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1.
Am J Hum Genet ; 107(5): 989-999, 2020 11 05.
Artículo en Inglés | MEDLINE | ID: mdl-33053334

RESUMEN

Osteogenesis imperfecta (OI) is characterized primarily by susceptibility to fractures with or without bone deformation. OI is genetically heterogeneous: over 20 genetic causes are recognized. We identified bi-allelic pathogenic KDELR2 variants as a cause of OI in four families. KDELR2 encodes KDEL endoplasmic reticulum protein retention receptor 2, which recycles ER-resident proteins with a KDEL-like peptide from the cis-Golgi to the ER through COPI retrograde transport. Analysis of patient primary fibroblasts showed intracellular decrease of HSP47 and FKBP65 along with reduced procollagen type I in culture media. Electron microscopy identified an abnormal quality of secreted collagen fibrils with increased amount of HSP47 bound to monomeric and multimeric collagen molecules. Mapping the identified KDELR2 variants onto the crystal structure of G. gallus KDELR2 indicated that these lead to an inactive receptor resulting in impaired KDELR2-mediated Golgi-ER transport. Therefore, in KDELR2-deficient individuals, OI most likely occurs because of the inability of HSP47 to bind KDELR2 and dissociate from collagen type I. Instead, HSP47 remains bound to collagen molecules extracellularly, disrupting fiber formation. This highlights the importance of intracellular recycling of ER-resident molecular chaperones for collagen type I and bone metabolism and a crucial role of HSP47 in the KDELR2-associated pathogenic mechanism leading to OI.


Asunto(s)
Huesos/metabolismo , Colágeno Tipo I/metabolismo , Proteínas del Choque Térmico HSP47/metabolismo , Osteogénesis Imperfecta/genética , Proteínas de Transporte Vesicular/metabolismo , Adulto , Alelos , Secuencia de Aminoácidos , Animales , Sitios de Unión , Huesos/patología , Pollos , Preescolar , Colágeno Tipo I/química , Colágeno Tipo I/genética , Retículo Endoplásmico/metabolismo , Retículo Endoplásmico/patología , Femenino , Fibroblastos/metabolismo , Fibroblastos/patología , Expresión Génica , Aparato de Golgi/metabolismo , Aparato de Golgi/patología , Proteínas del Choque Térmico HSP47/química , Proteínas del Choque Térmico HSP47/genética , Humanos , Lactante , Masculino , Osteogénesis Imperfecta/diagnóstico , Osteogénesis Imperfecta/metabolismo , Osteogénesis Imperfecta/patología , Linaje , Cultivo Primario de Células , Unión Proteica , Dominios y Motivos de Interacción de Proteínas , Estructura Secundaria de Proteína , Transporte de Proteínas , Alineación de Secuencia , Homología de Secuencia de Aminoácido , Proteínas de Transporte Vesicular/química , Proteínas de Transporte Vesicular/genética
2.
Handb Exp Pharmacol ; 261: 87-104, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32519163

RESUMEN

New therapeutic approaches have been established in the field of rare skeletal diseases (e.g., for osteogenesis imperfecta, achondroplasia, hypophosphatemic rickets, hypophosphatasia, and fibrodysplasia ossificans progressiva). After elucidation of the underlying genotypes and pathophysiologic alterations of these diseases, new treatment options have been designed. Most drugs are based on an interaction with the disease-specific cascade of enzymes and proteins involved in the disease. Thereby an approved treatment is available for children with severe forms of hypophosphatasia and hypophosphatemic rickets (asfotase alfa, burosumab). Additionally, there are different phase 3 trials ongoing assessing the efficacy and safety of drugs for osteogenesis imperfecta, achondroplasia, and fibrodysplasia ossificans progressiva (denosumab, vosoritide, palovarotene).Because all these diseases are rare, the number of investigated patients in the trials is small, and the knowledge about rare side effects and long-term outcome is limited. Therefore it is recommended to treat the patients in specialized centers where the effects of the drugs can be evaluated and data about safety, side effects, and efficacy can be collected.Based on the fact that most drugs for rare diseases are highly expensive clear indications for start of a treatment, evaluation of the therapy and recommendations how long a treatment has to be administrated are urgently needed.


