Griscelli Syndrome (Types 1, 2 and 3)

A class of three autosomal recessive disorders of melanosome transport, defined by pigmentary dilution with silvery-grey hair and irregular clumps of melanin in the hair shaft, in which the affected gene determines whether the disease is primarily neurological (type 1, MYO5A), immunological with haemophagocytic lymphohistiocytosis (type 2, RAB27A) or purely pigmentary (type 3, MLPH).

Update of the literature and regulatory information: 31 October 2026.

0. Initial Reference Table

1. Introduction

1.1. Original description

In 1978, Claude Griscelli and colleagues, in Paris, described two unrelated patients with partial albinism, frequent pyogenic infections and acute episodes of fever, neutropenia and thrombocytopenia [31]. The pigmentary dilution had features that set it apart from all the human albinisms then known: large clumps of pigment in the hair shaft, accumulation of melanosomes inside melanocytes, melanocytes with few, short dendritic processes and hypopigmented keratinocytes, a picture that the authors likened to the dilute mutant mouse [31]. Despite an adequate number of T and B lymphocytes, the patients had hypogammaglobulinaemia, did not produce antibodies, showed no delayed cutaneous hypersensitivity and did not reject skin grafts; the granulocytes were morphologically normal, without the giant granules of Chédiak-Higashi syndrome, and the family history suggested autosomal recessive transmission [3, 31]. One of the patients was an 11-year-old North African girl whose brother and sister, also with silvery hair, had died at 30 and 18 months [3]. In the same year, Griscelli and Pruniéras published the dermatological description of the new syndrome of pigmentary dilution with immunodeficiency, the origin of the eponym “Griscelli-Pruniéras” [7, 32].

In 1994, Klein and colleagues analysed seven consecutive patients and defined the natural history of the immunological form: onset between 4 months and 4 years, “accelerated phases” of lymphohistiocytic infiltration of several organs, including the brain and meninges, triggered by infections, with pancytopenia, hypofibrinogenaemia, hypertriglyceridaemia and hypoproteinaemia, absence of delayed hypersensitivity and reduced natural killer (NK) cell function [33]. The disease was lethal without bone marrow transplantation, with a mean age at death of 5 years; of the three patients transplanted, two died of infection in the immediate post-transplant period and one was cured after 5 years [33]. Up to then only 19 patients had been described [3].

1.2. Elejalde and the debate over the neurological form

In 1979, Elejalde and colleagues described, in three consanguineous Colombian families with common ancestors five generations earlier, a disease with profound CNS dysfunction, silvery-leaden hair, abnormal melanocytes and melanosomes and inclusion bodies in fibroblasts, bone marrow histiocytes and lymphocytes, which they named neuroectodermal melanolysosomal disease [34]. In 1999, Duran-McKinster and colleagues brought together seven Mexican patients with silvery hair and severe neurological dysfunction, without immune impairment, and allowed that Elejalde and Griscelli syndromes, although clinically distinct, might be allelic [35].

1.3. Molecular discovery

In 1997, Pastural and colleagues mapped the disease locus to 15q21, with a maximum LOD score (logarithm of the odds) of 4.40 in a region containing MYO5A, the human homologue of the mouse dilute gene, and described variants in two patients [1, 36]. One of the two variants, p.Arg1246Cys, described in a patient with immunodeficiency and an “accelerated phase”, was later recognised in an erratum as a common polymorphism, with healthy homozygous carriers; the pathogenic variant was p.Arg778Ter, in a Turkish girl with hypotonia, motor delay and intellectual disability from 3 months of age and no infections [8, 36]. In 2000, the same group found that in four other patients myosin Va was expressed and free of variants, and fine haplotype analysis suggested a second gene less than 7.3 cM away [37]. That year, Ménasché and colleagues narrowed the candidate interval to 3.1 cM and identified RAB27A variants in 16 patients: all patients with RAB27A variants, and none of those with MYO5A variants, developed haemophagocytic syndrome, and only RAB27A-deficient T lymphocytes had reduced cytotoxicity and granule exocytosis [38].

In 2002, Anikster and colleagues studied a Muslim Arab family with variable neurological involvement, haemophagocytic syndrome and immunological abnormalities, and found normal MYO5A and a homozygous 67.5 kb deletion removing RAB27A; they proposed that all patients with Griscelli syndrome would have RAB27A variants, with secondary neurological involvement, and that patients with MYO5A variants and primary neurological disease without an immune defect would have Elejalde syndrome [39]. In reply, the Paris group accepted the identity between Elejalde syndrome and the MYO5A-linked form at least in some patients and proposed testing RAB27A in patients with partial albinism and haemophagocytic syndrome, with or without neurological involvement, and MYO5A in patients with primary neurological disease without haemophagocytic syndrome, a distinction that gave rise to the designations type 1 and type 2 [1, 40]. The Turkish series of Sanal and colleagues, with 13 patients, supported the correlation: the eight with RAB27A variants presented with haemophagocytic syndrome, the two with homozygous MYO5A variants had primary neurological impairment without susceptibility to infection, and three had no RAB27A variant [41]. In 2003, Ménasché and colleagues identified in two of those three patients the causes of the form restricted to hypopigmentation: variants in MLPH, the orthologue of the mouse leaden gene (GS3), and a homozygous deletion of exon F of MYO5A, whose expression is restricted to some tissues [14].

1.4. Nomenclature and current classifications

OMIM maintains three phenotype entries (GS1 #214450, GS2 #607624, GS3 #609227) and a separate entry, without a molecular basis, for Elejalde syndrome (256710), which should not be confused with “Elejalde syndrome” 200995, a synonym of acrocephalopolydactylous dysplasia [1, 3, 5, 12]. Orphanet classifies Griscelli syndrome (ORPHA:381) as a rare skin disease with three clinical subtypes and keeps neuroectodermal melanolysosomal disease as a separate entity (ORPHA:33445) [7, 13]. In the 2024 IUIS classification of inborn errors of immunity, only GS2 appears, in the group of familial haemophagocytic lymphohistiocytosis syndromes with hypopigmentation, alongside Chédiak-Higashi syndrome (LYST) and Hermansky-Pudlak syndromes types 2 (AP3B1) and 10 (AP3D1) [19]. GeneReviews has no dedicated entry; the chapter on oculocutaneous albinism attributes less than 1% of cases of albinism to Griscelli syndrome and defines the three subtypes by the presence or absence of neurological and immunological deficits [16]. Textbooks of metabolic disease include Griscelli syndrome among the disorders of cellular trafficking with extraneurological manifestations (immunological, haemophagocytic and hypopigmentation), and the Oxford Desk Reference places it, with Chédiak-Higashi and Hermansky-Pudlak syndromes, among the diseases of immune dysregulation with hypopigmentation [42, 43]. Some reference texts still describe Griscelli syndrome as a disease due to MYO5A variants with immunodeficiency, a historical conflation of types 1 and 2 predating 2000 [44].

