1. Hair with metallic silvery-gray sheen.

B Fig. 3. Light microscopy of clinically normal skin shows hyperpigmented basal melanocytes with sparse pigmentation of adjacent keratinocytes. (A, Hematoxylin-eosin stain; original magnification ×100; B, Fontana-Masson stain; original magnification × 100.)

Fig. 2. Light microscopy of hair reveals irregular, large clumps of melanin pigment.

mosis, herpes, and hepatitis A, B, and C were negative. Long-bone plain radiography was normal. Bone marrow aspiration revealed slight hypocellularity with mild erythroid hyperplasia and hemophagocytosis. There was no evidence of an infiltrative or malignant process. Abdominal ultrasound showed hepatosplenomegaly with intrahepatic cholestasis and the absence of bile duct distension. Liver biopsy showed marked portal inflammation with focal hepatocellular necrosis. Dermatologic consultation was obtained at 6 weeks of age. Examination was notable for silvery-gray hair with a metallic sheen (Fig. 1). No cutaneous or ophthalmic pigmentary dilution were noted, and nystagmus was absent. The parents reported distant consanguinity. The clinical differential diagnosis included Chediak-Higashi syndrome (CHS), Griscelli syndrome, and Elejalde syndrome. A hair mount was performed, and light microscopy revealed irregular, large aggregations of melanin pigment (Fig. 2). Histologic examination of skin biopsy sections showed hyperpigmented basal melanocytes with sparse pigmentation in adjacent keratinocytes

(Fig. 3, A), highlighted in Fontana-Masson stained sections (Fig. 3, B). Transmission electron microscopy of skin revealed an accumulation of numerous normalsized stage IV mature melanosomes in the cytoplasm of melanocytes, with virtual absence of such melanosomes in adjacent keratinocytes (Fig. 4). The peripheral blood smear showed no giant cytoplasmic granules in leukocytes. On the basis of the combination of clinical presentation and the light and electron microscopic findings, the diagnosis of Griscelli syndrome was made. Immunophenotyping revealed normal percentages of CD3+, CD4+, and CD8+ peripheral lymphocytes, but low numbers of CD19+ (B) lymphocytes. Natural killer cell number was normal, but function was decreased by 51chromium release assay at 16 LU (lytic units, normal 20 to 250 LU). Proliferative responses to phytohemagglutinin, concanavalin A, and pokeweed mitogens were all normal. Quantitative immunoglobulin analyses were normal. Skin testing against Candida antigen was not performed in view of age and lack of known exposure. Lumbar puncture revealed mild cerebrospinal fluid lymphocytosis. Magnetic resonance imaging of the brain was normal. The patient received intrathecal methotrexate and intravenous methylprednisolone in preparation for bone marrow transplantation. Her hepatitis and pancy-

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Table I. Differentiation of syndromes with silvery hair Syndrome

Age at onset Inheritance Hair color Hair mount

Skin pigment dilution Skin light microscopy Skin electron microscopy Eyes Accelerated phases Immune defects Granulocytic granules Neurologic defects Other findings

Griscelli Infancy/early childhood Autosomal recessive Silvery/metallic Large unevenly distributed melanin aggregates, primarily in the medulla

Chediak-Higashi Infancy/early childhood Autosomal recessive Silvery/metallic Evenly distributed small granular melanin aggregates

+ Increased pigment in M; sparse pigment in K Numerous mature melanosomes in M; few melanosomes in K Normal except retinal hypopigmentation in 1 patient ++++ NK cell function; DTH; immunoglobulin levels None

+++ Pigmentary dilution of M and K Giant melanosomes in M and K Iris hypopigmentation, prominent red reflex, photophobia, nystagmus ++++ PMN chemotaxis; NK cell function; ADCC ++++

++++ None

+ None

Elejalde Infancy/early childhood Autosomal recessive Silvery/metallic Unevenly distributed clumpy melanin aggregates, larger in medulla ++ Normal Incomplete melanization of melanosomes in M Normal Not reported None None ++++ PAS+ cytoplasmic granules in H/F

