Pediatric Neurology 52 (2015) 535e538
Contents lists available at ScienceDirect
Pediatric Neurology journal homepage: www.elsevier.com/locate/pnu
Clinical Observations
Seizure as the Presenting Manifestation in Griscelli Syndrome Type 2 Inusha Panigrahi MD, DM a, Renu Suthar MD b, Amit Rawat MBBS, MD, PDCC c, *, Bijaylakshmi Behera MD b a
Genetic and Metabolic Unit, Department of Pediatrics, Advanced Pediatrics Centre, Postgraduate Institute of Medical Education and Research, Chandigarh, India b Department of Pediatrics, Advanced Pediatrics Centre, Postgraduate Institute of Medical Education and Research, Chandigarh, India c Pediatric Allergy and Immunology Unit, Department of Pediatrics, Advanced Pediatrics Centre, Postgraduate Institute of Medical Education and Research, Chandigarh, India
abstract BACKGROUND: Griscelli syndrome is an autosomal recessive disease that is characterized by hypopigmentation of the skin and hair, presence of large clumps of pigment in hair shafts, and accumulation of melanosomes in melanocytes; it resembles Chediak-Higashi syndrome. Griscelli syndrome type 2 is caused by mutations in the RAB27A gene and has predominant immunologic abnormalities. METHOD: A retrospective case analysis highlighting neurological complications in an individual with Griscelli syndrome type 2. RESULTS: We present a 1year-old girl with Griscelli syndrome type 2 in an Asian Indian family, confirmed by mutation analysis of the RAB27A gene. She presented with seizures and regression of developmental milestones following a brief febrile illness. Progressive neurological deterioration was associated with refractory status epilepticus. Neurological worsening may have resulted from the accelerated phase of the disease. CONCLUSION: Griscelli syndrome type 2 is a rare primary immunodeficiency state with characteristic silvery hair, partial albinism, and immunological abnormalities. Predominant neurological presentation is rare, but it represents isolated central nervous system hemophagocytosis. Keywords: Griscelli syndrome type II, hypopigmentation, melanosomes, seizures
Pediatr Neurol 2015; 52: 535-538 Ó 2015 Elsevier Inc. All rights reserved.
Introduction
Griscelli syndrome was first described in 1978 by Griscelli et al. as partial albinism associated with different degrees of pancytopenia.1 Its main clinical features include silvery-gray hair and immunological dysfunction. Griscelli syndrome is classified into three subtypes. Griscelli syndrome type 1 represents hypomelanosis with a primary neurological deficit without immunologic impairment.2 Mutations in
Article History: Received September 11, 2014; Accepted in final form January 17, 2015 * Communications should be addressed to: Dr. Rawat; Division of Pediatric Allergy and Immunology; Department of Pediatrics; Advanced Pediatrics Centre; Postgraduate Institute of Medical Education and Research Chandigarh 160012, India. E-mail address: [email protected] 0887-8994/$ e see front matter Ó 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.pediatrneurol.2015.01.010
MYO5A have been implicated in Griscelli type 1.3 Griscelli syndrome with immune impairment or Griscelli syndrome type 2 is caused by mutation in the RAB27A gene.3 RAB27A is expressed in the cytotoxic T lymphocytes and natural killer cells, where it plays an important role in docking and exocytosis of cytotoxic granules containing granzyme and perforin at the immunological synapse.3 Griscelli syndrome type 3 is characterized by hypomelanosis with no immunologic or neurological manifestations, and can be caused by mutation in the melanophilin or myosin V heavy chain (MYO5A) genes.4 The prevalence of Griscelli syndrome is not known in many populations but is likely to be missed clinically without proper evaluation. Griscelli type 2 has been included in the recent updated classification of primary immunodeficiency diseases under the category of “diseases of immune dysregulation.”5 The primary immunodeficiency seen in Griscelli syndrome type 2 is due to impairment of
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I. Panigrahi et al. / Pediatric Neurology 52 (2015) 535e538
FIGURE 1. Light microscopy of a hair shaft from the index case showing large irregular melanin granules (40). (The color version of this figure is available in the online edition.)
