RESUMO
Dupuytren's disease (DD) is a progressive fibromatosis that causes the formation of nodules and cords in the palmar aponeurosis leading to flexion contracture of affected fingers. The etiopathogenesis is multifactorial with a strong genetic predisposition. It is the most frequent genetic disorder of connective tissues. We have collected clinical data from 736 unrelated individuals with DD who underwent surgical treatment from Germany and Switzerland. We evaluated a standardised questionnaire, assessed the importance of different risk factors and compared subgroups with and without positive family history. We found that family history clearly had the strongest influence on the age at first surgery compared to environmental factors, followed by male sex. Participants with a positive family history were on average 55.9 years of age at the first surgical intervention, 5.2 years younger than probands without known family history (p = 6.7 × 10(-8) ). The percentage of familial cases decreased with age of onset from 55% in the 40-49 years old to 17% at age 80 years or older. Further risk factors analysed were cigarettes, alcohol, diabetes, hypertension, and epilepsy. Our data pinpoint the importance of genetic susceptibility for DD, which has long been underestimated.
Assuntos
Contratura de Dupuytren/genética , Predisposição Genética para Doença , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Contratura de Dupuytren/epidemiologia , Contratura de Dupuytren/cirurgia , Feminino , Alemanha/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Fatores de Risco , Inquéritos e Questionários , Suíça/epidemiologiaRESUMO
Craniometaphyseal dysplasia (CMD) is a bone dysplasia characterized by overgrowth and sclerosis of the craniofacial bones and abnormal modeling of the metaphyses of the tubular bones. Hyperostosis and sclerosis of the skull may lead to cranial nerve compressions resulting in hearing loss and facial palsy. An autosomal dominant form of the disorder (MIM 123000) was linked to chromosome 5p15.2-p14.1 (ref. 3) within a region harboring the human homolog (ANKH) of the mouse progressive ankylosis (ank) gene. The ANK protein spans the outer cell membrane and shuttles inorganic pyrophosphate (PPi), a major inhibitor of physiologic and pathologic calcification, bone mineralization and bone resorption. Here we carry out mutation analysis of ANKH, revealing six different mutations in eight of nine families. The mutations predict single amino acid substitutions, deletions or insertions. Using a helix prediction program, we propose for the ANK molecule 12 membrane-spanning helices with an alternate inside/out orientation and a central channel permitting the passage of PPi. The mutations occur at highly conserved amino acid residues presumed to be located in the cytosolic portion of the protein. Our results link the PPi channel ANK with bone formation and remodeling.
Assuntos
Doenças do Desenvolvimento Ósseo/genética , Joelho/patologia , Proteínas de Membrana/genética , Mutação , Crânio/patologia , Sequência de Aminoácidos , Anquilose/genética , Criança , Pré-Escolar , Feminino , Fêmur/patologia , Heterozigoto , Humanos , Masculino , Dados de Sequência Molecular , Linhagem , Proteínas de Transporte de Fosfato , Homologia de Sequência de AminoácidosRESUMO
MOMO syndrome, previously defined as Macrosomia, Obesity, Macrocephaly, and Ocular abnormalities (OMIM 157980) is a rare intellectual disability syndrome of unknown cause. We describe two further patients with MOMO syndrome. Reported data of patients with MOMO syndrome and our own findings indicate that overgrowth does not appear to be a specific feature. We propose to form the acronym "MOMO" from Macrocephaly, Obesity, Mental (intellectual) disability, and Ocular abnormalities, excluding macrosomia from the syndrome name. The combination of obesity, macrocephaly, and colobomas is unique, therefore these features can be used as major diagnostic criteria of MOMO syndrome.
