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OBJECTIVE: Our report describes clinical, genetic, and biochemical features of participants with a molecularly confirmed congenital disorder of glycosylation (CDG) enrolled in the Frontiers in Congenital Disorders of Glycosylation (FCDGC) Natural History cohort at year 5 of the study. METHODS: We enrolled individuals with a known or suspected CDG into the FCDGC Natural History Study, a multicenter prospective and retrospective natural history study of all genetic causes of CDG. We conducted a cross-sectional analysis of baseline study visit data from participants with confirmed CDG who were consented into the FCDGC Natural History Study (5U54NS115198) from October 2019 to November 2023. RESULTS: Three hundred thirty-three subjects consented to the FCDGC Natural History Study. Of these, 280 unique individuals had genetic data available that was consistent with a diagnosis of CDG. These 280 individuals were enrolled into the study between October 8, 2019 and November 29, 2023. One hundred forty-one (50.4%) were female, and 139 (49.6%) were male. Mean and median age at enrollment was 10.1 and 6.5 years, respectively, with a range of 0.22 to 71.4 years. The cohort encompassed individuals with disorders of N-linked protein glycosylation (57%), glycosylphosphatidylinositol anchor disorder (GPI anchor) (15%), disorders of Golgi homeostasis, trafficking and transport (12%), dolichol metabolism disorders (5%), disorders of multiple pathways (6%), and other (5%). The most frequent presenting symptom(s) leading to diagnosis were developmental delay/disability (77%), followed by hypotonia (56%) and feeding difficulties (42%). Mean and median time between first related symptom and diagnosis was 2.7 and 0.8 years, respectively. One hundred percent of individuals in our cohort had developmental differences/disabilities at the time of their baseline visit, followed by 97% with neurologic involvement, 91% with gastrointestinal (GI)/liver involvement, and 88% with musculoskeletal involvement. Severity of disease in individuals was scored on the Nijmegen Progression CDG Rating Scale (NPCRS) with 27% of scores categorized as mild, 44% moderate, and 29% severe. Of the individuals with N-linked protein glycosylation defects, 83% of those with data showed a type 1 pattern on carbohydrate deficient transferrin (CDT) analysis including 82/84 individuals with PMM2-CDG, 6% a type 2 pattern, 1% both type 1 and type 2 pattern and 10% a normal or nonspecific pattern. One hundred percent of individuals with Golgi homeostasis and trafficking defects with data showed a type 2 pattern on CDT analysis, while Golgi transport defect showed a type II pattern 73% of the time, a type 1 pattern for 7%, and 20% had a normal or nonspecific pattern. Most of the variants documented were classified as pathogenic or likely pathogenic using ACMG criteria. For the majority of the variants, the predicted molecular consequence was missense followed by nonsense and splice site, and the majority of the diagnoses are inherited in an autosomal recessive pattern but with disorders of all major nuclear inheritance included. DISCUSSION: The FCDGC Natural History Study serves as an important resource to build future research studies, improve clinical care, and prepare for clinical trial readiness. Herein is the first overview of CDG participants of the FCDGC Natural History Study.
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Defeitos Congênitos da Glicosilação , Humanos , Defeitos Congênitos da Glicosilação/genética , Defeitos Congênitos da Glicosilação/patologia , Masculino , Feminino , Estudos Transversais , Criança , Pré-Escolar , Adolescente , Glicosilação , Adulto , Estudos Retrospectivos , Lactente , Adulto Jovem , Estudos Prospectivos , Estudos de CoortesRESUMO
Patients with Fanconi anemia (FA) are often perceived to have poor growth when general population growth curves are utilized. We hypothesize that FA patients have unique growth and aimed to create FA-specific growth charts. Height and weight data from ages 0 to 20 years were extracted from medical records of patients treated at the Fanconi Anemia Comprehensive Care Clinic at the University of Minnesota. Height, weight, and BMI growth curves were generated and fitted to reference percentiles using the Lambda-Mu-Sigma method. FA-specific percentiles were compared to WHO standards for ages 0-2 and CDC references for ages 2-20. In FA males, the 50th height- and weight-for-age percentiles overlap with the 3rd reference percentile. In FA females, only the 50th height-for-age percentile overlaps with the 3rd reference percentile. For weight, FA females show progressive growth failure between 6 and 24 months followed by stabilization around the 50th percentile. The FA BMI-for-age percentiles show similar patterns to the weight-for-age percentiles but have different timing of onset of adiposity rebound and broader variability in females. Growth in FA patients follows a different trajectory than available normative curves. FA-specific growth charts may be useful to better guide accurate growth expectations, evaluations, and treatment.
