Griscelli Syndrome: Rab 27A Mutation

CASE REPORTS Griscelli Syndrome: Rab 27a Case Report Mutation A 13-day-old male baby born of second degree consanguineous parentage was brought for evaluation of excessively fair skin and silvery gray hair. His birth weight was 3.25 kg. Sheela S.R. The mother had conceived five times, resulting Latha Manoj* in one abortion, a normal female child who is Susy J. Injody** now 4 years old, and two elder male siblings who had the same clinical features as the proband and in addition had photophobia and An infant with partial albinism was suspected to have delay in motor and mental milestones. They Chediak-Higashi syndrome because two of his three both expired at around 15 months of age after elder siblings had albinism and died in childhood developing hepatosplenomegaly, neutropenia, following accelerated phase. Detailed investigations seizures and developmental regression. One of blood, hair and skin of the proband revealed that he child was investigated in detail for metabolic had Griscelli syndrome. problems and his peripheral smear failed to Key words : Griscelli syndrome, Accelerated phase, show any abnormal granules in the granulo- Mutation study. cytes. There was no history of any relatives affected by similar clinical presentation. Griscelli syndrome is a rare autosomal On examination the child had generalized recessive disease characterised by pigmentary excessively fair skin when compared with his dilution of skin and hair, variable cellular parents and living sibling. He had silvery gray immunodeficiency and an acute phase of scalp hair, white eyelashes, eyebrows and body uncontrolled T lymphocyte and macrophage hair ( Fig. 1). All other systems were within activation leading to fatal hemophagocytic normal limits. syndrome. It was first described by Griscelli in 1978, and since then only around 60 cases have been reported, mostly from the Turkish and Mediterranean population. To the best of our knowledge this is the first case reported from India, which has been proven by mutation syudy. From the Departments of Pediatrics,*Pathology, Indira Gandhi Co-operative Hospital, Kadavanthra, Cochin and Department of Pathology, DDC International, Cochin, Kerala 682 020, India. Correspondence to: Dr. Sheela SR, G-79, Ujjayini, Panampilly Nagar, Cochin 682 036, Kerala, India. E-mail: [email protected] Manuscript received: September 23, 2003; Initial review completed: December 8, 2003; Fig. 1. Typical silvery gray hair and hypopigmented Revision accepted: February 27, 2004. skin of the proband at 9 months INDIAN PEDIATRICS 944 VOLUME 41__ SEPTEMBER 17, 2004 CASE REPORTS The possibility of Chediak-Higashi nonsense mutation is the cause for Griscelli Syndrome (CHS) was considered, with the syndrome. Both parents were found to be two siblings dying due to the “accelerated heterozygous carriers of the same mutation. phase”. Peripheral smear of the proband failed The child is on regular follow up. He is to show any abnormal granules even after 1-year-old now and weighs 9 kg and has repeated examination. Intracytoplasmic normal motor and mental development for his granules were absent on the peripheral smear age. He has not yet developed any features of one of the elder siblings which was of the “accelerated phase”. Bone marrow examined while he was terminally ill from old transplantation is being considered. records. Serum copper and ceruloplasmin levels were normal. Microscopic examination Discussion of the hair shaft of the proband showed uneven Griscelli Syndrome (GS) is an extremely aggregations of large pigment granules, and rare autosomal recessive disorder hypopigmentation in the rest of the hair which characterized by partial albinism with silvery is the hallmark of Griscelli syndrome (Fig. 2). gray hair, eyebrows and eyelashes, in Light microscopy of skin showed large clumps association with cellular immunodeficiency, of melanin granules in melanocytes in the basal frequent infections, and neurological cell layer in Masson-Fontana stained sections, abnormalities. A fatal outcome occurs in the which is consistent with the skin changes of so-called “accelerated phase” of the disorder, Griscelli Syndrome (Fig. 3). which is caused by uncontrolled T lymphocyte Mutation study of the proband and the and macrophage activation(1). Thus it is parents were done at Hospital Necker-Enfants clinically similar to Chediak Higashi Malades, Paris. Rab27a gene was sequenced Syndrome. from the proband and a homozygous C550T The single most consistent cutaneous leading to R184X mutation (X is a stop expression of albinism in these patients is mutation) in Rab27a gene was identified.This silvery gray sheen to their hair(2). Microscopic Fig. 2. Microscopic examination of hair showing Fig. 3. Skin biopsy showing large clumps of uneven aggregation