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Cardiovascular disease (CVD) is the leading cause of mortality in the United States. Universal screening in all children aged 9 to 11 years and 17 to 21 years, and targeted screening in children with high-risk factors, can help in early identification and treatment of dyslipidemia during the youth, significantly reducing clinical CVD risk in adult life. Lifestyle modifications with heart-healthy diet and moderate-vigorous activity are fundamental in the management of pediatric dyslipidemia. Pharmacotherapy has been evolving in children, and statins, bile acid sequestrants, ezetimibe and PCSK9 inhibitors, fibrates, niacin, and omega-3 fish oils are available for use in pediatric population.

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 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.

Objective 3-M syndrome is characterized by severe short stature, syndromic features, and characteristic radiographic findings. Growth hormone (GH) has been used with variable success. Recombinant human insulin like growth factor-1 (rhIGF-1) has never been utilized. Case presentation We describe a child with severe growth retardation, macrocephaly, and skeletal abnormalities with evidence of GH insensitivity subsequently treated with rhIGF-1. He developed morbid obesity and comorbidities including voracious appetite, acanthosis nigricans, tonsillar hypertrophy, and severe obstructive sleep apnea with minimal height improvement. Genetic testing done at 11.5 years revealed a compound heterozygous mutation (c.2112G>A(p.W704X) and c.2559delC) in the CUL7 gene consistent with 3-M syndrome-1. rhIGF-1 therapy was discontinued. Conclusions This case highlights the novel use of rhIGF-1 therapy on a child with 3-M syndrome-1 with minimal height benefit but accelerated weight gain and serves as a reminder of the importance of re-evaluating therapy efficacy and side effect profile.

Nestor-Guillermo progeria syndrome (NGPS; OMIM 614008) is characterized by early onset and slow progression of symptoms including poor growth, lipoatrophy, pseudosenile facial appearance, and normal cognitive development. In contrast to other progeria syndromes, NGPS is associated with a longer lifespan and higher risk for developing severe skeletal abnormalities. It is an autosomal recessive condition caused by biallelic pathogenic variants in BANF1. There are two previously reported patients with NGPS, both Spanish with molecular diagnoses made in adulthood and having the same homozygous pathogenic variant c.34G > A; p.Ala12Thr. Presented here is a 2 year, 8 month old girl with short stature, poor weight gain, sparse hair, and dysmorphic facial features reminiscent of premature aging. Whole exome sequencing identified the same c.34G > A homozygous pathogenic variant in BANF1 as reported in the previous patients. This is the first reported case of a child and is supporting evidence for this recurrent loss of function variant.

BackgroundDespite major advances in understanding the molecular basis of various genetic lipodystrophy syndromes, some rare patients still remain unexplained.CasesWe report a novel autosomal recessive lipodystrophy affecting two sisters aged 17 and 19 years and characterised by early onset intellectual disability, and subsequent development of near-generalised loss of subcutaneous fat with diabetes mellitus, extreme hypertriglyceridemia, hepatic steatosis, short stature, clinodactyly, joint contractures, leiomyoma of uterus and cataracts in childhood. The lipodystrophy was more pronounced in the upper and lower extremities, and there was no associated muscular hypertrophy. Using whole exome sequencing in this consanguineous Hispanic pedigree, we report disease-causing homozygous p.Arg545His LMNA variant in the affected subjects, and confirm the lack of pathogenic variants in other known lipodystrophy genes. The mother and a younger brother were both heterozygous for p.Arg545His LMNA variant and were overweight with acanthosis nigricans without any evidence of lipodystrophy. Our patients are distinct from previously reported autosomal recessive lipodystrophy syndromes and have no overlap with other autosomal recessive laminopathies, including mandibuloacral dysplasia, Emery-Dreifuss muscular dystrophy and Charcot-Marie-Tooth neuropathy.ConclusionOur report of this unusual familial generalised lipodystrophy syndrome adds to the pleiotropy associated with biallelic autosomal recessive LMNA variants.

Dumping syndrome-associated hypoglycemia is caused by an exaggerated hyperinsulinemic response to glucose absorption in the small intestine. Diazoxide acts on the ATP-sensitive potassium channels and prevents insulin secretion and, thus, should be beneficial for the treatment of hypoglycemia secondary to dumping syndrome. We report on the efficacy of diazoxide in a pediatric patient with dumping syndrome. A 6-year-old girl born at 32 weeks’ gestation age with resultant short gut syndrome and liver failure, who had undergone liver, small bowel, and pancreas transplantation at 1 year of age, developed late dumping-like symptoms with postprandial hypoglycemia, headaches, tremors, and irritability. She experienced relief of symptoms with oral intake. An oral glucose tolerance test showed a fasting and 2-hour blood glucose of 3.9 and 2.8 mmol/L, respectively. A gastric emptying study confirmed the diagnosis of dumping. A diet with 2 g of fiber and cornstarch and antimotility medications failed to improve the dumping symptoms. Diazoxide was started orally at a dose of 3 mg/kg/d and was increased to 5 mg/kg/d, divided every 8 hours, after 1 month, with improvement of postprandial blood glucose values (3.6 to 5.0 mmol/L). No hypertrichosis, fluid retention, respiratory concerns, or other side effects were noted. Several duodenal dilations were performed, with resultant improvement of gastric emptying. She was eventually weaned from diazoxide, and no further episodes of substantial hypoglycemia occurred. In conclusion, diazoxide was efficacious and safe for the treatment of hypoglycemia secondary to dumping syndrome in children. It could be of particular use as a bridging therapy for children awaiting more definitive surgical interventions.