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Estatura , Índice de Massa Corporal , Peso Corporal , Anemia de Fanconi , Gráficos de Crescimento , Humanos , Feminino , Masculino , Anemia de Fanconi/diagnóstico , Anemia de Fanconi/patologia , Anemia de Fanconi/genética , Anemia de Fanconi/fisiopatologia , Criança , Adolescente , Pré-Escolar , Lactente , Adulto Jovem , Recém-NascidoRESUMO
OBJECTIVES: To determine the detection rate of IGF-1 variants in a clinical population and assess their implications. METHODS: IGF-1 variants were detected based on their predicted mass-to-charge ratios. Most variants were distinguished by their isotopic distribution and relative retention times. A67T and A70T were distinguished with MS/MS. Patient specimens with a detected variant were de-identified for DNA sequencing to confirm the polymorphism. RESULTS: Of the 243,808 patients screened, 1,099 patients containing IGF-1 variants were identified (0.45â¯%, or 4,508 occurrences per million). Seven patients were identified as homozygous or double heterozygous. Majority of variants (98â¯%) had amino acid substitutions located at the C-terminus (A62T, P66A, A67S, A67V, A67T, A70T). Isobaric variants A38V and A67V were detected more frequently in children than in adults. Six previously unreported variants were identified: Y31H, S33P, T41I, R50Q, R56K, and A62T. Compared with the overall population, z-score distribution of patients with IGF-1 variants was shifted toward negative levels (median z-score -1.4); however, it resembled the overall population when corrected for heterozygosity. Chromatographic peak area of some variants differed from that of the WT IGF-1 present in the same patient. CONCLUSIONS: In the IGF-1 test reports by LC-MS, the concentrations only account for half the total IGF-1 for patients with heterozygous IGF-1 variants. An IGF-1 variant may change the binding to its receptor and/or its binding proteins, affecting its activity and half-life in circulation. Variants located in or close to the C-domain may be pathogenic. Cross-species sequence comparison indicates that A38V and A70T may have some degree of pathogenicity.
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Fator de Crescimento Insulin-Like I , Espectrometria de Massas em Tandem , Criança , Humanos , Fator de Crescimento Insulin-Like I/genética , Ligação Proteica , Proteínas de Transporte , Polimorfismo GenéticoRESUMO
OBJECTIVE: To describe adherence to daily somatropin treatment and impact on height velocity within 1 year of treatment start among patients with pediatric growth hormone deficiency in a real-world US population. METHODS: This retrospective cohort study included pediatric patients aged ≥3 years to <16 years with pediatric growth hormone deficiency prescribed somatropin by a pediatric endocrinologist at a US-based center of excellence between January 1, 2015 and December 31, 2020. Patient data were collected using hospital electronic health records linked to a specialty pharmacy patient prescription records. Adherence, evaluated over 12 months, was measured using the proportion of days covered metric and patients were categorized as adherent if their proportion of days covered ≥80%. Height velocity was annualized to compare across adherent and nonadherent patients. RESULTS: One hundred eighty-one patients were identified and included in this study, of which 70.2% were male,73.5% were white, and mean age (standard deviation [SD]) at index was 12.1 (2.8). In the height velocity analysis, 174 patients were included and the mean (SD) annualized change in height was 10.2 (5.7) cm/y in the adherent group (n = 108) and 9.8 (7.6) in the nonadherent group (n = 66). The difference in height velocity between the groups was not statistically significant. CONCLUSIONS: Minor improvements in average height velocity were observed in the patient group who were adherent to somatropin therapy, although not statistically significant. Lack of observed significance may be due to small sample sizes, short observation period, a likely heterogenous population in terms of growth hormone prescribing, data bias due to single-center origin, or potential patient misclassification.
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Congenital disorders of glycosylation are a group of rare related disorders causing multisystem dysfunction, including ovarian failure in females that requires early estrogen replacement. Glycosylation defects also disrupt normal synthesis of several coagulation factors, increasing thrombotic risks and complicating hormone replacement. This series describes four females with different types of CDG who developed venous thromboses while on transdermal estrogen replacement. The authors highlight the knowledge gaps around anticoagulation for this population and propose further investigations.
