[Show abstract][Hide abstract] ABSTRACT: BACKGROUND:
PIK3CA-related overgrowth spectrum (PROS) include a group of disorders that affect only the terminal portion of a limb, such as type I macrodactyly, and conditions like fibroadipose overgrowth (FAO), megalencephaly-capillary malformation (MCAP) syndrome, congenital lipomatous asymmetric overgrowth of the trunk, lymphatic, capillary, venous, and combined-type vascular malformations, epidermal nevi, skeletal and spinal anomalies (CLOVES) syndrome and Hemihyperplasia Multiple Lipomatosis (HHML). Heterozygous postzygotic PIK3CA mutations are frequently identified in these syndromes, while timing and tissue specificity of the mutational event are likely responsible for the extreme phenotypic variability observed.
We carried out a combination of Sanger sequencing and targeted deep sequencing of genes involved in the PI3K/AKT/mTOR pathway in three patients (1 MCAP and 2 FAO) to identify causative mutations, and performed immunoblot analyses to assay the phosphorylation status of AKT and P70S6K in affected dermal fibroblasts. In addition, we evaluated their ability to grow in the absence of serum and their response to the PI3K inhibitors wortmannin and LY294002 in vitro.
RESULTS AND CONCLUSION:
Our data indicate that patients' cells showed constitutive activation of the PI3K/Akt pathway. Of note, PI3K pharmacological blockade resulted in a significant reduction of the proliferation rate in culture, suggesting that inhibition of PI3K might prove beneficial in future therapies for PROS patients.
[Show abstract][Hide abstract] ABSTRACT: Background
Cornelia de Lange syndrome (CdLS) is a rare autosomal-dominant disorder characterised by facial dysmorphism, growth and psychomotor developmental delay and skeletal defects. To date, causative mutations in the NIPBL (cohesin regulator) and SMC1A (cohesin structural subunit) genes account for > 50% and 6% of cases, respectively.
We recruited 50 patients with a CdLS clinical diagnosis or with features that overlap with CdLS, who were negative for mutations at NIPBL and SMC1A at molecular screening. Chromosomal rearrangements accounting for the clinical diagnosis were screened for using array Comparative Genomic Hybridisation (aCGH).
Four patients were shown to carry imbalances considered to be candidates for having pathogenic roles in their clinical phenotypes: patient 1 had a 4.2 Mb de novo deletion at chromosome 20q11.2-q12; patient 2 had a 4.8 Mb deletion at chromosome 1p36.23-36.22; patient 3 carried an unbalanced translocation, t(7;17), with a 14 Mb duplication of chromosome 17q24.2-25.3 and a 769 Kb deletion at chromosome 7p22.3; patient 4 had an 880 Kb duplication of chromosome 19p13.3, for which his mother, who had a mild phenotype, was also shown to be a mosaic.
Notwithstanding the variability in size and gene content of the rearrangements comprising the four different imbalances, they all map to regions containing genes encoding factors involved in cell cycle progression or genome stability. These functional similarities, also exhibited by the known CdLS genes, may explain the phenotypic overlap between the patients included in this study and CdLS. Our findings point to the complexity of the clinical diagnosis of CdLS and confirm the existence of phenocopies, caused by imbalances affecting multiple genomic regions, comprising 8% of patients included in this study, who did not have mutations at NIPBL and SMC1A. Our results suggests that analysis by aCGH should be recommended for CdLS spectrum cases with an unexplained clinical phenotype and included in the flow chart for diagnosis of cases with a clinical evaluation in the CdLS spectrum.