Asunto(s)
Hipofosfatasia , Miositis Osificante , Niño , Humanos , Enfermedades Raras/fisiopatología
3.
J Clin Densitom ; 22(2): 229-235, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-30309730

RESUMEN

INTRODUCTION/BACKGROUND: Osteogenesis imperfecta is a hereditary connective tissue disorder, resulting in low bone mass and high bone fragility. Dual-energy X-ray absorptiometry (DXA) and in adulthood also the trabecular bone score (TBS) are well established to assess bone health and fracture risk. The purpose of this investigation was to assess the usefulness of TBS in respect to different treatment regimes in children with osteogenesis imperfecta. Changes of areal bone mineral density (aBMD) and TBS using DXA scans of children treated with antiresorptive therapies were evaluated. METHODOLOGY: DXA scans (aBMD, TBS) of 8 children with OI were evaluated. The scans were taken during a 1 yr period of treatment with bisphosphonates and during 1 yr pilot trial using denosumab. Changes of aBMD and TBS during both treatment regimens were compared. RESULTS: During bisphosphonate treatment aBMD increased about 6.2%, while TBS increased about 2.1%. The difference between aBMD and TBS before and after bisphosphonate treatment was not significant (p = 0.25). During denosumab treatment aBMD increased around 25.1%, while TBS increased 6.7%. The change of aBMD was significant (p = 0.007), as was the difference between aBMD and TBS (p < 0.001). CONCLUSIONS: Denosumab had a significant effect on both aBMD and TBS but was significantly more pronounced in aBMD. These results suggest a stronger effect of denosumab on cortical bone and the growth plate in comparison to bisphosphonates. Beside the lack of paediatric reference data and the small sample size, the results suggest TBS to be a useful tool for monitoring skeletal changes during development, growth, and antiresorptive therapy in children with OI.


Asunto(s)
Conservadores de la Densidad Ósea/uso terapéutico , Hueso Esponjoso/diagnóstico por imagen , Hueso Cortical/diagnóstico por imagen , Denosumab/uso terapéutico , Difosfonatos/uso terapéutico , Vértebras Lumbares/diagnóstico por imagen , Osteogénesis Imperfecta/tratamiento farmacológico , Absorciometría de Fotón , Densidad Ósea , Niño , Preescolar , Femenino , Placa de Crecimiento/diagnóstico por imagen , Humanos , Masculino , Osteogénesis Imperfecta/diagnóstico por imagen , Resultado del Tratamiento
4.
Am J Hum Genet ; 96(3): 432-9, 2015 Mar 05.
Artículo en Inglés | MEDLINE | ID: mdl-25683121

RESUMEN

As a result of a whole-exome sequencing study, we report three mutant alleles in SEC24D, a gene encoding a component of the COPII complex involved in protein export from the ER: the truncating mutation c.613C>T (p.Gln205(∗)) and the missense mutations c.3044C>T (p.Ser1015Phe, located in a cargo-binding pocket) and c.2933A>C (p.Gln978Pro, located in the gelsolin-like domain). Three individuals from two families affected by a similar skeletal phenotype were each compound heterozygous for two of these mutant alleles, with c.3044C>T being embedded in a 14 Mb founder haplotype shared by all three. The affected individuals were a 7-year-old boy with a phenotype most closely resembling Cole-Carpenter syndrome and two fetuses initially suspected to have a severe type of osteogenesis imperfecta. All three displayed a severely disturbed ossification of the skull and multiple fractures with prenatal onset. The 7-year-old boy had short stature and craniofacial malformations including macrocephaly, midface hypoplasia, micrognathia, frontal bossing, and down-slanting palpebral fissures. Electron and immunofluorescence microscopy of skin fibroblasts of this individual revealed that ER export of procollagen was inefficient and that ER tubules were dilated, faithfully reproducing the cellular phenotype of individuals with cranio-lentico-sutural dysplasia (CLSD). CLSD is caused by SEC23A mutations and displays a largely overlapping craniofacial phenotype, but it is not characterized by generalized bone fragility and presented with cataracts in the original family described. The cellular and morphological phenotypes we report are in concordance with the phenotypes described for the Sec24d-deficient fish mutants vbi (medaka) and bulldog (zebrafish).


Asunto(s)
Craneosinostosis/genética , Anomalías del Ojo/genética , Hidrocefalia/genética , Osteogénesis Imperfecta/genética , Proteínas de Transporte Vesicular/genética , Alelos , Animales , Huesos/patología , Niño , Retículo Endoplásmico/metabolismo , Femenino , Heterocigoto , Humanos , Masculino , Mutación Missense , Linaje , Fenotipo , Conformación Proteica , Análisis de Secuencia de ADN , Proteínas de Transporte Vesicular/metabolismo , Pez Cebra/genética
5.
Br J Nutr ; 120(7): 763-776, 2018 10.
Artículo en Inglés | MEDLINE | ID: mdl-30109842

