SHORT syndrome is a rare autosomal dominant condition whose name is the acronym of short stature, hyperextensibility of joints, ocular depression, Rieger anomaly and teething delay (MIM 269880). Additionally, the patients usually present a low birth weight and height, lipodystrophy, delayed bone age, hernias, low body mass index and a progeroid appearance.
Holt-Oram syndrome (HOS) is a rare autosomal dominant disorder characterized by upper limb defects and congenital heart defects (CHD), which are often simple septal and conduction defects, less frequently complex CHDs. We report on a 9 year-old boy with clinical and radiologic features of HOS consisting of bilateral asymmetric hypoplastic thumbs, generalized brachydactyly, limited supination due to radioulnar synostosis, and sloping shoulders, and intermediate atrioventricular canal defect (AVCD) with aortic coarctation. A de novo, previously described mutation, (Arg279ter) was identified in the TBX5 gene. Molecular characterization of this mutation was carried out due to the atypical CHD. In order to investigate whether the mutated transcript of TBX5 was able to escape the post-transcriptional surveillance mechanism and to produce a truncated TBX5 protein, we analyzed the TBX5 transcript, and protein pattern in HOS, and WT cardiac tissues. Our results demonstrate that the mutant TBX5 transcript is cleared by the cellular mechanism of surveillance. This data provides some support for the hypothesis that a dominant negative mutation, which strongly impairs the WT allele, might be too hazardous to be maintained. The literature suggests that HOS is relatively common among syndromes associated with AVCD.
Noonan syndrome is an autosomal dominant developmental disorder with a high phenotypic variability, which shares clinical features with other rare conditions, including LEOPARD syndrome, cardiofaciocutaneous syndrome, Noonan-like syndrome with loose anagen hair, and Costello syndrome. This group of related disorders, so-called RASopathies, is caused by germline mutations in distinct genes encoding for components of the RAS-MAPK signalling pathway. Due to high number of genes associated with these disorders, standard diagnostic testing requires expensive and time consuming approaches using Sanger sequencing. In this study we show how targeted Next Generation Sequencing (NGS) technique can enable accurate, faster and cost-effective diagnosis of RASopathies.
Ebstein anomaly is an uncommon congenital heart defect (CHD), characterized by downward displacement of the tricuspid valve into the right ventricle. To uncover the genetic associations with Ebstein anomaly, we have searched chromosomal imbalances using standard cytogenetic and array-CGH analysis, and single gene conditions associated with syndromic Ebstein anomaly (with extracardiac anomalies), and screened GATA4 and NKX2.5 mutations in nonsyndromic patients (without extracardiac anomalies). Between January 1997 and September 2009, 44 consecutive patients with Ebstein anomaly were evaluated in two centers of Pediatric Cardiology. Ebstein anomaly was syndromic in 12 (27%) patients, and nonsyndromic in 32 (73%). A recognizable syndrome or complex was diagnosed by clinical criteria in seven patients. In one syndromic patient an 18q deletion was diagnosed by standard cytogenetic analysis. Array-CGH analysis performed in 10 of the 12 syndromic patients detected an interstitial deletion of about 4?Mb at 8p23.1 in one patient, and a deletion 1pter?>?1p36.32/dup Xpter-?>?Xp22.32 in another patient. In the 28 of 32 nonsyndromic patients who underwent molecular testing, no mutation in GATA4 and NKX2.5 genes were detected. We conclude that Ebstein anomaly is a genetically heterogeneous defect, and that deletion 1p36 and deletion 8p23.1 are the most frequent chromosomal imbalances associated with Ebstein anomaly. Candidate genes include the GATA4 gene (in patients with del 8p23.1), NKX2.5 (based on published patients with isolated Ebstein anomaly) and a hypothetical gene in patients with del 1p36).
