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Persistent hypoglycaemia in newborns and infants is most commonly caused by congenital hyperinsulinism (CHI). Most CHI studies report outcomes in children from both consanguineous and non-consanguineous families which can affect the phenotype-genotype analysis. The aim of this study was to analyze characteristics of patients with CHI in 21 non-consanguineous families from Serbia. This retrospective cohort study included a total of 21 patients with CHI treated in the Mother and Child Healthcare Institute of Serbia during the past 20 years. The prevalence of macrosomia at birth was very low in our cohort (4.8%). Median age at presentation was 6 days, with seizures as the presenting symptom in 76% of patients. Only four patients (19%) were diazoxide unresponsive, and eventually underwent pancreatectomy. Genetic testing was performed in 15 patients and genetic diagnosis was confirmed in 60%, with all patients being heterozygous for detected mutations. The ABCC8 gene mutations were detected in 55.6%, GLUD1 in three patients (33.3%) with HIHA syndrome and one patient had HNF4A gene mutation and unusual prolonged hyperglycaemia lasting 6 days after diazoxide cessation. Neurodevelopmental deficits persisted in 33% of patients.Conclusion: This is the first study regarding CHI patients in Serbia. It suggests that in countries with low consanguinity rate, majority of CHI patients are diazoxide responsive. The most common mutations were heterozygous ABCC8, followed by GLUD1 and HNF4A mutations, suggesting the potential benefit of population-tailored genetic analysis approach, targeting the mutations causing CHI via dominant inheritance model in regions with low consanguinity rates. What is Known: ⢠Persistent hypoglycaemia during infancy and early childhood is most commonly caused by congenital hyperinsulinism (CHI). ⢠Consanguinity is a very important factor regarding the genetics and phenotype of CHI, increasing the risk of autosomal recessive genetic disorders, including the severe, diazoxide-unresponsive forms caused by recessive inactivating mutations in ABCC8 and KCNJ11. What is New: ⢠Results of the present study which included CHI patients from 21 non-consanguineous families suggest that in countries with low consanguinity rates, majority of CHI patients can be diazoxide responsive, with most common mutations being heterozygous ABCC8, followed by GLUD1 and HNF4A mutations. ⢠Unusually prolonged hyperglycaemic reaction to diazoxide treatment in a patient with HNF4A mutation was also described in the present study.
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Hiperinsulinismo Congénito , Hiperinsulinismo , Niño , Preescolar , Hiperinsulinismo Congénito/genética , Consanguinidad , Humanos , Lactante , Recién Nacido , Mutación , Estudios Retrospectivos , Serbia/epidemiología , Receptores de Sulfonilureas/genéticaRESUMEN
The aim of the study was to explore whether diagnosis and managing children with progressive myoclonus epilepsy (PME) were improved during the last decade. METHODS: The retrospective study included children with PME treated in the Institute during the last 25â¯years. Investigation time was divided in two periods (groups): before December 2010 (the first group) and after this period up to December 2019 (the second group). Inclusion criteria are as follows: patients aged from 0.2-18â¯years and with PME. Evaluated parameters are etiology, age at seizure onset, diagnosis delay, epilepsy phenotype, and, as a measure of epilepsy control - status epilepticus (SE) frequency and recurrence rate. Statistical analysis included the following tests: Chi-Square, Mann-Whitney, and analysis of variance (ANOVA), using SPSS version 25. RESULTS: The study included 51 patients, 27 in the first, and 24 in the second group. The underlying diseases were: neuronal ceroid lipofuscinosis (NCL; 30), Gaucher (5), Niemann-Pick (4), mitochondrial (4), Lafora (3), Krabbe (2), and KCNC1 gene mutation (2). The average duration from initial symptoms to diagnosis was 3.2⯱â¯3â¯years (first group) vs. 1.4⯱â¯0.9â¯years (second). Both SE frequency rate (55.5% vs. 37.5%) and recurrence rate (66.7% vs. 22.2%) were higher in the first group, showing tendency towards, but not statistically significant difference. CONCLUSION: The diagnosis and epilepsy managing children with PME were improved during the last decade. Earlier genetic diagnosis, appropriate antiseizure medications, education of parents/caregivers of children in high risk for SE, and availability of effective prehospital rescue medications contributed to significantly decreased frequency and recurrence rate of SE.