BMC Medical Genetics 04/2013; 14(1):41. DOI:10.1186/1471-2350-14-41 · 2.08 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Progressive pseudorheumatoid dysplasia (PPRD) is a genetic, non-inflammatory arthropathy caused by recessive loss of function mutations in WISP3 (Wnt1-inducible signaling pathway protein 3; MIM 603400), encoding for a signaling protein. The disease is clinically silent at birth and in infancy. It manifests between the age of 3 and 6 years with joint pain and progressive joint stiffness. Affected children are referred to pediatric rheumatologists and orthopedic surgeons; however, signs of inflammation are absent and anti-inflammatory treatment is of little help. Bony enlargement at the interphalangeal joints progresses leading to camptodactyly. Spine involvement develops in late childhood and adolescence leading to short trunk with thoracolumbar kyphosis. Adult height is usually below the 3rd percentile. Radiographic signs are relatively mild. Platyspondyly develops in late childhood and can be the first clue to the diagnosis. Enlargement of the phalangeal metaphyses develops subtly and is usually recognizable by 10 years. The femoral heads are large and the acetabulum forms a distinct "lip" overriding the femoral head. There is a progressive narrowing of all articular spaces as articular cartilage is lost. Medical management of PPRD remains symptomatic and relies on pain medication. Hip joint replacement surgery in early adulthood is effective in reducing pain and maintaining mobility and can be recommended. Subsequent knee joint replacement is a further option. Mutation analysis of WISP3 allowed the confirmation of the diagnosis in 63 out of 64 typical cases in our series. Intronic mutations in WISP3 leading to splicing aberrations can be detected only in cDNA from fibroblasts and therefore a skin biopsy is indicated when genomic analysis fails to reveal mutations in individuals with otherwise typical signs and symptoms. In spite of the first symptoms appearing in early childhood, the diagnosis of PPRD is most often made only in the second decade and affected children often receive unnecessary anti-inflammatory and immunosuppressive treatments. Increasing awareness of PPRD appears to be essential to allow for a timely diagnosis.
American Journal of Medical Genetics Part C Seminars in Medical Genetics 08/2012; 160C(3):217-29. DOI:10.1002/ajmg.c.31333 · 3.91 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Pitt-Hopkins syndrome (PTHS) is an emerging condition characterized by severe intellectual disability (ID), typical facial gestalt, and additional features, such as breathing abnormalities. Because of the overlapping phenotype of severe ID with absent speech, epilepsy, microcephaly, large mouth, and constipation, differential diagnosis of PTHS with respect to Angelman, Rett, and Mowat-Wilson syndromes represents a relevant clinical issue, and many patients are currently undergoing genetic tests for different conditions that are assumed to fall within the PTHS clinical spectrum. During a search for TCF4 mutations in 78 patients with a suspected PTHS, haploinsufficiency of TCF4 was identified in 18. By evaluating clinical features of patients with a proven TCF4 mutation with those of patients without, we noticed that, in addition to the typical facial gestalt, the PTHS phenotype results from the various combination of the following characteristics: ID with severe speech impairment, normal growth parameters at birth, postnatal microcephaly, breathing abnormalities, motor incoordination, ocular anomalies, constipation, seizures, typical behavior, and subtle brain abnormalities. On the basis of these observations, here we propose a clinically based score system as useful tool for driving a first choice molecular test for PTHS. This scoring system is also proposed for a clinically based diagnosis of PTHS in absence of a proven TCF4 mutation.
American Journal of Medical Genetics Part A 07/2012; 158A(7):1604-11. DOI:10.1002/ajmg.a.35419 · 2.16 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Cornelia de Lange syndrome (CdLS) is a rare multisystemic congenital anomaly disorder that is characterised by intellectual disability and growth retardation, congenital heart defects, intestinal anomalies, facial dysmorphism (including synophyris and high arched eyebrows) and limb reduction defects. Mutations in three cohesin-associated genes encoding a key regulator (NIPBL, chr 5p13.2) and one structural component of the cohesin ring (SMC1A, chr Xp11) occur in about 65% of CdLS patients. NIPBL is the major causative gene, and accounts for 40-60% of CdLS patients as shown by a number of mutational screening studies that indicate a wide mutational repertoire of mainly small deletions and point mutations. Only a few data are available concerning the occurrence of large NIPBL rearrangements or intragenic deletions or duplications involving whole exons. We used multiplex ligation-dependent probe amplification (MLPA) to study 132 CdLS patients negative to the standard mutation NIPBL test out of a cohort of 200 CdLS patients. A total of 7 out of 132 patients were found to carry NIPBL alterations, including two large gene deletions extending beyond the gene, four intragenic multi- or single-exon deletions and one single-exon duplication. These findings show that MLPA leads to a 5.3% increase in the detection of mutations when used in addition to the standard NIPBL scan, and contributes per se to the molecular diagnosis of 3.5% (7/200) of clinically diagnosed CdLS patients. It is recommended that MLPA be included in the CdLS diagnostic flow chart.
