Methylphenidate improves motor functions in children diagnosed with Hyperkinetic Disorder

<p>Abstract</p> <p>Background</p> <p>A previous study showed that a high percentage of children diagnosed with Hyperkinetic Disorder (HKD) displayed a consistent pattern of motor function problems. The purpose of this study was to investigate the effect of methylphenidate (MPH) on such motor performance in children with HKD</p> <p>Methods</p> <p>25 drug-naïve boys, aged 8–12 yr with a HKD-F90.0 diagnosis, were randomly assigned into two groups within a double blind cross-over design, and tested with a motor assessment instrument, during MPH and placebo conditions.</p> <p>Results</p> <p>The percentage of MFNU scores in the sample indicating 'severe motor problems' ranged from 44–84%, typically over 60%. Highly significant improvements in motor performance were observed with MPH compared to baseline ratings on all the 17 subtests of the MFNU 1–2 hr after administration of MPH. There were no significant placebo effects. The motor improvement was consistent with improvement of clinical symptoms.</p> <p>Conclusion</p> <p>The study confirmed our prior clinical observations showing that children with ADHD typically demonstrate marked improvements of motor functions after a single dose of 10 mg MPH. The most pronounced positive MPH response was seen in subtests measuring either neuromotor inhibition, or heightened muscular tone in the gross movement muscles involved in maintaining the alignment and balance of the body. Introduction of MPH generally led to improved balance and a generally more coordinated and controlled body movement.</p

Weight status and hypertension among adolescent girls in Argentina and Norway: Data from the ENNyS and HUNT studies

<p>Abstract</p> <p>Background</p> <p>To provide data on overweight, obesity and hypertension among adolescent girls in Norway and Argentina.</p> <p>Methods</p> <p>Data was obtained from two population-based, cross-sectional and descriptive studies containing anthropometric and blood pressure measurements of 15 to 18 year old girls. The study included 2,156 adolescent girls from Norway evaluated between 1995 and 1997, and 669 from Argentina evaluated between 2004 and 2005.</p> <p>Results</p> <p>Around 15% of adolescent girls in Norway and 19% in Argentina are overweight or obese. Body mass index (BMI) distribution in these two countries is similar, with a low percentage (< 1%) of girls classified as thin. Norwegian adolescents show a height mean value 8 cm taller than the Argentinean. Obesity is strongly associated with systolic hypertension in both populations, with odds ratios of 11.4 [1.6; 82.0] and 28.3 [11.8; 67.7] in Argentina and Norway, respectively. No direct association between BMI and systolic hypertension was found, and only extreme BMI values (above 80^th- 90^thpercentile) were associated with hypertension.</p> <p>Conclusion</p> <p>This study confirms a current world health problem by showing the high prevalence of obesity in adolescents and its association with hypertension in two different countries (one developed and one in transition).</p

DAt-Kon – et verktøy for differensiering av atferds- og konsentrasjonsvansker hos barn