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Defeitos Congênitos da Glicosilação , Trombose , Feminino , Humanos , Glicosilação , Defeitos Congênitos da Glicosilação/genética , Defeitos Congênitos da Glicosilação/complicações , Puberdade , EstrogêniosRESUMO
The mucopolysaccharidosis (MPS) disorders have many potential new therapies on the horizon. Thus, historic control data on disease progression and variability are urgently needed. We conducted a 10-year prospective observational study of 55 children with MPS IH (N = 23), MPS IA (N = 10), non-neuronopathic MPS II (N = 13), and MPS VI (N = 9) to systematically evaluate bone and joint disease. Annual measurements included height, weight, and goniometry. Mixed effects modeling was used to evaluate changes over time. All participants had been treated with hematopoietic cell transplantation and/or enzyme replacement therapy. Height z-score decreased over time in MPS IH, MPS II, and MPS VI, but not MPS IA. Adult heights were 136 ± 10 cm in MPS IH, 161 ± 11 cm in MPS IA, 161 ± 14 cm in MPS II, and 128 ± 15 cm in MPS VI. Adult average BMI percentiles were high: 75 ± 30%ile in MPS IH, 71 ± 37%ile in MPS IA, 71 ± 25%ile in MPS II, and 60 ± 42%ile in MPS VI. Every participant had joint contractures of the shoulders, elbows, hips, and/or knees. Joint contractures remained stable over time. In conclusion, despite current treatments for MPS I, II, and VI, short stature and joint contractures persist. The elevation in average BMI may be related, in part, to physical inactivity due to the ongoing bone and joint disease. Data from this longitudinal historical control study may be used to expedite testing of experimental bone and joint directed therapies and to highlight the need for weight management as part of routine clinical care for patients with MPS.
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Contratura , Artropatias , Mucopolissacaridoses , Mucopolissacaridose II , Mucopolissacaridose I , Mucopolissacaridose VI , Criança , Adulto , Humanos , Estudos Prospectivos , Mucopolissacaridose I/tratamento farmacológico , Mucopolissacaridoses/terapia , Mucopolissacaridose VI/tratamento farmacológico , Mucopolissacaridose II/tratamento farmacológicoRESUMO
There are known geographical differences in growth hormone deficiency (GHD) patient populations and treatment practices. Here, we present a comparison of safety and effectiveness data from patients treated with recombinant human growth hormone (rhGH) in the USA versus other countries. PAtients TReated with Omnitrope® (PATRO) Children is an international, non-interventional study with Omnitrope® (somatropin, Sandoz Inc.). All visits and assessments are carried out according to routine clinical practice, and doses of Omnitrope® are given according to country-specific prescribing information. By September 2018, 294 patients had been enrolled in the USA (53% rhGH-naïve) and 6206 patients had been enrolled across 13 other countries (international group; 86% rhGH-naïve). The most common indication in both groups was GHD. Overall, 194 US patients (66%) and 2977 international patients (48%) experienced adverse events (AEs; 886 and 11,716 events, respectively), most of which were of mild or moderate intensity. The AEs were suspected to be treatment-related in five US patients (1.7%) and 452 international patients (7.3%). All reported neoplasms were benign, non-serious, and considered unrelated to rhGH therapy. No cases of diabetes mellitus or hyperglycemia were reported. In rhGH-naïve GHD patients, after 3 years of rhGH therapy, the improvement in mean height SD score from baseline was + 1.25 and + 1.35 in US and international patients, respectively. CONCLUSION: Omnitrope® treatment appears to be well tolerated and effective in US patients and those from other countries. Across the pediatric indications included, there was no evidence of an increased risk of developing uncommon or unexpected AEs with rhGH. TRIAL REGISTRATION: NA. WHAT IS KNOWN: ⢠Continued monitoring of patients treated with recombinant human growth hormone (rhGH) is important, particularly in terms of diabetogenic potential and the risk of malignancies. ⢠The PAtients TReated with Omnitrope® (PATRO) Children study is a long-term, post-marketing surveillance program for the rhGH Omnitrope®. WHAT IS NEW: ⢠Omnitrope® is well tolerated and effective in US patients, and those from other countries. ⢠Across all indications included, there were no unexpected adverse events and there was no evidence of an increased risk of developing malignancies or diabetes.
