Clinical presentations of 23 half-siblings from a mosaic neurofibromatosis type 1 sperm donor.

The Danish sperm donor number 7042 has fathered several offspring with neurofibromatosis type 1 (NF1) worldwide. NF1 is caused by loss-of-function mutations in the NF1 gene and more than 1000 NF1 mutations are identified. Analysis of the donor sperm demonstrated gonosomal mosaicism with an intragenic deletion involving exons 15-29 in the NF1 gene. At the two Danish reference centres for NF1 patients, we evaluated 23 half-siblings from the donor. Nine were diagnosed with NF1. The severity grade of NF1 progressed from minimal to mild/moderate within 3 years of follow-up. The NF1 phenotype shows great variability in intra- and inter-family expressivity and to date only two NF1 genotype-phenotype correlations have been established. This rare possibility of a long-term follow-up of a cohort of half-siblings with NF1 makes further studies including phenotypic variability and search for modifier genes possible. To achieve this goal, we have initiated The International Donor 7042 NF1 Offspring Registry. Research facilitated via this registry may reveal important new knowledge of clinical characteristics and prognostics for the specific NF1 genotype and thereby contribute to future individualised targeted clinical follow-up and treatment.

The efficacy and safety of long-term Norditropin® treatment in children with Prader-Willi syndrome.

Prader-Willi syndrome is a genetic disorder that is associated with short stature, partial growth hormone deficiency, small hands and feet, learning and behavioural problems, and hyperphagia leading to severe, often morbid, obesity. Growth hormone therapy is associated with an improvement in height and body composition. We evaluated the efficacy and safety of long-term growth hormone treatment in a retrospective observational multinational study of 41 prepubertal children (mean age 3.8±3.0 years) with genetically diagnosed Prader-Willi syndrome treated with growth hormone (0.03-0.06 mg/kg/day) for >12 months [mean duration 4.1 (range 0.9-9.5) years]. Height, weight, and body composition measurements were recorded at baseline and at 6 month intervals until last observation. Mean (SD) gain in height at 12 months was 0.9 (0.2) SD score (p<0.0001). At last observation (after approximately 6 years) mean gain in height was 1.3 (0.3) (p=0.0001) with 85% of children achieving height>- 2 SD score. Body composition improved during treatment with an estimated 9.1% increase in lean body mass and 9.1% decrease in fat mass at last observation (p=0.019). Scoliosis was reported in 3 patients at baseline and 8 patients at last observation. Sleep apnoea was recorded in 3 (7.3%) patients. There were no other severe adverse events reported. Long-term growth hormone treatment of prepubertal children with Prader-Willi syndrome was associated with significant improvements in height and body composition. Treatment was well tolerated. The development of scoliosis warrants monitoring by an orthopaedic specialist.

Two years of growth hormone treatment in adults with Prader-Willi syndrome do not improve the low BMD.

BACKGROUND: Bone mineral density (BMD) in adult patients with Prader-Willi syndrome (PWS) might be low due to high bone turnover. OBJECTIVES: The objective of the study was to investigate bone mass in a group of adult PWS subjects and study the effects of GH treatment on BMD and markers of bone turnover. DESIGN: Forty-six adults with genetically verified PWS were randomized to GH or placebo for 12 months, followed by open prospective GH for 24 additional months. BMD at the lumbar spine (LS) L1-4, the total hip, and the total body was assessed by dual-energy x-ray absorptiometry at baseline and every 12th month thereafter. Markers of bone turnover were measured at baseline and at the end of the controlled study. RESULTS: In this cohort of adult subjects with PWS, baseline BMD was reduced in all compartments compared with the reference (Z-scores). Men had lower Z-scores BMD than women in LS and total body (P < .05). With 12 months of GH, LS-BMD was significantly reduced compared with placebo. No changes in BMD were observed with continuous GH treatment for 24 months. The bone formation markers increased with GH therapy compared with placebo, whereas the resorption marker did not change. CONCLUSIONS: Adult PWS subjects, especially the men, have low bone mass that was not improved with GH treatment for 2 years. Because PWS subjects are short, BMD might be underestimated and should be adjusted for. Further studies, with adequate GH and sex hormone replacement throughout puberty and early adult life, are needed to better characterize PWS.

Phenotype in 18 Danish subjects with genetically verified CHARGE syndrome.