T-cell and natural killer cytotoxic activity, resulting in susceptibility to repeated infections, ultimately reaching a fatal accelerated phase characterized by hemophagocytic lymphohistiocytosis. This phase usually presents with periods of fever, hepatosplenomegaly, and pancytopenia.2,3 In addition, a wide spectrum of neurological features occur with cellular infiltration of the brain.6-8 We describe a 1-year-old girl with Griscelli syndrome type 2 who experienced seizures, regression of developmental milestones, and status epilepticus representing an isolated central nervous system (CNS) accelerated phase. Patient Description A 1-year-old girl with normal developmental milestones presented with a brief febrile episode 1 month earlier, followed by seizures and
developmental regression for the past 15 days. She was the first child born to a nonconsanguineous couple. Birth and the perinatal period was uncomplicated. Examination revealed a dolichocephalic head with silvery white hairs, round face, silvery eyelashes, brown-black irides, and tented upper lip. She had hepatosplenomegaly with the liver palpable 5 cm below right costal margin and the spleen 6 cm below the left costal margin. On neurological examination, she was irritable, did not recognize her parents, had poor visual fixation and following, normal tone, normally elicitable deep tendon reflexes, and extensor plantars. Because she had acute seizures, she was initially treated for meningitis. Her hemoglobin was 10.4 g/dL, white blood cell 3240/mm3, with 50% polymorphs, and a platelet count of 172 103/mm3. Her white blood cell counts fell during hospital stay with lowest of 1800/mm3. Peripheral blood smear examination did not show giant granules. C-reactive protein level was not elevated, and blood cultures and the evaluation for sepsis was unremarkable. Cerebrospinal fluid was acellular with normal protein and glucose and sterile cerebrospinal fluid cultures. Serum ammonia and metabolic screening were negative. Hair microscopy showed large pigment clusters in the hair shafts (Fig 1). Diagnosis of Griscelli syndrome type 2 was considered in view of silvery hairs, hepatosplenomegaly, neurological symptoms, and pigmentary dilution of hair shaft. Peripheral blood immunophenotyping for lymphocyte subsets by flow cytometry revealed a normal distribution of lymphocyte subsets with 71.85% T lymphocytes, 21.17% B lymphocytes (normal 15-39%), and 6.85% natural killer cells (normal 3-17%). Her absolute counts showed a CD3 count of 4016/mL (normal 1600-6700/mL), CD4 count of 3160/mL (normal 100-4600/mL), and a CD8 count of 695/mL (normal 400-2100/mL), with a CD4/CD8 ratio of 4.54 (1.3-3.9). Serum immunoglobulins estimated by end-point nephelometry were normal. However, natural killer cell cytotoxicity could not be assessed in this child. During her hospital stay, she experienced progressive worsening with repeated left focal seizures and status epilepticus. Electroencephalography was remarkable for abnormally slow background activity with lack of age-appropriate sleep markers suggestive of severe diffuse encephalopathic process. Brain magnetic resonance imaging (MRI) revealed multiple extensive T2/fluid attenuation inversion recovery hyperintense lesions in periventricular, subcortical, and cerebellar white matter, along with mild supratentorial ventriculomegaly (Fig 2 A and B). Leptomeningeal enhancement was also evident along the cerebellar folia and convexities. She was treated with intravenous phenytoin, levetiracetam, valproate, midazolam infusion, and
FIGURE 2. (A) T2-weighted magnetic resonance image of the brain axial section at the level of basal ganglia showing cortical atrophy, ex vacuo dilatation of ventricular system. Multiple bilateral T2 hyperintense lesions involving the periventricular areas , subcortical white matter, basal ganglia, and thalamus (arrow) suggest central nervous system lymphohistiocytosis. (B) T1 postcontrast axial sections at the level of fourth ventricle showing symmetrical hyperintensities involving cerebellar folia bilaterally, dentate nucleus, and leptomeningeal enhancement (arrowhead).
