RESUMO
Noonan and Cardio-facio-cutaneous (CFC) syndromes are characterized by typical dysmorphic features, cardiac defects, short stature, variable ectodermal anomalies, and intellectual disability. Both belong to the Ras/mitogen-activated protein kinase pathway group of disorders and clinical features overlap other related conditions, notably LEOPARD and Costello syndromes. KRAS mutations account for about 2% of reported Noonan and <5% of reported CFC cases. The mutation spectrum includes recurrent missense changes clustering in particular domains of the KRAS protein and conferring gain-of-function. We report three patients from two unrelated families with novel missense KRAS mutations, p.K147E and p.Y71H. Both mutations affect a residue which is highly conserved in KRAS and other RAS isoforms. One of the families includes a mother and son pair who represent the first report of a vertically transmitted KRAS mutation. In addition, the mother and son pair had peripheral neuropathy, complicated by Charcot arthropathy in the mother. An unusual phenotypic effect of the specific KRAS mutation or a coincidence of two independent disorders may be considered. KRAS mutation-associated phenotypes appear to be subject to considerable clinical heterogeneity. All three cases highlight the challenges of clinical assessment in KRAS mutation-positive patients, and the utility of molecular testing as an adjunct to diagnosis.
Assuntos
Mutação em Linhagem Germinativa , Fenótipo , Proteínas Proto-Oncogênicas/genética , Proteínas ras/genética , Artropatia Neurogênica/complicações , Artropatia Neurogênica/genética , Pré-Escolar , Diagnóstico Diferencial , Displasia Ectodérmica/complicações , Displasia Ectodérmica/genética , Fácies , Insuficiência de Crescimento/complicações , Insuficiência de Crescimento/genética , Feminino , Cardiopatias Congênitas/complicações , Cardiopatias Congênitas/genética , Humanos , Masculino , Proteínas Quinases Ativadas por Mitógeno/genética , Síndrome de Noonan/genética , Linhagem , Doenças do Sistema Nervoso Periférico/complicações , Doenças do Sistema Nervoso Periférico/genética , Proteínas Proto-Oncogênicas p21(ras)RESUMO
Microcephalic osteodysplastic primordial dwarfism type I (MOPD I) is a rare autosomal recessive developmental disorder characterized by extreme intrauterine growth retardation, severe microcephaly, central nervous system abnormalities, dysmorphic facial features, skin abnormalities, skeletal changes, limb deformations, and early death. Recently, mutations in the RNU4ATAC gene, which encodes U4atac, a small nuclear RNA that is a crucial component of the minor spliceosome, were found to cause MOPD I. MOPD I is the first disease known to be associated with a defect in small nuclear RNAs. We describe here the clinical and molecular data for 17 cases of MOPD I, including 15 previously unreported cases, all carrying biallelic mutations in the RNU4ATAC gene.
Assuntos
Alelos , Nanismo/genética , Retardo do Crescimento Fetal/genética , Microcefalia/genética , Mutação , Osteocondrodisplasias/genética , RNA Nuclear Pequeno/genética , Encéfalo/patologia , Nanismo/diagnóstico , Fácies , Feminino , Retardo do Crescimento Fetal/diagnóstico , Humanos , Lactente , Expectativa de Vida , Imageamento por Ressonância Magnética , Masculino , Microcefalia/diagnóstico , Osteocondrodisplasias/diagnóstico , FenótipoRESUMO
Hallermann-Streiff syndrome (HSS) is a rare inherited disorder characterized by malformations of the cranium and facial bones, congenital cataracts, microphthalmia, skin atrophy, hypotrichosis, proportionate short stature, teeth abnormalities, and a typical facial appearance with prominent forehead, small pointed nose, and micrognathia. The genetic cause of this developmental disorder is presently unknown. Here we describe 8 new patients with a phenotype of HSS. Individuals with HSS present with clinical features overlapping with some progeroid syndromes that belong to the laminopathies, such as Hutchinson-Gilford progeria syndrome (HGPS) and mandibuloacral dysplasia (MAD). HGPS is caused by de novo point mutations in the LMNA gene, coding for the nuclear lamina proteins lamin A and C. MAD with type A and B lipodystrophy are recessive disorders resulting from mutations in LMNA and ZMPSTE24, respectively. ZMPSTE24 in addition to ICMT encode proteins involved in posttranslational processing of lamin A. We hypothesized that HSS is an allelic disorder to HGPS and MAD. As the nuclear shape is often irregular in patients with LMNA mutations, we first analyzed the nuclear morphology in skin fibroblasts of patients with HSS, but could not identify any abnormality. Sequencing of the genes LMNA, ZMPSTE24 and ICMT in the 8 patients with HSS revealed the heterozygous missense mutation c.1930C>T (p.R644C) in LMNA in 1 female. Extreme phenotypic diversity and low penetrance have been associated with the p.R644C mutation. In ZMPSTE24 and ICMT, no pathogenic sequence change was detected in patients with HSS. Together, we found no evidence that HSS is another laminopathy.
