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Objective: The aims of the present study were to evaluate the role of the gap junction protein β-2 gene (GJB2), encoding connexin 26 (Cx26), in children with moderate to profound prelingual nonsyndromic sensorineural hearing impairment (HI) and to investigate the carrier frequencies of the GJB2 gene mutations in a control population in Northern Finland. Methods: Mutation analysis was performed by direct sequencing and carrier detection by conformation sensitive gel electrophoresis further confirmed by direct sequencing. Results: Cx26 mutations were found in 15 of 71 (21.1%) (67 families) children with HI. Homozygosity for the mutation 35delG was shown to be the cause of HI in 13 of 15 (86.7%) children. Homozygosity for the M34T genotype was found in one child, and compound heterozygosity for the M34T/V37I genotype was found in another. Five families of those with suspected familial HI (29.4%) and six families out of those with sporadic HI (12.0%) had a homozygous or compound heterozygous mutation. The carrier frequency for the mutation 35delG was 1 of 78 (4 of 313) and that for the M34T was 1 of 26 (12 of 313). Conclusion: 35delG/35delG genotype was found to be a significant cause of moderate to profound prelingual nonsyndromic sensorineural HI in Northern Finland. M34T/M34T genotype was seen in only one child, but the carrier frequency of the M34T allele was about three times higher than that of the 35delG mutation.

Objective: Primary hyperparathyroidism (PHPT), a common endocrine condition, is usually caused by sporadically occurring parathyroid adenoma. A subset of patients carry germline mutations in genes such as MEN1 (multiple endocrine neoplasia type 1), HRPT2 (hyperparathyroidism 2), and CASR (calcium-sensing receptor) predisposing to syndromic forms of PHPT or familial isolated hyperparathyroidism (FIHP). Recently, germline mutations in two novel genes AIP (aryl hydrocarbon receptor-interacting protein) and CDKN1B (cyclin-dependent kinase inhibitor 1B) have been found to be associated with endocrine tumors. The purpose of this study was to evaluate the role of MEN1, HRPT2, CASR, AIP, and CDKN1B genes in PHPT patients with clinical features suggestive of genetic predisposition. Patients and design: Medical records of patients treated for PHPT from 1974 to 2001 at Oulu University Hospital were reviewed. Patients with multiglandular or recurrent/persistent disease, other MEN1-related manifestations, aged 40 yr or younger at onset or with a family history of PHPT/MEN1-related tumor were invited to the study. Twenty patients with previously diagnosed MEN1 were excluded. Participants were interviewed and blood samples obtained for biochemical screening and mutation analysis of MEN1, HRPT2, CASR, AIP, and CDKN1B. Results: Of the 56 invited patients, 29 took part in the study. One patient was found to carry the c. 1356_1367del12 MEN1 founder mutation. Mutations in other genes were not detected. Conclusions: Apart from MEN1, mutations in other genes predisposing to PHPT seem to be rare or non-existing in Northern Finnish PHPT patients. No evidence was found for a role of AIP or CDKN1B in PHPT predisposition.

Clinical findings on three closely related, severely malformed infants and a 20-week-old fetus with an identical partial trisomy of chromosome 1 (1q42 leads to ter) have made possible the delineation of a new syndrome. The typical manifestations of this syndrome are: severe intrauterine and postnatal developmental retardation, trigonocephaly with wide sutures and fontanels, characteristic facial features, colobomata of the iris, small hands and feet, and early death.

The frequency of rare fragile sites was studied among 240 children in special schools for subnormal intelligence (IQ 52–85). 1/130 boys studied (0.8%) had the fragile site at Xq27.3 while it was not found in any girl (0/110). In two children an autosomal rare fragile site at 2ql 1.2 (2/240, 0.8%) was seen. In addition a constitutional chromosome abnormality was found in a further seven children (7/240, 2.9%).

The incidence of live-born children with Down syndrome was found to be 1.73/1000 (1:578) in northern Finland over the years 1965 to 1979. Despite a marked reduction in the proportion of older mothers, no significant change in the incidence was observed. Instead, an age-specific rise in the incidence for mothers aged 25 to 29 years could be shown during the last five-year period in years 1975 to 1979.