I. Panigrahi et al. / Pediatric Neurology 52 (2015) 535e538 thiopentone coma for status epilepticus. Status epilepticus remained refractory, and she also received ketamine infusion. Her neurological deterioration was presumed to be secondary to CNS hemophagocytosis. Bone marrow aspiration, however, showed no evidence of hemophagocytosis. The marrow was cellular, reactive with a myeloid:erythroid ratio of 19:1. Serum triglyceride level was 350 mg/dL, serum fibrinogen was 2.6 mg/dL, and serum ferritin could not be done. She was treated with intravenous methylprednisolone and was also planned for cytotoxic chemotherapy. She continued to have intractable seizures during her hospital stay and died on day 14 of hospitalization. RAB27A gene mutation analysis revealed homozygous splice mutation 239þ1 G-T in intron 3. The parents were heterozygous for the said mutation. Thus, the child was confirmed to have Griscelli syndrome type 2, in which neurological and immunological abnormalities can coexist, leading to early mortality.
Discussion
Silvery hair is a rare clinical manifestation seen in pediatric patients with “silvery hair syndrome” and ChediakHigashi syndrome, Griscelli syndrome, Elejalde disease, Hermansky-Pudlak syndrome type 2, and p14 deficiency.6 Griscelli syndrome type 2 is a rare primary immunodeficiency disease caused by a mutation in the RAB27A gene and is characterized by oculocutaneous hypopigmentation and variable cellular immunodeficiency2,3,7 Diagnosis of Griscelli syndrome was confirmed in the index patient with pigmentary abnormalities in the hair shaft, cellular immunodeficiency, and a mutation in the RAB27 gene. Neurological involvement in Griscelli syndrome is most common in type 1, but there are recent reports of an isolated CNS accelerated phase in Griscelli syndrome type 2.6,8-11 Reported neurological manifestations include seizures, neuroregression following viral infections, cerebellar ataxia, and increased intracranial pressure.10,11 Our patient presented with isolated neurological involvement with seizures, regression of milestones, and status epilepticus. Her clinical features and MRI changes favored an isolated CNS accelerated phase because there was no evidence of hemophagocytosis in her bone marrow. In Griscelli syndrome type 2 accelerated the phase is characterized by lymphocytic infiltration of various tissues including the CNS. Multiple subcortical, periventricular, internal capsule, cerebellar white matter T2, and fluid attenuation inversion recovery hyperintensities in MRI brain and spinal cord have been documented.6,9,11,12 One autopsy report describing an individual with Griscelli syndrome type 2 documented on gross examination a necrotizing lesion in the cerebrum and cerebellum that corresponded to lesions on the brain MRI. Histology of these lesions revealed lymphohistiocytic infiltration with breakdown of the parenchyma.11 RAB27A codes for a small guanosine triphosphatase involved in terminal phases of cytotoxic granule/melanosome exocytosis. MYO5A and RAB27A interact in the same molecular pathway, resulting in melanosome transport on actin filaments to dock at the plasma membrane.13 Menasche et al. suggested that patients with partial albinism and manifestations of hemophagocytic syndrome, with or without neurological involvement, should be screened for mutation in RAB27A.3 In our patient, the splice mutation 239þ1 G-T in intron 3 was detected in a homozygous state and was rechecked by parental mutation screening.
537
RAB27A mutation can manifest with varying presentations: an interesting report in two siblings with same mutation in RAB27A presented with different clinical features, one with isolated neurological accelerated phase and another presented with systemic hemophagocytosis.12 Most individuals with Griscelli syndrome from Asia are reported from Iran; in these families, a deletion hot spot (514del 5) has been identified.14 In another report from Kerala state, India, a homozygous C550T leading to R184X mutation (X is a stop mutation) in RAB27A gene was identified.15 The exact incidence of Griscelli syndrome in the Indian subcontinent is not known. Griscelli syndrome could be more common than expected, especially in regions with high rates of consanguinity. The present case is perhaps the first case of Griscelli type 2 with a proven mutation in RAB27A of the more than 150 cases of primary immunodeficiency disorders been seen at our tertiary care center during the past 15 years. High rates of consanguinity are seen in some ethnic groups in North India and some communities in South India with uncleeniece marriages. The treatment includes a trial of bone marrow stem cell transplantation. Eleven individuals who underwent transplantation were reported from Saudi Arabia.16 The median age at transplantation was 8.2 months (range, 436.3 months) and the median time from diagnosis to transplantation was 3.7 months (range, 1.4-19.5 months). Ten patients were alive and disease-free at a median of 4.8 years posthematopoietic stem cells transplant.16 The prognosis of disease is usually poor without transplantation; hence, prompt diagnosis and appropriate management are crucial for the family. Prenatal diagnosis is planned in the parents of our patient by mutation analysis on chorionic villous sample. We thank Hospital Necker-Enfants Malades, Paris, France, for help in mutation analysis.
