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PubMed2005

Exclusion of TCOF1 mutations in a case of bilateral Goldenhar syndrome and one familial case of microtia with meatal atresia.

A number of different disorders involving first and second branchial arch anomalies have been described as distinct entities, including Treacher-Collins-Franceschetti syndrome, Goldenhar syndrome, Nager syndrome and Miller syndrome. The significant phenotypic overlap between these disorders raises the issue of a common developmental origin. After the identification of mutations in TCOF1 as a general cause of the Treacher-Collins-Franceschetti syndrome, TCOF1 mutations were excluded in patients with unilateral signs of the Goldenhar syndrome spectrum. We also present two rare cases of bilateral Goldenhar syndrome and familial microtia with meatal atresia, respectively, in whom we also excluded TCOF1 mutations. Thus, genetic heterogeneity in different disorders of the first and second branchial arch development is supported.

DNA↗

PubMed2005

Sudden cardiac death: what is inside our genes?

Although sudden cardiac death in youths is generally rare, it is estimated that 10% to 20% of these deaths occur in previously healthy infants, children, adolescents and young adults without any findings on autopsy and with devastating consequences on the family. The majority of these deaths are caused by inherited arrhythmia syndromes, the so-called 'channelopathies'. In the present paper, the recent advances in the clinical and genetic background of long QT syndrome, short QT syndrome, catecholaminergic polymorphic ventricular tachycardia, Brugada syndrome and the overlapping phenotypes are reviewed, and the recently established connections between these syndromes and idiopathic ventricular fibrillation and sudden infant death syndrome are discussed.

Bundle-Branch Block↗

PubMed2006

Hypokalemic nephropathy in an adult patient with partial empty sella: a classic Bartter's syndrome, a Gitelman's syndrome or both?

Bartter's syndrome belongs to a group of hypokalemic renal channel diseases. These channels are located in the lipid layer of cell membranes where they exist as water channels through which ion transport is performed. Based on the type of genetic disorder and clinical presentation, Bartter's syndrome is classified as neonatal, classical and Gitelman's syndrome. Most of the cases have been noted in pediatric age groups and adult-onset cases are very rare. Moreover, an association between Bartter's syndrome and empty sella has recently been reported in 3 children. We report here the second case of an adult patient affected by Bartter's syndrome with partial empty sella. The patient showed some clinical and histological characteristics of both classic Bartter's syndrome and Gitelman's syndrome, suggesting that genotype and phenotype of Bartter's syndrome are not so clear-cut and that phenotypic overlap may occur, according to a recent hypothesis. Magnetic resonance imaging disclosed a partial empty sella. A thorough endocrinological investigation showed normal hypophyseal, thyroidal, adrenal and gonadal function. Good therapeutic effects were achieved using spironolactone, ACE-inhibitor and potassium supplementation, with normalization of the kalemia. At present, the value of the association of Bartter's syndrome and empty sella remains unclear and future studies are needed to clarify the importance of this association, both in children and in adult patients affected by Bartter's syndrome.

Adult↗

PubMed1981

Apert's syndrome: (acrocephalosyndactylism).

A case history is presented that illustrates the clinical and radiographic findings of an Apert's syndrome patient. The incidence of this condition at birth is approximately 1:160,000 with a greater frequency found in the children of older parents. A brief comparison is made with two similar syndromes. Carpenter's syndrome and LMBB syndrome. Recognition and diagnosis of each syndrome is difficult due to the phenotypic overlap and is achieved through an understanding of the similarities as well as the difference. In the Apert's syndrome patient, the hand and foot deformities present particular problems regarding everyday performance. The hands of these patients are generally surgically corrected to improve hand function through removal of the syndactylism or partial amputation. However, this was not performed on this patient for he was able to write legibly and had good pincer grasping ability. The feet in the Apert's syndrome patient present unique problems due to the malformations that exist rather than acquired deformities because of excessive joint motion. The structure of the foot is generally compatible with conventional shoewear. If the patient's psychological status warrants it, elective surgical intervention would be indicated to remove hypertrophic bone at weight-bearing areas to relieve pressure.