A clinical diagnosis of the Cat-Eye Syndrome (CES) was made in a female child with anal stenosis, congenital heart disease, bilateral preauricular skin tags and coloboma of the right fundus. The karyotype was 46XX/47XX, +mar. Q-banding revealed the marker chromosome to be metacentric and comparable in size to that of a G-group chromosome. One arm had brightly fluorescent satellites while the other exhibited a fluorescent polymorphism similar to the short arm of a D- or G-group chromosome. Chromosome analysis from blood cultures obtained from parents and three sibs did not demonstrate the presence of the marker chromosome. Comparison of the fluorescent polymorphisms revealed that the satellites on the marker were comparable in size and brightness to those of the maternal chromosome 22. C-banding demonstrated the marker to be dicentric. While there has been much speculation on the origin of the Cat-Eye Chromosome (CEC) based on clinical features in common with the trisomy 22 syndrome, autoradiographic studies and the general appearance of the marker, this case provides definitive evidence for the involvement of chromosome 22 in the origin of the marker chromosome. This chromosome is interpreted as the product of a Robertsonian translocation between the short arm and satellites of chromosome 22 and the short arm of another D- or G-group chromosome, most likely 13. Thus, the karyotype of the patient is 46XX/47XX, t(?13;22) (?13pter13q11::22q1122pter). Reinvestigation of patients with CES utilizing heritable polymorphisms may better elucidate the specific nature of the marker, and further delineate a possible basis for the heterogeneity of the disorder.

Editor—Multiple endocrine neoplasia type 1 (MEN 1, OMIM 131100) is transmitted as an autosomal dominant trait with an equal sex distribution and close to full penetrance. Hyperparathyroidism occurs in over 90% of the cases and is invariably associated with multiglandular disease. In addition, the patients may develop tumours of the endocrine pancreas, the anterior pituitary, and the adrenal cortex, as well as lipomas and carcinoids.1The MEN1 tumour suppressor gene at 11q13 was cloned by positional cloning and the protein, menin, has been found to bind specifically to JunD leading to inhibition of JunD activated transcription.2-5 Following the initial description of the disease gene, over 200 MEN1 germline mutations scattered throughout the entire gene have been reported. The majority of these mutations are unique and no clear cut genotype-phenotype correlation has been established so far.3 4 6-13 To date, only a few reports of a founder effect in MEN 1 families have been published.10 14 15 In all the cases, the evidence for a founder chromosome was based on the presence of a shared disease haplotype and a MEN1 mutation, in combination with a common geographical origin of the families involved. To date, more than 30 rare single gene diseases, mostly autosomal recessive, have been identified in the Finnish population.16 17 The clustering of mutations in the Finnish population can be explained by the mechanisms of isolation, genetic drift, and founder effect. The relatively small founder population, the geographical isolation, and the internal migration movement in the 1500s led to the formation of numerous founder populations. The Finnish population has been widely used in linkage disequilibrium studies for mapping disease gene loci. By combining genetic and clinical investigations with careful genealogical studies, several founder chromosomes for various genetic diseases have been established.17-19 …

Editor—Neurofibromatosis type 1 (NF1), also known as von Recklinghausen's disease, is an autosomal dominant neurocutaneous disease characterised by cafe au lait spots and neurofibromas. The gene responsible for the disorder is located in the chromosome region 17q11.2. The prevalence of NF1 has been estimated to be about 1/3500 in the USA and the United Kingdom,1-3 and its birth incidence has been reported to vary from 1/25584to 1/4292,5 the mutation rate being 3.1 × 10–5 to 6.5 × 10–5. The first population based study of NF1 was performed in Sweden by Samuelsson6in 1981, who found 74 adult NF1 patients in the Gothenburg region, implying a prevalence of 1/4600. In 1989, Huson et al 4 discovered 135 NF1 patients in 69 families in south east Wales, 83 of whom were index cases and 52 affected relatives, with a prevalence of 1/4150. The highest estimated prevalence for NF1, 1/2190, has been reported in Dunedin, New Zealand, by Fuller et al ,7 who also showed that the prevalence peaked in the age group 20-29 years. A fourth report from north east Italy by Clementi et al 5 quoted a prevalence of 1/6711 and a very high mutation rate of 6.5 × 10–5 gametes per generation. The purpose of the present work was to determine the prevalence and genetic characteristics of NF1 in northern Finland, including a survey of first degree relatives of patients and linkage data, to assist in the diagnosis of affected subjects. Clinical data on the patients will be reported separately. The study was carried out between October 1989 and December 1996 in the region of Oulu University Hospital (OUH) in northern Finland with a total population of 733 037 (31 December 1996).8The basic material consisted of families …