M, Melanocyte; K, keratinocyte; NK, natural killer; DTH, delayed type hypersensitivity; PMN, polymorphonuclear leukocyte; ADCC, antibodydependent cellular cytotoxicity; +, rarely present; ++, occasionally present; +++, frequently present; ++++, usually present; PAS, Periodic acidSchiff; H, histiocyte; F, fibroblast.

topenia gradually improved, necessitating only occasional transfusion of blood products. However, she presented at 15 weeks of age with spasticity and seizures and it was decided that she was not a suitable candidate for transplantation. DISCUSSION

In 1978 Griscelli et al.1,10 described two patients with partial albinism of hair and skin, frequent pyogenic infections, and acute episodes of fever, hepatosplenomegaly, neutropenia, and thrombocytopenia. The pigmentary changes were characterized microscopically by large pigment clumps within hair shafts and an accumulation of melanosomes in melanocytes with decreased melanocytic dendritic expansions. The large leukocytic granules characteristic of CHS were absent, and chemotaxis and bactericidal activity of granulocytes were normal. Since the original description, several additional patients with Griscelli syndrome have been reported. Many of these cases have involved multiple siblings and/or consanguineous parents, suggesting an autosomal reces-

sive mode of inheritance.2,3,5,6,8,9 Dermatologic findings in patients with Griscelli syndrome may be limited to the pigmentary abnormalities of hair,7 although cutaneous pigmentary dilution has occasionally been noted.1-4 The appearance of the hair has been variably described as silvery gray,1,4,6,7,10,11 silvery,5,8,9 grayish-golden,3 or dusty.2 Microscopic examination of hair shafts reveals uneven clusters of aggregated melanin pigment, accumulated mainly in the medullary area of the shaft. Histopathologic evaluation of skin biopsies shows hyperpigmented oval melanocytes with poorly pigmented adjacent keratinocytes, and electron microscopic evaluation of skin specimens shows epidermal melanocytes filled with numerous stage IV melanosomes arranged in a perinuclear distribution, without giant melanosomes. Adjacent keratinocytes ultrastructurally contain only sparse melanosomes.7 Neurologic involvement is a prominent feature in many patients with Griscelli syndrome.2-8 Clinical manifestations include intracranial hyper-

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Fig. 4. Transmission electron microscopy of clinically normal skin shows accumulation of numerous stage IV mature melanosomes (arrow) in cytoplasm of melanocytes, and virtual absence of melanosomes in adjacent keratinocytes (K). Bar = 6.5 µm.

tension,6,7 cerebellar signs,7,8 bulbar poliomyelitis,8 encephalopathy,2 hemiparesis,2 peripheral facial palsy,2 spasticity,2 hypotonia,3,4 seizures,2-4 psychomotor retardation,3-5 and progressive neurologic deterioration.2,4,5,7,8 Neurologic evaluations reveal cerebral lymphohistiocytic infiltration2,7 and erythrophagocytosis2 with nonspecific electroencephalographic patterns. Neuroradiologic studies have shown generalized white matter changes,7 increased signal intensity involving both gray and white matter,2 and white matter changes primarily in the posterior fossa.3 Immune evaluations most commonly reveal absent or impaired cutaneous delayed-type hypersensitivity, hypogammaglobulinemia, and impaired natural killer (NK) cell function. Lymphocyte proliferation in response to mitogens is generally intact, and granulocytic abnormalities are sporadic and inconsistent, with normal intracellular oxidative metabolism.7 Giant cytoplasmic granules in leukocytes are consistently absent.

