RESUMEN

RATIONALE: Shwachman-Diamond syndrome (SDS) is a rare autosomal recessive genetic disease, the diagnosis is a big challenge for clinician, as the clinical manifestations of the disease are diverse. Here, we report a girl who diagnosed with SDS with the symptoms of recurrent fever, elevated transaminase levels, and granulocytosis. The aspects of diagnosis and treatment were discussed and a literature review was conducted. PATIENT CONCERNS: A 15-month-old girl admitted to our hospital because of recurrent fever, granulocytopenia, and elevated transaminase levels. DIAGNOSIS AND INTERVENTIONS: The compound heterozygous variant of Shwachman-Bodian-Diamond syndrome c.258 + 2T > C:p.84Cfs3 and c.96C > G:p.Y32* were detected after sequencing the blood samples from the patient and her parents. Finally, she was diagnosed with SDS and she was treated with compound glycyrrhizin, granulocyte-colony stimulating factor, and antibiotic in the case of co-infection. OUTCOMES: During the follow-up, her liver function showed the level of transaminases decreased and she rarely had infection after the age of 15 months although neutropenia is still present. LESSONS: Patients with SDS lacks typical clinical symptoms, which presents a huge challenge for clinicians. Genetic testing techniques is playing an important role in the diagnosis of diseases. This patient without typical clinical manifestations such as exocrine pancreatic insufficiency and skeletal abnormality, we report this case aimed to strengthen the understanding of the disease.

Asunto(s)

Síndrome de Shwachman-Diamond , Humanos , Femenino , Lactante , Insuficiencia Pancreática Exocrina/diagnóstico , Insuficiencia Pancreática Exocrina/genética , Antibacterianos/uso terapéutico

RESUMEN

Intestinal disease is one of the earliest manifestations of cystic fibrosis (CF) in children and is closely tied to deficits in growth and nutrition, both of which are directly linked to future mortality. Patients are treated aggressively with pancreatic enzyme replacement therapy and a high-fat diet to circumvent fat malabsorption, but this does not reverse growth and nutritional defects. We hypothesized that defects in chylomicron production could explain why CF body weights and nutrition are so resistant to clinical treatments. We used gold standard intestinal lipid absorption and metabolism approaches, including mouse mesenteric lymph cannulation, in vivo chylomicron secretion kinetics, transmission electron microscopy, small intestinal organoids, and chylomicron metabolism assays to test this hypothesis. In mice expressing the G542X mutation in cystic fibrosis transmembrane conductance regulator (CFTR-/- mice), we find that defective FFA trafficking across the epithelium into enterocytes drives a chylomicron formation defect. Furthermore, G542X mice secrete small, triglyceride-poor chylomicrons into the lymph and blood. These defective chylomicrons are cleared into extraintestinal tissues at ∼10-fold faster than WT chylomicrons. This defect in FFA absorption resulting in dysfunctional chylomicrons cannot be explained by steatorrhea or pancreatic insufficiency and is maintained in primary small intestinal organoids treated with micellar lipids. These studies suggest that the ultrahigh-fat diet that most people with CF are counselled to follow may instead make steatorrhea and malabsorption defects worse by overloading the absorptive capacity of the CF small intestine.

Asunto(s)

Quilomicrones , Fibrosis Quística , Fibrosis Quística/metabolismo , Fibrosis Quística/patología , Fibrosis Quística/genética , Animales , Quilomicrones/metabolismo , Ratones , Ácidos Grasos no Esterificados/metabolismo , Regulador de Conductancia de Transmembrana de Fibrosis Quística/metabolismo , Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Regulador de Conductancia de Transmembrana de Fibrosis Quística/deficiencia , Insuficiencia Pancreática Exocrina/metabolismo , Insuficiencia Pancreática Exocrina/genética , Insuficiencia Pancreática Exocrina/patología , Transporte Biológico , Humanos , Mucosa Intestinal/metabolismo

RESUMEN

Johanson-Blizzard syndrome (JBS) is an autosomal recessive disorder. We established an induced pluripotent stem cell (iPSC) line from peripheral blood mononuclear cells of a 2-year-old boy with Johanson-Blizzard syndrome carrying a compound heterozygous mutation of c.3167C>G (p.S1056X) and c.1911 + 14C>G(splicing) in the UBR1 gene. This iPSC line was free of exogenous gene, expressed stemness markers, exhibited differentiation potential, had normal karyotype and harbored the same mutations found in the patient. The iPSC cellline can serve as a disease model in drug development and novel personalized therapies.

