Management of Severe Neutropenia in a Child With Chediak-Higashi Syndrome Using Granulocyte-Colony Stimulating Factor (G-CSF): A Case Report.

Chediak-Higashi syndrome (CHS) is a congenital immunodeficiency disorder characterized by recurrent bacterial infections, oculocutaneous albinism, and abnormal intracellular protein transport. The incidence of CHS is rare, with approximately 500 cases reported so far. One of the key immunological features of CHS is neutropenia. The management of CHS includes supportive treatment, chemotherapy, methylprednisolone, IL-2 administration, and hematopoietic stem cell transplantation (HSCT). However, neutropenia can persist even after these treatments. This case report presents the successful management of severe neutropenia in an 8-year-old girl diagnosed with CHS. The patient exhibited classic CHS features, including hypopigmentation and recurrent infections. Initial treatment with antibiotics led to the resolution of the fever, but severe neutropenia persisted. Granulocyte-colony stimulating factor (G-CSF) therapy was initiated, which resulted in a substantial increase in the absolute neutrophil count (ANC) with no adverse effects. Throughout treatment with G-CSF, the patient remained stable. The patient was finally referred to the tertiary care center for consideration of bone marrow transplantation. This case highlights the potential safety and efficacy of G-CSF in managing CHS-associated neutropenia.

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.

LYST deficiency impairs autophagic lysosome reformation in neurons and alters lysosome number and size.

Chediak-Higashi syndrome (CHS) is a rare, autosomal recessive disorder caused by biallelic mutations in the lysosomal trafficking regulator (LYST) gene. Even though enlarged lysosomes and/or lysosome-related organelles (LROs) are the typical cellular hallmarks of CHS, they have not been investigated in human neuronal models. Moreover, how and why the loss of LYST function causes a lysosome phenotype in cells has not been elucidated. We report that the LYST-deficient human neuronal model exhibits lysosome depletion accompanied by hyperelongated tubules extruding from enlarged autolysosomes. These results have also been recapitulated in neurons differentiated from CHS patients' induced pluripotent stem cells (iPSCs), validating our model system. We propose that LYST ensures the correct fission/scission of the autolysosome tubules during autophagic lysosome reformation (ALR), a crucial process to restore the number of free lysosomes after autophagy. We further demonstrate that LYST is recruited to the lysosome membrane, likely to facilitate the fission of autolysosome tubules. Together, our results highlight the key role of LYST in maintaining lysosomal homeostasis following autophagy and suggest that ALR dysregulation is likely associated with the neurodegenerative CHS phenotype.

Oral manifestations of Chediak-Higashi syndrome: A systematic review.

Chediak-Higashi syndrome (CHS) is an autosomal recessive disorder characterized by leukocytes with giant secretory granules and a myriad of clinical features. However, it is unknown whether oral lesions are part of the syndrome or are refractory to systemic treatment. Herein, we integrated the available data published in the literature on the oral manifestations of individuals with CHS. Searches on PubMed, Web of Science, Embase, Scopus, and LILACS were conducted to identify studies published up to March/2022. The Joanna Briggs Institute tool was used for the critical appraisal of studies. Fourteen articles (21 cases) were detected. The mean age of individuals was 15.9±8.8 years. There was a slight predominance of males (52.4%). The major manifestation was periodontal disease (81%), although ulceration of the oral mucosa (14.3%), gingival/labial abscess (4.8%), and periodontal abscess (4.8%) were also reported. Oral rehabilitation including dental implants (9.5%) was performed after tooth losses due to the poor prognosis of periodontal therapy. CHS is usually diagnosed in an early stage due to its systemic manifestations such as classic oculocutaneous albinism, recurrent infections, and a propensity for bleeding. Oral health providers should be aware of the manifestations of individuals with CHS. Special care, including oral prophylaxis, is indispensable.

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.

Investigating Determinants and Evaluating Deep Learning Training Approaches for Visual Acuity in Foveal Hypoplasia.

