Informe clínico de dismorfias múltiples con agregación familiar / Clinical report on multiple dysmorphias with familial aggregation

Se comunican las características clínicas de una mujer de 68 años de edad y sus dos hijas (36 y 33 años) que presentaban un conjunto de anomalías de probable origen hereditario. Se les efectuaron interconsultas con varias especialidades: medicina interna, genética, cardiología, radiología, angiología, psiquiatría, dermatología, otorrinolaringología, máxilo-facial, oftalmología y neurología. Los hallazgos comunes a las tres pacientes consistieron en tortuosidad de los vasos retinianos, glaucoma crónico de ángulo abierto, braquidactilias y otros dismorfismos en dedos de manos y pies, hallux valgus, telangiectasias en mejillas y tórax superior, orejas en ®asa», hiperostosis frontal, tórax excavado e insuficiencia mitral. El glaucoma neovascular se presentó en un ojo de cada hija. Este complejo padecimiento clínico, con alteraciones en miembros, faciales, cardiovasculares, oculares y en piel con una posible herencia de tipo autosómico dominante por su presencia en dos generaciones sucesivas, no se corresponde con ningún síndrome de los considerados en este informe

Presentation of the clinical characteristics of a 68-year-old woman and her two daughters, aged 36 and 33, who had a number of abnormalities of probable hereditary origin. Interconsultations were conducted with several specialties: internal medicine, genetics, cardiology, radiology, angiology, psychiatry, dermatology, otorhinolaryngology, maxillofacial, ophthalmology and neurology. The findings common to the three patients were retinal arterial tortuosity, chronic open angle glaucoma, brachydactyly and other dysmorphic disorders of fingers and toes, hallux valgus, telangiectasia in cheeks and upper thorax, protruding ears, frontal hyperostosis, pectus excavatum and mitral insufficiency. Both daughters had neovascular glaucoma in one of their eyes. This complex clinical condition, with disorders involving limbs, face, the cardiovascular system, eyes and skin, and a potential autosomal dominant inheritance in view of its presence in two successive generations, does not correspond to any of the syndromes considered in this report

The international biological program/human adaptability studies among the Skolt Sami in Finland (1966-1970).

BACKGROUND: The population is increasingly lighter pigmented moving in a northward direction in Europe until reaching the Arctic Circle, where the Samis (Lapps) are clearly more pigmented. METHODS: In 1966-1970, we investigated a total of 689 subjects in the villages of Sevettijärvi and Nellim, including persons with mixed Sami and Finnish heritage; of these, 487 (242 males, 245 females) had both parents classified as Skolt Sami. For estimation of the colour of the iris and hair, international scales were used. For translucency of the iris, pigmentation of the fundus was estimated in 3 different shades. The length and type of eyelashes were classified into 3 categories. To our knowledge, a simultaneous study of the pigmentation of eyebrows, eyelashes and eye fundus at different ages has not previously been published. RESULTS: The age differences of iris colour were highly significant. Iris colour in children varied markedly, and they generally had lighter colours than later in life. Age and sex effects on the translucency of irises were found. Male irises were more translucent. Fundus pigmentation was scanty in the youngest age groups, with full pigmentation being reached at 20 years. Among young individuals hair colour darkens with increasing age. Eyebrow colour was slightly lighter for both sexes in the youngest age groups that in older cohorts. Women had longer eyelashes than males. CONCLUSIONS: The main factor of the lighter skin is a higher ability to synthesize vitamin D, providing superior protection against rickets. The Skolt Samis are more pigmented than other Nordic people. In earlier times they had problems with rickets but our studies did not show any essential symptoms of rickets today. Visual acuity among Skolt Samis was good. They had lower prevalence of myopia compared to Finns. The stronger pigmentation of Skolt Samis is probably due to their origin from darker Eastern populations. Since our investigations were made, the Skolt Samis have been to a great part mixed with neighbouring populations and scattered throughout Finland. Even their old language is nowadays used mainly for traditional purposes. Therefore similar studies could not be performed anymore.

Association of LOXL1 gene with Finnish exfoliation syndrome patients.

In this study, three single-nucleotide polymorphisms (SNPs) on the lysyl oxidase-like 1 (LOXL1) gene associated with exfoliation syndrome (XFS) and exfoliation glaucoma (XFG) were investigated in the Finnish population. A case-control study of 59 sporadic patients with XFS, 82 with XFG, 71 with primary open-angle glaucoma (POAG) and 26 individuals without these disorders from the southern Finnish population, and a family study of an extended family with 28 patients with XFS or XFG and 92 unaffected relatives from Kökar islands, Southwestern Finnish archipelago, were conducted. Anonymous blood donors (n=404) were studied as population-based controls. Three SNPs, rs1048661 (R141L), rs3825942 (G153D) and rs2165241, of the LOXL1 gene were genotyped by PCR sequencing. Association and linkage analyses were carried out. In both case-control and family materials, significant association for allele G of rs1048661 (P=2.65 x 10(-5); P=0.0007), allele G of rs3825942 (P=2.24 x 10(-8); P=0.49) and allele T of rs2165241 (P=2.62 x 10(-13); P<0.0001) was found in XFS/XFG. However, linkage was not observed for LOXL1 risk alleles. The corresponding three-locus haplotype GGT increased the risk of XFS/ XFG nearly 15-fold relative to low-risk haplotype GAC (odds ratio (OR): 14.9, P=1.6 x 10(-16)). In conclusion, the earlier reported polymorphisms of the LOXL1 gene showed significant association also in the Finnish population.

