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Genotype - phenotype correlation in an adolescent girl with pathogenic PPARy genetic variation that caused severe hypertriglyceridemia and early onset type 2 diabetes [Case Report]

Gutierrez Alvarez, Ana; Yachelevich, Naomi; Kohn, Brenda; Brar, Preneet Cheema
Severe hypertriglyceridemia (HTG) (>885 mg/dL) can be caused by familial partial lipodystrophy type 3 (FPLD3), an autosomal dominant disorder caused by loss of function of the peroxisome proliferator-activated receptor gamma (PPARG), characterized by abnormal distribution of fat and metabolic derangements. This case reports a 16-year-old female (body mass index, 23.5 kg/m2) hospitalized twice for pancreatitis (triglycerides [TG] level >2,200 mg/dL). Her treatment management included bowel rest, insulin infusion, and plasmapheresis. A low-fat diet with 10 g of fat daily and 160 mg of fenofibrate daily decreased fasting TG to 411 mg/dL (range, 0-149 mg/dL). The patient had a normal leptin level. Panel testing of genes that impact TG metabolism revealed a known pathogenic variant in the PPARG gene (c.452A>G p.Tyr151Cys). A second variant detected in this gene, c.1003G>C (p.Val335Leu), is considered benign. Her glycosylated hemoglobin of 6.6% and 2-hour oral glucose tolerance test confirmed type 2 diabetes mellitus (T2DM). This study reports the earliest detection of T2DM in an adolescent with a pathogenic variant of PPARG. PPARG-related FPLD3 should be considered in lean children that present with severe HTG and insulin resistance, and subsequent treatment with proliferator-activated receptor gamma agonists, specifically thiazolidinediones, should be considered.
PMID: 34991302
ISSN: 2287-1012
CID: 5107322

Case Studies in Pediatric Lipid Disorders and Their Management [Case Report]

Ashraf, Ambika P; Sunil, Bhuvana; Bamba, Vaneeta; Breidbart, Emily; Brar, Preneet Cheema; Chung, Stephanie; Gupta, Anshu; Khokhar, Aditi; Kumar, Seema; Lightbourne, Marissa; Kamboj, Manmohan K; Miller, Ryan S; Patni, Nivedita; Raman, Vandana; Shah, Amy S; Wilson, Don P; Kohn, Brenda
CONTEXT:Identification of modifiable risk factors, including genetic and acquired disorders of lipid and lipoprotein metabolism, is increasingly recognized as an opportunity to prevent premature cardiovascular disease (CVD) in at-risk youth. Pediatric endocrinologists are at the forefront of this emerging public health concern and can be instrumental in beginning early interventions to prevent premature CVD-related events during adulthood. AIM:In this article, we use informative case presentations to provide practical approaches to the management of pediatric dyslipidemia. CASES:We present 3 scenarios that are commonly encountered in clinical practice: isolated elevation of low-density lipoprotein cholesterol (LDL-C), combined dyslipidemia, and severe hypertriglyceridemia. Treatment with statin is indicated when the LDL-C is ≥190 mg/dL (4.9 mmol/L) in children ≥10 years of age. For LDL-C levels between 130 and 189 mg/dL (3.4-4.89 mmol/L) despite dietary and lifestyle changes, the presence of additional risk factors and comorbid conditions would favor statin therapy. In the case of combined dyslipidemia, the primary treatment target is LDL-C ≤130 mg/dL (3.4 mmol/L) and the secondary target non-high-density lipoprotein cholesterol <145 mg/dL (3.7 mmol/L). If the triglyceride is ≥400 mg/dL (4.5 mmol/L), prescription omega-3 fatty acids and fibrates are considered. In the case of triglyceride >1000 mg/dL (11.3 mmol/L), dietary fat restriction remains the cornerstone of therapy, even though the landscape of medications is changing. CONCLUSION:Gene variants, acquired conditions, or both are responsible for dyslipidemia during childhood. Extreme elevations of triglycerides can lead to pancreatitis. Early identification and management of dyslipidemia and cardiovascular risk factors is extremely important.
PMID: 34363474
ISSN: 1945-7197
CID: 5107702

SARS-CoV-2 infection and paediatric endocrine disorders: Risks and management considerations