Assuntos
Anormalidades Múltiplas/diagnóstico , Coloboma/diagnóstico , Macrossomia Fetal/diagnóstico , Deficiência Intelectual/diagnóstico , Megalencefalia/diagnóstico , Obesidade/diagnóstico , Anormalidades Múltiplas/genética , Encéfalo/patologia , Pré-Escolar , Bandeamento Cromossômico , Coloboma/genética , Fácies , Feminino , Macrossomia Fetal/genética , Cabeça/anormalidades , Humanos , Lactente , Deficiência Intelectual/genética , Imageamento por Ressonância Magnética , Masculino , Megalencefalia/genética , Obesidade/genética , FenótipoRESUMO
We report on three patients from two families with apparently a novel clinical entity. The main features of which include unusual craniofacial dysmorphism with ptosis, prominent eyes, flat midface, Cupid's bow configuration of the upper lip, low-set, posteriorly rotated small ears, as well as conductive hearing loss, cleft palate, heart defect, and mild developmental delay. We suggest that this entity is an autosomal dominant disorder given the occurrence in a mother and daughter as well as in an unrelated boy.
Assuntos
Anormalidades Múltiplas , Transtornos Cromossômicos/genética , Deficiências da Aprendizagem , Adulto , Blefaroptose , Pré-Escolar , Fissura Palatina , Anormalidades Craniofaciais , Orelha/anormalidades , Anormalidades do Olho , Face/anormalidades , Feminino , Perda Auditiva , Cardiopatias Congênitas , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , SíndromeAssuntos
Anormalidades Craniofaciais , Sindactilia , Humanos , Intestinos/anormalidades , Mutação , Anormalidades da Pele , SíndromeRESUMO
Pontine tegmental cap dysplasia (PTCD) is a newly described hindbrain malformation with distinct neuroradiological findings. Only 12 cases of PTCD have been described so far, all sporadic. We report 2 further patients. Both children presented after birth with significant feeding problems due to impaired mouth opening (previously not reported) and sucking difficulties. Facial, cochlear, and glossopharyngeal nerves were involved resulting in bilateral sensory deafness and a significant swallowing disorder requiring a gastrostomy. In one patient the trigeminal sensory nerve was also involved causing severe bilateral corneal clouding with impaired vision. Both patients showed only minimal developmental progress since birth and had no speech production. Furthermore, they had vertebral and rib anomalies. The patients died at the age of 15 and 32 months, respectively, due to intercurrent infections. The majority of patients reported previously were affected less severely. The presented patients may represent the severe end of the spectrum.
Assuntos
Anormalidades Múltiplas/patologia , Hiperplasia/patologia , Ponte/anormalidades , Ponte/patologia , Nervo Trigêmeo/anormalidades , Pré-Escolar , Surdez/patologia , Feminino , Humanos , Hiperplasia/complicações , Lactente , Deficiência Intelectual/patologia , Imageamento por Ressonância Magnética/métodos , Nervo Trigêmeo/patologiaRESUMO
OBJECTIVE: Alkaptonuria (AKU) is a rare inborn error of metabolism of aromatic amino acids and considered to be an autosomal recessive trait caused by mutations in the homogentisate 1,2-dioxygenase (HGD) gene. A dominant pattern of inheritance has been reported but was attributed to extended consanguinity in many cases. However, we have observed a non-consanguineous family segregating AKU in a dominant manner over three generations. RESULTS: All affected individuals presented with typical features of AKU including darkening of the urine, ochronosis, arthropathy, and elevated urinary excretion of homogentisic acid. Sequence analysis of the HGD gene from genomic DNA of two affected individuals, uncle and niece, revealed a heterozygous missense mutation (M368V) in the uncle that was not present in his niece. Microsatellite genotyping demonstrated that both were heterozygous at the HGD locus and shared one haplotype. This haplotype did not contain a detectable HGD mutation. The haplotype was also found in a healthy son of the niece, making a dominant HGD mutation unlikely. Moreover, sequencing of cDNA from lymphoblastoid cells of the niece did not reveal an HGD mRNA with a potentially dominant-negative effect. CONCLUSION: Rare causes of the uncommon AKU inheritance in this family have to be considered, ranging from the coincidence of undetectable HGD mutations to a dominant mutation of a second, hitherto unknown AKU gene.
