Growth reference charts for children with hypochondroplasia.

Hypochondroplasia (HCH) is a rare skeletal dysplasia causing mild short stature. There is a paucity of growth reference charts for this population. Anthropometric data were collected to generate height, weight, and head circumference (HC) growth reference charts for children with a diagnosis of HCH. Mixed longitudinal anthropometric data and genetic analysis results were collected from 14 European specialized skeletal dysplasia centers. Growth charts were generated using Generalized Additive Models for Location, Scale, and Shape. Measurements for height (983), weight (896), and HC (389) were collected from 188 (79 female) children with a diagnosis of HCH aged 0-18 years. Of the 84 children who underwent genetic testing, a pathogenic variant in FGFR3 was identified in 92% (77). The data were used to generate growth references for height, weight, and HC, plotted as charts with seven centiles from 2nd to 98th, for ages 0-4 and 0-16 years. HCH-specific growth charts are important in the clinical care of these children. They help to identify if other comorbidities are present that affect growth and development and serve as an important benchmark for any prospective interventional research studies and trials.

Differences in retinopathy prevalence and associated risk factors across 11 countries in three continents: A cross-sectional study of 156,090 children and adolescents with type 1 diabetes.

OBJECTIVE: To examine the prevalence, time trends, and risk factors of diabetic retinopathy (DR) among youth with type 1 diabetes (T1D) from 11 countries (Australia, Austria, Denmark, England, Germany, Italy, Luxemburg, Netherlands, Slovenia, United States, and Wales). SUBJECTS AND METHODS: Data on individuals aged 10-21 years with T1D for >1 year during the period 2000-2020 were analyzed. We used a cross-sectional design using the most recent year of visit to investigate the time trend. For datasets with longitudinal data, we aggregated the variables per participant and observational year, using data of the most recent year to take the longest observation period into account. DR screening was performed through quality assured national screening programs. Multiple logistic regression models adjusted for the year of the eye examination, age, gender, minority status, and duration of T1D were used to evaluate clinical characteristics and the risk of DR. RESULTS: Data from 156,090 individuals (47.1% female, median age 15.7 years, median duration of diabetes 5.2 years) were included. Overall, the unadjusted prevalence of any DR was 5.8%, varying from 0.0% (0/276) to 16.2% between countries. The probability of DR increased with longer disease duration (aORper-1-year-increase  = 1.04, 95% CI: 1.03-1.04, p < 0.0001), and decreased over time (aORper-1-year-increase  = 0.99, 95% CI: 0.98-1.00, p = 0.0093). Evaluating possible modifiable risk factors in the exploratory analysis, the probability of DR increased with higher HbA1c (aORper-1-mmol/mol-increase-in-HbA1c  = 1.03, 95% CI: 1.03-1.03, p < 0.0001) and was higher among individuals with hypertension (aOR = 1.24, 95% CI: 1.11-1.38, p < 0.0001) and smokers (aOR = 1.30, 95% CI: 1.17-1.44, p < 0.0001). CONCLUSIONS: The prevalence of DR in this large cohort of youth with T1D varied among countries, increased with diabetes duration, decreased over time, and was associated with higher HbA1c, hypertension, and smoking.

Molecular characterization of DICER1-mutated pituitary blastoma.

Pituitary blastoma (PitB) has recently been identified as a rare and potentially lethal pediatric intracranial tumor. All cases that have been studied molecularly possess at least one DICER1 pathogenic variant. Here, we characterized nine pituitary samples, including three fresh frozen PitBs, three normal fetal pituitary glands and three normal postnatal pituitary glands using small-RNA-Seq, RNA-Seq, methylation profiling, whole genome sequencing and Nanostring® miRNA analyses; an extended series of 21 pituitary samples was used for validation purposes. These analyses demonstrated that DICER1 RNase IIIb hotspot mutations in PitBs induced improper processing of miRNA precursors, resulting in aberrant 5p-derived miRNA products and a skewed distribution of miRNAs favoring mature 3p over 5p miRNAs. This led to dysregulation of hundreds of 5p and 3p miRNAs and concomitant dysregulation of numerous mRNA targets. Gene expression analysis revealed PRAME as the most significantly upregulated gene (500-fold increase). PRAME is a member of the Retinoic Acid Receptor (RAR) signaling pathway and in PitBs, the RAR, WNT and NOTCH pathways are dysregulated. Cancer Hallmarks analysis showed that PI3K pathway is activated in the tumors. Whole genome sequencing demonstrated a quiet genome with very few somatic alterations. The comparison of methylation profiles to publicly available data from ~ 3000 other central nervous system tumors revealed that PitBs have a distinct methylation profile compared to all other tumors, including pituitary adenomas. In conclusion, this comprehensive characterization of DICER1-related PitB revealed key molecular underpinnings of PitB and identified pathways that could potentially be exploited in the treatment of this tumor.

Prevalence of Celiac Disease in 52,721 Youth With Type 1 Diabetes: International Comparison Across Three Continents.

