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Because the causes of combined pituitary hormone deficiency (CPHD) are complex, the etiology of congenital CPHD remains unknown in most cases. The aim of the study was to identify the genetic etiology of CPHD in a well-defined single-center cohort. In total, 34 children (12 girls) with congenital CPHD (growth hormone (GH) deficiency and impaired secretion of at least one other pituitary hormone) treated with GH in our center were enrolled in the study. Their median age was 11.2 years, pre-treatment height was -3.2 s.d., and maximal stimulated GH was 1.4 ug/L. Of them, 30 had central adrenal insufficiency, 27 had central hypothyroidism, ten had hypogonadotropic hypogonadism, and three had central diabetes insipidus. Twenty-six children had a midline defect on MRI. Children with clinical suspicion of a specific genetic disorder underwent genetic examination of the gene(s) of interest via Sanger sequencing or array comparative genomic hybridization. Children without a detected causal variant after the first-tier testing or with no suspicion of a specific genetic disorder were subsequently examined using next-generation sequencing growth panel. Variants were evaluated by the American College of Medical Genetics standards. Genetic etiology was confirmed in 7/34 (21%) children. Chromosomal aberrations were found in one child (14q microdeletion involving the OTX2 gene). The remaining 6 children had causative genetic variants in the GLI2, PROP1, POU1F1, TBX3, PMM2, and GNAO1 genes, respectively. We elucidated the cause of CPHD in a fifth of the patients. Moreover, our study supports the PMM2 gene as a candidate gene for CPHD and suggests pathogenic variants in the GNAO1 gene as a potential novel genetic cause of CPHD.
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BACKGROUND: Type 1 diabetes (T1D) is a disease closely linked to nutrition and modifications in various dietary components have been part of the effort to prevent or slow the progression of the disease even before the discovery of insulin. SUMMARY: The scientific focus in the prevention or progression modification of T1D is mostly centered on four dietary compounds and their modifications - gluten and its omission, vitamin D supplementation, omega-3 fatty acids supplementation, and decreasing of the amount of ingested carbohydrates. The aim of this narrative review was to provide an overview of nutritional interventions studied in children either as preventive methods or as modifiers in the early stages of T1D from autoantibody positive individuals to persons with newly diagnosed T1D. KEY MESSAGES: Our review shows that dietary modifications in various dietary components might be useful but none of them seems to provide universal effects in T1D prevention or progression modification. More research is therefore needed with focus on promising modes of action of individual dietary components.
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AIMS: To evaluate glucose control non-inferiority and time benefits of telemedicine follow-up in children with type 1 diabetes (CwD). METHODS: In a single-center 9-month-long randomized controlled study (clinicaltrials.gov NCT05484427), 50 children were randomized to either telemedicine group (TG) followed-up distantly by e-mail, or to face-to-face group (FFG) attending standard personal visits. The primary endpoint was non-inferiority of HbA1c at final visit (level of non-inferiority was set at 5 mmol/mol). The secondary endpoints were subcutaneous glucose monitoring parameters and time consumption from both study subjects' and the physicians' point of view. RESULTS: Non-inferiority of HbA1c in the TG was proven (mean HbA1C 45.8 ± 7.3 [TG] vs. 50.0 ± 12.6 [FFG] mmol/mol, 6.3 vs. 6.7 % DCCT, p = 0.17; between groups HbA1C difference 95 % CI -10.2 to 1.9 mmol/mol). Telemedicine saved time for participants (mean visit duration [MVD] 50 [TG] vs. 247 min [FFG], p < 0.001). There were no other differences between groups neither in CGM parameters nor physician's time consumption (MVD 19 [TG] vs. 20 min [FFG], p = 0.58). CONCLUSIONS: Nine-month telemedicine follow-up of the children with well-controlled T1D is not inferior to standard face-to-face visits. Telemedicine visits saved time for the participants but not for their diabetologists.
