Biallelic ANGPT2 loss-of-function causes severe early-onset non-immune hydrops fetalis.

BACKGROUND: Hydrops fetalis, a pathological fluid accumulation in two or more body compartments, is aetiologically heterogeneous. We investigated a consanguineous family with recurrent pregnancy loss due to severe early-onset non-immune hydrops fetalis. METHODS AND RESULTS: Whole exome sequencing in four fetuses with hydrops fetalis revealed that they were homozygous for the angiopoietin-2 (ANGPT2) variant Chr8 (GRCh37/Hg19): 6385085T>C, NM_001147.2:c.557A>G. The substitution introduces a cryptic, exonic splice site predicted to result in loss of 10 nucleotides with subsequent shift in reading frame, leading to a premature stop codon. RNA analysis in the heterozygous parents demonstrated loss of detectable mutant allele, indicative of loss-of-function via nonsense-mediated mRNA decay. Serum ANGPT2 levels were reduced in the parents. In a pregnancy with a healthy, heterozygous child, transiently increased fetal nuchal translucency was noted. CONCLUSION: Pathogenic heterozygous ANGPT2 missense variants were recently shown to cause autosomal dominant primary lymphoedema. ANGPT2 is a ligand of the TIE1-TIE2 (tyrosine kinase with immunoglobulin-like and epidermal growth factor-like domains 1 and 2) pathway. It is critical to the formation and remodelling of blood and lymphatic vessels and is involved in vessel maintenance. ANGPT2 knockout mice die from generalised lymphatic dysfunction. We show here that a homozygous pathogenic variant causes loss-of-function and results in severe early-onset hydrops fetalis. This is the first report of an autosomal recessive ANGPT2-related disorder in humans.

Agreement between anatomical M-mode and tissue Doppler imaging in the assessment of fetal atrioventricular annular plane displacement in uncomplicated pregnancies: A prospective longitudinal study.

AIM: To evaluate the level of agreement between M-mode and pulsed-wave tissue Doppler imaging (PW-TDI) techniques in assessing fetal mitral annular plane systolic excursion (MAPSE), tricuspid annular plane systolic excursion (TAPSE) and septal annular plane systolic excursion (SAPSE) in a low-risk population. METHODS: This prospective longitudinal study included healthy fetuses assessed from 18 to 40 weeks of gestation. Tricuspid annular plane systolic excursion, MAPSE and SAPSE were measured using anatomical M-mode and PW-TDI. The agreement between the two diagnostic tests was assessed using Bland-Altman analysis. RESULTS: Fifty fetuses were included in the final analysis. Mean values of TASPE were higher than that of MAPSE. There was a progressive increase of TAPSE, MAPSE and SAPSE values with advancing gestation. For each parameter assessed, there was an overall good agreement between the measurements obtained with M-mode and PW-TDI techniques. However, the measurements made with M-mode were slightly higher than those obtained with PW-TDI (mean differences: 0.03, 0.05 and 0.03 cm for TAPSE, MAPSE and SAPSE, respectively). When stratifying the analyses by gestational age, the mean values of TAPSE, MAPSE and SAPSE measured with M-Mode were higher compared to those obtained with PW-TDI, although the mean differences between the two techniques tended to narrow with increasing gestation. Tricuspid annular plane systolic excursion, MAPSE and SAPSE measurements were all significantly, positively associated with gestational age (all P < 0.001). CONCLUSION: Fetal atrioventricular annular plane displacement can be assessed with M-mode technique, or with PW-TDI as the velocity-time integral of the myocardial systolic waveform. Atrioventricular annular plane displacement values obtained with M-mode technique are slightly higher than those obtained with PW-TDI.

Vitamin D status in Greenland is influenced by diet and ethnicity: a population-based survey in an Arctic society in transition.