Genome-wide scan of exfoliation syndrome.

PURPOSE: Exfoliation syndrome (XFS) is an age-related ocular condition that is characterized by the accumulation of fibrillogranular extracellular material in intra- and extraocular tissues. The purpose of the present study was to identify the genetic basis of XFS in a large Finnish family. METHODS: A genome-wide scan with 1000 microsatellite markers was performed in an extended family from an island in the southwestern Finnish archipelago where XFS demonstrates an autosomal dominant mode of inheritance with incomplete penetrance. Two-point linkage analyses were performed with MLINK and multipoint linkage, using the Vitesse program. RESULTS: Five chromosomal regions with markers showing two-point LOD scores more than 1.5 was identified by using a dominant mode of inheritance for the XFS trait. The most promising locus was assigned to 18q12.1-21.33 with a maximum two-point LOD score of 3.45 and a multipoint LOD score of 4.2. Some evidence of linkage was obtained at chromosomes 2q, 17p, and 19q, which were suggested in earlier reports to be possible regions of linkage to primary open-angle glaucoma (POAG). CONCLUSIONS: The study presented herein offers a starting point to unravel the molecular background of XFS.

Exfoliation syndrome: prevalence and inheritance in a subisolate of the Finnish population.

PURPOSE: To estimate the prevalence of pseudoexfoliation syndrome or exfoliation syndrome (ES) in a cross-sectional study and during a long-term follow-up, and to analyse how ES has been inherited in a large pedigree on an isolated population of Kökar island in southern Finland. METHODS: In a population-based study conducted between 1960 and 1962, a comprehensive ophthalmological examination was performed on 595 subjects (85% of the population). From then until 2002, 965 subjects were examined at least once. A pedigree was constructed for all ES-affected subjects according to genealogical studies. The genetic contribution to ES was investigated in this pedigree by segregation analysis and the heritability of the intraocular pressure (IOP) quantitative trait estimated using SOLAR and SAGE software. RESULTS: In the cross-sectional study, the prevalence of ES was 8.1% for 247 subjects over 50 years of age (males 7%, females 9%) and increased to 18.4% for 70 subjects over 70 years of age (males 13%, females 25%). In addition, two females less than 50 years of age were ES-affected. Between 1960 and 2002, 76 (14.3%) of 530 subjects over 50 years of age had ES [23 males (10%) and 53 females (18%)]. Exfoliation glaucoma (EG) was found more often in males (11 patients, 48%) than in females (13 patients, 25%) whereas primary open-angle glaucoma (POAG) was almost as frequent in males (seven patients, 3%) as in females (five patients, 2%). The relative risk (RR) of glaucoma (ES versus no ES) was 11.9 [95% confidence interval (CI) 6.2-22.9] for all the subjects - 14.6 for males (95% CI 6.3-34.0) and 11.8 for females (95% CI 4.4-31.6). Seventy-five pedigrees of 78 ES-affected patients were linked together into one large pedigree with 110 nuclear families. The segregation ratio of ES was 18% (8% for males, 24% for females) when both parents were unaffected, and 16% (9% for males, 27% for females) when at least one parent was affected. The heritability of IOP was estimated to be 30%. CONCLUSION: In this population-based family study, ES is consistent with an autosomal dominant trait with incomplete penetrance, where the penetrance is more reduced in males than in females. However, the presence of ES was a greater risk factor for developing glaucoma in males than in females.

A novel CACNA1F gene mutation causes Aland Island eye disease.

PURPOSE: Aland Island eye disease (AIED), also known as Forsius-Eriksson syndrome, is an X-linked recessive retinal disease characterized by a combination of fundus hypopigmentation, decreased visual acuity, nystagmus, astigmatism, protan color vision defect, progressive myopia, and defective dark adaptation. Electroretinography reveals abnormalities in both photopic and scotopic functions. The gene locus for AIED has been mapped to the pericentromeric region of the X-chromosome, but the causative gene is unknown. The purpose of this study was to identify the mutated gene underlying the disease phenotype in the original AIED-affected family. METHODS: All exons of the CACNA1F gene were studied by DNA sequencing. CACNA1F mRNA from cultured lymphoblasts was analyzed by RT-PCR and cDNA sequencing. RESULTS: A novel deletion covering exon 30 and portions of flanking introns of the CACNA1F gene was identified in patients with AIED. Results from expression studies were consistent with the DNA studies and showed that mRNA lacked exon 30. The identified in-frame deletion mutation is predicted to cause a deletion of a transmembrane segment and an extracellular loop within repeat domain IV, and consequently an altered membrane topology of the encoded alpha1-subunit of the Ca(v)1.4 calcium channel. CONCLUSIONS: Mutations in CACNA1F are known to cause the incomplete form of X-linked congenital stationary night blindness (CSNB2). Since the clinical picture of AIED is quite similar to CSNB2, it has long been discussed whether these disorders are allelic or form a single entity. The present study clearly indicates that AIED is also caused by a novel CACNA1F gene mutation.