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Epilepsia , Epilepsias Mioclónicas Progresivas , Estado Epiléptico , Anciano , Niño , Estudios de Cohortes , Humanos , Epilepsias Mioclónicas Progresivas/complicaciones , Epilepsias Mioclónicas Progresivas/diagnóstico , Epilepsias Mioclónicas Progresivas/epidemiología , Estudios Retrospectivos , Canales de Potasio ShawRESUMEN
Almost any anatomical compartment may be involved in Gaucher disease (GD). Abdominal lymphadenopathy occurred during enzyme replacement therapy in more than a dozen children with GD so far. A fourteen-year-old boy from Serbia developed clinical signs of acute appendicitis six years after the onset of GD type 3 related abdominal lymphadenopathy. Ultrasound examination showed diffuse thickening of the intestinal wall in the ileocoecal region with periappendicular infiltration. An appendectomy was performed four months after conservative treatment with antibiotics. Histopathology revealed macrophages with cytological characteristics of Gaucher cells densely crammed in mesoappendiceal adipose tissue. Also the multifocal replacement of subserosal tissue by Gaucher cells and their infiltration to a variable depth of muscularis propria of the appendix were verified. Frank infiltration of the vermiform appendix with Gaucher cells represents a novel observation in a wide spectrum of manifestations reported in GD. A possible causative relationship of this infiltration with appendicitis is considered.
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Apendicitis/etiología , Enfermedad de Gaucher/complicaciones , Linfadenopatía/etiología , Enfermedad Aguda , Adolescente , Apendicectomía , Apendicitis/patología , Apendicitis/cirugía , Apéndice/patología , Apéndice/cirugía , Enfermedad de Gaucher/patología , Humanos , Ganglios Linfáticos/patología , Linfadenopatía/patología , Macrófagos/patología , MasculinoRESUMEN
Treatment with tetrahydrobiopterin (BH4) is the latest therapeutic option approved for patients with phenylketonuria (PKU)-one of the most frequent inborn metabolic diseases. PKU or phenylalanine hydroxylase (PAH) deficiency is caused by mutations in the PAH gene. Given that some PAH mutations are responsive to BH4 treatment while others are non-responsive, for every novel mutation that is discovered it is essential to confirm its pathogenic effect and to assess its responsiveness to a BH4 treatment in vitro, before the drug is administered to patients. We found a c.676C>A (p.Gln226Lys) mutation in the PAH gene in two unrelated patients with PKU. The corresponding aberrant protein has never been functionally characterized in vitro and its response to BH4 treatment is unknown. Computational analyses proposed that glutamine at position 226 is an important, evolutionary conserved amino acid while the substitution with lysine probably disturbs tertiary protein structure and impacts posttranslational PAH modifications. Using hepatoma cellular model, we demonstrated that the amount of mutant p.Gln226Lys PAH detected by Western blot was only 1.2% in comparison to wild-type PAH. The addition of sepiapterin, intracellular precursor of BH4, did not increase PAH protein yield thus marking p.Gln226Lys as BH4-non-responsive mutation. Therefore, computational, experimental, and clinical data were all in accordance showing that p.Gln226Lys is a severe pathogenic PAH mutation. Its non-responsiveness to BH4 treatment in hepatoma cellular model should be considered when deciding treatment options for PKU patients carrying this mutation. Consequently, our study will facilitate clinical genetic practice, particularly genotype-based stratification of PKU treatment.
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Biopterinas/análogos & derivados , Fenilalanina Hidroxilasa/genética , Fenilalanina Hidroxilasa/metabolismo , Fenilcetonurias/genética , Biopterinas/farmacología , Línea Celular Tumoral , Glutamina/genética , Humanos , Lisina/genética , Modelos Biológicos , Modelos Moleculares , Fenilalanina Hidroxilasa/química , Fenilcetonurias/tratamiento farmacológico , Fenilcetonurias/metabolismo , Mutación Puntual , Estructura Terciaria de Proteína , Análisis de Secuencia de ADNRESUMEN
The aim of our study was to assess the current state of newborn screening (NBS) in the region of southeastern Europe, as an example of a developing region, focusing also on future plans. Responses were obtained from 11 countries. Phenylketonuria screening was not introduced in four of 11 countries, while congenital hypothyroidism screening was not introduced in three of them; extended NBS programs were non-existent. The primary challenges were identified. Implementation of NBS to developing countries worldwide should be considered as a priority.
