RESUMEN
The incidence of pediatric diabetic ketoacidosis (DKA) increased during the peak of the COVID-19 pandemic. The objective of this study was to investigate whether rates of hyperosmolar therapy administration for suspected clinically apparent brain injury (CABI) complicating DKA also increased during this period as compared to the three years immediately preceding the pandemic and to compare the characteristics of patients with suspected CABI before the pandemic, patients with suspected CABI during the peak of the pandemic, and those with DKA but without suspected CABI during the pandemic. Patients aged ≤18 years presenting with DKA before (March 11, 2017-March 10, 2020) and during the peak of the pandemic (March 11, 2020-March 10, 2021) were identified through a rigorous search of two databases. Predefined criteria were used to diagnose suspected CABI. Biochemical, clinical, and sociodemographic data were collected from a comprehensive review of the electronic medical record. The proportion of patients with DKA who received hyperosmolar therapy was significantly higher (P = 0.014) during the pandemic compared to the prepandemic period; however, this was only significant among patients with newly diagnosed diabetes. Both groups with suspected CABI had more severe acidosis, lower Glasgow Coma Scale scores, and longer hospital admissions (P< 0.001 for all) than cases without suspected CABI. During the pandemic, the blood urea nitrogen concentration was significantly higher in patients with suspected CABI than those without suspected CABI, suggesting they were more severely dehydrated. The clinical, biochemical, and sociodemographic characteristics of patients with suspected CABI were indistinguishable before and during the pandemic. In conclusion, administration of hyperosmolar therapy for suspected CABI was more common during the peak of the COVID-19 pandemic, possibly a result of delayed presentation, highlighting the need for increased awareness and early recognition of the signs and symptoms of diabetes and DKA, especially during future surges of highly transmissible infections.
Asunto(s)
COVID-19 , Diabetes Mellitus Tipo 1 , Cetoacidosis Diabética , Coma Hiperglucémico Hiperosmolar no Cetósico , Humanos , Niño , Cetoacidosis Diabética/etiología , Cetoacidosis Diabética/complicaciones , Pandemias , Coma Hiperglucémico Hiperosmolar no Cetósico/diagnóstico , COVID-19/complicaciones , COVID-19/epidemiología , Hospitalización , Diabetes Mellitus Tipo 1/epidemiologíaRESUMEN
Cerebral edema (CE) is a potentially devastating complication of diabetic ketoacidosis (DKA) that almost exclusively occurs in children. Since its first description in 1936, numerous risk factors have been identified; however, there continues to be uncertainty concerning the mechanisms that lead to its development. Currently, the most widely accepted hypothesis posits that CE occurs as a result of ischemia-reperfusion injury, with inflammation and impaired cerebrovascular autoregulation contributing to its pathogenesis. The role of specific aspects of DKA treatment in the development of CE continues to be controversial. This review critically examines the literature on the pathophysiology of CE and attempts to categorize the findings by types of brain injury that contribute to its development: cytotoxic, vasogenic, and osmotic. Utilizing this scheme, we propose a multifactorial pathway for the development of CE in patients with DKA.
Asunto(s)
Edema Encefálico/etiología , Lesiones Encefálicas/etiología , Cetoacidosis Diabética/complicaciones , Cetoacidosis Diabética/metabolismo , Cetoacidosis Diabética/fisiopatología , HumanosRESUMEN
The steroid hormone aldosterone, produced by the zona glomerulosa (zG) of the adrenal gland, is a master regulator of plasma electrolytes and blood pressure. While aldosterone control by the renin-angiotensin system is well understood, other key regulatory factors have remained elusive. Here, we replicated a prior association between a non-coding variant in WNT2B and an increased risk of primary aldosteronism, a prevalent and debilitating disease caused by excessive aldosterone production. We further show that in both mice and humans, WNT2B is expressed in the mesenchymal capsule surrounding the adrenal cortex, in close proximity to the zG. Global loss of Wnt2b in the mouse results in a dysmorphic and hypocellular zG, with impaired aldosterone production. Similarly, humans harboring WNT2B loss-of-function mutations develop a novel form of Familial Hyperreninemic Hypoaldosteronism, designated here as Type 4. Additionally, we demonstrate that WNT2B signals by activating the non-canonical Wnt/planar cell polarity pathway. Our findings identify WNT2B as a key regulator of zG function and aldosterone production with important clinical implications. Highlights: WNT2B variant is associated with increased risk for primary aldosteronism Wnt2b knock-out mice show defects in adrenal morphology Wnt2b knock-out mice have hyperreninemic hypoaldosteronism WNT2B activates non-canonical Wnt/planar cell polarity signalingWNT2B deficiency causes a new form of familial hyperreninemic hypoaldosteronism.