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Diabetes Mellitus Tipo 1 , Telemedicina , Criança , Humanos , Glicemia , Hemoglobinas Glicadas , Automonitorização da Glicemia , HipoglicemiantesRESUMO
CONTEXT: Familial tall stature (FTS) is considered to be a benign variant of growth with a presumed polygenic etiology. However, monogenic disorders with possible associated pathological features could also be hidden under the FTS phenotype. OBJECTIVES: To elucidate the genetic etiology in families with FTS and to describe their phenotype in detail. DESIGN, SETTINGS AND PATIENTS: Children with FTS (height in both the child and his/her taller parent >2 SD) referred to the Endocrinology center of Motol University Hospital were enrolled to the study. Their DNA was examined cytogenetically and via next-generation sequencing panel of 786 genes associated with growth. The genetic results were evaluated by the American College of Molecular Genetics and Genomics guidelines. All of the participants underwent standard endocrinological examination followed by specialized anthropometric evaluation. RESULTS: In total, 34 children (19 girls) with FTS were enrolled in the study. Their median height and their taller parent's height were 3.1 SD and 2.5 SD, respectively. The genetic cause of FTS was elucidated in 11/34 (32.4%) children (47, XXX and 47, XYY karyotypes, SHOX duplication, and causative variants in NSD1 [in 2], SUZ12 [in 2], FGFR3, CHD8, GPC3, and PPP2R5D genes). Ten children had absent syndromic sings and 24 had dysmorphic features. CONCLUSION: Monogenic (and cytogenetic) etiology of FTS can be found among children with FTS. Genetic examination should be considered in all children with FTS regardless of the presence of dysmorphic features.
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INTRODUCTION: The aim of the study was to assess the differences in key parameters of type 1 diabetes (T1D) control associated with treatment and monitoring modalities including newly introduced hybrid closed-loop (HCL) algorithm in children and adolescents with T1D (CwD) using the data from the population-wide pediatric diabetes registry CENDA. METHODS: CwD younger than 19 years with T1D duration >1 year were included and divided according to the treatment modality and type of CGM used: multiple daily injection (MDI), insulin pump without (CSII) and with HCL function, intermittently scanned continuous glucose monitoring (isCGM), real-time CGM (rtCGM), and intermittent or no CGM (noCGM). HbA1c, times in glycemic ranges, and glucose risk index (GRI) were compared between the groups. RESULTS: Data of a total of 3,251 children (mean age 13.4 ± 3.8 years) were analyzed. 2,187 (67.3%) were treated with MDI, 1,064 (32.7%) with insulin pump, 585/1,064 (55%) with HCL. The HCL users achieved the highest median TIR 75.4% (IQR 6.3) and lowest GRI 29.1 (7.8), both p < 0.001 compared to other groups, followed by MDI rtCGM and CSII groups with TIR 68.8% (IQR 9.0) and 69.0% (7.5), GRI 38.8 (12.5) and 40.1 (8.5), respectively (nonsignificant to each other). These three groups did not significantly differ in their HbA1c medians (51.8 [IQR 4.5], 50.7 [4.5], and 52.7 [5.7] mmol/mol, respectively). NoCGM groups had the highest HbA1c and GRI and lowest TIR regardless of the treatment modality. CONCLUSION: This population-based study shows that the HCL technology is superior to other treatment modalities in CGM-derived parameters and should be considered as a treatment of choice in all CwD fulfilling the indication criteria.
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Diabetes Mellitus Tipo 1 , Humanos , Criança , Adolescente , Diabetes Mellitus Tipo 1/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Insulina/uso terapêutico , Hemoglobinas Glicadas , Automonitorização da Glicemia , Glicemia , Controle GlicêmicoRESUMO
BACKGROUND: The thalidomide disaster resulted in tremendous congenital malformations in more than 10,000 children in the late 1950s and early 1960s. SUMMARY: Although numerous putative mechanisms were proposed to explain thalidomide teratogenicity, it was confirmed only recently that thalidomide, rather its derivative 5-hydroxythalidomide (5HT) in a complex with the cereblon protein, interferes with early embryonic transcriptional regulation. 5HT induces selective degradation of SALL4, a principal transcriptional factor of early embryogenesis. Genetic syndromes caused by pathogenic variants of the SALL4 gene phenocopy thalidomide embryopathy with congenital malformations ranging from phocomelia, reduced radial ray, to defects of the heart, kidneys, ear, eye, and possibly cerebral midline and pituitary. SALL4 interacts with TBX5 and a handful of other transcriptional regulators and downregulates the Sonic hedgehog signaling pathway. Cranial midline defects, microcephaly, and short stature due to growth hormone deficiency have been occasionally reported in children carrying SALL4 pathogenic variants associated with generalized stunting of growth rather than just the loss of height attributable to the shortening of leg bones in many children with thalidomide embryopathy. KEY MESSAGES: Thus, SALL4 joins the candidate gene list for monogenic syndromic pituitary insufficiency. In this review, we summarize the journey from the thalidomide disaster through the functions of the SALL4 gene to its link to the hormonal regulation of growth.