RESUMEN

Intra-uterine growth restriction (IUGR) is associated with adverse metabolic outcome later in life. Healthy mice challenged with a Western-style diet (WSD) accumulated less body fat when previously fed a diet containing large lipid globules (complex lipid matrix (CLM)). This study was designed to clarify whether an early-life CLM diet mitigates 'programmed' visceral adiposity and associated metabolic sequelae after IUGR. In rats, IUGR was induced either by bilateral uterine vessel ligation (LIG) or sham operation (i.e. intra-uterine stress) of the dam on gestational day 19. Offspring from non-operated (NOP) dams served as controls. Male offspring of all groups were either fed CLM or 'normal matrix' control diet (CTRL) from postnatal days (PND) 15 to 42. Thereafter, animals were challenged with a mild WSD until dissection (PND 98). Fat mass (micro computer-tomograph scan; weight of fat compartments), circulating metabolic markers and expression of 'metabolic' genes (quantitative real-time PCR) were assessed. CLM diet significantly reduced visceral fat mass in LIG at PND 40. At dissection, visceral fat mass, fasted blood glucose, TAG and leptin concentrations were significantly increased in LIG-CTRL v. NOP-CTRL, and significantly decreased in LIG-CLM v. LIG-CTRL. Gene expression levels of leptin (mesenteric fat) and insulin-like growth factor 1 (liver) were significantly reduced in LIG-CLM v. LIG-CTRL. In conclusion, early-life CLM diet mitigated the adverse metabolic phenotype after utero-placental insufficiency. The supramolecular structure of dietary lipids may be a novel aspect of nutrient quality that has to be considered in the context of primary prevention of obesity and metabolic disease in at-risk populations.


Asunto(s)
Glucemia/metabolismo , Dieta , Grasas de la Dieta/farmacología , Retardo del Crecimiento Fetal/metabolismo , Fenómenos Fisiológicos Nutricionales del Lactante , Grasa Intraabdominal/metabolismo , Lípidos/farmacología , Animales , Biomarcadores/metabolismo , Dieta Occidental , Grasas de la Dieta/administración & dosificación , Grasas de la Dieta/metabolismo , Femenino , Humanos , Lactante , Proteína 1 de Unión a Factor de Crecimiento Similar a la Insulina/metabolismo , Leptina/sangre , Ligadura , Metabolismo de los Lípidos/efectos de los fármacos , Lípidos/administración & dosificación , Lípidos/sangre , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Mesenterio , Embarazo , Ratas Wistar , Triglicéridos/sangre , Útero/cirugía
6.
Pediatr Endocrinol Rev ; 15(Suppl 1): 123-129, 2017 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-29292876

RESUMEN

Osteogenesis imperfecta (OI) is a rare hereditary skeletal disease leading to recurrent fractures, short stature and impaired mobility. The phenotype varies from mildly affected patients to perinatal lethal forms. In most cases an impaired collagen production due to mutations in COL1A1 or COL1A2 cause this hereditary bone fragility syndrome with an autosomal dominant inheritance. Currently an interdisciplinary therapeutic approach with antiresorptive drugs, physiotherapy and surgical procedures is the state of the art therapy. The effect of such a therapy is evaluated by measuring different surrogate parameters like areal bone mineral density or by using different mobility tests or questionnaires. Up till now the impact of these parameters on quality of life of the patients is not evaluated. Currently pharmacological strategies are based on antiresorptive treatment with bisphosphonates. In this trial we investigated the effect of an antiresorptive therapy with the monoclonal antibody denosumab decreasing the activity of osteoclasts. Denosumab was administered subcutaneously in a dose of 1mg/kg body weight in 10 children with OI (5-10 years of age) every 12 weeks for 48 weeks. Areal bone mineral density, mobility, pain scores and quality of life were measured. The results showed a good effect of the treatment on bone mineral density but this improvement showed no correlation to pain and quality of life. In conclusion further trials have to define parameters to assess interventions which influence activities of daily life of the patients. An interdisciplinary approach including physicians, basic researchers and patient organisation is needed to focus research on topics improving quality of life of patients with severe skeletal diseases.


Asunto(s)
Denosumab/uso terapéutico , Osteogénesis Imperfecta , Densidad Ósea , Conservadores de la Densidad Ósea , Niño , Preescolar , Humanos , Osteogénesis Imperfecta/tratamiento farmacológico , Calidad de Vida
7.
J Clin Densitom ; 19(2): 208-15, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-26059565