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Diabetes Mellitus , Nanismo Hipofisário , Hormônio do Crescimento Humano , Neoplasias , Criança , Nanismo Hipofisário/induzido quimicamente , Nanismo Hipofisário/tratamento farmacológico , Transtornos do Crescimento/tratamento farmacológico , Transtornos do Crescimento/epidemiologia , Hormônio do Crescimento Humano/efeitos adversos , Humanos , Estudos Longitudinais , Neoplasias/tratamento farmacológico , Vigilância de Produtos Comercializados , Proteínas Recombinantes/efeitos adversosRESUMO
OBJECTIVE: Recombinant human growth hormone (somatropin) is recommended for children with growth hormone deficiency (GHD) to normalize adult height. Prior research has indicated an association between adherence to somatropin and height velocity. Further research is needed using real-world data to quantify this relationship; hence the objective of this study was to investigate the association between adherence to somatropin and change in height among children with GHD. METHODS: This retrospective cohort study included patients in the IQVIA PharMetrics Plus and Ambulatory Electronic Medical Records databases aged 3 to 15 years, with ≥1 GHD diagnosis code claim and newly initiated on somatropin between January 1, 2007 and November 30, 2019. Adherence was measured over the follow-up using the medication possession ratio (MPR); patients were classified as adherent (MPR ≥ 0.8) or nonadherent (MPR < 0.8). RESULTS: Among 201 patients initiated on somatropin, 74.6% were male, mean age was 11.4 years, and the mean follow-up was 343.3 days. Approximately 76.6% of patients were adherent to somatropin over the follow-up period. Adjusted growth trajectories were similar between adherent and nonadherent patients pre-treatment initiation (P = .15). Growth trajectories post-initiation were significantly different (P = .001). On average, adherent patients gained an additional 1.8 cm over 1 year compared with nonadherent patients, adjusted for covariates. CONCLUSION: Greater adherence to somatropin therapy is associated with improved height velocity. As suboptimal adherence to daily somatropin therapy is an issue for children with GHD, novel strategies to improve adherence may improve growth outcomes.
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Nanismo Hipofisário , Hormônio do Crescimento Humano , Adulto , Estatura , Criança , Nanismo Hipofisário/tratamento farmacológico , Feminino , Hormônio do Crescimento , Hormônio do Crescimento Humano/uso terapêutico , Humanos , Masculino , Adesão à Medicação , Proteínas Recombinantes/uso terapêutico , Estudos RetrospectivosRESUMO
Nonhuman animal models reveal that the hypothalamic-pituitary-adrenocortical (HPA) axis calibrates to the harshness of the environment during a sensitive period in infancy. Humans exposed to depriving institutional care in infancy show reduced HPA axis responsivity, even years after they are placed in supportive, well-resourced families. This study examined whether puberty opens a window of opportunity to recalibrate the HPA axis toward more typical reactivity when children shift from harsh deprived conditions in infancy into supportive conditions in childhood and adolescence. Participants (n = 129 postinstitutionalized, 68.2% female; n = 170 comparison, 52.4% female) completed 3 annual sessions beginning at ages 7 to 15 (M = 11.28, SD = 2.31). Each session assessed pubertal stage via nurse examination and cortisol reactivity to the Trier social stress test for children. The linear mixed-effects model controlling for sex and between-individual differences in pubertal stage showed a significant group by pubertal stage interaction: within-individual increases in pubertal stage were associated with increases in cortisol stress reactivity for postinstitutionalized youth but not nonadopted comparison youth. This study indicates that pubertal development reopens a window of opportunity for the HPA axis to recalibrate based on significant improvements in the supportiveness of the environment relative to that in infancy. The peripubertal period may be an important time in development where the caregiving environment has a substantial impact on the HPA axis and, perhaps, other stress-mediating systems. Future research is needed to examine the mechanisms of recalibration and whether HPA recalibration impacts physical and psychological health.
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Desenvolvimento do Adolescente , Hidrocortisona/metabolismo , Maturidade Sexual , Estresse Psicológico , Adolescente , Criança , Feminino , Humanos , Sistema Hipotálamo-Hipofisário , Individualidade , Estudos Longitudinais , Masculino , Sistema Hipófise-SuprarrenalRESUMO
In cross-sectional analyses, early institutional care is associated with shorter stature but not obesity during puberty in children adopted into US families. We examined whether shorter stature and leaner body composition in youth adopted internationally from institutions would continue as puberty progressed. We also examined whether current psychosocial stress would moderate the association between early institutional deprivation and growth during adolescence. Using an accelerated longitudinal design and linear mixed-effects models, we examined the height and body mass index (BMI) of 132 previously institutionalized (PI) and 176 nonadopted (NA) youth. We examined youth aged 7-15 at the beginning of the study three times across 2 years. Nurses assessed anthropometrics and pubertal status. Current psychosocial stress was measured using the Youth Life Stress Interview. Our results indicated that PI youth remained shorter and leaner across three assessments than NA youth. However, age-and-sex-adjusted BMI increased faster in PI youth. Psychosocial stress during puberty predicted greater age-and-sex-adjusted BMI, but this effect did not differ by group. The gap in BMI but not height appears to close between PI and NA youth. Higher psychosocial stress was associated with higher BMI during puberty.