DAt-Kon is a Norwegian assessment tool for behavioral and concentration problems in children as described by parents and close guardians in the home and school setting. The term ‘DAt-Kon’ is an acronym for ‘Differentiation of behavioral and concentration problems’. The tool, which has been developed by the present author, was designed for primary use within the municipality based Educational and Psychological Service (PPT). The most important task for the PPT is to provide educational support for children who present problems with learning or with adjustment to the various rules and expectations of the school system. DAt-Kon as a theoretical model is based on a humanistic/hermeneutical philosophical tradition. The fundamental idea is that the meaning of behavior is conveyed and decoded in the same manner as literal texts and can only be grasped through interpretation of communication. Another central assumption is that problem behavior in children is reflected not in the behavior itself, but in the concern and worry that the behavior evokes in the child’s surroundings. The “core” or primary source of a problem may be linked to the individual child as a “disorder”, “dysfunction”, “disability”, emotional state or temperamental “bias”, but problem behavior may be best understood as negative transactional cycles that develop when the child for some reason do not meet the expectations of its surroundings. What is perceived as problem behavior in one social or educational context may be seen as normal or even resourceful and positive behavior in other contexts. The social acceptance or rejection of the child’s individual solutions and adaptation to the expectations and reactions of its surroundings will in turn be decisive in the development of transactional cycles leading either to social acceptance or to further environmental concern and rejection. Problems with concentration or with adjustment to social rules are increasingly reported as a major concern in school. Many, perhaps most of these problems may be understood as general discipline or motivational problems related to pedagogical or system issues. In many cases though, more severe and individually related problems occur which cannot be easily addressed with general disciplinary or systems oriented approaches. DAt-Kon is a theoretical model for understanding and differentiation of the many individual paths and trajectories leading to concentration and behavior problems in children. It is also an assessment and reflection tool designed for use by the PPT in collaboration with teachers and parents in order to find appropriate and individually adapted measures of support for the child in school or in the home or peer setting. The assessment tool, DAt-Kon IV, consists of a set of questionnaires, answered by the parents and the class teacher or other professionals at school who know the child well. These questionnaires investigate important issues in the evaluation and differentiation of the many pathways leading to behavioral or concentration problems. The assessment consists of a behavior checklist consisting of 160 items in a parallel home and school version with pair wise almost identical items. In addition information involving the child’s resources, health status and important socioecological aspects of the home and school environment is gathered from both arenas. A developmental history of the child is provided by a separate form divided into 13 developmental themes. Scoring, analysis and presentation of the results is performed by the DAt-Kon Analysis, a specially designed computer program. The DAt-Kon model defines 16 core dimensions describing different trajectories of problem behavior associated with different developmental and contextual patterns. The computer analysis generates an individual problem profile, providing the best supported “working hypothesis” of the child’s problems, as described within the conceptual framework of the DAt-Kon model. The suggested hypotheses are used as a basis for team discussion and reflection within the Educational and Psychological Service (PPT), and collaboration with home and school, eventually with the social and health care services. A ‘hypothesis’ as presented by the DAt-Kon analysis is a tentative working formulation that may be challenged and modified in the subsequent discussion and reflection between assessment leader, parents and teachers, eventually leading to a new and more differentiated understanding of the child by all involved parts. The term ’hypothesis’ is used not in a strictly hypothetical- deductive sense, but as a hermeneutical tool in the elaboration and structuring of the information presented by parents and teachers. The goal of the assessment process is not diagnostic, but to support parents and teachers in the restructuring and reframing of their preconceptions of the child. The possible new frames of understanding obtained through collaborative reflections on the hypotheses suggested by the DAt-Kon analysis, will in turn provide teachers and parents with new ideas and ways to support and stimulate the child in its social and academic learning process. This dissertation investigates DAt-Kon as a theoretical model and as an assessment tool based on this model. While much research has been done on previous versions of the assessment instrument, none of the results has been published. The main purpose of this dissertation has been to give a preliminary empirical evaluation of DAt-Kon IV both as a psychometric instrument, and as a practical tool in the assessment and consulting tasks of the Educational and Psychological Service involving children referred for conduct and concentration problems in school. Another important aim has been to present the instrument as a theoretical model in a rather detailed way to provide a solid basis for the evaluation of the instrument, and to document the work lying behind the development. The empirical evaluation consists of three studies performed over a six year period. Two of these studies investigate the psychometric status of the instrument. The third study is based on a questionnaire answered by experienced users of DAt-Kon, evaluating to what extent the instrument fulfill the purpose and aims stated in the DAt-Kon model, and the ecological validity of the hypotheses derived from the DAt-Kon Analysis. The results of the first study, based on 742 case protocol sets received from 28 PPTs in the period 2002 – 2006, indicated that most of the 16 primary scales, and the 28 content scales included in the DAt-Kon IV, had an acceptable internal consistency, with Cronbach’s alpha values typically in the range of 0.75 to 0.85. Factor analyses of the primary scales showed a high agreement between the defined conceptual components of each of the 16 dimensions in the DAt-Kon model and the factor structure of the corresponding primary scale, suggesting a satisfactory construct validity of most of the primary scales. The results of the item analyses indicated a need to revise the structure of the content scales primarily to obtain a better coherence between the content structure of the primary scales and the corresponding content scales. Factor- and alpha analyses of the item set of the current content scales resulted in nine discarded scales, 18 scales with minor revisions of the item structure, and 11 new scales (30 in all). The reorganization resulted in a cleaner item structure with a substantial increase in internal consistency in most of the revised and new scales, compared to the old and discarded ones. No major changes were made to the item structure of the primary scales, nor in the phrasing of any of the items in any part of the assessment forms. The second study was performed on the same protocol set, and on the revised content scale structure. The primary aim of this study was to identify possible empirically derived profile patterns associated with the 16 dimensions of the DAt-Kon model. This was done by assigning case profiles generated by the DAt-Kon analysis into separate hypothesis groups based on the core problem hypotheses suggested by the program. The analyses resulted in 20 identified hypothesis groups, each with a distinct profile pattern. Each profile consisted of a core scale representing the hypothesis, together with characteristic associated and secondary problem patterns, as well as typical developmental histories. Four of the profile patterns consisted of combined hypotheses, typically describing sub patterns within a given core dimension. Kruskal-Wallis analyses showed that 13 of the hypothesis groups were significantly different when the core scale scores of each group were compared. For three very low frequency hypothesis groups (N<5), primarily in the problem area D: Relational disorders, differences between hypothesis groups were not possible to evaluate statistically. The results of the study suggest that the empirically identified profile patterns of most of the hypothesis groups have high construct validity as indicators of the corresponding hypothesized profile patterns of the DAt-Kon model. There is a need, though, for a further evaluation of the content validity of the profile patterns comparing the DAt-Kon results with concurrent results of other relevant assessment methods on a new and more representative protocol set. In a second part of the same study, central tendencies of the empirically derived profile patterns were used in the evaluation of the current norms applied by the DAt-Kon analysis. Highly significant differences were found between the mean core scale scores of the 16 “single” hypothesis groups – and the primary scale means of a control group without attention or behavior problems. The results showed that most of the core scales of each profile pattern had a normal distribution, and that the central tendencies within these scales were close to the critical cut off values adapted in the DAt-Kon IV scale norms (i.e. lying in the area between the scale Mean and -1½ SD). The results indicate no urgent need for a major revision of the current norms. There is little doubt however that a new study based on a more “clinically” representative sample and a more balanced gender and age distribution, would have contributed to a more accurate set of critical values, especially within the low frequency problem areas of the DAt-Kon circle. The third study was an evaluation study investigating the experienced usefulness and relevance of DAt-Kon IV among 88 trained users of the instrument within the PPT. The scoring patterns on the various questions and items in the questionnaire suggest that DAt-Kon IV is perceived as a highly relevant instrument for the PPT. The agreement between the user’s own evaluation of the core problems in each case and the corresponding hypotheses suggested by the DAt-Kon analysis was generally very high. These results indicate ecological validity of the instrument as measured by the subjective experiences of users operating within the target area that DAt-Kon was designed for. In the last part of the dissertation, the current status of DAt-Kon is discussed in the light of the presented theoretical framework and research findings, with special emphasis on ecological validity and the practical value of DAt-Kon as a tool for the Educational and Psychological Service. Possible limitations in the current model and assessment instrument are discussed. Recent changes in the organization and staffing of the PPT, and the heavy use of DAt-Kon as a referral tool for assessment and psychiatric evaluation at mental health institutions, may seem to undermine the intended role of DAt-Kon as an educationally oriented model and assessment tool. Different measures and strategies that might contribute to address this challenge are presented in the closing section of the dissertation

