先天性心脏病相关综合征的遗传学研究

先天性心脏病(congenitalheartdisease,CHD)是儿科常见的疾病,现已发现约有300多种临床综合征伴有CHD.对Alagille综合征、CHARGE联合征、Holt-Oram综合征、Noonan综合征、Turner综合征、VACTERL联合征、Williams综合征、22q11缺失综合征和13、18、21三体综合征与CHD相关流行病学、临床表型、遗传病因和诊断及其再发风险进行了综述,为产前和产后临床诊断,了解疾病预后和再发概率提供资料.     

Coarctation of the aorta and renal hypoplasia in a boy with Turner/Noonan surface anomalies and a 46,XY karyotype: A clinical model for the possible impairment of a putative lymphogenic gene(s) for Turner somatic stigmata

This paper describes a 12-year-old Japanese boy with coarctation of the aorta, renal hypoplasia, Turner/ Noonan surface anomalies, and a 46,XY karyotype. Although the patient might represent an exceptional case of Noonan syndrome, the combination of the somatic stigmata appears to be consistent with a mutation of the putative lymphogenic gene(s) for Turner somatic stigmata. Received: 24 June 1995 / Revised: 28 September 1995     

Wachstumsst?rungen als Leitsymptom

Short stature is a frequently encountered question in both the genetic and the pediatric clinic. The definition of short stature includes a body length/height below the 3rd percentile or of more than two standard deviations below the mean. The velocity of growth as well as growth patterns are fundamentally regulated by genetic factors, but may be modified by secondary effects. The spectrum of short stature syndromes includes disorders of growth hormone secretion or effect, skeletal dysplasias and complex malformation syndromes. Identifying the underlying defect greatly facilitates counseling about prognosis and possible management. The most relevant syndromes in daily clinical routine are discussed here: Turner syndrome, Léri-Weill syndrome, Russel-Silver syndrome, Noonan syndrome, and achondroplasia.     

Abnormal growth in noonan syndrome: genetic and endocrine features and optimal treatment

Noonan syndrome (NS) is a phenotypically heterogeneous syndrome which is frequently associated with short stature. Recent genetic investigations have identified mutations in five genes, namely PTPN11, KRAS, SOS1, NF1 and RAF1 in patients with the NS phenotype. PTPN11 is the commonest, being present in approximately 50% of cases. The degree of short stature in children does not associate closely with the presence of mutations, however some PTPN11-positive patients have decreased GH-dependent growth factors consistent with mild GH insensitivity. GH therapy, using doses similar to those approved for Turner syndrome (TS), induced short-term increases in height velocity over 1-3 years, and may improve final adult height with longer-term treatment.     

Mouse model of Noonan syndrome reveals cell type- and gene dosage-dependent effects of Ptpn11 mutation

Noonan syndrome is a common human autosomal dominant birth defect, characterized by short stature, facial abnormalities, heart defects and possibly increased risk of leukemia. Mutations of Ptpn11 (also known as Shp2), which encodes the protein-tyrosine phosphatase Shp2, occur in approximately 50% of individuals with Noonan syndrome, but their molecular, cellular and developmental effects, and the relationship between Noonan syndrome and leukemia, are unclear. We generated mice expressing the Noonan syndrome-associated mutant D61G. When homozygous, the D61G mutant is embryonic lethal, whereas heterozygotes have decreased viability. Surviving Ptpn11(D61G/+) embryos ( approximately 50%) have short stature, craniofacial abnormalities similar to those in Noonan syndrome, and myeloproliferative disease. Severely affected Ptpn11(D61G/+) embryos ( approximately 50%) have multiple cardiac defects similar to those in mice lacking the Ras-GAP protein neurofibromin. Their endocardial cushions have increased Erk activation, but Erk hyperactivation is cell and pathway specific. Our results clarify the relationship between Noonan syndrome and leukemia and show that a single Ptpn11 gain-of-function mutation evokes all major features of Noonan syndrome by acting on multiple developmental lineages in a gene dosage-dependent and pathway-selective manner.     