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Enfermedades Genéticas Congénitas/diagnóstico , Tamizaje Neonatal , Hipotiroidismo Congénito/diagnóstico , Hipotiroidismo Congénito/epidemiología , Europa (Continente) , Enfermedades Genéticas Congénitas/epidemiología , Humanos , Recién Nacido , Tamizaje Masivo/economía , Tamizaje Masivo/métodos , Tamizaje Neonatal/economía , Tamizaje Neonatal/métodos , Fenilcetonurias/diagnóstico , Fenilcetonurias/epidemiologíaRESUMEN
BACKGROUND: Childhood epilepsies are caused by heterogeneous underlying disorders where approximately 40% of the origins of epilepsy can be attributed to genetic factors. The application of next-generation sequencing (NGS) has revolutionized molecular diagnostics and has enabled the identification of disease-causing genes and variants in childhood epilepsies. The objective of this study was to use NGS to identify variants in patients with childhood epilepsy, to expand the variant spectrum and discover potential therapeutic targets. METHODS: In our study, 55 children with epilepsy of unknown etiology were analyzed by combining clinical-exome and whole-exome sequencing. Novel variants were characterized using various in silico algorithms for pathogenicity and structure prediction. RESULTS: The molecular genetic cause of epilepsy was identified in 28 patients and the overall diagnostic success rate was 50.9%. We identified variants in 22 different genes associated with epilepsy that correlate well with the described phenotype. SCN1A gene variants were found in five unrelated patients, while ALDH7A1 and KCNQ2 gene variants were found twice. In the other 19 genes, variants were found only in a single patient. This includes genes such as ASH1L, CSNK2B, RHOBTB2, and SLC13A5, which have only recently been associated with epilepsy. Almost half of diagnosed patients (46.4%) carried novel variants. Interestingly, we identified variants in ALDH7A1, KCNQ2, PNPO, SCN1A, and SCN2A resulting in gene-directed therapy decisions for 11 children from our study, including four children who all carried novel SCN1A genetic variants. CONCLUSIONS: Described novel variants will contribute to a better understanding of the European genetic landscape, while insights into the genotype-phenotype correlation will contribute to a better understanding of childhood epilepsies worldwide. Given the expansion of molecular-based approaches, each newly identified genetic variant could become a potential therapeutic target.
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INTRODUCTION: We evaluated a novel approach for investigation of lymphocyte dysregulation in Gaucher patients by including determination of IgH and TCR gene rearrangements together with levels of immunoglobulins, natural autoantibodies as well as presence of monoclonal protein. MATERIALS AND METHODS: Measurement of serum immunoglobulins, monoclonal immunoglobulins, selected autoantibodies, as well as analysis of immunoglobulin heavy chain and T cell receptor gene rearrangements. RESULTS: Immunoglobulin disorder was detected in 29.6% patients, 40.7% demonstrated presence of B cell clonality and 44.4% demonstrated presence of autoantibodies. In five patients in our series, the presence of IgH gene rearrangement was the only detectable indicator of B cell dysfunction. TCR gene rearrangements were not found in any of the patients. CONCLUSION: Based on our results, we propose IgH gene rearrangements as a new biomarker for investigation of B cell dysfunction occurring as a complication of Gaucher disease.
