Chediak Higashi Syndrome Diagnosis: An In-Depth Guide for Healthcare Professionals

Introduction

Chediak Higashi syndrome (CHS) is a rare, autosomal recessive genetic disorder characterized by a triad of clinical features: increased susceptibility to bruising, oculocutaneous albinism, and recurrent pyogenic infections. First identified by Beguez-Cesar in 1943, and further characterized by Chediak (1952) and Higashi (1954) who noted the abnormal distribution of myeloperoxidases in neutrophil granules, CHS arises from a mutation in the lysosomal trafficking regulator (LYST) gene. This genetic defect leads to impaired phagocytosis and a heightened predisposition to bacterial infections, making accurate and timely Chediak Higashi Diagnosis crucial for patient management.

Beyond immunological deficits, individuals with CHS may also exhibit neurological symptoms such as ataxia and neuropathies, particularly in atypical presentations of the disease. The hallmark of Chediak Higashi diagnosis at the cellular level is the presence of abnormally large intracytoplasmic granules, readily observable in white blood cells and bone marrow samples.

The clinical course of CHS is often marked by significant morbidity due to recurrent infections and the potential development of an accelerated phase characterized by lymphoproliferation affecting major organs. Tragically, approximately 80% of affected individuals succumb to the disease within the first decade of life. For those who survive into adulthood, progressive neurological decline becomes a major concern.

While allogeneic hematopoietic stem cell transplantation (HSCT) represents the only curative treatment for the hematological and immunological dysfunctions associated with CHS, it unfortunately does not halt the progression of neurological impairment. Therefore, early and accurate Chediak Higashi diagnosis is paramount for initiating timely interventions and improving patient outcomes. This article aims to provide a comprehensive guide to Chediak Higashi diagnosis, encompassing etiology, pathophysiology, clinical evaluation, and differential considerations for healthcare professionals.

Etiology

The fundamental cause of Chediak Higashi syndrome is a mutation in the LYST gene, also referred to as the CHS1 gene. This gene plays a critical role in regulating lysosomal trafficking, which encompasses the synthesis, fusion, and transport of cytoplasmic granules within cells. The LYST gene is located on the long arm of chromosome 1, specifically within the region 1q42-43. To date, approximately 40 distinct mutations within the LYST gene have been identified in individuals with CHS. These mutations span a range of genetic alterations, including nonsense mutations, missense mutations, deletions, and insertions, all disrupting the normal function of the LYST protein and leading to the characteristic cellular and clinical phenotype of Chediak Higashi syndrome. Understanding the genetic basis is the first step in achieving a definitive Chediak Higashi diagnosis.

Epidemiology

Determining the precise prevalence of Chediak Higashi syndrome remains challenging due to its rarity and phenotypic variability. Worldwide, fewer than 500 cases have been documented in medical literature. The difficulty in establishing an accurate prevalence stems from several factors. Firstly, the syndrome’s rarity means that individual cases might be reported multiple times in different publications. Secondly, the spectrum of clinical presentations is broad, ranging from severe, early-onset forms to milder, later-onset variants. This phenotypic heterogeneity contributes to underdiagnosis, as mildly affected individuals may go unrecognized or unreported, further complicating epidemiological assessments for Chediak Higashi diagnosis.

While Chediak Higashi syndrome affects individuals across all racial and ethnic groups, no specific racial predilection has been identified. Similarly, CHS can manifest across all age groups. However, the typical onset of the disease is in infancy or early childhood, generally before the age of five. This early onset emphasizes the importance of considering Chediak Higashi diagnosis in young children presenting with suggestive clinical features.

Pathophysiology

The core pathophysiology of Chediak Higashi syndrome revolves around the disruption of the lysosomal trafficking regulator (LYST) protein, encoded by the LYST or CHS1 gene. Mutations in this gene impair the normal functioning of lysosomes and lysosome-related organelles across various cell types. This disruption affects the storage and secretory functions of lysosomal granules in a wide array of cells, including leukocytes, fibroblasts, platelet dense bodies, neutrophil azurophilic granules, and melanocyte melanosomes. The consequence of this widespread lysosomal dysfunction is the formation of abnormally enlarged vesicles and non-functional lysosomes, a key pathological feature for Chediak Higashi diagnosis.

Microscopic examination of cells reveals the presence of large, fused, azurophilic granules. These giant granules are most prominently observed in granulocytes and monocytes but can also be detected in fibroblasts, Schwann cells, astrocytes, melanocytes, and hematopoietic cells. These abnormal granules arise from aberrant fusion between primary (azurophilic) and secondary (specific) granules within these cells.

