Frontiers in congenital disorders of glycosylation consortium, a cross-sectional study report at year 5 of 280 individuals in the natural history cohort.

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.

Development of specific growth charts for children with Fanconi anemia.

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.

Detection rate of IGF-1 variants and their implication to protein binding: study of over 240,000 patients.

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 (0.45 %, or 4,508 occurrences per million). Seven patients were identified as homozygous or double heterozygous. Majority of variants (98 %) 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.

Impact of Daily Growth Hormone Adherence on Height Velocity Among Children With Growth Hormone Deficiency (GHD).

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.

Thrombosis risk with estrogen use for puberty induction in congenital disorders of glycosylation.

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.

Persistent bone and joint disease despite current treatments for mucopolysaccharidosis types I, II, and VI: Data from a 10-year prospective study.

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.

p66Shc signaling does not contribute to tubular damage induced by renal ischemia-reperfusion injury in rat.

Renal ischemia-reperfusion (IR) injury is one of the major causes of acute kidney injury and represents a significant risk factor for renal transplantation. The level of renal damage is influenced by the ischemic duration and is caused by excessive amounts of produced reactive oxygen species (ROS). Adaptor protein p66Shc is known to regulate cellular and organ's sensitivity to oxidative stress and to contribute significantly to mitochondrial production of hydrogen peroxide in stress conditions. Studies carried out in cultured renal cells suggest that p66Shc-mediated mitochondrial dysfunction and ROS production are responsible for renal ischemic injury. We used our genetically modified rats, which either lack p66Shc expression, or express p66Shc variant, which constitutively generates increased quantities of hydrogen peroxide, to evaluate potential contribution of p66Shc signaling to renal damage in ischemia reperfusion rat model. Analysis of outer medulla tubule damage revealed the lack of contribution of either p66Shc expression or its constitutive signaling to IR injury in rat model.

Structures of two distinct conformations of holo-non-ribosomal peptide synthetases.

Many important natural products are produced by multidomain non-ribosomal peptide synthetases (NRPSs). During synthesis, intermediates are covalently bound to integrated carrier domains and transported to neighbouring catalytic domains in an assembly line fashion. Understanding the structural basis for catalysis with non-ribosomal peptide synthetases will facilitate bioengineering to create novel products. Here we describe the structures of two different holo-non-ribosomal peptide synthetase modules, each revealing a distinct step in the catalytic cycle. One structure depicts the carrier domain cofactor bound to the peptide bond-forming condensation domain, whereas a second structure captures the installation of the amino acid onto the cofactor within the adenylation domain. These structures demonstrate that a conformational change within the adenylation domain guides transfer of intermediates between domains. Furthermore, one structure shows that the condensation and adenylation domains simultaneously adopt their catalytic conformations, increasing the overall efficiency in a revised structural cycle. These structures and the single-particle electron microscopy analysis demonstrate a highly dynamic domain architecture and provide the foundation for understanding the structural mechanisms that could enable engineering of novel non-ribosomal peptide synthetases.

Safety and effectiveness of Omnitrope® (somatropin) in PATRO Children: a multi-center, post-marketing surveillance study comparison of US and international cohort data.

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.

Association of Daily Growth Hormone Injection Adherence and Height Among Children With Growth Hormone Deficiency.

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.

Pubertal stress recalibration reverses the effects of early life stress in postinstitutionalized children.

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.

Early-life stress and current stress predict BMI and height growth trajectories in puberty.

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.

Modulation of p66Shc impairs cerebrovascular myogenic tone in low renin but not low nitric oxide models of systemic hypertension.

Cerebral blood flow and perfusion are tightly maintained through autoregulation despite changes in transmural pressure. Oxidative stress impairs cerebral blood flow, precipitating cerebrovascular events. Phosphorylation of the adaptor protein p66Shc increases mitochondrial-derived oxidative stress. The effect of p66Shc gain or loss of function in nonhypertensive rats is unclear. We hypothesized that p66Shc gain of function would impair autoregulation of cerebral microcirculation under physiological and pathological conditions. Three previously established transgenic [salt-sensitive (SS) background] p66Shc rats were used, p66-Del/SS (express p66Shc with a nine-amino acid deletion), p66Shc-knockout (KO)/SS (frameshift premature termination codon), and p66Shc signaling and knock-in substitution of Ser36Ala (p66Shc-S36A)/SS (substitution of Ser36Ala). The p66Shc-Del were also bred on Sprague-Dawley (SD) backgrounds (p66-Del/SD), and a subset was exposed to a hypertensive stimulus [NG-nitro-l-arginine methyl ester (l-NAME)] for 4 wk. Active and passive diameters to increasing transmural pressure were measured and myogenic tone was calculated in all groups (SS and SD). Myogenic responses to increasing pressure were impaired in p66Shc-Del/SS rats relative to wild-type (WT)/SS and knock-in substitution of Ser36Ala (S36A; P < 0.05). p66-Del/SD rats did not demonstrate changes in active/passive diameters or myogenic tone relative to WT/SD but did demonstrate attenuated passive diameter responses to higher transmural pressure relative to p66-Del/SS. Four weeks of a hypertensive stimulus (l-NAME) did not alter active or passive diameter responses to increasing transmural pressure (P = 0.86-0.99), but increased myogenic responses relative to p66-Del/SD (P < 0.05). Collectively, we demonstrate the functional impact of p66Shc within the cerebral circulation and demonstrate that the genetic background of p66Shc rats largely drives changes in cerebrovascular function.NEW & NOTEWORTHY We demonstrate that the modulation of p66Shc signaling impairs cerebral artery myogenic tone in a low renin model of hypertension. This impairment is dependent upon the genetic background, as modulated p66Shc signaling in Sprague-Dawley rats does not impair cerebral artery myogenic tone.