RESUMO
Cardio-facio-cutaneous (CFC) and Costello syndrome (CS) are congenital disorders with a significant clinical overlap. The recent discovery of heterozygous mutations in genes encoding components of the RAS-RAF-MAPK pathway in both CFC and CS suggested a similar underlying pathogenesis of these two disorders. While CFC is heterogeneous with mutations in BRAF, MAP2K1, MAP2K2 and KRAS, HRAS alterations are almost exclusively associated with CS. We carried out a comprehensive mutation analysis in 51 CFC-affected patients and 31 individuals with CS. Twelve different BRAF alterations were found in twenty-four patients with CFC (47.0%), two MAP2K1 mutations in five (9.8%) and two MAP2K2 sequence variations in three CFC-affected individuals (5.9%), whereas three patients had a KRAS alteration (5.9%). We identified four different missense mutations of HRAS in twenty-eight cases with CS (90.3%), while KRAS mutations were detected in two infants with a phenotype meeting criteria for CS (6.5%). In 14 informative families, we traced the parental origin of HRAS alterations and demonstrated inheritance of the mutated allele exclusively from the father, further confirming a paternal bias in the parental origin of HRAS mutations in CS. Careful clinical evaluation of patients with BRAF and MAP2K1/2 alterations revealed the presence of slight phenotypic differences regarding craniofacial features in MAP2K1- and MAP2K2-mutation positive individuals, suggesting possible genotype-phenotype correlations.
Assuntos
Anormalidades Múltiplas/genética , Fácies , Cardiopatias Congênitas/genética , Mutação , Anormalidades da Pele/genética , Adulto , Criança , Análise Mutacional de DNA , Deficiências do Desenvolvimento , Humanos , Deficiência Intelectual , MAP Quinase Quinase 1/genética , MAP Quinase Quinase 2/genética , Fenótipo , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas p21(ras) , Síndrome , Proteínas ras/genéticaAssuntos
Neoplasias do Sistema Nervoso Central/genética , Hemangioma Cavernoso do Sistema Nervoso Central/genética , Proteínas Associadas aos Microtúbulos/genética , Mutação de Sentido Incorreto , Proteínas Proto-Oncogênicas/genética , Substituição de Aminoácidos , Códon/genética , Humanos , Proteína KRIT1Assuntos
Neoplasias do Sistema Nervoso Central/genética , Hemangioma Cavernoso do Sistema Nervoso Central/genética , Proteínas Associadas aos Microtúbulos/genética , Mutagênese Insercional , Proteínas Proto-Oncogênicas/genética , Sequência de Bases , Códon/genética , DNA/genética , Humanos , Proteína KRIT1Assuntos
Neoplasias do Sistema Nervoso Central/genética , Hemangioma Cavernoso do Sistema Nervoso Central/genética , Proteínas Associadas aos Microtúbulos/genética , Mutagênese Insercional , Proteínas Proto-Oncogênicas/genética , Sequência de Bases , Códon/genética , DNA/genética , Humanos , Proteína KRIT1Assuntos
Neoplasias do Sistema Nervoso Central/genética , Hemangioma Cavernoso do Sistema Nervoso Central/genética , Proteínas Associadas aos Microtúbulos/genética , Mutagênese Insercional , Proteínas Proto-Oncogênicas/genética , Sequência de Bases , Códon/genética , DNA/genética , Humanos , Proteína KRIT1Assuntos