1.5. Definition of the entities

Griscelli syndrome type 1 results from biallelic MYO5A variants and combines pigmentary dilution with a primary neurological deficit, present from early infancy, without immunodeficiency or risk of HLH [1, 14]. Griscelli syndrome type 2 results from biallelic RAB27A variants and is an inborn error of immunity with a defect of granule-dependent cytotoxicity and a predisposition to HLH; pigmentary dilution may be absent and neurological involvement, when present, generally results from inflammatory infiltration of the CNS [3, 20, 45]. Griscelli syndrome type 3 results from biallelic MLPH variants and is limited to pigmentary dilution [5, 14]. The clinical importance of the separation is unequal: GS2 is a haematological emergency with an indication for transplantation, whereas GS1 and GS3 have no indication for transplantation [25].

2. Molecular Genetics and Pathophysiology

2.1. The tripartite melanosome complex

Mature melanosomes are transported along microtubules to the periphery of the melanocyte, where they must be captured in the cortical actin network before being transferred to keratinocytes [46]. This capture depends on a complex of three proteins: the GTPase RAB27A, bound to the melanosome membrane in its active guanosine triphosphate (GTP)-bound form; melanophilin (MLPH, also called Slac2-a or exophilin-3), which acts as the intermediate link; and myosin Va (MYO5A), a motor that moves along actin filaments [24, 47]. The N-terminal Slp homology domain of melanophilin (SHD, Slp homology domain) binds the switch II region of active RAB27A, and the opposite end binds the tail of myosin Va in a region encoded by exon F, which is expressed specifically in the melanocyte [8, 24]. Failure of any element of the complex leaves melanosomes clustered around the nucleus, the dendrites devoid of pigment and the neighbouring keratinocytes poorly pigmented, because the defect is one of transport and not of melanin synthesis; tyrosinase and melanisation of the melanosomes are preserved [31, 46]. This is the basis of the pigmentary phenotype common to the three types: hair with a silvery-grey sheen and large, irregular clumps of pigment in the shaft [14].

2.2. Why the gene determines the phenotype

Myosin Va is also present in neurons, where it takes part in the transport of organelles and vesicles and in exocytosis, which explains the primary neurological deficit of GS1 and the neurological disease of the dilute mouse [1, 22]. It has no role in the exocytosis of lymphocyte cytotoxic granules: myosin Va-deficient T lymphocytes have normal cytotoxicity [38]. RAB27A, by contrast, is required in cytotoxic T lymphocytes and NK cells for the maturation, docking and priming (priming) of perforin-containing lytic granules at the immunological synapse, through binding to the effector MUNC13-4; its loss blocks granule release, prevents the elimination of infected cells and the termination of the immune response, and leads to the uncontrolled activation of lymphocytes and macrophages that defines HLH [20, 48]. Melanophilin participates only in the pigmentary branch of the RAB27A pathway, so GS3 spares the immune system and the nervous system [14, 46]. Homozygous deletion of exon F of MYO5A removes only the melanocyte isoform that binds melanophilin and preserves the brain function of myosin Va, reproducing the GS3 phenotype [8, 14].

In platelets, RAB27B, a closely related protein, compensates for the lack of RAB27A: the ashen mouse (Rab27a-deficient) has morphologically and functionally normal platelets, and transgenic expression of Rab27a or Rab27b corrects coat colour; since RAB27B is not expressed in melanocytes or in cytotoxic lymphocytes, the pathology of GS2 is concentrated in these cells [49]. This redundancy explains why platelet function and dense granules are preserved in all types of Griscelli syndrome, unlike in Hermansky-Pudlak and Chédiak-Higashi syndromes [15]. The murine models correspond to the three genes: dilute (Myo5a), ashen (Rab27a) and leaden (Mlph) [1, 14].

2.3. Table of the class

2.4. MYO5A and Griscelli syndrome type 1

The variants described in GS1 are mainly loss-of-function: p.Arg778Ter in Pastural's Turkish patient (1997), which truncates the 1078-amino-acid protein; a 47 bp insertion at nucleotide 4634 that removes most of the globular domain; and nonsense variants in two Egyptian families, including p.Gln704Ter in two siblings [1, 8]. In 2026 the variant NM_001382347.1:c.3508C>T p.(Gln1170Ter), in exon 26 of 42, was described in an Afghan child and classified as likely pathogenic under the ACMG/AMP (American College of Medical Genetics and Genomics/Association for Molecular Pathology) criteria [9, 22]. The numbering differs between the historical transcript NM_000259.3 and the MANE transcript NM_001382347.1 downstream of the alternatively expressed exons: the Spanish variant published as NM_000259.3:c.5152C>T p.(Gln1718Ter) corresponds, on MANE, to NM_001382347.1:c.5227C>T p.(Gln1743Ter) (NC_000015.10:g.52319067G>A), whereas c.3508C>T has the same numbering on both transcripts [9, 21]. The 2439 bp deletion removing exon F, described in a Turkish girl and, in 2014, in a 3-year-old boy with normal development, defines the purely pigmentary MYO5A-linked form [8, 14]. The p.Arg1246Cys variant is a polymorphism and should not be interpreted as pathogenic [8].

2.5. RAB27A and Griscelli syndrome type 2

The RAB27A gene has seven exons, the first two non-coding, and the protein has two regions that change conformation on GTP binding (switch I, encoded in exon 3, and switch II, between exons 4 and 5) [20]. In the review by Maimaris and colleagues, which brought together 149 patients published up to November 2023 or followed at Great Ormond Street Hospital, London, a genetic report was available for 139 (93%), with 56 distinct pathogenic variants distributed throughout the gene, including intronic and structural variants, and a predominance of homozygosity [20]. Structural variants are of practical relevance: the 67.5 kb founder deletion of Anikster's Arab family, and a tandem duplication of about 38 kb of exons 2 to 5, homozygous in seven consanguineous Saudi probands with a common haplotype, not detectable by sequencing and identified by copy number variant (CNV) analysis [3, 39].

The literature mainly uses transcript NM_004580; for these three variants the c. numbering coincides with that of the MANE transcript NM_183235.3 [9, 50].

2.6. Genotype–phenotype correlations in GS2

Maimaris and colleagues compared 56 patients with biallelic protein-truncating variants (PTV, protein-truncating variants) and 41 with hypomorphic variants (biallelic missense or combinations with residual expression) [20]. Patients with PTVs had more partial albinism (45/56, 80%, versus 20/41, 49%) and more systemic HLH (24/56, 43%, in the text of the article; the abstract gives 44/56, 79%) than patients with hypomorphic variants (9/41, 22%); isolated CNS HLH was more frequent with hypomorphic variants (8/41, 20%, versus 2/56, 4%; p=0.002; the abstract gives 42% and 2%), and only one patient with a PTV had no sign of albinism at all, against 19 with hypomorphic variants (2% versus 46%) [20]. The median age at onset was 0.4 years (interquartile range, IQR, 0.25–2.7) with PTVs and 5.4 years (IQR 1.65–9) with hypomorphic variants (p<0.0001), and survival was lower with PTVs [20]. The three founder variants illustrate the heterogeneity: among 19 patients homozygous for p.Arg82Cys, only 4 (21%) had systemic HLH and 4 (21%) albinism, and 5 (26%) CNS HLH; among 18 with c.514_518del, 15 (83%) had systemic HLH and 13 (72%) albinism, without isolated CNS HLH; among 12 with p.Arg184Ter, all had albinism, 3 (25%) systemic HLH and 5 (41%) CNS HLH [20].