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Experiências Adversas da Infância , Adolescente , Criança , Humanos , Índice de Massa Corporal , Estudos Transversais , Puberdade , EstaturaRESUMO
Adaptor protein p66Shc is overexpressed in smooth muscle cells of renal resistance vessels of hypertensive salt-sensitive rats and is involved in the regulation of renal vascular tone. We applied 2-photon laser scanning fluorescence microscopy to analyze spontaneous dynamic fluctuations in intracellular calcium concentrations ([Ca2+]i) in smooth muscle cells embedded in the walls of freshly isolated renal resistance arteries. The amplitude, number of events, and frequency of spontaneous [Ca2+]i oscillations triggered by endogenously released endothelin-1 were recorded in smooth muscle cells of the renal arteries. Endothelin receptor A antagonist BQ123 dramatically reduced the amplitude and frequency of spontaneous Ca2+ events, producing marked inhibition of renal vessels spontaneous motion. Spontaneous Ca2+ fluctuations in smooth muscle cells of p66Shc knockout (p66ShcKO) rats had significantly higher amplitude than in control rats. The frequency of spontaneous [Ca2+]i oscillations did not change in p66ShcKO rats, suggesting that p66Shc expression did not affect endothelin-1 release from resident endothelial cells. Acute application of endothelin-1 revealed significantly elevated production of the total [Ca2+]i in p66ShcKO rats. Spontaneous cytosolic Ca2+ oscillations in smooth muscle cells of renal vessels mediate their spontaneous motion via the endothelin-1/endothelin receptor A pathway. p66Shc decreases the amplitude of individual changes in [Ca2+]i, which mitigates the spontaneous motion of renal vessels.-Palygin, O., Miller, B. S., Nishijima, Y., Zhang, D. X., Staruschenko, A., Sorokin, A. Endothelin receptor A and p66Shc regulate spontaneous Ca2+ oscillations in smooth muscle cells controlling renal arterial spontaneous motion.
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Cálcio/metabolismo , Hipertensão/fisiopatologia , Músculo Liso Vascular/fisiologia , Receptor de Endotelina A/metabolismo , Artéria Renal/fisiologia , Proteína 1 de Transformação que Contém Domínio 2 de Homologia de Src/metabolismo , Resistência Vascular , Animais , Células Cultivadas , Endotelina-1/metabolismo , Hipertensão/metabolismo , Masculino , Músculo Liso Vascular/citologia , Ratos , Ratos Endogâmicos Dahl , Artéria Renal/citologiaRESUMO
As a period of heightened plasticity, puberty may provide a window of opportunity for recalibration of the hypothalamic-pituitary-adrenal (HPA) axis to current conditions. Our group has recently documented evidence for pubertal recalibration of HPA axis reactivity among children internationally adopted as infants from institutions into supportive, well-resourced homes. As a first step at examining potential mechanisms by which puberty may facilitate recalibration of the HPA axis, the current study assessed whether previously-institutionalized (PI) children differed from non-adopted (NA) comparison children in levels of the adrenal steroid hormone dehydroepiandrosterone (DHEA) and in its intra-individual covariation (coupling) with cortisol by adrenal pubertal stage. In an accelerated longitudinal design, 7- to 15-year-olds completed up to 3 annual assessments, which included nurse-conducted pubertal staging and the Modified Trier Social Stress Test for Children (TSST-M). Adrenal (pubic hair) rather than gonadal pubertal stage scores were used in the analysis. Paired salivary cortisol-DHEA samples were available at 60-80 min post-TSST-M. NA and PI children did not differ in DHEA levels, which were higher among children at more advanced pubertal stages (averaged across the sessions) for both groups. For NA children, post-stressor cortisol and DHEA were positively coupled across sessions at all average adrenal pubertal stages. For PI children who were, on average, at earlier adrenal pubertal stages, post-stressor cortisol and DHEA were not coupled, but PI children who were at later pubertal stages demonstrated positive cortisol-DHEA coupling similar to that of the NA children. We suggest that these findings provide insights into processes which may underlie pubertal recalibration of the HPA axis.