Assuntos
Alcaptonúria/diagnóstico , Homogentisato 1,2-Dioxigenase/genética , Mutação de Sentido Incorreto , Ocronose/diagnóstico , Adulto , Idoso , Alcaptonúria/enzimologia , Alcaptonúria/genética , Alcaptonúria/urina , Biomarcadores/urina , Análise Mutacional de DNA , Feminino , Frequência do Gene , Predisposição Genética para Doença , Haplótipos , Hereditariedade , Heterozigoto , Ácido Homogentísico/urina , Humanos , Masculino , Repetições de Microssatélites , Pessoa de Meia-Idade , Ocronose/enzimologia , Ocronose/genética , Ocronose/urina , Linhagem , FenótipoRESUMO
Segmental neurofibromatosis (NF) is generally thought to result from a postzygotic NF1 (neurofibromatosis type 1) gene mutation. However, this has not yet been demonstrated at the molecular level. Using fluorescence in situ hybridisation (FISH) we identified an NF1 microdeletion in a patient with segmental NF in whom café-au-lait spots and freckles are limited to a single body region. The mutant allele was present in a mosaic pattern in cultured fibroblasts from a café-au-lait spot lesion, but was absent in fibroblasts from normal skin as well as in peripheral blood leukocytes. These findings prove the hypothesis that the molecular basis of segmental cutaneous NF is a mutation in the NF1 gene and that the regional distribution of manifestations reflects different cell clones, commensurate with the concept of somatic mosaicism.
Assuntos
Deleção de Genes , Mosaicismo , Proteínas do Tecido Nervoso/genética , Neurofibromatoses/genética , Adolescente , Humanos , Hibridização in Situ Fluorescente , Masculino , Mutação , Neurofibromina 1 , FenótipoRESUMO
Craniometaphyseal dysplasia (CMD) was found in 6 generations of a large German kindred; 24 affected individuals were identified. The clinical diagnosis was confirmed by further examinations in 15 individuals, including 2 exhumed skeletons. Five deceased individuals were considered to be undoubtedly affected by reviewing photographs, and 4 must have had CMD from genealogical considerations. Pedigree analysis was performed over 8 generations back to persons born at the beginning of the 18th century in a central area of Germany. The trait could be traced back to a common male ancestor, born in 1790. Molecular genetic investigations on 3 generations of this kindred are in progress. In the present study we describe the clinical characteristics of the family.
Assuntos
Anormalidades Craniofaciais/genética , Ossos Faciais/anormalidades , Crânio/anormalidades , Anormalidades Craniofaciais/diagnóstico por imagem , Ossos Faciais/diagnóstico por imagem , Família , Feminino , Fêmur/anormalidades , Fêmur/diagnóstico por imagem , Alemanha , Humanos , Hiperostose/diagnóstico por imagem , Hiperostose/genética , Hipertelorismo/diagnóstico por imagem , Hipertelorismo/genética , Masculino , Linhagem , Radiografia , Esclerose/diagnóstico por imagem , Esclerose/genética , Crânio/diagnóstico por imagemRESUMO
We describe a new autosomal dominant type of metaphyseal dysplasia (MD) in five generations of a German kindred. The main characteristics are metaphyseal widening and undermodeling of the tubular bones with Erlenmeyer flask-like appearance of the distal femora (typical of MD), with unusually severe varus deformity of the radii and flat exostoses of the long bones localized in the metaphyses. The skull is unaffected. Allelism with craniometaphyseal dysplasia (CMD) was excluded by linkage analysis.