The dissociation between pigmentation and immunity has a structural explanation. Cetica and colleagues identified six patients with GS2 without albinism, with variants at residues Arg141, Tyr159 or Ser163 that prevent binding of RAB27A to MUNC13-4 without affecting binding to melanophilin [45]. Ohishi and colleagues described the variant NM_183235.3:c.428T>C p.(Val143Ala), which disturbs binding to the SLP2-A and MUNC13-4 proteins and preserves binding to melanophilin, and counted, up to 2020, 16 patients from 12 families with GS2 sine albinism, with variants at surface residues (Arg80, Arg82, Arg141, Val143) that probably contact MUNC13-4; the Arg184 variant, by contrast, destabilises the protein [48]. In 2026, Tanaka and colleagues showed, in two compound heterozygous Japanese children, that each allele can affect melanosome transport and cytotoxic function differently: the combination c.217T>C p.(Trp73Arg)/c.428T>C p.(Val143Ala) (NM_183235.3) preserved pigmentation because p.Val143Ala maintains binding to melanophilin, and c.345C>G p.(Ser115Arg) restored the peripheral distribution of melanosomes in RAB27A-deficient melanocytes, whereas degranulation was abolished in both children [52, 53]. Earlier biochemical studies showed that the substitutions NM_183235.3:c.454G>C p.(Ala152Pro) and c.389T>C p.(Leu130Pro) compromise folding and nucleotide binding, and that c.217T>G p.(Trp73Gly) prevents interaction with the specific effectors both in the melanocyte and in the cytotoxic cell [53, 54].

2.7. MLPH and Griscelli syndrome type 3

The recurrent variant is p.(Arg35Trp), in the SHD1 domain, which prevents binding to RAB27A: it has been described in a French patient of Turkish origin, in seven patients from three Muslim Arab families from the Hebron region (suggestive of a founder effect), in an Arab child and in an Algerian woman [5, 14, 46]. Normalised to the MANE transcript, it corresponds to NM_024101.7:c.103C>T p.(Arg35Trp) (NC_000002.12:g.237493529C>T), classified as pathogenic or likely pathogenic in ClinVar by several submitters without conflict [9, 55]. The literature gives discordant notations for the same protein change: “c.102C>T” in the 2012 series and “c.104G>T” in a 2026 report; on the MANE transcript, c.104G>T would correspond to p.(Arg35Leu), so the valid designation is c.103C>T [9, 46, 56]. Other variants described are p.Glu98Ter in a Turkish boy, p.Arg35Gln in two Ethiopian sisters and p.(Asp25His) (NM_024101.7:c.73G>C), also in SHD1, in the first Chinese patient, with reduced binding to RAB27A and perinuclear aggregation of melanosomes in transfected melanocytes [5, 24]. By 2021 only five MLPH variants associated with GS3 had been recorded [24].

2.8. Inheritance, penetrance and expressivity

All three types are autosomal recessive, with asymptomatic heterozygous parents; the sources consulted do not describe dominant inheritance or a phenotype in heterozygotes [1, 3, 5]. In GS2 consanguinity was present in 97 of 149 patients (65.1%) [20]. The expressivity of GS2 varies within the same family: siblings with the same variant may present one with isolated neurological disease and the other with systemic HLH, and in the Qatari series 2 of 12 homozygous carriers of p.Arg82Cys were asymptomatic [3, 50]. Asymptomatic patients identified by family screening remain at risk of HLH, whose occurrence depends on triggers, especially viral infections [20, 33].

3. Clinical Spectrum and Manifestations by System

3.1. Skin and hair in the three types

The common feature of the class is hair with a silvery-grey sheen, extending to the eyebrows and eyelashes, and skin lighter than that of siblings and parents [5, 16]. Cutaneous hypopigmentation is generally mild and may be absent: in three Egyptian patients with GS1 the hair was silvery without cutaneous hypopigmentation, and some patients develop tanned skin with sun exposure or hyperpigmented lesions in photoexposed areas [1, 5, 12]. A 7-year-old Indian girl with GS3 had silvery hair in the frontal and temporal regions and generalised hypo- and hyperpigmented macules, covered by fine greyish hairs [56]. In GS2, pigmentation is the most variable manifestation: among 149 patients, 75 (50%) had silvery-grey hair and 32 (21%) hypopigmented skin, 105 (70%) had at least one sign of partial albinism and 31 (21%) had none [20]. An Afghan child with GS1 had light brown hair, only lighter than that of the parents, and the defect became evident only on microscopy [22]. Dermatopathology shows increased, hyperpigmented basal melanocytes next to poorly pigmented keratinocytes [21]. Dermal granulomas have been described in GS2 [57].

3.2. Griscelli syndrome type 2: immunity and haemophagocytic lymphohistiocytosis

The cohort of 149 patients of Maimaris and colleagues (141 published and 8 new, from London) is the largest description of the natural history, with the limitations of a retrospective literature review subject to publication bias, in which the largest individual series had 16 patients [20]. The median age at diagnosis was 1.5 years (10 days to 42 years), the median age at onset 1.5 years (IQR 0.3–5), the median age at HLH 1.4 years (IQR 0.4–4.1) and the median age at death 4.75 years (IQR 0.96–10) [20]. The presenting manifestations were fever (94; 63%), splenomegaly (92; 62%), hepatomegaly (88; 59%), neurological manifestations (61; 41%) and muscle weakness or myalgia (33; 22%); 40 patients (27%) had a history of infections, more than half viral, and 12 (8%) were asymptomatic, identified through family history [20]. HLH occurred in 119 patients (80%; no information in 12): isolated systemic HLH in 52 (35%), systemic with CNS involvement in 49 (33%) and isolated CNS HLH in 18 (12%) [20]. Five patients (3%) developed lymphoma, two of them Epstein-Barr virus (EBV)-associated large B-cell lymphoma, treated with chemotherapy [20].

HLH manifests as prolonged fever, hepatosplenomegaly, cytopenias, hypertriglyceridaemia, hypofibrinogenaemia and very high ferritin, with haemophagocytosis in the marrow, liver, spleen or lymph nodes [23, 33]. In Klein's description (1994), the accelerated phases arose after viral and bacterial infections and included infiltration of the meninges and brain [33]. In the series of Ménasché (2000), the first episode occurred before 6 months in most of the 16 patients, at 3 years in three and at 8 years in one [3]. A neonatal presentation with hepatosplenomegaly, hepatitis, pancytopenia and silvery hair was described by Mancini and colleagues [3]. In the original description, the patients had hypogammaglobulinaemia and absent delayed hypersensitivity, findings that Klein interpreted as secondary; the current IUIS classification indicates normal circulating T and B lymphocytes and reduced NK and cytotoxic T-lymphocyte activity [19, 31, 33].