Asunto(s)

Ano Imperforado , Displasia Ectodérmica , Trastornos del Crecimiento , Pérdida Auditiva Sensorineural , Células Madre Pluripotentes Inducidas , Mutación , Ubiquitina-Proteína Ligasas , Humanos , Células Madre Pluripotentes Inducidas/metabolismo , Masculino , Ubiquitina-Proteína Ligasas/genética , Trastornos del Crecimiento/genética , Trastornos del Crecimiento/patología , Pérdida Auditiva Sensorineural/genética , Pérdida Auditiva Sensorineural/patología , Preescolar , Displasia Ectodérmica/genética , Displasia Ectodérmica/patología , Ano Imperforado/genética , Ano Imperforado/patología , Heterocigoto , Nariz/patología , Nariz/anomalías , Línea Celular , Insuficiencia Pancreática Exocrina/genética , Insuficiencia Pancreática Exocrina/patología , Sordera/genética , Sordera/patología , Diferenciación Celular , Discapacidad Intelectual/genética , Discapacidad Intelectual/patología , Hipotiroidismo , Enfermedades Pancreáticas

Asunto(s)

Leucemia Mieloide Aguda , Linfoma de Células B Grandes Difuso , Síndrome de Shwachman-Diamond , Humanos , Linfoma de Células B Grandes Difuso/patología , Linfoma de Células B Grandes Difuso/complicaciones , Leucemia Mieloide Aguda/patología , Leucemia Mieloide Aguda/complicaciones , Masculino , Adulto Joven , Lipomatosis/patología , Lipomatosis/complicaciones , Insuficiencia Pancreática Exocrina/complicaciones , Insuficiencia Pancreática Exocrina/genética , Insuficiencia Pancreática Exocrina/patología , Enfermedades de la Médula Ósea/patología , Adulto

Asunto(s)

Enfermedades de la Médula Ósea , Insuficiencia Pancreática Exocrina , Lipomatosis , Humanos , Animales , Ratas , Síndrome de Shwachman-Diamond , Insuficiencia Pancreática Exocrina/complicaciones , Insuficiencia Pancreática Exocrina/genética , Lipomatosis/genética , Enfermedades de la Médula Ósea/genética

RESUMEN

BACKGROUND AND AIMS: To systematically review the literature for reports on Wolcott-Rallison syndrome, focusing on the spectrum and natural history, genotype-phenotype correlations, patient and native liver survival, and long-term outcomes. METHODS: PubMed, Livio, Google Scholar, Scopus and Web of Science databases were searched. Data on genotype, phenotype, therapy, cause of death and follow-up were extracted. Survival and correlation analyses were performed. RESULTS: Sixty-two studies with 159 patients met the inclusion criteria and additional 30 WRS individuals were collected by personal contact. The median age of presentation was 2.5 months (IQR 2) and of death was 36 months (IQR 50.75). The most frequent clinical feature was neonatal diabetes in all patients, followed by liver impairment in 73%, impaired growth in 72%, skeletal abnormalities in 59.8%, the nervous system in 37.6%, the kidney in 35.4%, insufficient haematopoiesis in 34.4%, hypothyroidism in 14.8% and exocrine pancreas insufficiency in 10.6%. Episodes of acute liver failure were frequently reported. Liver transplantation was performed in six, combined liver-pancreas in one and combined liver-pancreas-kidney transplantation in two individuals. Patient survival was significantly better in the transplant cohort (p = .0057). One-, five- and ten-year patient survival rates were 89.4%, 65.5% and 53.1%, respectively. Liver failure was reported as the leading cause of death in 17.9% of cases. Overall survival was better in individuals with missense mutations (p = .013). CONCLUSION: Wolcott-Rallison syndrome has variable clinical courses. Overall survival is better in individuals with missense mutations. Liver- or multi-organ transplantation is a feasible treatment option to improve survival.