European journal of human genetics: EJHG 02/2012; 20(7):734-41. DOI:10.1038/ejhg.2012.7 · 4.35 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Renal coloboma syndrome, also known as papillorenal syndrome is an autosomal-dominant disorder characterized by ocular and renal malformations. Mutations in the paired-box gene, PAX2, have been identified in approximately half of individuals with classic findings of renal hypoplasia/dysplasia and abnormalities of the optic nerve. Prior to 2011, there was no actively maintained locus-specific database (LSDB) cataloguing the extent of genetic variation in the PAX2 gene and phenotypic variation in individuals with renal coloboma syndrome. Review of published cases and the collective diagnostic experience of three laboratories in the United States, France, and New Zealand identified 55 unique mutations in 173 individuals from 86 families. The three clinical laboratories participating in this collaboration contributed 28 novel variations in 68 individuals in 33 families, which represent a 50% increase in the number of variations, patients, and families published in the medical literature. An LSDB was created using the Leiden Open Variation Database platform: www.lovd.nl/PAX2. The most common findings reported in this series were abnormal renal structure or function (92% of individuals), ophthalmological abnormalities (77% of individuals), and hearing loss (7% of individuals). Additional clinical findings and genetic counseling implications are discussed.
Human Mutation 12/2011; 33(3):457-66. DOI:10.1002/humu.22020 · 5.14 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Costello syndrome is characterized by severe failure-to-thrive, short stature, cardiac abnormalities (heart defects, tachyarrhythmia, and hypertrophic cardiomyopathy (HCM)), distinctive facial features, a predisposition to papillomata and malignant tumors, postnatal cerebellar overgrowth resulting in Chiari 1 malformation, and cognitive disabilities. De novo germline mutations in the proto-oncogene HRAS cause Costello syndrome. Most mutations affect the glycine residues in position 12 or 13, and more than 80% of patients share p.G12S. To test the hypothesis that subtle genotype-phenotype differences exist, we report the first cohort comparison between 12 Costello syndrome individuals with p.G13C and individuals with p.G12S. The individuals with p.G13C had many typical findings including polyhydramnios, failure-to-thrive, HCM, macrocephaly with posterior fossa crowding, and developmental delay. Subjectively, their facial features were less coarse. Statistically significant differences included the absence of multifocal atrial tachycardia (P-value = 0.033), ulnar deviation of the wrist (P < 0.001) and papillomata (P = 0.003), and fewer neurosurgical procedures (P = 0.024). Fewer individuals with p.G13C had short stature (height below -2 SD) without use of growth hormone (P < 0.001). The noteworthy absence of malignant tumors did not reach statistical significance. Novel ectodermal findings were noted in individuals with p.G13C, including loose anagen hair resulting in easily pluckable hair with a matted appearance, different from the tight curls typical for most Costello syndrome individuals. Unusually long eye lashes requiring trimming are a novel finding we termed dolichocilia. These distinctive ectodermal findings suggest a cell type specific effect of this particular mutation. Additional patients are needed to validate these findings.
American Journal of Medical Genetics Part A 04/2011; 155A(4):706-16. DOI:10.1002/ajmg.a.33884 · 2.16 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Joubert syndrome is a disorder characterized by ataxia, developmental delay, oculomotor anomalies, and breathing irregularities, with cerebellar vermian and midbrain dysgenesis. The molar tooth sign, reflecting the midbrain dysgenesis of Joubert syndrome, is the neuroradiological hallmark and is an essential sign in the identification of this condition. Variable vermian agenesis, an expanded fourth ventricle, and a large posterior cranial fossa with a normal brainstem are typical of Dandy-Walker malformation. The authors report a case in which a Dandy-Walker malformation coexisted with Joubert syndrome, but initially prevented the ''molar tooth sign'' from being recognized because of an important cystic dilatation of the fourth ventricle. In this article, they discuss the importance of the re-examination of brain magnetic resonance features after decompression of the posterior cranial fossa in a patient with Dandy-Walker malformation and additional clinical neurological or systemic abnormalities typical of Joubert syndrome, to not miss the correct diagnosis.
[Show abstract][Hide abstract] ABSTRACT: Femur-fibular-ulna (FFU) complex is an unusual, sporadically occurring limb malformation disorder, characterized by a highly variable combination of congenital defects of the femur, the fibula and/or the ulna, which tend to be associated. We report the case of a fetus with FFU complex and additional striking metaphyseal anomalies of the lower limbs and an abnormal chondrocyte organization pattern. To our knowledge this is the first reported case of histologic metaphyseal alterations in association with the FFU complex.
[Show abstract][Hide abstract] ABSTRACT: 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.
Standard polymerase chain reaction and sequencing methods were used for mutation and single nucleotide polymorphism identification and control of cloned sequences. Array-CGH (Agilent, 244A Kit) was used for detection of deletions. Standard cloning techniques and the Snapshot method were used for analysis of mosaicism.