3.3. Griscelli syndrome type 2: central nervous system

Neurological involvement is frequent in GS2: 46% in the 2024 cohort and 67% of the patients published up to 2010 in Meeths' Swedish review, in which five of six own patients had neurological symptoms [20, 51]. Among the 149 patients, 55 (37%) had ataxia or strabismus, 21 (14%) seizures and 15 (10%) developmental delay or cognitive dysfunction [20]. The mechanism is lymphohistiocytic infiltration of the brain and meninges, documented at autopsy with haemorrhages and infiltrates in all sections and in cerebellar biopsies [3]. CNS disease may appear without any systemic sign: obstructive hydrocephalus at 32 months without haematological changes or organomegaly; isolated neurological deterioration at 6 years in a Jordanian boy, with siblings carrying the same variant who were neurologically normal; ataxia, spasticity and hypomyelination in a 5-year-old Egyptian girl without clinical signs of immunodeficiency; white matter disease without haemophagocytosis in an 11-year-old Arab girl [3]. The designation PAID was coined by Harfi (1992) for eight Saudi families with partial albinism, immunodeficiency and progressive demyelination, one of which had a RAB27A variant [3]. Neuroimaging may show white matter lesions, volume loss, hypogenesis of the corpus callosum and a simplified gyral pattern [57, 58]. In 2026 the case was published of a 5-year-old Italian girl with optic neuritis and low-titre positive anti-MOG (myelin oligodendrocyte glycoprotein) antibodies, treated as anti-MOG-associated disease for more than four years, with relapses in the brainstem and cerebellum and hydrocephalus, in whom the silvery hair led, at 9.6 years, to genetic testing and the diagnosis of GS2; she died at 10 years [59].

3.4. Griscelli syndrome type 2: late onset and forms without albinism

Sixteen of the 149 patients (11%) had onset of symptoms at 10 years or later: eight had homozygous missense variants and one a homozygous PTV; the most frequent presentation was systemic HLH (10; 63%), with CNS HLH in 8 (50%), viral infection at presentation in 8 (50%), EBV in 5 (31%), and 11 (69%) had no partial albinism [20]. An 18-year-old German woman presented with fever, cough, epistaxis, transient memory loss and shock, splenomegaly and pancytopenia (leucocytes 930/µl, haemoglobin 8.0 g/dl, platelets 17/nl), without apparent albinism, and the NK cell degranulation defect led to the diagnosis of GS2 [60]. The Qatari founder variant p.Arg82Cys is associated with atypical presentations, with isolated CNS HLH and normal pigmentation, which delay diagnosis; in the series of 12 patients from six Qatari families, the initial manifestation was cutaneous in 42%, neurological in 33% and immune in 25%, HLH occurred in 33% and the four deaths (33%) were attributed to HLH [20, 50].

3.5. Griscelli syndrome type 1

GS1 manifests in the first months of life with hypotonia, delayed motor development, intellectual disability and, in some patients, seizures, without recurrent infections or HLH [1, 38]. Pastural's original patient had hypotonia, motor delay and intellectual disability from 3 months of age [8]. Two Iraqi sisters, born to consanguineous parents, had erratic eye movements, seizures, hypotonia and psychomotor delay, and progressed to scoliosis and wheelchair dependence [1]. In two Egyptian families, the three patients had hypotonia and developmental delay, one had controlled seizures and magnetic resonance imaging (MRI) of one of them showed widened “bat-wing” Sylvian fissures; in one of the families, the younger brother, diagnosed and stimulated earlier, had mild delay with progress, unlike the older one [1, 8]. A 10-year-old Spanish girl, born to consanguineous parents and with a twin sister of similar phenotype, had developmental delay, epilepsy with tonic-clonic seizures, severe neuromuscular scoliosis and gastro-oesophageal reflux, and was under investigation for precocious puberty [21]. A Turkish patient with GS1 was alive at 21 years with severe mental and motor impairment as the only problem [25]. Patients with deletion of exon F of MYO5A have no neurological or immunological manifestations: the original Turkish patient had only pigmentary dilution up to 21 years of age [8, 25].

3.6. Elejalde syndrome

Patients described as having Elejalde syndrome have silvery hair, severe neurological impairment from infancy or early childhood (severe hypotonia, seizures, intellectual disability), hypopigmented skin that tans after sun exposure and, in some of them, ocular changes [12, 35]. In Duran-McKinster's Mexican series, neurological onset ranged from 1 month to 11 years; four patients had impairment from the first months and three had normal development followed by sudden regression; four died between 6 months and 3 years after onset [35]. Other patients had exotropia, nystagmus, ataxia, bilateral optic atrophy, impaired macular function, heat and sun intolerance and cerebellar and cortical atrophy, always with normal immunity [12]. By 2001 about ten cases had been published, including a 6-year-old Brazilian girl followed in São Paulo [61]. Bahadoran distinguished two groups: the original Colombian patients, with inclusion bodies in other cells and abnormal melanocyte maturation, and later patients, clinically and histologically indistinguishable from GS1 [12].

3.7. Griscelli syndrome type 3

GS3 is limited to pigmentation: silvery-grey hair, eyebrows and eyelashes and fair skin, without neurological or immunological disease [5, 14]. The original Turkish patient presented at 10 years and still had only pigmentary dilution at 24 years; two Turkish children had no other manifestations over 4 and 2 years of follow-up [5, 25]. In the series of Westbroek, five of seven patients from highly consanguineous families had only the pigmentary phenotype, and the additional abnormalities in two (psychomotor delay and marfanoid features) were attributed to other genes [46]. A 31-year-old Algerian woman had greyish-white hair since childhood and hyperpigmented lesions in photoexposed areas since 12 years of age [5]. A 3-year-old Arab child with GS3 also had hypoplastic left heart, considered independent because the affected brother had no heart disease [5, 62]. The mean age at diagnosis is around 10 years, which suggests underdiagnosis of a condition that does not prompt medical care [5].

3.8. Eyes

GeneReviews describes the ocular features of Griscelli syndrome as variable, without the typical constellation of oculocutaneous albinism [16]. The ocular findings reported are concentrated in GS1 and Elejalde syndrome (nystagmus, strabismus, diplopia, optic atrophy, retinal and macular changes) and, in GS2, result from inflammatory CNS disease (strabismus, optic neuritis) [12, 20, 25, 59]. The sources consulted do not describe systematic ophthalmological series.

3.9. Summary by type

4. Clinical Recognition and Warning Signs

4.1. When to suspect

The combination of silvery-grey hair, light eyebrows and eyelashes and skin lighter than that of relatives, in an infant or child, should lead to microscopy of the hair shaft and to the question that guides everything else: are there signs of systemic inflammation or CNS disease [21, 51]. Griscelli syndrome is also a cause to consider in the following settings:

4.2. Emergency signs

In a child with a Griscelli phenotype, persistent fever, hepatosplenomegaly, cytopenias, abnormal liver tests, hypofibrinogenaemia, raised ferritin, new neurological signs (seizures, altered consciousness, ataxia, cranial nerve palsies, signs of raised intracranial pressure) or cerebrospinal fluid (CSF) pleocytosis are signs of HLH, with an indication for admission, immediate investigation and discussion with a team experienced in HLH [23, 26]. Severity and clinical course, not the number of criteria met, guide the decision to treat; isolated CNS HLH frequently does not meet the systemic criteria [26].

