Hereditary hemorrhagic telangiectasia (HHT, Osler–Weber–Rendu disease) is an autosomal dominant inherited disease defined by the presence of epistaxis and mucocutaneous telangiectasias and arteriovenous malformations (AVMs) in internal organs. In most families (∼85%), HHT is caused by mutations in the ENG (HHT1) or the ACVRL1 (HHT2) genes. Here, we report the results of genetic testing of 113 Norwegian families with suspected or definite HHT. Variants in ENG and ACVRL1 were found in 105 families (42 ENG, 63 ACVRL1), including six novel variants of uncertain pathogenic significance. Mutation types were similar to previous reports with more missense variants in ACVRL1 and more nonsense, frameshift and splice‐site mutations in ENG. Thirty‐two variants were novel in this study. The preponderance of ACVRL1 mutations was due to founder mutations, specifically, c.830C>A (p.Thr277Lys), which was found in 24 families from the same geographical area of Norway. We discuss the importance of founder mutations and present a thorough evaluation of missense and splice‐site variants.

The serotonin transporter gene (5-HTT) possesses a functional promoter-region polymorphism, which is associated with temperament and personality traits, e.g. anxiety. In post-traumatic stress syndrome an additive gene-environmental interaction between the high expression allele of 5-HTT and frequent or repeating trauma is described. The aim of the present study was to examine the association between 5-HTT polymorphism and development of psychological distress shortly after detection of fetal anomaly. A prospective, observational study was performed at a tertiary referral center for fetal medicine. Pregnant women (n = 144) after gestational age 12 weeks were included within a week of the sonographic detection of a fetal structural anomaly. Psychological distress was assessed using the Impact of Events Scale (IES-22) (intrusion, avoidance, and arousal), Edinburgh Postnatal Depression Scale (EPDS) and the anxiety and depression subscales of the General Health Questionnaire (GHQ-28). Social dysfunction and health perception were assessed by the corresponding subscales of the GHQ-28. Fetal anomalies were classified according to severity and diagnostic or prognostic ambiguity at the time of assessment. The short (S) and long (L) polymorphisms of 5-HTT were genotyped (LL, SL, or SS). The length of the 5-HTT did not significantly influence the psychological distress (two-way ANOVA). The mean value of the GHQ subscale depression in women with 5-HTT LL, SL or SS was 1.3, 2.5 and 3.0, respectively (P = 0.069). The severity, and the ambiguity, of the prognosis or diagnosis were the significant explanatory variables. Numerically, but not statistically, the length of the 5-HTT gene is associated with psychological reaction shortly after detection of fetal structural anomaly by ultrasound.

We report on a family with three stillborn males, three affected males who were small for gestational age and died within 8 months, and one male who died at age 5 years. This boy had cone-shaped teeth and oligoodontia. He had serious bacterial infections and inflammatory bowel disease. Mutations in the NF-kappaB essential modulator (NEMO) gene have recently been shown to be the cause of a group of ectodermal dysplasia and immunodeficiency disorders (EDA-ID). Analysis of the NEMO gene revealed a nucleotide change in the consensus sequence of the splicing donor site of exon 6 IVS6 + 5G --> A(1027 + 5G --> A), which has not previously been described in EDA-ID. RT-PCR analysis of fibroblast RNA from an aborted affected male fetus demonstrated a skipping of exons 4, 5, and 6 which resulted in a truncated protein of about 35 kDa revealed by NEMO antibody. The skipping of exons 4, 5, and 6 did not affect the ORF of the C-terminal of NEMO encoded by exons 7, 8, 9, and 10, which contains a coiled-coil motif (CC2), a leucin-zipper (LZ), and a zinc finger motif (ZF) sub-domains of NEMO. IkappaBalpha degradation was strongly impaired in the fetal fibroblasts, suggesting an impaired NF-kappaB signaling. One healthy carrier had a completely skewed X-inactivation pattern with the normal X active, whereas the two other carriers had a random X-inactivation pattern. This family may represent a new phenotype within the EDA-ID disorders. From the heterogeneity in X-inactivation phenotype, we conclude that this mutation is not deleterious enough to be lethal for peripheral blood cells.

Lymphedema-cholestasis syndrome (LCS, Aagenaes syndrome) is the only known form of hereditary lymphedema associated with cholestasis. A locus, LCS1, has recently been mapped to chromosome 15q in a Norwegian kindred. In a consanguine Serbian Romani family with a neonate who had a combination of lymphedema and cholestasis with features atypical for Norwegian LCS, haplotype and linkage analysis of markers spanning the LCS1 region argue that a second LCS locus may exist. The infant may represent an instance of a previously undescribed lymphedema-cholestasis syndrome.