Vitamin D status as measured by plasma 25-hydroxyvitamin D (25(OH)D) is important to human health. Circumpolar people rely on dietary sources and societal changes in the Arctic are having profound dietary effects. The objective of the present study was to determine plasma 25(OH)D status and factors important to plasma 25(OH)D in populations in Greenland. Inuit and non-Inuit aged 50-69 years in the capital in West Greenland (latitude 64°15'N) and in a major town and remote settlements in East Greenland (latitude 65°35'N) were surveyed. Supplement use and lifestyle factors were determined by questionnaires. Inuit food scores were computed from a FFQ of seven traditional Inuit and seven imported food items. 25(OH)D2 and 25(OH)D3 levels were measured in the plasma. We invited 1 % of the population of Greenland, and 95 % participated. 25(OH)D3 contributed 99·7 % of total plasma 25(OH)D. Non-Inuit had the lowest median plasma 25(OH)D of 41 (25th-75th percentile 23-53) nmol/l compared with 64 (25th-75th percentile 51-81) nmol/l in Inuit (P< 0·001). Plasma 25(OH)D was below 20 and 50 nmol/l in 13·8 and 60·1 % of participants, respectively, with Inuit food item scores below 40 % (P< 0·001), and in 0·2 and 25·0 % of participants, respectively, with higher scores (P< 0·001). The Inuit diet was an important determinant of plasma 25(OH)D (P< 0·001) and its effect was modified by ethnicity (P= 0·005). Seal (P= 0·005) and whale (P= 0·015) were major contributors to plasma 25(OH)D. In conclusion, a decrease in the intake of the traditional Inuit diet was associated with a decrease in plasma 25(OH)D levels, which may be influenced by ethnicity. The risk of plasma 25(OH)D deficiency in Arctic populations rises with the dietary transition of societies in Greenland. Vitamin D intake and plasma 25(OH)D status should be monitored.

Changes in iodine excretion in 50-69-y-old denizens of an Arctic society in transition and iodine excretion as a biomarker of the frequency of consumption of traditional Inuit foods.

BACKGROUND: Iodine intake in Greenland has been hypothesized to exceed 10 times the recommended amount. The transition from a traditional Arctic society may change the iodine intake, but no field studies have been performed. OBJECTIVE: We aimed to ascertain iodine intakes, factors affecting iodine intake in circumpolar populations, and the usefulness of urinary iodine excretion as a biomarker for validation of Inuit food-frequency questionnaires. DESIGN: Data were collected in a cohort study of 4 Greenland population groups: Inuit living in the capital city, the major town, and settlements in East Greenland and non-Inuit. Supplement use and lifestyle factors were evaluated with questionnaires, and dietary habits were ascertained with a food-frequency questionnaire. Iodine was measured in spot urine samples. RESULTS: One percent of the population of Greenland was invited, and the participation rate was 95%. Less than 5% of Inuit but 55% of non-Inuit had urinary iodine excretion < 50 microg/24 h. Median urinary iodine excretion declined with the degree of decrease in the traditional lifestyle: it was 198, 195, 147, and 58 microg/24 h among Inuit in settlements, town, and city and in non-Inuit, respectively (P < 0.001). Participants were divided into diet groups calculated from Inuit food frequency. Iodine excretion decreased with increasing intake of imported foods (P < 0.001). In regression models, type of diet and the subject's lifestyle, sex, weight, ethnicity, and intake of iodine-containing supplements affected urinary iodine excretion. CONCLUSIONS: Circumpolar non-Inuit are at risk of iodine deficiency. Departure from the traditional Inuit diet lowers iodine intake, which should be monitored in Arctic societies. Urinary iodine excretion may be a useful biomarker of traditional Inuit food frequency.

Iodine content of traditional Greenlandic food items and tap water in East and West Greenland.

OBJECTIVES: The iodine intake level is important for the occurrence of thyroid disorders in a population. The iodine intake in Greenland has been proposed to be more than ten times the recommended level. However, no measurements have been performed to determine the iodine content of Greenlandic food items, drinking water, and beverages available in East and West Greenland. STUDY DESIGN: Food samples were collected at the local market, kalaalimineerniarfik, in Nuuk and Ammassalik, and tap water was obtained from all towns in Greenland. Beverages were purchased at Kalaallit Niuerfiat KNI Pisiniarfik. RESULTS: Iodine content of seal, whale, wild fowl, reindeer, and musk ox varied between 4 and 195 microg/kg with low values for terrestrial animals (< 10 microg/kg) and higher values for marine animals (10-195 microg/kg). The iodine content of fish varied from 9 microg/kg in freshwater fish to 1,380 microg/kg in a sample of cod. The iodine content of sea mammals was: blubber 130 microg/kg; viscera 70 microg/kg; meat 21 microg/kg. No difference was observed between animals from East Greenland and West Greenland (P > 0.1). Iodine content of tap water was below 3.3 microg/l for all towns. Two sorts of beer had a high iodine content, up to 240 microg/l. The iodine content of all other beverages was 5-38 microg/l. CONCLUSIONS: We found a relatively high iodine content in marine animals but low iodine content in tap water and beverages in Greenland. The food and drinking water evaluated in the present study indicate adequate iodine intake in this area and do not support the notion that Greenland is an area of excessive iodine intake.