The presence of these abnormal granules has profound functional consequences. Lymphocytes containing these large granules exhibit impaired antibody-dependent, cell-mediated cytotoxicity. Neutrophils from CHS patients display several functional defects, including neutropenia, impaired chemotaxis, and delayed phagolysosomal fusion. These neutrophil abnormalities collectively lead to compromised bactericidal activity, increasing susceptibility to infections. Furthermore, natural killer (NK) cell function is also reduced in CHS. Platelets in CHS patients are deficient in serotonin and adenosine phosphate-containing granules, resulting in impaired platelet aggregation and prolonged bleeding times. The identification of these characteristic granulocyte abnormalities in peripheral blood or bone marrow is a cornerstone of Chediak Higashi diagnosis.

History and Physical Examination

Clinical presentation of Chediak Higashi syndrome typically occurs early in life, with patients exhibiting a constellation of symptoms including recurrent infections, partial oculocutaneous albinism, and coagulation defects. The severity of the disease presentation is often correlated with the underlying molecular phenotype. Generally, mutations that result in a complete loss of LYST protein function tend to be associated with a severe, childhood-onset form of the disease. Conversely, missense mutations, which may result in partially functional protein, are often linked to milder, adolescent or adult-onset disease. However, it’s important to note that exceptions to this genotype-phenotype correlation have been reported, highlighting the complexity of Chediak Higashi diagnosis.

Beyond molecular phenotype, the cellular phenotype, specifically the degree of intracellular granule enlargement across different cell types, also contributes to disease severity. Studies examining melanocytes and fibroblasts from patients with varying clinical phenotypes have demonstrated a range of intracellular granule sizes, suggesting that cellular phenotype also plays a role in determining clinical manifestations of CHS and influencing the diagnostic approach for Chediak Higashi diagnosis.

Clinical Manifestations:

(a) Partial Oculocutaneous Albinism: This is a hallmark feature of CHS, although the degree of pigment dilution can vary significantly. It can manifest as reduced pigmentation in the skin, hair, and eyes, but can range from subtle to nearly absent. A characteristic feature often described in classic CHS is a metallic or “silvery” sheen to the hair.

Microscopic examination of hair shafts can reveal clumping of pigment within the hair, a helpful diagnostic clue. In the eyes, reduced iris pigmentation and retinal pigment dilution can occur. Visual acuity can be variably affected, ranging from normal vision to moderate visual impairment. Other ophthalmologic findings include photophobia (light sensitivity), an exaggerated red reflex, and nystagmus, which can be horizontal or rotary. The presence and characteristics of albinism are important factors considered during Chediak Higashi diagnosis.

(b) Immunodeficiency: A significant clinical concern in CHS is immunodeficiency, leading to recurrent and often severe infections, typically beginning in infancy. Patients are particularly susceptible to bacterial and fungal infections. Common causative pathogens include staphylococcal, streptococcal, pneumococcal, and beta-hemolytic bacterial species. Skin infections and upper respiratory tract infections are among the most frequent types of infections observed. Recently, periodontitis (severe gum disease) has been recognized as a significant indicator of underlying immune dysfunction in CHS and can be a valuable clinical clue prompting consideration of Chediak Higashi diagnosis.

It is important to note that atypical CHS variants may not present with the typical pattern of severe or unusual infections, making diagnosis more challenging in these cases.

(c) Bleeding Tendency: Bleeding symptoms in CHS are generally mild. Common manifestations include epistaxis (nosebleeds), mucosal bleeding (e.g., gum bleeding), and easy bruising. These bleeding symptoms are usually subtle and often do not require specific medical intervention, but are part of the overall clinical picture in Chediak Higashi diagnosis.

(d) Accelerated Phase: The accelerated phase is a severe complication occurring in approximately 85% of individuals with CHS and can arise at any age. It carries a poor prognosis and is a major cause of mortality in CHS. The accelerated phase is characterized by a constellation of systemic symptoms including fever, hepatosplenomegaly (enlarged liver and spleen), lymphadenopathy (enlarged lymph nodes), neutropenia, anemia, and sometimes thrombocytopenia (low platelet count). Histologically, there is diffuse lymphohistiocytic infiltration of various organs, including the liver, spleen, bone marrow, lymph nodes, and the central nervous system.