Abnormalities, Multiple↗

PubMed1996

A gene for familial paroxysmal dyskinesia (FPD1) maps to chromosome 2q.

Dyskinesias are hyperkinetic and involuntary movements that may result from any of a number of different genetic, infectious, and drug-induced causes. Some of the hereditary dyskinetic syndromes are characterized by paroxysmal onset of the abnormal movements. The classification of the familial paroxysmal dyskinesias (FPD) recognizes several distinct, although overlapping, phenotypes. Different forms of the disorder include attacks that are (1) induced by sudden movement (kinesiogenic); (2) spontaneous (non-kinesiogenic); and (3) induced by prolonged periods of exertion. Linkage analysis was pursued in a family segregating an autosomal dominant allele for non-kinesiogenic FPD. The disease allele was mapped to a locus on chromosome 2q31-36 (LOD score 4.64, theta = 0). Identification of distinct genetic loci for the paroxysmal dyskinesias will lead to a new genetic classification and to better understanding of these disorders.

Alleles↗

PubMed1996

[Dermacentor ticks in France and Germany. Molecular biological differences in species, ecology and epidemiological implications].

Dermacentor reticulatus and D. marginatus, two ixodid tick species occurring in France and Germany, exhibit morphologically overlapping phenotypes. The results of sequence analyses of the hypervariable rDNA gene region ITS 2 do not support conspecifidity. As in France, D. reticulatus has to be characterized as an epidemiologically effective vector of Babesia canis in Germany as well, with the endemic area being located at Kehl/Offenburg/Lahr/Emmendingen/Freiburg in Breisgau. Ecological investigations indicate that a spreading of D. reticulatus and, as a possible consequence, that of B. canis in Germany has to be expected.

Animals↗

PubMed1997

Molecular characterization of a 130-kb terminal microdeletion at 22q in a child with mild mental retardation.

We have analyzed a recently described 22q13.3 microdeletion in a child with some overlapping features of the cytologically visible 22q13.3 deletion syndrome. Patient NT, who shows mild mental retardation and delay of expressive speech, was previously found to have a paternal microdeletion in the subtelomeric region of 22q. In order to characterize this abnormality further, we have constructed a cosmid/P1 contig covering the terminal 150 kb of 22q, which encompasses the 130-kb microdeletion. The microdeletion breakpoint is within the VNTR locus D22S163. The cloning of the breakpoint sequence revealed that the broken chromosome end was healed by the addition of telomeric repeats, indicating that the microdeletion is terminal. This is the first cloned terminal deletion breakpoint on a human chromosome other than 16p. The cosmid/P1 contig was mapped by pulsed-field gel electrophoresis analysis to within 120 kb of the arylsulfatase A gene, which places the contig in relation to genetic and physical maps of the chromosome. The acrosin gene maps within the microdeletion, approximately 70 kb from the telomere. With the distal end of chromosome 22q cloned, it is now possible to isolate genes that may be involved in the overlapping phenotype of this microdeletion and 22q13.3 deletion syndrome.

Cell Line, Transformed↗

PubMed1997

Specific genetic changes of diagnostic importance in chromophobe renal cell carcinomas.

The histologic diagnosis of chromophobe renal cell carcinomas is often uncertain because of phenotype overlap among different types of kidney cancers. Recently, in a novel genetic classification of renal cell tumors, a combination of monosomies of chromosomes 1, 2, 3, 6, 10, 13, 17, and 21 have been suggested to have a diagnostic value for this unique type of tumor. Therefore, we have analyzed fresh and paraffin-embedded tissues obtained from 42 chromophobe renal cell carcinomas for allelic losses at the above-mentioned chromosomal regions by employing microsatellite markers. Loss of chromosomes 1, 2, 6, 10, 13, and 17 was detected in between 75% and 95% of tumors, and loss of chromosome 21 was observed in 54% of cases. All but one tumor showed a combination of monosomies at the specific chromosomes. Thus, applying the set of microsatellite markers used in this study, a PCR-based diagnosis of chromophobe renal cell carcinomas could be established within 1 to 2 days. The general applicability of this approach to fresh and paraffin-embedded tissues allows a correct genetic characterization in all cases where a diagnosis based on histopathology remains uncertain.