CHARGE (coloboma of the eye, heart defects, choanal atresia, retarded growth and development, genital hypoplasia and ear anomalies and/or hearing loss) syndrome is a rare genetic, multiple-malformation syndrome. About 80% of patients with a clinical diagnose, have a mutation or a deletion in the gene encoding chromodomain helicase DNA-binding protein 7 (CHD7). Genotype-phenotype correlation is only partly known. In this nationwide study, phenotypic characteristics of 18 Danish CHD7 mutation positive CHARGE individuals (N = 18) are presented. We studied patient records, clinical photographs, computed tomography, and magnetic resonance imaging (MRI). Information was not available for all traits in all subjects. Therefore, the results are presented as fractions. The following prevalence of cardinal symptoms were found: coloboma, 16/17; heart defects, 14/18; choanal atresia, 7/17; retarded growth and development, 11/13; genital abnormalities, 5/18; ear anomalies, 15/17 and sensorineural hearing loss, 14/15. Vestibular dysfunction (10/13) and swallowing problems (12/15) were other frequent cranial nerve dysfunctions. Three-dimensional reconstructions of MRI scans showed temporal bone abnormalities in >85%. CHARGE syndrome present a broad phenotypic spectrum, although some clinical features are more frequently occurring than others. Here, we suggest that genetic testing for CHD7 mutation should be considered in neonates with a specific combination of several clinical symptoms.

Skin signs in Ehlers-Danlos syndrome: clinical tests and para-clinical methods.

OBJECTIVE: The criteria for Ehlers-Danlos syndrome (EDS) and the hypermobility syndrome (HMS) should be reliable. Examination for general joint hypermobility has high reliability but there is only sparse information on the reliability of skin tests, and no information on the level of normal skin extensibility. The present study aimed to assess skin signs by means of clinical and para-clinical methods. METHODS: A total of 31 EDS patients and 28 healthy controls were examined blinded and in random order. Inter-examiner analysis of clinical tests for skin extensibility, consistency, scarring, and bruising was performed, followed by analyses of extensibility with the suction cup (SC), consistency with a soft tissue stiffness meter (STSM), and thickness with ultrasonography (US). Semi-quantitative assessment of skin extensibility in healthy controls was incorporated in the tests. RESULTS: The clinical analyses demonstrated kappa values of: 0.72 for extensibility, 0.23 for consistency, 0.53 for scarring, and 0.63 for bruising. Skin extensibility measurements in healthy controls (n = 28) were 2.79 and 2.93 cm (mean + 2 SD), respectively, by the two examiners. There were significant differences between patients with classical-type EDS and controls with respect to skin extensibility by SC (4.91 vs. 12.52 kPa/mm) and skin consistency by STSM (0.59 vs. 0.76 N). We found no difference in skin thickness. CONCLUSION: The reproducibility of the clinical skin tests was substantial to good, apart from the consistency measurements. We suggest that skin consistency is withdrawn as a diagnostic criterion. The upper level for normal skin extensibility should be 3 cm. SC and STSM are promising para-clinical methods, but their diagnostic sensitivity and specificity need to be determined.

Occurrence of trichomoniasis in women in Denmark, 1967-1997.

BACKGROUND: The Neisseria Unit at Statens Serum Institut (SSI), Copenhagen, Denmark administers laboratory surveillance systems for gonorrhea and chlamydia, however, no similar system has been available for trichomoniasis. OBJECTIVES: To describe changes in the occurrence of trichomoniasis in women and in the distribution according to age, and to compare these changes with those observed in women with gonorrhea or chlamydia. STUDY DESIGN: Data on the epidemiology of trichomoniasis were based on the annual laboratory records at the Neisseria Unit at SSI. Data on gonorrhea (1967-1997) and chlamydia (1994-1997) originated from the National Laboratory Surveillance Systems. RESULTS: During the period 1967 to 1997, the percentage of Trichomonas vaginalis-positive specimens showed a constant decrease from 19 to fewer than 2. The annual number of specimens received varied between a maximum of 31,626 in 1975 and a minimum of 3,291 in 1997. The median age of women with trichomoniasis increased from 31 to 39 years as compared with a change from 21 to 24 years in women with gonorrhea (1967-1997) and a median age of 22 years in women with chlamydia (1994-1997). CONCLUSIONS: A significant decline in the occurrence of trichomoniasis in women concurrent with a significant rise in the median age of women with the disorder was observed. During the periods investigated, women with trichomoniasis were significantly older than women with gonorrhea or chlamydia.

Failure to detect Chlamydia pneumoniae in calcific and degenerative arteriosclerotic aortic valves excised during open heart surgery.