Lipodystrophies are rare, heterogeneous, genetic or acquired, disorders characterised by varying degrees of body fat loss and associated metabolic complications, including insulin resistance, dyslipidaemias, hepatic steatosis and predisposition to atherosclerotic vascular disease. The four main types of lipodystrophy, excluding antiretroviral therapy-induced lipodystrophy in HIV-infected patients, are congenital generalised lipodystrophy (CGL), familial partial lipodystrophy (FPLD), acquired generalised lipodystrophy (AGL) and acquired partial lipodystrophy (APL). This paper reviews the literature related to the prevalence of dyslipidaemias and atherosclerotic vascular disease in patients with lipodystrophies. Patients with CGL, AGL and FPLD have increased prevalence of dyslipidaemia but not those with APL. Patients with CGL as well as AGL present in childhood, and have severe dyslipidaemias (mainly hypertriglyceridaemia) and early onset diabetes mellitus as a consequence of extreme fat loss. However, only a few patients with CGL and AGL have been reported to develop coronary heart disease. In contrast, data from some small cohorts of FPLD patients reveal increased prevalence of atherosclerotic vascular disease especially among women. Patients with APL have a relatively low prevalence of hypertriglyceridaemia and diabetes mellitus. Overall, patients with lipodystrophies appear to be at high risk of atherosclerotic vascular disease due to increased prevalence of dyslipidaemia and diabetes and efforts should be made to manage these metabolic complications aggressively to prevent atherosclerotic vascular disease.

Wiedemann-Rautenstrauch syndrome (WRS), also known as neonatal progeroid syndrome, is a rare disorder of unknown etiology. It has been proposed to be autosomal-recessive and is characterized by variable clinical features, such as intrauterine growth restriction and poor postnatal weight gain, characteristic facial features (triangular appearance to the face, convex nasal profile or pinched nose, and small mouth), widened fontanelles, pseudohydrocephalus, prominent scalp veins, lipodystrophy, and teeth abnormalities. A previous report described a single WRS patient with bi-allelic truncating and splicing variants in POLR3A. Here we present seven additional infants, children, and adults with WRS and bi-allelic truncating and/or splicing variants in POLR3A. POLR3A, the largest subunit of RNA polymerase III, is a DNA-directed RNA polymerase that transcribes many small noncoding RNAs that regulate transcription, RNA processing, and translation. Bi-allelic missense variants in POLR3A have been associated with phenotypes distinct from WRS: hypogonadotropic hypogonadism and hypomyelinating leukodystrophy with or without oligodontia. Our findings confirm the association of bi-allelic POLR3A variants with WRS, expand the clinical phenotype of WRS, and suggest specific POLR3A genotypes associated with WRS and hypomyelinating leukodystrophy.

Context Congenital generalized lipodystrophy, type 4 (CGL4) is a rare autosomal recessive disorder caused by mutations in caveolae-associated protein 1. Patients with CGL4 also have myopathy and cardiomyopathy with a predisposition for sudden death due to ventricular arrhythmias. However, the underlying pathology for these morbidities remains unknown. Therefore, we report on an autopsy of a Hispanic boy with CGL4. Case Description Our patient had early-onset generalized lipodystrophy, feeding difficulties, myopathy, atlanto-axial dislocation, and learning disabilities. He was diagnosed with catecholaminergic polymorphic ventricular tachycardia (CPVT) at age 8 years, had poor compliance with medications, and died suddenly at age 15.3 years. Autopsy showed marked loss of subcutaneous and omental fat with no inflammatory cells in adipose tissue and normal adipocytes in the parathyroid glands. There were adipocytes interdigitating cardiac muscle fibers, with fibro-fatty infiltration in the right ventricle, near coronary sinus, and atrioventricular node. There was no evidence of coronary heart disease. The quadriceps femoris muscle did not show adipocyte infiltration, inflammation, or fibrosis. The muscularis mucosa layer was thickened in the esophagus and at the gastro-duodenal junction, and the esophagus had prominent, large nerves in the subserosa. The liver weighed 3000 g, with minimal chronic inflammation and steatosis in 40% of parenchyma, primarily in zones 2 and 3. There was no spermatogenesis in the spermatic tubules. Conclusions Our data suggest that fibro-fatty infiltration of the right ventricle may contribute to CPVT in patients with CGL4. Thick muscularis mucosa and large nerves in the esophagus likely contributed to dysphagia and dysmotility. A lack of spermatids suggests infertility in affected male patients.