Asunto(s)

Epífisis , Trasplante de Hígado , Osteocondrodisplasias , Humanos , Osteocondrodisplasias/genética , Epífisis/anomalías , Epífisis/cirugía , Estudios de Seguimiento , Lactante , Insuficiencia Pancreática Exocrina/genética , Diabetes Mellitus/genética , Preescolar , Fallo Hepático Agudo/genética , Fallo Hepático Agudo/mortalidad , Fallo Hepático Agudo/cirugía , Hipotiroidismo/genética , Fenotipo , Estudios de Asociación Genética , Diabetes Mellitus Tipo 1 , eIF-2 Quinasa

RESUMEN

Shwachman-Diamond syndrome (SDS) is an autosomal recessive disorder characterized by exocrine pancreatic insufficiency and bone marrow failure. The depletion of SBDS protein by RNA interference has been shown to cause inhibition of cell proliferation in several cell lines. However, the precise mechanism by which the loss of SBDS leads to inhibition of cell growth remains unknown. To evaluate the impaired growth of SBDS-knockdown cells, we analyzed Epstein-Barr virus-transformed lymphoblast cells (LCLs) derived from two patients with SDS (c. 183_184TA > CT and c. 258 + 2 T > C). After 3 days of culture, the growth of LCL-SDS cell lines was considerably less than that of control donor cells. By annealing control primer-based GeneFishing PCR screening, we found that galectin-1 (Gal-1) mRNA expression was elevated in LCL-SDS cells. Western blot analysis showed that the level of Gal-1 protein expression was also increased in LCL-SDS cells as well as in SBDS-knockdown 32Dcl3 murine myeloid cells. We confirmed that recombinant Gal-1 inhibited the proliferation of both LCL-control and LCL-SDS cells and induced apoptosis (as determined by annexin V-positive staining). These results suggest that the overexpression of Gal-1 contributes to abnormal cell growth in SBDS-deficient cells.

Asunto(s)

Benzamidas , Enfermedades de la Médula Ósea , Infecciones por Virus de Epstein-Barr , Insuficiencia Pancreática Exocrina , Galectina 1 , Tirosina , Animales , Humanos , Ratones , Enfermedades de la Médula Ósea/genética , Proliferación Celular , Insuficiencia Pancreática Exocrina/genética , Insuficiencia Pancreática Exocrina/metabolismo , Galectina 1/genética , Herpesvirus Humano 4 , Proteínas , Síndrome de Shwachman-Diamond , Tirosina/análogos & derivados

RESUMEN

Shwachman-Diamond syndrome (SDS) is characterized by neutropenia, exocrine pancreatic insufficiency and skeletal abnormalities. SDS bone marrow haematopoietic progenitors show increased apoptosis and impairment in granulocytic differentiation. Loss of Shwachman-Bodian-Diamond syndrome (SBDS) expression results in reduced eukaryotic 80S ribosome maturation. Biallelic mutations in the SBDS gene are found in ~90% of SDS patients, ~55% of whom carry the c.183-184TA>CT nonsense mutation. Several translational readthrough-inducing drugs aimed at suppressing nonsense mutations have been developed. One of these, ataluren, has received approval in Europe for the treatment of Duchenne muscular dystrophy. We previously showed that ataluren can restore full-length SBDS protein synthesis in SDS-derived bone marrow cells. Here, we extend our preclinical study to assess the functional restoration of SBDS capabilities in vitro and ex vivo. Ataluren improved 80S ribosome assembly and total protein synthesis in SDS-derived cells, restored myelopoiesis in myeloid progenitors, improved neutrophil chemotaxis in vitro and reduced neutrophil dysplastic markers ex vivo. Ataluren also restored full-length SBDS synthesis in primary osteoblasts, suggesting that its beneficial role may go beyond the myeloid compartment. Altogether, our results strengthened the rationale for a Phase I/II clinical trial of ataluren in SDS patients who harbour the nonsense mutation.

Asunto(s)

Enfermedades de la Médula Ósea , Insuficiencia Pancreática Exocrina , Lipomatosis , Humanos , Síndrome de Shwachman-Diamond , Proteína p53 Supresora de Tumor/genética , Lipomatosis/genética , Codón sin Sentido , Mielopoyesis , Neutrófilos/metabolismo , Quimiotaxis , Enfermedades de la Médula Ósea/genética , Enfermedades de la Médula Ósea/terapia , Insuficiencia Pancreática Exocrina/genética , Ribosomas/metabolismo

Asunto(s)