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Patients with Griscelli syndrome are predisposed to the occurrence of “accelerated phases” similar to those encountered in CHS12,13 and virus-associated hemophagocytic syndrome,14,15 with lymphohistiocytic infiltration of many organs, leading to fever and hepatosplenomegaly. Laboratory findings include hemophagocytosis, pancytopenia, coagulopathy, elevated serum transaminase levels, and elevated triglycerides.7 These episodes have been associated with viral infections, most notably Epstein-Barr virus (EBV),7 which has also been associated with lymphoproliferative disease in patients with X-linked lymphoproliferative syndrome16 and with virusassociated hemophagocytic syndrome.14 It has also been suggested that EBV infection and the associated hemophagocytic syndrome may be responsible for the accelerated phases seen in CHS.12 The differential diagnosis of the disease in the patient presenting with silvery hair includes primarily the Griscelli, Chediak-Higashi, and Elejalde syndromes (Table I). The latter, also known as neuroectodermal-melanolysosomal disease, reveals spotty hair pigmentation similar to Griscelli syndrome, with incomplete melanization of melanosomes in skin melanocytes.17 In addition, nondegenerative CNS dysfunction is present and immunodeficiency absent. CHS differs from Griscelli syndrome by (1) the presence of abnormal giant cytoplasmic inclusions in leukocytes, (2) more frequent cutaneous pigmentary dilution, (3) aggregates of giant melanolysosomes in melanocytes and keratinocytes,7 (4) smaller, more evenly distributed pigment clumps in hair shafts,7 and (5) more consistently defective granulocyte activity. NK cell dysfunction has been described in both diseases,7,18,19 and both patients with CHS and Griscelli syndrome, but not those with Elejalde syndrome, are predisposed to “accelerated phases.” The diagnosis of Griscelli syndrome is made by clinical presentation combined with characteristic light and electron microscopic findings in hair shafts and skin, and absence of giant cytoplasmic granules in peripheral leukocytes. Prenatal diagnosis has been accomplished by examination of hair from fetal scalp skin biopsies performed at 21 weeks gestation,20 with confirmatory postabortion examination of the fetuses revealing silvery hair and identical microscopic hair abnormalities.

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Although morphologic examination of peripheral blood20 or cultured amniotic and chorionic villus21 cells can help to diagnose CHS prenatally, the immune deficiency characteristic of Griscelli syndrome cannot be detected before birth.20 The underlying molecular basis for Griscelli syndrome remained elusive until recently, when the genetic locus was found to co-localize on chromosome 15q21 with the myosin-Va gene.22 Interestingly, class V myosins are believed to play a role in membrane transport and organelle trafficking, functions that seem to overlap with those of the protein encoded by the gene responsible for Chediak Higashi syndrome, LYST. 23 Mutations in LYST may affect lysosomal trafficking, possibly through regulation of microtubule-mediated lysosome transport. The underlying molecular basis for Elejalde syndrome remains unknown. The prognosis for patients with Griscelli syndrome is grave. As in other genetic immunodeficiency diseases, bone marrow transplantation is the only hope for a cure, and appears to be most successful when performed early in the course of the disease.7,9,24 Induction of remission has been obtained with the combination of high-dose systemic methylprednisolone and etoposide and intrathecal methotrexate, cytosine arabinoside, and prednisone,11 and with a regimen of antithymocyte globulins, steroids, and cyclosporine,7 but these therapies are palliative rather than curative. In summary, the examination of a patient with metallic or silvery hair should include light microscopic analysis of hair shafts and skin biopsy samples. The results of these analyses, in combination with evaluations of immune function and examination of peripheral blood smears, will enable differentiation between the various syndromes with this clinical phenotype. We thank Sara Katz, MD, for assistance with the photomicroscopy, and Beiersdorf-Jobst, Inc. for a generous grant to support the cost of color photography. REFERENCES 1. Griscelli C, Durandy A, Guy-Grand D, Daguillard F, Herzog C, Prunieras M. A syndrome associating partial albinism and immunodeficiency. Am J Med 1978;65:691-702. 2. Gogus S, Topcu M, Kucukali T, Akcoren Z, Berkel I, Ersoy F, et al. Griscelli syndrome: report of three cases. Pediatr Pathol Lab Med 1995;15:309-19. 3. Brismar J, Harfi HA. Partial albinism with immunodeficiency: a rare syndrome with prominent posterior fossa

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4. 5. 6.

7. 8. 9.

10. 11.

12.

13. 14.

15.

16. 17.

18. 19.