Alleles↗

PubMed1997

Craniotubular dysplasia with severe postnatal growth retardation, mental retardation, ectodermal dysplasia, and loose skin: Lenz-Majewski-like syndrome.

The heterogeneous group of craniotubular dysplasias is characterized by modeling errors of the craniofacial and tubular bones. Some conditions in this category cause not only skeletal abnormalities but also a variety of mesoectodermal dysplasias, as exemplified in Lenz-Majewski syndrome (MIM 151050), which comprises craniodiaphyseal dysplasia, failure to thrive, mental retardation, proximal symphalangism, enamel hypoplasia, and loose skin. We report on a boy with a hitherto unknown multisystem disorder, including skeletal changes that were regarded as a form of craniotubular dysplasia. The patient had a large head, exophthalmos, a broad nasal root, anteverted nostrils, large auricles, thick lips, micrognathia, severe postnatal growth retardation with emaciation, severe mental retardation, sparse hair growth, enamel hypoplasia, and thin, loose skin with hyperlaxity. Skeletal changes consisted of thickened calvaria, sclerosis of the skull base and facial bones, thick ribs, and metaphyseal undermodeling of the tubular bones. In addition, generalized osteopenia was evident. The present disorder overlaps phenotypically with Lenz-Majewski syndrome; nevertheless, the absence of diaphyseal hyperostosis and proximal symphalangism in the present patient was not consistent with Lenz-Majewski syndrome.

Adult↗

PubMed1997

Deletion of PTEN in a patient with Bannayan-Riley-Ruvalcaba syndrome suggests allelism with Cowden disease.

We report on an 18-month-old boy with an interstitial deletion at 10q23.2-q24.1. This region includes the PTEN gene, mutations of which have been reported to cause Cowden disease. Our patient presented with manifestations of Bannayan-Riley-Ruvalcaba (BRR) syndrome. The BRR syndrome is a rare disorder which presents most commonly in childhood. Cowden disease is a disease of adulthood and is inadequately described in children. Because of the considerable phenotypic overlap between the two disorders, and the cytogenetic and molecular findings in our patient, we suggest that BRR syndrome and Cowden disease are allelic.

Adult↗

PubMedDate not supplied

Choroid plexus carcinomas and rhabdoid tumors: phenotypic and genotypic overlap.

Five of six poorly differentiated choroid plexus carcinomas identified at our institution contained cells displaying a rhabdoid phenotype. Immunoperoxidase stains showed focal positivity for cytokeratin, epithelial membrane antigen, glial fibrillary acidic protein, S100, and vimentin. The MIB-1 proliferative index ranged from 7.0% to 27.1%. All six tumors were p53 positive. Only the one child with Li-Fraumeni syndrome had a p53 germline mutation. Electron microscopy verified choroid plexus differentiation and the co-existence of rhabdoid cells. Of the five studied, four had deletions of chromosome 22 [three with monosomy 22 and one with del(22)(q12)]. Thus, there was a phenotypic and genotypic overlap between choroid plexus carcinomas and rhabdoid tumors.

Adolescent↗

PubMed1999

Hoxa-13 gene mutation results in abnormal seminal vesicle and prostate development.

The role of Hoxa-13 in postnatal morphogenesis of the male accessory sex organs was assessed by correlating the Hoxa-13 expression domain with phenotypic abnormalities in heterozygous Hypodactyly mutants. Hypodactyly is a naturally occurring semi-dominant mutation that results from a 50-base pair deletion in exon one of the Hoxa-13 allele. We demonstrate that Hoxa-13 is broadly expressed in the developing lower genitourinary tract and that the Hypodactyly mutation results in a specific phenotype characterized by decreased size and branching of the dorsolateral and ventral prostate and abnormal seminal vesicle morphology. This phenotype partially overlaps the genitourinary phenotype observed in Hoxd-13 deficient mice and comparison showed similar domains of Hoxa-13 and Hoxd-13 expression in the lower genitourinary tract. The similarity in expression and overlap in phenotype resulting from mutation is consistent with additive function and partial functional redundancy of Hoxa-13 and Hoxd-13 in male accessory sex organ development.