Purpose: To describe the relationships between foveal structure and visual function in a cohort of individuals with foveal hypoplasia (FH) and to estimate FH grade and visual acuity using a deep learning classifier. Design: Retrospective cohort study and experimental study. Participants: A total of 201 patients with FH were evaluated at the National Eye Institute from 2004 to 2018. Methods: Structural components of foveal OCT scans and corresponding clinical data were analyzed to assess their contributions to visual acuity. To automate FH scoring and visual acuity correlations, we evaluated the following 3 inputs for training a neural network predictor: (1) OCT scans, (2) OCT scans and metadata, and (3) real OCT scans and fake OCT scans created from a generative adversarial network. Main Outcome Measures: The relationships between visual acuity outcomes and determinants, such as foveal morphology, nystagmus, and refractive error. Results: The mean subject age was 24.4 years (range, 1-73 years; standard deviation = 18.25 years) at the time of OCT imaging. The mean best-corrected visual acuity (n = 398 eyes) was equivalent to a logarithm of the minimal angle of resolution (LogMAR) value of 0.75 (Snellen 20/115). Spherical equivalent refractive error (SER) ranged from -20.25 diopters (D) to +13.63 D with a median of +0.50 D. The presence of nystagmus and a high-LogMAR value showed a statistically significant relationship (P < 0.0001). The participants whose SER values were farther from plano demonstrated higher LogMAR values (n = 382 eyes). The proportion of patients with nystagmus increased with a higher FH grade. Variability in SER with grade 4 (range, -20.25 D to +13.00 D) compared with grade 1 (range, -8.88 D to +8.50 D) was statistically significant (P < 0.0001). Our neural network predictors reliably estimated the FH grading and visual acuity (correlation to true value > 0.85 and > 0.70, respectively) for a test cohort of 37 individuals (98 OCT scans). Training the predictor on real OCT scans with metadata and fake OCT scans improved the accuracy over the model trained on real OCT scans alone. Conclusions: Nystagmus and foveal anatomy impact visual outcomes in patients with FH, and computational algorithms reliably estimate FH grading and visual acuity.

iPS cells from Chediak-Higashi syndrome patients recapitulate the giant granules in myeloid cells.

BACKGROUND: Chediak-Higashi syndrome (CHS) is a congenital disease characterized by immunodeficiency, hemophagocytic lymphohistiocytosis, oculocutaneous albinism, and neurological symptoms. The presence of giant granules in peripheral blood leukocytes is an important hallmark of CHS. Here we prepared induced pluripotent stem cells (iPSCs) from CHS patients (CHS-iPSCs) and differentiated them into hematopoietic cells to model the disease phenotypes. METHODS: Fibroblasts were obtained from two CHS patients and then reprogrammed into iPSCs. The iPSCs were differentiated into myeloid cells; the size of the cytosolic granules was quantified by May-Grunwald Giemsa staining and myeloperoxidase staining. RESULTS: Two clones of iPSCs were established from each patient. The differentiation efficiency to CD33+ CD45+ myeloid cells was not significantly different in CHS-iPSCs compared with control iPSCs, but significantly larger granules were observed. CONCLUSIONS: We succeeded in reproducing a characteristic cellular phenotype, giant granules in myeloid cells, using CHS-iPSCs, demonstrating that iPSCs can be used to model the pathogenesis of CHS patients.

Case series on Silvery Hair Syndromes: Single Center Experience.

Background: Silvery Hair Syndromes (SHS), an autosomal recessive inherited disorder, includes Chediak-Higashi syndrome (CHS), Griscelli syndrome (GS), Hermansky-Pudlak syndrome (HPS), and Elejalde syndrome. Associated immunological and neurological defects and predilection for hemophagocytic lymphohistiocytosis (HLH) makes them a distinctive entity in pediatric practice. Thorough clinical examination, bedside investigations such as peripheral blood smear (PBS) and hair microscopy, and bone marrow (BM) examination are inexpensive and reliable diagnostic tools. Methods: We report 12 cases with SHS (CHS, n = 06; GS, n = 04; HPS, n = 02). Results: 8 out of 12 SHS children (CHS-05, GS-03) presented with HLH. Out of 5 cases of CHS with HLH, 2 died, 3rd is stable post-chemotherapy; 4th completed chemotherapy, underwent matched related hematopoietic stem cell transplant (HSCT), and is stable 8 months off treatment. The 5th child completed chemotherapy and is in process of transplant. One CHS child without HLH is thriving without any treatment. Of the 4 GS cases, 3 presented with HLH and received chemotherapy (HLH 2004 protocol). One lost follow-up after initial remission; another had recurrence 7 months off treatment and discontinued further treatment. The third child had recurrence 1.5 years after initial chemotherapy; HLH 2004 protocol was restarted followed by HSCT from matched sibling donor; is currently well, 2.5 years post-transplant. One child with GS had neurological features with no evidence of HLH and did not take treatment. Of 2 children with HPS, one presented with severe sepsis and the other with neurological problems. They were managed symptomatically. Conclusion: In SHS with HLH, chemotherapy followed by allogeneic hematopoietic stem cell transplantation is a promising curative option.

Genetics of non-syndromic and syndromic oculocutaneous albinism in human and mouse.