The role of TIGR and OPTN in Finnish glaucoma families: a clinical and molecular genetic study.

PURPOSE: The aim of the present study was to analyze the role of the two primary open angle glaucoma (POAG) genes, trabecular meshwork-induced glucocorticoid response (TIGR/MYOC) and optineurin (OPTN), in Finnish glaucoma families originating from southern coast of Finland. METHODS: In total, 136 patients were examined to determine their ophthalmological status. Genealogical studies were performed using church records. Direct PCR-sequencing of the coding regions of the TIGR and OPTN genes was performed in 11 subjects. RESULTS: Inheritance resembling autosomal dominant mode was detected in eight families with open-angle glaucoma. Glaucoma was diagnosed in 53 subjects, of them 44 had POAG, 7 had exfoliative glaucoma (EG), and 2 had other types of glaucoma. Of the first degree relatives, 22 out of 79 (28%) were glaucoma suspects. No mutations in these families were identified. Instead, two polymorphisms in the TIGR gene and three polymorphisms in the OPTN gene, in which one was novel, were found in three phenotypes: POAG, exfoliative glaucoma, and exfoliation syndrome. CONCLUSIONS: Our results give evidence that novel, unidentified genes will underlie POAG and exfoliation syndrome in the Finnish population.

Sex ratio and proportion of affected sons in sibships with X-chromosomal recessive traits: maximum likelihood estimation in truncated multinomial distributions.

If mothers are carriers of a recessive male sex-linked disorder, their children may include females, healthy males and affected males. The composition of the possible sibships follows a multinomial distribution. If the mothers are diagnosed as carriers independently of their offspring, then the distributions are not truncated, but if they are classified as carriers after the birth of at least one affected son, the distributions are truncated. In order to avoid ascertainment bias, the statistical analyses of the corresponding data must differ. We present procedures for estimation in both the untruncated and the truncated case. The formulae obtained are applied to family data for X-chromosomal recessive retinoschisis (RS) from the region of Satakunta in southwestern Finland. Earlier studies indicated that, among the offspring of RS carriers, the sex ratio was increased. In our model, therefore, we include both the proportion of males and the proportion of affected individuals among the males. The sex ratio was significantly increased (131.0), but the proportion of affected males was slightly lower than expected (42.5%). RS seems to be the only known genetic disorder in which the offspring of carriers of the mutation include a statistically significant surplus of males.

Exfoliation syndrome: frequency, gender distribution and association with climatically induced alterations of the cornea and conjunctiva.

PURPOSE: To investigate exfoliation syndrome (ES) in order to elucidate gender distribution and the roles of genetic and climatic factors in its manifestation. MATERIAL AND METHODS: We studied the gender distribution of ES and the association between ES and the appearance of certain climatically induced disorders (pterygium, climatic droplet keratopathy) and the size of pingueculae in populations living in the Arctic region, in temperate regions and in tropical regions. This involved a total of 11 samples taken in eight different countries, comprising 2206 persons of both genders over the age of 50 years. RESULTS: A total of 1051 males were investigated for ES and 147 of them (14.0%) were found to have it. The corresponding figures for females were 1093 and 177 (16.2%). After standardization according to age, no systematic difference between the genders was found in the study. The frequency of ES varied greatly. It was not observed at all in the Inuit (Eskimos) but was found most frequently (about 30%) among the Saami (Lapps), Aland Islanders, Finns, Icelanders and Russians over 70 years of age. After the age of 50, the frequency of ES increases rapidly with age in all populations. However, the curves for ES in people living in the tropics show a delay of about 10 years. In contrast, the frequency of climatically caused changes (pterygium, climatic keratopathy and pronounced pinguecula) mostly peaks at the age of 50 years and is highest in the tropics and in the Arctic. Males in these regions tended to be more affected by climatically caused changes than females. Likewise, in tropical climates, where radiation from the sun is strong, and in Lapland and Novosibirsk, where there is radiation from snow, males showed more evidence of ES than females. However, examination of 506 patients from a private practice in South Finland, who were under observation for glaucoma or for risk of glaucoma, showed females to be in the majority of those with ES. CONCLUSIONS: As a rule, climate does not appear to influence the occurrence of ES. However, in tropical countries, where radiation from the sun is strong, ES was more common among males than among females. In the light of its peculiar population distribution, even when climatic factors are considered, there would appear to be an important genetic factor involved in the manifestation of ES.