De Novo and Inherited Pathogenic Variants in KDM3B Cause Intellectual Disability, Short Stature, and Facial Dysmorphism.

By using exome sequencing and a gene matching approach, we identified de novo and inherited pathogenic variants in KDM3B in 14 unrelated individuals and three affected parents with varying degrees of intellectual disability (ID) or developmental delay (DD) and short stature. The individuals share additional phenotypic features that include feeding difficulties in infancy, joint hypermobility, and characteristic facial features such as a wide mouth, a pointed chin, long ears, and a low columella. Notably, two individuals developed cancer, acute myeloid leukemia and Hodgkin lymphoma, in childhood. KDM3B encodes for a histone demethylase and is involved in H3K9 demethylation, a crucial part of chromatin modification required for transcriptional regulation. We identified missense and truncating variants, suggesting that KDM3B haploinsufficiency is the underlying mechanism for this syndrome. By using a hybrid facial-recognition model, we show that individuals with a pathogenic variant in KDM3B have a facial gestalt, and that they show significant facial similarity compared to control individuals with ID. In conclusion, pathogenic variants in KDM3B cause a syndrome characterized by ID, short stature, and facial dysmorphism.

Analyzing the waveshape of brain oscillations with bicoherence.

Oscillations are characteristic features of brain activity and have traditionally been categorized into frequency bands. Despite this categorization, brain oscillations have non-sinusoidal waveshape features, which have recently been discussed for their potential to mislead cross-frequency coupling measures. Waveshape characteristics deserve attention in their own right, as they are a direct reflection of the underlying neurophysiology and have shown to be altered in conditions such as Parkinson's disease. Here, we want to contribute to waveshape analysis in three steps: (1) While "shape" is most intuitively described in the time domain, complementary information is provided by frequency domain. In particular we show, that the bispectrum of an oscillation directly reflects waveshape properties such as differences in the steepness of its rise and decay phases, as well as differences in the duration of its crests and troughs. (2) Methods for the extraction of brain oscillations need to be chosen with care, as the ubiquitous use of bandpass filters causes waveshape distortions. We illustrate common problems and introduce a waveshape-preserving spatial filter for the purpose of waveshape analysis. (3) In an exemplary analysis of resting-state alpha rhythms, bicoherence provides evidence that shape characteristics of alpha rhythms exist on a spectrum. In addition, the bispectral view identifies significant mu rhythm anomalies in schizophrenia and suggests potential causes relating to waveshape.

Growth failure in focal dermal hypoplasia.

Focal dermal hypoplasia (FDH) is a rare genetic disorder caused by mutations in the PORCN gene located on the X chromosome. Short stature was previously noted to be a common finding in FDH, however the etiology of this is unclear. The present study sought to elucidate specific causes for short stature by assessing growth charts, determining bone ages and auxologic measurements, examining laboratory data for the common causes of growth failure, assessing dietary intake, and performing a growth hormone stimulation test. Sixteen patients with FDH between the ages of 3 and 18 years of age consented to the study. While 11 out of 16 patients had short stature based on height less than 2 standard deviations below mid-parental target height percentile and bone age not suggestive of likely catch-up growth, only four had a BMI less than the 5th percentile for age. Laboratory studies did not support a gastrointestinal, allergy or autoimmune cause of growth failure. Three patients had results suggestive of possible growth hormone deficiency. Although short stature is a common feature in FDH, our data suggests that severe undernutrition is not common in this group and that there may be underlying treatable causes for this short stature in some patients.

Localizing bicoherence from EEG and MEG.

We propose a new method for the localization of nonlinear cross-frequency coupling in EEG and MEG data analysis, based on the estimation of bicoherences at the source level. While for the analysis of rhythmic brain activity, source directions are commonly chosen to maximize power, we suggest to maximize bicoherence instead. The resulting nonlinear cost function can be minimized effectively using a gradient approach. We argue, that bicoherence is also a generally useful tool to analyze phase-amplitude coupling (PAC), by deriving formal relations between PAC and bispectra. This is illustrated in simulated and empirical LFP data. The localization method is applied to EEG resting state data, where the most prominent bicoherence signatures originate from the occipital alpha rhythm and the mu rhythm. While the latter is hardly visible using power analysis, we observe clear bicoherence peaks in the high alpha range of sensorymotor areas. We additionally apply our method to resting-state data of subjects with schizophrenia and healthy controls and observe significant bicoherence differences in motor areas which could not be found from analyzing power differences.

Pathogenesis and prevention of type 2 diabetes: parental determinants, breastfeeding, and early childhood nutrition.

Among the factors predisposing to type 2 diabetes in children, adolescents, and young adults, the health and behavior of both the mother and father are critical. Prevention and treatment of parental nutritional disorders (including obesity and malnutrition), promotion of breastfeeding, and avoidance of overfeeding of young children are essential for childhood health and metabolic function. Focusing research and policy on parental influences on childhood health should reduce the risks of obesity and type 2 diabetes in future generations.

Application of a Standard Cross-Specialty Workup for Diagnosis and Metabolic Screening of Obese Adolescents With Polycystic Ovary Syndrome.