RESUMEN

Conventional lateral spine and hand radiographs are the standard tools to evaluate vertebral morphometry and bone age in children. Beside bone mineral density analyses, dual-energy X-ray absorptiometry (DXA) measurements with lower radiation exposure provide high-resolution scans which are not approved for diagnostic purposes. Data about the comparability of conventional radiographs and DXA in children are missing yet. The purpose of the trial was to evaluate whether conventional hand and spine radiographs can be replaced by DXA scans to diminish radiation exposure. Thirty-eight children with osteogenesis imperfecta or secondary osteoporosis or short stature (male, n=20; age, 5.0-17.0 yr) were included and assessed once by additional DXA (GE iDXA) of the spine or the left hand. Intraclass correlation coefficients (ICCs) were used to express agreement between X-ray and iDXA assessment. Evaluation of the spine morphometry showed reasonable agreement between iDXA and radiography (ICC for fish-shape, 0.75; for wedge-shape, 0.65; and for compression fractures, 0.70). Bone age determination showed excellent agreement between iDXA and radiography (ICC, 0.97). IDXA-scans of the spine in a pediatric population should be used not only to assess bone mineral density but also to evaluate anatomic structures and vertebral morphometry. Therefore, iDXA can replace some radiographs in children with skeletal diseases.


Asunto(s)
Absorciometría de Fotón/métodos , Osteogénesis Imperfecta/diagnóstico , Osteoporosis/diagnóstico , Radiografía/métodos , Columna Vertebral/diagnóstico por imagen , Adolescente , Determinación de la Edad por el Esqueleto/métodos , Estatura , Densidad Ósea , Desarrollo Óseo , Niño , Preescolar , Investigación sobre la Eficacia Comparativa , Femenino , Alemania , Humanos , Masculino , Salud Radiológica/métodos , Reproducibilidad de los Resultados
8.
Cardiol Young ; 26(5): 876-84, 2016 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-26279316

RESUMEN

BACKGROUND: Limited data exist on the vitamin D status in Fontan patients. We determined the prevalence and potential risk factors of vitamin D deficiency in this patient subset. Methods and results Data were collected from 27 Fontan patients (55.6% male, mean age 8.1±5.3 years). Protein-losing enteropathy was diagnosed in six patients (22.2%). Vitamin D deficiency was defined as a serum 25-hydroxyvitamin D level of <20 ng/ml. The neutrophil-to-lymphocyte ratio, a marker of systemic inflammation, was calculated. Associations between laboratory measurements and patient characteristics were explored. Mean serum 25-hydroxyvitamin D level was 14.1±10.4 ng/ml. Vitamin D deficiency was found in 19/27 patients (70.3%). Only skin type was associated with vitamin D deficiency (p=0.04). Hyperparathyroidism was present in 5/21 (23.8%) patients, and was more prevalent in patients with protein-losing enteropathy (p<0.001). Parathyroid hormone levels correlated with parameters of systemic inflammation (neutrophil-to-lymphocyte ratio: r=0.484, p=0.026; relative lymphocyte count: r=-0.635, p=0.002). Vitamin D supplementation significantly increased serum 25-hydroxyvitamin D levels (p<0.0001), and was accompanied by a reduction in parathyroid hormone concentrations (p=0.032). CONCLUSIONS: A high prevalence of vitamin D deficiency was found among Fontan patients, independent of age, time after Fontan procedure, ventricular morphology, and presence of protein-losing enteropathy. A potentially important link between parathyroid hormone levels and systemic inflammation is suggested.


Asunto(s)
Procedimiento de Fontan , Hiperparatiroidismo Secundario/epidemiología , Hormona Paratiroidea/sangre , Enteropatías Perdedoras de Proteínas/epidemiología , Deficiencia de Vitamina D/epidemiología , Vitamina D/análogos & derivados , Adolescente , Biomarcadores/sangre , Niño , Preescolar , Femenino , Humanos , Masculino , Estudios Retrospectivos , Vitamina D/sangre , Adulto Joven
9.
Wien Med Wochenschr ; 165(13-14): 278-84, 2015 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-26055811

RESUMEN

Osteogenesis imperfecta is a rare hereditary disease mostly caused by mutations impairing collagen synthesis and modification. Recently recessive forms have been described influencing differentiation and activity of osteoblasts and osteoclasts. Most prominent signs are fractures due to low traumata and deformities of long bones and vertebrae. Additional patients can be affected by dwarfism, scoliosis Dentinogenesis imperfecta, deafness and a blueish discoloration of the sclera. During childhood state of the art medical treatment are i.v. bisphosphonates to increase bone mass and to reduce fracture rate. Surgical interventions are needed to treat fractures, to correct deformities and should always be accompanied by physiotherapeutic and rehabilitative interventions.