Background: FPLD2, a rare autosomal dominant disorder due to heterozygous missense mutations in LMNA, is characterized by gradual loss of subcutaneous (sc) fat from the limbs starting during late childhood and predisposition to metabolic complications, such as diabetes, dyslipidemia and hepatic steatosis. Some patients, especially females, accumulate excess sc fat in the chin, neck, supraclavicular and perineal regions. We report disfiguring and disabling lipomatoses in unusual locations with thiazolidinedione therapy in two women with FPLD2. Clinical Cases: A 57-year-old white female with FPLD2, due to heterozygous p.R482Q LMNA mutation, developed recurrent large lipomatoses in the axillae at age 33 years, and later in the posterior neck (buffalo hump), mons pubis and above sacrum. She developed diabetes at age 30 and was started on pioglitazone 45 mg daily, which was switched to rosiglitazone 8 mg daily at age 43 years. Supra-sacral lipomatoses were approximately 40 cm X 20 cm bilaterally and continued to grow despite lipectomy and multiple liposuctions. Rosiglitazone was stopped at age 56 years, and she reported no further increase in the size of lipomatoses. Her other medications included colesevelam, atorvastatin, metformin, glimepiride, lisinopril, losartan, hydrochlorothiazide, aspirin, insulin and dulaglutide. Her 54-year-old younger sister with FPLD2 (heterozygous p.R482Q LMNA mutation) was treated with lisinopril, metoprolol, atorvastatin, liraglutide, and insulin glargine and aspart, but no history of taking thiazolidinediones, and she never developed any lipomatoses. Another 43-year-old white female with FPLD2, due to heterozygous p.S583L LMNA mutation, was noticed to have lipomatous deposits in the axillae, medial gluteal region, labia and perineal regions. She developed diabetes mellitus at age 36 years and took metformin for 6 years and pioglitazone 30 mg daily for one year before she noticed the lipomatoses. Her other medications included atorvastatin, aldactone and vitamin D3. Pioglitazone was stopped and after one year, she reported reduction in the size of lipomatoses. Conclusion: Thiazolidinediones are selective peroxisomal proliferator-activated receptor-γ agonists and induce weight gain by increasing fat mass, especially subcutaneous depots. Our cases suggest that thiazolidinediones can cause undesired growth of non-lipodystrophic adipose tissue in patients with FPLD2 and thus should be avoided.

Background: Néstor-Guillermo progeria syndrome (NGPS; OMIM 614008) is caused by biallelic pathogenic variants in BANF1 (barrier-to-autointegration factor 1) on chromosome 11q13. It characterized by early onset and slow progression of symptoms including poor growth, lipoatrophy, pseudo-senile facial appearance, and normal cognitive development. Two adult patients have been reported. This is the first reported case of a child with NGPS who presented to endocrine clinic with failure to grow. Clinical Case: Two year, 8 month old Hispanic female born at 40 weeks gestation with birth weight 3.5 kg. At 1 year, she had short stature, poor weight gain, and thinning hair. There were no developmental concerns. Family history was remarkable for consanguinity. At presentation, her weight was 8.5 kilograms) and height 80 centimeters (both A (p.Ala12Thr) inherited from each of the unaffected parents. Conclusion: Progeria syndromes are unusual but diagnosable causes of failure to grow and can be diagnosed based on clinical suspicion. This patient represents the first child reported with NGPS.

1. Nivedita Patni, MD* 2. Kathleen Collins, MD† 3. Perrin White, MD* 1. *Division of Pediatric Endocrinology, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 2. †Division of Allergy, Immunology, and Rheumatology, Department of Pediatrics, Stanford University, Palo Alto, CA An 8-week-old boy presents with 2 days of worsening jaundice, lethargy, and poor feeding, without fever, vomiting, or diarrhea. At term he weighed 3,400 g (43rd percentile), had hypoglycemia on day 1, and received hyperbilirubinemia phototherapy for 5 days. Physical examination is noteworthy for a lethargic and jaundiced boy weighing 4,300 g (8th percentile). The liver edge is 4 cm below the costal margin. The phallus is 1.7 × 0.7 cm, with no hypospadias, normal scrotum, and descended testes. Initial laboratory results are as follows: blood glucose, less than 20 mg/dL (