Animals↗

PubMed1991

Mutation in a gene for type I procollagen (COL1A2) in a woman with postmenopausal osteoporosis: evidence for phenotypic and genotypic overlap with mild osteogenesis imperfecta.

Mutations in the two genes for type I collagen (COL1A1 or COL1A2) cause osteogenesis imperfecta (OI), a heritable disease characterized by moderate to extreme brittleness of bone early in life. Here we show that a 52-year-old postmenopausal woman with severe osteopenia and a compression fracture of a thoracic vertebra had a mutation in the gene for the alpha 2(I) chain of type I collagen (COL1A2) similar to mutations that cause OI. cDNA was prepared from the woman's skin fibroblast RNA and assayed for the presence of a mutation by treating DNA heteroduplexes with carbodiimide. The results indicated a sequence variation in the region encoding amino acid residues 660-667 of the alpha 2(I) chain. Further analysis demonstrated a single-base mutation that caused a serine-for-glycine substitution at position 661 of the alpha 2(I) triple-helical domain. The substitution produced posttranslational overmodification of the collagen triple helix, as is seen with most glycine substitutions that cause OI. The patient had a history of five previous fractures, slightly blue sclerae, and slight hearing loss. Therefore, the results suggest that there may be phenotypic and genotypic overlap between mild osteogenesis imperfecta and postmenopausal osteoporosis, and that a subset of women with postmenopausal osteoporosis may have mutations in the genes for type I procollagen.

Adult↗

PubMed1999

Case of partial trisomy 9p and partial trisomy 14q resulting from a maternal translocation: overlapping manifestations of characteristic phenotypes.

We report on a female infant with partial trisomy 9p (pter-->p13) and partial trisomy 14q (pter-->q22) resulting from a 3:1 segregation of a maternal reciprocal translocation (9;14)(p13;q22). Both trisomy 9p and partial trisomy 14q have been described as recognized phenotypes with characteristic patterns of anomalies. This patient appears to be the first reported with a partial duplication of both 9p and 14q resulting in an overlapping phenotype including minor facial anomalies, cleft palate, and hand-foot anomalies. However, the facial findings were more pronounced than commonly observed in cases with only one or the other duplicated chromosome regions, resulting in a distinctive appearance.

Chromosome Banding↗

PubMed2006

Phenotypic and genetic overlap between autistic traits at the extremes of the general population.

OBJECTIVE: To investigate children selected from a community sample for showing extreme autistic-like traits and to assess the degree to which these individual traits--social impairments (SIs), communication impairments (CIs), and restricted repetitive behaviors and interests (RRBIs)--are caused by genes and environments, whether all of them are caused by the same genes and environments, and how often they occur together (as required by an autism diagnosis). METHOD: The most extreme-scoring 5% were selected from 3,419 8-year-old pairs in the Twins Early Development Study assessed on the Childhood Asperger Syndrome Test. Phenotypic associations between extreme traits were compared with associations among the full-scale scores. Genetic associations between extreme traits were quantified using bivariate DeFries-Fulker extremes analysis. RESULTS: Phenotypic relationships between extreme SIs, CIs, and RRBIs were modest. There was a degree of genetic overlap between them, but also substantial genetic specificity. CONCLUSIONS: This first twin study assessing the links between extreme individual autistic-like traits (SIs, CIs, and RRBIs) found that all are highly heritable but show modest phenotypic and genetic overlap. This finding concurs with that of an earlier study from the same cohort that showed that a total autistic symptoms score at the extreme showed high heritability and that SIs, CIs, and RRBIs show weak links in the general population. This new finding has relevance for both clinical models and future molecular genetic studies.