PTPN11 gene analysis in 74 Brazilian patients with Noonan syndrome or Noonan-like phenotype

Mutations in the PTPN11 gene are known to cause a large fraction of the cases of Noonan syndrome. The objective of this study was to determine the PTPN11 gene mutation rate in a cohort of clinically well-characterized Brazilian patients with Noonan or Noonan-like syndromes and to study the genotype-phenotype correlation. Fifty probands with Noonan syndrome ascertained according to well-established diagnostic criteria, 3 with LEOPARD syndrome, 5 with Noonan-like/multiple giant cell lesion syndrome, and 3 with neurofibromatosis/ Noonan were enrolled in this study. Mutational analysis was performed using denaturing high-performance liquid chromatography (DHPLC) followed by sequencing of amplicons with an aberrant elution profile. We detected missense mutations in the PTPN11 gene in 21 probands with Noonan syndrome (42%), in all 3 patients with LEOPARD syndrome, and in 1 case with Noonan-like/multiple giant cell lesion syndrome. One patient with neurofibromatosis-Noonan syndrome had a mutation in both the PTPN11 and NF1 genes. The only anomalies that reached statistical significance when comparing probands with and without mutations were the hematological abnormalities. Our data confirms that Noonan syndrome is a genetically heterogeneous disorder, with mutations in the PTPN11 gene responsible for roughly 50% of the cases. A definitive genotype-phenotype correlation has not been established, but the T73I mutation seems to predispose to a myeloproliferative disorder. Regarding Noonan-like syndromes, mutation of the PTPN11 gene is the main causal factor in LEOPARD syndrome, and it also plays a role in neurofibromatosis-Noonan syndrome. Noonan- like/multiple giant cell lesion syndrome, part of the spectrum of Noonan syndrome, is also heterogeneous.     

Neonatal Noonan syndrome with a molluscoid cutaneous excess over the scalp.

The Noonan syndrome is a multiple congenital anomalies syndrome with variable expressivity and autosomal dominant inheritance. We report an observation of a newborn with Noonan syndrome and an unusual molluscoid cutaneous excess over the scalp that might represent a new skin manifestation in Noonan Syndrome rather than a consequence of lymphatic dysplasia.     

Developmental and behavioural phenotype in Noonan syndrome?

Developmental and behavioural phenotype in Noonan syndrome? Noonan syndrome is characteristic by facial dysmorphology, congenital heart defects, short stature, developmental retardation and severe early feeding disorders in many cases. Data from a postal survey on physical development, feeding difficulties, developmental problems and behavioural aspects in 26 children are reported. The findings suggest developmental and behavioural difficulties in 46 per cent, but do not support the notion of a behavioural phenotype specific to Noonan syndrome. Having to cope with early surgery, feeding, developmental and behavioural problems establishes a need for psychological counseling for families receiving a diagnosis of Noonan syndrome.     

Chromosome 13 long arm interstitial deletion associated with features of Noonan phenotype

A 22-year-old Caucasian mildly retarded male presented with facial features of high nasal bridge, prominent supraorbital ridges, some malar hypoplasia, prognathism, short philtrum, and prominent full lips associated with shortness of stature, nuchal webbing, and esotropia. His cardiac exam and genital development were normal. The diagnosis of Noonan syndrome had been previously entertained. A chromosome analysis revealed an interstitial deletion of a chromosome 13 at (q21.32q22.3).     

CFC syndrome: a syndrome distinct from Noonan syndrome

We report two children with a common pattern of birth defects. Both have very sparse, curly hair, nystagmus and mental retardation. The first one has Noonan syndrome habitus associated with keratosis plantaris and nystagmus; the second one has a slightly Noonan-like face, macrocephaly, keratosis pilaris, and hypertrophic cardiomyopathy. They represent the extreme of a spectrum of congenital defects recently reported independently as CFC syndrome by Reynolds and as "Noonan-like short stature syndrome with sparse hair" by Baraitser and Patton. The clinical features are reviewed and the autonomy of the syndrome with regards to Noonan syndrome, is disputed, since every sign seems to occur independently in Noonan syndrome. The father of the second case probably has a minor syndrome expression, pointing to probable autosomal dominant inheritance.     

Genetics and variation in phenotype in Noonan syndrome

Noonan syndrome is a well-known clinical entity comprising multiple congenital anomalies characterized by typical facial features, short stature and congenital heart defect. Approximately 50% of cases are sporadic. Familial cases are generally autosomal dominant. In 2001 a gene responsible for Noonan syndrome, PTPN11, encoding for the non-receptor protein tyrosine phosphatase SHP-2, was identified. Mutation analysis of the PTPN11 gene was carried out in Nijmegen in 150 patients with Noonan syndrome. Mutations were found in 68 patients (45%), the most common being A922G in exon 8. In exon 4 a mutation was found that encoded the C-SH2 domain of the PTPN11 gene in two unique patients who shared some uncommon features. A 218C-->T mutation was found in exon 3 in one patient with Noonan syndrome and mild juvenile myelomonocytic leukaemia.     