Aminofenoles , Benzodioxoles , Regulador de Conductancia de Transmembrana de Fibrosis Quística , Fibrosis Quística , Indoles , Pirazoles , Quinolonas , Humanos , Fibrosis Quística/tratamiento farmacológico , Fibrosis Quística/genética , Benzodioxoles/uso terapéutico , Aminofenoles/uso terapéutico , Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Adulto , Indoles/uso terapéutico , Quinolonas/uso terapéutico , Pirazoles/uso terapéutico , Piridinas/uso terapéutico , Genotipo , Femenino , Quinolinas/uso terapéutico , Masculino , Combinación de Medicamentos , Pirrolidinas/uso terapéutico , Insuficiencia Pancreática Exocrina/tratamiento farmacológico , Insuficiencia Pancreática Exocrina/etiología , Insuficiencia Pancreática Exocrina/genética , Agonistas de los Canales de Cloruro/uso terapéutico

RESUMEN

Shwachman-Diamond syndrome (SDS) is an autosomal recessive inherited disorder caused by biallelic mutations in the Shwachman-Bodian-Diamond syndrome (SBDS) gene. SBDS protein is involved in ribosome biogenesis; therefore SDS is classified as a ribosomopathy. SBDS is localized at mitotic spindles and stabilizes microtubules. Previously, we showed that SBDS interacts with ring finger protein 2 (RNF2) and is degraded through RNF2-dependent ubiquitination. In this study, we investigated when and where SBDS interacts with RNF2 and the effects of the interaction on cells. We found that SBDS co-localized with RNF2 on centrosomal microtubules in the mitotic phase (M phase), whereas SBDS and RNF2 localized to the nucleolus and nucleoplasm in the interphase, respectively. The microtubule-binding assay revealed that SBDS interacted directly with microtubules and RNF2 interacted with SBDS bound to microtubules. In addition, SBDS was ubiquitinated and degraded by RNF2 during the M phase. Moreover, RNF2 overexpression accelerated mitotic progression. These findings suggest that SBDS delays mitotic progression, and RNF2 releases cells from suppression through the ubiquitination and subsequent degradation of SBDS. The interaction between SBDS and RNF2 at mitotic spindles might be involved in mitotic progression as a novel regulatory cascade.

Asunto(s)

Enfermedades de la Médula Ósea , Insuficiencia Pancreática Exocrina , Humanos , Enfermedades de la Médula Ósea/genética , Enfermedades de la Médula Ósea/metabolismo , Proteínas/metabolismo , Síndrome de Shwachman-Diamond/complicaciones , Síndrome de Shwachman-Diamond/metabolismo , Huso Acromático/metabolismo , División Celular , Insuficiencia Pancreática Exocrina/genética , Insuficiencia Pancreática Exocrina/metabolismo , Complejo Represivo Polycomb 1/metabolismo

RESUMEN

BACKGROUND: Shwachman-Diamond syndrome (SDS) is a rare congenital disorder caused by mutations in the SBDS gene and characterized by exocrine pancreatic deficiency, hematologic dysfunction, and skeletal growth failure. Although the hematologic features and characteristics of the somatic disorders commonly associated with SDS are well known, emerging data from case reports and patient registries suggest that SDS may also be associated with an increased risk of diabetes mellitus. However, currently available data on SDS-associated diabetes are limited and do not allow conclusions regarding prevalence and incidence rates, clinical course, and outcomes. CASE PRESENTATION: Here we report the case of a 5-year-old girl with SDS who underwent bone marrow transplantation at the age of 3 months and developed autoantibody-positive type 1 diabetes mellitus at the age of 1.8 years. The manifestation and course of diabetes development were mild, complicated by concurrent spontaneous episodes of hypoglycemia even before the onset of antidiabetic treatment. Currently, adequate metabolic control can be achieved by dietary intervention. CONCLUSIONS: Considering that the SBDS protein regulates mitosis and ribosomal biosynthesis and that its suppression may cause immunologic instability and chronic inflammation, this case provides insight into the phenotype of rare Shwachman-Diamond syndrome-associated diabetes mellitus, which may be characterized by significant age-dependent differences in clinical course.