Oculocutaneous albinism (OCA) is the most frequent presentation of albinism, a heterogeneous rare genetic condition generally associated with variable alterations in pigmentation and with a profound visual impairment. There are non-syndromic and syndromic types of OCA, depending on whether the gene product affected impairs essentially the function of melanosomes or, in addition, that of other lysosome-related organelles (LROs), respectively. Syndromic OCA can be more severe and associated with additional systemic consequences, beyond pigmentation and vision alterations. In addition to OCA, albinism can also be presented without obvious skin and hair pigmentation alterations, in ocular albinism (OA), and a related genetic condition known as foveal hypoplasia, optic nerve decussation defects, and anterior segment dysgenesis (FHONDA). In this review, we will focus only in the genetics of skin pigmentation in OCA, both in human and mouse, updating our current knowledge on this subject.

Case Report: Partial Uniparental Disomy Unmasks a Novel Recessive Mutation in the LYST Gene in a Patient With a Severe Phenotype of Chédiak-Higashi Syndrome.

Chédiak-Higashi syndrome (CHS) is a rare autosomal recessive (AR) immune disorder that has usually been associated to missense, nonsense or indels mutations in the LYST gene. In this study, we describe for the first time the case of a CHS patient carrying a homozygous mutation in the LYST gene inherited as a result of a partial uniparental isodisomy (UPiD) of maternal origin. Sanger sequencing of the LYST cDNA and single nucleotide polymorphism (SNP)-arrays were performed to identify the causative mutation and to explain the molecular mechanism of inheritance, respectively. Partial-UPiD leads to a copy neutral loss of heterozygosity (CN-LOH) of the telomeric region of chromosome 1 (1q41q44), unmasking the potential effect of the mutation detected. The mutation (c.8380dupT) is an insertion located in exon 32 of the LYST gene resulting in a premature stop codon and leading to the loss of all the conserved domains at the C-terminal of the LYST protein. This would account for the severe phenotype observed. We also reviewed the only two previously reported cases of CHS as a result of a uniparental disomy. In this study, we show that the combination of different strategies, including the use of SNP-arrays, is pivotal to fine-tune the diagnosis of rare AR disorders, such as CHS. Moreover, this case highlights the relevance of uniparental disomy as a potential mechanism of CHS expression in non-consanguineous families.

Mauve/LYST limits fusion of lysosome-related organelles and promotes centrosomal recruitment of microtubule nucleating proteins.

Lysosome-related organelles (LROs) are endosomal compartments carrying tissue-specific proteins, which become enlarged in Chediak-Higashi syndrome (CHS) due to mutations in LYST. Here, we show that Drosophila Mauve, a counterpart of LYST, suppresses vesicle fusion events with lipid droplets (LDs) during the formation of yolk granules (YGs), the LROs of the syncytial embryo, and opposes Rab5, which promotes fusion. Mauve localizes on YGs and at spindle poles, and it co-immunoprecipitates with the LDs' component and microtubule-associated protein Minispindles/Ch-TOG. Minispindles levels are increased at the enlarged YGs and diminished around centrosomes in mauve-derived mutant embryos. This leads to decreased microtubule nucleation from centrosomes, a defect that can be rescued by dominant-negative Rab5. Together, this reveals an unanticipated link between endosomal vesicles and centrosomes. These findings establish Mauve/LYST's role in regulating LRO formation and centrosome behavior, a role that could account for the enlarged LROs and centrosome positioning defects at the immune synapse of CHS patients.

Primary immunodeficiency associated with hypopigmentation: A differential diagnosis approach

Primary immunodeficiency diseases (PIDs) are a group of more than 400 disorders representing aberrant functioning or development of immune system. Hypopigmentation syndromes also characterize a distinguished cluster of diseases. However, hypopigmentation may also signify a feature of genetic diseases associated with immunodeficiency, such as Chediak–Higashi syndrome, Griscelli syndrome type 2, Hermansky–Pudlak syndrome type 2 and type 10, Vici syndrome, and P14/LAMTOR2 deficiency, all of which are linked with dysfunction in vesicular/endosomal trafficking. Regarding the highly overlapping features, these disorders need a comprehensive examination for prompt diagnosis and effective management. As an aid to clinician, distinguishing the pathophysiology, clinical phenotype, and diagnosis as well as treatment options of the six mentioned PID disorders associated with hypopigmentation are described and discussed in this review (AU)

Primary immunodeficiency associated with hypopigmentation: A differential diagnosis approach.

Primary immunodeficiency diseases (PIDs) are a group of more than 400 disorders representing aberrant functioning or development of immune system. Hypopigmentation syndromes also characterize a distinguished cluster of diseases. However, hypopigmentation may also signify a feature of genetic diseases associated with immunodeficiency, such as Chediak-Higashi syndrome, Griscelli syndrome type 2, Hermansky-Pudlak syndrome type 2 and type 10, Vici syndrome, and P14/LAMTOR2 deficiency, all of which are linked with dysfunction in vesicular/endosomal trafficking. Regarding the highly overlapping features, these disorders need a comprehensive examination for prompt diagnosis and effective management. As an aid to clinician, distinguishing the pathophysiology, clinical phenotype, and diagnosis as well as treatment options of the six mentioned PID disorders associated with hypopigmentation are described and discussed in this review.