Asunto(s)
Osteogénesis Imperfecta/fisiopatología , Osteogénesis Imperfecta/terapia , Colágeno Tipo I/genética , Cadena alfa 1 del Colágeno Tipo I , Terapia Combinada , Análisis Mutacional de ADN , Difosfonatos/administración & dosificación , Femenino , Fijación de Fractura , Fracturas Espontáneas/genética , Fracturas Espontáneas/fisiopatología , Fracturas Espontáneas/terapia , Tamización de Portadores Genéticos , Humanos , Lactante , Recién Nacido , Infusiones Intravenosas , Masculino , Osteoblastos/fisiología , Osteoclastos/fisiología , Osteogénesis Imperfecta/genética , Modalidades de Fisioterapia
10.
Calcif Tissue Int ; 93(6): 565-70, 2013 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-24091809

RESUMEN

Recently, homozygous mutations in BMP1 were identified as a cause of bone fragility in children with high areal bone mineral density. We examined iliac bone tissue from a 12-year-old boy with a homozygous mutation that leads to a p.Gly12Arg change in the signal peptide of BMP1, an enzyme that cleaves C-propeptide off the procollagen type I molecule. Histomorphometric analyses revealed marked hyperosteoidosis, with osteoid volume per bone volume at approximately 11 SD above the mean value for controls. At the same time, quantitative backscattered electron imaging showed drastic hypermineralization of mineralized bone matrix. CaPeak, representing the most frequently observed calcium content of mineralized matrix in trabecular bone, was 9 SD above the mean for the control population, corresponding to a 21 % higher calcium content in the patient specimen than in the average control sample. These results are similar to those that were previously reported in an individual who had a mutation in the C-propeptide cleavage site of procollagen type I. It thus appears that disturbed C-propeptide cleavage impairs mineralization in two ways: first, the onset of mineralization is delayed, leading to an increased amount of unmineralized osteoid, and second, once mineralization starts, too much mineral is incorporated into the bone matrix, resulting in hypermineralization.


Asunto(s)
Proteína Morfogenética Ósea 1/genética , Homocigoto , Hiperostosis/diagnóstico , Hiperostosis/genética , Mutación , Densidad Ósea , Matriz Ósea , Huesos/metabolismo , Huesos/patología , Calcificación Fisiológica/genética , Niño , Difosfonatos/química , Humanos , Masculino , Osteogénesis Imperfecta/genética , Valores de Referencia , Dispersión de Radiación
13.
J Clin Endocrinol Metab ; 108(11): e1199-e1204, 2023 10 18.
Artículo en Inglés | MEDLINE | ID: mdl-37256841

RESUMEN

CONTEXT: Treatment of children with classical congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency is challenging. Linear growth and adult height are compromised according to recent publications. However, most of these data were obtained in the era before CAH newborn screening. DESIGN: Body height of patients with classical CAH diagnosed before and after the establishment of newborn screening were analyzed retrospectively. PATIENTS AND METHODS: We identified 600 patients with classical CAH (227 male) with data on near-adult height (NAH), target height (TH), and information on newborn screening from the electronic German CAH registry (German Society for Paediatric Endocrinology and Diabetology). Newborn screening was performed in 101 (16.8%) patients. All patients received hydrocortisone with or without fludrocortisone.To assess the effects of newborn screening, a linear regression model adjusted/stratified for sex and phenotype was used (SAS 9.4). RESULTS: TH corrected NAH (mean; 95% confidence interval) was closer to 0 in patients with CAH and newborn screening [-0.25 standard deviation score (SDS); -0.44 to -0.06] than in patients without newborn screening (-0.44 SDS; -0.52 to -0.36) (P = .069). Screening had no effect on NAH in female patients. In male patients, NAH was significantly better (P = .033) with screening than without screening. After stratifying for CAH phenotype, screening did not affect the NAH of patients with salt-wasting CAH. Patients with simple-virilizing CAH had a significantly better cNAH (P = .034) with screening (0.15 SDS; -0.28-0.59) than without screening (-0.35 SDS; -0.52 to -0.18). CONCLUSIONS: Our data suggest that newborn screening might be associated with improved NAH in male CAH patients and in patients with simple-virilizing CAH.


Asunto(s)
Hiperplasia Suprarrenal Congénita , Niño , Recién Nacido , Humanos , Masculino , Femenino , Adulto , Hiperplasia Suprarrenal Congénita/diagnóstico , Estudios Retrospectivos , Tamizaje Neonatal , Hidrocortisona/farmacología , Glucocorticoides/farmacología , Estatura
14.
Orphanet J Rare Dis ; 18(1): 219, 2023 07 27.
Artículo en Inglés | MEDLINE | ID: mdl-37501185

