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. OBJECTIVE: To elucidate the genetic etiology in families with FTS and to describe their phenotype in detail. METHODS: Children with FTS (the life-maximum height in both the child and his/her taller parent > 2 SD for age and sex) referred to the Endocrinology center of Motol University Hospital were enrolled into the study. Their DNA was examined cytogenetically and via a 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 signs 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.
- MeSH
- dítě MeSH
- fenotyp MeSH
- genetické testování * metody MeSH
- lidé MeSH
- mladiství MeSH
- poruchy růstu genetika diagnóza MeSH
- předškolní dítě MeSH
- tělesná výška * genetika MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- mladiství MeSH
- mužské pohlaví MeSH
- předškolní dítě MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
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.
- Publikační typ
- časopisecké články MeSH
Vztah složení naší stravy a vzniku a léčby diabetes mellitus 1. typu (DM1) je znám již od dob před objevením inzulinu, kdy se poprvé objevila snaha pomocí dietních opatření zpomalit či zastavit progresi onemocnění. Kromě toho je k dietě přistupováno i jako k doplňkové léčbě k inzulinoterapii, jejímž účelem má být snaha o dosažení terapeutických cílů. V rámci dietních opatření v souvislosti s DM1 byl dosud zejména zkoumán vliv umělé dětské výživy, lepku, respektive jeho vysazení, vitaminu D, omega-3 mastných kyselin a sníženého příjmu sacharidů v rámci takzvané nízkosacharidové diety. Cílem tohoto přehledového článku je uceleně shrnout nejnovější vědecké poznatky o nutričních intervencích v různých fázích DM1.
Nutrition and type 1 diabetes (T1D) have been closely linked even before the discovery of insulin where the dietary interventions have been part of the effort to prevent or slow the progression of the disease. Additionally, alternative dietary approaches are sought as an adjuvant therapy to insulin use. The focus is given to these dietary approaches – infant formula, gluten and its exclusion, vitamin D, omega-3 fatty acids and limiting of the carbohydrate intake. The aim of this review is to summarize the scientific knowledge regarding dietary interventions in different stages of T1D.
- MeSH
- bezlepková dieta klasifikace metody MeSH
- diabetes mellitus 1. typu * diagnóza dietoterapie imunologie MeSH
- dieta s omezením sacharidů klasifikace metody MeSH
- dietoterapie * klasifikace metody MeSH
- dítě MeSH
- kalcitriol terapeutické užití MeSH
- kojenec MeSH
- kyseliny mastné omega-3 terapeutické užití MeSH
- lidé MeSH
- strava, jídlo, výživa MeSH
- Check Tag
- dítě MeSH
- kojenec MeSH
- lidé MeSH
- Publikační typ
- přehledy MeSH
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.
- MeSH
- dospělí MeSH
- Duaneův retrakční syndrom * genetika patologie MeSH
- fenotyp MeSH
- horní končetina patologie MeSH
- hypopituitarismus * genetika MeSH
- ledviny patologie MeSH
- lidé MeSH
- lidský růstový hormon * MeSH
- předškolní dítě MeSH
- transkripční faktory genetika MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- mužské pohlaví MeSH
- předškolní dítě MeSH
- Publikační typ
- kazuistiky MeSH
Od začátku války na Ukrajině přijala Česká republika více než 360 000 uprchlíků (United Nations High Council for Refugees, 2023), z nichž velkou část tvořily děti, včetně dětí s diabetem 1. typu (T1D). Celkem jsme v devíti centrech léčby dětského diabetu od února 2022 do června 2023 registrovali 124 dětí s T1D z Ukrajiny, které jsme následně sledovali ve tříměsíčních intervalech. Během prvního roku jejich pobytu v ČR došlo k významnému zlepšení průměrného HbA1c o 2,2 mmol/mol za ambulantní návštěvu (p=0,01, CI [-3,2; -1,1]). Největší pokles HbA1c jsme pozorovali u skupiny, u které byly nově nasazeny kontinuální monitory glykemie (CGM) (průměrný pokles o 2,9 mmol/mol za ambulantní návštěvu). Naše výsledky ukazují na nezastupitelnou roli CGM v managementu diabetu 1. typu.
Czechia has received over 360 000 refugees since the beginning of the war on Ukraine (United Nations High Council for Refugees, 2023). A majority of those refugees were women and children including children with type 1 diabetes (T1D). Throughout the duration of our study (February 2022 - June 2023) a total of 124 Ukrainian children with T1D presented into one of the 9 participating centers for pediatric diabetes. We followed up these children every 3 months for HbA1c, CGM values, therapy type and anthropologic measures. During the first year of their stay in Czechia, the HbA1c of these children decreased significantly by 2,2 mmol/mol per visit (p=0.01, CI [-3.2; -1.1]). HbA1c decreased the most in children who newly received CGM in Czechia with average decrease of 2,9 mmol/mol per visit. Our results show further underline the importance of CGM use in T1D management.
- MeSH
- analýza dat MeSH
- diabetes mellitus 1. typu * MeSH
- dítě MeSH
- hodnocení výsledků zdravotní péče MeSH
- kontinuální monitorování glukózy * přístrojové vybavení MeSH
- lidé MeSH
- management nemoci MeSH
- ozbrojené konflikty MeSH
- uprchlíci * MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- Geografické názvy
- Ukrajina MeSH
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.
- MeSH
- adrenální insuficience diagnóza etiologie MeSH
- diferenciální diagnóza MeSH
- dítě MeSH
- hypogonadismus diagnóza etiologie MeSH
- hypotyreóza diagnóza etiologie klasifikace MeSH
- kraniofaryngeom * diagnóza komplikace MeSH
- lidé MeSH
- nemoci endokrinního systému * diagnóza etiologie klasifikace MeSH
- růstový hormon nedostatek MeSH
- vodní a elektrolytová nerovnováha diagnóza etiologie klasifikace MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- Publikační typ
- přehledy MeSH
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 ČENDA. 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.
- MeSH
- diabetes mellitus 1. typu * farmakoterapie MeSH
- dítě MeSH
- glykovaný hemoglobin MeSH
- hypoglykemika terapeutické užití MeSH
- inzulin terapeutické užití MeSH
- krevní glukóza MeSH
- lidé MeSH
- mladiství MeSH
- regulace glykemie MeSH
- selfmonitoring glykemie MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- mladiství MeSH
- Publikační typ
- časopisecké články MeSH
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.
- MeSH
- dítě MeSH
- gestační stáří MeSH
- hypotrofický novorozenec MeSH
- insulinu podobný růstový faktor I MeSH
- lidé MeSH
- lidský růstový hormon * genetika MeSH
- nanismus * MeSH
- novorozenec MeSH
- poruchy růstu genetika diagnóza MeSH
- protein SHOX MeSH
- Silverův-Russellův syndrom * genetika MeSH
- tělesná výška genetika MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- novorozenec MeSH
- Publikační typ
- časopisecké články MeSH
- MeSH
- lidé MeSH
- lidský růstový hormon * terapeutické užití MeSH
- nanismus * MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- úvodníky MeSH