Chediak-Higashi Syndrome With Epstein-Barr Virus Triggered Hemophagocytic Lymphohistiocytosis: A Case Report.

Chediak-Higashi syndrome (CHS) is a rare, autosomal-recessive disorder characterized by oculocutaneous albinism, recurrent bacterial infections, progressive neurologic abnormalities, coagulation defects and a high risk of developing hemophagocytic lymphohistiocytosis characterized by pancytopenia, high fever, and lymphohistiocytic infiltration of liver, spleen, and lymph nodes. Treatment of accelerated-phase CHS is difficult with poor prognosis. Here, we report a two-and-a-half-year-old male child who was diagnosed with Chediak-Higashi Syndrome based on silvery hair, pathognomonic hair microscopy and giant azurophilic granules in granulocytes. The patient was in advanced stage of HLH induced by an Epstein-Barr virus (EBV) infection and given etoposide, cyclosporine and dexamethasone according to hemophagocytic lymphohistiocytosis (HLH)-2004 protocol but did not survive.

Dr. Antonio María Béguez César (1895-1975): fundador y maestro de la Sociedad Cubana de Pediatría de Santiago de Cuba / Dr. Antonio María Béguez César (1895-1975): founder and teacher of the Pediatrics Cuban Society in Santiago de Cuba

Con este artículo se buscó ampliar los datos biográficos del eminente científico cubano Antonio María Béguez César y divulgar aspectos poco conocidos de su prolífica existencia. Para ello se consultaron los archivos personales de la familia Béguez López y el índice de autores y materias del Boletín de la Sociedad Cubana de Pediatría y de la Revista Cubana de Pediatría, donde se consigna su bibliografía activa; además, se analizaron documentos de la época y se consideraron los testimonios de familiares, colegas y amigos del ilustre pediatra santiaguero. El trabajo forma parte del proyecto investigativo "Estrategia para incrementar la visibilidad del hallazgo científico del pediatra Dr. Antonio María Béguez César", que revela al descubridor de la "neutropenia crónica maligna familiar con granulaciones atípicas de los leucocitos", entidad clínica inscrita entre los diez hitos de la inmunología cubana, que ha sido erróneamente divulgada en el mundo científico-médico como síndrome de Chédiak-Higashi.

This work aimed at widen the biographical data of the eminent Cuban scientist Antonio María Béguez César and to spread not very well-known aspects of his prolific existence. The personal files of Béguez López family and the index of authors and matters of the Pediatrics Cuban Society Bulletin and the Pediatrics Cuban Magazine were consulted, where his active bibliography is consigned; also, documents of that time were analyzed and testimonies of family, colleagues and friends of the distinguished pediatrician from Santiago were considered. The work is part of the investigative project "Strategy to increase the visibility of the pediatrician Dr. Antonio María Béguez César scientific finding" that reveals the discoverer of "the family malignant chronic neutropenia with atypical granulations of the leukocytic cells", clinical entity inscribed among the ten landmarks of the Cuban immunology that has been erroneously spread in the scientific-medical world as Chediak-Higashi syndrome.

Identification of a compound heterozygote in LYST gene: a case report on Chediak-Higashi syndrome.

BACKGROUND: Chediak-Higashi Syndrome (CHS) is a rare autosomal recessive disease caused by loss of function of the lysosomal trafficking regulator protein. The causative gene LYST/CHS1 was cloned and identified in 1996, which showed significant homology to other species such as bovine and mouse. To date, 74 pathogenic or likely pathogenic mutations had been reported. CASE PRESENTATION: Here we describe a compound heterozygote in LYST gene, which was identified in a 4-year-old female patient. The patient showed skin hypopigmentation, sensitivity to light, mild splenomegaly and reduction of platelets in clinical examination. Giant intracytoplasmic inclusions were observed in the bone marrow examination, suggesting the diagnosis of CHS. Amplicon sequencing was performed to detect pathogenic mutation in LYST gene. The result was confirmed by two-generation pedigree analysis base on sanger sequencing. CONCLUSION: A compound heterozygote in LYST gene, consisting of a missense mutation c.5719A > G and an intron mutation c.4863-4G > A, was identified from the patient by using amplicon sequencing. The missense mutation is reported for the first time. Two-generation pedigree analysis showed these two mutations were inherited from the patient's parents, respectively. Our result demonstrated that amplicon sequencing has great potential for accelerating and improving the diagnosis of rare genetic diseases.