References 1. Griscelli C, Durandy A, Guy-Grand D, et al. A syndrome associating partial albinism and immunodeficiency. Am J Med. 1978;65: 691-702. 2. Menasche G, Pastural E, Feldmann J, et al. Mutations in RAB27A cause Griscelli syndrome associated with haemophagocytic syndrome. Nat Genet. 2000;25:173-176. 3. Menasche G, Fischer A, de Saint Basile G. Griscelli syndrome types 1 and 2. Am J Hum Genet. 2002;71:1237-1238. 4. OMIM (Online Mendelian inheritance in man). Baltimore: Johns Hopkins University, Center for Medical Genetics. Available at: http://www3.ncbi.nlm.nih.gov/omim/(Feb 2012). 5. Al-Herz W, Bousfiha A, Casanova J-L, et al. Primary immunodeficiency diseases: an update on the classification from the International Union of Immunological Societies Expert Committee for Primary Immunodeficiency. Front Immunol. 2014;5:162. 6. Is¸ikay S. Cerebellar involvement of Griscelli syndrome type 2. BMJ Case Rep. 2014 Oct 14;2014. 7. Mamishi S, Modarressi MH, Pourakbari B, et al. Analysis of RAB27A gene in Griscelli syndrome type 2: novel mutations including a deletion hotspot. J Clin Immunol. 2008;28:384-389. 8. Anikster Y, Huizing M, Anderson PD, et al. Evidence that Griscelli syndrome with neurological involvement is caused by mutations in RAB27A, not MYO5A. Am J Hum Genet. 2002;71:407-414. 9. Saini AG, Nagaraju S, Sahu JK, Rawat A, Vyas S, Singhi P. Teaching neuroImages: Griscelli syndrome and CNS lymphohistiocytosis. Neurology. 2014 Apr 8;82:e122-e123.
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10. Aksu G, Kütükçüler N, Genel F, Vergin C, Omowaire B. Griscelli syndrome without hemophagocytosis in an eleven-year-old girl: expanding the phenotypic spectrum of Rab27A mutations in humans. Am J Med Genet A. 2003;116A: 329-333. 11. Bindua PS, et al. Neuroimaging findings in Griscelli syndrome type 2 with primary neurological presentation. J Pediatr Neuroradiol. 2014; 3:81-86. 12. Mishra K, Singla S, Sharma S, et al. Griscelli syndrome type 2: a novel mutation in RAB27A gene with different clinical features in 2 siblings: a diagnostic conundrum. Korean J Pediatr. 2014;57:91-95.
13. Kuroda TS, Mikoshiba K. Slac2-a/melanophilin, the missing link between Rab27 and myosin Va: implications of a tripartite protein complex for melanosome transport. J Biol Chem. 2002;277: 12432-12436. 14. Malhotra AK, Bhaskar G, Nanda M, Kabra M, Singh MK, Ramam M. Griscelli syndrome. J Am Acad Dermatol. 2006;55:337-340. 15. Sheela SR, Latha M, Injody SJ. Griscelli syndrome: Rab 27a mutation. Indian Pediatr. 2004;41:944-947. 16. Al-Ahmari A, Al-Ghonaium A, Al-Mansoori M, et al. Hematopoietic SCT in children with Griscelli syndrome: a single-center experience. Bone Marrow Transplant. 2010;45:1294-1299.