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Linfocitos B/inmunología , Linfocitos B/metabolismo , Enfermedad de Gaucher/genética , Enfermedad de Gaucher/inmunología , Hipergammaglobulinemia/genética , Hipergammaglobulinemia/inmunología , Adolescente , Adulto , Niño , Preescolar , Femenino , Humanos , Cadenas Pesadas de Inmunoglobulina/genética , Masculino , Persona de Mediana Edad , Receptores de Antígenos de Linfocitos T/genética , Receptores de Antígenos de Linfocitos T/inmunología , Adulto JovenRESUMEN
Since bone pathology is a major concern in type 1 Gaucher disease (GD1), we evaluated bone mineral density (BMD) in adults receiving velaglucerase alfa in the seminal Phase I/II and extension trial. Ten treatment-naïve symptomatic patients with GD1 (four men, six women; median age 35years, range 18-62years) were included; of these, four patients were receiving bisphosphonates at enrollment. Using WHO criteria to classify the lumbar spine (LS) and femoral neck (FN) BMD T-scores, respectively, one (10%) and four (40%) patients had osteoporosis; eight (80%) and five (50%) had osteopenia; and one each (10%) was in the normal range, at baseline. By Month 69, two LS and one FN osteopenic patients normalized and one FN osteoporotic patient became osteopenic; change was seen only in patients not receiving bisphosphonates. Significant improvements in BMD Z-scores were seen at the LS by Month 24 and at the FN by Month 33 and were continuous thereafter. In linear mixed models, Z-scores were significantly lower than the reference population at baseline and improved significantly with treatment (LS and FN both P<0.01); analysis of the subgroup of patients not receiving bisphosphonates showed similar results. In conclusion, in this small cohort, velaglucerase alfa was associated with clinically meaningful and statistically significant LS and FN BMD improvements as early as Month 24 (LS) and 33 (FN), despite dose reduction and significant baseline skeletal pathology. These results suggest that velaglucerase alfa may hold promise in the management of skeletal pathology associated with GD1.
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Conservadores de la Densidad Ósea/farmacología , Conservadores de la Densidad Ósea/uso terapéutico , Densidad Ósea/efectos de los fármacos , Enfermedad de Gaucher/tratamiento farmacológico , Enfermedad de Gaucher/metabolismo , Glucosilceramidasa/farmacología , Glucosilceramidasa/uso terapéutico , Adolescente , Adulto , Difosfonatos/farmacología , Difosfonatos/uso terapéutico , Terapia de Reemplazo Enzimático , Femenino , Humanos , Masculino , Persona de Mediana Edad , Resultado del Tratamiento , Adulto JovenRESUMEN
Significant part of Southeastern Europe (with a population of 76 million) has newborn screening (NBS) programs non-harmonized with developed European countries. Initial survey was conducted in 2013/2014 among 11 countries from the region (Albania, Bulgaria, Bosnia and Herzegovina (BIH), Croatia, Kosovo, Macedonia, Moldova, Montenegro, Romania, Serbia, and Slovenia) to assess the main characteristics of their NBS programs and their future plans. Their cumulative population at that time was ~52,5 million. At that time, none of the countries had an expanded NBS program, while phenylketonuria screening was not introduced in four and congenital hypothyroidism in three of 11 countries. We repeated the survey in 2020 inviting the same 11 countries, adding Cyprus, Greece, Hungary, and Malta (due to their geographical position in the wider region). The aims were to assess the current state, to evaluate the change in the period, and to identify the main obstacles impacting the implementation of expanded NBS and/or reaching a wider population. Responses were collected from 12 countries (BIH-Federation of BIH, BIH-Republic of Srpska, Bulgaria, Croatia, Greece, Hungary, Kosovo, North Macedonia, Malta, Montenegro, Romania, Serbia, Slovenia) with a population of 68.5 million. The results of the survey showed that the regional situation regarding NBS only modestly improved in this period. All of the surveyed countries except Kosovo screened for at least congenital hypothyroidism, while phenylketonuria was not screened in four of 12 countries. Croatia and Slovenia implemented an expanded NBS program using tandem mass spectrometry from the time of last survey. In conclusion, the current status of NBS programs in Southeastern Europe is very variable and is still underdeveloped (or even non-existent) in some of the countries. We suggest establishing an international task-force to assist with implementation and harmonization of basic NBS services where needed.