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Criança Adotada , Criança Institucionalizada , Desidroepiandrosterona/metabolismo , Hidrocortisona/metabolismo , Puberdade/metabolismo , Adolescente , Adoção/psicologia , Criança , Criança Adotada/psicologia , Estudos de Coortes , Desidroepiandrosterona/análise , Feminino , Humanos , Hidrocortisona/análise , Sistema Hipotálamo-Hipofisário/metabolismo , Estudos Longitudinais , Masculino , Sistema Hipófise-Suprarrenal/metabolismo , Testes Psicológicos , Puberdade/fisiologia , Puberdade/psicologia , Saliva/química , Saliva/metabolismo , Estresse Psicológico/metabolismoRESUMO
BACKGROUND: Mucopolysaccharidosis I (MPS IH) is a lysosomal storage disease treated with hematopoietic cell transplantation (HCT) because it stabilizes cognitive deterioration, but is insufficient to alleviate all somatic manifestations. Intravenous laronidase improves somatic burden in attenuated MPS I. It is unknown whether laronidase can improve somatic disease following HCT in MPS IH. The objective of this study was to evaluate the effects of laronidase on somatic outcomes of patients with MPS IH previously treated with HCT. METHODS: This 2-year open-label pilot study of laronidase included ten patients (age 5-13 years) who were at least 2 years post-HCT and donor engrafted. Outcomes were assessed semi-annually and compared to historic controls. RESULTS: The two youngest participants had a statistically significant improvement in growth compared to controls. Development of persistent high-titer anti-drug antibodies (ADA) was associated with poorer 6-min walk test (6MWT) performance; when patients with high ADA titers were excluded, there was a significant improvement in the 6MWT in the remaining seven patients. CONCLUSIONS: Laronidase seemed to improve growth in participants <8 years old, and 6MWT performance in participants without ADA. Given the small number of patients treated in this pilot study, additional study is needed before definitive conclusions can be made.
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Terapia de Reposição de Enzimas , Transplante de Células-Tronco Hematopoéticas , Iduronidase/administração & dosagem , Mucopolissacaridose I/terapia , Administração Intravenosa , Adolescente , Desenvolvimento do Adolescente , Criança , Desenvolvimento Infantil , Pré-Escolar , Esquema de Medicação , Terapia de Reposição de Enzimas/efeitos adversos , Feminino , Estado Funcional , Humanos , Iduronidase/efeitos adversos , Masculino , Mucopolissacaridose I/diagnóstico , Mucopolissacaridose I/enzimologia , Mucopolissacaridose I/fisiopatologia , Projetos Piloto , Fatores de Tempo , Resultado do TratamentoRESUMO
X-linked stapes gusher syndrome is a genetic form of deafness with distinct radiographic features on temporal bone CT. Hypothalamic hamartoma is a congenital glioneuronal anomaly of the hypothalamus. We report a potential association between these two rare anomalies that, to our knowledge, has not been reported. Two brothers presented with sensorineural hearing loss and almost identical inner ear and hypothalamic abnormalities, consistent with a diagnosis of X-linked stapes gusher syndrome and hypothalamic hamartoma. Genetic testing revealed identical mutations in the POU3F4 gene associated with X-linked stapes gusher syndrome. Furthermore, multiple vestibular diverticula were seen in both brothers, which have also not been reported with X-linked stapes gusher syndrome. This case suggests that POU3F4 mediated X-linked stapes gusher syndrome may also lead to multiple vestibular diverticula and hypothalamic hamartoma and, therefore, brain magnetic resonance imaging (MRI) could be considered in patients presenting with these inner ear findings.
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Hamartoma/diagnóstico por imagem , Hamartoma/genética , Perda Auditiva Neurossensorial/genética , Doenças Hipotalâmicas/diagnóstico por imagem , Doenças Hipotalâmicas/genética , Doenças do Labirinto/diagnóstico por imagem , Doenças do Labirinto/genética , Fatores do Domínio POU/genética , Pré-Escolar , Divertículo/complicações , Divertículo/diagnóstico por imagem , Divertículo/genética , Orelha Interna/diagnóstico por imagem , Hamartoma/complicações , Perda Auditiva Neurossensorial/complicações , Humanos , Doenças Hipotalâmicas/complicações , Doenças do Labirinto/complicações , Imageamento por Ressonância Magnética/métodos , Masculino , Estribo/diagnóstico por imagem , Síndrome , Tomografia Computadorizada por Raios X/métodosRESUMO
BACKGROUND: This is a cross-sectional study aiming to understand the early characteristics and background of bone health impairment in clinically well children with Fontan circulation. METHODS: We enrolled 10 clinically well children with Fontan palliation (operated >5 years before study entrance, Tanner stage ≤3, age 12.1 ± 1.77 years, 7 males) and 11 healthy controls (age 12.0 ± 1.45 years, 9 males) at two children's hospitals. All patients underwent peripheral quantitative CT. For the Fontan group, we obtained clinical characteristics, NYHA class, cardiac index by MRI, dual x-ray absorptiometry, and biochemical studies. Linear regression was used to compare radius and tibia peripheral quantitative CT measures between Fontan patients and controls. RESULTS: All Fontan patients were clinically well (NYHA class 1 or 2, cardiac index 4.85 ± 1.51 L/min/m2) and without significant comorbidities. Adjusted trabecular bone mineral density, cortical thickness, and bone strength index at the radius were significantly decreased in Fontan patients compared to controls with mean differences -30.13 mg/cm3 (p = 0.041), -0.31 mm (p = 0.043), and -6.65 mg2/mm4 (p = 0.036), respectively. No differences were found for tibial measures. In Fontan patients, the mean height-adjusted lumbar bone mineral density and total body less head z scores were -0.46 ± 1.1 and -0.63 ± 1.1, respectively, which are below the average, but within normal range for age and sex. CONCLUSIONS: In a clinically well Fontan cohort, we found significant bone deficits by peripheral quantitative CT in the radius but not the tibia, suggesting non-weight-bearing bones may be more vulnerable to the unique haemodynamics of the Fontan circulation.
