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Cohen syndrome is an autosomal recessive condition associated with developmental delay, facial dysmorphism, pigmentary retinopathy, and neutropenia. The pleiotropic phenotype, combined with insufficient clinical data, often leads to an erroneous diagnosis and has led to confusion in the literature. Here, we report the results of a comprehensive genotype-phenotype study on the largest cohort of patients with Cohen syndrome assembled to date. We found 22 different COH1 mutations, of which 19 are novel, in probands identified by our diagnostic criteria. In addition, we identified another three novel mutations in patients with incomplete clinical data. By contrast, no COH1 mutations were found in patients with a provisional diagnosis of Cohen syndrome who did not fulfill the diagnostic criteria ("Cohen-like" syndrome). This study provides a molecular confirmation of the clinical phenotype associated with Cohen syndrome and provides a basis for laboratory screening that will be valuable in its diagnosis.

Cohen syndrome is an uncommon autosomal recessive disorder whose diagnosis is based on the clinical picture of nonprogressive psychomotor retardation and microcephaly, characteristic facial features, retinal dystrophy, and intermittent neutropenia. We have refined the critical region on chromosome 8q22 by haplotype analysis, and we report the characterization of a novel gene, COH1, that is mutated in patients with Cohen syndrome. The longest transcript (14,093 bp) is widely expressed and is transcribed from 62 exons that span a genomic region of approximately 864 kb. COH1 encodes a putative transmembrane protein of 4,022 amino acids, with a complex domain structure. Homology to the Saccharomyces cerevisiae VPS13 protein suggests a role for COH1 in vesicle-mediated sorting and transport of proteins within the cell.

Purpose: To analyze the mechanisms of myopia in Cohen syndrome (Mendelian Inheritance in Man [MIM] no. 216550)., Methods: A cross-sectional study of 22 Finnish patients (age range, 2-57 years) with Cohen syndrome, which maps to chromosome 8q22, was undertaken to record cycloplegic refraction, keratometry (corneal power and radius of curvature), biometry (anterior chamber depth [ACD], lens thickness [LT], axial [AL] and vitreal length [VL]), and Hoffer Q-modeled lens power. These components of refraction were correlated to age and spherical equivalent (SE) at the corneal plane. Contribution to total myopia of refractive (corneal and lenticular) and axial components was modeled by multiple linear regression and by estimating the effect of deviation from population mean values., Results: The mean SE in patients with Cohen syndrome older than 10 years was -9.35 D; the mean cylinder power, +1.70 D; and the mean anisometropia, 0.53 D. Relative to the emmetropic eye of a young adult, the AL and VL (mean, 23.9 and 16.6 mm, respectively) and lens power (mean, 30.30 D) were higher in 74% and 93% of patients, respectively, and the ACD (mean, 2.5 mm) was smaller and the LT (mean, 4.9 mm) and corneal power (mean, 45.63 D) higher than average in all patients. Corneal power (r = 0.513, P = 0.021) increased with age, but AL and VL (P = 0.46 and 0.54, respectively) and lens power (P = 0.89) did not correlate with age. The lens power decreased with AL (r = -0.564, P = 0.029) and tended to increase with corneal power (r = 0.475, P = 0.074). Multiple linear regression identified AL and corneal power as independent predictors of SE. Based on deviation from population means, the lens power explained 55%, corneal power 23%, and AL 22% of total myopia. ACD decreased and LT increased markedly with age, rendering angle-closure glaucoma a possibility., Conclusions: Myopia in Cohen syndrome is mainly refractive in type and is due to high corneal and lenticular power, which is otherwise rare in young patients. It may be superimposed on axial myopia, probably related to polygenic factors that determine myopia in the general population. The refractive myopia in Cohen syndrome may result from dysgenesis and atrophy of the cornea, ciliary body, and iris, which in turn cause iridial and zonular laxity and spherophakia.

This article elucidates the clinical picture in Cohen syndrome (MIM 216550), an autosomal recessive disorder that is overrepresented in Finland. The diagnosis is based on the typical clinical picture: nonprogressive psychomotor retardation, motor clumsiness and microcephaly, typical facial features, childhood hypotonia and hyperextensibility of the joints, ophthalmologic findings of retinochoroidal dystrophy and myopia in patients over 5 years of age, and granulocytopenia. In a nationwide study, 29 Finnish patients were investigated. Magnetic resonance images of the brain with quantitative structure analyses revealed a relatively enlarged corpus callosum (CC). The youngest patients had normal EEGs, while all others had low-voltage EEGs. Of the patients, 22% had profound, 61% severe, 6% moderate, and 11% mild retardation. In an adaptive behavior scale (AAMD), patients had high scores in the positive domains (self-direction, responsibility, and socialization), whereas maladaptive behavior was almost lacking. Only the youngest patients had unimpaired visual function. Vision started to deteriorate early but slowly. Progressive myopia and retinochoroidal dystrophy were found in all of the patients over 5 years of age. All of the patients had isolated granulocytopenia. The heart anatomy was normal. However, decreased left ventricular function with advancing age was found. No significant endocrine abnormalities were discovered. Fingers were slender but short, with a typical metacarpophalangeal pattern profile. The manifestations vary at different ages. The Finnish Cohen patients are clinically highly homogeneous, their disease gene being located on chromosome 8. Heterogeneity probably exists among other patients claimed to have Cohen syndrome., (Copyright 2001 Wiley-Liss, Inc.)