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Anormalidades Múltiplas , Doenças Fetais , Talidomida , Fatores de Transcrição , Humanos , Anormalidades Múltiplas/induzido quimicamente , Anormalidades Múltiplas/genética , Proteínas Hedgehog , Talidomida/efeitos adversos , Fatores de Transcrição/genética , Extremidade SuperiorRESUMO
INTRODUCTION: Among children born small for gestational age, 10-15% fail to catch up and remain short (SGA-SS). The underlying mechanisms are mostly unknown. We aimed to decipher genetic aetiologies of SGA-SS within a large single-centre cohort. METHODS: Out of 820 patients treated with growth hormone (GH), 256 were classified as SGA-SS (birth length and/or birth weight <-2 SD for gestational age and life-minimum height <-2.5 SD). Those with the DNA triplet available (child and both parents) were included in the study (176/256). Targeted testing (karyotype/FISH/MLPA/specific Sanger sequencing) was performed if a specific genetic disorder was clinically suggestive. All remaining patients underwent MS-MLPA to identify Silver-Russell syndrome, and those with unknown genetic aetiology were subsequently examined using whole-exome sequencing or targeted panel of 398 growth-related genes. Genetic variants were classified using ACMG guidelines. RESULTS: The genetic aetiology was elucidated in 74/176 (42%) children. Of these, 12/74 (16%) had pathogenic or likely pathogenic (P/LP) gene variants affecting pituitary development (LHX4, OTX2, PROKR2, PTCH1, POU1F1), the GH-IGF-1 or IGF-2 axis (GHSR, IGFALS, IGF1R, STAT3, HMGA2), 2/74 (3%) the thyroid axis (TRHR, THRA), 17/74 (23%) the cartilaginous matrix (ACAN, various collagens, FLNB, MATN3), and 7/74 (9%) the paracrine chondrocyte regulation (FGFR3, FGFR2, NPR2). In 12/74 (16%), we revealed P/LP affecting fundamental intracellular/intranuclear processes (CDC42, KMT2D, LMNA, NSD1, PTPN11, SRCAP, SON, SOS1, SOX9, TLK2). SHOX deficiency was found in 7/74 (9%), Silver-Russell syndrome in 12/74 (16%) (11p15, UPD7), and miscellaneous chromosomal aberrations in 5/74 (7%) children. CONCLUSIONS: The high diagnostic yield sheds a new light on the genetic landscape of SGA-SS, with a central role for the growth plate with substantial contributions from the GH-IGF-1 and thyroid axes and intracellular regulation and signalling.