Background: Molecular basis of diet responsive hypercholesterolemia remains unclear. We report diet-responsive severe hypercholesterolemia in a young female with cardiofaciocutaneous syndrome type 3 (CFC3) due to a heterozygous pathogenic MAP2K1 variant, suggesting a role of common MAPK variants in LDL-cholesterol (LDL-C) response to diet. Clinical case: A 3-year-old Caucasian female with CFC3 (macrocephaly, frontal bossing, wide nasal root with depressed bridge, anteverted nares, low set fleshy ears, congenital pulmonic valve stenosis, postnatal growth deficiency, hypotonia, and neurocognitive impairment) due to a de novo heterozygous c.389A>G, p.Tyr130Cys pathogenic variant in MAP2K1, presented with extremely elevated serum total cholesterol of 446 mg/dL, triglycerides of 239 mg/dL, HDL-cholesterol of 53 mg/dL, LDL-C of 335 mg/dL (normal range < 110 mg/dL) and serum apolipoprotein B level 219 mg/dL (normal range < 90 mg/dL). Her LDL-C was 252 mg/dL a year ago and 215 mg/dL one month prior to presentation. Reducing total dietary fat to 20–25% of total energy and saturated fat to A; p.Asp748Asn, (Minor allele frequency 0.00008) in the patient and her father. Whole exome sequencing of the patient and both parents showed no known disease-causing variants in LDLR, APOB, PCSK9, LDLRAP1, APOE, STAP1, LIPA, ABCG5, ABCG8 and other known hyperlipidemia-related genes. There are no previous reports of hypercholesterolemia in patients with CFC3. MAP2K1 stimulates various MAP kinases upon wide variety of extra- and intracellular signal and is involved in cell proliferation, differentiation, transcription regulation and development. Previous studies of the relationship between p42/44MAPK activation and LDLR expression in human hepatoma HepG2-derived cell line showed that that activation of the Raf-1/MEK/p42/44MAPK cascade induces LDLR expression and modulation of the Raf-1 kinase signal strength can determine LDLR expression levels. Thus, extent of MAPK activation can alter signaling of LDLR, resulting in hypercholesterolemia. Conclusion: Our case report suggests that MAP2K1 may play a significant role in LDLR signaling, and some MAP2K1 variants may be associated with diet-responsive hypercholesterolemia. Larger studies are required to assess dietary response to LDL-C in subjects with MAP2K1 variants.

BACKGROUND: Despite major advances in understanding the molecular basis of various genetic lipodystrophy syndromes, some rare patients still remain unexplained. CASES: We report a novel autosomal recessive lipodystrophy affecting two sisters aged 17 and 19 years and characterised by early onset intellectual disability, and subsequent development of near-generalised loss of subcutaneous fat with diabetes mellitus, extreme hypertriglyceridemia, hepatic steatosis, short stature, clinodactyly, joint contractures, leiomyoma of uterus and cataracts in childhood. The lipodystrophy was more pronounced in the upper and lower extremities, and there was no associated muscular hypertrophy. Using whole exome sequencing in this consanguineous Hispanic pedigree, we report disease-causing homozygous p.Arg545His LMNA variant in the affected subjects, and confirm the lack of pathogenic variants in other known lipodystrophy genes. The mother and a younger brother were both heterozygous for p.Arg545His LMNA variant and were overweight with acanthosis nigricans without any evidence of lipodystrophy. Our patients are distinct from previously reported autosomal recessive lipodystrophy syndromes and have no overlap with other autosomal recessive laminopathies, including mandibuloacral dysplasia, Emery-Dreifuss muscular dystrophy and Charcot-Marie-Tooth neuropathy. CONCLUSION: Our report of this unusual familial generalised lipodystrophy syndrome adds to the pleiotropy associated with biallelic autosomal recessive LMNA variants.

Background: Homozygous mutations in lamin A/C (LMNA) gene are extremely rare and have been reported to cause mandibuloacral dysplasia type A, Emery-Dreifuss muscular dystrophy-3, Charcot-Marie-Tooth axonal neuropathy type2B1, progeroid syndrome and severe familial partial lipodystrophy. We report a novel syndrome of familial generalized lipodystrophy due to homozygous p.Arg545His LMNA mutation in two sisters. Clinical Cases: The proband, a 18.5-year-old Hispanic female, was diagnosed with speech delay at age 4 years; and developed lipodystrophy and acanthosis nigricans at age 10. She was diagnosed with diabetes and elevated serum aspartate and alanine aminotransferases at 11 years of age; and extreme hypertriglyceridemia (serum triglycerides >10,000 mg/dL), xanthomas and three episodes of acute pancreatitis at 14 years of age. Her liver biopsy showed hepatocytes with pleomorphic and enlarged mitochondria and variably enlarged glycogenated nuclei, with macro-vesicular and micro-vesicular steatosis in 2% of hepatocytes. At age 16, she had severe metabolic abnormalities despite low fat diet, metformin 1000 mg, insulin > 600 units, fish oil 4 g, gemfibrozil 600 mg, and lisinopril 10 mg per day. Subcutaneous metreleptin 2.5 mg/d was initiated which improved glycemic control, liver enzymes and triglycerides, with no further episode of acute pancreatitis. She currently takes metreleptin and insulin 140 units daily. She recently developed right hydrosalpinx, 1.8 cm posterior uterine fibroids, and 2.1 cm endometriosis. Her 17-year-old sister had speech delay in infancy, and recurrent pyelonephritis, and lost sc fat in early childhood. She developed hypothyroidism, elevated transaminases, and diabetes at age 10, 14, and 16 years, respectively. She had one episode of acute pancreatitis and an incidental 6.8 cm ovarian cyst was found at age 16 years. Both of them have generalized loss of sc fat, more from the extremities than from the trunk, thin lips with perioral pigmentation, dry skin, short 5th finger with clindodactyly, and bilateral ankle contractures. The proband also had bilateral knee contractures. They have no acro-osteolysis, buffalo hump, double chin, myopathy or neuropathy. Whole exome sequencing of both the patients revealed homozygous mutation chr1:156107470G>A, p.Arg545His (rs142191737, minor allele frequency 0.000038 in Latinos) in LMNA (http://gnomad.broadinstitute.org). The mother and a younger brother are both heterozygous for p.Arg545His variant and are healthy without any lipodystrophy. Conclusions: Homozygous p.Arg545His LMNA mutation results in a novel syndrome of childhood-onset familial generalized lipodystrophy with early onset diabetes, hypertriglyceridemia, and hepatic steatosis, speech delay and joint contractures. Metreleptin therapy may be helpful in improving metabolic derangements.