Initially, the accelerated phase was misdiagnosed as a malignancy like lymphoma, but it is now recognized as hemophagocytic lymphohistiocytosis (HLH), a condition characterized by excessive immune activation and multi-organ inflammation. HLH in CHS is driven by inappropriate stimulation of macrophages in the bone marrow and lymphoid organs, leading to phagocytosis of blood cells and excessive production of pro-inflammatory cytokines. The precise triggers for the accelerated phase remain unclear, but infections, particularly Epstein-Barr virus (EBV), are suspected to play a role in hastening its development, although this is not definitively proven. The absence of functional natural killer (NK) cells is also believed to contribute to the development of the accelerated phase. Due to its severity and high mortality, prompt recognition and management of the accelerated phase are critical aspects of Chediak Higashi diagnosis and patient care. Approximately 90% of patients who develop the accelerated phase die within the first 10 years of life.

(e) Neurologic Manifestations: Neurological features in CHS can emerge even in early adulthood, despite successful hematopoietic stem cell transplantation that corrects the hematologic and immunologic defects. These neurological changes reflect the progressive neurodegenerative nature of CHS. Neurological manifestations can include stroke, coma, ataxia (loss of coordination), tremor, motor and sensory neuropathies, and absent deep tendon reflexes. The presence and progression of neurological symptoms are important considerations in the long-term management and prognosis following Chediak Higashi diagnosis.

(f) Atypical Phenotype: A subset of individuals with CHS exhibits atypical or milder phenotypes, which may lead to underdiagnosis. Features of atypical CHS can include:

• Subtle or absent oculocutaneous albinism.
• Decreased platelet-dense bodies with mild bleeding symptoms.
• Severe infections in childhood that become less frequent with age, or infections that are generally less significant.
• Progressive neurological symptoms such as intellectual disabilities, tremors, gait disturbances, and parkinsonism.

Neurological manifestations in atypical CHS are often inconsistent and nonspecific. Neurodegeneration may be the predominant symptom, with only subtle or minimal alterations in pigmentation, immune function, and bleeding abnormalities. Crucially, even in atypical cases, abnormal granules within leukocytes are consistently present, making leukocyte examination a valuable tool for Chediak Higashi diagnosis across the phenotypic spectrum.

Evaluation for Chediak Higashi Diagnosis

Clinically, Chediak Higashi diagnosis should be considered in individuals presenting with a combination of the following features: immunodeficiency, pigment dilution of the skin, hair, or eyes, congenital or transient neutropenia, and unexplained neurological symptoms or neurodegeneration.

Diagnostic Testing:

The definitive Chediak Higashi diagnosis relies on identifying the characteristic abnormally large granules within cells. Microscopic examination can reveal these giant granules in various cell types, including melanocytes, leukocytes and their bone marrow precursors, fibroblasts, central and peripheral nervous tissue, and hair. Peripheral blood smear examination is a readily accessible and valuable initial diagnostic test.

Molecular genetic testing is available to detect biallelic pathogenic variants in the LYST gene. Genetic confirmation through LYST gene sequencing provides a definitive Chediak Higashi diagnosis and is particularly useful in atypical cases or for carrier testing and prenatal diagnosis.

Once Chediak Higashi diagnosis is confirmed, further evaluations are necessary to assess the extent and complications of the disease:

(a) Assessment for Accelerated Phase:

• Splenomegaly (enlarged spleen)
• History of recurrent or unexplained fever
• Cytopenia affecting at least two cell lines (e.g., anemia, leukopenia, thrombocytopenia)
• Increased serum ferritin concentration (a marker of inflammation and iron overload)
• Increased levels of soluble interleukin-2 receptor (sIL-2R) (a marker of immune activation)
• Signs of hemophagocytosis in bone marrow or cerebrospinal fluid (CSF)
• Evidence of liver dysfunction (hypertriglyceridemia or hypofibrinogenemia)

(b) Comprehensive Neurological Examination: A thorough neurological evaluation is essential to characterize the presence and extent of neurological involvement.

(c) Screening for Lymphoma: Due to the clinical similarities between the accelerated phase of CHS and lymphoma, particularly hemophagocytic lymphohistiocytosis, screening for lymphoma may be considered in the differential diagnosis and initial evaluation.

(d) Genetic Consultation: Genetic counseling is recommended for patients and families following Chediak Higashi diagnosis to discuss inheritance patterns, recurrence risks, carrier testing, and prenatal diagnosis options.