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BACKGROUND: In children and adolescents, primary hyperparathyroidism (pHPT) is rare, associated with severe morbidity, and has different clinical characteristics than in adults. The aim of this study was to analyze differences in clinical and laboratory characteristics between children and adolescents with pHPT. METHODS: A retrospective cohort study was conducted to analyze pHPT characteristics in young patients, who have been operated at our institution. All patients were divided into two groups: group of patients ≤15â¯years (children) and group of patients >15 and ≤20â¯years (adolescents). RESULTS: Out of 1363 pHPT patients surgically treated during the study period, 14 patients (1%) were younger than 20â¯years: 6 children and 8 adolescents. Male-to-female ratio in children was 2:1, and in adolescents 1:1.7. Kidney stones were found in 62.5% of the adolescents and in none of the children patients. Bone form of the disease was the most frequent in children (in 83.1%), while in adolescents the kidney form was the most frequent (in 50%). Only 16.7% of children and 25% of adolescents did not have classical symptoms. All adolescent patients had single parathyroid adenoma, while 4 children patients had single parathyroid adenoma, one patient had hyperplasia, and one had parathyroid carcinoma. Both preoperative serum calcium and PTH levels were higher in children than in adolescents (3.87â¯mmol/L vs. 3.17â¯mmol/L; 812â¯ng/mL vs. 392â¯ng/mL, respectively). In all patients vitamin D level was low. All patients had normal postoperative values of serum calcium and PTH. CONCLUSION: There is a significant difference in clinical and biochemical characteristics between children and adolescent pHPT patients. Therefore, these two groups should be analyzed and treated separately. TYPE OF STUDY: Retrospective comparative study. LEVEL OF EVIDENCE: Level III.
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Hiperparatiroidismo Primario , Adolescente , Factores de Edad , Calcio/sangre , Niño , Humanos , Hiperparatiroidismo Primario/complicaciones , Hiperparatiroidismo Primario/epidemiología , Hiperparatiroidismo Primario/cirugía , Cálculos Renales , Hormona Paratiroidea/sangre , Estudios RetrospectivosRESUMEN
BACKGROUND: Glycogen storage disease type Ib (GSD-Ib) is an inherited metabolic disorder caused by autosomal recessive mutations in SLC37A4 coding for the glucose-6-phosphate transporter. Neutropenia represents major feature of GSD-Ib along with metabolic disturbances. Previous research in GSD-Ib patients did not reveal significant genotype-phenotype correlation. Our objective was to explore the frequency and severity of neutropenia and it's complications in relation to genotype of GSD-Ib patients. METHODS: We estimated cumulative incidence of neutropenia and severe neutropenia, relation of genotype to absolute neutrophil count (ANC), and dynamics of ANC during serious bacterial infections (SBI) in a cohort of Serbian GSD Ib patients. Impact of genotype on GSD Ib-related inflammatory bowel disease (IBD) was also assessed. RESULTS: Absolute neutrophil count (ANC)â¯<â¯1500/mm3 was present in all 33 patients, with severe neutropenia (ANC<500/mm3) occurring in 60.6% of patients. The median age at neutropenia onset was 24 months, while severe neutropenia developed at median of 4.5 years. The ANC was elevated during 90.5% episodes of SBI. Genotypes c.81T>A/c.785G>A and c.81T>A/c.1042_1043delCT are associated with earlier onset of neutropenia. Patients carrying c.785G>A mutation express a higher capacity for ANC increase during SBI. Inflammatory bowel disease was diagnosed in 8 patients (24.2% of total) with median age of onset at 7 years. Risk for IBD occurrence was not significantly affected by gender, genotype and severity of neutropenia. CONCLUSIONS: We may conclude that certain mutations in SLC37A4 influence the risk for severe neutropenia occurrence but also affect the capacity to increase ANC during SBI.