4.3. Newborn screening

There is no biochemical newborn screening for Griscelli syndrome. The Belgian Baby Detect study, of universal genomic newborn screening in the Wallonia-Brussels Federation, enrolled 6824 newborns and included Griscelli syndrome and familial haemophagocytic lymphohistiocytosis in its list of conditions; the study is completed, and the sources consulted do not include published results for these conditions [63]. Before the molecular era, prenatal diagnosis was made by microscopy of fetal hair [3].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Diagnostic criteria

There are no formal criteria for Griscelli syndrome as a class; diagnosis rests on pigmentary dilution with the characteristic hair shaft pattern and on the identification of biallelic variants in one of the three genes, which assigns the type [14, 25]. Microscopy confirms the category but does not distinguish the three types, and normal pigmentation does not exclude GS2 [20, 22]. The HLH episode in GS2 is diagnosed by the revised Histiocyte Society criteria (2024), validated in a case–control study of 366 children under 16 years with FHL (n=341) or GS2 (n=25) against 374 children with systemic juvenile idiopathic arthritis and 690 with febrile infections or sepsis [23]. Under the 2024 criteria, the diagnosis of FHL (and, by extension, of HLH in GS2) is established by one of three routes:

NK cell activity has been removed from the list of clinical criteria; the HLH-2004 criteria without this variable had an accuracy of 99% against infections and systemic inflammation [23]. Genetic or cellular data alone indicate risk and are diagnostic only in the presence of signs or symptoms, which include isolated CNS inflammation and isolated hepatitis or liver failure [23].

5.2. Hair shaft microscopy

Light microscopy of plucked hairs is rapid, inexpensive and non-invasive [21]. In Griscelli syndrome, the shaft shows large, irregular clumps of melanin, concentrated mainly in the medulla, with an intermittent distribution; in Chédiak-Higashi syndrome, the granules are regular, evenly distributed and larger than normal [21, 64]. Valente and colleagues, in São Paulo, showed that ordinary light identifies both patterns but does not reliably distinguish them, and that polarised light separates them: the Chédiak-Higashi shaft has bright, polychromatic birefringence, while the Griscelli shaft appears uniformly white [64]. In the Afghan child with GS1 and light brown hair, microscopy showed heterogeneous pigmentation with fine (<2 µm) and coarse (>4 µm) aggregates [22]. In GS2 without albinism the shaft may be normal; transmission electron microscopy in a Japanese child showed mature melanosomes evenly distributed in the cortex [52]. Skin biopsy shows basal melanocytes packed with melanosomes and hypopigmented neighbouring keratinocytes; electron microscopy reveals irregular melanin aggregates, stage IV melanosomes and short dendrites [21].

5.3. Immunological and functional work-up

When a Griscelli phenotype is present, the initial work-up includes a full blood count with blood film (no giant granules in neutrophils, unlike Chédiak-Higashi), liver tests, ferritin, triglycerides, fibrinogen and sCD25 [15, 23]. Cytotoxic lymphocyte function is assessed by degranulation, measuring surface CD107a expression by flow cytometry after stimulation; the combined assay of NK cells and CD8+ T lymphocytes is more sensitive and specific than that of NK cells alone [23]. In the London laboratory, the result is abnormal when the increase in CD107a between the stimulated and unstimulated sample is less than 0.5% in cytotoxic T lymphocytes after anti-CD3 and/or less than 5% in NK cells after phytohaemagglutinin; thresholds are specific to each laboratory [20, 23]. In the two Japanese children with GS2, NK degranulation was 4.0% and 3.5% (controls 30–38%) and that of CD8+ T lymphocytes 0.7% and 1.4% (controls 17–21%) [52]. Perforin expression is normal in GS2, which separates it from FHL type 2 [17, 23].

The assay has demonstrated limits. Among 46 patients with GS2 with an available result, 41 (88%) had reduced or absent granule release; five patients from an extended Qatari family, homozygous for p.Arg82Cys, had normal or equivocal degranulation and NK cytotoxicity assays on repeated occasions [20]. In the Swedish series, three of six patients had NK activity within the reference range, albeit low [51]. A normal assay does not exclude GS2, and genetic testing is necessary even with normal function [20].

5.4. Genetic testing

The first-line test is sequencing of the three genes, in a hypopigmentation or HLH panel, or by exome, which should include copy number variant analysis: the duplication of about 38 kb of exons 2 to 5 of RAB27A is not detected by sequencing, and the 2439 bp deletion of exon F of MYO5A and the 67.5 kb deletion of RAB27A require deletion detection methods [3, 8, 39]. An undetected pathogenic variant in RAB27A is a real possibility: in a Mexican girl with a GS2 phenotype, reduced NK cytotoxicity and reduced RAB27A expression, no variant was found in the gene [57]. Under the 2024 criteria, biallelic combinations of large deletions, nonsense variants or well-characterised aberrations suffice for the genetic diagnosis; a combination with at least one rare missense or non-coding variant, or a variant of uncertain significance (VUS), requires functional validation [23]. The report should state the gene, the transcript and version (NM_183235.3 for RAB27A, NM_001382347.1 for MYO5A and NM_024101.7 for MLPH, which are the MANE transcripts), the HGVS (Human Genome Variation Society) nomenclature, zygosity, the ACMG/AMP class and the parental segregation study [9, 23]. The notation of some published variants is inconsistent with the reference transcript (for example, MLPH p.Arg35Trp described as c.102C>T or c.104G>T), so comparison with the literature should be made by genomic coordinate or by normalised notation [9, 46, 56].

5.5. Practical algorithm

5.6. Prenatal and preimplantation diagnosis

Once the familial variants have been identified, prenatal diagnosis on chorionic villi or amniotic fluid and preimplantation genetic testing (PGT) are possible [22]. Before the genes were identified, Durandy and colleagues made the prenatal diagnosis of Griscelli syndrome by examination of fetal hair, with 12 at-risk fetuses negative and 4 positive across the albinism-immunodeficiency syndromes as a whole [3].

6. Differential Diagnosis

6.1. Comparative table

6.2. Chédiak-Higashi syndrome

This is the closest differential of GS2, because it also combines partial albinism, a defect of granule-dependent cytotoxicity and HLH, and it appears in the same group of the IUIS classification [15, 19]. It is distinguished by giant granules in all leucocytes, a mild bleeding diathesis, late-onset degenerative neurological disease, which transplantation does not prevent, and the hair shaft pattern; in Griscelli syndrome, platelets have normal dense granules and function and neutrophils have no giant granules [15]. Since the original description, the absence of giant granules and the normal activity of leucocyte-specific protease, very low in Chédiak-Higashi, have separated the two syndromes [3, 66].

6.3. Hermansky-Pudlak syndromes types 2 and 10

They share albinism and the cytotoxicity defect with GS2, but the bleeding diathesis due to absent dense granules and complete oculocutaneous albinism are specific to Hermansky-Pudlak syndromes [18, 19]. In HPS2 the risk of HLH is low, because the cytotoxic defect is moderate: in a survey of 22 patients, only one developed fatal HLH, and that patient also had a heterozygous RAB27A variant [65].

6.4. Familial haemophagocytic lymphohistiocytosis

Without abnormal pigmentation, GS2 is clinically indistinguishable from FHL. In the Swedish series, five of six patients with GS2 had initially been diagnosed with FHL, and the authors concluded that GS2 may go unnoticed in light-haired children [51]. In patients with primary HLH and normal pigmentation without a variant in the FHL genes, sequencing of RAB27A should be part of the work-up [45].