Asunto(s)

Enfermedades de la Médula Ósea , Diabetes Mellitus Tipo 1 , Insuficiencia Pancreática Exocrina , Lipomatosis , Humanos , Síndrome de Shwachman-Diamond , Insuficiencia Pancreática Exocrina/complicaciones , Insuficiencia Pancreática Exocrina/diagnóstico , Insuficiencia Pancreática Exocrina/genética , Lipomatosis/complicaciones , Lipomatosis/diagnóstico , Lipomatosis/genética , Enfermedades de la Médula Ósea/complicaciones , Enfermedades de la Médula Ósea/diagnóstico , Enfermedades de la Médula Ósea/terapia , Diabetes Mellitus Tipo 1/complicaciones , Diabetes Mellitus Tipo 1/diagnóstico , Diabetes Mellitus Tipo 1/genética , Progresión de la Enfermedad

RESUMEN

OBJECTIVE: To explore the characteristics of Shwachman-Diamond syndrome (SDS) in Chinese children in order to provide a reference for early diagnosis. METHODS: With Shwachman-Diamond syndrome, SDS, SBDS gene and inherited bone marrow failure as the keywords, the search period was set from January 2002 to October 2022. Relevant literature was retrieved from the Wanfang Database and China National Knowledge Infrastructure (CNKI) database. In addition, by using Shwachman-diamond syndrome as a keyword, the search period was also retrieved from the Web of Science, PubMed, and MEDLINE databases from January 2002 to October 2022. A child with SDS treated at the Tongji Hospital was also included. A total of 44 cases with complete clinical data were analyzed with reference to the International Standard for SDS Diagnosis. Chi-square test and t test were used for statistical analysis. Evidence-based research was carried out in the form of systematic review. The epidemiology, clinical characteristics and key points of early diagnosis of the Chinese SDS children were summarized and compared with the international data. RESULTS: The main characteristics of SDS in Chinese children were summarized as follows: The ratio of males to females was about 1.3 : 1, the median age of onset was 3 months, and the median age of diagnosis was 14 months. The first symptoms were often exocrine pancreatic insufficiency (31.8%) and granulocytopenia with infection (31.8%). According to the international consensus, the incidence rates of the three major diseases of SDS were hemocytopenia (95.4%), pancreatic disease (72.7%), and bone abnormality (40.9%). The common factors underlying SDS disease were variants of the SBDS gene (c.258+2T>C and c.183_184TA>CT), albeit there was no significant correlation between genotype and phenotype (P > 0.05). Compared with international reports, the clinical manifestations and genotypes of Chinese SDS children are different (P < 0.05). CONCLUSION: The SDS children have an early age of onset and significant individual difference. It is necessary to analyze the case-related data to facilitate early recognition, diagnosis and clinical intervention.

Asunto(s)

Síndrome de Shwachman-Diamond , Femenino , Humanos , Masculino , Enfermedades de la Médula Ósea/diagnóstico , Enfermedades de la Médula Ósea/genética , Enfermedades de la Médula Ósea/terapia , China , Pueblos del Este de Asia , Insuficiencia Pancreática Exocrina/diagnóstico , Insuficiencia Pancreática Exocrina/genética , Insuficiencia Pancreática Exocrina/terapia , Síndrome de Shwachman-Diamond/diagnóstico , Síndrome de Shwachman-Diamond/genética , Síndrome de Shwachman-Diamond/terapia

RESUMEN

Shwachman-Diamond syndrome is a rare inherited bone marrow failure syndrome characterized by neutropenia, exocrine pancreatic insufficiency, and skeletal abnormalities. In 10-30% of cases, transformation to a myeloid neoplasm occurs. Approximately 90% of patients have biallelic pathogenic variants in the SBDS gene located on human chromosome 7q11. Over the past several years, pathogenic variants in three other genes have been identified to cause similar phenotypes; these are DNAJC21, EFL1, and SRP54. Clinical manifestations involve multiple organ systems and those classically associated with the Shwachman-Diamond syndrome (bone, blood, and pancreas). Neurocognitive, dermatologic, and retinal changes may also be found. There are specific gene-phenotype differences. To date, SBDS, DNAJC21, and SRP54 variants have been associated with myeloid neoplasia. Common to SBDS, EFL1, DNAJC21, and SRP54 is their involvement in ribosome biogenesis or early protein synthesis. These four genes constitute a common biochemical pathway conserved from yeast to humans that involve early stages of protein synthesis and demonstrate the importance of this synthetic pathway in myelopoiesis.