Contents lists available at ScienceDirect
Pediatric Neurology journal homepage: www.elsevier.com/locate/pnu
Clinical Observations
Seizure as the Presenting Manifestation in Griscelli Syndrome Type 2 Inusha Panigrahi MD, DM a, Renu Suthar MD b, Amit Rawat MBBS, MD, PDCC c, *, Bijaylakshmi Behera MD b a
Genetic and Metabolic Unit, Department of Pediatrics, Advanced Pediatrics Centre, Postgraduate Institute of Medical Education and Research, Chandigarh, India b Department of Pediatrics, Advanced Pediatrics Centre, Postgraduate Institute of Medical Education and Research, Chandigarh, India c Pediatric Allergy and Immunology Unit, Department of Pediatrics, Advanced Pediatrics Centre, Postgraduate Institute of Medical Education and Research, Chandigarh, India
abstract BACKGROUND: Griscelli syndrome is an autosomal recessive disease that is characterized by hypopigmentation of the skin and hair, presence of large clumps of pigment in hair shafts, and accumulation of melanosomes in melanocytes; it resembles Chediak-Higashi syndrome. Griscelli syndrome type 2 is caused by mutations in the RAB27A gene and has predominant immunologic abnormalities. METHOD: A retrospective case analysis highlighting neurological complications in an individual with Griscelli syndrome type 2. RESULTS: We present a 1year-old girl with Griscelli syndrome type 2 in an Asian Indian family, confirmed by mutation analysis of the RAB27A gene. She presented with seizures and regression of developmental milestones following a brief febrile illness. Progressive neurological deterioration was associated with refractory status epilepticus. Neurological worsening may have resulted from the accelerated phase of the disease. CONCLUSION: Griscelli syndrome type 2 is a rare primary immunodeficiency state with characteristic silvery hair, partial albinism, and immunological abnormalities. Predominant neurological presentation is rare, but it represents isolated central nervous system hemophagocytosis. Keywords: Griscelli syndrome type II, hypopigmentation, melanosomes, seizures
Pediatr Neurol 2015; 52: 535-538 Ó 2015 Elsevier Inc. All rights reserved.
Introduction
Griscelli syndrome was first described in 1978 by Griscelli et al. as partial albinism associated with different degrees of pancytopenia.1 Its main clinical features include silvery-gray hair and immunological dysfunction. Griscelli syndrome is classified into three subtypes. Griscelli syndrome type 1 represents hypomelanosis with a primary neurological deficit without immunologic impairment.2 Mutations in
Article History: Received September 11, 2014; Accepted in final form January 17, 2015 * Communications should be addressed to: Dr. Rawat; Division of Pediatric Allergy and Immunology; Department of Pediatrics; Advanced Pediatrics Centre; Postgraduate Institute of Medical Education and Research Chandigarh 160012, India. E-mail address: [email protected] 0887-8994/$ e see front matter Ó 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.pediatrneurol.2015.01.010
MYO5A have been implicated in Griscelli type 1.3 Griscelli syndrome with immune impairment or Griscelli syndrome type 2 is caused by mutation in the RAB27A gene.3 RAB27A is expressed in the cytotoxic T lymphocytes and natural killer cells, where it plays an important role in docking and exocytosis of cytotoxic granules containing granzyme and perforin at the immunological synapse.3 Griscelli syndrome type 3 is characterized by hypomelanosis with no immunologic or neurological manifestations, and can be caused by mutation in the melanophilin or myosin V heavy chain (MYO5A) genes.4 The prevalence of Griscelli syndrome is not known in many populations but is likely to be missed clinically without proper evaluation. Griscelli type 2 has been included in the recent updated classification of primary immunodeficiency diseases under the category of “diseases of immune dysregulation.”5 The primary immunodeficiency seen in Griscelli syndrome type 2 is due to impairment of
536
I. Panigrahi et al. / Pediatric Neurology 52 (2015) 535e538
FIGURE 1. Light microscopy of a hair shaft from the index case showing large irregular melanin granules (40). (The color version of this figure is available in the online edition.)