OBJECTIVE: Celiac disease (CD) has a recognized association with type 1 diabetes. We examined international differences in CD prevalence and clinical characteristics of youth with coexisting type 1 diabetes and CD versus type 1 diabetes only. RESEARCH DESIGN AND METHODS: Data sources were as follows: the Prospective Diabetes Follow-up Registry (DPV) (Germany/Austria); the T1D Exchange Clinic Network (T1DX) (U.S.); the National Paediatric Diabetes Audit (NPDA) (U.K. [England/Wales]); and the Australasian Diabetes Data Network (ADDN) (Australia). The analysis included 52,721 youths <18 years of age with a clinic visit between April 2013 and March 2014. Multivariable linear and logistic regression models were constructed to analyze the relationship between outcomes (HbA1c, height SD score [SDS], overweight/obesity) and type 1 diabetes/CD versus type 1 diabetes, adjusting for sex, age, and diabetes duration. RESULTS: Biopsy-confirmed CD was present in 1,835 youths (3.5%) and was diagnosed at a median age of 8.1 years (interquartile range 5.3-11.2 years). Diabetes duration at CD diagnosis was <1 year in 37% of youths, >1-2 years in 18% of youths, >3-5 years in 23% of youths, and >5 years in 17% of youths. CD prevalence ranged from 1.9% in the T1DX to 7.7% in the ADDN and was higher in girls than boys (4.3% vs. 2.7%, P < 0.001). Children with coexisting CD were younger at diabetes diagnosis compared with those with type 1 diabetes only (5.4 vs. 7.0 years of age, P < 0.001) and fewer were nonwhite (15 vs. 18%, P < 0.001). Height SDS was lower in those with CD (0.36 vs. 0.48, adjusted P < 0.001) and fewer were overweight/obese (34 vs. 37%, adjusted P < 0.001), whereas mean HbA1c values were comparable: 8.3 ± 1.5% (67 ± 17 mmol/mol) versus 8.4 ± 1.6% (68 ± 17 mmol/mol). CONCLUSIONS: CD is a common comorbidity in youth with type 1 diabetes. Differences in CD prevalence may reflect international variation in screening and diagnostic practices, and/or CD risk. Although glycemic control was not different, the lower height SDS supports close monitoring of growth and nutrition in this population.

Pituitary blastoma: a pathognomonic feature of germ-line DICER1 mutations.

Individuals harboring germ-line DICER1 mutations are predisposed to a rare cancer syndrome, the DICER1 Syndrome or pleuropulmonary blastoma-familial tumor and dysplasia syndrome [online Mendelian inheritance in man (OMIM) #601200]. In addition, specific somatic mutations in the DICER1 RNase III catalytic domain have been identified in several DICER1-associated tumor types. Pituitary blastoma (PitB) was identified as a distinct entity in 2008, and is a very rare, potentially lethal early childhood tumor of the pituitary gland. Since the discovery by our team of an inherited mutation in DICER1 in a child with PitB in 2011, we have identified 12 additional PitB cases. We aimed to determine the contribution of germ-line and somatic DICER1 mutations to PitB. We hypothesized that PitB is a pathognomonic feature of a germ-line DICER1 mutation and that each PitB will harbor a second somatic mutation in DICER1. Lymphocyte or saliva DNA samples ascertained from ten infants with PitB were screened and nine were found to harbor a heterozygous germ-line DICER1 mutation. We identified additional DICER1 mutations in nine of ten tested PitB tumor samples, eight of which were confirmed to be somatic in origin. Seven of these mutations occurred within the RNase IIIb catalytic domain, a domain essential to the generation of 5p miRNAs from the 5' arm of miRNA-precursors. Germ-line DICER1 mutations are a major contributor to PitB. Second somatic DICER1 "hits" occurring within the RNase IIIb domain also appear to be critical in PitB pathogenesis.

Body composition, exercise and energy expenditure in survivors of acute lymphoblastic leukaemia.

Survivors of acute lymphoblastic leukaemia (ALL) are recognised to become overweight and this seems to worsen with increasing length of follow up. Increases in body fat appear to be more marked in girls than in boys and in those who have received prophylactic cranial irradiation. Physiological responses to exercise, both at submaximal and maximal levels, are different in ALL survivors compared to controls. Heart rate appears to be increased at low intensity exercise, possibly to maintain adequate cardiac output. Maximal aerobic capacity is reduced, signifying a lower level of physical fitness. Total daily energy expenditure (TDEE) under free living conditions appears limited due to low participation in physical activity. Associations exist between measures of energy expenditure and body fat, but whether these are cause or effect has yet to proven.

GH replacement does not increase the risk of recurrence in patients with craniopharyngioma.