Treatment and Management

Treatment of Clinical Symptoms:

(a) Hematological and Immunological Deficiency:

• Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative therapy for the hematological and immunological defects in Chediak Higashi syndrome. Therefore, HSCT should be pursued as early as possible after Chediak Higashi diagnosis is established, ideally before the development of the accelerated phase.
• HSCT outcomes are significantly more favorable when performed prior to the onset of the accelerated phase. Thus, it is crucial to rule out or achieve remission of the accelerated phase before proceeding with HSCT.
• If signs of the accelerated phase are present, treatment to induce remission of hemophagocytosis is necessary prior to HSCT.
• Treatment guidelines for the accelerated phase in CHS are aligned with those for familial hemophagocytic lymphohistiocytosis and typically involve combination therapy with dexamethasone, cyclosporine A, and etoposide. Approximately 75% of individuals achieve remission within eight weeks of this therapy. However, relapses are not uncommon, and treatment response may decline over time.
• The reported 5-year survival rate following HSCT in CHS is approximately 62%. Success rates are higher in individuals who receive HLA-matched donor transplants. Transplantation performed during the accelerated phase is associated with a higher mortality rate. However, patients who achieve remission of the accelerated phase prior to HSCT have improved outcomes.

(b) Ocular Symptoms:

• Visual acuity can be optimized by correcting refractive errors with eyeglasses or contact lenses.
• Sunglasses are essential to protect light-sensitive eyes from harmful UV radiation and manage photophobia.

(c) Hypopigmentation:

• Individuals with hypopigmentation should use sunscreen diligently to minimize the risk of sun damage and skin cancers. The sun protection factor (SPF) should be adjusted based on the severity of hypopigmentation.

(d) Neurological Manifestations:

• Neurological symptoms in CHS are progressive. Rehabilitation therapy, including physical therapy, occupational therapy, and speech therapy, should be initiated early and continued throughout the disease course to manage neurological deficits and maintain functional abilities.

Prevention of Secondary Complications:

• Minimizing exposure to infectious agents is crucial. Strict hygiene practices, such as frequent handwashing, are essential to prevent infections.
• Nonsteroidal anti-inflammatory drugs (NSAIDs) should be avoided as they can exacerbate bleeding tendencies in CHS.
• Prompt and aggressive antibiotic therapy is necessary to treat bacterial infections.
• The use of prophylactic antibiotics prior to dental or invasive procedures is controversial. However, it may be considered in individuals with significant immunodeficiency and neutropenia.
• Immunizations should be administered according to standard schedules to prevent vaccine-preventable infections.
• Prior to invasive procedures, intravenous desmopressin may be administered 30 minutes beforehand to help control bleeding. Platelet transfusions may be necessary in cases of significant trauma or extensive bleeding.

Monitoring:

(a) Classical Chediak Higashi:

• Specific surveillance guidelines for classical CHS are not established.
• The current standard of care is to proceed with evaluation for HSCT as soon as possible following Chediak Higashi diagnosis.
• Regular ophthalmologic examinations are necessary to monitor for ocular complications.

(b) Atypical or Adult-Onset Chediak Higashi:

Annual screening is recommended for individuals with atypical or adult-onset CHS and should include:

• Abdominal ultrasound to detect hepatosplenomegaly.
• Complete blood count (CBC) to monitor for cytopenias.
• Liver function tests to assess for liver disease, including hypofibrinogenemia and hypertriglyceridemia.
• Serum ferritin levels to monitor for inflammation and iron overload.
• Soluble interleukin-2 receptor (sIL-2R) levels to monitor immune activation.
• Bone marrow biopsy or lumbar puncture if there is suspicion of CNS involvement or accelerated phase.
• Ophthalmologic examination.

Management in Pregnancy:

Limited data exists regarding pregnancy in individuals with Chediak Higashi syndrome. However, available reports suggest that CHS does not typically impact pregnancy or labor, and the course of the disease does not appear to be significantly altered in pregnant mothers with CHS.

Differential Diagnosis

The differential diagnosis of Chediak Higashi syndrome includes other genetic conditions characterized by oculocutaneous albinism.

Hermansky-Pudlak Syndrome and Griscelli Syndrome:

• Griscelli syndrome is another rare genetic disorder that shares features with Chediak Higashi syndrome, including partial oculocutaneous albinism, pancytopenia, hemophagocytosis, and combined humoral and cell-mediated immunodeficiency.
• Hermansky-Pudlak syndrome is characterized by oculocutaneous albinism, bleeding disorders, and the accumulation of ceroid lipofuscin in various organs.
• A key differentiating factor is that both Hermansky-Pudlak syndrome and Griscelli syndrome lack the characteristic abnormal giant granules in neutrophils that are pathognomonic for Chediak Higashi syndrome. Therefore, peripheral blood smear examination is crucial in differentiating these conditions from CHS in the diagnostic process.