Multiple endocrine neoplasia type 1 (MEN 1) is an autosomal dominant disease characterized by neoplasia of the parathyroid glands, the endocrine pancreas, and the anterior pituitary gland. In addition, families with isolated endocrine neoplasia, notably familial isolated hyperparathyroidism (FIHP) and familial acromegaly, have also been reported. However, whether these families constitute MEN 1 variants or separate entities remains speculative as the genetic bases for these diseases are unclear. The gene for MEN 1 has recently been cloned and characterized. Using single strand conformation analysis (SSCA) and sequencing, we performed mutation analysis in: a) a total of 55 MEN 1 families from 7 countries, b) 13 isolated MEN 1 cases without family history of the disease, c) 8 acromegaly families, and d) 4 FIHP families. Mutations were identified in 27 MEN 1 families and 9 isolated cases. The 22 different mutations spread across most of the 9 translated exons and included frameshift (11), nonsense (6), splice (2), missense mutations (2), and in-frame deletions (1). Among the 19 Finnish MEN 1 probands, a 1466del12 mutation was identified in 6 families with identical 11q13 haplotypes and in 2 isolated cases indicating a common founder. One frameshift mutation caused by 359del4 (GTCT) was found in 1 isolated case and 4 kindreds of different origin and haplotypes; this mutation therefore represents a common "warm" spot in the MEN1 gene. By analyzing the DNA of the parents of an isolated case one mutation was confirmed to be de novo. No mutation was found in any of the acromegaly and small FIHP families, suggesting that genetic defects other than the MEN1 gene might be involved and that additional such families need to be analyzed.

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder characterised by tumours of the parathyroids, pancreas and anterior pituitary. The MEN1 gene has been localised to a 2-Mb region of chromosome 11q13 by meiotic mapping studies in MEN1 families. Such studies may have a limited resolution of approximately 1 cM (i.e. 1 Mb) and we have therefore investigated 96 MEN1 families (40 British, 17 French, 12 Finnish, 7 Swedish, 7 Dutch, 7 North American, 2 Australian, 1 New Zealand, 1 German, 1 Spanish and 1 Danish) for linkage disequilibrium, in order to facilitate a finer mapping resolution. We have utilised five microsatellite DNA sequence polymorphisms from the candidate region and have accurately determined their allele sizes, which ranged from 161 bp to 272 bp. The heterozygosity and number of alleles (given in brackets), respectively, at the loci were: D11S1883 (76%, 11), D11S457 (55%, 5), PYGM (94%, 18), D11S1783 (10%, 4) and D11S449 (87%, 16). Allelic association was assessed by Chi-square 2 x n contingency tables, by Fisher exact 2 x n contingency tables and by a likelihood-based approach. The results of haplotype analysis revealed 91 different affected haplotypes in the 96 families, an identical affected haplotype being observed in no more than two families. These results indicate the absence of an ancestral affected haplotype. Significant linkage disequilibrium (P < 0.005) could be established amongst the microsatellite loci but not between the loci and MEN1 in either the total population or in any of the geographical sub-populations, The absence of linkage disequilibrium between MEN1 and the polymorphic loci is probably the result of the occurrence of multiple different disease-causing mutations in MEN1.