In this study, we present the results of LMX1B screening of 20 Nail-Patella syndrome patients. The molecular defect was found in 17 patients. We report five novel mutations and a approximately 2 Mb deletion in chromosome 9q encompassing the entire LMX1B gene in a patient with a complex phenotype. We present evidence of somatic mosaicism in unaffected parents in two cases, which, to our knowledge, are the first reported cases of inheritance of a mutated LMX1B allele in Nail-Patella syndrome patients from a mosaic parent.
The study of the described case series provides some original observations in an "old" genetic disorder.
Genetics in medicine: official journal of the American College of Medical Genetics 07/2010; 12(7):431-9. DOI:10.1097/GIM.0b013e3181e21afa · 7.33 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The aim of this study was to examine trends of Down syndrome (DS) in relation to maternal age and termination of pregnancies (ToP) in 20 registries of the International Clearinghouse for Birth Defects Surveillance and Research (ICBDSR).
Trends of births with DS (live-born and stillborn), ToP with DS, and maternal age (percentage of mothers older than 35 years) were examined by year over a 12-year period (1993-2004). The total mean number of births covered was 1550,000 annually.
The mean percentage of mothers older than 35 years of age increased from 10.9% in 1993 to 18.8% in 2004. However, a variation among the different registers from 4-8% to 20-25% of mothers >35 years of age was found. The total mean prevalence of DS (still births, live births, and ToP) increased from 13.1 to 18.2/10,000 births between 1993 and 2004. The total mean prevalence of DS births remained stable at 8.3/10,000 births, balanced by a great increase of ToP. In the registers from France, Italy, and the Czech Republic, a decrease of DS births and a great increase of ToP was observed. The number of DS births remained high or even increased in Canada Alberta, and Norway during the study period.
Although an increase in older mothers was observed in most registers, the prevalence of DS births remained stable in most registers as a result of increasing use of prenatal diagnostic procedures and ToP with DS.
Birth Defects Research Part A Clinical and Molecular Teratology 06/2010; 88(6):474-9. DOI:10.1002/bdra.20666 · 2.09 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Brachytelephalangic chondrodysplasia punctata (CDPX1) is an X-linked recessive disorder caused by mutations in the arylsulfatase E (ARSE) gene, characterized by the presence of stippled epiphyses on radiograms in infancy and early childhood. Other features include hypoplasia of the midface and of the nasal bone, short stature, brachytelephalangy, and ectopic calcifications. Patients display marked clinical variability and there is no clear genotype-phenotype correlation. We report on a 14-month-old boy who presented with respiratory stridor due to tracheal calcifications. He had mild midface hypoplasia and brachytelephalangy, but lacked other features of CDPX1, such as short stature and epiphyseal stippling. Analysis of ARSE detected a deletion involving exons 7-10. His maternal grandfather harbored the same defect but lacked any clinical manifestation. These findings underscore two important points. First, the absence of stippled epiphyses on radiograms should not be considered an exclusion criteria for ARSE mutation screening in patients with other features of the disease, especially after the neonatal period. Second, counseling to parents of affected children should be cautious because although the theoretical risk of inheriting the ARSE mutation is 50% for every male child of a carrier mother, it is not possible to determine whether he will develop features of CDPX1 and the eventual severity of symptoms. The actual risk of developing the disease is probably lower than 50%. Conversely, normal prenatal sonography does not rule out potentially severe complications such as tracheal stenosis.
American Journal of Medical Genetics Part A 11/2009; 149A(11):2464-8. DOI:10.1002/ajmg.a.33039 · 2.16 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: N-myristoylation is a common form of co-translational protein fatty acylation resulting from the attachment of myristate to a required N-terminal glycine residue.1,2 We show that aberrantly acquired N-myristoylation of SHOC2, a leucine-rich repeat-containing protein that positively modulates RAS-MAPK signal flow,3–6 underlies a clinically distinctive condition of the neuro-cardio-facial-cutaneous disorders family. Twenty-five subjects with a relatively consistent phenotype previously termed Noonan-like syndrome with loose anagen hair [OMIM 607721]7 shared the 4A>G missense change (Ser2Gly) in SHOC2 that introduces an N-myristoylation site, resulting in aberrant targeting of SHOC2 to the plasma membrane and impaired translocation to the nucleus upon growth factor stimulation. Expression of SHOC2S2G
in vitro enhanced MAPK activation in a cell type-specific fashion. Induction of SHOC2S2G in Caenorhabditis elegans engendered protruding vulva, a neomorphic phenotype previously associated with aberrant signaling. These results document the first example of an acquired N-terminal lipid modification of a protein causing human disease.