Neoplasias do Sistema Nervoso Central/genética , Hemangioma Cavernoso do Sistema Nervoso Central/genética , Proteínas Associadas aos Microtúbulos/genética , Mutagênese Insercional , Proteínas Proto-Oncogênicas/genética , Sequência de Bases , Códon/genética , DNA/genética , Humanos , Proteína KRIT1Assuntos
Neoplasias do Sistema Nervoso Central/genética , Hemangioma Cavernoso do Sistema Nervoso Central/genética , Proteínas Associadas aos Microtúbulos/genética , Mutagênese Insercional , Proteínas Proto-Oncogênicas/genética , Sequência de Bases , Códon/genética , DNA/genética , Humanos , Proteína KRIT1Assuntos
Neoplasias do Sistema Nervoso Central/genética , Hemangioma Cavernoso do Sistema Nervoso Central/genética , Proteínas Associadas aos Microtúbulos/genética , Proteínas Proto-Oncogênicas/genética , Deleção de Sequência , Sequência de Bases , Códon/genética , DNA/genética , Humanos , Proteína KRIT1Assuntos
Neoplasias do Sistema Nervoso Central/genética , Hemangioma Cavernoso do Sistema Nervoso Central/genética , Proteínas Associadas aos Microtúbulos/genética , Mutação Puntual , Proteínas Proto-Oncogênicas/genética , Humanos , Íntrons , Proteína KRIT1 , Sítios de Splice de RNA , Splicing de RNA/genéticaAssuntos
Neoplasias do Sistema Nervoso Central/genética , Hemangioma Cavernoso do Sistema Nervoso Central/genética , Proteínas Associadas aos Microtúbulos/genética , Proteínas Proto-Oncogênicas/genética , Deleção de Sequência , Sequência de Bases , Códon/genética , DNA/genética , Humanos , Proteína KRIT1Assuntos
Neoplasias do Sistema Nervoso Central/genética , Hemangioma Cavernoso do Sistema Nervoso Central/genética , Proteínas Associadas aos Microtúbulos/genética , Proteínas Proto-Oncogênicas/genética , Deleção de Sequência , Sequência de Bases , Códon/genética , DNA/genética , Humanos , Proteína KRIT1Assuntos
Aneuploidia , Cromossomos Humanos Par 15/genética , Repetições de Microssatélites/genética , Ribonucleoproteínas Nucleares Pequenas/genética , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/patologia , Autoantígenos , Pré-Escolar , Deficiências do Desenvolvimento/patologia , Feminino , Cardiopatias Congênitas/patologia , Hemangioma/patologia , Humanos , Hibridização in Situ Fluorescente , Cariotipagem , Microcefalia/patologia , Distrofias Musculares/patologia , Polidactilia/patologia , Proteínas Centrais de snRNPRESUMO
We report an infant with severe hypotonia, feeding problems and failure to thrive in the neonatal period, followed by developmental delay. In addition, pale skin, eyelid and pedal edema, cryptorchidism and micrognathia were present. The tentative diagnosis of Prader-Labhart-Willi syndrome was made and confirmed by specific molecular testing at the age of 5 months. The Prader-Labhart-Willi syndrome is usually diagnosed in older infants when the main clinical features such as obesity, short stature, hypogonadism and developmental delay become obvious, in most of the patients typical clinical features are present already in the neonatal period. In conclusion, in neonates and young infants presenting with hypotonia and feeding problems, the Prader-Labhart-Willi syndrome should be considered.
