A mutation in the receptor binding site of GDF5 causes Mohr-Wriedt brachydactyly type A2.

BACKGROUND: Brachydactyly type A2 (OMIM 112600) is characterised by hypoplasia/aplasia of the second middle phalanx of the index finger and sometimes the little finger. BDA2 was first described by Mohr and Wriedt in a large Danish/Norwegian kindred and mutations in BMPR1B were recently demonstrated in two affected families. METHODS: We found and reviewed Mohr and Wriedt's original unpublished annotations, updated the family pedigree, and examined 37 family members clinically, and radiologically by constructing the metacarpo-phalangeal profile (MCPP) pattern in nine affected subjects. Molecular analyses included sequencing of BMPR1B, linkage analysis for STS markers flanking GDF5, sequencing of GDF5, confirmation of the mutation by a restriction enzyme assay, and localisation of the mutation inferred from the very recently reported GDF5 crystal structure, and by superimposing the GDF5 protein sequence onto the crystal structure of BMP2 bound to Bmpr1a. RESULTS: A short middle phalanx of the index finger was found in all affected individuals, but other fingers were occasionally involved. The fourth finger was characteristically spared. This distinguishes Mohr-Wriedt type BDA2 from BDA2 caused by mutations in BMPR1B. An MCPP analysis most efficiently detected mutation carrier status. We identified a missense mutation, c.1322T>C, causing substitution of a leucine with a proline at amino acid residue 441 within the active signalling domain of GDF5. The mutation was predicted to reside in the binding site for BMP type 1 receptors. CONCLUSION: GDF5 is a novel BDA2 causing gene. It is suggested that impaired activity of BMPR1B is the molecular mechanism responsible for the BDA2 phenotype.

Evidence for genetic heterogeneity in lymphedema-cholestasis syndrome.

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.

A correlative study of prenatal ultrasound and post-mortem findings in fetuses and infants with an abnormal karyotype.

OBJECTIVE: To compare ultrasound and post-mortem findings in 98 fetuses and infants with an abnormal karyotype. DESIGN: Criteria for inclusion were an ultrasound examination at the National Center for Fetal Medicine (NCFM), an abnormal karyotype, and an autopsy performed during the period 1985-94. RESULTS: Trisomy 18 and 21 were the two most common abnormal karyotypes. The highest number of congenital anomalies was observed in cases with trisomy 13 and 18; congenital heart defects (CHD) were most prevalent among fetuses with trisomy 18. In 80% of cases there was full agreement between the ultrasound and autopsy findings; in another 8% of cases there was nearly complete concordance. Thus, in 88% of cases, the main prenatal sonographic diagnosis was correct. In 6% major autopsy findings were not detected by ultrasound examination, in 1% none of the autopsy findings were detected by routine ultrasound and in 5% ultrasound findings were not verified at autopsy. Where the correlation was related to individual autosomal trisomies, structural anomalies were most often correctly diagnosed in fetuses with trisomy 13, with the main diagnosis correct in all cases; second in accuracy were the ultrasound diagnoses in fetuses with trisomy 21 with the main diagnosis correct in 96%; for trisomy 18 the concordance was less good, with the main diagnosis correct in 71%. CONCLUSION: The present comparison of sonographic diagnoses with post-mortem findings demonstrates good accordance between the two methods. It also demonstrates the importance of awareness of the anomalies known to occur with different aneuploidies.

Mapping of the locus for cholestasis-lymphedema syndrome (Aagenaes syndrome) to a 6.6-cM interval on chromosome 15q.

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.

Genetics of the Berardinelli-Seip syndrome (congenital generalized lipodystrophy) in Norway: epidemiology and gene mapping. Berardinelli-Seip Study Group.

Five of the six families with the Berardinelli-Seip syndrome in Norway cluster in six adjacent rural municipalities of south-western Norway. The six patients from this area were born between 1951 and 1973, none between 1974 and 1995. The absence of new cases may be explained by a decrease in the intraregion marriage rate and inbreeding. Genealogical investigations show that the mutation must have occurred at least 400 years ago. The sixth family was clinically different and geographically sporadic from a Finnish-descent rural East Norwegian population. A genetic linkage study of all six families revealed fresh crossovers versus the disease allele in nine DNA marker systems and the absence of recombination in three (maximum lod score + 1.3). None of the last showed allelic association. These families are included in an international effort to map the CLBS locus. The patients have been included in the homozygosity testing of totally 28 patients in an international collaborative study. The three patients, assumed identical in descent from both parents, were jointly homozygous in none of the 250 dinucleotide markers tested. A heterochromatic 9qh + segregated from one parent in two families.