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Nanismo , Hormônio do Crescimento Humano , Síndrome de Silver-Russell , Criança , Recém-Nascido , Humanos , Fator de Crescimento Insulin-Like I , Transtornos do Crescimento/genética , Transtornos do Crescimento/diagnóstico , Síndrome de Silver-Russell/genética , Idade Gestacional , Recém-Nascido Pequeno para a Idade Gestacional , Hormônio do Crescimento Humano/genética , Estatura/genética , Proteína de Homoeobox de Baixa EstaturaRESUMO
INTRODUCTION: The SALL4 gene encodes a transcription factor that is essential for early embryonic cellular differentiation of the epiblast and primitive endoderm. It is required for the development of neural tissue, kidney, heart, and limbs. Pathogenic SALL4 variants cause Duane-radial ray syndrome (Okihiro syndrome), acro-renal-ocular syndrome, and Holt-Oram syndrome. We report a family with vertical transmission of a SALL4 pathogenic variant leading to radial hypoplasia and kidney dystopia in several generations with additional growth hormone deficiency (GHD) in the proband. CASE PRESENTATION: Our male proband was born at the 39th week of gestation. He was born small for gestational age (SGA; birth weight 2,550 g, -2.2 SDS; length 47 cm, -2.0 SDS). He had bilateral asymmetrical radial ray malformation (consisting of radial hypoplasia, ulnar flexure, and bilateral aplasia of the thumb) and pelvic kidney dystopia, but no cardiac malformations, clubfoot, ocular coloboma, or Duane anomaly. He was examined for progressive short stature at the age of 3.9 years, where his IGF-1 was 68 µg/L (-1.0 SD), and growth hormone (GH) after stimulation 6.2 µg/L. Other pituitary hormones were normal. A brain CT revealed normal morphology of the cerebral midline and the pituitary. He had a dental anomaly - a central mandibular ectopic canine. MRI could not be done due to the presence of metal after multiple corrective plastic surgeries of his hands. His mother's and father's heights are 152.3 cm (-2.4 SD) and 177.8 cm (-0.4 SD), respectively. His father has a milder malformation of the forearm. The affected paternal grandfather (height 164 cm; -2.3 SD) has a radial ray defect with missing opposition of the thumb. The family reports a similar phenotype of radial dysplasia in the paternal grandfather's mother. The proband started GH therapy at age 6.5 years when his height was 109 cm (-2.8 SDS) and he experienced catch-up growth as expected in GHD. Puberty started spontaneously at the age of 12.5 years. At age 13, his height was 158.7 cm (-0.2 SDS). Whole-exome sequencing revealed a nonsense variant in the SALL4 gene c.1717C>T (p.Arg573Ter) in the proband, his father, and paternal grandfather. CONCLUSION: This is the first observation of a patient with a congenital upper limb defect due to a pathogenic SALL4 variant who has isolated GHD with no apparent cerebral or facial midline anomaly and has been successfully treated with growth hormone.
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Síndrome da Retração Ocular , Hormônio do Crescimento Humano , Hipopituitarismo , Pré-Escolar , Humanos , Masculino , Síndrome da Retração Ocular/genética , Síndrome da Retração Ocular/patologia , Hipopituitarismo/genética , Rim/patologia , Fenótipo , Fatores de Transcrição/genética , Extremidade Superior/patologia , AdultoRESUMO
Objective: To compare parameters of glycemic control among three types of hybrid closed loop (HCL) systems in children with T1D (CwD) using population-wide data from the national pediatric diabetes registry CENDA. Methods: CwD aged <19 years treated with Medtronic MiniMed 780G (780G), Tandem t:slim X2 (Control-IQ) or do-it-yourself AndroidAPS (AAPS) systems for >12 months and monitored by CGM >70% of the time were included. HbA1c, times in glycemic ranges, and Glycemia Risk Index (GRI) were used for cross-sectional comparison between the HCL systems. Results: Data from 512 CwD were analyzed. 780G, Control-IQ and AAPS were used by 217 (42.4%), 211 (41.2%), and 84 (16.4%) CwD, respectively. The lowest HbA1c value was observed in the AAPS group (44 mmol/mol; IQR 8.0, p<0.0001 vs any other group), followed by Control-IQ and 780G groups (48 (IQR 11) and 52 (IQR 10) mmol/mol, respectively). All of the systems met the recommended criteria for time in range (78% in AAPS, 76% in 780G, and 75% in Control-IQ users). CwD using AAPS spent significantly more time in hypoglycemia (5% vs 2% in 780G and 3% in Control-IQ) and scored the highest GRI (32, IQR 17). The lowest GRI (27, IQR 15) was seen in 780G users. Conclusion: Although all HCL systems proved effective in maintaining recommended long-term glycemic control, we observed differences that illustrate strengths and weaknesses of particular systems. Our findings could help in individualizing the choice of HCL systems.