RESUMEN
Background: Recent data estimate the prevalence of pediatric obesity at 19.3%. Emphasis on primary prevention and early identification is needed to avoid development of serious medical and psychosocial sequelae. The objective of this initiative is to assess baseline knowledge and comfort among trainees at an inner-city pediatric residency program in identifying children with overweight/obesity, evaluating associated risk factors and comorbidities, and providing effective counseling. Methods: Key topics from 2 major guidelines on pediatric obesity assessment, prevention, and treatment were incorporated into the development of a resident questionnaire, which consisted of 12 knowledge-based questions and a Likert scale evaluating self-perceived knowledge and comfort on 7 skills. Results: Forty-six percent of eligible residents completed the questionnaire (n = 28). The mean score on the objective knowledge-based section was 44% ± 13%, with no differences by training year. The percentage of residents with correct responses by topic ranged from 14% to 79%. The mean self-perceived knowledge rating was 3.56 ± 0.86. The mean self-perceived comfort rating was 3.53 ± 0.89. Neither the self-perceived knowledge nor comfort rating was a significant predictor of performance on the objective knowledge-based section when controlling for postgraduate year status. Conclusions: Significant gaps in knowledge were discovered among pediatric residents with regard to appropriate screening, assessment, and counseling practices related to pediatric overweight/obesity. These deficits were not consistently reflected in residents' self-perceived knowledge and comfort ratings. The results of this initiative highlight the need for incorporation of standardized curricula on childhood overweight/obesity into pediatric resident education.
Asunto(s)
Internado y Residencia , Obesidad Infantil , Niño , Curriculum , Conocimientos, Actitudes y Práctica en Salud , Humanos , Obesidad Infantil/epidemiología , Obesidad Infantil/prevención & control , Encuestas y CuestionariosRESUMEN
OBJECTIVES: Exogenous exposure to transdermal testosterone is often overlooked as a cause of precocious sexual development in children. CASE PRESENTATION: A 16-month-old male presented for a second opinion consultation before commencing treatment with bicalutamide and anastrozole for a presumptive diagnosis of familial gonadotropin-independent male-limited sexual precocity. Enlargement of the penis was first observed at four months of age. The initial evaluation showed isolated elevation of his plasma testosterone level; however, by 16 months, his testosterone level was prepubertal and no pathogenic variants in the LHC GR gene were identified. The history revealed that his grandfather, who had cared for him regularly in the first year of life, had used testosterone gel for treatment of hypogonadism. CONCLUSIONS: Despite the 2009 "black box" warning issued by the United States Food and Drug Administration (FDA) regarding potential consequences of transdermal testosterone exposure to women and children, this continues to be an important cause of sexual precocity in children. Children are often subjected to unnecessary and costly evaluation before this exposure is recognized, underscoring the importance of obtaining a thorough medical, family, and social history tailored to the differential diagnosis.
Asunto(s)
Andrógenos/efectos adversos , Hipogonadismo/tratamiento farmacológico , Pubertad Precoz/patología , Testosterona/efectos adversos , Administración Cutánea , Humanos , Lactante , Masculino , Pubertad Precoz/inducido químicamenteRESUMEN
Carbohydrate restriction, used since the 1700s to prolong survival in people with diabetes, fell out of favor after the discovery of insulin. Despite costly pharmacological and technological developments in the last few decades, current therapies do not achieve optimal outcomes, and most people with diabetes remain at high risk for micro- and macrovascular complications. Recently, low-carbohydrate diets have regained popularity, with preliminary evidence of benefit for body weight, postprandial hyperglycemia, hyperinsulinemia, and other cardiometabolic risk factors in type 2 diabetes and, with more limited data, in type 1 diabetes. High-quality, long-term trials are needed to assess safety concerns and determine whether this old dietary approach might help people with diabetes attain clinical targets more effectively, and at a lower cost, than conventional treatment.