Cohen syndrome (MIM no. 216550) is an autosomal recessive disorder with a typical clinical picture. Since the first report, most publications have represented single case reports. In this study, our aim was to describe cardiac, endocrine and radiological abnormalities in 22 Cohen patients of Finnish descent. Detailed investigations of the heart revealed the anatomy of the heart to be normal with no evidence for clinically significant mitral prolapse. However, a decreased left ventricular function with advancing age was identified. No significant endocrine abnormalities were found at the examination of pituitary, adrenal and thyroid function. The height was either normal or patients were moderately short (mean height standard deviation score (SDS) - 2) at all ages, associated, however, often with the marked kyphosis. Truncal obesity was seen in 4/22 patients. X-rays of the chest, lumbar and thoracic spine, long bones, ankles and metacarpophalangeal pattern profiles revealed kyphosis, scoliosis and calcaneo planovalgus as common features. Fingers of these patients were slender but short with a characteristic metacarpophalangeal pattern profile.

Our purpose was to perform the first systematic brain magnetic resonance imaging (MRI) study of a substantial number of Cohen syndrome (MIM n:o 216550) patients. 18 Cohen patients and 26 healthy volunteers were examined by MRI (1.0 T). All Cohen patients had essential features of this syndrome: typical facial and structural features, mental retardation, microcephaly, ophthalmologic symptoms, granulocytopenia and cheerful psychic disposition. All our patients belong to the recently published study of refined mapping of the Cohen syndrome gene by linkage disequilibrium. As visual analysis of MR images revealed an impression of a large corpus callosum (CC), quantitative analysis was performed. Sagittal diameter of the body of the CC was larger than that of controls (p = 0.02), whereas all sagittal diameters of the brain stem were markedly smaller (p < 0.0001), as was the midline internal skull surface (MISS) (p < 0.0001). The CC surface did not significantly differ from that of controls significantly. Our main finding, a relatively enlarged corpus callosum, has not previously been reported to associate with mental retardation. Though MRI alone can not confirm the diagnosis and no definite measurements can be recommended for clinical use, any clinical suspicion of this syndrome receives reinforcement through MRI: a relatively enlarged corpus callosum in a microcephalic head and normal signal intensities of the grey and white matters.

The Cohen syndrome is a rare autosomal recessively inherited disorder. Contrary to many case reports published elsewhere, the phenotype is uniform in Finland including nonprogressive mental and motor retardation, typical dysmorphic features, granulocytopenia and marked ophthalmological changes. By linkage analysis in five Finnish multiplex nuclear families, the COH1 locus for the Cohen syndrome was recently assigned to a 10-cM region between loci D8S270 and D8S521 on the long arm of chromosome 8. Here we present results of linkage disequilibrium and haplotype analysis in an extended panel of 16 Finnish COH1 families using new markers localized in the COH1 region. By inferring historical recombinations in conserved haplotypes the COH1 gene was assigned in the region of marker loci D8S1808, D8S1762 and D8S546. Calculations of genetic distances based on linkage disequilibrium suggest that the most likely localization of COH1 is in the immediate vicinity of marker locus D8S1762. Haplotype analysis suggests the occurrence of one main COH1 mutation and possibly one or two rare ones in Finland. This information will be useful in the positional cloning of the gene.

Cohen syndrome is an autosomal recessive disorder characterized by mental and motor retardation, short stature, microcephaly, several dysmorphic features, major ocular symptoms and granulocytopenia. Major research challenges are the confusing nosology and the pleiotropy of the gene. We report the mapping of a locus (CHS1) by linkage analysis in as few as four two-generation pedigrees with uniform clinical features. CHS1 was assigned to an interval of approximately 10 cM between D8S270 and D8S521. Our results provide a tool to a more accurate definition of Cohen syndrome(s) and a starting point for the positional cloning of CHS1.

Six new patients with the Cohen syndrome are reported from Finland and 25 published cases from elsewhere are reviewed. New findings are consanguinity among two pairs of parents, granulocytopenia, and marked ophthalmological changes: decreased visual acuity, hemeralopia, constricted visual fields, chorioretinal dystrophy with bull's-eye-like maculae and pigmentary deposits, optic atrophy, and isoelectric electroretinogram. Previously known features of the Cohen syndrome (non-progressive mental retardation, short stature, microcephaly, peculiar facies, slender hands and feet, floppiness, delayed puberty) are confirmed or revised. The ophthalmological features merit attention in the previous and future suspected cases of the Cohen syndrome. Autosomal recessive inheritance can be taken for granted.

Estimates of the incidence of the Meckel syndrome (MS) from different parts of the world vary from 1:140,000 to 1:13,250 births. In this nationwide study performed in Finland, the incidence of 1:14,400 births was found by retrospective ascertainment during the period 1970-1979, while the incidence was 1:8,500 births when prospective monitoring was performed in 1980-1981. The most probable incidence in Finland is about 1:9,000 births. Autosomal recessive inheritance of MS is confirmed in this study. The ratio of affected sibs, corrected for truncate complete ascertainment, was 0.261. No consanguinity between parents was found, as marriages between close relatives are rare in Finland and the ancestors were not traced back far enough to find remote consanguinities.

We describe a lethal malformation syndrome in 28 newborn infants from 18 families. The main manifestations were hydrocephalus (often with an unusual structure of the brain and the occipital bone), very small mandible, polydactyly, congenital heart defect, abnormalities of the respiratory organs, and (different from the Meckel syndrome) normal kidneys. Polyhydramnios and stillbirth or neonatal death were the rule. Autosomal recessive inheritance is evident. This syndrome is another in the group of rare recessive disorders which are found in Finland. Because of the 25% recurrence risk and possibilities for prenatal diagnosis, this syndrome should be recognized by paediatricians and, because of the frequent stillbirths, also by obstetricians and pathologists. The name hydrolethalus syndrome (hydramnios, hydrocephalus, lethality) may be of help in this.