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Absorciometria de Fóton/métodos , Densidade Óssea/fisiologia , Doenças Ósseas Metabólicas/diagnóstico , Osso e Ossos/metabolismo , Técnica de Fontan , Cardiopatias Congênitas/cirurgia , Tomografia Computadorizada por Raios X/métodos , Doenças Ósseas Metabólicas/etiologia , Doenças Ósseas Metabólicas/metabolismo , Osso e Ossos/diagnóstico por imagem , Criança , Estudos Transversais , Feminino , Cardiopatias Congênitas/diagnóstico , Humanos , Imagem Cinética por Ressonância Magnética/métodos , MasculinoRESUMO
BACKGROUND: SHC1 proteins (also called SHCA) exist in three functionally distinct isoforms (p46SHC, p52SHC, and p66SHC) that serve as intracellular adaptors for several key signaling pathways in breast cancer. Despite the broad evidence implicating SHC1 gene products as a central mediator of breast cancer, testing the isoform-specific roles of SHC1 proteins have been inaccessible due to the lack of isoform-specific inhibitors or gene knockout models. METHODS: Here, we addressed this issue by generating the first isoform-specific gene knockout models for p52SHC and p66SHC, using germline gene editing in the salt-sensitive rat strain. Compared with the wild-type (WT) rats, we found that genetic ablation of the p52SHC isoform significantly attenuated mammary tumor formation, whereas the p66SHC knockout had no effect. Rats were dosed with 7,12-dimethylbenz(a)anthracene (DMBA) by oral gavage to induce mammary tumors, and progression of tumor development was followed for 15 weeks. At 15 weeks, tumors were excised and analyzed by RNA-seq to determine differences between tumors lacking p66SHC or p52SHC. RESULTS: Compared with the wild-type (WT) rats, we found that genetic ablation of the p52SHC isoform significantly attenuated mammary tumor formation, whereas the p66SHC knockout had no effect. These data, combined with p52SHC being the predominant isoform that is upregulated in human and rat tumors, provide the first evidence that p52SHC is the oncogenic isoform of Shc1 gene products in breast cancer. Compared with WT tumors, 893 differentially expressed (DE; FDR < 0.05) genes were detected in p52SHC KO tumors compared with only 18 DE genes in the p66SHC KO tumors, further highlighting that p52SHC is the relevant SHC1 isoform in breast cancer. Finally, gene network analysis revealed that p52SHC KO disrupted multiple key pathways that have been previously implicated in breast cancer initiation and progression, including ESR1 and mTORC2/RICTOR. CONCLUSION: Collectively, these data demonstrate the p52SHC isoform is the key driver of DMBA-induced breast cancer while the expression of p66SHC and p46SHC are not enough to compensate.
Assuntos
Neoplasias da Mama/genética , Transformação Celular Neoplásica/genética , Proteína 1 de Transformação que Contém Domínio 2 de Homologia de Src/genética , Animais , Neoplasias da Mama/metabolismo , Transformação Celular Neoplásica/metabolismo , Modelos Animais de Doenças , Feminino , Perfilação da Expressão Gênica , Técnicas de Inativação de Genes , Humanos , Imuno-Histoquímica , Neoplasias Mamárias Animais , Isoformas de Proteínas , Ratos , Proteína 1 de Transformação que Contém Domínio 2 de Homologia de Src/metabolismo , TranscriptomaRESUMO
Early in her career, Jacqueline Noonan, a pediatric cardiologist, recognized that a number of children with valvular pulmonary stenosis had similar facial features. Dr. Noonan reported the clinical characteristics of this condition including short stature, hypertelorism, ptosis, mild mental retardation, undescended testes, and skeletal malformations. Further characterization of Noonan Syndrome led to the development of clinical criteria for the diagnosis of the condition. Identification of the first genetic cause of Noonan Syndrome, mutation of ptpn11 was reported in 2001. Multiple subsequent genes have been identified as causes of Noonan Syndrome and the related Rasopathies.