BACKGROUND: A significant number of patients with craniopharyngioma are GH deficient. The safety of GH replacement in these subjects has not been established. OBJECTIVE: To assess the effect of GH replacement upon recurrence in patients with craniopharyngioma. PATIENTS AND METHODS: All the patients with craniopharyngioma followed-up at the Departments of Endocrinology or Paediatrics in Oxford and treated or not with GH were studied retrospectively. These were recruited from the databases of the departments consisting of subjects diagnosed between January 1964 and July 2005. The impact of GH replacement upon recurrence was evaluated after adjusting for possible confounding factors. RESULTS: Forty-one subjects received GH replacement. Nine of them did not have follow-up imaging during GH therapy and were not included in the statistical analyses. The remaining 32 (22 males/10 females) received GH for a mean period of 6.3 +/- 4.6 years (median 5.1, range 0.8-22); 21 started during childhood (13 of them continued after the achievement of final height with an adult dose) and 11 during adult life. The mean duration of their follow-up (from surgery until last assessment) was 10.8 +/- 9.2 years (range 1.9-40). Fifty-three subjects had not received GH therapy (30 men/23 women). The mean duration of their follow-up (from surgery until last assessment) was 8.3 +/- 8.8 years (range 0.5-36). During the observation period, 4 patients treated with GH and 22 non-GH treated ones developed tumour recurrence. After adjusting for sex, age at tumour diagnosis and type of tumour therapy (gross total removal, partial removal, surgery + irradiation), GH treatment was not a significant independent predictor of recurrence (P = 0.06; hazard ratio = 0.309). Similar results were obtained when the impact of GH replacement was assessed according to its duration (P = 0.18; hazard ratio = 0.991/month of treatment). None of the nine patients with insufficient imaging data for inclusion in the statistical analyses [5 men/4 women, 3 treated with GH during childhood/6 during adult life, mean duration of GH therapy 2.9 +/- 2.4 years (median 1.8, range 0.4-7)] showed clinical features suggestive of recurrence during the period of GH replacement. CONCLUSION Based on the data of the craniopharyngiomas database in Oxford, there is no evidence that GH replacement is associated with an increased risk of tumour recurrence.

Critical role of the ubiquitin ligase activity of UHRF1, a nuclear RING finger protein, in tumor cell growth.

Early cellular events associated with tumorigenesis often include loss of cell cycle checkpoints or alteration in growth signaling pathways. Identification of novel genes involved in cellular proliferation may lead to new classes of cancer therapeutics. By screening a tetracycline-inducible cDNA library in A549 cells for genes that interfere with proliferation, we have identified a fragment of UHRF1 (ubiquitin-like protein containing PHD and RING domains 1), a nuclear RING finger protein, that acts as a dominant negative effector of cell growth. Reduction of UHRF1 levels using an UHRF1-specific shRNA decreased growth rates in several tumor cell lines. In addition, treatment of A549 cells with agents that activated different cell cycle checkpoints resulted in down-regulation of UHRF1. The primary sequence of UHRF1 contains a PHD and a RING motif, both of which are structural hallmarks of ubiquitin E3 ligases. We have confirmed using an in vitro autoubiquitination assay that UHRF1 displays RING-dependent E3 ligase activity. Overexpression of a GFP-fused UHRF1 RING mutant that lacks ligase activity sensitizes cells to treatment with various chemotherapeutics. Taken together, our results suggest a general requirement for UHRF1 in tumor cell proliferation and implicate the RING domain of UHRF1 as a functional determinant of growth regulation.

Body composition of long-term survivors of acute lymphoblastic leukaemia.

BACKGROUND: Long-term quality of life is of growing importance in children previously treated for malignancy. Obesity defined indirectly from indices of height and weight, has been described in long-term survivors of acute lymphoblastic leukaemia (ALL) and hypothesised to be a consequence of previous cranial irradiation. PROCEDURE: In this study, measures of whole and regional body composition using skinfold and dual energy X-ray absorptiometry (DEXA) measurements have been made in 35 long-term survivors of ALL who had received cranial irradiation and chemotherapy. To assess the influence of cranial irradiation, results were compared with those obtained in 21 children treated for other malignancies, who received chemotherapy alone and with 31 healthy sibling controls. RESULTS: Girls treated for ALL were significantly fatter than those treated for other malignancies or healthy control siblings whether measured by skinfold thickness (median (range) 37.4% (17.9-41.3) vs. 24.6% (19.1-35.0) and 28.8% (19.6-43.1), respectively, P<0.01) or DEXA (33.5% (20.5-42.8) vs. 25.5% (16.5-31.0) and 24.5% (18.8-53.6), respectively, P<0.01). Boys treated for ALL were not significantly fatter than boys in the other two groups. Measures of whole body percent fat derived from DEXA were persistently less than those derived from skinfold measurements with a mean (95% CI) difference of 2.4% (1.7-3.1, P<0.001) for all groups combined. In ALL survivors, using regression equations for skinfold thicknesses derived from controls with DEXA as the 'gold standard' method, fat mass was significantly overestimated. CONCLUSION: Female survivors of ALL are significantly fatter than those of other malignancies and healthy sibling controls. Caution should be observed in the application of published equations, derived from the normal population, for the calculation of body composition in children treated for ALL. The mechanism of onset of obesity remains unclear, but is probably multifactorial and related to previous cranial irradiation.