Asunto(s)
Diabetes Mellitus Tipo 1 , Diabetes Mellitus Tipo 2 , Dieta Baja en Carbohidratos , Insulina/metabolismo , Factores de Riesgo Cardiometabólico , Diabetes Mellitus Tipo 1/dietoterapia , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 2/dietoterapia , Diabetes Mellitus Tipo 2/metabolismo , Humanos , Hiperglucemia/metabolismoRESUMEN
OBJECTIVES: Graves' disease (GD) is rare in children under age five years. Antithyroid drugs are typically first-line therapy but carry the risks of agranulocytosis and liver dysfunction. CASE PRESENTATION: A male infant with multiple congenital anomalies, left ventricular hypertrophy, and neurologic dysfunction developed GD at five months of life. The presence of chronic hepatitis complicated medical management. Potassium iodide was effective temporarily, but urgent thyroidectomy was required at nine months of age. Postoperatively, the patient developed a thyroid function pattern consistent with impaired pituitary sensitivity to thyroid hormone (TH) that responded to the addition of liothyronine. Exome sequencing revealed a heterozygous de novo duplication of the ATAD3 gene cluster, suggesting a possible mitochondrial disorder. CONCLUSIONS: This case describes the youngest child to date to be diagnosed with endogenous GD and to successfully undergo definitive treatment with thyroidectomy. An underlying defect in mitochondrial function is suspected, suggesting a potential novel pathophysiologic link to early-onset thyroid autoimmunity. Additionally, this case illustrated the development of impaired pituitary sensitivity to TH following thyrotoxicosis of postnatal onset, which may contribute to our understanding of hypothalamic-pituitary-thyroid (HPT) axis development.
Asunto(s)
Enfermedad de Graves/terapia , ATPasas Asociadas con Actividades Celulares Diversas/genética , Enfermedad de Graves/genética , Enfermedad de Graves/metabolismo , Humanos , Lactante , Masculino , Proteínas de la Membrana/genética , Proteínas Mitocondriales/genética , Tiroidectomía , Tiroxina/sangreRESUMEN
WNT2B is a member of the Wnt family, a group of signal transduction proteins involved in embryologic development and stem cell renewal and maintenance. We recently reported homozygous nonsense variants in WNT2B in three individuals with severe, neonatal-onset diarrhea, and intestinal failure. Here we present a fourth case, from a separate family, with neonatal diarrhea associated with novel compound heterozygous WNT2B variants. One of the two variants was a frameshift variant (c.423del [p.Phe141fs]), while the other was a missense change (c.722 G > A [p.G241D]) that we predict through homology modeling to be deleterious, disrupting post-translational acylation. This patient presented as a neonate with severe diet-induced (osmotic) diarrhea and growth failure resulting in dependence on parenteral nutrition. Her gastrointestinal histology revealed abnormal cellular architecture particularly in the stomach and colon, including oxyntic atrophy, abnormal distribution of enteroendocrine cells, and a paucity of colonic crypt glands. In addition to her gastrointestinal findings, she had bilateral corneal clouding and atypical genital development later identified as a testicular 46,XX difference/disorder of sexual development. Upon review of the previously reported cases, two others also had anterior segment ocular anomalies though none had atypical genital development. This growing case series suggests that variants in WNT2B are associated with an oculo-intestinal (and possibly gonadal) syndrome, due to the protein's putative involvement in multiple developmental and stem cell maintenance pathways.
