Griscelli Syndrome Type 2 (GS with Hemophagocytic Syndrome)
Clinical Features and Genetic Patterns
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The Griscelli syndrome type 2 (GS2; OMIM #607624) is characterized by hypomelanosis with immunologic abnormalities with or without neurological impairment. The GS2 phenotype currently corresponds to the original patients reported by Griscelli et al. (1978). GS2 patients exhibit various degrees of skin hypopigmentation Opens in new window and a silvery-gray sheen of the hair with large pigment aggregates in hair shafts.
In most patients at least one episode of hemophagocytic syndrome (HS) Opens in new window or hemophagocytic lymphohistiocytosis (HLH) Opens in new window (the so-called accelerated phase), which is a lymphohistiocytic proliferation of unknown origin consisting of:
- multivisceral infiltration,
- hypofibrinogenemia, and
It is triggered by infectious episodes (usually viral but also bacterial) and is associated with a poor prognosis.
When a remission is obtained, recurrent, accelerated phases with increasing severity are seen.
The immunodeficiency is characterized by absent delayed-type cutaneous hypersensitivity and impaired natural killer cell function. No abnormal cytoplasmic granules are present in leukocytes.
Patients with GS2 have immunologic abnormalities during the course of the hemophagocytic syndrome leading to leukocyte brain infiltration that sometimes result in secondary neurological involvement with diffuse white matter abnormalities seen at MRI.
Main signs include hyperreflexia, seizures Opens in new window, signs of intracranial hypertension, (e.g., vomiting or altered consciousness), strabismus, dysatrhia, ataxia, or regression of developmental milestones.
The primary clinical differentiation between GS2 and GS1 Opens in new window is that the former has no primary neurological features. Occasionally, neurological problems may be first sign of the accelerated phase.
CT and MRI Diagnostic
CT and MRI findings are usually normal at birth. When the disease manifests, imaging findings are normal: CT can show areas of coarse calcification in the globus pallidus bilaterally, left parietal white matter, periventricular and left brachium pontis.
Patients with GS2 can manifest unilateral hypodense signals in the genu and posterior limb of the internal capsule (compatible with inflammatory changes), as well as a posterior aspects of both thalami, together with minimal generalized atrophy.
CT scanning can also suggest cell infiltration of the brain. The subcortical white matter can be affected as occurs in the GS1 variant.
Cause: Gene Description
GS2 is caused by mutations Opens in new window in the RAB27A gene which encodes a GTP-binding protein (rab27) that functions in the targeting and fusion of transport vesicles with their appropriate acceptor membranes.
Like other rab proteins, rab27 requires geranylgenarylation of two consensus C-terminal cysteine residues in order to be anchored to membranes.
Truncation of the carboxy-terminal part of rab27 would render it inactive. To date all patients with GS and mutations in RAB27A have developed the hemophagocytic syndrome.
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