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Antiportadores/genética , Enfermedad del Almacenamiento de Glucógeno Tipo I/genética , Enfermedades Inflamatorias del Intestino/complicaciones , Proteínas de Transporte de Monosacáridos/genética , Neutropenia/genética , Adolescente , Adulto , Niño , Preescolar , Estudios de Cohortes , Femenino , Estudios de Asociación Genética , Genotipo , Enfermedad del Almacenamiento de Glucógeno Tipo I/complicaciones , Humanos , Incidencia , Enfermedades Inflamatorias del Intestino/genética , Masculino , Mutación , Neutropenia/sangre , Neutropenia/líquido cefalorraquídeo , Neutropenia/fisiopatología , Neutrófilos/citología , Fenotipo , SerbiaRESUMEN
OBJECTIVES: Primary hyperparathyroidism in juveniles is extremely rare condition, but in the last few decades the incidence is increasing. The aim of this study was to compare biochemical and clinical characteristics of juvenile and adult primary hyperparathyroidism patients. METHODS: A retrospective case-control study was conducted from 2004 until 2017 in high volume endocrine surgery center. Juvenile group consisted of all primary hyperparathyroidism patients younger than 20 who have undergone parathyroidectomy, and two-fold more patients older than 20 were classified in control (adult) group. RESULTS: A total of 14 patients with the age ≤20 years were included in the juvenile group, while 28 patients older than 20 were selected for the control group. Female-to-male ratio in juveniles was 1:1, and in adults 8:1 (p = 0.005). The most common form of the disease in juveniles was bone disease (42.9%) and most of adults were asymptomatic (39.3%). Mean preoperative serum calcium level was significantly higher in juveniles than in adults, 3.47 ± 0.74 mmol/L vs. 2.96 ± 0.25 mmol/L, p = 0.025. Mean preoperative PTH level was higher in juveniles than in control group, 572.6 ± 533.3 ng/L vs. 331.8 ± 347.5 ng/L, p = 0.089. CONCLUSION: Clinical manifestations of primary hyperparathyroidism significantly differ in juvenile and adult patients. Juvenile primary hyperparathyroidism represents more severe form of the disease, often with end-organ damages, and it should be considered in patients with unspecific symptoms.
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Hiperparatiroidismo Primario/epidemiología , Adolescente , Adulto , Factores de Edad , Calcio/sangre , Estudios de Casos y Controles , Femenino , Humanos , Hiperparatiroidismo Primario/sangre , Hiperparatiroidismo Primario/cirugía , Incidencia , Masculino , Persona de Mediana Edad , Hormona Paratiroidea/sangre , Paratiroidectomía , Adulto JovenAsunto(s)
Enfermedad de Gaucher/patología , Leucopenia/patología , Subgrupos Linfocitarios/patología , Adolescente , Adulto , Anciano , Niño , Preescolar , Femenino , Citometría de Flujo , Enfermedad de Gaucher/complicaciones , Humanos , Leucopenia/complicaciones , Masculino , Persona de Mediana Edad , Índice de Severidad de la EnfermedadRESUMEN
Glycogen storage disease type Ib (GSD Ib) is an autosomal recessive disorder, caused by a deficiency of ubiquitously expressed SLC37A4 protein. Deficiency of SLC37A4 leads to abnormal storage of glycogen in the liver and kidneys, resulting in long-term complications of renal disease and hepatocellular adenomas, whose mechanisms are poorly understood. Molecular markers of the adaptive responses to the metabolic stress caused by a deficiency of SLC37A4, such as markers related to the endoplasmic reticulum (ER) stress and unfolded protein response (UPR), have not been extensively studied. The aim of this study was to investigate the expression of molecular markers of the UPR response and apoptosis related to a deficiency of SLC37A4 in kidney cells. For that purpose, we intended to establish a human kidney cell model system for GSD Ib. The novel variant c.248G>A, found in GSD Ib patients, was introduced into the Flp-In™T-REx™-293 cell line using CRISPR/Cas9-mediated precise gene editing method, resulting in significant decrease of SLC37A4 gene expression. In this model system we used RT-qPCR analysis to investigate the expression of molecular markers of the UPR response (ATF4, DDIT3, HSPA5, and XBP1s) and apoptosis (BCL2, BAX). We demonstrated that under chronic metabolic stress conditions caused by SLC37A4 deficiency, the ER stress-induced UPR was triggered, resulting in suppression of the UPR molecular markers and cell survival promotion (decreased expression levels of ATF4, DDIT3, HSPA5, with the exception of XBP1s). However, persistent metabolic stress overrides an adaptation and induces apoptosis through increased expression of pro-apoptotic markers (decreased ratio of BCL2/BAX genes). We established a cellular model system characterized by a deficiency of SLC37A4, which presents pathological manifestations of GSD Ib in the kidney. Expression analysis in a novel model system supports the hypothesis that renal dysfunction in the GSD Ib is partly due to the ER stress and increased apoptosis.