Asunto(s)
Diarrea/genética , Trastornos del Desarrollo Sexual/genética , Anomalías del Ojo/genética , Glicoproteínas/genética , Errores Innatos del Metabolismo/genética , Nicho de Células Madre , Proteínas Wnt/genética , Adulto , Diarrea/patología , Trastornos del Desarrollo Sexual/patología , Anomalías del Ojo/patología , Femenino , Mucosa Gástrica/metabolismo , Mucosa Gástrica/patología , Genitales/metabolismo , Genitales/patología , Glicoproteínas/metabolismo , Humanos , Lactante , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patología , Masculino , Errores Innatos del Metabolismo/patología , Mutación Missense , Fenotipo , Proteínas Wnt/metabolismoRESUMEN
The phenotypic variability associated with pathogenic variants in Lysine Acetyltransferase 6B (KAT6B, a.k.a. MORF, MYST4) results in several interrelated syndromes including Say-Barber-Biesecker-Young-Simpson Syndrome and Genitopatellar Syndrome. Here we present 20 new cases representing 10 novel KAT6B variants. These patients exhibit a range of clinical phenotypes including intellectual disability, mobility and language difficulties, craniofacial dysmorphology, and skeletal anomalies. Given the range of features previously described for KAT6B-related syndromes, we have identified additional phenotypes including concern for keratoconus, sensitivity to light or noise, recurring infections, and fractures in greater numbers than previously reported. We surveyed clinicians to qualitatively assess the ways families engage with genetic counselors upon diagnosis. We found that 56% (10/18) of individuals receive diagnoses before the age of 2 years (median age = 1.96 years), making it challenging to address future complications with limited accessible information and vast phenotypic severity. We used CRISPR to introduce truncating variants into the KAT6B gene in model cell lines and performed chromatin accessibility and transcriptome sequencing to identify key dysregulated pathways. This study expands the clinical spectrum and addresses the challenges to management and genetic counseling for patients with KAT6B-related disorders.
Asunto(s)
Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Histona Acetiltransferasas/genética , Mutación , Fenotipo , Anomalías Múltiples/diagnóstico , Anomalías Múltiples/genética , Alelos , Blefarofimosis/diagnóstico , Blefarofimosis/genética , Estudios de Cohortes , Hipotiroidismo Congénito/diagnóstico , Hipotiroidismo Congénito/genética , Anomalías Craneofaciales/diagnóstico , Anomalías Craneofaciales/genética , Facies , Asesoramiento Genético , Sitios Genéticos , Genotipo , Cardiopatías Congénitas/diagnóstico , Cardiopatías Congénitas/genética , Humanos , Discapacidad Intelectual/diagnóstico , Discapacidad Intelectual/genética , Inestabilidad de la Articulación/diagnóstico , Inestabilidad de la Articulación/genética , Riñón/anomalías , Masculino , Rótula/anomalías , Trastornos Psicomotores/diagnóstico , Trastornos Psicomotores/genética , Escroto/anomalías , Anomalías Urogenitales/diagnóstico , Anomalías Urogenitales/genéticaRESUMEN
Cerebral perfusion was evaluated in 87 subjects prospectively enrolled in three study groups-healthy controls (HC), patients with insulin resistance (IR) but not with diabetes, and type 2 diabetes mellitus (T2DM). Participants received a comprehensive 8-hour clinical evaluation and arterial spin labeling magnetic resonance imaging (MRI). In order of decreasing significance, an association was found between cerebral blood flow (CBF) and sex, waist circumference, diastolic blood pressure (BP), end tidal CO2, and verbal fluency score (R(2)=0.27, F=5.89, P<0.001). Mean gray-matter CBF in IR was 4.4 mL/100 g per minute lower than in control subjects (P=0.005), with no hypoperfusion in T2DM (P=0.312). Subjects with IR also showed no CO2 relationship (slope=-0.012) in the normocapnic range, in contrast to a strong relationship in healthy brains (slope=0.800) and intermediate response (slope=0.445) in diabetic patients. Since the majority of T2DM but few IR subjects were aggressively treated with blood glucose, cholesterol, and BP lowering medications, our finding could be attributed to the beneficial effect of these drugs.