Silvery Gray Hair Syndrome With Hemophagocytic Lymphohistiocytosis: A Case Report

Griscelli syndrome (GS) is a rare autosomal recessive disorder, which has been classified into three subtypes based on clinical and genetic differences. GS subtype 2 is commonly associated with hemophagocytic lymphohistiocytosis (HLH) and recurrent infections due to immunodeficiency. In this study, we describe a four-month-old boy with genetically proven GS2, with neurological and immunological manifestations. He presented with fever, refusal of feeds, drowsiness, and multiple episodes of seizures. Examination revealed hypopigmented skin, silvery gray hair, and organomegaly. The child developed features of HLH, fulfilling clinical and laboratory criteria. Neuroimaging findings were in concordance with HLH of the central nervous system. Microscopic examination of the hair showed clumps of melanin pigment along the hair shaft. All findings were in favor of GS type 2, complicated with HLH, which was later confirmed with a homozygous deletion of the RAB27A gene on exome sequencing. Unfortunately, the baby succumbed to death due to severe sepsis and multiorgan dysfunction. The silvery gray hair, with typical hair microscopic findings, and association with HLH are strong indicators for this potentially fatal condition and aid in prompt diagnosis and initiation of treatment. Hematopoietic stem cell transplantation is the only lifesaving treatment option.


Introduction
Griscelli syndrome (GS) is a rare autosomal recessive immunodeficiency syndrome due to defective intravesicular trafficking mechanisms of melanosomes in melanocytes.This was first described by Griscelli and Siccardi in 1978 [1] and is characterized by deficient pigmentation of the skin and hair, and large clumps of pigment in the hair shafts.GS is classified into three types based on the genetic loci involved.GS Type 1 presents as hypopigmentation with neurological manifestations without immunodeficiency.GS Type 2 presents as hypopigmentation with immunological abnormalities, with or without neurological manifestations, and GS Type 3 presents only as hypopigmentation, without immunologic or neurological manifestations [2].GS Type 2 is mostly diagnosed between four months to seven years of age [3], though the youngest reported is one month, with no sex predilection.It is due to RAB27A gene mutation and is associated with impaired lymphocyte and natural killer cell function.It can be associated with uncontrolled activation and proliferation of T lymphocytes and macrophages in response to infections.Activated immune cells infiltrate various organs, leading to hemophagocytosis and subsequently to a fatal condition known as hemophagocytic lymphohistiocytosis (HLH) [4].To date, approximately 160 cases of GS have been reported in the literature, the majority from the Mediterranean and Turkish regions.Around 14 cases of GS 2 have been reported from India [4,5].Here, we describe a four-month-old boy with genetically proven GS2, with neurological and immunological manifestations.

Case Presentation
A four-month-old boy, the firstborn out of a third-degree consanguineous marriage, with an uneventful perinatal history and development until presentation, was admitted with fever, refusal of feeds, drowsiness, and multiple episodes of seizures.Examination showed no obvious dysmorphic features.The child's anthropometric parameters were appropriate for age.Table 1 depicts the hematological investigation done on day 1 of admission.He had fair skin with a silver-gray sheen on his scalp hair, eyebrows, and eyelashes.The anterior fontanelle was not bulging (Figure 1).Neurological examination revealed a depressed sensorium with a Glasgow Coma Scale (GCS) of 7/15, global hypotonia, exaggerated deep tendon reflexes, and an extensor plantar response, for which the child was shifted to the pediatric intensive care unit.Hepatosplenomegaly was present, and fundus examination revealed no abnormality.The patient required escalation of inotropes and antibiotics, antifungal treatment, and intravenous immunoglobulin (IVIg).Whole blood and fresh frozen plasma were transfused for severe anemia and a deranged coagulation profile.The child was started on the induction phase of the HLH treatment 2004 protocol with dexamethasone, etoposide, and cyclosporin.Hematopoietic stem cell transplantation (HSCT) was planned, and blood samples were sent for whole exome sequencing.Unfortunately, the baby succumbed to death due to severe sepsis and multi-organ dysfunction.The whole exome sequencing report later confirmed the clinical diagnosis of GS type 2 with a homozygous deletion of the RAB27A gene on exons 3-5, classified as likely pathogenic.Genetic counseling of the parents was undertaken for Sanger sequencing and prenatal testing during the next pregnancy.

