|Year : 2019 | Volume
| Issue : 3 | Page : 103-105
RAB27A mutation in a patient with griscelli syndrome type 2, successfully cured by hematopoietic stem cell transplantation: Sustained remission
Abdullah A Baothman1, Fatima Mehdawi2, Loie Goronfolah1, Hani Almalki3
1 King Abdullah International Medical Research Center; College of Medicine, King Saud Bin Abdulaziz University for Health Sciences; Department of Pediatrics, King Abdulaziz Medical City-Western Region, Ministry of The National Guard-Health Affairs, Jeddah, Saudi Arabia
2 Department of Pediatrics, King Abdul-Aziz University Hospital, Jeddah, Saudi Arabia
3 King Abdullah International Medical Research Center; College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, King Abdulaziz Medical City-Western Region, Jeddah, Saudi Arabia
|Date of Web Publication||14-Nov-2019|
Dr. Hani Almalki
King Abdullah International Medical Research Center, King Abdulaziz Medical City, Western Region, Jeddah, Saudi Arabia. King Saud Bin Abdulaziz University for Health Sciences, King Abdulaziz Medical City, Western Region, Jeddah
Source of Support: None, Conflict of Interest: None
Griscelli syndrome (GS) is a rare autosomal recessive disorder. It features with clinical constellation of skin hypopigmentation, silvery-gray hair, associated with neurological involvement (type I), or defective cell-mediated immunity with hemophagocytosis (type II) that leads to recurrent infection, and patients succumb to death in early childhood or isolated “quiet” GS (type III). To our knowledge, more than sixty patients have been reported mainly from the Mediterranean region with the first reported Saudi cases, reported by Harfi et al. in 1992. The outcome of GS is guarded if not treated early due to recurrent fulminant infections, disease recurrence, and the impending severity of central nervous system disease. Hematopoietic stem cell transplantation (HSCT) is the single current therapeutic treatment for GS II. HSCT, therefore, should be performed as early as possible to prevent potential complications. The reported patient had sustained remission and normal hematopoietic function after allogeneic bone marrow transplant from a human leukocyte antigen-identical sibling donor. GS II syndrome should be considered in any child with hypopigmented skin, silvery-gray hair, and primary immunodeficiency. Early recognition and early HSCT intervention are associated with favorable outcome.
Keywords: Griscelli Type II, hemophagocytic lymphohistiocytosis, RAB27A
|How to cite this article:|
Baothman AA, Mehdawi F, Goronfolah L, Almalki H. RAB27A mutation in a patient with griscelli syndrome type 2, successfully cured by hematopoietic stem cell transplantation: Sustained remission. J Appl Hematol 2019;10:103-5
|How to cite this URL:|
Baothman AA, Mehdawi F, Goronfolah L, Almalki H. RAB27A mutation in a patient with griscelli syndrome type 2, successfully cured by hematopoietic stem cell transplantation: Sustained remission. J Appl Hematol [serial online] 2019 [cited 2020 Aug 8];10:103-5. Available from: http://www.jahjournal.org/text.asp?2019/10/3/103/271023
| Introduction|| |
Griscelli syndrome type 2 (GS II) is a rare autosomal recessive fatal disease, characterized by oculocutaneous albinism and primary immunodeficiency. It can be caused by mutations in either myosin-VA or RAB27A genes. The gene responsible for GS II is located in 15q21.6 in the Rab27a (RAB27A), which encodes GTPase protein the defect of which causes melanosomes and cytotoxic lysosome granule transport defects that result in hypopigmentation and immunodeficiency., In thefirst few years of life, due to uncontrolled T-lymphocytes and macrophages, hemophagocytic lymphohistiocytosis (HLH) in such patients can be initiated by infections and can be fatal in the absence of hematopoietic stem cell transplantation (HSCT). Here, we describe a Saudi infant with GS II who presented with a novel mutation in the RAB27A gene, successfully cured by sibling donor human leukocyte antigen (HLA)-matched allogeneic bone marrow transplantation (aBMT).
| Case Report|| |
A 45-day-old baby boy, a product of nonconsanguineous parents, presented to the emergency department with a history of fever, irritability, and decreased activity. Family history revealed that a brother died at the age of 40 days due to sepsis and pancytopenia, with unknown diagnosis, in addition to a history of a cousin from the mother's side died from unconfirmed HLH. On examination, the patient complexion is fair with gray hair and multiple hypopigmented lesions. In addition, he was febrile with no evidence of infectious foci. The liver was 3 cm below the costal margin, and the spleen was 5 cm below the costal margin. No focal neurological deficit was detected.
The initial investigation showed hemoglobin 7 g/dl, white blood cell 4 × 109/L and platelet 79 × 109, and elevated C-reactive protein, and the blood smear revealed a moderate thrombocytopenia, lymphocytosis, polychromasia, and no giant cytoplasmic granules in leukocyte. Liver function test showed moderately elevated bilirubin and raised liver enzymes (total bilirubin: 29.9 [3.4–20.5] ummol/L, alanine aminotransferase: 219 [<58] IU/L, and aspartate aminotransferase: 150 [5–34] IU/L). The blood coagulation profile was normal except for elevated D-dimer. Renal profile and electrolytes were normal.