RESUMEN

Foramen magnum stenosis is a serious, and potentially life-threatening complication of achondroplasia. The foramen magnum is smaller in infants with achondroplasia, compared with the general population, and both restricted growth in the first 2 years and premature closure of skull plate synchondroses can contribute to narrowing. Narrowing of the foramen magnum can lead to compression of the brainstem and spinal cord, and result in sleep apnoea and sudden death. There is a lack of clarity in the literature on the timing of regular monitoring for foramen magnum stenosis, which assessments should be carried out and when regular screening should be ceased. The European Achondroplasia Forum (EAF) is a group of clinicians and patient advocates, representative of the achondroplasia community. Members of the EAF Steering Committee were invited to submit suggestions for guiding principles for the detection and management of foramen magnum stenosis, which were collated and discussed at an open workshop. Each principle was scrutinised for content and wording, and anonymous voting held to pass the principle and vote on the level of agreement. A total of six guiding principles were developed which incorporate routine clinical monitoring of infants and young children, timing of routine MRI screening, referral of suspected foramen magnum stenosis to a neurosurgeon, the combination of assessments to inform the decision to decompress the foramen magnum, joint decision making to proceed with decompression, and management of older children in whom previously undetected foramen magnum stenosis is identified. All principles achieved the ≥ 75% majority needed to pass (range 89-100%), with high levels of agreement (range 7.6-8.9). By developing guiding principles for the detection and management of foramen magnum stenosis, the EAF aim to enable infants and young children to receive optimal monitoring for this potentially life-threatening complication.


Asunto(s)
Acondroplasia , Enfermedades Óseas , Síndromes de la Apnea del Sueño , Niño , Lactante , Humanos , Adolescente , Preescolar , Foramen Magno/cirugía , Constricción Patológica/diagnóstico , Constricción Patológica/complicaciones , Acondroplasia/diagnóstico , Acondroplasia/terapia , Acondroplasia/complicaciones , Síndromes de la Apnea del Sueño/diagnóstico , Médula Espinal , Enfermedades Óseas/complicaciones
15.
Endocr Connect ; 10(5): 561-569, 2021 May 19.
Artículo en Inglés | MEDLINE | ID: mdl-33909597

RESUMEN

OBJECTIVE: Treatment of classic congenital adrenal hyperplasia (CAH) is necessary to compensate for glucocorticoid/mineralocorticoid deficiencies and to suppress androgen excess. Hydrocortisone (HC) is preferred in growing children with classic CAH but recommendations regarding dosage/administration are inconsistent. The aim of this study was to evaluate HC dosing in children with CAH in relation to chronological age, sex, and phenotype based on a multicenter CAH registry. DESIGN: The CAH registry was initiated in 1997 by the AQUAPE in Germany. On December 31st 2018, data from 1571 patients were included. METHODS: A custom-made electronic health record software is used at the participating centers. Pseudonymized data are transferred for central analysis. Parameters were selected based on current guidelines. Descriptive analyses and linear regression models were implemented with SAS 9.4. RESULTS: We identified 1288 patients on exclusive treatment with hydrocortisone three times daily (604 boys; median age 7.2 years; 817 salt-wasting phenotype, 471 simple-virilizing phenotype). The mean (lower-upper quartiles) daily HC dose (mg/m² body surface area) was 19.4 (18.9-19.8) for patients <3 months (n = 329), 15.0 (14.6-15.3) for age ≥3-12 months (n = 463), 14.0 (13.7-14.3) for age 1-5.9 years (n = 745), 14.2 (14.0-14.5) for age 6 years to puberty entry (n = 669), and 14.9 (14.6-15.2) during puberty to 18 years (n = 801). Fludrocortisone was administered in 74.1% of patients with a median daily dosage of 88.8 µg. CONCLUSION: Our analyses showed that still a high proportion of children are treated with HC doses higher than recommended. This evaluation provides comprehensive information on nationwide hydrocortisone substitution dosages in children with CAH underlining the benefit of systematic data within a registry to assess daily practice.

