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Griscelli syndrome type 2
This condition primarily affects children, causing light-coloured skin and hair, and severe immune system dysfunction. It is a serious disorder that can lead to life-threatening complications without appropriate medical care.
Overview
Griscelli syndrome type 2 (GS2) is a rare inherited condition that affects various bodily systems, most notably the immune system, skin and hair pigmentation, and brain development. Individuals with GS2 typically have unusually light-coloured hair and skin, a form of partial albinism, alongside significant immune system deficiencies [PMID:16127632]. These immune problems can lead to recurrent infections and a severe, potentially life-threatening complication known as haemophagocytic lymphohistiocytosis (HLH). HLH involves an overactive immune response that damages organs throughout the body.
GS2 is one of several types of Griscelli syndrome, distinguished by its specific genetic cause and the involvement of the immune system. The condition is considered rare, meaning it affects a very small number of people. Because of its complex presentation and the severity of its symptoms, early diagnosis and management are crucial for individuals with GS2.
Symptoms & clinical features
The symptoms of Griscelli syndrome type 2 generally appear in early childhood. A key feature is hypopigmentation, which means reduced pigmentation, resulting in silvery-grey hair and abnormally light skin colour. Unlike some forms of albinism, the eyes are usually not as severely affected, though some individuals may have reduced vision or involuntary eye movements (nystagmus) [PMID:16127632].
Beyond pigmentation changes, individuals with GS2 typically experience significant immune system problems. This can lead to frequent, severe infections, sometimes caused by unusual or opportunistic pathogens. The most serious immune complication is haemophagocytic lymphohistiocytosis (HLH). Symptoms of HLH include persistent fever, enlarged liver and spleen (hepatosplenomegaly), low blood counts (cytopenias), and neurological changes such as irritability, seizures, and developmental delays. These neurological symptoms can arise directly from HLH or as a primary feature of GS2 itself [PMID:16127632].
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Affected organs
Griscelli syndrome type 2 primarily affects several key organ systems. The skin and hair follicles are impacted, leading to characteristic silvery-grey hair and light skin due to abnormal melanin distribution. The immune system is profoundly affected, resulting in immunodeficiency and a high risk of developing haemophagocytic lymphohistiocytosis (HLH), which can cause widespread inflammation and damage to organs like the liver, spleen, bone marrow, and brain.
The central nervous system can also be affected, leading to developmental delays, intellectual disability, and other neurological symptoms like seizures, even in the absence of HLH. The gastrointestinal system may experience issues due to recurrent infections or HLH. While other organs may be indirectly affected by the systemic inflammation of HLH, the main direct impacts are on the immune system, skin, hair, and brain.
Risks & severity
Griscelli syndrome type 2 is a severe condition with significant health risks, primarily due to the immune system dysfunction and the potential for haemophagocytic lymphohistiocytosis (HLH). HLH is a life-threatening complication where the immune system becomes overactive, leading to severe inflammation and damage to various organs if not treated promptly [PMID:24765624]. Without treatment, HLH is often fatal.
The neurological features of GS2 can range in severity, from mild developmental delays to significant intellectual disability and seizures. The age of onset for symptoms is typically in infancy or early childhood. The severity of the condition and its prognosis largely depend on the timely diagnosis and effective management of both the underlying immune deficiency and any episodes of HLH.
Genetic causes
Griscelli syndrome type 2 is caused by genetic changes (pathogenic variants) in the RAB27A gene. This gene provides instructions for making a protein that plays a crucial role in cell trafficking, specifically in moving certain vesicles within cells. In pigment cells (melanocytes), the RAB27A protein is essential for transporting melanosomes - small sacs containing melanin, the pigment that gives skin, hair, and eyes their colour - to the surface of the cell where the pigment can be transferred to hair and skin cells [PMID:12420042].
When the RAB27A gene has pathogenic variants, the protein it produces is either non-functional or missing. This disrupts the normal transport of melanosomes, causing them to clump together within the melanocytes instead of being distributed evenly. This abnormal distribution is what leads to the characteristic light skin and silvery hair seen in GS2. The RAB27A protein also plays a vital role in immune cells, particularly natural killer (NK) cells and cytotoxic T lymphocytes, which are important for fighting infections. Dysfunction of RAB27A in these cells impairs their ability to effectively eliminate infected cells, contributing to the severe immune problems and the development of HLH [PMID:24765624].
- RAB27A RAB27A, member RAS oncogene family
Inheritance pattern
Griscelli syndrome type 2 is inherited in an autosomal recessive pattern. This means that an individual must inherit two copies of the altered gene - one from each parent - to develop the condition. If a person inherits only one copy of the altered gene, they are considered a carrier. Carriers typically do not show any symptoms of the condition themselves but can pass the altered gene on to their children.