The purpose of this study was to develop a paranasal sinus CT scoring system that could be used as a diagnostic tool to discriminate cystic fibrosis (CF) patients from control patients examined for sinonasal disease. The model should include as few and easily applicable criteria as possible, supported by statistical analyses and clinical judgement. We used data from 116 CF and 136 control patients. The CF patients were grouped according to the number of confirmed CF mutations: genetically verified (CF-2), or based on sweat testing and clinical findings alone (CF-1, CF-0). Nine paranasal sinus CT criteria, including development, pneumatisation variants and inflammatory patterns, were evaluated. The final model included three criteria: (a) frontal and (b) sphenoid sinus development, and (c) absence of three pneumatisation variants. This model discriminated CF-2 from controls with overlap of summed scores in only 8 of 206 patients. When this model was applied in the CF-1 and CF-0 groups, two populations seemed to exist. A larger group with summed scores overlapping that of the CF-2 group and a smaller group with summed scores overlapping that of the control group. We conclude that this CT scoring system may support, as well as exclude, a CF diagnosis in cases of diagnostic uncertainty.

PURPOSE:To describe variations of paranasal sinus development in patients with cystic fibrosis (CF) and in non-CF patients examined for inflammatory sinonasal disease. We focused on anatomic variants that predispose to orbital and cerebral penetration during functional endoscopic sinus surgery (FESS), e.g. hypoplasia of the maxillary sinus and low ethmoid roof.MATERIAL AND METHODS:One hundred and sixteen CF patients (3-54 years, median 18) and 136 control patients (7-51 years, median 31) were examined with coronal CT of the paranasal sinuses. CF patients were grouped according to number of confirmed mutations: CF-2 (n=70), CF-1 (n=32), CF-0 (n=14). CT images were evaluated with respect to paranasal sinus development, pneumatization variants and bony variants.RESULTS:Frontal sinus aplasia and maxillary, ethmoid, and sphenoid sinus hypoplasia were markedly more frequent in CF-2 than in control patients. No CF-2 patient had pneumatization variants such as Haller cells or concha bullosa. Low ethmoid roof was seen in 30% of CF-2 children, but in no control children. CF-1 and CF-0 groups had prevalences of aplasia and hypoplasia intermediate to that of CF-2 and control patients.CONCLUSION:Genetically verified CF patients had less developed sinuses, lacked pneumatization variants, and more often had anatomic variants that predispose to complications during FESS. Normally developed sinuses and pneumatization variants in some genetically unverified CF patients (CF-1, CF-0) suggest that these patients may be erroneously diagnosed.

Patients with cholestasis-lymphedema syndrome (CLS) suffer severe neonatal cholestasis that usually lessens during early childhood and becomes episodic; they also develop chronic severe lymphedema. The genetic cause of CLS is unknown. We performed a genome screen, using DNA from eight Norwegian patients with CLS and from seven unaffected relatives, all from an extended pedigree. Regions potentially shared identical by descent in patients were further characterized in a larger set of Norwegian patients. The patients manifest extensive allele and haplotype sharing over the 6.6-cM D15S979-D15S652 region: 30 (83.3%) of 36 chromosomes of affected individuals carry a six-marker haplotype not found on any of the 32 nontransmitted parental chromosomes. All Norwegian patients with CLS are likely homozygous for the same disease mutation, inherited from a shared ancestor.

Purpose: To measure and compare the size of the sphenoid sinuses in patients with cystic fibrosis (CF) to patients with inflammatory sinonasal disease, and to correlate the size with number of CF mutations in each patient. Material and Methods: Ninety-six CF patients aged 5–47 years (median 19 years) and 130 control patients aged 7–51 years (median 32 years) were examined using coronal CT of the paranasal sinuses. In each patient, the CT image with the largest coronal area of the sphenoid sinuses was scanned into a Macintosh computer with image processing and analysis software. Largest coronal area and largest circumference of the right and left sphenoid sinuses were automatically measured. Additionally, antero-posterior extension of the sphenoid sinuses was calculated from the lateral scanograms. CF patients were grouped according to number of confirmed mutations (CF-0, CF-1, or CF-2). Results: CF patients generally had small sphenoid sinuses. the largest differences for all parameters were observed between the CF-2 and the control groups (p<0.0001). No CF-2 patient had pneumatization beyond the presphenoid. the CF-0 and CF-1 groups consisted of two populations, one overlapping the CF-2 group and another overlapping the control group. Conclusion: Hypoplasia of the sphenoid sinuses is a characteristic finding in CF patients. When pneumatization of the basisphenoid is present, the existing CF diagnosis should be questioned.