6.5. Elejalde syndrome and other causes of silvery hair with neurological disease

Elejalde syndrome is clinically indistinguishable from GS1, and several authors have proposed that, at least in some patients, the two are the same entity; the original Colombian description had inclusion bodies in fibroblasts and histiocytes that are not part of GS1 [12, 39]. In a child with silvery hair and neurological disease, the sequence is to distinguish a primary neurological disease (GS1, Elejalde, Menkes, Cross syndrome) from an inflammatory CNS disease due to HLH (GS2, Chédiak-Higashi), because the latter has urgent and potentially curative treatment [51, 57].

7. Treatments and Risk Management Strategies

7.1. Principles and reference documents

There is no specific guideline for Griscelli syndrome. Management of GS2 follows the Histiocyte Society documents on HLH (the revised 2024 diagnostic criteria and the 2018 consensus recommendations on etoposide therapy and transplantation) and the guidelines of the inborn errors working party of the EBMT/ESID (European Society for Blood and Marrow Transplantation/European Society for Immunodeficiencies) on HSCT, published in 2021 and updated in 2026 [23, 26, 67, 68]. GS1 and GS3 have no specific treatment and no indication for HSCT, because they have no haematopoietic defect [25, 69]. The full dosing of HLH drugs, adjustments, interactions and the information in the Portuguese SmPCs follow the protocols for primary haemophagocytic lymphohistiocytosis; the elements relevant to GS2 are summarised here.

7.2. Griscelli syndrome type 2: treatment of haemophagocytic lymphohistiocytosis

The aim is to control hyperinflammation so as to reach transplantation in remission, because remission at the time of HSCT is a key determinant of survival [20, 67]. Prompt application of the HLH-94 protocol, which includes etoposide, can be life-saving (strong consensus), should be undertaken in consultation with an HLH expert and is decided by severity and course, not merely by the number of criteria; a germline variant without active disease is not an indication to start HLH-94 [26]. In the HLH-94 and HLH-2004 registries, between 1994 and 2004, the five patients with GS2 responded to treatment, were all transplanted and were alive at a mean follow-up of 5.6 years, albeit with neurological sequelae [70]. In the 2024 review, 22 of 119 patients with HLH (18%) received HLH-94 and 15 (13%) HLH-2004 as first line; for CNS HLH, some reports describe high-dose corticosteroids and mycophenolate mofetil [20].

The doses in the table are those of the HLH-94 and HLH-2004 protocols, which included children under 16 and 18 years of age, respectively; they are calculated per m² of body surface area (ciclosporin per kg, and intrathecal methotrexate by age), with no maximum dose defined in the source [26, 71].

The HLH-2004 protocol was published in 2007 [72]. Ciclosporin was brought forward to the start in HLH-2004 because it inhibits interferon-γ production, but this change did not significantly improve outcomes (5-year survival of 61% in HLH-2004 against 54% in HLH-94), and for this reason the 2018 consensus keeps HLH-94 as the reference [26, 71]. Isolated CNS HLH, which often does not meet the systemic criteria and may be mistaken for encephalitis, vasculitis, acute disseminated encephalomyelitis or multiple sclerosis, benefits from timely systemic therapy according to published experience [26]. Supportive care includes Pneumocystis jirovecii and broad-spectrum antifungal prophylaxis and weekly testing for EBV, cytomegalovirus, adenovirus and fungi; patients in whom treatment is deferred should be reassessed at least daily [26]. HLH is often triggered by viral infections, especially EBV, which should be sought [20, 26].

In refractory, recurrent or progressive disease, or in intolerance of conventional therapy, emapalumab (Gamifant®), an anti-interferon-γ monoclonal antibody, is approved in the United States for adults and children with primary HLH [27]. The starting dose on the label is 1 mg/kg by 1-hour intravenous infusion twice weekly (every 3 to 4 days), which can be increased to a maximum of 10 mg/kg according to clinical and laboratory criteria, with concomitant dexamethasone, until HSCT [27]. Screening for latent tuberculosis is required before starting; herpes zoster, Pneumocystis and fungal prophylaxis and monitoring for herpes zoster, adenovirus, EBV and cytomegalovirus are recommended; infusion reactions occurred in 27% of patients with primary HLH, the most frequent adverse reactions (≥20%) were infections, hypertension, infusion reactions and fever, and the label carries a warning about the increased risk of infection with live vaccines [27]. In the registration trial NI-0501-04 (NCT01818492), 5 of the 27 children (19%) had GS2 [27]. In the European Union the marketing authorisation was refused, and the refusal was upheld after re-examination in November 2020 [73]. Ruxolitinib, a JAK1/2 kinase inhibitor, has no approved indication in HLH; it was used in 2026 reports of GS2 (10 mg/day in the re-induction of a CNS relapse in a Japanese child who went on to transplantation; 5 mg twice daily in the Italian girl, who died before transplantation), without these reports establishing a recommended dose [52, 59]. The EBMT/ESID guidelines consider that the efficacy of anti-interferon-γ antibodies and JAK inhibitors has still to be evaluated in prospective studies, and the 2026 update mentions their promise for improving engraftment and reducing toxicity [67, 68].

7.3. Griscelli syndrome type 2: haematopoietic stem cell transplantation

Allogeneic HSCT is the only curative therapy for GS2 and is indicated in all patients who have had HLH, as soon as remission is achieved; familial HLH is, for the EBMT/ESID, a clear indication for transplantation, and in the genetic forms pre-emptive transplantation should be considered [20, 68]. HLA typing of the patient and siblings and the donor search should begin as soon as the diagnosis is likely; in the first series with peripheral blood transplantation, the authors stressed that the search for an unrelated donor may consume valuable time [69]. The main published results are:

Of the complications recorded in 34 transplanted patients in the 2024 review, 18 (52.9%) had no complications, 4 (11.8%) were left with neurological sequelae, 6 (17.6%) had sepsis or infection, fatal in 5 (14.7%), and 5 of the 6 patients who died had had systemic or CNS HLH before transplantation [20]. In the Paris series, neurological HLH before transplantation was the main determinant of sequelae: of the seven patients with prior neurological involvement, four survived and two were left with sequelae [74]. Conditioning regimens have evolved from myeloablative schedules with busulfan and cyclophosphamide, of high toxicity, to reduced-toxicity schedules; the combination of fludarabine and melphalan improved early survival but with less favourable chimerism, late viral reactivation and late acute graft-versus-host disease, and mixed chimerism is more frequent with treosulfan- and melphalan-based regimens [67]. T-cell chimerism above 20–30% is probably sufficient to protect against relapse [67]. Thiotepa crosses the blood–brain barrier, which may be advantageous in forms with CNS involvement, and prophylactic defibrotide is recommended in children under 18 months or with liver involvement, given the risk of veno-occlusive disease [67]. Individualised busulfan dosing by therapeutic drug monitoring is now standard [68]. Serotherapy (antithymocyte globulin or alemtuzumab) should be considered in conditioning if the disease is not in complete remission [67].

7.4. Asymptomatic patients

Siblings with biallelic variants identified by family screening are at risk of HLH and should be monitored closely, with immediate treatment at the first sign; some members of the Histiocyte Society committee use prophylactic ciclosporin until transplantation in asymptomatic siblings with severe biallelic variants identified at birth [26]. The 2024 review describes five patients transplanted pre-emptively without prior HLH and considers that these patients may benefit from pre-emptive transplantation, but that the p.Arg82Cys variant, with mild phenotypes and functional assays that are sometimes normal, poses a dilemma regarding the indication and timing, to be decided case by case on the basis of the risk of HLH, the risk of malignancy, the family history and the available donor [20]. The 2026 EBMT/ESID update recommends considering pre-emptive transplantation in most genetic forms of HLH [68].