[Show abstract][Hide abstract] ABSTRACT: BackgroundThere is no agreement on the prevalence, natural history and outcome of infantile spasms (IS) in neurofibromatosis type 1
(NF1). By contrast, its prevalence and outcome are well characterised in the setting of other neurocutaneous disorders (e.g.
Materials and methodsThe aim of the present study was to try to establish a genotype–phenotype correlation in IS in the setting of NF1. A retrospective
(years 1990–2000) and prospective (years 2000–2006) study in three paediatric centres in Italy were taken as referral populations
for: (1) children with NF1 and (2) neurological problems in childhood.
ResultsTen NF1 patients have had IS. The calculated population-based: (1) prevalence of IS in NF1 (0.76%) was higher than the reported
frequency of IS in the general population (0.02–0.05%) and (2) frequency of NF1 in the IS series in two out of three centres
(0.62–0.90%) was lower than the estimated frequencies in the literature (1.5–3.0%). Patients had psychomotor delay preceding
the spasms (50%), symmetrical spasms (50%), typical (80%) and modified (20%) hypsarrhythmia and foci of spikes and waves and
a good response to corticosteroid treatment (50%). Outcome was good in 30%. Imaging revealed high-signal foci in atypical
locations (sub-cortical and central brain regions). Deoxyribonucleic acid analysis revealed three novel NF1 gene mutations
without genotype–phenotype correlation.
ConclusionEven though the combination of IS and NF1 does not seem to be coincidental, it is certainly an unusual event in NF1—rarer
than in other neurocutaneous disorders. Spasms in NF1 are not associated with specific genetic defects.
Child s Nervous System 02/2009; 25(2):211-216. DOI:10.1007/s00381-008-0706-5 · 1.11 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A condition is described which is characterized by chorio-retinal dysplasia, microcephaly and mental retardation, transmitted in an autosomal dominant fashion with variable expressivity. It is suggested that this condition is a distinct autosomal dominant syndrome.
[Show abstract][Hide abstract] ABSTRACT: An increasing number of observations suggestive for a causal link between pesticide exposure and reproductive dysfunctions have appeared in literature during recent years. The present epidemiological analysis was undertaken to evaluate whether living in rural areas, where large amounts of pesticides are applied, represents a risk factor for infertility. Fertility rate (FR) was taken as statistical indicator for potential changes in fertility mediated by pesticides. The study analyzed a large population from an agricultural area of the North Eastern Italy, the Veneto Region. According to the estimated quantities of sprayed pesticides, the area was divided in three sub-areas with expected low, intermediate and high pesticide exposure. Comparisons of FR failed to detect significant differences among populations from the three selected areas, while regression analysis showed a significant decrease of FR relative to the total amount of pesticides used. Although several investigative shortcomings prevent the results from being conclusive, this study seemingly challenges the hypothesis that living in rural areas where large amounts of pesticides are applied represents a risk factor for fertility.
[Show abstract][Hide abstract] ABSTRACT: Holoprosencephaly (HPE) is a developmental field defect of the brain that results in incomplete separation of the cerebral hemispheres that includes less severe phenotypes, such as arhinencephaly and single median maxillary central incisor. Information on the epidemiology of HPE is limited, both because few population-based studies have been reported, and because small studies must observe a greater number of years in order to accumulate sufficient numbers of births for a reliable estimate.
We collected data from 2000 through 2004 from 24 of the 46 Birth Defects Registry Members of the International Clearinghouse for Birth Defects Surveillance and Research. This study is based on more than 7 million births in various areas from North and South America, Europe, and Australia.
A total of 963 HPE cases were registered, yielding an overall prevalence of 1.31 per 10,000 births. Because the estimate was heterogeneous, possible causes of variations among populations were analyzed: random variation, under-reporting and over-reporting bias, variation in proportion of termination of pregnancies among all registered cases and real differences among populations.
The data do not suggest large differences in total prevalence of HPE among the studied populations that would be useful to generate etiological hypotheses.
Birth Defects Research Part A Clinical and Molecular Teratology 08/2008; 82(8):585-91. DOI:10.1002/bdra.20479 · 2.09 Impact Factor