Chlamydia pneumoniae has been associated with atherosclerosis, although no causal association has been established. Employing culture and polymerase chain reaction in aortic valves with calcific and degenerative arteriosclerotic changes from 23 non-consecutive patients undergoing aortic valve replacement, C. pneumoniae was not detected in any of the valves. 19/22 patients had serological evidence of past infection with C. pneumoniae. Our findings do not provide supportive evidence for the hypothesis that C. pneumoniae is associated with calcific or degenerative arteriosclerotic aortic heart valve disease.

Nasopharyngeal bacteria found on blood agar plates from healthy children in Greenland.

We have systematically studied the aerobic nasopharyngeal bacteria isolated from swabs by unselective subculturing on 5% horse blood agar and chocolate agar in 70 healthy children aged 0-1, 3-5 and 8 years in Nuuk and Sisimiut, Greenland. The purpose was to provide a basis for a better understanding of the infectious pathology and blind antibiotic treatment against potential pathogens thereby improving standard antimicrobial treatment of upper respiratory tract infections (URTI) and otitis media (OM) among children in Greenland. The study serves also as a baseline for future microbiological and immunological research projects. The children were clinically examined for any infectious diseases and a medical history was obtained which allowed for selection of children without a history of severe clinical infection. Nasopharyngeal swabs obtained via the oral route were instantly spread on 5% blood agar and chocolate agar culture plates and incubated aerobically. Subsequently, potentially pathogenic as well as non-pathogenic bacteria were identified by conventional methods. Healthy children in Greenland carry grossly the same aerobic bacterial flora as children in other parts of the world but potentially pathogenic bacteria were found in very high frequency (94%). Staphylococcus aureus, Streptococcus pneumoniae and Moraxella catarrhalis were found in higher frequencies in the youngest children. Haemophilus influenzae non-b was found in high frequencies in all age groups (67-76%). H. influenzae type b was carried by 11.4%. Group A streptococci were found more frequently in older children and in children from Sisimiut. Of M. catarrhalis strains 88% produced beta-lactamase. Neisseria meningitidis, Mycoplasma pneumoniae and chlamydiae were not detected at all. The high carrier frequency of potentially pathogenic bacteria in healthy children in Greenland may be related to the high frequency of URTI's and episodes of OM among children in Greenland.

Chlamydia pneumoniae in children with otitis media.

In this study the polymerase chain reaction was used to test for the presence of Chlamydia pneumoniae DNA in 118 middle-ear aspirates from 20 children with acute otitis media (AOM) and 53 children with otitis media with effusion (OME). C. pneumoniae was detected in 8 samples obtained from 5 children with OME and, together with Streptococcus pneumoniae, in a sample from 1 child with AOM. The mean age of these five children (6.6 +/- 1.4 years) was significantly higher than that of the 48 children with OME in whom C. pneumoniae could not be detected (4.3 +/- 1.9 years). The presence of C. pneumoniae in 9.4% of the examined children with OME suggests that C. pneumoniae might be a significant supplementary factor in the etiology of this common children's disease.

Microbiology of semen specimens from males attending a fertility clinic.

The relationship between semen quality, pyospermia and bacteriology was studied in 201 semen specimens from male patients attending a fertility clinic. Semen quality parameters were within normal limits in 115 (57%) patients, slightly reduced in 60 (30%), and 26 (13%) had findings indicating reduced fertility. Twelve patients (6%) had pyospermia. In 182 patients, 552 microorganisms were detected, including Enterobacteriaceae (2.8%), Gardnerella vaginalis (9.6%), Chlamydia trachomatis (1.6%), Mycoplasma genitalium (0.9%), and Ureaplasma urealyticum (11.8%). Semen quality was neither related to occurrence of microorganisms nor pyospermia. However, pyospermia was associated with simultaneous growth of Gardnerella vaginalis and Ureaplasma urealyticum. The exact nature of this association could not be ascertained, in as far as the males were not questioned about urethritis symptoms.

High rate of nasopharyngeal carriage of potential pathogens among children in Greenland: results of a clinical survey of middle-ear disease.

Nasopharyngeal and middle-ear colonization with bacteria and viruses, including Mycoplasma pneumoniae and chlamydiae, was investigated in a survey of 54 children with acute otitis media (AOM) and 201 control children without AOM in Greenland. In total, 98% with AOM and 91% without AOM carried potentially pathogenic bacteria in the nasopharynx. Two or more potentially pathogenic species were carried by 78% with AOM and 57% without AOM. Haemophilus influenzae was found in 92% and 77%, respectively, but only Streptococcus pneumoniae was found significantly more often in the nasopharynx of children with AOM than in age-matched controls (P < .03). The two species were found in 22 of 24 ear-discharge specimens. Nine children (three with AOM) had chlamydiae in the nasopharynx, and seven of them reported rhinitis. Enteroviruses or rhinoviruses were detected in 23 nasopharyngeal specimens from 39 children with AOM, in 13 such specimens from 39 children without AOM (P = .040), and in 4 of 14 ear-discharge specimens. The potentially pathogenic load in the nasopharynx was massive, suggesting an association with the high prevalence of otitis media among children in Greenland.