PURPOSE: Polycystic ovary syndrome (PCOS) is a common disorder. The used diagnostic criteria and screening for related metabolic disease in adolescent girls with PCOS vary with medical specialty, causing discrepancies in care. We sought to improve and standardize care to guidelines for adolescents with PCOS and obesity. METHODS: This is a quality improvement project in a multispecialty, tertiary care children's hospital. Providers in Adolescent Medicine, Gynecology, Pediatric Endocrinology, and Endocrine-Metabolic clinics participated. Diagnostic testing and metabolic screening data were collected for new patient encounters with PCOS and obesity, with two improvement cycles from December 2012 to March 2017. Providers received education on diagnostics tests and metabolic screening recommendations, and electronic medical record tools were created. The number of diagnostic and metabolic screening tests ordered per cycle and per clinic were analyzed and compared with baseline. RESULTS: The preintervention cycle included 74 encounters-44 in Cycle 1 and 58 in Cycle 2. Diagnostic test completeness improved by Cycle 2 (46%-68%) for all clinics. Screening for metabolic disease only improved in Gynecology (27%-71%). Adolescent Medicine, Endocrinology, and Endocrine-Metabolic used note templates, and Adolescent Medicine and Gynecology used order sets. Note templates were associated with more diagnostic tests ordered in Endocrinology (30%-88%; p = .002). CONCLUSIONS: Implementation of quality improvement measures improved the number of diagnostic and metabolic screening tests performed in new patient encounters for PCOS, although the most effective strategy varied by clinic type and electronic medical record habits. Similar efforts should be implemented to standardize care at other institutions.

Beyond Pairwise Interactions: The Totally Antisymmetric Part of the Bispectrum as Coupling Measure of at Least Three Interacting Sources.

In this paper we make two contributions to the analysis of brain oscillations with CFC techniques. First, we introduce a new bispectral CFC measure which is selective to couplings between three or more brain sources. This measure can be derived from ordinary cross-bispectra by performing a total-antisymmetrization operation on them. Significant coupling values can then be attributed to at least three interacting signals. This selectivity to the number of sources can be helpful to test hypotheses on the number of brain sources involved in the generation of commonly observed brain oscillations, such as the alpha rhythm. In a second step we present the correct empirical distribution for the coupling measure, which is necessary to properly assess the significance of coupling results. More importantly however, this corrected statistic is not limited to our particular measure, but holds for all complex-valued coupling estimators. We illustrate how the very common misassumption of empirical normality of such estimators can lead to a systematic underestimation of p-values, the breakdown of multiple comparison control procedures and in consequence a drastic inflation of the number of false positives.

Effects of HIV infection on the metabolic and hormonal status of children with severe acute malnutrition.

BACKGROUND: HIV infection occurs in 30% of children with severe acute malnutrition in sub-Saharan Africa. Effects of HIV on the pathophysiology and recovery from malnutrition are poorly understood. METHODS: We conducted a prospective cohort study of 75 severely malnourished Ugandan children. HIV status/CD4 counts were assessed at baseline; auxologic data and blood samples were obtained at admission and after 14 days of inpatient treatment. We utilized metabolomic profiling to characterize effects of HIV infection on metabolic status and subsequent responses to nutritional therapy. FINDINGS: At admission, patients (mean age 16.3 mo) had growth failure (mean W/H z-score -4.27 in non-edematous patients) that improved with formula feeding (mean increase 1.00). 24% (18/75) were HIV-infected. Nine children died within the first 14 days of hospitalization; mortality was higher for HIV-infected patients (33% v. 5%, OR = 8.83). HIV-infected and HIV-negative children presented with elevated NEFA, ketones, and even-numbered acylcarnitines and reductions in albumin and amino acids. Leptin, adiponectin, insulin, and IGF-1 levels were low while growth hormone, cortisol, and ghrelin levels were high. At baseline, HIV-infected patients had higher triglycerides, ketones, and even-chain acylcarnitines and lower leptin and adiponectin levels than HIV-negative patients. Leptin levels rose in all patients following nutritional intervention, but adiponectin levels remained depressed in HIV-infected children. Baseline hypoleptinemia and hypoadiponectinemia were associated with increased mortality. CONCLUSIONS: Our findings suggest a critical interplay between HIV infection and adipose tissue storage and function in the adaptation to malnutrition. Hypoleptinemia and hypoadiponectinemia may contribute to high mortality rates among malnourished, HIV-infected children.

Severe acute malnutrition in childhood: hormonal and metabolic status at presentation, response to treatment, and predictors of mortality.

OBJECTIVE: Malnutrition is a major cause of childhood morbidity and mortality. To identify and target those at highest risk, there is a critical need to characterize biomarkers that predict complications prior to and during treatment. METHODS: We used targeted and nontargeted metabolomic analysis to characterize changes in a broad array of hormones, cytokines, growth factors, and metabolites during treatment of severe childhood malnutrition. Children aged 6 months to 5 years were studied at presentation to Mulago Hospital and during inpatient therapy with milk-based formulas and outpatient supplementation with ready-to-use food. We assessed the relationship between baseline hormone and metabolite levels and subsequent mortality. RESULTS: Seventy-seven patients were enrolled in the study; a subset was followed up from inpatient treatment to the outpatient clinic. Inpatient and outpatient therapies increased weight/height z scores and induced striking changes in the levels of fatty acids, amino acids, acylcarnitines, inflammatory cytokines, and various hormones including leptin, insulin, GH, ghrelin, cortisol, IGF-I, glucagon-like peptide-1, and peptide YY. A total of 12.2% of the patients died during hospitalization; the major biochemical factor predicting mortality was a low level of leptin (P = .0002), a marker of adipose tissue reserve and a critical modulator of immune function. CONCLUSIONS: We have used metabolomic analysis to provide a comprehensive hormonal and metabolic profile of severely malnourished children at presentation and during nutritional rehabilitation. Our findings suggest that fatty acid metabolism plays a central role in the adaptation to acute malnutrition and that low levels of the adipose tissue hormone leptin associate with, and may predict, mortality prior to and during treatment.