16.
J Bone Miner Res ; 35(9): 1685-1694, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32395832

RESUMEN

Bone strength and fracture risk do not only depend on bone density, but also on bone structure. The trabecular bone score (TBS) evaluates homogeneity of bone microarchitecture indirectly by measuring gray-level variations of two-dimensional (2D) DXA images. Although TBS is well-established for adults, there have been only few publications in pediatrics. In this monocentric retrospective analysis, we investigated TBS in children and adolescents with cerebral palsy (CP), a patient group vulnerable to low bone mineral mass due to impaired mobility. The influence of different parameters on TBS and areal BMD (aBMD) were evaluated, as well as the relationship between TBS and aBMD. We compared TBS values of our study population to a reference population. A total of 472 lumbar spine-dual-energy X-ray absorptiometry (LS-DXA) scans of children and adolescents with CP (205 female), aged between 4 and 18 years, were analyzed. The DXA-scans were part of the routine examination. The children had no records of fractures or specific bone diseases. Our study population with CP had similar TBS as the reference population. TBS did not increase with age until an inflection point at 10 years in females, and 12 years in males. Girls had significantly higher TBS than boys (p = .049) and pubertal girls aged 8 to 13 years had significantly higher TBS than prepubertal girls (p = .009). TBS standard deviation score for age (SDS-TBS) and aBMD Z-scores correlated weakly (p < .001; R = 0.276 [males], R = 0.284 [females]). Other than for aBMD Z-scores, SDS-TBS was not influenced by age-adjusted height Z-scores and there was no significant difference in SDS-TBS when grouped by mobility levels, using the Gross Motor Function Classification System (GMFCS). Our results indicate that children with CP have a similar homogeneous distribution of trabecular microarchitecture as controls. Puberty initiation appears to be essential for increase of TBS with age and for sex differences. TBS seems less influenced by body composition, height, and mobility than aBMD. © 2020 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.


Asunto(s)
Parálisis Cerebral , Pediatría , Absorciometría de Fotón , Adolescente , Densidad Ósea , Hueso Esponjoso/diagnóstico por imagen , Parálisis Cerebral/diagnóstico por imagen , Niño , Preescolar , Femenino , Humanos , Vértebras Lumbares/diagnóstico por imagen , Masculino , Estudios Retrospectivos
17.
Paediatr Drugs ; 21(2): 95-106, 2019 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-30941653

RESUMEN

Increasing knowledge in the field of rare diseases has led to new therapeutic approaches in the last decade. Treatment strategies have been developed after elucidation of the underlying genetic alterations and pathophysiology of certain diseases (e.g., in osteogenesis imperfecta, achondroplasia, hypophosphatemic rickets, hypophosphatasia and fibrodysplasia ossificans progressiva). Most of the drugs developed are specifically designed agents interacting with the disease-specific cascade of enzymes and proteins involved. While some are approved (asfotase alfa, burosumab), others are currently being investigated in phase III trials (denosumab, vosoritide, palovarotene). To offer a multi-disciplinary therapeutic approach, it is recommended that patients with rare skeletal disorders are treated and monitored in highly specialized centers. This guarantees the greatest safety for the individual patient and offers the possibility of collecting data to further improve treatment strategies for these rare conditions. Additionally, new therapeutic options could be achieved through increased awareness, not only in the field of pediatrics but also in prenatal and obstetric specialties. Presenting new therapeutic options might influence families in their decision of whether or not to terminate a pregnancy with a child with a skeletal disease.


Asunto(s)
Enfermedades Musculoesqueléticas/tratamiento farmacológico , Enfermedades Raras/tratamiento farmacológico , Fosfatasa Alcalina/uso terapéutico , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales Humanizados , Niño , Denosumab/uso terapéutico , Femenino , Humanos , Inmunoglobulina G/uso terapéutico , Mutación , Embarazo , Pirazoles/uso terapéutico , Proteínas Recombinantes de Fusión/uso terapéutico , Estilbenos/uso terapéutico
18.
Orphanet J Rare Dis ; 14(1): 219, 2019 09 18.
Artículo en Inglés | MEDLINE | ID: mdl-31533771

RESUMEN

BACKGROUND: Osteogenesis imperfecta (OI) is a rare disease leading to hereditary bone fragility. Nearly 90% of cases are caused by mutations in the collagen genes COL1A1/A2 (classical OI) leading to multiple fractures, scoliosis, short stature and nonskeletal findings as blue sclera, hypermobility of joints, bone pain and delayed motor function development. Bisphosphonates are used in most moderate and severely affected patients assuming that an increase of bone mineral density might reduce fractures and bone pain in patients with OI. Denosumab as a RANK ligand antibody inhibiting osteoclast maturation has been approved for osteoporosis treatment in adults. First data from small clinical trials promised a high efficacy of Denosumab in children with OI. Aim of this analysis was a retrospective evaluation of an individualized biomarker-associated treatment regime with Denosumab in 10 children with classical OI which were followed for 1 year after their participation in a pilot trial with Denosumab. Therefore urinary deoxypyridinoline levels were evaluated frequently as an osteoclastic activity marker and depending on that levels Denosumab injections were scheduled individually. METHODS: Ten patients (age range: 6.16-12.13 years; all participated in the former OI-AK phase 2 trial (NCT01799798)) were included in the follow-up period. Denosumab was administered subcutaneously depending on the individual urinary excretion course of deoxypyridinoline (DPD/Crea) as osteoclastic activity marker with 1 mg/kg body weight. DPD/Crea levels were evaluated before denosumab administration and afterwards. If patients present after an initial decrease after injection with a re-increase up to the DPD/crea level before Denosumab injection next dosage was planned. Changes of areal bone mineral density (aBMD) using dual energy x-ray absorptiometry of the lumbar spine after 12 month was evaluated. Safety was assessed by bone metabolism markers and side effect reporting. RESULTS: During follow-up mean relative change of lumbar aBMD was - 6.4%. Lumbar spine aBMD z-Scores decreased from - 1.01 ± 2.61 (mean ± SD) to - 1.91 ± 2.12 (p = 0.015). Mobility changed not significantly (GMFM-88 -6.49 ± 8.85% (p = 0.08). No severe side effects occurred. Dose intervals could be extended in the mean from 12 weeks previously to 20.3 weeks. CONCLUSIONS: On average, it was possible to prolong the intervals between drug administrations and to reduce the total dose about by 25% without a decrease of mobility or change of vertebral shape despite a reduction of lumbar aBMD during 1 year of biomarker-directed Denosumab treatment. Further trials are necessary to balance side effects and highest efficacy in children.