Molecular analysis of 46,XY females and regional assignment of a new Y-chromosome-specific probe

Summary The relationship between Y-chromosome abnormalities and gonadal differentiation was investigated in six phenotypic females with a 46,XY karyotype and one patient with ambiguous genitalia secondary to apparently nonmosaic 46,XY mixed gonadal dysgenesis. No alterations were found in the Y chromosomes of six of these individuals by the use of either cytogenetic or molecular techniques. Cytogenetic analysis with high-resolution G-banding and Q-banding revealed a small deletion in the short arm of the Y chromosome in one female patient with some features of Turner syndrome. Southern hybridization with Y-specific probes showed a loss of DNA within deletion intervals 1, 2, and 3 of the Y chromosome. A new Y-chromosome-specific DNA probe that hybridizes to deletion interval 3 is described.     

Gain-of-Function Mutations in RIT1 Cause Noonan Syndrome,a RAS/MAPK Pathway Syndrome

RAS GTPases mediate a wide variety of cellular functions, including cell proliferation, survival, and differentiation. Recent studies have revealed that germline mutations and mosaicism for classical RAS mutations, including those in HRAS, KRAS, and NRAS, cause a wide spectrum of genetic disorders. These include Noonan syndrome and related disorders (RAS/mitogen-activated protein kinase [RAS/MAPK] pathway syndromes, or RASopathies), nevus sebaceous, and Schimmelpenning syndrome. In the present study, we identified a total of nine missense, nonsynonymous mutations in RIT1, encoding a member of the RAS subfamily, in 17 of 180 individuals (9%) with Noonan syndrome or a related condition but with no detectable mutations in known Noonan-related genes. Clinical manifestations in the RIT1-mutation-positive individuals are consistent with those of Noonan syndrome, which is characterized by distinctive facial features, short stature, and congenital heart defects. Seventy percent of mutation-positive individuals presented with hypertrophic cardiomyopathy; this frequency is high relative to the overall 20% incidence in individuals with Noonan syndrome. Luciferase assays in NIH 3T3 cells showed that five RIT1 alterations identified in children with Noonan syndrome enhanced ELK1 transactivation. The introduction of mRNAs of mutant RIT1 into 1-cell-stage zebrafish embryos was found to result in a significant increase of embryos with craniofacial abnormalities, incomplete looping, a hypoplastic chamber in the heart, and an elongated yolk sac. These results demonstrate that gain-of-function mutations in RIT1 cause Noonan syndrome and show a similar biological effect to mutations in other RASopathy-related genes.     

Proteomic analysis of amniotic fluid in pregnancies with Turner syndrome fetuses

Turner syndrome, occurring in 1:2500 female births, is caused by the complete or partial absence of one X chromosome. Amniotic fluid supernatant proteins from five second trimester pregnancies with Turner syndrome fetuses and five normal ones were analyzed by 2DE, MALDI-TOF-MS, and Western blot. Serotransferin, lumican, plasma retinol-binding protein, and apolipoprotein A-I were increased in Turner syndrome, while kininogen, prothrombin, and apolipoprotein A-IV were decreased. Since differentially expressed proteins are likely to cross the placenta barrier and be detected in maternal plasma, proteomic analysis may enhance research for noninvasive prenatal diagnosis of Turner syndrome.     

Portal vein thrombosis and high factor VIII in Turner syndrome

BACKGROUNDS/AIMS: Turner syndrome is not usually associated with thrombotic events. The aim of this study is to report 3 Turner syndrome patients with portal vein thrombosis and, in 2 of them, high factor VIII. These findings are compared to values in Turner syndrome patients without thrombosis and controls. METHODS: In different years, 3 patients with Turner syndrome were initially seen at the Gastroenterology Clinic of Hospital de Clínicas de Porto Alegre, Brazil, for portal vein thrombosis. After the most common causes of portal vein thrombosis and thrombophilias had been excluded, the 2 surviving patients were studied for clotting factors VIII, IX and von Willebrand factor. The same factors were also assessed in 25 Turner syndrome patients without thrombosis and 25 normal girls. RESULTS: One of the patients with portal vein thrombosis died before the study. In the 2 surviving patients, factors VIII and von Willebrand levels were >150 IU/dl, which is considered to be high. In Turner syndrome patients without thrombosis, the mean factor VIII level was 127.2 +/- 41.1 IU/dl and for von Willebrand factor 101.2 +/- 26.9 IU/dl, while in control girls these were 116.0 +/- 27.6 and 94.28 +/- 27.5 IU/dl, respectively. Factor VIII and von Willebrand factor were not different between these 2 groups. When non-O blood group Turner syndrome patients and normal girls were compared, the former had significantly higher levels of factor VIII. CONCLUSIONS: This is the first report on the unusual finding of portal thrombosis in patients with Turner syndrome in whom high levels of factor VIII and von Willebrand factor were found. Factor VIII is higher in the non-O blood group Turner syndrome patients without thrombosis when compared to normal girls.     