Pseudo-Chediak-Higashi Anomaly:

Giant granules resembling those seen in Chediak Higashi syndrome can also be observed in acute and chronic myeloid leukemia. This phenomenon is referred to as the Pseudo-Chediak-Higashi anomaly. Clinical context and bone marrow examination are essential to differentiate this acquired anomaly from true Chediak Higashi syndrome.

Other Conditions to Consider:

• Cross syndrome, characterized by hypopigmentation, central nervous system involvement (developmental delay), and ocular defects.
• Endosomal adaptor p14 deficiency, a syndrome identified in 2007, which includes short stature, partial albinism, congenital neutropenia, and lymphoid deficiency. While neutrophils in this condition may show azurophilic granules and abnormal microbicidal phagosome function, the inclusions are typically microgranules, in contrast to the giant inclusions characteristic of Chediak Higashi syndrome.
• Familial hemophagocytic lymphohistiocytosis (FHL) is an autosomal recessive disorder caused by mutations in one of five FHL genes (FHL1–FHL5), leading to five disease subtypes. Symptoms of FHL include prolonged fever, hepatosplenomegaly, neurological abnormalities (ataxia, coma, hemiplegia, convulsions, increased intracranial pressure). Onset can be in infancy, childhood, or adulthood. While HLH is a feature of the accelerated phase of CHS, FHL is a distinct primary immunodeficiency disorder and should be considered in the differential diagnosis, especially in cases presenting with HLH-like symptoms without the classic features of CHS.

Prognosis

The prognosis for Chediak Higashi syndrome is generally poor, particularly for individuals with the classic, severe form of the disease. The most common causes of mortality are recurrent infections and the development of the accelerated phase with lymphoproliferation into major organs. Sadly, approximately 80% of individuals with CHS die within the first decade of life. Those who survive into adulthood often develop progressive neurological symptoms, impacting their quality of life. Early Chediak Higashi diagnosis and timely HSCT offer the best chance for improved survival and quality of life, although neurological progression may still occur.

Deterrence and Patient Education

Genetic Counseling:

Chediak Higashi syndrome is an autosomal recessive genetic disorder. Therefore, parents of affected individuals are obligate heterozygotes (carriers) for the disease, meaning they carry one copy of the mutated LYST gene and one normal copy. Molecular genetic testing can be performed to confirm carrier status in parents and at-risk relatives.

For parents who are both carriers of a LYST gene mutation, each subsequent pregnancy carries a:

• 25% chance of having a child with Chediak Higashi syndrome.
• 50% chance of having a child who is a carrier of the LYST gene mutation (like the parents).
• 25% chance of having a child who is neither affected nor a carrier.

This recurrence risk information is crucial for genetic counseling provided to families following Chediak Higashi diagnosis in a child.

Evaluation of At-Risk Relatives:

Early evaluation of siblings of affected individuals is essential, as timely Chediak Higashi diagnosis in presymptomatic siblings allows for consideration of HSCT before the development of severe complications like the accelerated phase.

• Molecular genetic testing can be used to determine the genetic status of siblings if the specific pathogenic LYST gene variants in the family are known.
• If the specific variants are unknown, or if genetic testing is not immediately available, examination of peripheral blood smears to detect the characteristic leukocyte inclusions can be performed as an initial screening test for at-risk siblings.

Ideally, genetic risk assessment and carrier status determination should be performed before pregnancy. Genetic counseling, including a thorough discussion of risks and reproductive options, should be offered to adults who are known carriers, are at risk of being carriers, or are already affected with CHS. Preimplantation genetic diagnosis (PGD) is an option for couples who are both carriers and are undergoing in vitro fertilization (IVF), allowing for the selection of embryos unaffected by CHS for implantation.

DNA banking should be offered to affected individuals. DNA extracted from blood samples (typically white blood cells) can be stored for potential future use, as advances in genetic testing and gene therapy may offer new diagnostic or therapeutic options in the future.