Miller, Ryan; Ashraf, Ambika P; Gourgari, Evgenia; Gupta, Anshu; Kamboj, Manmohan K; Kohn, Brenda; Lahoti, Amit; Mak, Daniel; Mehta, Shilpa; Mitchell, Deborah; Patel, Neha; Raman, Vandana; Reynolds, Danielle G; Yu, Christine; Krishnan, Sowmya
Background:Coronavirus-19 (COVID-19) is a disease caused by the SARS-CoV-2 virus, the seventh coronavirus identified as causing disease in humans. The SARS-CoV-2 virus has multiple potential pathophysiologic interconnections with endocrine systems, potentially causing disturbances in glucose metabolism, hypothalamic and pituitary function, adrenal function and mineral metabolism. A growing body of data is revealing both the effects of underlying endocrine disorders on COVID-19 disease outcome and the effects of the SARS-CoV-2 virus on endocrine systems. However, comprehensive assessment of the relationship to endocrine disorders in children has been lacking. Content:In this review, we present the effects of SARS-CoV-2 infection on endocrine systems and review the current literature on complications of COVID-19 disease in underlying paediatric endocrine disorders. We provide recommendations on management of endocrinopathies related to SARS-CoV-2 infection in this population. Summary and outlook:With the surge in COVID-19 cases worldwide, it is important for paediatric endocrinologists to be aware of the interaction of SARS-CoV-2 with the endocrine system and management considerations for patients with underlying disorders who develop COVID-19 disease. While children and adults share some risk factors that influence risk of complications in SARS-CoV-2 infection, it is becoming clear that responses in the paediatric population are distinct and outcomes from adult studies cannot be extrapolated. Evidence emerging from paediatric studies provides some guidance but highlights the need for more research in this area.
PMCID:8209869
PMID: 34268455
ISSN: 2398-9238
CID: 4965852

Should Lipoprotein(a) be Measured in Youth?

Kohn, Brenda; Ashraf, Ambika P; Wilson, Don P
PMID: 32822740
ISSN: 1097-6833
CID: 4650112

Universal cholesterol screening of youth-Are pediatric lipidologists smarter than a fifth grader? [Editorial]

Kohn, Brenda; Wilson, Don P
PMID: 33039346
ISSN: 1933-2874
CID: 4651812

Familial X-Linked Acrogigantism: Postnatal Outcomes and Tumor Pathology in a Prenatally Diagnosed Infant and His Mother

Wise-Oringer, Brittany K; Zanazzi, George J; Gordon, Rebecca J; Wardlaw, Sharon L; William, Christopher; Anyane-Yeboa, Kwame; Chung, Wendy K; Kohn, Brenda; Wisoff, Jeffrey H; David, Raphael; Oberfield, Sharon E
CONTEXT/BACKGROUND:X-linked acrogigantism (X-LAG), a condition of infant-onset acrogigantism marked by elevated GH, IGF-1, and prolactin (PRL), is extremely rare. Thirty-three cases, including three kindreds, have been reported. These patients have pituitary adenomas that are thought to be mixed lactotrophs and somatotrophs. CASE DESCRIPTION/METHODS:The patient's mother, diagnosed with acrogigantism at 21 months, underwent pituitary tumor excision at 24 months. For over 30 years, stable PRL, GH, and IGF-1 concentrations and serial imaging studies indicated no tumor recurrence. During pre-conception planning, X-LAG was diagnosed: single-nucleotide polymorphism (SNP) microarray showed chromosome Xq26.3 microduplication. After conception, SNP microarray on a chorionic villus sample showed the same microduplication in the fetus, confirming familial X-LAG. The infant grew rapidly with rising PRL, GH, and IGF-1 concentrations and an enlarging suprasellar pituitary mass, despite treatment with bromocriptine. At 15 months, he underwent tumor resection. The pituitary adenoma resembled the mother's pituitary adenoma, with tumor cells arranged in trabeculae and glandular structures. In both cases, many tumor cells expressed PRL, GH, and PIT1. Furthermore, the tumor expressed other lineage-specific transcription factors, as well as SOX2 and OCT4, demonstrating the multipotentiality of X-LAG tumors. Both showed an elevated Ki-67 proliferation index-5.6% (mother) and 8.5% (infant)-the highest reported in X-LAG. CONCLUSIONS:This is the first prenatally diagnosed case of X-LAG. Clinical follow-up and biochemical evaluation have provided insight into the natural history of this disease. Expression of stem cell markers and several cell lineage-specific transcription factors suggests that these tumors are multipotential.
PMID: 31166600
ISSN: 1945-7197
CID: 3922962

Improving Long-term Outcomes of Youth with Lipid Abnormalities- Expanding the Role of Pediatric Endocrinologists