A new autosomal recessively inherited disease of the central nervous system involving childhood epilepsy and mental deterioration is described. Twenty three patients (11 males and 12 females) belonging to 11 families from northern Finland have been identified. A common ancestor has been found for nine families. The mean age of onset of epilepsy was 6.7 years (range 5-10 years) and the epilepsy was characterised by generalised tonic-clonic seizures increasing in frequency up to puberty. One third of the patients also had complex partial seizures during childhood. During young adulthood the epileptic activity began to decrease, but complete remission did not occur. Electroencephalography showed progressive slowing of the background activity with relatively scanty epileptiform activity. Out of four ictal recordings the paroxysmal activity was initiated focally in two cases. Clonazepam and sodium valproate had some antiepileptic effect, clonazepam being the more beneficial of the two. Mental development, which was originally normal, began to deteriorate two to five years after the onset of epilepsy, and the deterioration continued during adulthood in spite of good epilepsy control, leading to mental retardation by middle age. The pathogenesis of the disorder, called the Northern epilepsy syndrome, is unknown. Linkage analysis using DNA markers linked to the EPM1 gene for progressive myoclonus epilepsy of Unverricht-Lundborg type showed that the Northern epilepsy syndrome is not allelic to EPM1.

Nonketotic hyperglycinemia (NKH) is an autosomal recessive metabolic disorder caused by the defects in the glycine cleavage system (GCS; EC 2.1.2.10), a multienzyme system that consists of four individual components. NKH is a rare disorder in many countries, but with a very high incidence in northern Finland. To understand the genetic background of this high incidence, we examined the GCS in a typical case of NKH at the molecular level. The activity of P protein, a component of the GCS, was not detected in the lymphoblasts of the patient, while P protein mRNA of a normal size and level was present in the cells. Structural analysis of P protein mRNA from the patient revealed a single nucleotide substitution from G to T in the protein coding region, which resulted in an amino acid alteration from Ser564 to Ile564. No P protein activity was detected when the mutant P protein with this amino acid substitution was expressed in COS 7 cells. The patient was homozygous for this mutation. Furthermore, this mutation was present in 70% (14 of 20) of P protein gene alleles in Finnish patients with NKH, whereas it was not found in 20 alleles of non-Finnish patients. The results suggest that this mutation is responsible for the high incidence of NKH in Finland.

A family having two boys with progressive encephalomyopathy and fumaric aciduria due to fumarase deficiency is described. Both patients initially presented with polyhydramnios and enlarged cerebral ventricles in utero, with subsequent cerebral atrophy, severe developmental delay, infantile spasms, and hypsarythmia on electroencephalogram. Fumarase activity in blood mononuclear cells and In the mitochondrial and cytosolic fractions of cultured skin fibroblasts was less than 0.5% of the control mean or undetectable. The older boy died at the age of 5 years and 4 months and the younger one is now 2 years and 10 months. The unrelated parents are symptomless and the other three children in the family are clinically healthy. Fumarase activities in the blood mononuclear cells of the father, mother, sister, and two brothers were 59%, 52%, 52%, 120%, and 44% of the control mean, respectively. The results strongly support autosomal recessive inheritance of fumarase deficiency and suggest its consideration in children with congenital hydrocephalus, progressive brain atrophy, and infantile spasms.

Angelman syndrome is a neuro-developmental disorder caused by genetic abnormalities affecting the maternal gene expression in the chromosome region 15q11-q13. In a study group of 45 Finnish Angelman patients, a recurrence of a del(15)(q11q13) was detected in one family. The mother's chromosomes 15 were structurally normal, whereas the patients and their unaffected brother shared an identical maternally derived haplotype outside the deletion region. These findings are suggestive of maternal germ-line mosaicism of del(15)(q11q13).

Fragile-X syndrome, a frequent cause of inherited mental retardation, is characterised in almost all cases by a CGG-repeat expansion that is located within the FMR-1 gene and that prevents the expression of fragile-X mental retardation protein (FMRP). We describe a test that simultaneously allows the rapid detection of FMRP in fetal lymphocytes and distinguishes these from fetal erythrocytes. Routine molecular genetic methods fail in the rare cases where protein expression is blocked, although there is no repeat expansion. Furthermore, they are unsuitable in cases of advanced pregnancy. Our test proves extremely valuable under both these circumstances.