When two carriers of a RAB27A pathogenic variant have children, there is a 25% (1 in 4) chance with each pregnancy that their child will inherit two altered copies of the gene and develop Griscelli syndrome type 2. There is a 50% (2 in 4) chance that the child will be a carrier, and a 25% (1 in 4) chance that the child will inherit two normal copies of the gene and neither have the condition nor be a carrier.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
Diagnosis & testing
The diagnosis of Griscelli syndrome type 2 is often suspected based on the characteristic clinical features, including silvery-grey hair, partial albinism, recurrent infections, and neurological symptoms. If haemophagocytic lymphohistiocytosis (HLH) develops, specific diagnostic criteria for HLH are also used.
Confirmation of GS2 typically involves genetic testing, which can identify pathogenic variants in the RAB27A gene. This testing is usually performed following a referral to a clinical genetics service. In the UK, genetic testing for suspected inherited conditions often follows pathways outlined by the NHS Genomic Medicine Service, with relevant R-codes for specific gene panels or whole exome sequencing. Genetic counselling is an important part of the diagnostic process, offering support and information to families regarding the condition and its inheritance.
Management & lifestyle
Management for Griscelli syndrome type 2 focuses on treating the symptoms, preventing infections, and addressing the immune system dysfunction. Because of the risk of severe infections, individuals with GS2 often receive prophylactic antibiotics (medication to prevent infection).
The most effective treatment for the immune system dysfunction and to prevent or treat haemophagocytic lymphohistiocytosis (HLH) is generally a haematopoietic stem cell transplant (HSCT), also known as a bone marrow transplant [PMID:16127632]. This procedure replaces the faulty immune cells with healthy ones from a donor. Referral to a specialist immunologist and haematologist is crucial to determine if HSCT is an appropriate option. Ongoing care involves multidisciplinary teams, including paediatricians, neurologists, dermatologists, and genetic counsellors, to monitor for complications and provide supportive care.
UK care pathway
In the UK, individuals suspected of having Griscelli syndrome type 2 would typically be referred by their GP or paediatrician to a clinical genetics service. These services are part of the NHS Genomic Medicine Service (GMS) and can arrange for appropriate genetic testing, often utilising gene panels or whole exome sequencing, which are catalogued by specific R-codes for diagnostic pathways. Once a diagnosis is confirmed, patients are usually managed by a multidisciplinary team of specialists at expert centres. Genetic counsellors play a vital role in supporting families, explaining inheritance patterns, and discussing implications for other family members.
Frequently asked questions
Is Griscelli syndrome type 2 contagious?
No, Griscelli syndrome type 2 is a genetic condition, meaning it is caused by changes in a person's genes. It cannot be caught from another person or passed on through contact.
What does 'autosomal recessive' inheritance mean for my family?
Autosomal recessive inheritance means that both parents must be carriers of a gene change for their child to inherit the condition. Carriers usually do not have symptoms themselves. For each child born to two carrier parents, there is a one in four chance of having the condition.
Can Griscelli syndrome type 2 be cured?
While there isn't a simple 'cure', a haematopoietic stem cell transplant (bone marrow transplant) is considered the most effective treatment for the immune system problems and can be life-saving for individuals with Griscelli syndrome type 2.
How is Griscelli syndrome type 2 diagnosed in the UK?
In the UK, diagnosis typically begins with a referral to a clinical genetics service through your GP or paediatrician. Genetic testing, often involving specific gene panels or whole exome sequencing under NHS Genomic Medicine Service guidelines, is used to confirm the presence of pathogenic variants in the RAB27A gene.
What is haemophagocytic lymphohistiocytosis (HLH)?
HLH is a severe, life-threatening complication of Griscelli syndrome type 2 where the immune system becomes overactive and causes inflammation and damage to organs throughout the body. It requires urgent medical attention and treatment.
References
- Henter JI, Sieni E, Eriksson J. Diagnostic guidelines for familial hemophagocytic lymphohistiocytosis revisited. Blood. 2024. PMID: 39046779
- Maimaris J, Roa-Bautista A, Sohail M. Griscelli Syndrome Type 2: Comprehensive Analysis of 149 New and Previously Described Patients with RAB27A Deficiency. Journal of clinical immunology. 2024. PMID: 39607447
- Emanuel PO, Sternberg LJ, Phelps RG. Griscelli syndrome. Skinmed. 2007. PMID: 17483661
- Gailson T, Pandit S, Chandrasekaran S. Griscelli syndrome type 2. QJM : monthly journal of the Association of Physicians. 2020. PMID: 31199490
- Kendir-Demirkol Y, Yeter B, Yararbaş K. First Co-Occurrence of Griscelli Syndrome Type 2 and Neurofibromatosis Type 1. Molecular syndromology. 2024. PMID: 38841328
- Güney-Esken G, Erol ÖD, Pervin B. Development, characterization, and hematopoietic differentiation of Griscelli syndrome type 2 induced pluripotent stem cells. Stem cell research & therapy. 2021. PMID: 33985578
- Sefsafi Z, Hasbaoui BE, Kili A. Macrophage activation syndrome associated with griscelli syndrome type 2: case report and review of literature. The Pan African medical journal. 2018. PMID: 29875956
- Ohishi Y, Ammann S, Ziaee V. Griscelli Syndrome Type 2 Sine Albinism: Unraveling Differential RAB27A Effector Engagement. Frontiers in immunology. 2020. PMID: 33362801