PubMed Health⌕ Search

SEARCH · PubMed Health

Results for “Phenotypic variability”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 343 records · Page 19Linked to original sources
PubMedDate not supplied

Variable phenotypes in a family kindred with adrenoleukodystrophy.

Adrenoleukodystrophy, an X-linked recessive disorder characterized by progressive demyelination of the central nervous system and adrenal insufficiency, usually manifests at 4-8 years of age. We report a 20-month-old male who presented with the sudden onset of status epilepticus and cortical blindness; initially, he had complete resolution of these findings, but experienced a relapse 3 months later. The initial computed tomographic scans depicted cerebral edema and possible "watershed infarcts:" however, over the next 2 weeks before discharge from the hospital, the cortical blindness and ataxia both resolved. During the next 2 months, he exhibited no symptoms: he had no seizures and his neurologic examinations were normal. Three months after the initial hospitalization, he developed what the mother believed was "a weakness on his right side." Magnetic resonance imaging confirmed severe white matter disease. Adrenoleukodystrophy was clinically suspected and an assay of plasma levels confirmed an elevation of C26 long-chain saturated fatty acid levels. After the patient's diagnosis of adrenoleukodystrophy was confirmed, long-chain fatty acid levels were obtained on his 5-year-old brother and his mother. This child had the earliest known onset of X-linked adrenoleukodystrophy.

Adrenoleukodystrophy↗
PubMed2004

Variable phenotype related to a novel PAX 6 mutation (IVS4+5G>C) in a family presenting congenital nystagmus and foveal hypoplasia.

PURPOSE: Several ocular defects have been identified as a consequence of the PAX6 gene mutations. With regard to the implication of this gene in unusual phenotypes, we report a family presenting with congenital nystagmus, foveal hypoplasia, and iris hypoplasia or atypical coloboma. DESIGN: Observational case report. METHODS: The entire transcribed region of the PAX6 gene was submitted to mutation search at the DNA and mRNA levels in five affected members of a French family in test with 82 normal subjects. RESULTS: A novel heterozygous PAX6 gene splice mutation (IVS4 + 5G>C) was identified. The mutation is located in IVS4 within the consensus donor splice site. A mutant mRNA lacking exon 4 as the sole defect was evidenced. The resultant protein was predicted to contain a cryptic ATG initiation codon in exon 3 and a slightly altered paired-domain in an open reading frame extended by 13 amino acids. CONCLUSIONS: The association of anterior segment anomalies and foveal hypoplasia with one of the slightest alterations of the PAX6 protein described to date confirms the association of variant phenotypes with hypomorphic alleles. Mutation screening of the PAX6 gene could be useful in elucidating the origin of complex ocular malformations.

Adult↗
PubMed2005

RASA1: variable phenotype with capillary and arteriovenous malformations.

Capillary malformation-arteriovenous malformation (CM-AVM) is a newly discovered hereditary disorder. Its defining features are atypical cutaneous multifocal capillary malformations often in association with high-flow lesions: cutaneous, subcutaneous, intramuscular, intraosseous and cerebral arteriovenous malformations and arteriovenous fistulas. Some patients have Parkes Weber syndrome - a large congenital cutaneous vascular stain in an extremity, with bony and soft tissue hypertrophy and microscopic arteriovenous shunting. In the past, arteriovenous malformations and arteriovenous fistulas had been considered non-hereditary. A classical genetic approach was used to identify the locus. Candidate gene screening pinpointed mutations in RASA1 (p120-RASGAP) - a RasGTPase. RASA1 reverts active GTP-bound Ras into inactive GDP-bound form. Murine Rasa1 knockout and tetraploid-aggregated embryos with RNA interference exhibited abnormal vascular development. Lack of RASA1 activity caused inhibition of cell motility, possibly through p190-RhoGAP. Thus, RASA1 defects probably cause abnormal angiogenic remodeling of the primary capillary plexus that cannot be compensated for by other RasGAPs: RASA2, RASAL and NF1. Signaling pathways involving RASA1 might offer novel targets for treatment of high-flow vascular anomalies.

Animals↗
PubMed2004

Population structure and history of a phenotypically variable teiid lizard (Ameiva chrysolaema) from Hispaniola: the influence of a geologically complex island.