DAt-Kon – et verktøy for differensiering av atferds- og konsentrasjonsvansker hos barn

PhD thesis in Special EducationDAt-Kon is a Norwegian assessment tool for behavioral and concentration problems in children as described by parents and close guardians in the home and school setting. The term ‘DAt-Kon’ is an acronym for ‘Differentiation of behavioral and concentration problems’. The tool, which has been developed by the present author, was designed for primary use within the municipality based Educational and Psychological Service (PPT). The most important task for the PPT is to provide educational support for children who present problems with learning or with adjustment to the various rules and expectations of the school system. DAt-Kon as a theoretical model is based on a humanistic/hermeneutical philosophical tradition. The fundamental idea is that the meaning of behavior is conveyed and decoded in the same manner as literal texts and can only be grasped through interpretation of communication. Another central assumption is that problem behavior in children is reflected not in the behavior itself, but in the concern and worry that the behavior evokes in the child’s surroundings. The “core” or primary source of a problem may be linked to the individual child as a “disorder”, “dysfunction”, “disability”, emotional state or temperamental “bias”, but problem behavior may be best understood as negative transactional cycles that develop when the child for some reason do not meet the expectations of its surroundings. What is perceived as problem behavior in one social or educational context may be seen as normal or even resourceful and positive behavior in other contexts. The social acceptance or rejection of the child’s individual solutions and adaptation to the expectations and reactions of its surroundings will in turn be decisive in the development of transactional cycles leading either to social acceptance or to further environmental concern and rejection. Problems with concentration or with adjustment to social rules are increasingly reported as a major concern in school. Many, perhaps most of these problems may be understood as general discipline or motivational problems related to pedagogical or system issues. In many cases though, more severe and individually related problems occur which cannot be easily addressed with general disciplinary or systems oriented approaches. DAt-Kon is a theoretical model for understanding and differentiation of the many individual paths and trajectories leading to concentration and behavior problems in children. It is also an assessment and reflection tool designed for use by the PPT in collaboration with teachers and parents in order to find appropriate and individually adapted measures of support for the child in school or in the home or peer setting. The assessment tool, DAt-Kon IV, consists of a set of questionnaires, answered by the parents and the class teacher or other professionals at school who know the child well. These questionnaires investigate important issues in the evaluation and differentiation of the many pathways leading to behavioral or concentration problems. The assessment consists of a behavior checklist consisting of 160 items in a parallel home and school version with pair wise almost identical items. In addition information involving the child’s resources, health status and important socioecological aspects of the home and school environment is gathered from both arenas. A developmental history of the child is provided by a separate form divided into 13 developmental themes. Scoring, analysis and presentation of the results is performed by the DAt-Kon Analysis, a specially designed computer program. The DAt-Kon model defines 16 core dimensions describing different trajectories of problem behavior associated with different developmental and contextual patterns. The computer analysis generates an individual problem profile, providing the best supported “working hypothesis” of the child’s problems, as described within the conceptual framework of the DAt-Kon model. The suggested hypotheses are used as a basis for team discussion and reflection within the Educational and Psychological Service (PPT), and collaboration with home and school, eventually with the social and health care services. A ‘hypothesis’ as presented by the DAt-Kon analysis is a tentative working formulation that may be challenged and modified in the subsequent discussion and reflection between assessment leader, parents and teachers, eventually leading to a new and more differentiated understanding of the child by all involved parts. The term ’hypothesis’ is used not in a strictly hypothetical- deductive sense, but as a hermeneutical tool in the elaboration and structuring of the information presented by parents and teachers. The goal of the assessment process is not diagnostic, but to support parents and teachers in the restructuring and reframing of their preconceptions of the child. The possible new frames of understanding obtained through collaborative reflections on the hypotheses suggested by the DAt-Kon analysis, will in turn provide teachers and parents with new ideas and ways to support and stimulate the child in its social and academic learning process. This dissertation investigates DAt-Kon as a theoretical model and as an assessment tool based on this model. While much research has been done on previous versions of the assessment instrument, none of the results has been published. The main purpose of this dissertation has been to give a preliminary empirical evaluation of DAt-Kon IV both as a psychometric instrument, and as a practical tool in the assessment and consulting tasks of the Educational and Psychological Service involving children referred for conduct and concentration problems in school. Another important aim has been to present the instrument as a theoretical model in a rather detailed way to provide a solid basis for the evaluation of the