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Antiportadores/genética , Edición Génica/métodos , Enfermedad del Almacenamiento de Glucógeno Tipo I/genética , Enfermedades Renales/etiología , Proteínas de Transporte de Monosacáridos/genética , Mutación Puntual , Apoptosis , Sistemas CRISPR-Cas , Línea Celular , Chaperón BiP del Retículo Endoplásmico , Estrés del Retículo Endoplásmico , Marcadores Genéticos , Enfermedad del Almacenamiento de Glucógeno Tipo I/complicaciones , Humanos , Enfermedades Renales/genética , Modelos Biológicos , Mutación , Respuesta de Proteína DesplegadaRESUMEN
Parathyroid carcinoma is extremely rare in pediatric population. The authors report a case of 15-year-old girl with extremely elevated serum calcium (4.1 mmol/L) and parathyroid hormone (1170 pg/mL), with palpable neck mass. After en bloc resection, the patient remained normocalcemic within the next 2 years. To the best of our knowledge, this is the fourteenth documented case of parathyroid carcinoma in patients younger than 16 years. Even though parathyroid carcinoma is very uncommon in children with good prognosis, this diagnosis has to be considered when a child has severe hypercalcemia, elevated parathyroid hormone and palpable neck mass.
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Neoplasias de las Paratiroides/diagnóstico , Neoplasias de las Paratiroides/cirugía , Adolescente , Factores de Edad , Femenino , Humanos , Hipercalcemia/etiología , Hormona Paratiroidea/sangreRESUMEN
Phenylketonuria (PKU) management is aimed at preventing neurocognitive and psychosocial dysfunction by keeping plasma phenylalanine concentrations within the recommended target range. It can be questioned, however, whether universal plasma phenylalanine target levels would result in optimal neurocognitive outcomes for all patients, as similar plasma phenylalanine concentrations do not seem to have the same consequences to the brain for each PKU individual. To better understand the inter-individual differences in brain vulnerability to high plasma phenylalanine concentrations, we aimed to identify untreated and/or late-diagnosed PKU patients with near-normal outcome, despite high plasma phenylalanine concentrations, who are still alive. In total, we identified 16 such cases. While intellectual functioning in these patients was relatively unaffected, they often did present other neurological, psychological, and behavioral problems. Thereby, these "unusual" PKU patients show that the classical symptomatology of untreated or late-treated PKU may have to be rewritten. Moreover, these cases show that a lack of intellectual dysfunction despite high plasma phenylalanine concentrations does not necessarily imply that these high phenylalanine concentrations have not been toxic to the brain. Also, these cases may suggest that different mechanisms are involved in PKU pathophysiology, of which the relative importance seems to differ between patients and possibly also with increasing age. Further research should aim to better distinguish PKU patients with respect to their cerebral effects to high plasma phenylalanine concentrations.
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Fenilalanina/sangre , Fenilcetonurias/psicología , Adolescente , Adulto , Encéfalo/metabolismo , Niño , Diagnóstico Tardío , Femenino , Humanos , Individualidad , Discapacidad Intelectual/genética , Masculino , Persona de Mediana Edad , Fenilcetonurias/sangre , Fenilcetonurias/diagnóstico , Adulto JovenRESUMEN
BACKGROUND: Phenylketonuria (PKU) is often considered as the classical example of a genetic disorder in which severe symptoms can nowadays successfully be prevented by early diagnosis and treatment. In contrast, untreated or late-treated PKU is known to result in severe intellectual disability, seizures, and behavioral disturbances. Rarely, however, untreated or late-diagnosed PKU patients with high plasma phenylalanine concentrations have been reported to escape from intellectual disability. The present study aimed to review published cases of such PKU patients. METHODS: To this purpose, we conducted a literature search in PubMed and EMBASE up to 8th of September 2017 to identify cases with 1) PKU diagnosis and start of treatment after 7 years of age; 2) untreated plasma phenylalanine concentrations ≥1200 µmol/l; and 3) IQ ≥80. Literature search, checking reference lists, selection of articles, and extraction of data were performed by two independent researchers. RESULTS: In total, we identified 59 published cases of patients with late-diagnosed PKU and unexpected favorable outcome who met the inclusion criteria. Although all investigated patients had intellectual functioning within the normal range, at least 19 showed other neurological, psychological, and/or behavioral symptoms. CONCLUSIONS: Based on the present findings, the classical symptomatology of untreated or late-treated PKU may need to be rewritten, not only in the sense that intellectual dysfunction is not obligatory, but also in the sense that intellectual functioning does not (re)present the full picture of brain damage due to high plasma phenylalanine concentrations. Further identification of such patients and additional analyses are necessary to better understand these differences between PKU patients.
