ABSTRACT
Schinzel-Giedion syndrome (SGS) is a rare developmental disorder characterized by multiple malformations, severe neurological alterations and increased risk of malignancy. SGS is caused by de novo germline mutations clustering to a 12bp hotspot in exon 4 of SETBP1. Mutations in this hotspot disrupt a degron, a signal for the regulation of protein degradation, and lead to the accumulation of SETBP1 protein. Overlapping SETBP1 hotspot mutations have been observed recurrently as somatic events in leukemia. We collected clinical information of 47 SGS patients (including 26 novel cases) with germline SETBP1 mutations and of four individuals with a milder phenotype caused by de novo germline mutations adjacent to the SETBP1 hotspot. Different mutations within and around the SETBP1 hotspot have varying effects on SETBP1 stability and protein levels in vitro and in in silico modeling. Substitutions in SETBP1 residue I871 result in a weak increase in protein levels and mutations affecting this residue are significantly more frequent in SGS than in leukemia. On the other hand, substitutions in residue D868 lead to the largest increase in protein levels. Individuals with germline mutations affecting D868 have enhanced cell proliferation in vitro and higher incidence of cancer compared to patients with other germline SETBP1 mutations. Our findings substantiate that, despite their overlap, somatic SETBP1 mutations driving malignancy are more disruptive to the degron than germline SETBP1 mutations causing SGS. Additionally, this suggests that the functional threshold for the development of cancer driven by the disruption of the SETBP1 degron is higher than for the alteration in prenatal development in SGS. Drawing on previous studies of somatic SETBP1 mutations in leukemia, our results reveal a genotype-phenotype correlation in germline SETBP1 mutations spanning a molecular, cellular and clinical phenotype.
Subject(s)
Abnormalities, Multiple/genetics , Carrier Proteins/genetics , Craniofacial Abnormalities/genetics , Genetic Predisposition to Disease/genetics , Hand Deformities, Congenital/genetics , Hematologic Neoplasms/genetics , Intellectual Disability/genetics , Mutation , Nails, Malformed/genetics , Nuclear Proteins/genetics , Abnormalities, Multiple/metabolism , Abnormalities, Multiple/pathology , Blotting, Western , Carrier Proteins/metabolism , Cell Line , Cell Proliferation/genetics , Cell Transformation, Neoplastic/genetics , Child , Child, Preschool , Craniofacial Abnormalities/metabolism , Craniofacial Abnormalities/pathology , Female , Gene Expression Profiling , Genetic Association Studies , Germ-Line Mutation , HEK293 Cells , Hand Deformities, Congenital/metabolism , Hand Deformities, Congenital/pathology , Hematologic Neoplasms/metabolism , Hematologic Neoplasms/pathology , Humans , Infant , Infant, Newborn , Intellectual Disability/metabolism , Intellectual Disability/pathology , Male , Nails, Malformed/metabolism , Nails, Malformed/pathology , Nuclear Proteins/metabolism , PhenotypeABSTRACT
Long-term observations of individuals with the so-called Langer-Giedion (LGS) or tricho-rhino-phalangeal type II (TRPS2) are scarce. We report here a on follow-up of four LGS individuals, including one first described by Andres Giedion in 1969, and review the sparse publications on adults with this syndrome which comprises ectodermal dysplasia, multiple cone-shaped epiphyses prior to puberty, multiple cartilaginous exostoses, and mostly mild intellectual impairment. LGS is caused by deletion of the chromosomal segment 8q24.11-q24.13 containing among others the genes EXT1 and TRPS1. Most patients with TRPS2 are only borderline or mildly cognitively delayed, and few are of normal intelligence. Their practical skills are better than their intellectual capability, and, for this reason and because of their low self-esteem, they are often underestimated. Some patients develop seizures at variable age. Osteomas on processes of cervical vertebrae may cause pressure on cervical nerves or dissection of cerebral arteries. Joint stiffness is observed during childhood and changes later to joint laxity causing instability and proneness to trauma. Perthes disease is not rare. Almost all males become bald at or soon after puberty, and some develop (pseudo) gynecomastia. Growth hormone deficiency was found in a few patients, TSH deficiency so far only in one. Puberty and fertility are diminished, and no instance of transmission of the deletion from a non-mosaic parent to a child has been observed so far. Several affected females had vaginal atresia with consequent hydrometrocolpos.