instrument, and to document the work lying behind the development. The empirical evaluation consists of three studies performed over a six year period. Two of these studies investigate the psychometric status of the instrument. The third study is based on a questionnaire answered by experienced users of DAt-Kon, evaluating to what extent the instrument fulfill the purpose and aims stated in the DAt-Kon model, and the ecological validity of the hypotheses derived from the DAt-Kon Analysis. The results of the first study, based on 742 case protocol sets received from 28 PPTs in the period 2002 – 2006, indicated that most of the 16 primary scales, and the 28 content scales included in the DAt-Kon IV, had an acceptable internal consistency, with Cronbach’s alpha values typically in the range of 0.75 to 0.85. Factor analyses of the primary scales showed a high agreement between the defined conceptual components of each of the 16 dimensions in the DAt-Kon model and the factor structure of the corresponding primary scale, suggesting a satisfactory construct validity of most of the primary scales. The results of the item analyses indicated a need to revise the structure of the content scales primarily to obtain a better coherence between the content structure of the primary scales and the corresponding content scales. Factor- and alpha analyses of the item set of the current content scales resulted in nine discarded scales, 18 scales with minor revisions of the item structure, and 11 new scales (30 in all). The reorganization resulted in a cleaner item structure with a substantial increase in internal consistency in most of the revised and new scales, compared to the old and discarded ones. No major changes were made to the item structure of the primary scales, nor in the phrasing of any of the items in any part of the assessment forms. The second study was performed on the same protocol set, and on the revised content scale structure. The primary aim of this study was to identify possible empirically derived profile patterns associated with the 16 dimensions of the DAt-Kon model. This was done by assigning case profiles generated by the DAt-Kon analysis into separate hypothesis groups based on the core problem hypotheses suggested by the program. The analyses resulted in 20 identified hypothesis groups, each with a distinct profile pattern. Each profile consisted of a core scale representing the hypothesis, together with characteristic associated and secondary problem patterns, as well as typical developmental histories. Four of the profile patterns consisted of combined hypotheses, typically describing sub patterns within a given core dimension. Kruskal-Wallis analyses showed that 13 of the hypothesis groups were significantly different when the core scale scores of each group were compared. For three very low frequency hypothesis groups (N<5), primarily in the problem area D: Relational disorders, differences between hypothesis groups were not possible to evaluate statistically. The results of the study suggest that the empirically identified profile patterns of most of the hypothesis groups have high construct validity as indicators of the corresponding hypothesized profile patterns of the DAt-Kon model. There is a need, though, for a further evaluation of the content validity of the profile patterns comparing the DAt-Kon results with concurrent results of other relevant assessment methods on a new and more representative protocol set. In a second part of the same study, central tendencies of the empirically derived profile patterns were used in the evaluation of the current norms applied by the DAt-Kon analysis. Highly significant differences were found between the mean core scale scores of the 16 “single” hypothesis groups – and the primary scale means of a control group without attention or behavior problems. The results showed that most of the core scales of each profile pattern had a normal distribution, and that the central tendencies within these scales were close to the critical cut off values adapted in the DAt-Kon IV scale norms (i.e. lying in the area between the scale Mean and -1½ SD). The results indicate no urgent need for a major revision of the current norms. There is little doubt however that a new study based on a more “clinically” representative sample and a more balanced gender and age distribution, would have contributed to a more accurate set of critical values, especially within the low frequency problem areas of the DAt-Kon circle. The third study was an evaluation study investigating the experienced usefulness and relevance of DAt-Kon IV among 88 trained users of the instrument within the PPT. The scoring patterns on the various questions and items in the questionnaire suggest that DAt-Kon IV is perceived as a highly relevant instrument for the PPT. The agreement between the user’s own evaluation of the core problems in each case and the corresponding hypotheses suggested by the DAt-Kon analysis was generally very high. These results indicate ecological validity of the instrument as measured by the subjective experiences of users operating within the target area that DAt-Kon was designed for. In the last part of the dissertation, the current status of DAt-Kon is discussed in the light of the presented theoretical framework and research findings, with special emphasis on ecological validity and the practical value of DAt-Kon as a tool for the Educational and Psychological Service. Possible limitations in the current model and assessment instrument are discussed. Recent changes in the organization and staffing of the PPT, and the heavy use of DAt-Kon as a referral tool for assessment and psychiatric evaluation at mental health institutions, may seem to undermine the intended role of DAt-Kon as an educationally oriented model and assessment tool. Different measures and strategies that might contribute to address this challenge are presented in the closing section of the dissertation