[Familial occurrence of Chlamydia pneumoniae infection]. / Familiaer forekomst af Chlamydia pneumoniae-infektion.

The clinical courses of six patients involved in a family outbreak of Chlamydia pneumoniae respiratory tract infection are described. The diagnosis was established by use of culture, polymerase chain reaction and determination of species specific antibodies. The patients had mild influenza-like symptoms with sore throat, occluded eustachian tubes and long-lasting cough. All patients received recommended antibiotic treatment regimens. Two out of the six patients needed further antibiotic treatment to obtain clinical and microbiological cure.

Menopausal age and sex hormones in postmenopausal women with alcoholic and non-alcoholic liver disease.

In order to evaluate age at menopause and serum sex hormone profiles in postmenopausal women with stable chronic liver disease, six non-cirrhotic alcoholics, 13 with alcoholic cirrhosis, eight with non-alcoholic cirrhosis, and 46 healthy controls were studied. In all three groups, patients were significantly (p less than 0.05) younger at the time of natural menopause than controls. Compared to controls, non-cirrhotic alcoholic women had significantly (p less than 0.05) reduced levels of DHAS, significantly (p less than 0.05) more alcoholic cirrhotic women had detectable oestradiol concentrations, elevated concentrations of oestrone and sex hormone binding globulin (SHBG) and reduced levels of 5 alpha-dihydrotestosterone (DHT), while women with non-alcoholic cirrhosis had significantly elevated concentrations of SHBG and reduced levels of oestrone sulphate, DHT, androstenedione and dehydroepiandrosterone sulphate (DHAS) (p less than 0.05). The observed changes may be a consequence of liver disease since similar changes were observed in patients with alcoholic and non-alcoholic liver disease, but an additional effect of alcohol cannot be excluded.

Sex hormones in postmenopausal women with primary biliary cirrhosis.

To evaluate serum sex hormone profiles in nonalcoholic postmenopausal women with liver disease, 25 women with primary biliary cirrhosis (11 in cirrhotic stage) and 46 healthy controls were studied. The patients had significantly (p less than 0.05) elevated serum concentrations of estrone and androstenedione and significantly (p less than 0.05) lower concentrations of estrone sulfate, dehydroepiandrosterone sulfate and 5 alpha-dihydrotestosterone compared with the 46 controls. Serum concentrations of sex hormone binding globulin, testosterone, non-sex hormone binding globulin-bound testosterone and non-protein-bound testosterone did not differ significantly (p greater than 0.05) between primary biliary cirrhosis patients and controls. Patients in the cirrhotic stage had significantly (p less than 0.05) higher concentrations of sex hormone binding globulin than did controls. Patients in the cirrhotic stage had significantly (p less than 0.05) higher sex hormone binding globulin and estrone sulfate levels compared with noncirrhotic patients with primary biliary cirrhosis. Otherwise, no significant differences were observed between cirrhotic and noncirrhotic patients. The observed changes in steroid concentrations may be a consequence of hepatic dysfunction.

An international study of the relationship between alcohol consumption and postmenopausal estradiol levels.

Because of the beneficial effect of estrogens on the risk of cardiovascular disease and osteoporosis in postmenopausal women, the factors which influence endogenous postmenopausal estrogen levels are of substantial importance. The major source of postmenopausal estrogen is the aromatization of androgens to estrogens. Because alcohol is reported to increase aromatization rates, the relationship between serum estradiol and moderate alcohol consumption was examined in a group of 128 healthy Pittsburgh postmenopausal women, and a significant direct association was found. In order to address the generalizability of this finding, 3 comparable study populations of healthy postmenopausal women were recruited: 62 in Copenhagen, 34 in Lisbon and 20 in Madrid. Although no association was detected in the Madrid study sample, in both the Copenhagen and Lisbon study populations, not only were estradiol levels significantly increased in alcohol users as compared to abstainers, but also estradiol levels were significantly correlated with total weekly drinks consumed. Based on these findings in study samples of healthy postmenopausal women from Pittsburgh, Copenhagen and Lisbon, we conclude that the increase in estradiol levels seen with moderate alcoholic beverage consumption is not an isolated finding and speculate that moderate alcohol consumption by healthy postmenopausal women may have beneficial effects.