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Discapacidad Intelectual/sangre , Discapacidad Intelectual/etiología , Fenilcetonurias/sangre , Fenilcetonurias/complicaciones , Femenino , Humanos , Masculino , Fenilalanina/sangreRESUMEN
X-linked adrenoleukodistrophy is a severe neurodegenerative disorder with impaired very long chain fatty acid metabolism. The disease associated ABCD1 gene encodes a peroxisomal membrane protein which belongs to the superfamily of ATP-binding cassette transporters. We investigated eight male X-ALD patients diagnosed among 142 suspected patients referred for investigation. Plasma levels of very long chain fatty acids were measured at our laboratory using capillary gas chromatography. Eight cases of childhood X-ALD were diagnosed. This is the first published series of Serbian patients with X-ALD. In addition, diagnosis identifies carriers, which could be benefit for genetic counselling and prenatal diagnosis.
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BACKGROUND: Postprandial hyperinsulinemic hypoglycemia (PHH) is an increasingly recognized complication of gastric bypass surgery in obese adults, distinct from the "dumping syndrome". CASE PRESENTATION: Upon birth, primary repair of esophageal atresia was performed, and at the age of 14 months definite esophageal reconstruction was performed. At the age of 3 years, recurrent brief episodes of symptomatic hypoglycemia started. At the age of 5.7 years the girl was admitted to our clinic and investigations indicated hyperinsulinemic hypoglycemia. Oral glucose tolerance test (OGTT) and continuous glucose monitoring results revealed frequent postprandial hypoglycemic events, which were always preceded by early postprandial hyperglycemia. It was concluded that the patient had PHH caused by a delayed and hyperinsulinemic response to carbohydrate intake as a result of esophagogastric surgery. Treatment with acarbose was titrated using flash glucose monitoring, which resulted in satisfactory glucose regulation. CONCLUSIONS: This is the first described case of a child with PHH following esophageal reconstruction.
Asunto(s)
Atresia Esofágica/cirugía , Derivación Gástrica/efectos adversos , Hiperinsulinismo/etiología , Hipoglucemia/etiología , Obesidad Mórbida/cirugía , Procedimientos de Cirugía Plástica/efectos adversos , Complicaciones Posoperatorias , Niño , Femenino , Humanos , Hiperinsulinismo/patología , Hipoglucemia/patología , Obesidad Mórbida/complicaciones , Periodo Posprandial , Pronóstico , Factores de RiesgoRESUMEN
Phenylketonuria (PKU) is a metabolic disease caused by mutations in the phenylalanine hydroxylase (PAH) gene. Although the PAH genotype remains the main determinant of PKU phenotype severity, genotype-phenotype inconsistencies have been reported. In this study, we focused on unanalysed sequences in non-coding PAH gene regions to assess their possible influence on the PKU phenotype. We transiently transfected HepG2 cells with various chloramphenicol acetyl transferase (CAT) reporter constructs which included PAH gene non-coding regions. Selected non-coding regions were indicated by in silico prediction to contain transcription factor binding sites. Furthermore, electrophoretic mobility shift assay (EMSA) and supershift assays were performed to identify which transcriptional factors were engaged in the interaction. We found novel KLF1 motif in the PAH promoter, which decreases CAT activity by 50 % in comparison to basal transcription in vitro. The cytosine at the c.-170 promoter position creates an additional binding site for the protein complex involving KLF1 transcription factor. Moreover, we assessed for the first time the role of a multivariant variable number tandem repeat (VNTR) region located in the 3'-region of the PAH gene. We found that the VNTR3, VNTR7 and VNTR8 constructs had approximately 60 % of CAT activity. The regulation is mediated by the C/EBPalpha transcription factor, present in protein complex binding to VNTR3. Our study highlighted two novel promoter KLF1 and 3'-region C/EBPalpha motifs in the PAH gene which decrease transcription in vitro and, thus, could be considered as PAH expression modifiers. New transcription motifs in non-coding regions will contribute to better understanding of the PKU phenotype complexity and may become important for the optimisation of PKU treatment.