Subject(s)
Langer-Giedion Syndrome/complications , Langer-Giedion Syndrome/diagnosis , Adolescent , Adult , Aged , Child , Child, Preschool , Chromosome Banding , Chromosome Mapping , Comparative Genomic Hybridization , Facies , Follow-Up Studies , Humans , Langer-Giedion Syndrome/genetics , Male , Middle Aged , Phenotype , Young AdultABSTRACT
As representaçöes que pais e educadores fazem da sexualidade de pessoas com a síndrome de Down (SD) referem, muitas vezes, a atitudes agressivas ou, entäo, condutas assexuadas, exclusivamente fundamentadas na afetividade. Este trabalho faz uma análise da literatura referente à sexualidade e à reproduçäo em portadores dessa síndrome e avalia as possibilidades de recorrência do distúrbio a partir da segregaçäo cromossômica em portadores de diferentes tipos de trissomia 21. Diversas publicaçöes mostram a existência de diferentes níveis de maturidade e de adaptaçäo social na SD que, associados a fatores como excesso de cuidados parentais, falta de amigos e preconceito social, constituem barreiras para a vivência plena da sexualidade. Os relatos de procriaçäo em portadores da síndrome de Down revelam progênie normal ou com a síndrome, com maior prevalência de filhos normais. A análise de segregaçäo cromossômica mostra probabilidade de 50 por cento para conceptos com trissomia 21 e de 25 por cento de filhos normais em casais com SD, caso os mesmos sejam férteis. O percentual restante corresponde a conceptos certamente inviáveis, com tetrassomia 21. Quando apenas um dos parceiros é portador da SD, a probabilidade de filhos normais ou com a síndrome passa para 50 por cento. Nos casos de SD com trissomia por rearranjo estrutural como nas translocaçöes 14/21 ou 21/21, a probabilidade de filhos normais é também de 50 por cento. Portadores de mosaicismo podem apresentar riscos inferiores a esse percentual a depender da freqüência de células trissômicas no tecido gonadal. O direito à sexualidade e, por outro lado, o alto risco genético de recorrência da síndrome evidenciam näo apenas a necessidade de se discutir a questäo, como também a importância do apoio emocional e da educaçäo sexual para a pessoa com SD
ABSTRACT
O trabalho apresenta uma análise de fatores causais da síndrome de Down e sua patogênese. Faz também uma revisão da história natural dessa síndrome e dos efeitos da trissomia da banda cromossômica 21q22, considerada crítica para o distúrbio. Embora esse desequilíbrio cromossômico esteja necessariamente presente na síndrome de Down, a relevância do determinismo genético é questionada a partir da observação da possibilidade de desenvolvimento do potencial cognitivo em sujeitos afetados pela síndrome, após a aplicação de programas de estimulação neuromotora e psicopedagógicos
Subject(s)
Trisomy , Cognition Disorders , Genetics , Down SyndromeABSTRACT
O trabalho apresenta uma analise de fatores causais da sindrome de Down e sua patogenese. Faz tambem uma revisao da historia natural dessa sindrome e dos efeitos da trissomia da banda cormossomica 21q22, considerada critica para o disturbio. Embora esse desequilibrio cromossomico esteja necessariamente presente na sindorme de Down, a relevancia do determinismo genetico e questionada a partir da observacao da possibilidade de desenvolvimento potencial cognitivo em sujeitos afetados pela sindrome, apos a aplicacao de programas de estimulacao neuromotora e psicopedagogicos.