Context Familial partial lipodystrophy, Dunnigan variety (FPLD2) is a rare autosomal-dominant disorder due to heterozygous missense lamin A/C (LMNA) mutations. Subjects with FPLD2 gradually lose fat from the upper and lower extremities but gain fat in the face and neck around puberty. However, the precise onset of body fat changes and metabolic complications during childhood remains unknown. Objective To compare metabolic parameters and regional body fat in children with FPLD2 with the sex- and age-matched controls from the National Health and Nutrition Examination Survey (NHANES) 2005 to 2010. Methods We measured fasting serum triglycerides, glucose, and skinfold thicknesses in all children (aged 1 to 18 years) harboring FPLD2-causing LMNA mutations and determined regional body fat by dual-energy X-ray absorptiometry in those aged ≥8 years. Results Thirty-two affected females and 14 males participated. The lower limb fat in all affected females, except one, was below or equal to the first percentile and in two affected males was below the fifth percentile for NHANES. One female subject with FPLD2 followed from age 6 to 16 years revealed marked loss of extremity fat much before thelarche. Serum triglycerides were higher in females with FPLD2 aged 7 to 18 years compared with controls (median 208 vs 70 mg/dL; P < 0.0001) and showed inverse correlation with extremity skinfolds. Serum triglycerides in males with FPLD2 were not significantly different than controls. Conclusions The onset of fat loss from the extremities, especially in girls with FPLD2, occurs well before the onset of puberty. High serum triglycerides are seen in young females with FPLD2 with severe loss of fat from the extremities.

Objective: Lipodystrophy syndromes are extremely rare disorders of deficient body fat associated with potentially serious metabolic complications, including diabetes, hypertriglyceridemia, and steatohepatitis. Due to their rarity, most clinicians are not familiar with their diagnosis and management. This practice guideline summarizes the diagnosis and management of lipodystrophy syndromes not associated with HIV or injectable drugs. Participants: Seventeen participants were nominated by worldwide endocrine societies or selected by the committee as content experts. Funding was via an unrestricted educational grant from Astra Zeneca to the Pediatric Endocrine Society. Meetings were not open to the general public. Evidence: A literature review was conducted by the committee. Recommendations of the committee were graded using the system of the American Heart Association. Expert opinion was used when published data were unavailable or scarce. Consensus Process: The guideline was drafted by committee members and reviewed, revised, and approved by the entire committee during group meetings. Contributing societies reviewed the document and provided approval. Conclusions: Lipodystrophy syndromes are heterogeneous and are diagnosed by clinical phenotype, supplemented by genetic testing in certain forms. Patients with most lipodystrophy syndromes should be screened for diabetes, dyslipidemia, and liver, kidney, and heart disease annually. Diet is essential for the management of metabolic complications of lipodystrophy. Metreleptin therapy is effective for metabolic complications in hypoleptinemic patients with generalized lipodystrophy and selected patients with partial lipodystrophy. Other treatments not specific for lipodystrophy may be helpful as well (eg, metformin for diabetes, and statins or fibrates for hyperlipidemia). Oral estrogens are contraindicated., Multiple worldwide endocrine societies developed practice guidelines for diagnosis and management of lipodystrophy syndromes based on current evidence.