Asunto(s)

Enfermedades de la Médula Ósea , Insuficiencia Pancreática Exocrina , Lipomatosis , Humanos , Síndrome de Shwachman-Diamond , Lipomatosis/genética , Lipomatosis/metabolismo , Lipomatosis/patología , Enfermedades de la Médula Ósea/genética , Enfermedades de la Médula Ósea/patología , Mutación , Insuficiencia Pancreática Exocrina/genética , Insuficiencia Pancreática Exocrina/metabolismo , Insuficiencia Pancreática Exocrina/patología , Partícula de Reconocimiento de Señal/genética

RESUMEN

Pediatric patients with exocrine pancreatic insufficiency (EPI) have symptoms that include abdominal pain, weight loss or poor weight gain, malnutrition, and steatorrhea. This condition can be present at birth or develop during childhood for certain genetic disorders. Cystic fibrosis (CF) is the most prevalent disorder in which patients are screened for EPI; other disorders also are associated with pancreatic dysfunction, such as hereditary pancreatitis, Pearson syndrome, and Shwachman-Diamond syndrome. Understanding the clinical presentation and proposed pathophysiology of the pancreatic dysfunction of these disorders aids in diagnosis and treatment. Testing pancreatic function is challenging. Directly testing aspirates produced from the pancreas after stimulation is considered the gold standard, but the procedures are not standardized or widely available. Instead, indirect tests are often used in diagnosis and monitoring. Although indirect tests are more widely available and easier to perform, they have inherent limitations due to a lack of sensitivity and/or specificity for EPI.

Asunto(s)

Fibrosis Quística , Insuficiencia Pancreática Exocrina , Recién Nacido , Humanos , Niño , Heces , Elastasa Pancreática , Insuficiencia Pancreática Exocrina/diagnóstico , Insuficiencia Pancreática Exocrina/genética , Páncreas/fisiología , Fibrosis Quística/diagnóstico , Fibrosis Quística/genética , Fibrosis Quística/complicaciones

RESUMEN

Shwachman-Diamond syndrome (SDS) is an inherited multisystem ribosomopathy characterized by exocrine pancreatic deficiency, bone marrow failure, and predisposition to myeloid malignancies. The pathobiology of SDS results from impaired ribosomal maturation due to the deficiency of SBDS and the inability to evict the antiassociation factor eIF6 from the 60S ribosomal subunit. Clinical outcomes for patients with SDS who develop myeloid malignancies are extremely poor because of high treatment-related toxicities and a high rate of refractory disease/relapse even after allogeneic hematopoietic stem cell transplant (HSCT). Registry data indicate that outcomes are improved for patients with SDS who undergo routine bone marrow surveillance and receive an HSCT before developing an overt malignancy. However, the optimal approach to hematologic surveillance and the timing of HSCT for patients with SDS is not clearly established. Recent studies have elucidated distinct patterns of somatic blood mutations in patients with SDS that either alleviate the ribosome defect via somatic rescue (heterozygous EIF6 inactivation) or disrupt cellular checkpoints, resulting in increased leukemogenic potential (heterozygous TP53 inactivation). Genomic analysis revealed that most myeloid malignancies in patients with SDS have biallelic loss-of-function TP53 mutations. Single-cell DNA sequencing of SDS bone marrow samples can detect premalignant biallelic TP53-mutated clones before clinical diagnosis, suggesting that molecular surveillance may enhance the detection of incipient myeloid malignancies when HSCT may be most effective. Here, we review the clinical, genetic, and biologic features of SDS. In addition, we present evidence supporting the hematologic surveillance for patients with SDS that incorporates clinical, pathologic, and molecular data to risk stratify patients and prioritize transplant evaluation for patients with SDS with high-risk features.

Asunto(s)

Enfermedades de la Médula Ósea , Insuficiencia Pancreática Exocrina , Lipomatosis , Trastornos Mieloproliferativos , Humanos , Síndrome de Shwachman-Diamond , Enfermedades de la Médula Ósea/genética , Enfermedades de la Médula Ósea/terapia , Enfermedades de la Médula Ósea/diagnóstico , Insuficiencia Pancreática Exocrina/genética , Insuficiencia Pancreática Exocrina/terapia , Lipomatosis/genética , Lipomatosis/terapia , Recurrencia Local de Neoplasia , Susceptibilidad a Enfermedades