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Diabetes Mellitus Tipo 1 , Hipoglicemia , Humanos , Criança , Diabetes Mellitus Tipo 1/tratamento farmacológico , Hemoglobinas Glicadas , Glicemia , Estudos Transversais , Insulina/uso terapêutico , Sistemas de Infusão de Insulina , Automonitorização da Glicemia , Hipoglicemia/induzido quimicamente , Hipoglicemia/epidemiologia , Sistema de RegistrosRESUMO
Familial short stature (FSS) describes vertically transmitted growth disorders. Traditionally, polygenic inheritance is presumed, but monogenic inheritance seems to occur more frequently than expected. Clinical predictors of monogenic FSS have not been elucidated. The aim of the study was to identify the monogenic etiology and its clinical predictors in FSS children. Of 747 patients treated with growth hormone (GH) in our center, 95 with FSS met the inclusion criteria (pretreatment height ≤-2 SD in child and his/her shorter parent); secondary short stature and Turner/Prader-Willi syndrome were excluded criteria. Genetic etiology was known in 11/95 children before the study, remaining 84 were examined by next-generation sequencing. The results were evaluated by American College of Medical Genetics and Genomics (ACMG) guidelines. Nonparametric tests evaluated differences between monogenic and non-monogenic FSS, an ROC curve estimated quantitative cutoffs for the predictors. Monogenic FSS was confirmed in 36/95 (38%) children. Of these, 29 (81%) carried a causative genetic variant affecting the growth plate, 4 (11%) a variant affecting GH-insulin-like growth factor 1 (IGF1) axis and 3 (8%) a variant in miscellaneous genes. Lower shorter parent's height (P = 0.015) and less delayed bone age (BA) before GH treatment (P = 0.026) predicted monogenic FSS. In children with BA delayed less than 0.4 years and with shorter parent's heights ≤-2.4 SD, monogenic FSS was revealed in 13/16 (81%) cases. To conclude, in FSS children treated with GH, a monogenic etiology is frequent, and gene variants affecting the growth plate are the most common. Shorter parent's height and BA are clinical predictors of monogenic FSS.
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Objective: We evaluated the safety and feasibility of open-source automated insulin delivery AndroidAPS in adolescents and young adults with type 1 diabetes (T1D) and compared its efficacy in three different scenarios: hybrid closed loop (HCL) with meal boluses, meal announcement only (MA), and full closed loop (FCL). Research Design and Methods: In an open-label, prospective, randomized crossover trial (clinicaltrials.gov NCT04835350), 16 adolescents with T1D (10 females) with mean age of 17 years (range 15-20), glycated hemoglobin 56 mmol/mol (range 43-75), and mean duration of diabetes 5.9 years (9-15) underwent three distinct 3-day periods of camp living, comparing the above-mentioned scenarios of AndroidAPS. We used modified and locked version of AndroidAPS 3.1.03, which was called Pancreas4ALL for study purposes. The order of MA and FCL periods was assigned randomly. The primary endpoints were feasibility and safety of the system represented by percentage of time of glucose control by the system and time in hypoglycemia below 3 mmol/L. Results: The glycemia was controlled by the system 95% time of the study and the proportion of time below 3 mmol/L did not exceed 1% over the whole study period (0.72%). The HCL scenario reached significantly higher percentage of time below 3 mmol/L (HCL 1.05% vs. MA 0.0% vs. FCL 0.0%; P = 0.05) compared to other scenarios. No difference was observed among the scenarios in the percentage of time between 3.9 and 10 mmol/L (HCL 83.3% vs. MA 79.85% vs. FCL 81.03%, P = 0.58) corresponding to mean glycemia (HCL 6.65 mmol/L vs. MA 7.34 mmol/L vs. FCL 7.05 mmol/L, P = 0.28). No difference was observed in the mean daily dose of insulin or in the daily carbohydrate intake. No serious adverse event occurred during the study period. Conclusions: Our pilot study showed that FCL might be a realistic mode of treatment for people with T1D.
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Diabetes Mellitus Tipo 1 , Insulina , Feminino , Adolescente , Adulto Jovem , Humanos , Adulto , Insulina/uso terapêutico , Diabetes Mellitus Tipo 1/tratamento farmacológico , Hipoglicemiantes , Projetos Piloto , Estudos Prospectivos , Sistemas de Infusão de Insulina , Insulina Regular Humana/uso terapêutico , Estudos Cross-Over , GlicemiaRESUMO
Introduction: Currently, just a few major parameters are used for cardiovascular (CV) risk quantification to identify many of the high-risk subjects; however, they leave a lot of them with an underestimated level of CV risk which does not reflect the reality. Material and methods: The submitted study design of the Kosice Selective Coronarography Multiple Risk (KSC MR) Study will use computer analysis of coronary angiography results of admitted patients along with broad patients' characteristics based on questionnaires, physical findings, laboratory and many other examinations. Results: Obtained data will undergo machine learning protocols with the aim of developing algorithms which will include all available parameters and accurately calculate the probability of coronary artery disease. Conclusions: The KSC MR study results, if positive, could establisha base for development of proper software for revealing high-risk patients, as well as patients with suggested positive coronary angiography findings, based on the principles of personalised medicine.