Motor regulation problems and pain in adults diagnosed with ADHD

Background: Most children who are diagnosed with attention deficit-hyperactivity disorder (ADHD) have moderate-to-severe motor problems using the Motor Function Neurological Assessment battery (MFNU). The MFNU focuses on specific muscle adjustment problems associated with ADHD, especially motor inhibition problems and high muscle tone. Here we investigated whether adults with ADHD/hyperkinetic disorder (HKD) have similar motor problems. In our clinical experience, adults with ADHD often complain about back, shoulder, hip, and leg pain. We also investigate reported pain in adults with ADHD. Methods: Twenty-five adult outpatients diagnosed with ADHD/HKD who were responders to methylphenidate (MPH) were compared to 23 non-ADHD controls on 16 MFNU subtests and using a ‘total score ’ (‘TS’) parameter. The MFNU test leader was blinded to group identity. The two groups were also compared using the Pain Drawing and Numerical Pain Rating Scale. Results: The adult ADHD group had significantly (p &lt;.001) more motor problems (higher TS) than controls. On the muscle regulation subtests, 36–96 % of the ADHD group showed ‘moderate ’ to ‘severe ’ problems compared to 13–52 % of the control group, and 80 % of the ADHD group reported widespread pain. Highly significant differences were found between the ADHD and control groups for the variables ‘pain level ’ (p &lt;.001) and ‘pain location’ (p &lt;.001). Significant correlations were found between TS and ‘pain location ’ and between TS and ‘pain level’. Conclusions: These findings suggest that similar to children with ADHD, adults diagnosed with ADHD also have motor inhibition problems and heightened muscle tone. The presence of significantly higher pain levels and more widespread pain in the ADHD group compared to non-ADHD controls might indicate that pain is a long-term secondary effect of heightened muscle tone and restricted movement that can be demonstrated in children and adults by the MFNU battery