Autistic Disorder↗

PubMed1993

Discordant phenotype of two overlapping deletions involving the PAX3 gene in chromosome 2q35.

Waardenburg syndrome (WS), the most common form of inherited congenital deafness, is a pleiotropic, autosomal dominant condition with variable penetrance and expressivity. WS is clinically and genetically heterogeneous. The basis for the phenotypic variability observed among and between WS families is unknown. However, mutations within the paired-box gene, PAX3, have been associated with a subset of WS patients. In this report we use cytogenetic and molecular genetic techniques to study a patient with WS type 3, a form of WS consisting of typical WS type 1 features plus mental retardation, microcephaly, and severe skeletal anomalies. Our results show that the WS3 patient has a de novo paternally derived deletion, del (2)(q35q36), that spans the genetic loci PAX3 and COL4A3. A molecular analysis of a chromosome 2 deletional mapping panel maps the PAX3 locus to 2q35 and suggests the locus order: centromere-(INHA, DES)-PAX3-COL4A3-(ALPI, CHRND)-telomere. Our analyses also show that a patient with a cleft palate and lip pits, but lacking diagnostic WS features, has a deletion, del (2)(q33q35), involving the PAX3 locus. This result suggests that not all PAX3 mutations are associated with a WS phenotype and that additional regional loci may modify or regulate the PAX3 locus and/or the development of a WS phenotype.

Bone and Bones↗

PubMed1990

The Baller-Gerold syndrome: phenotypic and cytogenetic overlap with Roberts syndrome.

A case is reported where the major clinical features of craniostenosis and radial aplasia led to an initial diagnosis of Baller-Gerold syndrome. Mild fibular hypoplasia on skeletal survey led to review of the diagnosis and the similarity of the facial phenotype to that of Roberts syndrome was noted. Chromosome analysis showed the premature centromere separation characteristic of this condition. This case raises the question as to whether the Baller-Gerold syndrome can be considered as a distinct entity. It is suggested that cases diagnosed as having Baller-Gerold syndrome should have cytogenetic analysis and that known Roberts syndrome survivors are reviewed for signs of craniostenosis.

Adult↗

PubMed1996

Phenotypic and genotypic overlap between atelosteogenesis type 2 and diastrophic dysplasia.

Mutations in the diastrophic dysplasia sulfate transporter gene DTDST have been associated with a family of chondrodysplasias that comprises, in order of increasing severity, diastrophic dysplasia (DTD), atelosteogenesis type 2 (AO2), and achondrogenesis type 1B (ACG1B). To learn more about the molecular basis of DTDST chondrodysplasias and about genotype-phenotype correlations, we studied fibroblast cultures of three new patients: one with AO-2, one with DTD, and one with an intermediate phenotype (AO2/DTD). Reduced incorporation of inorganic sulfate into macromolecules was found in all three. Each of the three patients was found to be heterozygous for a c862t transition predicting a R279W substitution in the third extracellular loop of DTDST. In two patients (DTD and AO2/DTD), no other structural mutation was found, but polymerase chain reaction amplification and single-strand conformation polymorphism analysis of fibroblast cDNA showed reduced mRNA levels of the wild-type DTDST allele: these two patients may be compound heterozygotes for the "Finnish" mutation (as yet uncharacterized at the DNA level), which causes reduced expression of DTDST. The third patient (with AO2) had the R279W mutation compounded with a novel mutation, the deletion of cytosine 418 (delta c418), predicting a frameshift with premature termination. Also the delta c418 allele was underrepresented in the cDNA, in accordance with previous observations that premature stop codons reduce mRNA levels. The presence of the DTDST R279W mutation in a total of 11 patients with AO2 or DTD emphasizes the overlap between these conditions. This mutation has not been found so far in 8 analyzed ACG1B patients, suggesting that it allows some residual activity of the sulfate transporter.

Anion Transport Proteins↗