Levonorgestrel-impregnated Intrauterine device reduces occurrence of hyperplastic polyps: a population-based follow-up cohort study.

BACKGROUND: The main objective was to investigate if occurrence of hyperplastic polyps was reduced by use of the levonorgestrel-impregnated intrauterine system (LNG-IUS, Mirena®; Bayer) and if the LNG-IUS was more effective compared to oral medroxyprogesterone acetate (MPA) or observation-only. PATIENTS AND METHODS: Patients (N=59) with hyperplastic polyps were given LNG-IUS, 10 mg oral MPA taken 10 days per cycle, or had observation-only for six months. Diagnosis of histological specimens was performed by light microscopy according to the WHO classification and D-score prior to and after six months therapy. RESULTS: No polyps were found in women treated with LNG-IUS (18/18). Five women treated with cyclic MPA (5/20, 25%) and two (2/21, 9%) with observation had normal endometrium without polyps after six months. CONCLUSION: No former study has shown that LNG-IUS is effective at reducing the occurrence of hyperplastic endometrial polyps. The effect is superior to that of oral progestin and observation-only.

Thyroid hyperactivity with high thyroglobulin in serum despite sufficient iodine intake in chronic cold adaptation in an Arctic Inuit hunter population.

OBJECTIVE: Adult man hosts brown adipose tissue with the capacity to consume energy and dissipate heat. This is essential for non-shivering thermogenesis and its activation depends on sympathetic activity and thyroid hormones. This led us to evaluate the impact of chronic cold exposure on thyroid activity and thyroid hormones in serum in Arctic residents. DESIGN: Comparative, population-based study (n = 535) performed in Greenland. METHODS: Hunters were compared with other men, and Inuit in remote settlements in East Greenland with no modern housing facilities were compared with the residents of the capital city in West Greenland and residents of a major town in East Greenland in a cross-sectional study. We used interview-based questionnaires, measured TSH, free thyroxine, free triiodothyronine (fT(3)), thyroglobulin (TG) antibody and TG (a measure of thyroid activity) in serum, and iodine and creatinine in spot urine samples. RESULTS: Serum TG was the highest among hunters (P = 0.009) and settlement dwellers (P = 0.001), who were most markedly exposed to cold, even though they had the highest urinary iodine excretion (hunters, P < 0.001; settlement dwellers, P < 0.001). Hunters and settlement dwellers also had the lowest fT(3) (hunters, P < 0.001; settlement dwellers, P < 0.001) after adjusting for gender, age, smoking habits, alcohol intake and iodine excretion in multivariate linear regression models. TSH was not influenced by measures of cold exposure (hunter, P = 0.36; residence, P = 0.91). CONCLUSIONS: Cold exposure influenced thyroid hormones and TG in serum in Arctic populations consistent with consumption of thyroid hormone and higher thyroid hormone turnover. Findings emphasise that changes in thyroid activity are essential in cold adaptation in Arctic residents.

Benign course of long-standing hepatitis B virus infection among Greenland Inuit?

OBJECTIVE: Chronic hepatitis B virus (HBV) infection can present in different ways, from inactive carrier to liver failure or cancer. The role of the virus subtype is controversial. The purpose of this study was to characterize HBV infection in detail and its impact on general health, body-build and liver biochemistry. MATERIAL AND METHODS: The study comprised a population-based cohort of Inuit exposed to HBV 3-7 decades ago in the capital in West Greenland, a coastal town and four settlements in rural East Greenland. Participants included 95% of the invited Inuit: 229 men, 205 women, aged 50-69 years. RESULTS: Only 25% of the participants had never had HBV infection. HBsAg was positive in 86 participants (20.0%), more being found positive in rural East Greenland than in the city in West Greenland (28.9% versus 2.7%; p < 0.001). HBV-DNA was positive in 61 of those with median HBV-DNA 40,000 copies/ml. HBV genotype could be determined in 52: 47 participants had genotype B, 4 genotype D, and 1 had both B and D. At sequencing, genotype B resembled subtype Bj, but with more than 5% diversity in the C-gene it could be a new subtype B. Pre-core mutation was found in 55 of 56 participants investigated. None of the participants had signs of liver disease, and HBV infection did not influence body-build or liver biochemistry. CONCLUSIONS: More than 75% of participants had a marker of present or previous HBV infection but the infection seemed dormant. The majority harbored a special variant of genotype B that might be a new subtype giving a relatively benign disease. The role of detailed subtyping of HBV for prognostic evaluation should be investigated in more detail.