Objective: The existence of genotype–phenotype correlation in multiple endocrine neoplasia type 1 (MEN1) is controversial. Two founder mutations of the MEN1 gene in Northern Finland gave us an opportunity to compare clinical features among heterozygotes of different mutations. Design and methods: Study cohort included 82 MEN1 heterozygotes who were tested for MEN1 during the years 1982–2001. Medical records were reviewed for manifestations of MEN1, other tumours and cause of death by the end of August 2003. Logistic regression analysis was used in evaluating the impact of age, gender and mutational status of affected heterozygotes on the likelihood of developing manifestations of MEN1. Results: Founder mutations 1466del12 and 1657insC were found in 39 and 29 individuals, and D418N, G156R and R527X mutations in 9, 3 and 2 individuals respectively. Except for pituitary adenoma and nonfunctional pancreatic tumour (NFPT), age was a risk factor for all the disease manifestations. For NFPT, frameshift/nonsense mutations (1657insC, R527X) gave an odds ratio (OR) of 3.26 (95% confidence intervals (CI), 1.27–8.33; P = 0.014) compared with in-frame/missense mutations (1466del12, D418N, G156R); including the founder mutation carriers (n = 68) only, the 1657insC mutation gave an OR of 3.56 (CI, 1.29–9.83; P = 0.015). For gastrinoma, in-frame/missense mutations predicted the risk with an OR of 6.77 (CI, 1.31–35.0; P = 0.022), and in the founder mutations group the 1466del12 mutation gave an OR of 15.09 (CI, 1.73–131.9, P = 0.014). Conclusions: In this study population, NFPT was more common in the frameshift/nonsense or 1657insC mutation carriers, whereas gastrinoma was more common in the in-frame/missense or 1466del12 mutation carriers.

Estimation of mortality and the natural course of a disease is usually based on information of carefully studied individuals with or at risk for a specific disease. Genealogical information has rarely been accurate enough for such studies. With the help of church records and multiple endocrine neoplasia type 1 (MEN1) family information of the two founder MEN1 mutations in Northern Finland (1466del12 and 1657insC), we could trace back common ancestors born in the beginning of the 1700s (1466del12) and approximately 1850 (1657insC) and find 67 probable gene carriers born between 1728 and 1929, which were identified among their offspring. Information was gathered from 34 obligatory MEN1 gene carriers and 31 spouses. The mean age (+/- sd) of death of affected males (n = 16) was 61.1 +/- 12.0 yr vs. 65.8 +/- 15.3 yr for unaffected males (n = 16) and for affected females (n = 16) was 67.2 +/- 10.7 yr vs. 67.7 +/- 14.7 yr for unaffected females (n = 13). The ages of death of the obligatory heterozygotes did not differ from that of the spouses in sex groups or from the sex-matched life expectancy estimates derived from Finnish national statistics. Causes of death differed significantly between female probands and spouses. In conclusion, obligatory MEN1 gene carrier status did not show a harmful effect on survival in this retrospective analysis tracing back to almost 300 yr.

Angelman syndrome (AS) is a neurogenetic disorder associated with a loss of maternal gene expression in chromosome region 15q11-q13 due to either maternal deletion, paternal uniparental disomy (UPD), imprinting mutation, or mutation in the UBE3A gene. UBE3A encodes an ubiquitin-protein ligase and shows brain-specific imprinting. We have done conformation sensitive gel electrophoresis (CSGE) mutation analysis of the UBE3A coding region in nine AS patients, who had shown a normal biparental inheritance and methylation pattern of the 15q11-q13. Disease-causing mutations were identified in five of them: three deletions (1930delAG, 3093delAAGA) and two missense mutations (902A → C, 975T → C). Both deletions have also been detected in other AS patients, suggesting these sites may be prone to deletions in the UBE3A gene. All AS cases were sporadic, but a mosaicism for mutation 902A → C was present in a patient's mother. Screening for the UBE3A mutations in the AS patients was found useful both for the confirmation of diagnosis and genetic counseling. CSGE was found to be a sensitive and simple screening method for these mutations. © 2003 Wiley-Liss, Inc.