Context Patients with type 1 hyperlipoproteinemia (T1HLP), a rare genetic disorder, have extreme chylomicronemia and recurrent episodes of acute pancreatitis. Currently, the only therapeutic option is to consume an extremely low-fat diet because the triglyceride-lowering medications are not efficacious. Objective To determine the efficacy of orlistat, a gastric and pancreatic lipase inhibitor, in reducing serum triglyceride levels in patients with T1HLP. Design and Setting We conducted a randomized, open-label, clinical trial with a four-period, two-sequence (“orlistat” and “off orlistat” for 3 months), crossover study design. Patients Two unrelated young Asian Indian males (11 and 9 years old) with T1HLP due to homozygous large GPIHBP1 deletions were enrolled at the UT Southwestern Medical Center. The patients were randomized to receive 3 months of orlistat or no therapy (off), then crossed over to the other arm, and this sequence was then repeated. Fasting serum triglyceride levels, fat-soluble vitamins, and gastrointestinal side effects were assessed. Results Compared with the two off periods, orlistat therapy reduced serum triglycerides by 53.3% and 53.0% in patient 1 and 45.8% and 62.2% in patient 2. There was no deficiency of fat-soluble vitamin levels, and their growth continued. There were no serious adverse effects of orlistat; patient 1 had a mild increase in passage of gas and bloating, and patient 2 had constipation with mild stool leakage. Conclusion Orlistat is safe and highly efficacious in lowering serum triglycerides in children with T1HLP and should be the first-line therapy in conjunction with an extremely low-fat diet.

A rare presentation of hypothalamic tumors in infants and young children is profound emaciation and generalized loss of sc adipose tissue, also known as "diencephalic syndrome." Similar loss of sc fat can be observed in children with acquired generalized lipodystrophy or congenital generalized lipodystrophy. Precise diagnosis may be challenging early in the course of the disease, especially in the absence of metabolic abnormalities.We report three males who presented with poor weight gain and generalized loss of sc fat at birth to 3 years of age consistent with generalized lipodystrophy, with subsequent development of pilocytic astrocytoma. Two of them had hypothalamic tumors, and one had a multicentric tumor with a large right parietal mass. Our patients are unique because the onset of lipodystrophy occurred 2.5 to 7.3 years before the diagnosis of brain tumor, and all of them gained body fat or weight after surgical removal and/or chemotherapy. One patient had hepatosplenomegaly and impaired glucose tolerance, and another patient had severe hyperglycemia and hypertriglyceridemia during the course of the disease. Two patients presented with central precocious puberty and advanced bone age at the chronological age of 6 years.It is likely that pilocytic astrocytoma may induce generalized lipodystrophy by paraneoplastic antiadipocyte antibody formation or by excessive hormones or cytokine secretion resulting in excess lipolysis from adipocytes. We conclude that young children presenting with idiopathic acquired generalized lipodystrophy or atypical congenital generalized lipodystrophy, with or without metabolic abnormalities, should prompt investigation for brain tumors.

Background Extreme hypertriglyceridemia (eHTG; serum triglycerides ≥ 2000 mg/dL) poses a significant risk for acute pancreatitis. There is paucity of data regarding the prevalence and etiology of eHTG in children. Objective To determine the prevalence, clinical features and etiologies of patients with eHTG at a tertiary children's hospital in the United States and in the United States National Health and Nutrition Examination Survey (NHANES). Methods A retrospective analysis was conducted of the electronic medical records of the Children's Medical Center, Dallas, from 2000–2015, and the NHANES data from 2005–2014 for eHTG. Results Of 30,623 children, 36 (∼ 1 in 1000) had eHTG and one-third of them developed acute pancreatitis. They tended to be female (61%), Hispanic (39%), and nonobese (median body mass index z-score 1.60 and 1.25 in males and females, respectively). Most patients had secondary causes such as uncontrolled diabetes mellitus (30%), L-asparaginase and high-dose corticosteroid therapy for acute lymphoblastic leukemia (28%), and sirolimus/tacrolimus therapy after solid organ transplantation (14%). Five patients (14%) had type 1 hyperlipoproteinemia (T1HLP; familial chylomicronemia syndrome). The NHANES data revealed that none of the 2362 children had eHTG, and the prevalence in adults was 0.02%. Conclusions Extreme HTG is rare in children and majority of the children had secondary causes. Patients with diabetes mellitus or receiving drugs, such as, L-asparaginase, corticosteroids, and sirolimus, should be closely monitored for eHTG. Prevalence of T1HLP is approximately 1 in 6000 at a tertiary care center with an estimated population prevalence of 1 in 3,00,000. Early neonatal screening and intervention for T1HLP can prevent life-threatening morbidities such as acute pancreatitis.