Instability of lymphocyte chromosomes in a girl with Rothmund-Thomson syndrome.

Rothmund-Thomson syndrome is a rare autosomal recessive syndrome characterised by poikiloderma of the face and extremities, alopecia, short stature, and skeletal defects. We report a patient with the characteristic features of Rothmund-Thomson syndrome who also had lymphocyte chromosome abnormalities. She has a small flat face with short palpebral fissures and micrognathia together with severe skeletal abnormalities of the upper extremities with absence of both radii, short dysmorphic ulnae, a rudimentary right thumb, and aplasia of the left thumb. She also has anal atresia with a rectovaginal fistula. From the age of 3 months she developed poikiloderma skin changes on the face and extensor surfaces of the extremities. Mental development seems to be normal. Lymphocyte chromosomes in the neonatal period showed an unidentified marker chromosome in eight of a total of 32 cells. A repeat analysis at the age of 10 months showed three abnormal cells out of 100 analysed: 47,XX,-7,+i(7q),+7p, 46,XX,t(3;18)(p14.2;q22), and 49,XX,+del(3)(p11.2),+mar,+mar. A skin biopsy from an affected area showed poor growth and five of 48 cells analysed had structural abnormalities. The father had one of 48 cells with an additional marker chromosome and two cells with different 7;14 translocations. The abnormal chromosome complements in lymphocytes indicate that there may be in vivo chromosome instability in Rothmund-Thomson syndrome.

[Genetic disease in general practice. An interview study among general practitioners in Oppland and Oslo]. / Genetisk sykdom i allmennpraksis. En intervjuundersøkelse blant allmennpraktikere i Oppland og Oslo.

We interviewed 51 Norwegian general practitioners selected at random about their knowledge and practice of medical genetics. Of these doctors, 29 worked in Oslo and 22 in Oppland county. About 90% of the doctors working in Oslo knew where to refer patients for genetic counselling, while 55% of the doctors working in the area outside Oslo had this knowledge. We believe that this difference is because Oslo has a municipal genetic clinic and is the only area in Norway with an adequate genetic counselling service according to WHO standards. This article presents the results from this survey, and discusses genetic diseases in general practice and the organisation of medical genetic services in Norway.

Campomelic dysplasia--an underdiagnosed condition?

Campomelic dysplasia (CD) is a rare skeletal dysplasia. The incidence, reported in the literature, is 0.05-0.09 per 10,000 live births. During the period December 1985-December 1990 there were 18,350 live births with 4 cases of CD at Aker University Hospital in Oslo, Norway. This gives an incidence of CD in our observation period of 2.2 per 10,000. Eliminating our first case, because of Pakistani decent, the total incidence is 1.6 per 10,000 among Norwegian infants which is much higher than the incidence previously mentioned. Perhaps CD is under-reported and a high proportion of patients remain undiagnosed. We present four cases and discuss the incidence.

Rubinstein-Taybi syndrome caused by submicroscopic deletions within 16p13.3.

The Rubinstein-Taybi syndrome (RTS) is a well-defined complex of congenital malformations characterized by facial abnormalities, broad thumbs and big toes, and mental retardation. The breakpoint of two distinct reciprocal translocations occurring in patients with a clinical diagnosis of RTS was located to the same interval on chromosome 16, between the cosmids N2 and RT1, in band 16p13.3. By using two-color fluorescence in situ hybridization, the signal from RT1 was found to be missing from one chromosome 16 in 6 of 24 patients with RTS. The parents of five of these patients did not show a deletion of RT1, indicating a de novo rearrangement. RTS is caused by submicroscopic interstitial deletions within 16p13.3 in approximately 25% of the patients. The detection of microdeletions will allow the objective conformation of the clinical diagnosis in new patients and provides an excellent tool for the isolation of the gene causally related to the syndrome.

