Successful use of emapalumab in refractory hemophagocytic lymphohistiocytosis in a child with Chédiak-Higashi syndrome: a case report.

BACKGROUND: Hemophagocytic lymphohistiocytosis is a life-threatening disease heralded by fever, cytopenia, hepatosplenomegaly, and multisystem organ failure. Its association with genetic mutations, infections, autoimmune disorders, and malignancies is widely reported. CASE PRESENTATION: A 3-year-old male Arab Saudi patient with insignificant past medical history and parental consanguinity presented with abdominal distension of moderate severity and persistent fever despite receiving antibiotics. This was accompanied by hepatosplenomegaly and silvery hair. The clinical and biochemical profiles were suggestive of Chédiak-Higashi syndrome with hemophagocytic lymphohistiocytosis. The patient received the hemophagocytic lymphohistiocytosis-2004 chemotherapy protocol and had multiple hospital admissions mainly due to infections and febrile neutropenia. After achieving the initial remission, the patient's disease reactivated and did not respond to reinduction with the hemophagocytic lymphohistiocytosis-2004 protocol. Due to the disease reactivation and intolerance of conventional therapy, the patient commenced emapalumab. The patient was successfully salvaged and underwent an uneventful hematopoietic stem cell transplantation. CONCLUSIONS: Novel agents such as emapalumab can be helpful for the management of refractory, recurrent, or progressive disease, while avoiding the toxicities of conventional therapy. Due to a paucity of available data on emapalumab, additional data are needed to establish its role in hemophagocytic lymphohistiocytosis treatment.

Chediak Higashi Syndrome with Hemophagocytic Lymphohistiocytosis.

INTRODUCTION: Chediak-Higashi syndrome (CHS) is caused by dysfunction of lysosomal trafficking and presents with hypopigmentation, bleeding tendencies, neurological symptoms, and NK cell dysfunction. Hemophagocytic lymphohistiocytosis (HLH) can complicate CHS due to the abnormal function of NK cells. CASE PRESENTATION: This 1.5-year-old light-skinned gray-haired girl microscopically had abnormal hair pigment clumps and lilac inclusions in the myeloid series, characteristic of CHS. She presented with HLH, requiring treatment with etoposide and dexamethasone followed by cyclosporine and dexamethasone. CONCLUSION: CHS is one of the underlying primary causes of HLH.

Understanding neutropenia secondary to intrinsic or iatrogenic immune dysregulation.

As a key member of the innate and adaptive immune response, neutrophils provide insights into the hematopoietic and inflammatory manifestations of inborn errors of immunity (IEI) and the consequences of immunotherapy. The facile recognition of IEI presenting with neutropenia provides an avenue for hematologists to facilitate early diagnosis and expedite biologically rationale care. Moreover, enhancing the understanding of the molecular mechanisms driving neutropenia in IEI-decreased bone marrow reserves, diminished egress from the bone marrow, and decreased survival-offers an opportunity to further dissect the pathophysiology driving neutropenia secondary to iatrogenic immune dysregulation, eg, immune checkpoint inhibitors and chimeric antigen receptor T-cell therapy.

Chediak-Higashi syndrome: neurocognitive and behavioral data from infancy to adulthood after bone marrow transplantation.

Chediak-Higashi syndrome (CHS) is a rare autosomal disorder characterized by immunodeficiency, albinism, and progressive neurologic abnormalities. While survivors of the childhood-onset disease are known to exhibit learning disabilities and neuropsychiatric disorders followed by middle-age dementia, we lack detailed data on the progression. We present the case of a young adult with records from infancy to the first signs of deterioration. An early neuropsychological and neuropsychiatric profiling is crucial to intervention selection as children with CHS may not benefit from regular special education. Our patient never showed neuropsychiatric symptoms but high levels of socioemotional adaptability.

Hemophagocytic Lymphohistiocytosis in Patients With Primary Immunodeficiency.