RESUMEN

Hepatobiliary involvement is a hallmark in cystic fibrosis (CF), as the causative CF Transmembrane Conductance Regulator (CFTR) defect is expressed in the biliary tree. However, bile acid (BA) compositions in regard to pancreatic insufficiency, which is present at an early stage in about 85% of CF patients, have not been satisfactorily understood. We assess the pattern of serum BAs in people with CF (pwCF) without CFTR modulator therapy in regard to pancreatic insufficiency and the CFTR genotype. In 47 pwCF, 10 free and 12 taurine- and glycine-conjugated BAs in serum were prospectively assessed. Findings were related to genotype, pancreatic insufficiency prevalence (PIP)-score, and hepatic involvement indicated by serum liver enzymes, as well as clinical and ultrasound criteria for CF-related liver disease. Serum concentrations of total primary BAs and free cholic acid (CA) were significantly higher in pwCF with higher PIP-scores (p = 0.025, p = 0.009, respectively). Higher total BAs were seen in pwCF with PIP-scores ≥0.88 (p = 0.033) and with pancreatic insufficiency (p = 0.034). Free CA was higher in patients with CF-related liver involvement without cirrhosis, compared to pwCF without liver disease (2.3-fold, p = 0.036). pwCF with severe CFTR genotypes, as assessed by the PIP-score, reveals more toxic BA compositions in serum. Subsequent studies assessing changes in BA homeostasis during new highly effective CFTR-modulating therapies are of high interest.

Asunto(s)

Fibrosis Quística , Insuficiencia Pancreática Exocrina , Hepatopatías , Humanos , Fibrosis Quística/complicaciones , Fibrosis Quística/genética , Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Ácidos y Sales Biliares , Insuficiencia Pancreática Exocrina/complicaciones , Insuficiencia Pancreática Exocrina/genética , Mutación , Ácido Cólico , Taurina , Glicina/genética

RESUMEN

OBJECTIVE: To analyze the association between phenotypic and genotypic characteristics and disease severity in individuals with cystic fibrosis treated at a reference center in Minas Gerais, Brazil. METHODS: This is a retrospective study that collected clinical and laboratory data, respiratory and gastrointestinal manifestations, type of treatment, Shwachman-Kulczycki score, and mutations from the patients' medical records. RESULTS: The sample included 50 participants aged one to 33 years, 50% of whom were female. Out of the one hundred alleles of the Cystic Fibrosis Transmembrane Conductance Regulator gene, the most prevalent mutations were DeltaF508 (45%) and S4X (18%). Mutation groups were only associated with pancreatic insufficiency (p=0.013) and not with disease severity (p=0.073). The latter presented an association with colonization by Pseudomonas aeruginosa and Staphylococcus aureus (p=0.007) and with underweight (p=0.036). Death was associated with age at diagnosis (p=0.016), respiratory symptomatology (p=0.013), colonization (p=0.024), underweight (p=0.017), and hospitalization (p=0.003). CONCLUSIONS: We could identify the association of mutations with pancreatic insufficiency; the association of Staphylococcus aureus colonization and underweight with disease severity; and the lack of association between mutations and disease severity. Environmental factors should be investigated more thoroughly since they seem to have an important effect on disease severity.

Asunto(s)

Fibrosis Quística , Insuficiencia Pancreática Exocrina , Fibrosis Quística/diagnóstico , Fibrosis Quística/genética , Insuficiencia Pancreática Exocrina/genética , Femenino , Humanos , Masculino , Estudios Retrospectivos , Índice de Severidad de la Enfermedad , Delgadez