Poland anomaly (PA) is a pectoral muscle hypoplasia/aplasia variably associated with ipsilateral thoracic (TA) and/or upper limb anomalies (ULA). PA is usually sporadic and sometimes familial, making recurrence risk an issue in genetic counseling. Multidisciplinary evaluation of 240 PA patients was carried out, including physical examination of patients and their parents in 190 PA (subjects of the study). Familial conditions were classified into three groups. Group1: true familial PA (F-PA): pectoral muscle defects with familial recurrence: 8(4.2%). Group2: familial Poland-like anomaly families (F-PLA): PA index case and ?1 relative(s) showing normal pectoral muscles but ULA and/or TA common in PA: 16(8.4%). Group3: sporadic PA (S-PA): 166(87.4%). F-PA indicated a stronger male (87.5%) and left side (62.5%) prevalence, but fewer ULA (37.5%) compared to the other two groups. Maternal transmission (6/8) was more common in F-PA. Statistical significance was not reached due to the small number of F-PA and F-PLA. Karyotyping and array-comparative genomic hybridization were performed in 13 families. Three maternally inherited copy number variants were identified in three patients: 1p31.1 deletion, Xp11.22 duplication, and 16q23.1 duplication. Interestingly, the probands mother carrying the 16q23.1 duplication displayed moderate breast and areola asymmetry, but normal pectoral muscles on ultrasound. Though there is no recent review discussing recurrence of PA, we reviewed 31 published PA families. On the basis of our study and previous reports, familial PA is not uncommon. Nonetheless, no information can be derived either regarding a molecular basis or clinical tools with which to identify cases with recurrence risk.
Nail-Patella syndrome (MIM 161200) is a rare autosomal dominant disorder characterized by hypoplastic or absent patellae, dystrophic nails, dysplasia of the elbows, and iliac horn. In 40% of cases, a glomerular defect is present and, less frequently, ocular damage is observed. Inter- and intrafamilial variable expressivity of the clinical phenotype is a common finding. Mutations in the human LMX1B gene have been demonstrated to be responsible for Nail-Patella syndrome in around 80% of cases.
The molecular characterization of balanced chromosomal rearrangements have always been of advantage in identifying disease-causing genes. Here, we describe the breakpoint mapping of a de novo balanced translocation t(7;12)(q11.22;q14.2) in a patient presenting with a failure to thrive associated with moderate mental retardation, facial anomalies, and chronic constipation. The localization of the breakpoints and the co-occurrence of Williams-Beuren syndrome and 12q14 microdeletion syndrome phenotypes suggested that the expression of some of the dosage-sensitive genes of these two segmental aneuploidies were modified in cells of the proposita. However, we were unable to identify chromosomes 7 and/or 12-mapping genes that showed disturbed expression in the lymphoblastoids of the proposita. This case showed that position-effect might operate in some tissues, but not in others. It also illustrates the overlap of phenotypes presented by patients with the recently described 12q14 structural rearrangements.
Mayer-Rokitansky-Kuster-Hauser syndrome (MRKH) consists of congenital aplasia of the uterus and the upper part of vagina due to anomalous development of Müllerian ducts, either isolated or associated with other congenital malformations, including renal, skeletal, hearing and heart defects. This disorder has an incidence of approximately 1 in 4500 newborn girls and the aetiology is poorly understood.
Poland syndrome (PS) has been described as unilateral pectoral muscle deficiency variably associated with ipsilateral thoracic and upper limb anomalies. Bilateral hypoplasia/aplasia of the pectoralis muscle and upper limb defects in association with variable thoracic muscles, chest wall deformities and lower limb defects have been infrequently reported in the literature. We report on a 3(1/2)-year-old girl with clinical features consisting in bilateral asymmetric pectoral muscle defects (complete agenesis on the left side and agenesis of the sternocostal head on the right side), nipple hypoplasia, left rib defect, and right hand symbrachydactyly. In this study, we reviewed the bilateral features present in our patient and those described in the literature. Hypotheses explaining bilateral features in PS are reviewed.
Poland syndrome is a rare congenital anomaly characterized by complete or partial agenesis of the pectoralis major muscle variably associated with other thoracic malformations, upper limb malformations, or both. More than 20 patients with dextrocardia and left-sided Poland syndrome have been previously described. The association between these 2 rare anomalies suggests a causal relationship, but the etiopathogenetic mechanism has not been clarified yet. We studied the clinical correlation between these 2 anomalies, and we tried to elucidate whether dextrocardia or Poland syndrome comes first.