Ameiva chrysolaema is distributed across the island of Hispaniola in the West Indies. The species is restricted to dry lowlands between major mountain ranges and along the southern and eastern coasts. Phylogenetic and phylogeographic analyses of mtDNA sequence variation from 14 sampling localities identify at least three independent evolutionary lineages, separated from one another by major mountain ranges. Nested clade phylogeographic analysis (NCPA) suggests a complex history of population fragmentation, consistent with geological evidence of seawater incursions into the Azua and Enriquillo basins during the Pliocene/Pleistocene (approximately 1.6 mya). Significantly negative Fu's F(S) values and parameters of mismatch distributions suggest that formerly fragmented populations have recently expanded their ranges. Significantly large average population clade distances (APCD) for two sampling localities in the Azua basin suggest secondary contact at these localities of previously separated populations. The distribution of haplotypes among polymorphic populations of A. chrysolaema suggests that variation in dorsal pattern represents a polymorphism within evolutionary lineages. Ameiva leberi is ecologically indistinguishable from and syntopic with A. chrysolaema. Genetic data suggest that A. leberi is a junior synonym of A. chrysolaema.

Animals↗
PubMed1996

Shwachman syndrome: exocrine pancreatic dysfunction and variable phenotypic expression.

BACKGROUND & AIMS: Shwachman syndrome is an inherited condition with multisystemic abnormalities, including exocrine pancreatic dysfunction. The aim of this study was to evaluate the occurrence and progression of features in a large cohort of patients. METHODS: Clinical records of 25 patients with Shwachman syndrome were reviewed. RESULTS: Mean birth weight (2.92 +/- 0.51 kg) was at the 25th percentile. However, by 6 months of age, mean heights and weights were less than the 5th percentile. After 6 months of age, growth velocity was normal. Severe fat maldigestion due to pancreatic insufficiency was present in early life (fecal fat, 26% +/- 17% of fat intake; age, < 2 years). Serial assessment of exocrine pancreatic function showed persistent deficits of enzyme secretion, but 45% of patients showed moderate age-related improvements leading to pancreatic sufficiency. Neutropenia was the most common hematologic abnormality (88%), but leukopenia, thrombocytopenia, and anemia were also frequently encountered. Patients with hypoplasia of all three bone marrow cellular lines (n = 11) had the worst prognosis; 5 patients died, 2 of sepsis and 3 of acute myelogenous leukemia. Other findings included hepatomegaly and/or abnormal liver function test results and skeletal abnormalities. CONCLUSIONS: A wide and varied spectrum of phenotypic abnormalities among patients with Shwachman syndrome is described. Pancreatic acinar dysfunction is an invariable abnormality. Patients with severe bone marrow involvement may have a guarded prognosis.

Abnormalities, Multiple↗
PubMed1993

Variable phenotypes in velocardiofacial syndrome with chromosomal deletion.

Velocardiofacial syndrome (VCF) has overlapping features with DiGeorge sequence; both result from a developmental field defect and probably represent contiguous gene deletion syndromes. The association of chromosome 22q11 deletion with DiGeorge sequence led us to do molecular analysis of chromosome 22 in 18 patients with VCF, who ranged in age from 6 to 42 years. All 18 patients had monosomy for the chromosome region 22q11. Retrospectively, we correlated the presence of the deletion with various clinical findings: 100% had cleft palate, 67% the facial phenotype, 83% cardiac disease, 94% learning disabilities, 70% ophthalmologic findings, 50% short stature, 22% psychiatric disorders, and 17% hypocalcemia. Both severely phenotypically affected and mildly affected patients had the deletion. These findings stress the importance of continued surveillance of all patients with VCF for the many medical problems that may not be present at initial diagnosis. We conclude that the presence of the gene deletion does not predict the phenotypic expression in VCF. Further studies to characterize the size of the gene deletion may facilitate better prediction of the phenotype.

Abnormalities, Multiple↗
PubMed2001

ALS with variable phenotypes in a six-generation family caused by leu144phe mutation in the SOD1 gene.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neurological disorder. The mutations of Cu/Zn superoxide dismutase gene (SOD1) are responsible for familial ALS. We investigated a large family of Istro-Rumanian origin characterized by an autosomal dominant ALS occurring in 18 cases (three of which are still alive) throughout six generations. METHODS: Clinical data were available for nine patients from the 2nd generation onward, among which one contained the neuropathological details. The mean age at onset of the disease (+/-SD) was 57.3+/-8.9 years (range 49-72), while the duration of the disease spanned over a length of time equal to 4.9+/-1.96 years (range 1.5-7). The analysis of the coding region of SOD1 was done by PCR and direct sequencing. The SOD1 activity was measured by using the red and mononuclear cells belonging to three of the patients. RESULTS: The leu144phe mutation of SOD1 was identified in four patients while a normal sequence was found in five healthy related subjects. The molecular defect was responsible for a decrease in SOD1 activity. Most of patients in this family presented clinical manifestations of ALS (in particular, the lower limb onset variant) not as severe as typical ALS caused by other SOD1 mutations. However, one patient suffering from hyperthyroidism for 17 years, showed an early onset and a rapidly progressing ALS coupled with dementia. CONCLUSIONS: We described a large family with a relatively not severe phenotype of ALS (due to a leu144phe SOD1 mutation) that was compromised in one patient by a concomitant hyperthyroidism.