Enhancing Healthcare Team Outcomes

Chediak Higashi syndrome is a complex and life-threatening rare genetic disorder. Optimal management necessitates a collaborative, interprofessional healthcare team. This team ideally includes:

• Geneticist: For Chediak Higashi diagnosis confirmation, genetic counseling, and carrier testing.
• Neurologist: To manage neurological manifestations.
• Ophthalmologist: To manage ocular complications.
• Infectious Disease Specialist: To manage recurrent infections.
• Hematologist/Oncologist: To manage hematological issues and the accelerated phase, and to coordinate HSCT.
• Laboratory Specialist: For peripheral blood smear examination and specialized laboratory testing to support Chediak Higashi diagnosis.
• Primary Care Physician/Nurse Practitioner: To provide ongoing medical care, monitor for complications, and educate the caregiver.

Effective communication and care coordination among team members are essential to optimize patient outcomes. Patient and caregiver education is paramount. The primary caregiver and nurse practitioner play a crucial role in educating families on strategies to prevent complications, including:

• Emphasizing meticulous hand hygiene to minimize infection risk.
• Avoiding NSAIDs to prevent exacerbation of bleeding.
• Ensuring medication adherence.
• Maintaining up-to-date immunizations.

Despite best efforts, Chediak Higashi syndrome remains a challenging condition with a high mortality rate. Unfortunately, there is currently no definitive cure beyond HSCT for the hematologic and immunologic components, and neurological progression remains a significant long-term concern. More than 80% of patients still succumb to the disease in the first decade of life. Survivors often face significant long-term health challenges and reduced quality of life. Continued research efforts are crucial to develop more effective therapies and improve the prognosis for individuals affected by Chediak Higashi syndrome.

References

1.Justiz Vaillant AA, Stang CM. StatPearls [Internet]. StatPearls Publishing; Treasure Island (FL): Aug 14, 2023. Lymphoproliferative Disorders. PubMed: 30725847
2.Kiyoi T, Liu S, Sahid MNA, Shudou M, Ogasawara M, Mogi M, Maeyama K. Morphological and functional analysis of beige (Chèdiak-Higashi syndrome) mouse mast cells with giant granules. Int Immunopharmacol. 2019 Apr;69:202-212. PubMed: 30738290
3.Zhang Y, Gao ZY, Yu XJ, Lu DP. [Umbilical cord blood transplantation in the treatment of Chediak-Higashi syndrome with hemophagocytic syndrome: a case report and literature review]. Zhonghua Xue Ye Xue Za Zhi. 2017 Nov 14;38(11):986-988. PMC free article: PMC7342796 PubMed: 29224327
4.Bowman SL, Bi-Karchin J, Le L, Marks MS. The road to lysosome-related organelles: Insights from Hermansky-Pudlak syndrome and other rare diseases. Traffic. 2019 Jun;20(6):404-435. PMC free article: PMC6541516 PubMed: 30945407
5.Toro C, Morimoto M, Malicdan MC, Adams DR, Introne WJ. Chediak-Higashi Syndrome. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews® [Internet]. University of Washington, Seattle; Seattle (WA): Mar 3, 2009. PubMed: 20301751
6.Maaloul I, Talmoudi J, Chabchoub I, Ayadi L, Kamoun TH, Boudawara T, Kallel CH, Hachicha M. Chediak-Higashi syndrome presenting in accelerated phase: A case report and literature review. Hematol Oncol Stem Cell Ther. 2016 Jun;9(2):71-5. PubMed: 26254864
7.Pluthero FG, Di Paola J, Carcao MD, Kahr WHA. NBEAL2 mutations and bleeding in patients with gray platelet syndrome. Platelets. 2018 Sep;29(6):632-635. PubMed: 29869935
8.Donmez FY, Agildere AM. Recurrent childhood PRES. Neurol Sci. 2015 Sep;36(9):1603-9. PubMed: 25894844
9.Wu XL, Zhao XQ, Zhang BX, Xuan F, Guo HM, Ma FT. A novel frameshift mutation of Chediak-Higashi syndrome and treatment in the accelerated phase. Braz J Med Biol Res. 2017 Mar 23;50(4):e5727. PMC free article: PMC5423745 PubMed: 28355352
10.Penn EB, Goudy SL. Pediatric inflammatory adenopathy. Otolaryngol Clin North Am. 2015 Feb;48(1):137-51. PubMed: 25439552
11.Nagai K, Ochi F, Terui K, Maeda M, Ohga S, Kanegane H, Kitoh T, Kogawa K, Suzuki N, Ohta S, Ishida Y, Okamura T, Wakiguchi H, Yasukawa M, Ishii E. Clinical characteristics and outcomes of chédiak-Higashi syndrome: a nationwide survey of Japan. Pediatr Blood Cancer. 2013 Oct;60(10):1582-6. PubMed: 23804531