Assuntos
Deficiência Intelectual , Síndrome de Noonan , Humanos , MutaçãoRESUMO
OBJECTIVE: To evaluate the extent to which pubertal timing alters the classification of extremes of attained stature across race-ethnicity groups of youths in the US. STUDY DESIGN: We performed analyses of height and Tanner staging data of 3206 cross-sectional national sample of youths ages 8-18 years (53% male, n = 1606), 72% of whom were non-Hispanic white, 9% Mexican American, and 19% non-Hispanic black . Specialized growth models were used to derive Tanner-stage-age-adjusted z scores (TSAHAZ). The prevalence of shortness (<-1SD) and tallness (≥+1SD) status was quantified using TSAHAZ. RESULTS: Highly variable patterns of prevalence of shortness and tallness via chronologic age height z score (CAHAZ) were observed in results stratified by race-ethnicity and sex. Tallness CAHAZ prevalence was high among non-Hispanic white and non-Hispanic black male youths relative to Mexican American (40.0%-43.3% vs 20.5%) with a similar pattern in female youths. In both sexes, this pattern was eliminated with TSAHAZ, with Mexican American youth becoming statistically not different from their non-Hispanic white and non-Hispanic black peers. CONCLUSIONS: Differences in timing of puberty between race-ethnicity groups affects estimated prevalence of shortness and tallness of attained height that remains uncaptured with CAHAZ. Adjustment for pubertal development might help isolate crucial determinants of attained stature and other aspects of body composition that may be most responsive to intervention programs in populations. The curves developed by adjusting for pubertal status may help the clinician avoid misclassification of children with early and late pubertal development.
Assuntos
Estatura , Puberdade , Grupos Raciais/estatística & dados numéricos , Adolescente , Criança , Feminino , Inquéritos Epidemiológicos , Humanos , Masculino , Modelos Estatísticos , Estudos de Amostragem , Estados Unidos/epidemiologiaRESUMO
The safety of growth hormone (GH) therapy in children has been studied extensively. The identification of Creutzfeldt-Jacob disease in individuals who received pituitary-derived GH led to heightened surveillance for safety issues related to recombinant human GH (rhGH). An excellent safety profile of rhGH has been demonstrated in large Phase IV registries comprising > 600,000 patient-years of rhGH exposure and long-term safety cohorts of adults treated with GH as children. Increased mortality risk has been reported but eliminated when corrected for small size at birth. Increased risk of mortality from cerebrovascular disease has been reported but interpretation of these events remains difficult due to the lack of appropriate control groups and a lack of replication of these findings in other studies. The advent of new long-acting growth hormone (LAGH) products provides an opportunity for the development of cohorts of individuals receiving LAGH replacement therapy for continued long-term safety studies.
Assuntos
Sistema de Registros , Terapia de Reposição Hormonal , Hormônio do Crescimento Humano , Humanos , Proteínas RecombinantesRESUMO
OBJECTIVES: To evaluate obesity and overweight in children with congenital adrenal hyperplasia (CAH) and associations with glucocorticoids, fludrocortisone and disease control. Adjusting body mass index-for-height-age (BMIHA ) percentile is proposed to correct misclassification of obese/overweight status in CAH children with advanced bone age and tall-for-age stature. DESIGN: Longitudinal. PATIENTS: One hundred and ninety-four children with CAH seen from 1970 to 2013: 124 salt wasting (SW); 70 simple virilizing (SV); 102 females. MEASUREMENTS: Body mass index (BMI) end-points were overweight (85-94 percentile) and obese (≥95 percentile). RESULTS: Approximately 50% of the children had at least one BMI measurement ≥95 percentile and about 70% had at least one ≥85 percentile. Using BMIHA percentiles, obesity incidence decreased slightly in SW children (47-43%) and markedly in SV children (50-33%); however, overweight status was not reduced. Only 6% of SW and 1% of SV children were persistently obese (≥3 clinic visits) when BMIHA was applied, whereas overweight status persisted in 35% of SW and 33% of SV children. Most obesity or overweight when using BMIHA occurred before age 10 and there was no association with hydrocortisone (HC) or fludrocortisone dosing. Adiposity rebound for SW children occurred by 3·3 years and in SV females by age 3·8 years, over a year earlier than the adiposity rebound for healthy children. CONCLUSION: Children with CAH are at higher risk for early onset obesity and overweight with or without using BMIHA but rates of persistent obesity were lower than previously reported. Careful HC dosing during early childhood is needed to prevent increased weight gain and an early adiposity rebound.