RESUMEN

Objective: To investigate the clinical phenotypes and genotypic spectrum of exocrine pancreatic insufficiency in children with cystic fibrosis. Methods: This was a retrospective analysis of 12 children with cystic fibrosis who presented to Children's Hospital of Fudan University from December 2017 to December 2021. Clinical features, fecal elastase-1 level, genotype, diagnosis and treatment were systematically reviewed. Results: A total of 12 children, 7 males and 5 females, diagnosis aged 5.4 (2.0, 10.6) years, were recruited. Common clinical features included chronic cough in 12 cases, malnutrition in 7 cases, steatorrhea in 7 cases, bronchiectasis in 5 cases and electrolyte disturbance in 4 cases. Exocrine pancreatic insufficiency were diagnosed in 8 cases,the main clinical manifestations were steatorrhea in 7 cases, of which 5 cases started in infancy; 6 cases were complicated with malnutrition, including mild in 1 case, moderate in 2 cases and severe in 3 cases; 3 cases had abdominal distension; 2 cases had intermittent abdominal pain; 4 cases showed fatty infiltration or atrophy of pancreas and 3 cases showed no obvious abnormality by pancreatic magnetic resonance imaging or B-ultrasound. All 8 children were given pancreatic enzyme replacement therapy, follow-up visit of 2.3 (1.2,3.2) years. Diarrhea significantly improved in 6 cases, and 1 case was added omeprazole due to poor efficacy. A total of 20 variations of CFTR were detected in this study, of which 7 were novel (c.1373G>A,c.1810A>C,c.270delA,c.2475_2478dupCGAA,c.2489_c.2490insA, c.884delT and exon 1 deletion). Conclusions: There is a high proportion of exocrine pancreatic insufficiency in Chinese patients with cystic fibrosis. The main clinical manifestations are steatorrhea and malnutrition. Steatorrhea has often started from infancy. Pancreatic enzyme replacement therapy can significantly improve the symptoms of diarrhea and malnutrition.

Asunto(s)

Fibrosis Quística , Insuficiencia Pancreática Exocrina , Desnutrición , Enfermedades Pancreáticas , Esteatorrea , Fibrosis Quística/complicaciones , Fibrosis Quística/diagnóstico , Fibrosis Quística/genética , Diarrea/complicaciones , Insuficiencia Pancreática Exocrina/complicaciones , Insuficiencia Pancreática Exocrina/genética , Femenino , Genotipo , Humanos , Masculino , Desnutrición/complicaciones , Enfermedades Pancreáticas/complicaciones , Enfermedades Pancreáticas/genética , Fenotipo , Estudios Retrospectivos , Esteatorrea/complicaciones , Esteatorrea/genética

Asunto(s)

Fibrosis Quística , Insuficiencia Pancreática Exocrina , Alelos , Fibrosis Quística/complicaciones , Fibrosis Quística/genética , Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Insuficiencia Pancreática Exocrina/genética , Humanos , Recién Nacido , Mutación

RESUMEN

Introduction. Shwachman-Diamond Syndrome (SDS) is an autosomal-recessive disorder characterized by neutropenia, pancreatic exocrine insufficiency, skeletal dysplasia, and an increased risk for leukemic transformation. Biallelic mutations in the SBDS gene have been found in about 90% of patients. The clinical spectrum of SDS in patients is wide, and variability has been noticed between different patients, siblings, and even within the same patient over time. Herein, we present two SDS siblings (UPN42 and UPN43) carrying the same SBDS mutations and showing relevant differences in their phenotypic presentation. Study aim. We attempted to understand whether other germline variants, in addition to SBDS, could explain some of the clinical variability noticed between the siblings. Methods. Whole-exome sequencing (WES) was performed. Human Phenotype Ontology (HPO) terms were defined for each patient, and the WES data were analyzed using the eVai and DIVAs platforms. Results. In UPN43, we found and confirmed, using Sanger sequencing, a novel de novo variant (c.10663G > A, p.Gly3555Ser) in the KMT2A gene that is associated with autosomal-dominant Wiedemann−Steiner Syndrome. The variant is classified as pathogenic according to different in silico prediction tools. Interestingly, it was found to be related to some of the HPO terms that describe UPN43. Conclusions. We postulate that the KMT2A variant found in UPN43 has a concomitant and co-occurring clinical effect, in addition to SBDS mutation. This dual molecular effect, supported by in silico prediction, could help to understand some of the clinical variations found among the siblings. In the future, these new data are likely to be useful for personalized medicine and therapy for selected cases.

Asunto(s)

Enfermedades de la Médula Ósea , Insuficiencia Pancreática Exocrina , N-Metiltransferasa de Histona-Lisina , Proteína de la Leucemia Mieloide-Linfoide , Síndrome de Shwachman-Diamond , Variación Biológica Poblacional , Enfermedades de la Médula Ósea/genética , Insuficiencia Pancreática Exocrina/genética , N-Metiltransferasa de Histona-Lisina/genética , Humanos , Proteína de la Leucemia Mieloide-Linfoide/genética , Síndrome de Shwachman-Diamond/genética , Hermanos