Hemophagocytic lymphohistiocytosis (HLH) is characterized by uncontrolled and excessive immune responses with high mortality. We aimed to define mortality-related parameters in HLH secondary to primary immunodeficiency (PID). A total of 28 patients with HLH between the years 2013 and 2017 were enrolled in the study. The patients were evaluated in 2 groups including PID with hypopigmentation (n=7) (Chédiak-Higashi syndrome [CHS] and Griscelli syndrome type 2 [GS2]) and other PIDs (n=21). The median age of the study population was 23 (4.3 to 117.0) months at the time of the diagnosis of HLH. Central nervous system involvement was recorded in 7 (GS2/CHS patients [n=4], other PIDs [n=3], P=0.026), and death was observed in 9 patients (GS2/CHS patients [n=1], other PIDs [n=8], P=0.371). Five patients (3 GS2/CHS and 2 other PID patients) underwent hematopoietic stem cell transplantation. Low serum albumin level was the only variable associated with the mortality and albumin levels less than the cut-off value of 3.07 g/dL increased mortality 5.8 times in patients with HLH secondary to PID. We presented a single-center experience consisting of patients with HLH secondary to PID with a mortality rate of 32.1%. Hypoalbuminemia was the only risk factor to increase the overall mortality rate of HLH.

Association of Anti N-methyl-D-aspartate (NMDA) Receptor Encephalitis with Chediak-Higashi Syndrome.

BACKGROUND: Neurological manifestations of Chediak-Higashi syndrome mainly include peripheral neuropathy, ataxia, tremors, cranial nerve palsies, intellectual decline and seizures. CASE CHARACTERISTICS: A 2 years 10 month old girl with silvery hair syndrome presented with sub-acute onset behavioral issues, ataxia and multiple type abnormal movements. Cerebrospinal fluid examination was positive for Anti NMDA receptor antibodies. Hair shaft examination and peripheral blood film findings were suggestive of Chediak Higashi syndrome. MESSAGE: Anti NMDA receptor encephalitis may be associated with Chediak Higashi Syndrome.

Mouse models and strain-dependency of Chédiak-Higashi syndrome-associated neurologic dysfunction.

Chédiak-Higashi syndrome (CHS) is a lethal disorder caused by mutations in the LYST gene that involves progressive neurologic dysfunction. Lyst-mutant mice exhibit neurologic phenotypes that are sensitive to genetic background. On the DBA/2J-, but not on the C57BL/6J-background, Lyst-mutant mice exhibit overt tremor phenotypes associated with loss of cerebellar Purkinje cells. Here, we tested whether assays for ataxia could measure this observed strain-dependency, and if so, establish parameters for empowering phenotype- and candidate-driven approaches to identify genetic modifier(s). A composite phenotypic scoring system distinguished phenotypes in Lyst-mutants and uncovered a previously unrecognized background difference between wild-type C57BL/6J and DBA/2J mice. Accelerating rotarod performance also distinguished phenotypes in Lyst-mutants, but at more advanced ages. These results establish that genetic background, Lyst genotype, and age significantly influence the severity of CHS-associated neurologic deficits. Purkinje cell quantifications likewise distinguished phenotypes of Lyst-mutant mice, as well as background differences between wild-type C57BL/6J and DBA/2J mice. To aid identification of potential genetic modifier genes causing these effects, we searched public datasets for cerebellar-expressed genes that are differentially expressed and/or contain potentially detrimental genetic variants. From these approaches, Nos1, Prdx2, Cbln3, Gnb1, Pttg1 were confirmed to be differentially expressed and leading candidates.

Acute Transient Sixth Nerve Palsy in Chediak-Higashi Syndrome.

Neurologic disorders in Chediak-Higashi syndrome are usually late presentations and also may manifest long after bone marrow stem cell transplantation. To the authors' knowledge, transient neurological deficit has not been reported yet. They describe a 6-year-old boy with Chediak-Higashi syndrome in the accelerated phase who presented with transient sixth nerve palsy. [J Pediatr Ophthalmol Strabismus. 2018;55:e22-e25].