Ashraf, Ambika P; Kohn, Brenda; Wilson, Don P
BACKGROUND:There is disturbingly high prevalence of dyslipidemia in youth. Although, pediatric endocrinologists are aware of the significant cardiovascular (CV) risk associated with monogenic disorders of lipid and lipoprotein metabolism, relatively few recognize the CV disease (CVD)-related morbidity and premature mortality incurred by common endocrine disorders associated with dyslipidemia, such as diabetes mellitus, growth hormone deficiency, congenital adrenal hyperplasia, and hypopituitarism. AIM/OBJECTIVE:In this article we discuss the expanding role of pediatric endocrinologists in cardiovascular health and risk prevention. METHODS:We reviewed available literature and summarized discussions with opinion leaders in pediatric endocrinology to 1) provide an overview of this timely topic; 2) identify opportunities for targeted education; and 3) discuss ways of expanding clinical services to improve outcomes. RESULTS:In addition to well-known genetic disorders of lipid and lipoprotein metabolism, youth with common endocrine disorders, including type 1 and type 2 diabetes, would benefit from cholesterol screening and, in some, early intervention including use of lipid-lowering medications. Despite the growing need, the location and extent of services available to youth with dyslipidemia and the availability of providers with experience in treatment of dyslipidemia are largely unknown, but likely inadequate to provide accessible, timely, and cost-effective intervention. CONCLUSION/CONCLUSIONS:With a new awareness of opportunities to prevent premature CVD in youth including those with common endocrine disorders, and CVD-related events during adulthood, there is an urgent need for additional clinical services and targeted education of current as well as future pediatric endocrinologists.
PMID: 31120509
ISSN: 1945-7197
CID: 3936042

Use of the microbiome in the management of children with type 2 diabetes mellitus

Brar, Preneet Cheema; Kohn, Brenda
PURPOSE OF REVIEW/OBJECTIVE:The purpose of this review is to present recent data that defines our current understanding of the role of the gut microbiome in the development of T2DM. RECENT FINDINGS/RESULTS:Recent studies focus on the physiology and molecular pathways of the gut microbiome-host interaction. Short-chain fatty acids (SCFAs) derived from the fermentation of plant-based nonsoluble fiber bind to G-protein-coupled receptors (GPR) GPR 41 and GPR 43 to induce enteroendocrine molecules that control appetite, and to upregulate intestinal gluconeogenesis gene expression that controls glucose regulation. "Metabolic endotexemia" reflects a state of low-grade systemic inflammation that results from lipopolysaccharide (LPS) release from the gut into the systemic circulation in response to a high-fat diet. Inflammatory pathways induced by LPS, activation of toll-like receptor-4 (TLR-4), and other inflammatory signaling pathways are mediators of systemic inflammation, insulin resistance and type II diabetes mellitus. SUMMARY/CONCLUSIONS:Recent scientific data support that derangements in the composition of the microbiota, termed "microbiome dysbiosis" is a factor in the development of "metabolic endotoxemia" and T2DM. Therapeutic options that target the gut microbiome in the treatment of T2DM are explored.
PMID: 31299021
ISSN: 1531-698x
CID: 3976892

Pancreatic Neuroendocrine Tumor in a Young Child With Tuberous Sclerosis Complex 1 [Case Report]

Mehta, Shilpa; Rusyn, Larisa; Ginsburg, Howard; Hajdu, Cristina; Kohn, Brenda
Pancreatic neuroendocrine tumors (PNETs) occur in the context of tuberous sclerosis complex (TSC). To date, PNETs in association with TSC have been described almost exclusively in adults and in the context of TSC2. We present the evaluation of a PNET in a young child with TSC1. A 3-year, 6-month-old boy with TSC1 was found on surveillance to have a small pancreatic lesion measuring 0.4 cm on magnetic resonance imaging (MRI). The lesion showed interval enlargement to 1 cm on serial MRI studies during the ensuing 16 weeks. Endocrine laboratory tests did not reveal a functional tumor. The patient underwent enucleation of the pancreatic lesion. Microscopic examination defined a well-differentiated PNET, grade II/intermediate grade with a mitotic rate of two mitotic figures per 10 high-powered field and Ki-67 proliferation index of ∼15%. The tumor was positive for the TSC1 gene mutation. The patient was free of tumor recurrence at the 5-year follow-up examination, as determined by endocrine surveillance and annual MRI of the abdomen. In the reported data, PNET in patients with TSC has been primarily reported in association with TSC2. Our case demonstrates that patients with TSC1 can develop PNETs, even at an early age. The international TSC consensus group 2012 recommendation was to obtain MRI of the abdomen every 1 to 3 years for surveillance of renal angiomyolipomas and renal cystic disease. It might be beneficial to add a pancreatic protocol to the surveillance guidelines to evaluate for PNET.
PMCID:6546344
PMID: 31187078
ISSN: 2472-1972
CID: 3930012

Pituitary disorders of childhood : diagnosis and clinical management

Kohn, Brenda
Cham, Switzerland : Humana Press, [2019]
Extent: xiii, 362 p. ; 24 cm.
ISBN: 9783030113391
CID: 3977062