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The aim of this review is to describe the therapeutic effect of thymol on various human diseases, followed by its bioavailability in humans and animals. Based on our knowledge from the current literature, after thymol addition, thymol metabolites-mostly thymol sulphate and glucuronide-are detected in the plasma and urine of humans and in the plasma, intestinal content, faeces and tissues in rats, pigs, chickens, horses and rabbits after enzymatic cleavage. In rabbits, thymol absorption from the gastrointestinal tract, its distribution within the organism, its accumulation in tissues and its excretion from the organism have been described in detail. It is necessary and important for these studies to suggest the appropriate dose needed to achieve the required health benefits not only for animals but also for humans. Information from this review concerning the mode of action of thymol in animal organisms could also be applied to human medicine and may help in the utilisation of herbal medicine in humans and in veterinary healthcare. This review summarises the important aspects of thymol's effects on health and its bioavailability in organisms, particularly in rabbits. In future, herbal-based drugs must be extensively investigated in terms of their mode of action, efficiency of administration and clinical effect.
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Introduction: The growth hormone deficiency (GHD) diagnosis is controversial especially due to low specificity of growth hormone (GH) stimulation tests. It is therefore believed that children diagnosed with GHD form a heterogeneous group with growth disorder frequently independent on GH function. No study evaluating the complex etiology of growth failure in children with diagnosed GHD has been performed thus far. Aims: To discover genetic etiology of short stature in children with diagnosed GHD from families with short stature. Methods: Fifty-two children diagnosed with primary GHD and vertically transmitted short stature (height SDS in the child and his/her shorter parent <-2 SD) were included to our study. The GHD diagnosis was based on growth data suggestive of GHD, absence of substantial disproportionality (sitting height to total height ratio <-2 SD or >+2 SD), IGF-1 levels <0 for age and sex specific SD and peak GH concentration <10 ug/L in two stimulation tests. All children were examined using next-generation sequencing methods, and the genetic variants were subsequently evaluated by American College of Medical Genetics standards and guidelines. Results: The age of children at enrollment into the study was 11 years (median, IQR 9-14 years), their height prior to GH treatment was -3.0 SD (-3.6 to -2.8 SD), IGF-1 concentration -1.4 SD (-2.0 to -1.1 SD), and maximal stimulated GH 6.3 ug/L (4.8-7.6 ug/L). No child had multiple pituitary hormone deficiency or a midbrain region pathology. Causative variant in a gene that affects growth was discovered in 15/52 (29%) children. Of them, only 2 (13%) had a genetic variant affecting GH secretion or function (GHSR and OTX2). Interestingly, in 10 (67%) children we discovered a primary growth plate disorder (ACAN, COL1A2, COL11A1, COL2A1, EXT2, FGFR3, NF1, NPR2, PTPN11 [2x]), in one (7%) a genetic variant impairing IGF-1 action (IGFALS) and in two (12%) a variant in miscellaneous genes (SALL4, MBTPS2). Conclusions: In children with vertically transmitted short stature, genetic results frequently did not correspond with the clinical diagnosis of GH deficiency. These results underline the doubtful reliability of methods standardly used to diagnose GH deficiency.