Adjusting for Pubertal Status Reduces Overweight and Obesity Prevalence in the United States.

OBJECTIVE: To compare pediatric overweight and obesity prevalence among non-Hispanic white, Mexican American, and non-Hispanic black US youths before and after adjusting body mass index (BMI) for pubertal status, as assessed by Tanner stage. STUDY DESIGN: We analyzed cross-sectional anthropometric and pubertal data from non-Hispanic white, Mexican American, and non-Hispanic black youths in the National Health and Nutrition Examination Survey (NHANES) III. We developed specialized Tanner stage and chronological age-adjusted models to establish Tanner-stage adjusted BMI z-scores, which were then used to determine adjusted overweight/obesity prevalence. We compared pediatric overweight/obesity prevalence before and after pubertal status adjustment. RESULTS: Among 3206 youths aged 8-18 years (50% male; 26% non-Hispanic white, 35% Mexican American, 39% non-Hispanic black), adjusting BMI for Tanner stage significantly reduced overweight (males, from 29% to 21%; females, from 29% to 17%) and obesity (males, from 14% to 7%; females, from 11% to 5%) prevalence across all races/ethnicities. The obesity prevalence reduction was more pronounced in Mexican Americans (males, 11% reduction; females, 9% reduction) and non-Hispanic blacks (males and females, 10% reduction) compared with non-Hispanic whites (males, 6% reduction; females, 5% reduction). Similar patterns were seen in overweight prevalence. CONCLUSIONS: Adjusting for pubertal status reduced the prevalence of overweight/obesity in non-Hispanic white, Mexican American, and non-Hispanic black youth. This suggests that adjusting for puberty incorporates changes otherwise not captured when only considering the age of a child. Adjusting BMI for pubertal status may be important when interpreting a youth's weight status and consideration for obesity management, as well as when interpreting pediatric overweight/obesity prevalence data.

Double p52Shc/p46Shc Rat Knockout Demonstrates Severe Gait Abnormalities Accompanied by Dilated Cardiomyopathy.

The ubiquitously expressed adaptor protein Shc exists in three isoforms p46Shc, p52Shc, and p66Shc, which execute distinctly different actions in cells. The role of p46Shc is insufficiently studied, and the purpose of this study was to further investigate its functional significance. We developed unique rat mutants lacking p52Shc and p46Shc isoforms (p52Shc/46Shc-KO) and carried out histological analysis of skeletal and cardiac muscle of parental and genetically modified rats with impaired gait. p52Shc/46Shc-KO rats demonstrate severe functional abnormalities associated with impaired gait. Our analysis of p52Shc/46Shc-KO rat axons and myelin sheets in cross-sections of the sciatic nerve revealed the presence of significant anomalies. Based on the lack of skeletal muscle fiber atrophy and the presence of sciatic nerve abnormalities, we suggest that the impaired gait in p52Shc/46Shc-KO rats might be due to the sensory feedback from active muscle to the brain locomotor centers. The lack of dystrophin in some heart muscle fibers reflects damage due to dilated cardiomyopathy. Since rats with only p52Shc knockout do not display the phenotype of p52Shc/p46Shc-KO, abnormal locomotion is likely to be caused by p46Shc deletion. Our data suggest a previously unknown role of 46Shc actions and signaling in regulation of gait.

Endothelin receptor A and p66Shc regulate spontaneous Ca2+ oscillations in smooth muscle cells controlling renal arterial spontaneous motion.

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.

Pubertal recalibration of cortisol-DHEA coupling in previously-institutionalized children.

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.

Clinical trial of laronidase in Hurler syndrome after hematopoietic cell transplantation.

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.

Hypothalamic hamartomas and inner ear diverticula with X-linked stapes gusher syndrome - new associations?

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.

Real-time teledermatology clinics in a tertiary public hospital: A clinical audit.

BACKGROUND: Our metropolitan hospital provides a real-time videoconference teledermatology clinic to enable patients in rural and remote Queensland to access a specialist for dermatology care. METHODS: Retrospective clinical audit of all patient referrals to the videoconference teledermatology clinic for a two-year period. RESULTS: A total of 483 consultations for 178 patients were conducted by the teledermatology clinic. Most patients were from remote and very remote regions of Queensland with a mean distance from our metropolitan hospital to the patient's town of residence of 1295 km. The most common reason for referral, as per the referral form, was rash (32%), followed by acne (12%) and dermatitis (11%). Most (78%) referrals came from general practitioners. Around 8% of patients seen in the teledermatology clinic were converted to in-person review; 81% of patients were managed via teledermatology, and 10% of patients did not attend the scheduled teleconsultation. CONCLUSION: The outpatient teledermatology clinic run through the Telehealth Centre of a metropolitan hospital is an effective way of delivering a general dermatology consultation service to rural and remote patients in a timely manner.