[Karyotyping of fetuses with developmental disorders. A 5-year material 1985-89]. / Karyotyping av fostre med utviklingsavvik. Et fem års materiale 1985-89.

During the period 1985 to 1989 foetal chromosomal analysis was performed in 121 of 318 pregnant women with foetal malformations detected by ultrasound. There were six failures. The percentage of foetuses karyotyped for developmental disorders increased from 13% in 1985 to 62% in 1989. An abnormal chromosomal pattern was found in 28 (24%) of the foetus. The pregnancy was terminated in 86% of cases with abnormal karyotype. The corresponding number in the group with normal chromosomes was 51%. The authors discuss the malformations leading to karyotyping, the methods used for karyotyping, the results of these tests and the consequences for the pregnancies.

Tentative assignment of a locus for Rubinstein-Taybi syndrome to 16p13.3 by a de novo reciprocal translocation, t(7;16)(q34;p13.3).

During a systematic chromosomal survey of 7 unrelated patients with Rubinstein-Taybi syndrome, an apparently balanced de novo reciprocal translocation, t(7;16)(q34;p13.3), was detected in an affected boy. The involvement of the region 16p13.3 coincides with the position of one of the breakpoints in another de novo reciprocal translocation associated with Rubinstein-Taybi syndrome, suggesting that a locus for this syndrome maps to 16p13.3.

[Prenatal ultrasonic diagnosis and Down's syndrome]. / Prenatal ultralyddiagnostikk og Downs syndrom.

A total of 8,923 children were born at the Regional Hospital, Trondheim, Norway between 1 January 1986 and 30 June 1989 to mothers from surrounding municipalities. Among these children, 14 were diagnosed after birth as having Down's syndrome. A proportion of 85% of the pregnant women in these municipalities had had a routine examination with ultrasound in the 16th to 22nd weeks of gestation at the Ultrasound Laboratory at the Regional Hospital. Ten of the children/fetuses with Down's syndrome in the study population had been subjected to a routine scan. Five of the ten were suspected to have Down's syndrome after the routine scan, and the diagnosis was confirmed by prenatal chromosomal analysis. (All these five fetuses were examined in 1987-88, which means that five of seven were detected in 1987-88). Another two fetuses (out of three) were suspected to have Down's syndrome after an ultrasound scan later in pregnancy. The diagnoses were confirmed by chromosome analyses after birth. One fetus was diagnosed in a 38 year old woman by amniocentesis in the 15th week of gestation. Our study suggests that routine ultrasonic scans can detect a significant proportion of fetuses with Down's syndrome in the second trimester.

[Cytogenetic analysis in acute leukemia]. / Cytogenetiske undersøkelser ved akutt leukemi.

Leukemic cells often show clonal cytogenetic abnormalities. Some of these are strongly associated with certain morphological subgroups and seem to be of prognostic importance. Cytogenetic studies and molecular genetic investigations using recombinant DNA technology have contributed to our understanding of the development of leukemia. This article reviews earlier work on cytogenetic findings in acute leukemia, and adds our own experiences.

Deficiency of fumarylacetoacetase without hereditary tyrosinemia.

A variant of the enzyme fumarylacetoacetase (FAH) (E.C.3.7.1.2) in healthy individuals, determined by the enzyme activity, is reported. Analysis of family members of probands with low FAH activity suggests that the enzyme variant causing low activity could be the product of a pseudodeficiency gene. Assumed homozygotes for this gene have only slightly higher enzyme activity than patients with the metabolic disorder hereditary tyrosinemia I (hepatorenal type). No clinical abnormalities have been found in association with the postulated gene.

Lethal acute gamma radiation accident at Kjeller, Norway. Report of a case.

On September 2, 1982, a 64-year-old man accidently received a heavy dose of gamma radiation in a plant for sterilization by radiation. He developed an acute radiation syndrome. The leukocyte count rapidly diminished to low values, and extensive chromosome injuries could be demonstrated in cultured lymphocytes. He was hospitalized in an isolated room, and received large doses of antibiotics, and transfusions of leukocytes, platelets and blood. He died anuric on the 13th day. From spectroscopic analyses of electron-spin resonance in irradiated material the mean dose in the whole body was estimated to be 22.5 +/- 2 Gy. The course of the illness and the findings at autopsy are briefly described.