20.

white matter changes. Am J Neuroradiol 1992;13:38793. Haraldsson A, Weemaes CMR, Bakkeren JAJM, Happle R. Griscelli disease with cerebral involvement. Eur J Pediatr 1991;150:419-22. Hurvitz H, Gillis R, Klaus S, Klar A, Gross-Kieselstein F, Okon E. A kindred with Griscelli disease: spectrum of neurologic involvement. Eur J Pediatr 1993;152:402-5. Kanitakis J, Cambazard F, Roca-Miralles M, Souillet G, Philippe N. Griscelli-Prunieras disease (partial albinism with immunodeficiency): report of a new case with light and electron-microscopic study of the skin. Eur J Dermatol 1991;3(1):206-13. Klein C, Philippe N, Le Deist F, Fraitag S, Prost C, Durandy A, et al. Partial albinism with immunodeficiency (Griscelli syndrome). J Pediatr 1994;125:886-95. Sanal O, Kucukali T, Ersoy F, Tinaztepe K, Gogus S. Griscelli’s syndrome: clinical features of three siblings. Turk J Pediatr 1993;35:115-9. Schneider LC, Berman RS, Shea CR, Perez-Atayde AR, Weinstein H, Geha RS. Bone marrow transplantation (BMT) for the syndrome of pigmentary dilution and lymphohistiocytosis (Griscelli’s syndrome). J Clin Immunol 1990;10(3):146-53. Griscelli C, Prunieras M. Pigment dilution and immunodeficiency: a new syndrome. Int J Dermatol 1978; 17(10):788-91. Gurgey A, Sayli T, Gunay M, Ersoy F, Kicukali T, Kale G, et al. High-dose methylprednisolone and VP-16 in treatment of Griscelli syndrome with central nervous system involvement. Am J Hematol 1994;47:331-8. Rubin CM, Burke BA, McKenna RW, McClain KL, White JG, Nesbit ME, et al. The accelerated phase of Chediak-Higashi syndrome: an expression of the virusassociated hemophagocytic syndrome? Cancer 1985;56:524-30. Lokuarachchi SK, Lamabadasuriya SP, Kodikara arachchi S, Fernando R. Chediak-Higashi syndrome. Ceylon Med J 1995;40:42-3. Blanche S, Caniglia M, Fischer A, Griscelli C. EpsteinBarr virus-associated hemophagocytic syndrome: clinical presentation and treatment. Pediatr Hematol Oncol 1989;6:233-5. Risdall RJ, McKenna RW, Nesbit ME, Krivit W, Balfour HH, Simmons RL, et al. Virus-associated hemophagocytic syndrome: a benign histiocytic proliferation distinct from malignant histiocytosis. Cancer 1979;44:9931002. Sullivan JL, Byron KS, Brewster FE, Purtilo DT. Deficient natural killer cell activity in X-linked lymphoproliferative syndrome. Science 1980;210(31):543-5. Elejalde BR, Holguin J, Valencia A, Gilbert EF, Molina J, Marin G, et al. Mutations affecting pigmentation in man: I, Neuroectodermal melanolysosomal disease. Am J Med Genet 1979;3:65-80. Targan SR, Oseas R. The “lazy” NK cells of ChediakHigashi syndrome. J Immunol 1983;130(6):2671-4. Diamond HR, Souza MHFO, Silva MLM, Tabak DG, Ferman S, M-Silva VM, et al. Natural killer cell activity in a patient with Chediak-Higashi syndrome submitted to bone marrow transplantation. Pediatr Hematol Oncol 1995;12:399-402. Durandy A, Breton-Gorius J, Guy-Grand D, Dumez C, Griscelli C. Prenatal diagnosis of syndromes associating albinism and immune deficiencies (Chediak-Higashi syndrome and variant). Prenat Diagn 1993;13:13-20.

300 Mancini, Chan, and Paller 21. Diukman R, Tanigawara S, Cowan MJ, Golbus MS. Prenatal diagnosis of Chediak-Higashi syndrome. Prenat Diagn 1992;12:877-85. 22. Pastural E, Barrat FJ, Dufourcq-Lagelouse R, Certain S, Sanal O, Jabado N, et al. Griscelli disease maps to chromosome 15q21 and is associated with mutations in the Myosin-Va gene. Nature Gen 1997;16:289-92. 23. Barbosa MDFS, Nguyen QA, Tchernev VT, Ashley JA,

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Detter JC, Blaydes SM, et al. Identification of the homologous beige and Chediak-Higashi syndrome genes. Nature 1996;382:262-4. 24. Fischer A, Griscelli C, Friedrich W, Kubanek B, Levinsky R, Morgan G, et al. Bone-marrow transplantation for immunodeficiencies and osteopetrosis: European survey 1968-1985. Lancet 1986;2:1080-3.