Only a proportion of breast cancer families has germline mutations in the BRCA1 or BRCA2 genes, suggesting the presence of additional susceptibility genes. Finding such genes by linkage analysis has turned out to be difficult due to the genetic heterogeneity of the disease, phenocopies and incomplete penetrance of the mutations. Isolated populations may be helpful in reducing the level of genetic heterogeneity and in providing useful starting points for further genetic analyses. Here, we report results from a genome-wide linkage analysis of 14 high-risk breast cancer families from Finland. These families tested negative for BRCA1 and BRCA2 germline mutations and showed no linkage to the 13q21 region, recently proposed as an additional susceptibility locus. Suggestive linkage was seen at marker D2S364 (2q32) with a parametric two-point LOD score of 1.61 (theta=0), and an LOD score of 2.49 in nonparametric analyses. Additional genotyping of a 40 cM chromosomal region surrounding the region of interest yielded a maximum parametric two-point LOD score of 1.80 (theta=0) at D2S2262 and a nonparametric LOD score of 3.11 at an adjacent novel marker 11291M1 in BAC RP11-67G7. A nonparametric multipoint LOD score of 3.20 was seen at 11291M1 under the assumption of dominant inheritance. While not providing proof of linkage considering the small number of families and large number of laboratory and statistical analyses performed, these results warrant further studies of the 2q32 chromosomal region as a candidate breast cancer susceptibility locus. Both linkage and association studies are likely to be useful, particularly in other isolated populations.

Non-specific X-linked mental retardation is a heterogeneous group of disorders with an incidence of approximately 1 in 500 males. A recently identified gene in Xq12, encoding a Rho-GTPase-activating protein, was found to be mutated in individuals with mental retardation. We describe here two sisters with a 46,XY karyotype and a microdeletion of the oligophrenin-1 gene and 1.1 Mb of flanking DNA. We have characterised the molecular interval defining this microdeletion syndrome with the fibre-FISH technique. A visual physical map of 1.2 Mb was constructed which spans the oligophrenin-1 gene and the androgen receptor gene. The analysis of the patients revealed a deletion which extended from the 5' end of the AR gene to a region approximately 80 kb proximal to the EPLG2 gene. The clinical manifestations of the two sisters include psychomotor retardation, seizures, ataxia, hypotonia and complete androgen insensitivity. Cranial MRI scans show enlargement of the cerebral ventricles and cerebellar hypoplasia. Our findings give further support for the involvement of the oligophrenin-1 gene in specific morphological abnormalities of the brain which is of importance in the investigation of male patients presenting with mental retardation. In combination with our results from physical mapping we suggest that a region around the oligophrenin-1 locus is relatively bereft of vital genes.

Objective: To identify genetic changes, other than the MEN1 gene, that might be involved in the tumorigenesis and progression of multiple endocrine neoplasia type 1 (MEN1)-related tumours. Methods: We used comparative genomic hybridization (CGH) and loss of heterozygosity (LOH) to study tumours from various sites in a patient with MEN1. Results: Gain of genetic material was not found. Frequent losses of genetic material were found in chromosomes 1, 4, 5, 6, 9, 11 and 18. Besides the chromosome 11 where the MEN1 gene is located, the other regions are known to harbour important tumour suppressor genes. Conclusions: These results suggest the involvement of other cancer-related genes in the tumorigenesis and progression of MEN1 tumours that warrant further investigations.

The epidemiology of childhood hearing impairments was studied in a clinical series of the birth cohorts for 1973-82 and 1983-92 from a geographically well-defined area. The overall prevalence of hearing impairments with PTA 0.5-4 kHz ≥ 40 dB was 1.2/1000 live births. Even in the later cohort, the median age at ascertainment was 2.6 years for the congenital or early acquired group and 3.0 years for all impairments. Risk indicators for hearing impairment were present in half of the children, and those referred for the risk were ascertained at the median age of 1.1 years. The delay from suspicion to ascertainment was over a year in about one fifth of cases, while the median time from referral to ascertainment was only 1.8 months. The planning and implementation of neonatal hearing screening are suggested, and general information is given on paedoaudiology for both parents and professionals. A database could be beneficial in increasing the systemacy of the diagnostic process.

We describe the clinical findings and biochemical features of a male child suffering from a so far undescribed lethal connective tissue disorder characterised by extreme hypermobility of the joints, lax skin, cataracts, severe growth retardation, and insufficient production of type I and type III procollagens. His features are compared with Ehlers-Danlos type IV, De Barsy syndrome, and geroderma osteodysplastica, as these disorders show some symptoms and signs shared with our patient. The child died because of failure of the connective tissue structures joining the skull and the spine, leading to progressive spinal stenosis. The aortic valve was translucent and insufficient. The clinical symptoms and signs, together with histological findings, suggested a collagen defect. Studies on both skin fibroblast cultures and the patient's serum showed reduced synthesis of collagen types I and III at the protein and RNA levels. The sizes of the mRNAs and newly synthesised proteins were normal, excluding gross structural abnormalities. These findings are not in accordance with any other collagen defect characterised so far.