Background Lamin A/C (LMNA) gene mutations cause a heterogeneous group of progeroid disorders, including Hutchinson-Gilford progeria syndrome, mandibuloacral dysplasia, and atypical progeroid syndrome (APS). Five of the 31 previously reported patients with APS harbored a recurrent de novo heterozygous LMNA p.T10I mutation. All five had generalized lipodystrophy, as well as similar metabolic and clinical features, suggesting a distinct progeroid syndrome. Methods We report nine new patients and follow-up of two previously reported patients with the heterozygous LMNA p.T10I mutation and compare their clinical and metabolic features with other patients with APS. Results Compared with other patients with APS, those with the heterozygous LMNA p.T10I mutation were younger in age but had increased prevalence of generalized lipodystrophy, diabetes mellitus, acanthosis nigricans, hypertriglyceridemia, and hepatomegaly, together with higher fasting serum insulin and triglyceride levels and lower serum leptin and high-density lipoprotein cholesterol levels. Prominent clinical features included mottled skin pigmentation, joint contractures, and cardiomyopathy resulting in cardiac transplants in three patients at ages 13, 33, and 47 years. Seven patients received metreleptin therapy for 0.5 to 16 years with all, except one noncompliant patient, showing marked improvement in metabolic complications. Conclusions Patients with the heterozygous LMNA p.T10I mutation have distinct clinical features and significantly worse metabolic complications compared with other patients with APS as well as patients with Hutchinson-Gilford progeria syndrome. We propose that they be recognized as having generalized lipodystrophy-associated progeroid syndrome. Patients with generalized lipodystrophy-associated progeroid syndrome should undergo careful multisystem assessment at onset and yearly metabolic and cardiac evaluation, as hyperglycemia, hypertriglyceridemia, hepatic steatosis, and cardiomyopathy are the major contributors to morbidity and mortality.

The LMNA gene contains 12 exons and encodes lamins A and C by alternative splicing within exon 10. While mutations in lamin A specific residues cause several diseases including lipodystrophy, progeria, muscular dystrophy, neuropathy and cardiomyopathy, only three families with mutations in lamin C-specific residues are reported with cardiomyopathy, neuropathy and muscular dystrophy so far. Therefore, we report two brothers with juvenile-onset generalized lipodystrophy due to a lamin C-specific mutation. The proband, a 23-year-old Caucasian male was reported to have generalized lipodystrophy at 3 weeks of age, developed diabetes, hypertriglyceridemia, hypertension and liver problems and died with complications of cirrhosis and kidney failure. His younger brother, a 37-year-old Caucasian male developed generalized lipodystrophy around 2 years of age and was diagnosed with diabetes, hypertriglyceridemia, fatty liver and hypertension at 36 years of age. Their father also died of end stage renal disease at age 52 years. Exome sequencing of the proband revealed an extremely rare missense heterozygous variant c.1711_1712CG>TC; p.(Arg571Ser) in LMNA which was confirmed by Sanger sequencing in both the patients. Interestingly, the mutation had no effect on mRNA splicing or relative expression of lamin A or C mRNA and protein in the lymphoblasts. Our observations suggest that mutant lamin C disrupts its interaction with other cellular proteins resulting in generalized lipodystrophy due to defective development and maintenance of adipose tissue.

Congenital generalized lipodystrophy (CGL) is a heterogeneous autosomal recessive disorder characterized by a near complete lack of adipose tissue from birth and, later in life, the development of metabolic complications, such as diabetes mellitus, hypertriglyceridaemia and hepatic steatosis. Four distinct subtypes of CGL exist: type 1 is associated with AGPAT2 mutations; type 2 is associated with BSCL2 mutations; type 3 is associated with CAV1 mutations; and type 4 is associated with PTRF mutations. The products of these genes have crucial roles in phospholipid and triglyceride synthesis, as well as in the formation of lipid droplets and caveolae within adipocytes. The predominant cause of metabolic complications in CGL is excess triglyceride accumulation in the liver and skeletal muscle owing to the inability to store triglycerides in adipose tissue. Profound hypoleptinaemia further exacerbates metabolic derangements by inducing a voracious appetite. Patients require psychological support, a low-fat diet, increased physical activity and cosmetic surgery. Aside from conventional therapy for hyperlipidaemia and diabetes mellitus, metreleptin replacement therapy can dramatically improve metabolic complications in patients with CGL. In this Review, we discuss the molecular genetic basis of CGL, the pathogenesis of the disease's metabolic complications and therapeutic options for patients with CGL.

Background The ongoing H1N1 influenza pandemic has created a significant amount of health concern. Adequate dissemination of correct information about H1N1 influenza could help in decreasing the disease spread and associated anxiety in the population. Purpose This study aims to examine the effective use of the popular Internet video site YouTube as an information source during the initial phase of the H1N1 outbreak. Methods YouTube was searched on June 26, 2009, using the keywords swine flu , H1N1 influenza , and influenza for videos uploaded in the past 3 months containing relevant information about the disease. The videos were classified as useful, misleading, or as news updates based on the kind of information contained. Total viewership, number of days since upload, total duration of videos, and source of upload were noted. Results A total of 142 videos had relevant information about H1N1 influenza. In all, 61.3% of videos had useful information about the disease, whereas 23% were misleading. Total viewership share of useful videos was 70.5%, whereas that of misleading videos was 17.5%, with no significant difference in viewership/day. The CDC contributed about 12% of the useful videos, with a significant viewership share of 47%. No significant differences were seen in viewership/day for useful videos based on the kind of information they contained. Conclusions YouTube has a substantial amount of useful information about H1N1 influenza. A source-based preference is seen among the viewers, and CDC-uploaded videos are being used in an increasing proportion as a source of authentic information about the disease.