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Nanismo Hipofisário , Hormônio do Crescimento Humano , Adolescente , Criança , Feminino , Humanos , Masculino , Nanismo Hipofisário/diagnóstico , Nanismo Hipofisário/genética , Nanismo Hipofisário/tratamento farmacológico , Fator de Crescimento Insulin-Like I/genética , Reprodutibilidade dos TestesRESUMO
AIMS/HYPOTHESIS: The proportion of children with type 1 diabetes (T1D) who have experience with low-carbohydrate diet (LCD) is unknown. Our goal was to map the frequency of LCD among children with T1D and to describe their clinical and laboratory data. METHODS: Caregivers of 1040 children with T1D from three centers were addressed with a structured questionnaire regarding the children's carbohydrate intake and experience with LCD (daily energy intake from carbohydrates below 26% of age-recommended values). The subjects currently on LCD were compared to a group of non-LCD respondents matched to age, T1D duration, sex, type and center of treatment. RESULTS: A total of 624/1040 (60%) of the subjects completed the survey. A total of 242/624 (39%) subjects reported experience with voluntary carbohydrate restriction with 36/624 (5.8%) subjects currently following the LCD. The LCD group had similar HbA1c (45 vs. 49.5, p = 0.11), lower average glycemia (7.0 vs. 7.9, p = 0.02), higher time in range (74 vs. 67%, p = 0.02), lower time in hyperglycemia >10 mmol/L (17 vs. 20%, p = 0.04), tendency to more time in hypoglycemia <3.9 mmol/L(8 vs. 5%, p = 0.05) and lower systolic blood pressure percentile (43 vs. 74, p = 0.03). The groups did not differ in their lipid profile nor in current body height, weight or BMI. The LCD was mostly initiated by the parents or the subjects themselves and only 39% of the families consulted their decision with the diabetologist. CONCLUSIONS/INTERPRETATION: Low carbohydrate diet is not scarce in children with T1D and is associated with modestly better disease control. At the same time, caution should be applied as it showed a tendency toward more frequent hypoglycemia.
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Diabetes Mellitus Tipo 1/dietoterapia , Dieta com Restrição de Carboidratos , Glicemia/análise , Estatura , Índice de Massa Corporal , Peso Corporal , Criança , Diabetes Mellitus Tipo 1/metabolismo , Dieta com Restrição de Carboidratos/efeitos adversos , Dieta com Restrição de Carboidratos/estatística & dados numéricos , Feminino , Hemoglobinas Glicadas/análise , Humanos , Lipídeos/sangue , Masculino , Inquéritos e QuestionáriosRESUMO
OBJECTIVE: Data on closed loop systems in young children with type 1 diabetes (T1D) are limited. We tested the efficacy and safety of an open-source, do-it-yourself automated insulin delivery system AndroidAPS in preschool and school-aged children. RESEARCH DESIGN AND METHODS: This retrospective study analyzed diabetes control in 18 preschool (3-7 years) and 18 school-aged children (8-14 years) with T1D who switched from a sensor-augmented pump (SAP) to AndroidAPS. We compared the CGM parameters and HbA1c levels 3 months before and 6 months after the initiation of AndroidAPS therapy and evaluated frequency of severe adverse events during AndroidAPS use, the most frequent reasons for its interruption, and the experience and psychosocial benefits of AndroidAPS use. RESULTS: General glycemic control was significantly improved after the switch from SAP to AndroidAPS. Time in range (TIR) increased in both preschool (70.8%-78.6%, p = 0.004) and school-aged children (77.2%-82.9%, p < 0.001), whereas HbA1c levels decreased (preschool children 53.8-48.5 mmol/mol, p < 0.001; school-aged children 52.6-45.1 mmol/mol, p = 0.001). Time spent in range of 3.0-3.8 mmol/L increased slightly in school children (2.6%-3.8%, p = 0.040), but not in preschool children (3.0%-3.0%, p = 0.913). Time spent at <3 mmol/L remained unchanged in both preschool (0.95%-0.67%, p = 0.432) and school-aged children (0.8%-0.8%, p = 1.000). No episodes of severe hypoglycemia or DKA and significant improvement of quality of life were reported by AndroidAPS users. CONCLUSIONS: AndroidAPS seems effective for T1D control both in preschool and school-age children but further validation by prospective studies is necessary.