Microdeletion 1q21.1 (del 1q21.1) and the reciprocal microduplication 1q21.1 (dup 1q21.1) are newly recognized genomic disorders, characterized by developmental delay, dysmorphic features and congenital malformations. Congenital heart defect (CHD) is a major feature of del 1q21.1, and has been occasionally reported in dup 1q21.1. We report here a family segregating del 1q21.1 in 3 members. Two of the affected family members had CHD, including the proband with syndromic atrial septal defect, pulmonary valve stenosis (PVS), and muscular ventricular septal defects, and the maternal uncle with non-syndromic PVS. This finding prompted investigation of the role of recurrent rearrangements of chromosome 1q21.1 in the pathogenesis of PVS. We gathered 38 patients with PVS (11 syndromic and 27 non-syndromic), and searched for genomic rearrangements of 1q21.1. A dup 1q21.1 was detected in a single sporadic non-syndromic patient. Review of the CHDs in published del 1q21.1 and dup 1q21.1 subjects showed a great heterogeneity in anatomic types. In conclusion, the present family illustrates recurrent CHD in del 1q21.1, expressing either as syndromic in one family member or as non-syndromic in the another one. The spectrum of CHDs associated with del 1q21.1 and dup 1q21.1 can occasionally include PVS.
In 2011, the RDDR network was developed in central Italy to provide support in the diagnosis of dysmorphic newborns. RDDR has been developed as an online electronic system that currently links 20 neonatology centres in central Italy, representing the submitting nodes that transmit patient clinical histories and the relevant photographical documentation to the software, which is password-protected. Accepted cases appropriate for the RDDR are reviewed by the RDDRs dysmorphology experts who, through a forum section, provide diagnostic suggestions and recommendations for further investigation and patient management. Their remarks are summarised in clinical expert reports and sent to the submitting nodes. The results of the first 22 submitted cases are reviewed in this paper. The RDDR was developed on the basis of a related European tool, Dyscerne, a network of centres of expertise for dysmorphology.
The Poland anomaly (PA) comprises unilateral absence or hypoplasia of the pectoralis major muscle and a variable degree of ipsilateral hand and upper limb anomalies. Various hand and upper limb anomalies classifications in PA have been previously published. In this work, a new classification of hand and upper limb anomalies in PA is proposed, on the basis of the clinical and instrumental evaluation of 175 patients.
Congenital heart defects affect 60-85% of patients with RASopathies. We analysed the clinical and molecular characteristics of atrioventricular canal defect in patients with mutations affecting genes coding for proteins with role in the RAS/MAPK pathway. Between 2002 and 2011, 101 patients with cardiac defect and a molecularly confirmed RASopathy were collected. Congenital heart defects within the spectrum of complete or partial (including cleft mitral valve) atrioventricular canal defect were diagnosed in 8/101 (8%) patients, including seven with a PTPN11 gene mutation, and one single subject with a RAF1 gene mutation. The only recurrent mutation was the missense PTPN11 c.124?A>G change (T42A) in PTPN11. Partial atrioventricular canal defect was found in six cases, complete in one, cleft mitral valve in one. In four subjects the defect was associated with other cardiac defects, including subvalvular aortic stenosis, mitral valve anomaly, pulmonary valve stenosis and hypertrophic cardiomyopathy. Maternal segregation of PTPN11 and RAF1 gene mutations occurred in two and one patients, respectively. Congenital heart defects in the affected relatives were discordant in the families with PTPN11 mutations, and concordant in that with RAF1 mutation. In conclusion, our data confirm previous reports indicating that atrioventricular canal defect represents a relatively common feature in Noonan syndrome. Among RASopathies, atrioventricular canal defect was observed to occur with higher prevalence among subjects with PTPN11 mutations, even though this association was not significant possibly because of low statistical power. Familial segregation of atrioventricular canal defect should be considered in the genetic counselling of families with RASopathies.
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