Inflammatory demyelinating neuropathy heralding accelerated chediak-higashi syndrome.

INTRODUCTION: Chediak-Higashi syndrome (CHS) is a very rare autosomal recessive disorder (gene CHS1/LYST) characterized by partial albinism, recurrent infections, and easy bruising. Survivors develop a constellation of slowly progressive neurological manifestations. METHODS: We describe clinical, laboratory, electrophysiological, and genetic findings of a patient who developed an immune-mediated demyelinating neuropathy as the main clinical feature of CHS. RESULTS: The patient presented with subacute flaccid paraparesis, absent reflexes, and reduced vibration sense. Protein and immunoglobulins (Igs) were elevated in the cerebrospinal fluid. Electrodiagnostic tests indicated an acquired chronic demyelinating polyneuropathy. Intravenous Ig and immunosuppressant treatment resulted in neurological improvement. The patient later developed organomegaly and pancytopenia. Bone-marrow smear revealed giant azurophilic granules pathognomonic for CHS. Two novel mutations in the LYST gene were identified through whole exome sequencing [c.7786C>T and c.9106 + 1G>T]. CONCLUSIONS: This case expands the clinical phenotype of CHS and highlights inflammatory demyelinating neuropathy as a manifestation of the disease. Muscle Nerve 55: 756-760, 2017.

Neurologic involvement in patients with atypical Chediak-Higashi disease.

OBJECTIVE: To delineate the developmental and progressive neurodegenerative features in 9 young adults with the atypical form of Chediak-Higashi disease (CHD) enrolled in a natural history study. METHODS: Patients with atypical clinical features, but diagnostically confirmed CHD by standard evaluation of blood smears and molecular genotyping, underwent complete neurologic evaluation, MRI of the brain, electrophysiologic examination, and neuropsychological testing. Fibroblasts were collected to investigate the cellular phenotype and correlation with the clinical presentation. RESULTS: In 9 mildly affected patients with CHD, we documented learning and behavioral difficulties along with developmental structural abnormalities of the cerebellum and posterior fossa, which are apparent early in childhood. A range of progressive neurologic problems emerge in early adulthood, including cerebellar deficits, polyneuropathies, spasticity, cognitive decline, and parkinsonism. CONCLUSIONS: Patients with undiagnosed atypical CHD manifesting some of these wide-ranging yet nonspecific neurologic complaints may reside in general and specialty neurology clinics. The absence of the typical bleeding or infectious diathesis in mildly affected patients with CHD renders them difficult to diagnose. Identification of these individuals is important not only for close surveillance of potential CHD-related systemic complications but also for a full understanding of the natural history of CHD and the potential role of the disease-causing protein, LYST, to the pathophysiology of other neurodevelopmental and neurodegenerative disorders.

Optic neuropathy in late-onset neurodegenerative Chédiak-Higashi syndrome.

BACKGROUND: The classic form of Chédiak-Higashi syndrome (CHS), an autosomal recessive disorder of lysosomal trafficking with childhood onset caused by mutations in ITALIC! LYST, is typified ophthalmologically by ocular albinism with vision loss attributed to foveal hypoplasia or nystagmus. Optic nerve involvement and ophthalmological manifestations of the late-onset neurodegenerative form of CHS are rarely reported and poorly detailed. METHODS: Case series detailing ophthalmological and neurological findings in three adult siblings with the late-onset form of CHS. RESULTS: All three affected siblings lacked features of ocular albinism and demonstrated significant optic nerve involvement as evidenced by loss of colour and contrast vision, central visual field loss, optic nerve pallor, retinal nerve fibre layer thinning by optical coherence tomography (OCT) and abnormal visual evoked potential, with severity corresponding linearly to age of the sibling and severity of neurological disease. Further, unusual prominence of a 'third line' on macular OCT that may be due to abnormal melanosomes was seen in all three siblings and in their father. Neurological involvement included parkinsonism, cerebellar ataxia and spastic paraparesis. CONCLUSIONS: This report expands the ophthalmological phenotype of the late-onset neurodegenerative form of CHS to include optic neuropathy with progressive vision loss, even in the absence of ocular albinism, and abnormal prominence of the interdigitation zone between cone outer segment tips and apical processes of retinal pigment epithelium cells on macular OCT.