T-cell and natural killer cytotoxic activity, resulting in susceptibility to repeated infections, ultimately reaching a fatal accelerated phase characterized by hemophagocytic lymphohistiocytosis. This phase usually presents with periods of fever, hepatosplenomegaly, and pancytopenia.2,3 In addition, a wide spectrum of neurological features occur with cellular infiltration of the brain.6-8 We describe a 1-year-old girl with Griscelli syndrome type 2 who experienced seizures, regression of developmental milestones, and status epilepticus representing an isolated central nervous system (CNS) accelerated phase. Patient Description A 1-year-old girl with normal developmental milestones presented with a brief febrile episode 1 month earlier, followed by seizures and
developmental regression for the past 15 days. She was the first child born to a nonconsanguineous couple. Birth and the perinatal period was uncomplicated. Examination revealed a dolichocephalic head with silvery white hairs, round face, silvery eyelashes, brown-black irides, and tented upper lip. She had hepatosplenomegaly with the liver palpable 5 cm below right costal margin and the spleen 6 cm below the left costal margin. On neurological examination, she was irritable, did not recognize her parents, had poor visual fixation and following, normal tone, normally elicitable deep tendon reflexes, and extensor plantars. Because she had acute seizures, she was initially treated for meningitis. Her hemoglobin was 10.4 g/dL, white blood cell 3240/mm3, with 50% polymorphs, and a platelet count of 172 103/mm3. Her white blood cell counts fell during hospital stay with lowest of 1800/mm3. Peripheral blood smear examination did not show giant granules. C-reactive protein level was not elevated, and blood cultures and the evaluation for sepsis was unremarkable. Cerebrospinal fluid was acellular with normal protein and glucose and sterile cerebrospinal fluid cultures. Serum ammonia and metabolic screening were negative. Hair microscopy showed large pigment clusters in the hair shafts (Fig 1). Diagnosis of Griscelli syndrome type 2 was considered in view of silvery hairs, hepatosplenomegaly, neurological symptoms, and pigmentary dilution of hair shaft. Peripheral blood immunophenotyping for lymphocyte subsets by flow cytometry revealed a normal distribution of lymphocyte subsets with 71.85% T lymphocytes, 21.17% B lymphocytes (normal 15-39%), and 6.85% natural killer cells (normal 3-17%). Her absolute counts showed a CD3 count of 4016/mL (normal 1600-6700/mL), CD4 count of 3160/mL (normal 100-4600/mL), and a CD8 count of 695/mL (normal 400-2100/mL), with a CD4/CD8 ratio of 4.54 (1.3-3.9). Serum immunoglobulins estimated by end-point nephelometry were normal. However, natural killer cell cytotoxicity could not be assessed in this child. During her hospital stay, she experienced progressive worsening with repeated left focal seizures and status epilepticus. Electroencephalography was remarkable for abnormally slow background activity with lack of age-appropriate sleep markers suggestive of severe diffuse encephalopathic process. Brain magnetic resonance imaging (MRI) revealed multiple extensive T2/fluid attenuation inversion recovery hyperintense lesions in periventricular, subcortical, and cerebellar white matter, along with mild supratentorial ventriculomegaly (Fig 2 A and B). Leptomeningeal enhancement was also evident along the cerebellar folia and convexities. She was treated with intravenous phenytoin, levetiracetam, valproate, midazolam infusion, and
FIGURE 2. (A) T2-weighted magnetic resonance image of the brain axial section at the level of basal ganglia showing cortical atrophy, ex vacuo dilatation of ventricular system. Multiple bilateral T2 hyperintense lesions involving the periventricular areas , subcortical white matter, basal ganglia, and thalamus (arrow) suggest central nervous system lymphohistiocytosis. (B) T1 postcontrast axial sections at the level of fourth ventricle showing symmetrical hyperintensities involving cerebellar folia bilaterally, dentate nucleus, and leptomeningeal enhancement (arrowhead).
