Genotype-Phenotype Correlation in 153 Adult Patients With Congenital Adrenal Hyperplasia due to 21-Hydroxylase Deficiency: Analysis of the United Kingdom Congenital Adrenal Hyperplasia Adult Study Executive (CaHASE) Cohort

CONTEXT: In congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency, a strong genotype-phenotype correlation exists in childhood. However, similar data in adults are lacking. OBJECTIVE: The objective of the study was to test whether the severity of disease-causing CYP21A2 mutations influences the treatment and health status in adults with CAH. RESEARCH DESIGN AND METHODS: We analyzed the genotype in correlation with treatment and health status in 153 adults with CAH from the United Kingdom Congenital adrenal Hyperplasia Adult Study Executive cohort. RESULTS: CYP21A2 mutations were distributed similarly to previously reported case series. In 7 patients a mutation was identified on only 1 allele. Novel mutations were detected on 1.7% of alleles (5 of 306). Rare mutations were found on 2.3% of alleles (7 of 306). For further analysis, patients were categorized into CYP21A2 mutation groups according to predicted residual enzyme function: null (n = 34), A (n = 42), B (n = 36), C (n = 34), and D (n = 7). Daily glucocorticoid dose was highest in group null and lowest in group C. Fludrocortisone was used more frequently in patients with more severe genotypes. Except for lower female height in group B, no statistically significant associations between genotype and clinical parameters were found. Androgens, blood pressure, lipids, blood glucose, and homeostasis model assessment of insulin resistance were not different between groups. Subjective health status was similarly impaired across groups. CONCLUSIONS: In adults with classic CAH and women with nonclassic CAH, there was a weak association between genotype and treatment, but health outcomes were not associated with genotype. The underrepresentation of males with nonclassic CAH may reflect that milder genotypes result in a milder condition that is neither diagnosed nor followed up in adulthood. Overall, our results suggest that the impaired health status of adults with CAH coming to medical attention is acquired rather than genetically determined and therefore could potentially be improved through modification of treatment

What to consider when pseudohypoparathyroidism is ruled out: IPPSD and differential diagnosis

Background: Pseudohypoparathyroidism (PHP) is a rare disease whose phenotypic features are rather difficult to identify in some cases. Thus, although these patients may present with the Albright''s hereditary osteodystrophy (AHO) phenotype, which is characterized by small stature, obesity with a rounded face, subcutaneous ossifications, mental retardation and brachydactyly, its manifestations are somewhat variable. Indeed, some of them present with a complete phenotype, whereas others show only subtle manifestations. In addition, the features of the AHO phenotype are not specific to it and a similar phenotype is also commonly observed in other syndromes. Brachydactyly type E (BDE) is the most specific and objective feature of the AHO phenotype, and several genes have been associated with syndromic BDE in the past few years. Moreover, these syndromes have a skeletal and endocrinological phenotype that overlaps with AHO/PHP. In light of the above, we have developed an algorithm to aid in genetic testing of patients with clinical features of AHO but with no causative molecular defect at the GNAS locus. Starting with the feature of brachydactyly, this algorithm allows the differential diagnosis to be broadened and, with the addition of other clinical features, can guide genetic testing. Methods: We reviewed our series of patients (n = 23) with a clinical diagnosis of AHO and with brachydactyly type E or similar pattern, who were negative for GNAS anomalies, and classify them according to the diagnosis algorithm to finally propose and analyse the most probable gene(s) in each case. Results: A review of the clinical data for our series of patients, and subsequent analysis of the candidate gene(s), allowed detection of the underlying molecular defect in 12 out of 23 patients: five patients harboured a mutation in PRKAR1A, one in PDE4D, four in TRPS1 and two in PTHLH. Conclusions: This study confirmed that the screening of other genes implicated in syndromes with BDE and AHO or a similar phenotype is very helpful for establishing a correct genetic diagnosis for those patients who have been misdiagnosed with "AHO-like phenotype" with an unknown genetic cause, and also for better describing the characteristic and differential features of these less common syndromes

Mega-analysis methods in ENIGMA: the experience of the generalized anxiety disorder working group

The ENIGMA group on Generalized Anxiety Disorder (ENIGMA‐Anxiety/GAD) is part of a broader effort to investigate anxiety disorders using imaging and genetic data across multiple sites worldwide. The group is actively conducting a mega‐analysis of a large number of brain structural scans. In this process, the group was confronted with many methodological challenges related to study planning and implementation, between‐country transfer of subject‐level data, quality control of a considerable amount of imaging data, and choices related to statistical methods and efficient use of resources. This report summarizes the background information and rationale for the various methodological decisions, as well as the approach taken to implement them. The goal is to document the approach and help guide other research groups working with large brain imaging data sets as they develop their own analytic pipelines for mega‐analyses

Fluvial Incisions in the North-Western Pyrenees (Aspe Valley, France): Dissection of a Former Planation Surface and Some Tectonic Implications

International audienceThe Pyrenean range results from the collision between the Iberian and Eurasian plates which started during the Santonian. Iberia has shown no more relevant motion with respect to Europe since Early Miocene times. In this regard, the Pyrenees can no longer be considered as an active plate boundary from Miocene onwards. Dissected remnants of a high elevation low relief surface (HELRS) are encountered all along the Pyrenean range. All authors agree on the tardi- to post-shortening age of this surface, but doubt remains on its original elevation. In particular, whether a substantial post-shortening uplift occurred after the generation of the Pyrenean planation surface is still debated.Based on a geomorphological study of the entrenchment of the Aspe River in the North-Western Pyrenees, we evidence a Lower Miocene to present-day multi-stage history of dissection of the HELRS in the North-Western Pyrenees. Each incision stage is recorded by erosional triangular facets and associated stepped remnants of palaeovalleys. Compared analysis of the patterns of incisions characterizing (i) the Axial Zone of the range and (ii) its northern border allows to evidence differential vertical motion. We finally discuss the process(es) controlling the deduced uplift of the Western Pyrenean Axial Zone

Preorogenic Folds and Syn-Orogenic Basement Tilts in an Inverted Hyperextended Margin: The Northern Pyrenees Case Study

International audienceThe Chaînons Béarnais (CB, North Pyrenean Zone) resulted from the Cenozoic contractional reactivation of the salt tectonics-bearing, hyperextended margin that initiated at the Europe-Iberia transition during the Early Cretaceous. In this tectonic scenario, assessing the relative contribution of extension and contraction to the present-day structure is crucial to reconstruct the hyperextended margin geometry and to quantify the subsequent shortening. This study undertakes this issue by defining the relationship between folding and two bedding-independent references: peak temperature isotherms and paleomagnetic data. Isotherms were reconstructed from 76 new measurements of Raman spectroscopy on carbonaceous materials (RSCM) and indicate temperatures at the time of peak metamorphism in the CB (110-85 Ma, end of extension). They are shallowly to moderately northwards dipping and cut across most of the folds deforming the Mesozoic units. Paleomagnetic data from 29 sites evidence a widespread remagnetization carried by pyrrhotite that was probably blocked during the early Paleogene (before the onset of continental collision) and postdated folding in the CB. Abnormal inclinations in this remagnetization suggest syn-collision tilts up to 60°to the north in the back limb of the Axial Zone. Based on the presented data set, we propose that the folding of the cover above the evaporitic décollement was almost fully completed by the end of the Cretaceous extension, with~85-100% of the dip of fold limbs being acquired before the remagnetization time. Cenozoic contraction reactivated the extensional faults in the shallow basement as top-to-the-S thrusts, leading to the passive transport and northwards tilting of the folded cover