Assuntos
Exostose Múltipla Hereditária/diagnóstico por imagem , Fêmur/anormalidades , Osteocondrodisplasias/genética , Rádio (Anatomia)/anormalidades , Criança , Feminino , Fêmur/diagnóstico por imagem , Genes Dominantes , Ligação Genética , Alemanha , Humanos , Masculino , Osteocondrodisplasias/diagnóstico por imagem , Linhagem , Radiografia , Rádio (Anatomia)/diagnóstico por imagemRESUMO
We discuss an unlabelled specimen of tetraphocomelia and bilaterally cleft lip from the former Virchow Museum of our Medical School. Identity of the subject with a case of what was later termed "Roberts syndrome" published by Rudolf Virchow in 1898 is demonstrated. Rediscovery of this important historical case is gratifying, since almost 95% of the specimens of Virchow's collection were lost during World War II. We have restudied Virchow's case. Recent CT scan images of the fetus are presented. We review data from the literature and present new clinical details. The fate of the original clinical data after passing through three reviews is documented briefly. We also reconstruct Virchow's view on phocomelia and its consequences for later research.
Assuntos
Anormalidades Múltiplas/história , Fenda Labial/história , Ectromelia/história , Anormalidades Múltiplas/patologia , Fenda Labial/patologia , Ectromelia/patologia , História do Século XIX , História do Século XX , Humanos , Recém-Nascido , Masculino , Síndrome , Tomografia Computadorizada por Raios XRESUMO
Molecular genetics recently uncovered the mystery of the protean picture of McCune-Albright syndrome by identification of the somatic gain of function mutations in the GNAS1 gene. Here we present an adult patient with fibrous dysplasia and an endocrinopathy resulting in unusual giant height. The clinical diagnosis in the patient could be confirmed by molecular investigations in tissues involved in the process of fibrous dysplasia.
Assuntos
Displasia Fibrosa Poliostótica/genética , Subunidades alfa Gs de Proteínas de Ligação ao GTP/genética , Gigantismo/genética , Mosaicismo , Adolescente , Adulto , Osso e Ossos/diagnóstico por imagem , Análise Mutacional de DNA , Face/anormalidades , Displasia Fibrosa Poliostótica/diagnóstico por imagem , Gigantismo/diagnóstico por imagem , Humanos , Imageamento por Ressonância Magnética , Masculino , Reação em Cadeia da Polimerase , Crânio/diagnóstico por imagem , Síndrome , Tomografia Computadorizada por Raios XRESUMO
We report a 21-year-old male with symptomatic optic glioma who does not fulfill the diagnosis of neurofibromatosis 1 (NF1) according to standard NIH criteria. Analysis of the NF1 gene revealed a recurrent mutation in exon 37 (C6792A or Y2264X). This nonsense mutation causes skipping of exon 37 during the splicing process and is predicted to result in a protein shortened by 34 amino acid residues. The mutation was detected in all tissues examined (blood lymphocytes, oral mucosa, and dermal fibroblasts). The same mutation was previously found in 3 patients with clinically confirmed NF1. To our knowledge, this is the first report of an adult patient carrying a putative (non-mosaic) NF1 gene mutation in multiple tissues but not fulfilling the NIH criteria for the clinical diagnosis of NF1.
Assuntos
Genes da Neurofibromatose 1 , Mutação , Neurofibromatose 1/genética , Adulto , Códon sem Sentido/genética , Análise Mutacional de DNA , Glioma/genética , Humanos , Masculino , Neurofibromatose 1/diagnóstico , Neoplasias do Nervo Óptico/genéticaRESUMO
We report on a 13-year-old patient followed since birth. He is the only offspring of young, non-consanguineous German parents. His mother has an isolated left cleft of lip and a cleft palate. At birth, our patient presented with bilaterally cleft lip/cleft palate, phocomelia of upper limbs with normal hands, and mild symmetrical deficiencies of the long bones of the lower limbs. Haematological evaluation demonstrated a leukaemoid reaction during a urinary tract infection as well as intermittent thrombocytopenia and episodes of marked eosinophilia during the first two years of life. Intellectual development has been normal. Comparison with two similar cases from the literature suggests a non-random phenotypic overlap of Roberts syndrome (MIM 268300) and TAR syndrome (MIM 274000). Such clinical constellations may be key observations to understand the genetic relationship of Roberts syndrome and TAR syndrome in future phenotype-genotype correlations.