I. Panigrahi et al. / Pediatric Neurology 52 (2015) 535e538 thiopentone coma for status epilepticus. Status epilepticus remained refractory, and she also received ketamine infusion. Her neurological deterioration was presumed to be secondary to CNS hemophagocytosis. Bone marrow aspiration, however, showed no evidence of hemophagocytosis. The marrow was cellular, reactive with a myeloid:erythroid ratio of 19:1. Serum triglyceride level was 350 mg/dL, serum fibrinogen was 2.6 mg/dL, and serum ferritin could not be done. She was treated with intravenous methylprednisolone and was also planned for cytotoxic chemotherapy. She continued to have intractable seizures during her hospital stay and died on day 14 of hospitalization. RAB27A gene mutation analysis revealed homozygous splice mutation 239þ1 G-T in intron 3. The parents were heterozygous for the said mutation. Thus, the child was confirmed to have Griscelli syndrome type 2, in which neurological and immunological abnormalities can coexist, leading to early mortality.
Discussion
Silvery hair is a rare clinical manifestation seen in pediatric patients with “silvery hair syndrome” and ChediakHigashi syndrome, Griscelli syndrome, Elejalde disease, Hermansky-Pudlak syndrome type 2, and p14 deficiency.6 Griscelli syndrome type 2 is a rare primary immunodeficiency disease caused by a mutation in the RAB27A gene and is characterized by oculocutaneous hypopigmentation and variable cellular immunodeficiency2,3,7 Diagnosis of Griscelli syndrome was confirmed in the index patient with pigmentary abnormalities in the hair shaft, cellular immunodeficiency, and a mutation in the RAB27 gene. Neurological involvement in Griscelli syndrome is most common in type 1, but there are recent reports of an isolated CNS accelerated phase in Griscelli syndrome type 2.6,8-11 Reported neurological manifestations include seizures, neuroregression following viral infections, cerebellar ataxia, and increased intracranial pressure.10,11 Our patient presented with isolated neurological involvement with seizures, regression of milestones, and status epilepticus. Her clinical features and MRI changes favored an isolated CNS accelerated phase because there was no evidence of hemophagocytosis in her bone marrow. In Griscelli syndrome type 2 accelerated the phase is characterized by lymphocytic infiltration of various tissues including the CNS. Multiple subcortical, periventricular, internal capsule, cerebellar white matter T2, and fluid attenuation inversion recovery hyperintensities in MRI brain and spinal cord have been documented.6,9,11,12 One autopsy report describing an individual with Griscelli syndrome type 2 documented on gross examination a necrotizing lesion in the cerebrum and cerebellum that corresponded to lesions on the brain MRI. Histology of these lesions revealed lymphohistiocytic infiltration with breakdown of the parenchyma.11 RAB27A codes for a small guanosine triphosphatase involved in terminal phases of cytotoxic granule/melanosome exocytosis. MYO5A and RAB27A interact in the same molecular pathway, resulting in melanosome transport on actin filaments to dock at the plasma membrane.13 Menasche et al. suggested that patients with partial albinism and manifestations of hemophagocytic syndrome, with or without neurological involvement, should be screened for mutation in RAB27A.3 In our patient, the splice mutation 239þ1 G-T in intron 3 was detected in a homozygous state and was rechecked by parental mutation screening.
537
RAB27A mutation can manifest with varying presentations: an interesting report in two siblings with same mutation in RAB27A presented with different clinical features, one with isolated neurological accelerated phase and another presented with systemic hemophagocytosis.12 Most individuals with Griscelli syndrome from Asia are reported from Iran; in these families, a deletion hot spot (514del 5) has been identified.14 In another report from Kerala state, India, a homozygous C550T leading to R184X mutation (X is a stop mutation) in RAB27A gene was identified.15 The exact incidence of Griscelli syndrome in the Indian subcontinent is not known. Griscelli syndrome could be more common than expected, especially in regions with high rates of consanguinity. The present case is perhaps the first case of Griscelli type 2 with a proven mutation in RAB27A of the more than 150 cases of primary immunodeficiency disorders been seen at our tertiary care center during the past 15 years. High rates of consanguinity are seen in some ethnic groups in North India and some communities in South India with uncleeniece marriages. The treatment includes a trial of bone marrow stem cell transplantation. Eleven individuals who underwent transplantation were reported from Saudi Arabia.16 The median age at transplantation was 8.2 months (range, 436.3 months) and the median time from diagnosis to transplantation was 3.7 months (range, 1.4-19.5 months). Ten patients were alive and disease-free at a median of 4.8 years posthematopoietic stem cells transplant.16 The prognosis of disease is usually poor without transplantation; hence, prompt diagnosis and appropriate management are crucial for the family. Prenatal diagnosis is planned in the parents of our patient by mutation analysis on chorionic villous sample. We thank Hospital Necker-Enfants Malades, Paris, France, for help in mutation analysis.