Asunto(s)
Denosumab/uso terapéutico , Osteogénesis Imperfecta/tratamiento farmacológico , Densidad Ósea/efectos de los fármacos , Conservadores de la Densidad Ósea/uso terapéutico , Niño , Colágeno Tipo I/genética , Cadena alfa 1 del Colágeno Tipo I , Difosfonatos/uso terapéutico , Femenino , Estudios de Seguimiento , Humanos , Hipercalciuria/tratamiento farmacológico , Masculino , Mutación/genética , Estudios Retrospectivos
19.
J Pediatr Endocrinol Metab ; 31(1): 25-31, 2018 Jan 26.
Artículo en Inglés | MEDLINE | ID: mdl-29197219

RESUMEN

Background Growth hormone (GH) treatment in children with short stature homeobox-containing gene (SHOX) deficiency is recognized to increase height velocity (HV) and adult height. Prediction of growth response continues to be a challenge. A comparatively accurate method is the Cologne prediction model developed in children with GH deficiency. The aim was to investigate whether this model also applies to patients with SHOX deficiency. Methods Included were 48 patients with SHOX deficiency confirmed by DNA analysis and treated with 0.05 mg/kg/day of somatropin. Prediction by the Cologne model uses the following variables: relative bone age (BA) retardation, baseline insulin-like growth factor-I (IGF-I), urinary deoxypyridinoline (DPD) cross-links at 4 weeks and HV at 3 months. Results HV and height standard deviation scores (SDS) increased significantly during the first year of treatment. Predicted and observed HV (cm/year) showed a Pearson correlation coefficient of 0.50 (p<0.001; root-mean-square error=1.63) and for first-year change in height SDS a Pearson correlation coefficient of 0.751 (p<0.001; root-mean-square error=0.32). Poor response could be adequately predicted using SDS change, with sensitivity and specificity both above 70% for certain thresholds. CONCLUSIONS: The results demonstrate that the Cologne model can be used to predict growth response in patients with SHOX deficiency with reasonable precision in the first treatment year, comparable to prediction in patients with GH deficiency.


Asunto(s)
Estatura/genética , Trastornos del Crecimiento/genética , Hormona de Crecimiento Humana/administración & dosificación , Modelos Estadísticos , Mutación , Proteína de la Caja Homeótica de Baja Estatura/genética , Estatura/efectos de los fármacos , Femenino , Trastornos del Crecimiento/tratamiento farmacológico , Humanos , Masculino , Valor Predictivo de las Pruebas , Estudios Prospectivos , Proteína de la Caja Homeótica de Baja Estatura/deficiencia
20.
Child Neurol Open ; 5: 2329048X18780477, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-29977975

RESUMEN

The aim of this study was to determine the effect of a new method of vibration-assisted neuromuscular rehabilitation in patients with spinal muscular atrophy types II and III. In this retrospective observational study, 38 children (mean age: 4.64 ± 1.95 years) were analyzed. The physiotherapy program, Auf die Beine, combines 6 months of home-based side-alternating whole-body vibration with interval blocks of intensive, goal-directed rehabilitation: 13 days at the start and 6 days after 3 months. Assessments were applied at the beginning (M0), after 6 months of home-based training (M6), and after 6 months of follow-up (M12). Motor abilities were assessed by the Gross Motor Function Measure 66 and Hammersmith Functional Mobility Scale. The Gross Motor Function Measure showed an increase of 1.69 (3.73) points (P = .124) and the Hammersmith Functional Mobility Scale a significant increase of 2.73 ± 1.79 points (P = .007) after 12 months; however, whether this leads to a long-term clinical benefit requires further investigation.

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