Chediak-Higashi syndrome presenting in accelerated phase: A case report and literature review.

Chediak-Higashi syndrome (CHS) is a rare autosomal recessive lysosomal disorder characterized by frequent infections, oculocutaneous albinism, bleeding diathesis, and progressive neurologic deterioration. In 85% of cases, CHS patients develop the accelerated phase characterized by pancytopenia, high fever, and lymphohistiocytic infiltration of liver, spleen, and lymph nodes. Treatment of accelerated-phase CHS is difficult and the prognosis is poor. Here, we report a case of CHS in a 2-year-old boy who presented in the accelerated phase of the disease. CHS diagnosis was made on the basis of clinical characteristics, hair analysis, and identification of pathognomonic giant azurophilic granules in peripheral blood and bone marrow.

A severe systemic presentation of pigmented villonodular synovitis in a child with underlying Chediak-Higashi syndrome.

Pigmented villonodular synovitis (PVNS), a condition of synovial hyperproliferation that mostly affects large joints, is rare in children and conventionally lacks systemic symptoms. This report describes a complex paediatric patient who underwent bone marrow transplantation to control the accelerated phase of the Chediak-Higashi syndrome. Diffuse PVNS developed in one knee 2.75 years later. Progression of PVNS was accompanied by the development of severe systemic symptoms, which resolved rapidly following subtotal surgical debridement. The patient remains well with minimal elevation of inflammatory marker levels 10.5 years later. As PVNS and Chediak-Higashi syndrome are both very rare diseases we propose a potential unifying hypothesis for this combination.

Infantile hemophagocytic lymphohistiocytosis in a case of chediak-higashi syndrome caused by a mutation in the LYST/CHS1 gene presenting with delayed umbilical cord detachment and diarrhea.

A 2-month-old female infant, born to consanguineous parents, presented with infections in skin and upper respiratory tract. She was notable for delayed umbilical cord detachment, partial albinism, and neurological irritability. Giant granules were present in white blood cells. The intracellular perforin content in CD8 T cells seems to correlate to the immune activation state of the patient with 82% and 8% perforin-containing CD8 T cells at active and nonactive hemophagocytic lymphohistiocytosis (HLH) disease, respectively. HLH was confirmed by hemophagocytosis in bone marrow and absent natural killer cell activity. The patient carried a homozygous G>A mutation in the 3' splice site of intron 24 of the LYST/CHS1 gene, leading to the use of an alternative YAG splice site located in exon 25, introducing a premature STOP codon (L2355fsX2370; NP_000072.2). The early-onset accelerated phase in this severe phenotype of Chediak-Higashi syndrome was probably induced by rotaviral infection. Interestingly, the intracellular perforin content in CD8 T cells seems to correlate to the immune activation state of the patient. Late separation of the umbilical cord in concordance with clinical symptoms should lead to evaluation of a possible neutrophil dysfunction including Chediak-Higashi syndrome before onset of HLH.

Motor neuronopathy in Chediak-Higashi syndrome.

Chediak-Higashi syndrome is a rare autosomal recessive disease characterized by partial oculocutaneous albinism, recurrent pyogenic infections and the presence of giant granules in many cells such as leucocytes (hallmark of the disease). Neurological symptoms are rare. We describe two sisters who presented the same phenotype of slowly progressive motor neuronopathy (with Babinski sign in one patient); biopsy of the sural nerve showed an abnormal endoneurial accumulation of lipofuscin granules. We discuss these two observations and compare them with the few case reports of neuropathy in Chediak-Higashi syndrome.