All viral serology reported negative for Epstein–Barr virus, Cytomegalovirus (CMV), rubella, parvovirus B19, and toxoplasmosis. Lactate dehydrogenase, ferritin, and triglyceride levels were elevated. T-cell subset showed low total T-cells and specifically low natural killer (NK) cells (CD16/CD56) 40 μ/L (248 ± 141 μ/l).
Immunoglobulin (Ig) levels for IgG, IgM, and IgA were normal. Bone marrow showed increased histiocytic cells with moderate increased hemophagocytic activity. The analysis of cerebrospinal fiuid was normal. The patient responded to the treatment according to HLH-2004 protocol, which includes cyclosporin, VP16, and steroid.
Later, molecular analysis revealed a novel homozygous mutation in a single-base substitution (c.400 A>C in Rab27 A) leading to an amino acid change (pLys134Gln) and thus confirming the diagnosis of GS II.
The patient underwent aBMT from a HLA-identical sibling donor. The conditioning regimens consisted of fiudarabine 45 mg/m2 once daily (from day 7 to day 4) and busulfan 3.5 mg/kg/day. Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine (CsA) and mycophenolate mofetil (MMF). CsA was administered i.v. at a dose of 4 mg/kg/day in two divided doses starting from day 3 until patients were able to tolerate oral medication. The dose was titrated to maintain plasma levels between 150 and 250 mg/l. MMF dosage was 15 mg/m2 i.v. every 8 h from day 0 until day 28, then tapered over 2 weeks. The marrow was infused unmanipulated. CMV-negative, irradiated blood products were transfused. He received Igs every 2 weeks for 90 days as well as acyclovir (45 mg/kg per day) from day 5 to day 30. Pneumocystis pneumonia prophylaxis continued for a year following BMT. He was engrafted well with time to engraftment of 15 days for neutrophils and 28 days for platelets. He developed Grade II acute cutaneous GVHD as per Glucksberg et al. classification. Subsequently, he developed limited chronic GVHD. He also developed Grade IV sinusoidal obstruction syndrome, which resolved subsequently. Donor chimerism constantly revealed stable mixed one. The patient is currently 4-year post-aBMT with normal immune and hematopoietic function.
| Discussion|| |
GS is a rare autosomal recessive disorder. It features with clinical constellation of skin hypopigmentation, silvery-gray hair, associated with neurological involvement (type I), or defective cell-mediated immunity with hemophagocytosis (type II) that leads to recurrent infection, and patients succumb to death in early childhood or isolated “quiet” GS (type III)., The responsible gene GS II is caused by mutations in the RAB27A encoding gene, located in chromosomal 15q21, the protein of which is involved in exocytic pathways, especially the cytotoxic granule exocytosis which results in appearance of an uncontrolled T-lymphocyte that leads to HLH. So far more than sixty patients have been reported mainly from the Mediterranean region. Harfi et al. reported thefirst Saudi cases in eight families characterized by partial albinism with immunodeficiency (PAID) and progressive demyelination of brain white matter, referred to as PAID syndrome. One patient lately discovered genetically to have RAB27A gene mutation. The onset is usually between 4 months and 4 years, and the clinical symptoms are usually triggered by a virus or bacteria or even by fungal organisms that accelerated the child condition toward HLH. The immunodeficiency in GS is characterized by low T-cells and low NK cells. Igs are usually normal.
A number of alterations in the RAB27A gene have been implicated in GS II. The majority of mutations are frameshift or truncating changes. Only a few missense mutations have been reported in GSII. A novel missense mutation was identified in our patient leading to an amino acid alteration from lysine to glutamine. The severity of disease and the number of accelerated phases can vary between patients, with various genetic mutations. The outcome is guarded if not treated early due to recurrent fulminant infections, disease recurrence, and the impending severity of CNS disease. Chemotherapy such as etoposide, CsA, and antithymocyte globulin is usually ineffective to attain long-term disease control. HSCT is the single current therapeutic treatment for GS II. HSCT, therefore, should be performed as early as possible to prevent potential complications. The curative HSCT may suggest that hematopoietic cell is responsible for the fatal outcome. The preeminent results of HSCT have been attained in patients with inactive disease status.,,, The largest cohort study (11 patients) reported an excellent overall survival, especially for patients who had early HSCT. GS II syndrome should be considered in any child with hypopigmented skin, silvery-gray hair, and primary immunodeficiency. Early recognition and early HSCT intervention are associated with favorable outcome. The great degree of consanguinity in the Mediterranean area could describe the higher incidence of occasional primary immunodeficiency syndromes associated with skin and hair hypopigmentation. Educational programs and family counseling are important in these regions.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient's parents have given their consent for his images and other clinical information to be reported in the journal. The patient's parents understand that his name and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Confiicts of interest
There are no confiicts of interest.
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