Evidence for a Turner syndrome locus or loci at Xp11.2-p22.1.

Turner syndrome is the complex human phenotype associated with complete or partial monosomy X. Principle features of Turner syndrome include short stature, ovarian failure, and a variety of other anatomic and physiological abnormalities, such as webbed neck, lymphedema, cardiovascular and renal anomalies, hypertension, and autoimmune thyroid disease. We studied 28 apparently nonmosaic subjects with partial deletions of Xp, in order to map loci responsible for various components of the Turner syndrome phenotype. Subjects were carefully evaluated for the presence or absence of Turner syndrome features, and their deletions were mapped by FISH with a panel of Xp markers. Using a statistical method to examine genotype/phenotype correlations, we mapped one or more Turner syndrome traits to a critical region in Xp11.2-p22.1. These traits included short stature, ovarian failure, high-arched palate, and autoimmune thyroid disease. The results are useful for genetic counseling of individuals with partial monosomy X. Study of additional subjects should refine the localization of Turner syndrome loci and provide a rational basis for exploration of candidate genes.     

Which Neurodevelopmental Disorders Get Researched and Why?

Aim

There are substantial differences in the amount of research concerned with different disorders. This paper considers why.

Methods

Bibliographic searches were conducted to identify publications (1985–2009) concerned with 35 neurodevelopmental disorders: Developmental dyslexia, Developmental dyscalculia, Developmental coordination disorder, Speech sound disorder, Specific language impairment, Attention deficit hyperactivity disorder, Autistic spectrum disorder, Tourette syndrome, Intellectual disability, Angelman syndrome, Cerebral palsy, Cornelia de Lange syndrome, Cri du chat syndrome, Down syndrome, Duchenne muscular dystrophy, Fetal alcohol syndrome, Fragile X syndrome, Galactosaemia, Klinefelter syndrome, Lesch-Nyhan syndrome, Lowe syndrome, Marfan syndrome, Neurofibromatosis type 1, Noonan syndrome, Phenylketonuria, Prader-Willi syndrome, Rett syndrome, Rubinstein-Taybi syndrome, Trisomy 18, Tuberous sclerosis, Turner syndrome, Velocardiofacial syndrome, Williams syndrome, XXX and XYY. A publication index reflecting N publications relative to prevalence was derived.

Results

The publication index was higher for rare than common conditions. However, this was partly explained by the tendency for rare disorders to be more severe.

Interpretation

Although research activity is predictable from severity and prevalence, there are exceptions. Low rates of research, and relatively low levels of NIH funding, characterise conditions that are the domain of a single discipline with limited research resources. Growth in research is not explained by severity, and was exceptionally steep for autism and ADHD.     

De novo DNA microdeletion in a girl with Turner syndrome and Duchenne muscular dystrophy

Summary The single X chromosome of a girl with Turner syndrome 45,X and typical Duchenne muscular dystrophy was investigated at the chromosomal and DNA levels. No visible abnormality of the residual X chromosome was found upon high-resolution R-banding. The DNA was analysed by Southern blotting and hybridization with seven cloned probes mapping in the Xp21 region where the Duchenne locus is thought to be located. A molecular deletion was detected with probes pERT 87.1, pERT 87.8, and pERT 87.15. The other probes (754, C7, 99.6, and RC8) gave a normal signal. The DNA alleles seen in the two parents indicated that the deletion found in the propositus had occurred de novo on a maternal X chromosome.     

The cardio-facio-cutaneous (CFC) syndrome: autosomal dominant inheritance in a large family.

A large, three generation-family with firm evidence of autosomal dominant transmission of the cardio-faciocutaneous (CFC) syndrome is reported. This observation questions once more the validity of separating the CFC syndrome from the Noonan syndrome as two distinct entities.