| Abstract|| |
Griscelli syndrome (GS) is a rare autosomal recessive disorder caused by mutation in the MYO5A (GS1), RAB27A (GS2), and MLPH (GS3) genes, characterized by a common feature, partial albinism. The common variant of three, GS type 2, in addition, shows primary immunodeficiency which leads to recurrent infections and hemophagocytic lymphohistiocytosis. We, herewith, describe a case of GS type 2, in a 4-year-old male child who presented with chronic and recurrent fever, lymphadenopathy, hepatosplenomegaly, and secondary neurological deterioration; highlighting the cytological and histopathological features of lymph nodes. Hair shaft examination of the child confirmed the diagnosis.
Keywords: Griscelli syndrome type 2, hemophagocytic lymphohistiocytosis, lymphadenopathy
|How to cite this article:|
Rajyalakshmi R, Chakrapani R. Griscelli syndrome type 2: A rare and fatal syndrome in a South Indian boy. Indian J Pathol Microbiol 2016;59:113-6
| Introduction|| |
Griscelli syndrome (GS) is a rare autosomal recessive disorder due to mutations of the genes which are involved in the transport of melanosomes in melanocytes. This disorder is classified into three subtypes (GS1, GS2, and GS3) based on genetic loci involved. The genes involved are MYO5A (GS1), RAB27A (GS2), and MLPH (GS3) resulting in partial albinism as a common manifestation. While GS3 is limited to partial albinism alone, GS1 also shows severe primary neurological impairment. ,,, GS2, the common variant of the three, is characterized by immunodeficiency and secondary neurological deficits which manifest as severe infection in infants and in association with hypopigmentation of hair and skin. The disease is rare with around 101 cases reported in the medical literature worldwide,  of which 10 cases are from India.  The prognosis is poor with death in early childhood due to hemophagocytic lymphohistiocytosis (HLH) and its complications. , We describe a male child with silvery-gray hair, immune defects, and neurological deterioration. To the best of our knowledge, this is the first case describing the cytomorphological features of the lymph node in a case of GS type 2.
| Case report|| |
A 4-year-old male child was brought with the complaint of fever and enlarged neck nodes of 8 months duration and difficulty in walking since 6 months. History revealed episodes of fever occurring once in every 2 months since 1-year of age.
He was the first child of consanguineous parents and had normal milestones of development till past 6 months. His younger sibling is healthy.
Clinical examination revealed a moderately built, moderately nourished, and anemic child with a 4 3 cm right cervical lymph node. He had silver gray hair of the scalp, eyebrows, and eyelashes. His face showed hypopigmented patches [Figure 1]a.
|Figure 1: (a) Silvery - gray hair of the scalp, eyebrows, and eyelashes with hypopigmented patches on the skin of face in a case of Griscelli syndrome. (b) Computed tomography scan of brain showing demyelination of bilateral cerebral white matter|
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Investigations showed anemia with 9.2 g% hemoglobin and thrombocytopenia with a platelet count of 35,000 cells/cu mm. Total leukocyte count was 7100 cells/cu mm and peripheral smear examination revealed neutropenia with lymphocytosis (78% lymphocytes, 18% neutrophils,
and 04% monocytes). His erythrocyte sedimentation rate was 13 mm in the 1 st h.
Liver function tests were abnormal with elevated serum bilirubin (2.14 mg/dl), SGOT (278 U/L), SGPT (203U/L), and serum alkaline phosphatase (461U/L). Serology for chronic fever which included brucellosis, infectious mononucleosis, and hepatitis were negative.
His chest X-ray showed pneumonitis with bilateral pleural effusions.
An ultrasound done during the episodes of fever revealed hepatosplenomegaly and periportal lymphadenopathy. Computed tomography brain showed hyperdense lesions in the bilateral cerebral white matter, suggestive of demyelination [Figure 1]b.
Fine needle aspiration cytology of the cervical lymph node showed cellular smears composed of lymphocytes admixed with plenty of histiocytes. Some of the histiocytes showed engulfed lymphocytes. An opinion of lymphohistiocytic disorder was made on cytology [Figure 2]a
|Figure 2: (a) Fine needle aspiration cytology of cervical lymph node showing histiocytes and lymphocytes with a histiocyte engulfing lymphocytes (inset). (b) Biopsy of cervical lymph node showing sheets of histiocytes. (c) Hemophagocytosis. (d) Whole mount examination of patient hair showing clumps of pigment in medulla, in comparison with normal hair|
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Histopathology of excised lymph node showed loss of lymph nodal architecture with replacement by lymphohistiocytic proliferation. Some of the histiocytes showed hemophagocytosis [Figure 2]b and c.