Second-Tier Next Generation Sequencing Integrated in Nationwide Newborn Screening Provides Rapid Molecular Diagnostics of Severe Combined Immunodeficiency

Severe combined immunodeficiency (SCID) and other T cell lymphopenias can be detected during newborn screening (NBS) by measuring T cell receptor excision circles (TRECs) in dried blood spot (DBS) DNA. Second tier next generation sequencing (NGS) with an amplicon based targeted gene panel using the same DBS DNA was introduced as part of our prospective pilot research project in 2015. With written parental consent, 21 000 newborns were TREC-tested in the pilot. Three newborns were identified with SCID, and disease-causing variants in IL2RG, RAG2, and RMRP were confirmed by NGS on the initial DBS DNA. The molecular findings directed follow-up and therapy: the IL2RG-SCID underwent early hematopoietic stem cell transplantation (HSCT) without any complications; the leaky RAG2-SCID received prophylactic antibiotics, antifungals, and immunoglobulin infusions, and underwent HSCT at 1 year of age. The child with RMRP-SCID had complete Hirschsprung disease and died at 1 month of age. Since January 2018, all newborns in Norway have been offered NBS for SCID using 1st tier TRECs and 2nd tier gene panel NGS on DBS DNA. During the first 20 months of nationwide SCID screening an additional 88 000 newborns were TREC tested, and four new SCID cases were identified. Disease-causing variants in DCLRE1C, JAK3, NBN, and IL2RG were molecularly confirmed on day 8, 15, 8 and 6, respectively after birth, using the initial NBS blood spot. Targeted gene panel NGS integrated into the NBS algorithm rapidly delineated the specific molecular diagnoses and provided information useful for management, targeted therapy and follow-up i.e., X rays and CT scans were avoided in the radiosensitive SCID. Second tier targeted NGS on the same DBS DNA as the TREC test provided instant confirmation or exclusion of SCID, and made it possible to use a less stringent TREC cut-off value. This allowed for the detection of leaky SCIDs, and simultaneously reduced the number of control samples, recalls and false positives. Mothers were instructed to stop breastfeeding until maternal cytomegalovirus (CMV) status was determined. Our limited data suggest that shorter time-interval from birth to intervention, may prevent breast milk transmitted CMV infection in classical SCID

Primary immunodeficiency diseases: Genomic approaches delineate heterogeneous Mendelian disorders

Background Primary immunodeficiency diseases (PIDDs) are clinically and genetically heterogeneous disorders thus far associated with mutations in more than 300 genes. The clinical phenotypes derived from distinct genotypes can overlap. Genetic etiology can be a prognostic indicator of disease severity and can influence treatment decisions. Objective We sought to investigate the ability of whole-exome screening methods to detect disease-causing variants in patients with PIDDs. Methods Patients with PIDDs from 278 families from 22 countries were investigated by using whole-exome sequencing. Computational copy number variant (CNV) prediction pipelines and an exome-tiling chromosomal microarray were also applied to identify intragenic CNVs. Analytic approaches initially focused on 475 known or candidate PIDD genes but were nonexclusive and further tailored based on clinical data, family history, and immunophenotyping. Results A likely molecular diagnosis was achieved in 110 (40%) unrelated probands. Clinical diagnosis was revised in about half (60/110) and management was directly altered in nearly a quarter (26/110) of families based on molecular findings. Twelve PIDD-causing CNVs were detected, including 7 smaller than 30 Kb that would not have been detected with conventional diagnostic CNV arrays. Conclusion This high-throughput genomic approach enabled detection of disease-related variants in unexpected genes; permitted detection of low-grade constitutional, somatic, and revertant mosaicism; and provided evidence of a mutational burden in mixed PIDD immunophenotypes