7.5. Comparative regulatory status

7.6. Trials and treatment series

The emapalumab trial is single-arm, without a comparator, with patients who continued dexamethasone and, in some cases, ciclosporin and intrathecal therapy, which prevents the effect of the antibody from being isolated and was the basis for the European refusal [27, 73]. HLH-2004 showed no significant benefit of upfront ciclosporin compared with HLH-94, and the survival figures refer to the entire HLH population, not to GS2 alone [26, 71]. The transplantation series in GS2 are retrospective, single-centre or compiled from the literature, with publication bias, and do not allow conditioning regimens to be compared [20, 74]. No therapeutic trials specific to Griscelli syndrome are registered on ClinicalTrials.gov; study NCT01652092, of HSCT in primary immunodeficiencies with alemtuzumab, busulfan and fludarabine, is active, not recruiting [76].

7.7. Developments in the last 12 months

In preclinical research, correction of variants in exons 3 and 7 of RAB27A by CRISPR/Cas9 with homology-directed repair in patients' mesenchymal stem cells and induced pluripotent stem cells reached an efficiency of 10% with the best guide RNA (2024), and as early as 2004 retroviral transfer of RAB27A had restored the cytotoxicity of CD8+ T lymphocytes from a Brazilian boy [77, 78]. None of these approaches had reached a clinical trial in the sources consulted.

7.8. Griscelli syndrome type 1 and Elejalde syndrome

Treatment is supportive: early stimulation and intervention, treatment of epilepsy and follow-up of neuromuscular scoliosis, which may lead to loss of ambulation [1, 21]. In an Egyptian family, the brother diagnosed and stimulated earlier had mild delay and made progress, unlike the older brother with severe delay, which the authors attributed to early intervention [1]. Transplantation is not indicated, because the deficit is neuronal and not haematopoietic [25, 69]. The sources consulted do not describe antiepileptic drugs with specific efficacy in GS1; treatment follows the seizure type.

7.9. Griscelli syndrome type 3

No specific therapy is required [25]. The essential clinical action is to confirm that the gene is MLPH and not RAB27A, to avoid both unnecessary surveillance and preparation for transplantation and the omission of HLH surveillance in GS2 [20, 25]. The hyperpigmented lesions in photoexposed areas described in adults with GS3 and the fair skin justify advice on sun protection, by extrapolation from the general care of hypopigmented skin [5].

7.10. Agents and circumstances to avoid

In GS2, viral infections, particularly EBV, are the most frequent trigger of primary HLH, and any fever should be assessed promptly [20, 26]. The sources consulted do not include a specific list of drugs or vaccines to avoid in GS2; by analogy with Chédiak-Higashi syndrome, whose GeneReviews entry contraindicates live vaccines because of the immunodeficiency, administration of live vaccines before transplantation should be decided with the immunology team [15]. During treatment with emapalumab the label warning on live vaccines applies [27]. Unlike Chédiak-Higashi, platelet function is normal in Griscelli syndrome, so the restrictions on non-steroidal anti-inflammatory drugs in that syndrome do not apply for haemorrhagic reasons [15].

7.11. Pregnancy, fertility and lactation

The sources consulted do not describe pregnancies in transplanted women with GS2 or in women with GS1. An Algerian woman with GS3 was seen at 32 weeks of gestation, with a personal and family history of recurrent miscarriage whose relationship to GS3 was not established [5]. The emapalumab label has no data in pregnant women; in a study in female mice, a murine surrogate antibody crossed the placenta without fetal harm [27]. Fertility preservation should be discussed before conditioning for HSCT: in the 18-year-old German woman with GS2, oocyte cryopreservation was carried out before transplantation [60].

7.12. Transition to adulthood

GS2 may appear for the first time in adolescence or adulthood, up to 42 years of age, so adult internists and haematologists should be aware of the possibility [20, 26]. Transplanted survivors require long-term follow-up of neurological sequelae and chimerism, and adults with GS1 require rehabilitation and adult neurology care [25, 74].

8. Reproductive Options and Family Counselling

8.1. Recurrence risk

In all three types, when both parents are heterozygous, each pregnancy has a 25% probability of an affected child, 50% of an asymptomatic carrier and 25% of a child who is neither affected nor a carrier [21, 22]. Heterozygous carriers have no manifestations described in the sources consulted [3, 5]. The great majority of published families are consanguineous (65.1% in the GS2 cohort), and in a family with multiple consanguinity other recessive diseases may coexist, as happened in two children with GS3 and additional anomalies attributed to other genes [20, 46]. The children of an affected adult are obligate carriers; their risk of having affected children depends on whether the other parent is a carrier, which is more likely in consanguineous marriages or in populations with founder variants [20].

8.2. Cascade testing and siblings

In GS2, the siblings of a patient should be tested as soon as the familial variants are known, including newborns, because a presymptomatic affected sibling can be monitored, receive early treatment and be transplanted before the first HLH episode; 12 of the 149 patients in the 2024 cohort were diagnosed in this way [20, 26]. An HLA-matched sibling can be a donor only if unaffected, which testing for the familial variants clarifies; in the 2024 cohort, five transplants used matched siblings [20]. The intrafamilial variability described in GS2, with one neurologically affected sibling and another with systemic HLH, or with asymptomatic siblings carrying the same variant, precludes using the proband's phenotype to predict that of a sibling [3, 50]. The 2024 review recommends genetic counselling and screening in families and regions with founder variants, such as Qatar for p.Arg82Cys [20].

8.3. Prenatal and preimplantation diagnosis

With the familial variants identified, prenatal diagnosis and PGT are available [22]. In GS2, knowing the diagnosis before or soon after birth allows surveillance from the first day and consideration of pre-emptive transplantation [20, 68]. In GS3, a condition with no impact on health, a request for prenatal diagnosis raises questions that should be discussed in counselling; the sources consulted do not address this point.

8.4. Counselling of minors

Testing of minor siblings of a patient with GS2 has direct medical benefit and should not be deferred [20, 26]. Carrier testing in healthy minors has no immediate medical benefit and the sources consulted make no specific recommendation for Griscelli syndrome.

9. Special Considerations: Population Diversity and Epidemiology

9.1. Frequency

There are no population-based studies of incidence or prevalence. Orphanet records about 150 cases or families for the class, about 102 for GS2, about 20 for GS1 and about 13 for GS3, all with a prevalence class of less than 1/1,000,000; these figures are counts of published cases and not frequency estimates [2, 4, 6, 7]. The 2024 review brought together 149 patients with GS2 published up to November 2023 or followed in London [20]. In 2012 only two patients with GS3 and about 20 with GS1 had been published, including those described as having Elejalde syndrome [25], and by 2021 five MLPH variants had been recorded [24]. Griscelli syndrome accounts for less than 1% of cases of albinism [16]. GS3, because it does not cause disease, is probably underdiagnosed [5, 46], and GS2 without albinism may be diagnosed as FHL [51].