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Automonitorização da Glicemia , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/tratamento farmacológico , Hipoglicemiantes/administração & dosagem , Sistemas de Infusão de Insulina , Insulina/administração & dosagem , Adolescente , Fatores Etários , Glicemia/metabolismo , Criança , Pré-Escolar , Feminino , Hemoglobinas Glicadas/metabolismo , Humanos , Masculino , Estudos Retrospectivos , Fatores de Tempo , Resultado do TratamentoRESUMO
CONTEXT: Collagens are the most abundant proteins in the human body. In a growth plate, collagen types II, IX, X, and XI are present. Defects in collagen genes cause heterogeneous syndromic disorders frequently associated with short stature. Less is known about oligosymptomatic collagenopathies. OBJECTIVE: This work aims to evaluate the frequency of collagenopathies in familial short stature (FSS) children and to describe their phenotype, including growth hormone (GH) treatment response. METHODS: Eighty-seven FSS children (pretreatment height ≤â -2 SD both in the patient and his or her shorter parent) treated with GH were included in the study. Next-generation sequencing was performed to search for variants in the COL2A1, COL9A1, COL9A2, COL9A3, COL10A1, COL11A1, and COL11A2 genes. The results were evaluated using American College of Medical Genetics and Genomics guidelines. The GH treatment response of affected children was retrospectively evaluated. RESULTS: A likely pathogenic variant in the collagen gene was found in 10 of 87 (11.5%) children. Detailed examination described mild asymmetry with shorter limbs and mild bone dysplasia signs in 2 of 10 and 4 of 10 affected children, respectively. Their growth velocity improved from a median of 5.3 cm/year to 8.7 cm/year after 1 year of treatment. Their height improved from a median of -3.1 SD to -2.6 SD and to -2.2 SD after 1 and 3 years of therapy, respectively. The final height reached by 4 of 10 children differed by -0.67 to +1.0 SD and -0.45 to +0.5 SD compared to their pretreatment height and their affected untreated parent's height, respectively. CONCLUSION: Oligosymptomatic collagenopathies are a frequent cause of FSS. The short-term response to GH treatment is promising.
Assuntos
Colágeno/genética , Transtornos do Crescimento , Lâmina de Crescimento/patologia , Adolescente , Adulto , Criança , Pré-Escolar , Colágeno/deficiência , Colágeno Tipo XI/genética , República Tcheca/epidemiologia , Bases de Dados Factuais , Feminino , Estudos de Associação Genética , Transtornos do Crescimento/tratamento farmacológico , Transtornos do Crescimento/epidemiologia , Transtornos do Crescimento/genética , Transtornos do Crescimento/patologia , Lâmina de Crescimento/crescimento & desenvolvimento , Lâmina de Crescimento/metabolismo , Hormônio do Crescimento Humano/deficiência , Hormônio do Crescimento Humano/uso terapêutico , Humanos , Masculino , Fenótipo , Estudos Retrospectivos , Adulto JovemRESUMO
CONTEXT: The C-type natriuretic peptide receptor encoded by the NPR2 gene is a paracrine regulator of the growth plate; heterozygous NPR2 variants cause short stature with possible presence of different signs of bone dysplasia. To date, the effect of growth hormone (GH) treatment has been described in a few individuals with NPR2 gene variants with inconsistent results. OBJECTIVES: To identify NPR2 gene variants among children with familial short stature (FSS) and to describe their phenotype, including GH treatment response. DESIGN, SETTINGS AND PATIENTS: Out of 747 patients with short stature treated with GH in a single center, 87 with FSS met the inclusion criteria (pretreatment height ≤ -2 standard deviation in both the patient and the shorter parent, unknown genetic etiology). Next-generation sequencing methods were performed to search for NPR2 gene variants. The results were evaluated using the American College of Medical Genetics and Genomics guidelines. The GH treatment response (growth velocity improvement and height standard deviation score development over the first 5 years of treatment) was evaluated. RESULTS: In 5/87 children (5.7%), a (likely) pathogenic variant in the NPR2 gene was identified (p.Ile558Thr [in 2], p.Arg205*, p.Arg557His, p.Ser603Thr). Two children had disproportionate short-limbed short stature, 1 a dysplastic 5th finger phalanx. The growth velocity in the first year of GH treatment accelerated by 3.6 to 4.2 cm/year; the height improved by 1.2 to 1.8 SD over 5 years of treatment. CONCLUSIONS: NPR2 gene variants cause FSS in a significant proportion of children. Their GH treatment response is promising. Studies including final height data are necessary to assess the long-term efficacy of this therapy.