We report a case of a 17-year-old girl with a history of congenital human immunodeficiency virus (HIV) infection and lipodystrophy secondary to highly active antiretroviral therapy (HAART). She developed severe worsening of preexisting hypertriglyceridemia after treatment with oral contraceptive pills (OCP) for polycystic ovary syndrome. Her hypertriglyceridemia improved upon OCP discontinuation. Although it is known that estrogen combined with progestins have a negative effect on triglycerides and high-density lipoprotein (HDL) cholesterol levels, to our knowledge the association of HAART-related lipodystrophy and severe hypertriglyceridemia after OCP use has not been reported in the literature. We recommend avoiding the use of OCPs in patients with lipodystrophy due to the increased risk of worsening hypertriglyceridemia.

Type I hyperlipoproteinemia (T1HLP) usually presents with extreme hypertriglyceridemia, recurrent episodes of acute pancreatitis, lipemia retinalis, and cutaneous eruptive xanthomas. We report a unique 10-year-old male of Indian origin who presented in neonatal period with transient obstructive jaundice and xanthomas in the pancreas and kidneys. Serum triglycerides stabilized with extremely low-fat diet although he subsequently developed pancreatic atrophy. Extreme hypertriglyceridemia failed to respond to treatment with fenofibrate, fish oil, and orlistat. Whole-exome sequencing of the parents and patient was performed. Copy number variation analysis revealed a large deletion in chromosome 8 containing the entire GPIHBP1, which was confirmed by Sanger sequencing to be 54,623 bp deletion. Review of the literature revealed a slightly higher maximum triglyceride levels in those with homozygous null vs missense mutations suggesting severe disease in those with nonfunctional vs dysfunctional GPIHBP1 protein. Visceral xanthomas and pancreatic atrophy can be part of the spectrum of clinical features in patients with T1HLP. We highlight the need to perform copy number variations analysis of whole-exome sequencing data for finding disease-causing variants. There is also an urgent need to develop novel targeted therapies for patients with T1HLP.

The association between primary hypothyroidism and precocious puberty secondary to ovarian hyperstimulation has been recognized for over a century. Here, we report the case of a 9-year-old girl with severe primary hypothyroidism, who presented with premature menarche, enlarged pituitary gland, enlarged ovaries with multiple cysts, and elevated prolactin and alpha-feto protein levels. Pituitary and ovarian radiology findings, and alpha-feto protein levels normalized a few weeks after hypothyroidism treatment was started. Reviewing the literature we found several reports of increased levels of tumor markers in girls with this association. Thyroid function tests should be always part of the evaluation of patients with precocious puberty especially if the bone age is delayed. Tumor markers and liver function tests may be abnormal in patients with severe hypothyroidism and improve soon after thyroid hormone replacement is started.

Introduction Tobacco consumption is a major source of mortality and morbidity in India. Prevalence of smokeless tobacco (ST) consumption in India is around 20%. Studies have shown increased prevalence of cardiovascular disease risk factors and an increased incidence of adverse cardiovascular events among the ST consumers. This is a cross-sectional study done to look into the association of exclusive smokeless tobacco consumption with hypertension, in an adult male rural population of north India. Methods All male residents of a village in north India above 15 years of age, who did not have any acute or chronic morbidity were included after taking an informed consent. Subjects were interviewed regarding their demographic profile, socioeconomic status and tobacco consuming habits. Current smokeless tobacco user was defined as one who has ever consumed tobacco orally in past 1 month. Blood pressure of the subjects was also recorded. Cut offs used for systolic and diastolic hypertension were 140 mm hg and 90 mm Hg respectively. Results 443 subjects were included in the study. Prevalence of exclusive ST users was 21% while 19.4% consumed both forms and 26.6% did not take any form of tobacco. Mean systolic and diastolic BP were significantly higher in exclusive ST users(systolic BP=139.2+17.4,diastolic BP = 86.8+11.5)as compared to the non users(systolic BP= 135.7+18.8 , diastolic BP= 82.6 +11.5; p value < 0.05). The prevalence of diastolic hypertension was significantly higher in exclusive ST users as compared to non users ( 40.9%, 22.9% ;p value = 0.01) . The OR for diastolic hypertension in male ST users was 2.3( 95% C.I. = 1.3-4.3). Prevalence of systolic hypertension was higher in exclusive ST users too though this was not statistically significant (43%,36.4%;p value = 0.39.). Conclusions ST consumption is associated with increased prevalence of high BP in the adult male rural population.This is an indicator of increased predisposition to major adverse cardiac events later in their life time. Prevention of ST consumption could be an important intervention in preventing the ongoing upswing in prevalence of chronic heart disease.