An epidemiological and genetic investigation of myotonia congenita was carried out in northern Finland. Altogether 58 patients were identified (of whom 54 lived in the study area) in 23 families, with a prevalence of 7.3 per 100000. The majority of the families originated from a sparsely populated area in western Lapland. The mean age at onset of the disease was 11 years with a range of 2 to 45 years. The mean time that had passed before verification of the clinical disease was 18 (SD 14) years. The sex ratio M/F was 2.2/1.0. Forty-seven cases were familial and 11 were sporadic. In six families/pedigrees the inheritance was compatible with autosomal recessive and in two families with autosomal dominant inheritance. In five additional families, in which autosomal recessive inheritance seemed most plausible, vertical transmission was also noticed. This could be explained either by consanguinity of the parents or by variant expression of the mutation(s) involved. Our results suggest that myotonia congenita is unusually frequent in northern Finland, most probably as a consequence of an enrichment of the gene mutation(s) in the population.

We describe a family in which seven members in three generations were affected with a rare spinal neurofibromatosis. The affected adults showed, at the ages of 32, 37, 38, and 61, respectively, multiple spinal neurofibromas symmetrically affecting all spinal roots. Two patients were operated on for histopathologically proven cervical spinal neurofibromas. All patients had cafe au lait spots, one had several freckles in the axillary area, and two had possible dermal neurofibromas, but iris Lisch-nodules were not present. Other signs of neurofibromatosis types 1 and 2 were absent. A linkage study of the family suggested close linkage to the NF1 locus and excluded it from the NF2 locus. The DNA analysis of histopathologically verified spinal neurofibromas in two patients showed no evidence of LOH at 17q11.2. The findings in the present family, together with those in a family previously described, suggest a clinically distinct form of neurofibromatosis with extensive spinal neurofibromas and cafe au lait macules, which may be allelic to the NF1 gene.

Fragile X syndrome results from the expansion of the CGG repeat in the FMR1 gene. Expansion has been suggested to be a postzygotic event with the germline protected. From an analysis of intact ovaries of full mutation fetuses, we now show that only full expansion alleles can be detected in oocytes (but in the unmethylated state). Similarly, the testes of a 13-week full mutation fetus show no evidence of premutations while a 17-week full mutation fetus exhibits some germ cells with attributes of premutations. These data discount the hypothesis that the germline is protected from full expansion and suggest full mutation contraction in the immature testis. Thus, full expansion may already exist in the maternal oocyte, or postzygotic expansion, if it occurs, arises quite early in development prior to germline segregation.

We present here a 7 year old girl with the clinical signs of Wolf-Hirschhorn syndrome (WHS). Only on high resolution banding was a deletion of 4p16.3 suspected in both the proband and the father. Further studies using simultaneous R banding and FISH, with cosmid probe pc847.351 containing the mildly repetitive fragment 847-EC, confirmed the diagnosis and showed a paternal balanced translocation t(4;8)(p16.3;q24.3).

The lethal congenital contracture syndrome (LCCS) is an autosomal recessive syndrome (McKusick 253310) leading to perinatal death owing to early onset degeneration of the anterior horn motor neurones of the spinal cord. The neuropathological findings in the LCCS closely resemble those of spinal muscular atrophy (SMA). Since all the three types of SMA have been localised to the same gene locus on the long arm of chromosome 5, we analysed samples from seven families with 10 LCCS fetuses with the microsatellite markers assigned to the SMA 5q region. Linkage analyses between the SMA linked DNA markers and the disease allele in the LCCS families excluded the critical chromosomal region around the SMA locus as the critical chromosomal region for the LCCS locus.