of large pigment melanin granules in the basal cell layer granules (× 400). (Masson-Fontana × 400) INDIAN PEDIATRICS 945 VOLUME 41__ SEPTEMBER 17, 2004 CASE REPORTS examination of the hair shaft provides strong MyoVa mutation as this gene regulates support for the diagnosis of these syndromes, organelle transport in melanocytes and in and allows one to distinguish between them. In neuronal cells. Impairment of intracellular both syndromes the hair shaft contains a typical trafficking and secretion of several lysosomal pattern of uneven accumulation of large proteins including melanin from melanocytes pigment granules, instead of the homogeneous and the lytic enzymes from cytotoxic cells distribution of small pigment granules seen in occur in GS and CHS. The secretory defect normal hair. In GS the clusters of melanin accounts for the hypopigmentation and the pigment on the hair shaft are six times larger cellular immunodeficiency(4). The immuno- than in CHS. logic abnormalities are restricted to the patients with Rab27a mutation as the capacity of the The hallmark of CHS is the presence of lymphocytes and NK cells of these patients to giant intracytoplasmic granules in virtually all lyse target cells is impaired or absent, due to a granulated cells, which is never observed in consistent inability to secrete cytotoxic GS. Light microscopy of the skin in GS shows granules. MyoVa defect does not affect hyperpigmented melanocytes with poorly cytotoxic granule secretion and hence they pigmented adjacent keratinocytes, instead of never develop accelerated phase. the homogeneous distribution of melanin granules in melanocytes and keratinocytes as Elejalde syndrome or Melanolysosomal seen in normal epidermis(3). neuroectodermal syndrome is another rare The disease is mapped on chromosome autosomal recessive disorder with striking 15q21 locus and mutations of MyoVa or resemblance to GS and they manifest with Rab27a gene can lead to GS. Although hypopigmentation, silvery hair and early onset pigmentary dilution is identical in both groups, severe psychomotor retardation without only patients with Rab27a mutations have immne deficiency strongly suggesting that abnormal lymphocyte cytotoxic activity which Elejalde syndrome and GS with MyoVa result in haemophagocytic syndrome. Severe mutation are allelic(5). Griscelli, Chediak neurological impairment with no immune Higashi and Elejalde syndromes are compared deficiency is the characteristic feature with in Table I. TABLE I–Comparison of Griscelli, Chediak-Higashi and Elejalde Syndromes. Griscelli Chediak-Higashi Elejalde syndrome syndrome syndrome Hypopigmentation + + + Silvery hair + + + Immune deficiency + + – Neurological impairment + MyoVa – ++ – Rab27a Intracytoplasmic granules – + – Clusters of melanin pigments in hair microscopy ++ + ++ Impaired transfer of melanin to keratinocytes in skin biopsy + + + Mode of inheritance AR AR AR INDIAN PEDIATRICS 946 VOLUME 41__ SEPTEMBER 17, 2004 CASE REPORTS Same mutation in Rab27a as the one immunodeficiency. Am J Med 1978; 65 : 691- observed in the proband reported here was 702. previously identified in Turkish, Italian, 2. Klein C, Philippe N, Le Deist F, Fraitag S, Prost Danish, English and Mauritius patients C, Durandy A, et al. Partial albinism with but ours is the first patient analysed from immunodeficiency (Griscelli syndrome). J India (6). Pediatr 1994; 125: 886- 895. 3. Mancini AJ, Chan LS, Paller AS. Partial albinism The prognosis for long term survival in GS with immunodeficiency: Griscelli syndrome: due to Rab27a defect is relatively poor. This Report of a case and review of the literature. J Am disorder is rapidly fatal during the accelerated Acad Dermatol 1998; 38: 295-300. phase of the disease. Etoposide was found to be 4. Pastural E, Ersoy F, Yalman N. Two genes are effective in some cases during the accelerated responsible for Griscelli syndrome at the same phase(7). Antithymocyte globulin and 15q21 locus. Genomics 2000; 63: 299-306. cyclosporin A have also achieved remission in 5. Bahadoran P, Ortonne J P, Ballotti R, de Saint a few cases(8). Allogenic bone marrow Basile G. Comment on Elejalde syndrome and transplantation is the only curative treat- relationship with Griscelli syndrome. Am J Med ment(9). In MyoVa defect the neurological Genet 2003; 116A: 408-409. impairment and psychomotor delay do not 6. Menasche G, Pastural E, Feldmann J, Certain S, improve and hence there is no role for bone Ersoy F, de Saint Basile G, et al. Mutations in marrow transplantation. Rab27a cause Griscelli syndrome associated with hemophagocytic syndrome. Nat Genet 2000; Acknowledgements 25:173-176. The authors would like to thank Dr. 7. Fischer A, Virelizier JL, Arenzana-Seisdedos F, Genevieve de Saint Basile of Hospital

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