The geographic distribution of 272 cystic fibrosis (CF) mutations has been studied by assessing the origin of 27,177 CF chromosomes from 29 European countries and three countries from the North of Africa. The most common mutations are delta F308 (66.8%), G542X (2.6%), N1303K (1.6%), G551D (1.5%) and W1282X (1.0%). The delta F508 mutation has the highest frequency in Denmark (87.2%) and the lowest in Algeria (26.3%). Mutation G542X is common in the Mediterranean countries, with a mean frequency of 6.1%. N1303K is found in most of the western and Mediterranean countries and has the highest frequency in Tunisia (17.2%). The wide distribution of these mutations suggests an ancient origin. G551D is common in north-west and central Europe, but is uncommon in other parts of Europe. W1282X has the highest frequency in Israel (36.2%), being also common in most Mediterranean countries and north Africa. Seventeen mutation have frequencies between 0.1 and 0.9%, 1717-1G-->A (0.83%), R553X (0.75%), R1162X (0.51%), 621 + 1G-->T (0.54%) and 2183AA-->G (0.36%), being the most common ones. Some mutations reach relatively high frequencies in some extended geographic regions, such as mutation 394delTT in northern Europe (1.1-28.8%), R117H in northwestern Europe (1.3-3.0%), R553X in central Europe (1.1-24.4%), 1717-1G-->A in Belgium and France (1.1-5.3%), and 2183AA-->G in Italy and Greece (3.2%). Other mutations are only common in small regions: T338I (Sardinia), 711 + 1G-->T (Tunisia), R1162X (Algeria and north of Italy), 1609delCA (east of Spain), 1811 + 1.6kbA-->G (southeastern Spain), R1066C (Portugal), S549R (Algeria), R334W (Crete), 621 + 1G-->T (Central Greece), 3849 + 10kbC-->T (Israel), 2789 + 5G-->A (south of Greece), 451 + 1G--A (Israel), R347P (south of Bulgaria), 1677delTA (south of Bulgaria and Turkey), G85E (south of Greece), R347H (Turkey), 3905insT (Switzerland), 1078delT (Brittany), 1898 + 1G-->A (Wales), A455E (The Netherlands), delta I507 (Brittany), 3659delC (Sweden) and R560T (northern Ireland). Most of these mutations must have an origin and diffusion in the specific European population subgroup. Overall 55 mutations are common in one or several countries or regions of Europe and 217 mutations are rare with relative frequencies of lower than 1% in any of these regions and countries. This information might facilitate mutation analysis of CF in the different regions of Europe.

A new X-linked recessive deafness syndrome was recently reported and mapped to Xq22 (Mohr-Tranebjærg syndrome). In addition to deafness, the patients had visual impairment, dystonia, fractures, and mental deterioration. The female carriers did not have any significant manifestations of the syndrome. We examined X chromosome inactivation in 8 obligate and 12 possible carriers by using a polymerase chain reaction analysis of the methylation-dependent amplification of the polymorphic triplet repeat at the androgen receptor locus. Seven of 8 obligate carriers and 1 of 5 carriers by linkage analysis had an extremely skewed pattern in blood DNA not found in 30 normal females. The X inactivation pattern in fibroblast DNA from 2 of the carriers with the extremely skewed pattern was also skewed but to a lesser degree than in blood DNA. One obligate carrier had a random X inactivation pattern in both blood and fibroblast DNA. A selection mechanism for the skewed pattern is therefore not likely. The extremely skewed X inactivation in 8 females of 3 generations in this family may be caused by a single gene that influences skewing of X chromosome inactivation. © 1996 Wiley-Liss, Inc.

Wiedemann-Beckwith syndrome (WBS) is a syndrome including exomphalos, macroglossia, and generalized overgrowth. The locus has been assigned to 11p15.5, and genomic imprinting may play a part in the expression of one or more genes involved. Most cases are sporadic. An excess of female monozygotic twins discordant for WBS have been reported, and it has been proposed that this excess could be related to the process of X chromosome inactivation. We have therefore studied X chromosome inactivation in 13-year-old monozygotic twin girls who were discordant for WBS. In addition, both twins had Tourette syndrome. The twins were monochorionic and therefore the result of a late twinning process. This has also been the case in previously reported discordant twin pairs with information on placentation. X chromosome inactivation was determined in DNA from peripheral blood cells by PCR analysis at the androgen receptor locus. The affected twin had a completely skewed X inactivation, where the paternal allele was on the active X chromosome in all cells. The unaffected twin had a moderately skewed X inactivation in the same direction, whereas the mother had a random pattern. Further studies are necessary to establish a possible association between the expression of WBS and X chromosome inactivation.

In a systematic screening for mutations in the gene encoding the cystic fibrosis transmembrane regulator among Danish cystic fibrosis (CF) patients, we identified a mutation in exon 3 (394delTT); this mutation was found to be relatively common in Denmark. We therefore screened for 394delTT in Sweden and Norway, where it turned out to be the second most frequent mutation, accounting for 4% of all CF mutations. It also occurs with a high frequency in Finland, but has not been found in larger surveys of mutations in the CFTR gene. Thus, 394delTT seems to be a specific Nordic CF mutation.

We have searched for the delta F508 mutation in 77 Norwegian cystic fibrosis patients. Of the 154 chromosomes tested, 93 (60%) carried the delta F508 mutation. Haplotypes at the D7S23 locus (KM19 and XV2C markers) were determined. Of 81 chromosomes with the F508 mutation, the B haplotype was found on 77. We found three patients with the G551D and one patient with the R553X mutation in exon 11 of the CFTR locus.