Objective and Background: To find an explanation at the molecular level for the high prevalence of myotonia congenita in northern Finland and the exceptional pattern of inheritance of the disease in many families, and to study genotype-phenotype correlation in the patients. Methods: Forty-six patients with myotonia congenita and 16 unaffected relatives from 24 families were studied. All 23 exons and their flanking regions of the gene for the chloride channel protein ( ClC-1 ) were sequenced from at least one patient from all families. Results: There were three different mutations of ClC-1 in the patients: one in exon 11, a T-to-G transversion that resulted in the substitution of cysteine for phenylalanine at amino acid position 413 (F413C); one in exon 15, a C-to-T transition that resulted in the substitution of valine for alanine at amino acid position 531 (A531V); and one in exon 23, a C-to-T transition that resulted in the substitution of a stop codon for an arginine codon at amino acid position 894 (R894X). Conclusions: Molecular studies showed that even in families with apparent dominant inheritance, the actual mode of inheritance was autosomal recessive. This was explained not only by the observed consanguinity in some families but by an enrichment of three different mutations of the ClC-1 gene and a consequent high number of compound heterozygotes in the population. One of the mutations is unique to northern Finland. The conspicuous enrichment of the mutations is likely due to the founder effect and isolation by distance, as in other diseases in the Finnish heritage.

In an evaluation of the possible chromosome damage caused by cytostatic agents 11 nurses with long-term exposure to such agents were studied. Five laboratory workers and 11 hospital clerks served as referents. The number of chromosomally aberrant lymphocytes was significantly higher in the group of nurses than in the group of laboratory workers or hospital clerks. The number of chromosome-type breaks was increased significantly among the nurses as compared to the reference groups. There was no significant difference in the number of chromatid-type breaks between the groups. The observed increase in chromosome-type aberrations may have been due to long-term occupational exposure to cytostatic agents.

In a material of about 3600 facial clefts eleven oblique clefts were observed (3.1%o). The most frequent types were the medial oro-ocular and naso-ocular clefts and their combinations. There were two atypical cases and one lateral oro-ocular variety. The oblique clefts were frequently associated with other types of clefts and/or more distant anomalies. No genetic, chromosomal or environmental factors were found to explain their etiology. Amniotic bands could possibly be thought to be responsible for the severe malformations in two instances. The lacrimal apparatus was always involved to some degree with the exception of a few incomplete forms. In the alveolar arch the clefts seemed to be situated between the medial incisor and the canine.

In a material of about 3,600 facial clefts eleven oblique clefts were observed (3.1%). The most frequent types were the medial oro-ocular and naso-ocular clefts and their combinations. There were two atypical cases and one lateral oro-ocular variety. The oblique clefts were frequently associated with other types of clefts and/or more distant anomalies. No genetic chromosomal or environmental factors were found to explain their etiology. Amniotic bands could possibly be thought to be responsible for the severe malformations in two instances. The lacrimal apparatus was always involved to some degree with the exception of a few incomplete forms. In the alveolar arch the cleft seemed to be situated between the medial incisor and the canine.

Clinical findings on three closely related, severely malformed infants and a 20-week-old fetus with an identical partial trisomy of chromosome 1 (1q42 leads to ter) have made possible the delineation of a new syndrome. The typical manifestations of this syndrome are: severe intrauterine and postnatal developmental retardation, trigonocephaly with wide sutures and fontanels, characteristic facial features, colobomata of the iris, small hands and feet, and early death.

Wegener's granulomatosis is a very rare disease in children; only 10 cases have been reported in the literature. The present report describes 3 cases where Wegener's granulomatosis developed at an early stage, beginning with upper respiratory tract symptoms. All the 3 children have been successfully treated with a combination of azathioprine and corticosteroids.

An ultrasonic diagnosis of a lethal, autosomally recessive syndrome of multiple congenital contractures was made in seven high-risk pregnancies on the 13rd to 17th gestational weeks. The diagnostic findings were the development of progressive subcutaneous oedema from the 13th gestational week on and the decrease of fetal limb movements.

One hundred and fifty male patients with mental retardation of unknown origin were studied cytogenetically. Six patients (4%) were: marker X-positive. All these index cases were found in a subgroup of patients with no dysmorphic features, significant neurological findings or childhood psychosis. In this subgroup the frequency was 8.8%. One of the index cases had a family history suggestive of X-linked mental retardation, four had retarded 1st degree relatives and one had no family history of mental retardation.