Bone marrow aspiration smears were blood mixed and showed normal hematopoiesis.
Correlating the clinical features with the other investigations, the possibility of GS type 2 was suspected. Whole mount examination of hair under light microscopy showed large clumps of pigment in the medulla in contrast to normal hair, confirming the diagnosis [Figure 2]d.
The patient denied skin biopsy and the molecular study was not done due to financial constraints.
| Discussion|| |
Griscelli, initially described this syndrome, in the year 1978. 
GS is due to mutations involving three genes with a common function of melanosome transport. The protein products of these three genes, Myosin - Va, Rab27a, and melanophilin form a heterotrimeric protein complex which transfers melanosomes from the center to the periphery of a melanocyte. Hence, a mutation in any one of the genes results in partial albinism , [Figure 3]a.
|Figure 3: (a and b) Pathophysiology of Griscelli syndrome and pathogenesis of Griscelli syndrome type 2|
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The genetic abnormality and clinical presentation of the three types of GS are summarized in [Table 1]. ,,,,,
|Table 1: Genetic abnormality and clinical presentation in the three types of GS|
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Type 2 is the most common type of all the three, while type 3 is the least common. 
GS type 3 is characterized by partial albinism alone,  whereas type 1 shows primary neurological defects such as congenital cerebellar atrophy manifesting as developmental delay and mental retardation in addition to pigment dilution. ,
GS type 2 is due to mutations in RAB27A gene which is located on chromosome 15q21.1. , This gene encodes for a low molecular weight GTPase, Rab27a, which in addition to intracellular transport of melanosomes, plays an essential role in exocytosis of cytolytic granules in cytotoxic T-lymphocytes and NK cells and secretory vesicles in endocrine cells. ,
Deleterious mutations in RAB27A gene have two important consequences. Failure of peripheral transfer of melanosomes results in their clumping within the melanocytes of skin and hair, manifesting as partial albinism clinically. They also exhibit cytotoxic defects which trigger the often fatal hemophagocytic syndrome. HLH is due to systemic activation of macrophages and CD8+ cytotoxic T-lymphocytes. The activated macrophages phagocytose the progenitors in bone marrow and formed elements in peripheral tissues. The mediators released from these macrophages and T-lymphocytes cause bone marrow suppression leading to cytopenias and its consequences. Infiltration of various tissues during these phases (accelerated phase) result in organomegaly. ,,,,, Involvement of the brain in some of these cause neurological deterioration as seen in our case [Figure 3]b.
Despite the presence of an adequate number of T- and B-lymphocytes, these patients are hypogammaglobulinemic, due to deficient antibody production, and hence, are incapable of manifesting delayed hypersensitivity. 
Skin biopsy shows enlarged hyperpigmented basal melanocytes with sparsely pigmented adjacent keratinocytes  and lymph nodes show histiocytic proliferation with hemophagocytosis.
Hair shafts show uneven clusters of aggregated melanin pigment mainly in the medulla. ,
Ultrastructural studies show the type IV melanosomes (mature melanosomes) and shortened dendritic processes in basal melanocytes. ,
Twenty-seven different mutations in the RAB27A locus have been described as causing GS2.  Most of these mutations were homozygous nonsense or frameshift mutations leading to the absence of- or abnormality of- the protein. 
Severe infection in infants, in association with hypopigmentation of hair and skin may indicate either GS or Chediak-Higashi syndrome (CHS). Unlike GS, hair shafts in CHS show even distribution of pigment clumps along with giant cytoplasmic granules in leukocytes. , Skin biopsy shows giant melanosomes both in melanocytes and keratinocytes in CHS. 
Other primary lymphohistiocytic syndromes such as familial lymphohistiocytosis, X-linked lymphoproliferative disease, and secondary HLH do not exhibit albinism, although they develop accelerated phases similar to that seen in GS.
Prognosis is poor and accelerated phases with HLH can be fatal. Average age at death is 5 years. 
The only possibility of curing this disease is bone marrow transplantation or peripheral blood stem cell transplantation. Only patients with mutations in RAB27A (type 2 GS) should receive this treatment. Due to the risk of early relapse or severe infection, therapeutic intervention should be carried out as early as possible. 
Greater awareness of this rare and potentially fatal entity is essential for early diagnosis, which is possible by simple hair shaft examination.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
We are especially grateful to the family members for their cooperation.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]