Assuntos
Fenda Labial/patologia , Hematologia , Deformidades Congênitas dos Membros/patologia , Adolescente , Anemia Aplástica/patologia , Fissura Palatina/patologia , Cardiopatias/congênito , Cardiopatias/patologia , Humanos , Rim/anormalidades , Rim/patologia , Deformidades Congênitas dos Membros/diagnóstico por imagem , Masculino , Radiografia , Síndrome , Trombocitopenia/patologiaRESUMO
X-linked hydrocephalus (HSAS) (MIM *307000), MASA syndrome (MIM *303350), and complicated spastic paraplegia (SPG1) (MIM *312900) are closely related. Soon after delineation, SPG1 was incorporated into the spectrum of MASA syndrome. HSAS and MASA syndrome show great clinical overlap; DNA linkage analysis places the loci at Xq28. In an increasing number of families with MASA syndrome or HSAS, mutations in L1CAM, a gene located at Xq28, have been reported. In order to further delineate the clinical spectrum, we studied 6 families with male patients presenting with MASA syndrome, HSAS, or a mixed phenotype. We summarized data from previous reports and compared them with our data. Clinical variability appears to be great, even within families. Problems in genetic counseling and prenatal diagnosis, the possible overlap with X-linked corpus callosum agenesis and FG syndrome, and the different forms of X-linked complicated spastic paraplegia are discussed. Since adducted thumbs and spastic paraplegia are found in 90% of the patients, the condition may be present in males with nonspecific mental retardation. We propose to abandon the designation MASA syndrome and use the term HSAS/MASA spectrum, incorporating SPG1.
Assuntos
Hidrocefalia/genética , Deficiência Intelectual/genética , Paraplegia/genética , Cromossomo X , Agenesia do Corpo Caloso , Feminino , Aconselhamento Genético , Idade Gestacional , Humanos , Hidrocefalia/fisiopatologia , Lactente , Recém-Nascido , Deficiência Intelectual/fisiopatologia , Masculino , Paraplegia/fisiopatologia , Linhagem , Gravidez , Diagnóstico Pré-Natal , Estudos Retrospectivos , SíndromeRESUMO
We report on two independent alterations of the NF1 gene in a three-generation kindred with neurofibromatosis type 1 (NF1). Using temperature gradient gel electrophoresis (TGGE) in a mutation analysis of exon 31 of the NF1 gene we detected the previously reported nonsense mutation R1947X. This C-to-T transition at codon 1947 in exon 31 is considered to represent a mutation "hot spot" of the NF1 gene due to 5mCpG deamination. All living family members together with their genomic DNA were included in this investigation. However, the mutation R1947X was absent from two undoubtedly affected siblings of the propositus. Another NF1 mutation (889-2A-->G) was identified in the two sibs by the protein truncation test (PTT). The novel splice site mutation 889-2A-->G results in a skip of NF1 exon 7 during splicing and protein truncation due to frameshift. The two NF1 alterations are linked to different paternal haplotypes. In our study of a three-generation kindred, R1947X represents a de novo mutation whereas 889-2A-->G is an inherited splice mutation. Implications for phenotype variation are discussed.