Assuntos
Síndrome de Prader-Willi/diagnóstico , Ribonucleoproteínas Nucleares Pequenas , Autoantígenos/genética , Cromossomos Humanos Par 15 , Diagnóstico Diferencial , Humanos , Lactente , Recém-Nascido , Masculino , Exame Neurológico , Reação em Cadeia da Polimerase , Síndrome de Prader-Willi/genética , Proteínas Centrais de snRNPRESUMO
Tricho-rhino-phalangeal syndrome (TRPS) is characterized by craniofacial and skeletal abnormalities. Three subtypes have been described: TRPS I, caused by mutations in the TRPS1 gene on chromosome 8; TRPS II, a microdeletion syndrome affecting the TRPS1 and EXT1 genes; and TRPS III, a form with severe brachydactyly, due to short metacarpals, and severe short stature, but without exostoses. To investigate whether TRPS III is caused by TRPS1 mutations and to establish a genotype-phenotype correlation in TRPS, we performed extensive mutation analysis and evaluated the height and degree of brachydactyly in patients with TRPS I or TRPS III. We found 35 different mutations in 44 of 51 unrelated patients. The detection rate (86%) indicates that TRPS1 is the major locus for TRPS I and TRPS III. We did not find any mutation in the parents of sporadic patients or in apparently healthy relatives of familial patients, indicating complete penetrance of TRPS1 mutations. Evaluation of skeletal abnormalities of patients with TRPS1 mutations revealed a wide clinical spectrum. The phenotype was variable in unrelated, age- and sex-matched patients with identical mutations, as well as in families. Four of the five missense mutations alter the GATA DNA-binding zinc finger, and six of the seven unrelated patients with these mutations may be classified as having TRPS III. Our data indicate that TRPS III is at the severe end of the TRPS spectrum and that it is most often caused by a specific class of mutations in the TRPS1 gene.
Assuntos
Cromossomos Humanos Par 8/genética , Deformidades Congênitas dos Membros/genética , Deformidades Congênitas dos Membros/patologia , Mutação/genética , Osteocondrodisplasias/classificação , Osteocondrodisplasias/genética , Adolescente , Adulto , Sequência de Aminoácidos , Antropometria , Sequência de Bases , Estatura , Criança , Pré-Escolar , Análise Mutacional de DNA , Proteínas de Ligação a DNA/metabolismo , Fatores de Ligação de DNA Eritroide Específicos , Éxons/genética , Feminino , Genótipo , Humanos , Lactente , Deformidades Congênitas dos Membros/diagnóstico por imagem , Deformidades Congênitas dos Membros/fisiopatologia , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Osteocondrodisplasias/diagnóstico por imagem , Osteocondrodisplasias/patologia , Linhagem , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Radiografia , Síndrome , Fatores de Transcrição/metabolismo , Dedos de Zinco/genéticaRESUMO
Two sisters born to consanguineous Lebanese parents had mental retardation and epilepsy, brachymetacarpalia, hirsutism, bulbous soft nose, thick floppy ears with abnormal configuration and gingival hypertrophy. One girl presented additionally with tetralogy of Fallot and the other with congenital hypothyroidism and bilateral ureteral stenosis. These manifestations resemble the syndrome of hypertrichosis-gingival fibromatosis-mental retardation and seizures of Anavi et al. [1989: Dev Med Child Neurol 31:538-542] but our two girls additionally have brachymetacarpia. The inheritance seems to be autosomal recessive. These two sisters may represent a hitherto undescribed syndrome. We discuss the findings in our patients in relation to the literature.
Assuntos
Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/patologia , Diagnóstico Diferencial , Saúde da Família , Feminino , Hipertrofia Gengival/patologia , Hirsutismo/patologia , Humanos , Recém-Nascido , Deficiência Intelectual , Metacarpo/anormalidades , Metacarpo/patologia , Núcleo Familiar , Convulsões/patologia , Síndrome , Tetralogia de Fallot/patologiaRESUMO
The Aarskog syndrome or facio-genital dysplasia (FGDY, MIM No. 305400) is an X-linked condition characterized by short stature, macrocephaly, facial, genital and skeletal anomalies. It is caused by mutation of the FGD1 gene mapped to the Xp11.21 region. To date, only one point mutation has been reported in an affected family, consisting of the insertion of an additional guanine residue at nucleotide 2122 of exon 7, which causes premature translational termination. We now report the finding of two novel FGD1 mutations, a missense mutation in a family of Italian origin and a deletion of 3 exons in a sporadic case from Germany. These mutations confirm the role of FGD1 as the gene responsible for the Aarskog syndrome.