Chediak-Higashi syndrome in accelerated phase masquerading as severe acute malnutrition.

A toddler presented with poor appetite, weight loss and frequent respiratory tract infections for the past 6 months, fever and increasing paleness for the past 2 months and bilateral pedal oedema for the past 1 month. Anthropometry confirmed severe acute malnutrition. Clinical and laboratory evaluation revealed that the child also had hypopigmented hair and skin, splenohepatomegaly, pancytopenia and hypoalbuminaemia. The coexistence of hypopigmentation and suspected low immunity prompted us to investigate the child's hair, peripheral blood smear and bone marrow. Hair under light microscopy showed evenly distributed, large melanin granules, suggestive of Chediak-Higashi syndrome (CHS). Peripheral blood smear and bone marrow aspirate examinations revealed abnormal large intracytoplasmic granules, which was diagnostic of CHS. The child's investigations revealed coexistent hemophagocytic lymphohistiocytosis, confirming the diagnosis of CHS in 'accelerated phase', which is fatal if not treated. The parents prematurely took the child home against medical advice, before definitive therapy could be instituted.

Autosomal-recessive complicated spastic paraplegia with a novel lysosomal trafficking regulator gene mutation.

BACKGROUND: Autosomal-recessive hereditary spastic paraplegias (AR-HSP) consist of a genetically diverse group of neurodegenerative diseases characterised by pyramidal tracts dysfunction. The causative genes for many types of AR-HSP remain elusive. We tried to identify the gene mutation for AR-HSP with cerebellar ataxia and neuropathy. METHODS: This study included two patients in a Japanese family with their parents who are first cousins. Neurological examination and gene analysis were conducted in the two patients and two normal family members. We undertook genome-wide linkage analysis employing single nucleotide polymorphism arrays using the two patients' DNAs and exome sequencing using one patient's sample. RESULTS: We detected a homozygous missense mutation (c.4189T>G, p.F1397V) in the lysosomal trafficking regulator (LYST) gene, which is described as the causative gene for Chédiak-Higashi syndrome (CHS). CHS is a rare autosomal-recessive syndrome characterised by hypopigmentation, severe immune deficiency, a bleeding tendency and progressive neurological dysfunction. This mutation was co-segregated with the disease in the family and was located at well-conserved amino acid. This LYST mutation was not found in 200 Japanese control DNAs. Microscopic observation of peripheral blood in the two patients disclosed large peroxidase-positive granules in both patients' granulocytes, although they had no symptoms of immune deficiency or bleeding tendency. CONCLUSIONS: We diagnosed these patients as having adult CHS presenting spastic paraplegia with cerebellar ataxia and neuropathy. The clinical spectrum of CHS is broader than previously recognised. Adult CHS must be considered in the differential diagnosis of AR-HSP.

Hemophagocyctic lymphohistiocytosis developed in a Japanese boy with Chédiak-Higashi syndrome.

Chédiak-Higashi syndrome (CHS) is one of the primary immunodeficiency syndromes accompanied by oculocutaneous albinism. It is characterized by existence of giant granule of neutrophils, and development of symptoms of hemophagocytic lymphohistiocytosis. CHS is a rare disorder and recognition of the disease is indispensable for its diagnosis. In our case, a four-month-old boy, virus-associated hemophagocytic syndrome (VAHS) was suspected from generation of fever, hepatosplenomegaly, and existence of atypical lymphocytes on admission. However, elevation of serum AST, LDH and ferritin were quite slight as VAHS, and rapid exacerbation of the findings was not seen. Associated virus was undetected. He was finally diagnosed as CHS developing hemophagocyctic lymphohistiocytosis based on the existence of a giant granule of neutrophils in the peripheral blood smear and oculocutaneous albisum and laboratory findings. Clinical outcome was successful after receiving HLA-matched unrelated bone marrow transplantation.