Assuntos
Genes da Neurofibromatose 1 , Neurofibromatose 1/genética , Mutação Puntual , Cromossomos Humanos Par 17/genética , Impressões Digitais de DNA , Feminino , Genótipo , Haplótipos , Humanos , Masculino , Modelos Estatísticos , Paternidade , Linhagem , Fenótipo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Análise de Sequência de DNARESUMO
BACKGROUND: The diagnostic criteria of Proteus syndrome include various lesions of localized overgrowth such as digital gigantism, hemihyperplasia with unilateral macrocephaly, epidermal nevus, and mesodermal hamartomas such as lipoma, lymphangioma, hemangioma, or fibroma. Hyperplasia of the plantar dermal tissue may result in a characteristic cerebriform appearance. However, hypoplastic lesions involving various tissues such as subcutaneous fat or muscles also may be observed in this syndrome. This paradoxical phenomenon has so far been underestimated, and the presence of circumscribed lesions of dermal hypoplasia has been entirely ignored. OBSERVATIONS: We report 4 cases of Proteus syndrome associated with large patches of dermal hypoplasia, resulting in a more prominent appearance of venous vasculature. CONCLUSIONS: Patchy dermal hypoplasia appears to be a characteristic feature within the spectrum of Proteus syndrome. The anomaly should not be confused with partial lipohypoplasia that may likewise be associated with this multisystem birth defect. From a review of the literature, we conclude that patchy dermal hypoplasia may have occurred in several previous cases. In the future, recognition of this cutaneous anomaly may help to establish the diagnosis in otherwise doubtful cases. To explain the coexistence of lesions of dermal hyperplasia and hypoplasia, we propose the genetic concept of "twin spotting." At the gene locus of Proteus syndrome the embryo would carry 1 allele giving rise to dermal overgrowth, whereas the corresponding allele would be responsible for a diminished proliferation of cutaneous fibroblasts. Somatic recombination may result in 2 different populations of cells homozygous for either allele.
Assuntos
Hipoplasia Dérmica Focal/etiologia , Síndrome de Proteu/complicações , Criança , Feminino , Humanos , MasculinoRESUMO
The formation of dermal neurofibromas is a hallmark of the neurofibromatosis type 1 (NF1). A total loss of the NF1 gene product by stochastic events inactivating the wild type allele in Schwann cells should precede the development of neurofibromas. Dermal neurofibromas tend to be located mainly on the surface of the trunk and not in the body periphery. This distribution partly resembles the density of sensitive nerve endings in the epidermis. Our hypothesis is that a better correlation concerns the pattern of normal body surface temperature. According to our clinical observations we assume that in skin areas with higher temperatures the number of visible dermal neurofibromas is higher than in colder areas such as the arms/legs or nose. It is known that differences in temperature are able to determine differentiation. We suggest that the regulation of skin temperature is also involved in the formation of NF1 dermal neurofibromas and is related to the intrafamilial variability in NF1.
Assuntos
Neurofibromatose 1/patologia , Temperatura Cutânea , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Neurofibroma/genética , Neurofibroma/patologia , Neurofibromatose 1/genética , Termografia/métodosRESUMO
Two sisters with Larsen syndrome are presented. The clinically unaffected parents originate from the South of Egypt and are first cousins. Further family history was non-contributory. Autosomal recessive inheritance of Larsen syndrome is most likely in this family.
Assuntos
Anormalidades Múltiplas/genética , Genes Dominantes/genética , Genes Recessivos/genética , Criança , Face/anormalidades , Feminino , Humanos , Artropatias/genética , Núcleo Familiar , SíndromeRESUMO
X-linked hydrocephalus and the X-linked MASA syndrome (Mental retardation. Adducted thumbs, Shuffling gait and Aphasia) both have a variable clinical spectrum with great overlap. Data from DNA linkage analysis placed the locus for both conditions at Xq28. On clinical and molecular grounds it has been hypothesized that both MASA syndrome and X-linked hydrocephalus are caused by a mutation in the same gene at Xq28. There is no significant clinical marker in the obligate female carriers and prenatal diagnosis by ultrasound is not reliable; DNA analysis can offer an improved genetic counseling for the families and more reliable prenatal diagnosis. In the gene encoding for Ll, a neural cell adhesion molecule and located at Xq28, several different mutations have been reported in X-linked hydrocephalus families and in a MASA family. We report data on DNA linkage analysis in 6 families with X-linked hydrocephalus/MASA syndrome. These data illustrate the importance of DNA linkage analysis in the individual family; they also show, however, the problem of studying small families. Genetic heterogeneity cannot be excluded.