Discussion
Managing GS requires a delicate balance between addressing the immunodeficiency and neurological components.The prognosis is variable and mostly depends on the specific subtype of GS, emphasizing the need for case-specific treatment and management plans.The distinctive feature of all three types is the partial albinism of the skin and silvery gray hair [2].The key differences between the three types of GS are depicted below (Table 3).

TABLE 3: Classification of Griscelli's syndrome
The constellation of symptoms of silvery gray hair, with features of sepsis and HLH, raised the possibilities of GS, Chédiak-Higashi, and Hermansky-Pudlak syndrome.The presence of neurological symptoms, absence of ecchymosis, and typical hair microscopic findings ruled out Hermansky-Pudlak syndrome.Similarly, the absence of inclusions in granulocytes on peripheral blood examination and the absence of typical hair microscopic findings ruled out Chédiak-Higashi syndrome as well [6].The classic hair microscopic finding of large melanin clumps gave the diagnostic clue toward GS.Neurological symptoms are more common in GS1 than in GS2.In GS2, neurological manifestation is not due to primary brain involvement but is actually related to the development of HLH.This is because the RAB27A gene, causative of GS2, is not expressed in neuronal cells [2].The RAB27A gene is needed for the anchorage of melanosomes in melanocytes as well as for the exocytosis of cytolytic granules in cytotoxic lymphocytes and NK cells [7,8].Mutation of this gene leads to cytotoxic defects which trigger uncontrolled lymphocyte and macrophage activation, eventually leading to HLH in the accelerated phase, triggered by viral and bacterial infections leading to severe complications [4].Usually, central nervous system (CNS) manifestations precede systemic manifestations.Therefore, the development of HLH in this baby hinted more towards GS2 than GS1.
On CSF analysis in children with CNS HLH, CSF proteinosis is one of the most common abnormalities as seen in our case [9].The neuroimaging findings in CNS HLH are variable and can range from normal to atrophy to diffuse parenchymal lesions.The various described patterns of CNS HLH are multifocal and bilateral white matter lesions with a high rate of symmetric involvement, hyperintensities involving deep nuclei, brain stem, and cerebellum with or without necrosis, and nodular or discoid contrast enhancement.
The MRI brain findings in our patient are consistent with these described patterns suggestive of CNS HLH [10,11].Overall, patients with GS have a complicated clinical course with recurrent infections and HLH.
Their quality of life depends on the degree of neurological involvement.HLH-directed therapy followed by HSCT is the only curative treatment for patients with GS2, which needs to be undertaken promptly [12].Without treatment, the condition is fatal.In our patient, we planned HSCT but it could not be performed as the child succumbed to death secondary to severe sepsis.Parents have been counseled for prenatal testing as we can prevent the recurrence of this autosomal recessive condition.

Conclusions
GS2 is a rare immune deficiency disorder characterized by silvery gray hair associated with immune deficiency and is an important cause of primary HLH.The microscopic examination of the hair shaft is a simple diagnostic tool.The clinical clues, along with molecular markers of HLH, CSF, and neuroimaging findings, should prompt quick diagnosis and initiation of treatment.Hematopoietic stem cell transplantation is the only life-saving treatment option in these patients.

FIGURE 1 :
FIGURE 1: Clinical image showing a patient with fair skin, silvery gray colored hair and eyebrows MRI brain, plain and contrast, was suggestive of white matter hyperintensities involving the brainstem, deep nuclei, subcortical white matter, and cerebellar peduncles, with diffusion restriction in the bilateral occipital lobe and bilateral thalamo-capsular region.The contrast MRI study showed nodular and ring-enhancing lesions (Figure2).

FIGURE 2 :
FIGURE 2: MRI brain -plain and contrast imagesA and B: Fluid-attenuated inversion recovery (FLAIR) axial section showing brainstem and cerebellar peduncle hyperintensities; C: T2 axial section showing basal ganglia and thalamic hyperintensities and subcortical white matter hyperintensity; D: T1 contrast axial section showing nodular contrast enhancement in cerebellar white matter; E: Diffusion-weighted image showing restricted diffusion in the bilateral occipital and insular cortex.