References 1. Griscelli C, Durandy A, Guy-Grand D, et al. A syndrome associating partial albinism and immunodeficiency. Am J Med. 1978;65: 691-702. 2. Menasche G, Pastural E, Feldmann J, et al. Mutations in RAB27A cause Griscelli syndrome associated with haemophagocytic syndrome. Nat Genet. 2000;25:173-176. 3. Menasche G, Fischer A, de Saint Basile G. Griscelli syndrome types 1 and 2. Am J Hum Genet. 2002;71:1237-1238. 4. OMIM (Online Mendelian inheritance in man). Baltimore: Johns Hopkins University, Center for Medical Genetics. Available at: http://www3.ncbi.nlm.nih.gov/omim/(Feb 2012). 5. Al-Herz W, Bousfiha A, Casanova J-L, et al. Primary immunodeficiency diseases: an update on the classification from the International Union of Immunological Societies Expert Committee for Primary Immunodeficiency. Front Immunol. 2014;5:162. 6. Is¸ikay S. Cerebellar involvement of Griscelli syndrome type 2. BMJ Case Rep. 2014 Oct 14;2014. 7. Mamishi S, Modarressi MH, Pourakbari B, et al. Analysis of RAB27A gene in Griscelli syndrome type 2: novel mutations including a deletion hotspot. J Clin Immunol. 2008;28:384-389. 8. Anikster Y, Huizing M, Anderson PD, et al. Evidence that Griscelli syndrome with neurological involvement is caused by mutations in RAB27A, not MYO5A. Am J Hum Genet. 2002;71:407-414. 9. Saini AG, Nagaraju S, Sahu JK, Rawat A, Vyas S, Singhi P. Teaching neuroImages: Griscelli syndrome and CNS lymphohistiocytosis. Neurology. 2014 Apr 8;82:e122-e123.
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I. Panigrahi et al. / Pediatric Neurology 52 (2015) 535e538
10. Aksu G, Kütükçüler N, Genel F, Vergin C, Omowaire B. Griscelli syndrome without hemophagocytosis in an eleven-year-old girl: expanding the phenotypic spectrum of Rab27A mutations in humans. Am J Med Genet A. 2003;116A: 329-333. 11. Bindua PS, et al. Neuroimaging findings in Griscelli syndrome type 2 with primary neurological presentation. J Pediatr Neuroradiol. 2014; 3:81-86. 12. Mishra K, Singla S, Sharma S, et al. Griscelli syndrome type 2: a novel mutation in RAB27A gene with different clinical features in 2 siblings: a diagnostic conundrum. Korean J Pediatr. 2014;57:91-95.
13. Kuroda TS, Mikoshiba K. Slac2-a/melanophilin, the missing link between Rab27 and myosin Va: implications of a tripartite protein complex for melanosome transport. J Biol Chem. 2002;277: 12432-12436. 14. Malhotra AK, Bhaskar G, Nanda M, Kabra M, Singh MK, Ramam M. Griscelli syndrome. J Am Acad Dermatol. 2006;55:337-340. 15. Sheela SR, Latha M, Injody SJ. Griscelli syndrome: Rab 27a mutation. Indian Pediatr. 2004;41:944-947. 16. Al-Ahmari A, Al-Ghonaium A, Al-Mansoori M, et al. Hematopoietic SCT in children with Griscelli syndrome: a single-center experience. Bone Marrow Transplant. 2010;45:1294-1299.