9.2. Geographical distribution and founder populations

The patients with GS2 described are concentrated in populations with high consanguinity: in the 2024 cohort, patients of Qatari (20; 14%) and Turkish (15; 10%) ancestry were the most numerous [20]. The three founder variants of RAB27A have been identified mainly in European and Middle Eastern populations: p.Arg82Cys only in patients from Qatar, where 12 patients from six families of a consanguineous tribe have been described [20, 50]. A founder duplication of RAB27A was found in seven consanguineous Saudi families [3], and a 67.5 kb founder deletion in a Muslim Arab family [39]. The MLPH p.(Arg35Trp) variant suggests a founder effect in the Hebron region [5]. Elejalde syndrome was originally described in families from Colombia and later in Mexico [34, 35]. In Europe, there are series or cases from France (the founding Paris series), the United Kingdom, Sweden, Germany, Italy and Spain [20, 21, 33, 51, 59, 60]. Contrary to the expectation that albinism is underdiagnosed in fair skin, partial albinism was more frequent in patients of European ancestry [20].

In Brazil, the sources consulted include the São Paulo study of hair shaft microscopy with polarised light, a case of Elejalde syndrome in São Paulo and a Brazilian boy with GS2, compound heterozygous (a splicing variant and NM_183235.3:c.352C>T p.(Gln118Ter)), in whose cells transfer of RAB27A restored cytotoxicity [3, 53, 61, 64, 78]. The sources consulted include no data from Portugal; this absence does not demonstrate that there are no Portuguese patients.

9.3. Reference networks and patient organisations

10. Illustrative Clinical Case

AmirKashani and colleagues published in 2026, in the journal Case Reports in Immunology, the case of an Afghan girl seen in an immunology clinic at 27 months [22]. She was the first child of consanguineous parents, born by caesarean section with normal Apgar scores, with no family history of similar disease, miscarriages or neonatal deaths [22]. The parents noticed hypotonia at 2 months; the child held her head up unsupported only at 7 months, sat with support after 12 months and, at 24 months, rolled over, stood with support and made a few meaningless sounds [22]. She had no seizures or visual impairment, and growth was normal; at 12 months she had been investigated for anaemia, with a working diagnosis of thalassaemia minor [22]. Her hair had been light brown since birth, lighter than that of her parents, without the typical silvery appearance, and her skin did not attract attention [22].

At 24 months a neurometabolic assessment of the developmental delay was carried out; immunological studies showed no cytotoxicity defect [22]. Exome sequencing identified the homozygous MYO5A variant c.3508C>T, which creates a premature stop codon in exon 26 of 42, classified as likely pathogenic under the ACMG criteria PVS1 and PM2; both parents were heterozygous [22]. Normalised to the MANE transcript, the variant is NM_001382347.1:c.3508C>T p.(Gln1170Ter) (NC_000015.10:g.52353930G>A), with the same numbering on the historical transcript NM_000259.3 [9]. Only after the genetic result was the hair examined under the microscope, which showed heterogeneous pigmentation along each hair and between neighbouring hairs, melanin irregularly distributed in the cortex and scattered clumps, with fine (<2 µm) and coarse (>4 µm) aggregates (figure 1 of the article: https://pmc.ncbi.nlm.nih.gov/articles/PMC13311309/figure/fig-0001/) [22]. The diagnosis was GS1, and the family received genetic counselling on the 25% recurrence risk and on prenatal and preimplantation diagnosis [22].

The case illustrates three points. The first is that the pigmentary phenotype of GS1 may be subtle, and that hair microscopy can reveal the defect in a child without silvery hair [22]. The second is that, in a child with hypotonia and delay, the absence of immunodeficiency and of a cytotoxic defect is consistent with GS1 and rules out GS2, whose neurological disease is inflammatory and treatable [20, 38]. The third is that the diagnosis was made by exome and not by clinical suspicion, which suggests that other children with GS1 and inconspicuous pigmentation are among the patients with undiagnosed developmental delay; the authors present it as the first case of GS1 without the characteristic silvery hair [22].

11. Prognosis and Long-Term Follow-up

11.1. Prognosis by type

In GS2 without transplantation, the prognosis is grave: the 1994 description considered the disease invariably lethal without transplantation, with a mean age at death of 5 years, and Orphanet describes it as fatal, in most cases, in the first decade [4, 33]. In the published cohort of 149 patients, mortality was 34% (50/149), with a median age at death of 4.75 years; all patients with systemic HLH who were not transplanted soon afterwards died or were left with significant morbidity, and mortality was 14% in transplanted patients against 58% in non-transplanted patients with known follow-up [20]. Patients with PTVs had worse survival than those with hypomorphic variants, and patients without partial albinism had, according to the available data, a more favourable course [20]. After transplantation, cure of the immune defect is the rule in the published series (86% survival in the 2024 compilation, 70% cure in the Paris series, 10 of 11 patients alive and disease-free in Riyadh), but neurological sequelae persist in some patients and depend mainly on CNS involvement before transplantation [20, 74, 75]. Lymphoma, including EBV-associated lymphoma, occurred in 3% of the cohort [20].

In GS1, the neurological deficit persists; survival into adulthood with severe mental and motor impairment, progression to scoliosis and wheelchair dependence, and a more favourable course when intervention was early have been described [1, 25]. In Elejalde syndrome, four of seven Mexican patients died between 6 months and 3 years after neurological onset [35]. In GS3 and in the form with deletion of exon F of MYO5A, the prognosis is that of the general population, with patients healthy at 21 and 24 years [25].

11.2. Surveillance

12. Summary and Final Considerations

Griscelli syndrome brings together three autosomal recessive diseases that share a defect in the capture of melanosomes at the periphery of the melanocyte, and therefore the same silvery-grey hair with irregular clumps of melanin in the shaft, but that differ in the role of each gene outside the skin: myosin Va in neurons (GS1, primary neurological deficit), RAB27A in the cytotoxic granules of lymphocytes (GS2, haemophagocytic lymphohistiocytosis) and melanophilin only in the melanocyte (GS3, purely pigmentary phenotype). Identifying the gene is the central decision, because GS2 is a treatable emergency curable by transplantation, whereas GS1 and GS3 have no indication for transplantation. The most frequent and most severe form is GS2: in the published cohort of 149 patients, 80% had HLH, 46% CNS involvement, 21% had no albinism and mortality was 34%, lower in those transplanted. Variants that spare binding to melanophilin and destroy binding to MUNC13-4 explain GS2 without albinism, and the late-onset forms, up to 42 years of age, and the isolated neurological forms make sequencing of RAB27A, with CNV analysis, a test to include in the investigation of any primary HLH or unexplained CNS inflammation. The degranulation assay is sensitive but may be normal in some genotypes, and the 2024 Histiocyte Society criteria accept the diagnosis by the genetic, cellular or clinical route. Treatment of HLH follows the HLH-94 protocol as a bridge to transplantation, with emapalumab approved in the USA for refractory disease and refused in the European Union, and transplantation, preferably with the disease in remission and before CNS involvement, cures the immune defect in most patients. Siblings should be tested early, and in asymptomatic affected siblings pre-emptive transplantation should be considered. GS1, overlapping at least in part with Elejalde syndrome, and GS3 are rare, probably underdiagnosed, and recognising them avoids both missing a case of GS2 and unnecessary interventions.

13. References

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