Age of Onset↗
PubMed2005

An unusual familial chromosome 9 "variant" with variable phenotype: characterization by CGH analysis.

Heterochromatin confined to pericentromeric and secondary constriction regions plays a major role in morphological variation of chromosome 9, because of its size and affinity for pericentric inversion. We report on a 6-year-old boy with growth and language delay, minor facial anomalies and unusual chromosome 9 variant with an extra-band in the centromeric region on the conventional karyotype. Subsequent analysis by FISH and CGH identified this variant as a dicentric chromosome 9 with a duplication of the 9p12-q21 region. An identical chromosome 9 variant was found in the mild language retarded brother and in the phenotypically normal father and grandfather. The presumed mechanism accounting for the phenotypic discordance observed in this family and the usefulness of CGH in characterization of such variants are discussed. To our knowledge, this is the first investigation of an unusual chromosome 9 variant by CGH.

Child↗
PubMed2000

Intrafamilial phenotypic variability of Hallervorden-Spätz syndrome in a Tunisian family.

We report clinical features, CT-scan and MRI findings of three siblings with Hallervorden-Spätz disease, one of them followed for more than 20years. Patient 1 presented at age 10 with progressive generalized dystonia. Five years later she had violent dystonic spasms with opisthotonos and marked oro-mandibular involvement. Later, dystonia stabilized and examination showed dysarthria, multiple deformities related to dystonic posturing, retinal degeneration and no cognitive impairment. Cerebral CT-scan showed bilateral pallidal lucencies and T2 cerebral MRI showed the "eye of the tiger" sign.Patient 2 developed delusions and hallucinations at age 18 with acute phases of hetero-aggressivity diagnosed as "schizophrenic" in a psychiatric hospital. At age 20, he developed oromandibular dystonia, severe dysarthria and epilepsy. Cerebral MRI showed the same "eye of the tiger" sign.Patient 3 presented at age 37 with isolated psychiatric features similar to those of patient 2, also diagnosed "schizophrenic" in a psychiatric hospital. Neurological examination showed mild postural tremor of the hands and intermittent cervical dystonia. He was stabilized with neuroleptic treatment.This family shows marked intrafamilial variability of age at onset, symptom at onset (with "schizophrenic" features unusually described and leading to misdiagnosis), clinical presentation (almost entirely dystonic in one patient and almost entirely psychiatric in two others) and course of the disease (slowly progressive in one sibling, rapidly deteriorating in the second and stabilization in the third). Classification and nosology of subtypes of HSD are discussed.

Journal Article↗
PubMed2002

A familial cryptic subtelomeric deletion 12p with variable phenotypic effect.

A 15-year-old-boy and his mother, both carrying a cryptic deletion within 12p13.33, are described. The proband has a mild phenotype with moderate mental retardation and severe behavioural problems. The mother had some learning difficulties at school. Conventional GTL-banded high-resolution chromosome analysis showed normal karyotypes. Subsequent analysis by fluorescence in situ hybridization using a set of probes specific for the subtelomeric regions of all chromosomes, plus a series of probes at 12p13.33 extending from the 12p telomere, showed that both mother and son carry a 1.65 Mb terminal deletion in this region. There are 10 predicted genes within the deleted region. The unanticipated familial nature of the deletion emphasizes the value of family studies in all cases with subtelomeric abnormalities. It also demonstrates the difficulty in making a clinical diagnosis of individuals with this deletion. To the best of the present authors' knowledge, the proband and his mother are the first patients described with a submicroscopic deletion at 12p13.33.

Abnormalities, Multiple↗
PubMed2004

BIGH3 mutation in a Bangladeshi family with a variable phenotype of LCDI.

AIMS: To report a Bangladeshi family displaying intrafamilial phenotypic heterogeneity of lattice corneal dystrophy type I (LCDI) and to identify the causative mutation. METHODS: Molecular genetic analysis was performed on DNA extracted from all members of the family. Exons of BIGH3 gene were amplified by polymerase chain reaction. Gene mutation and polymorphisms were identified by heteroduplex and sequence analyses. Segregation of the mutation in the family was confirmed by restriction digestion of amplified gene fragments. RESULTS: A heterozygous C --> T transition at the first nucleotide position of codon 124 of the BIGH3 gene was detected in the three affected members and not in the unaffected members of the family. CONCLUSIONS: This is the first report of BIGH3 gene mutation in a Bangladeshi family with phenotypic heterogeneity. This study confirms that BIGH3 gene screening should be undertaken for proper classification of corneal dystrophy, especially in the absence of histopathological examination.

Adult↗
PubMed2001

Unexpected and variable phenotypes in a family with JAK3 deficiency.

Mutations of the Janus kinase 3 (JAK3) have been previously described to cause an autosomal recessive variant of severe combined immunodeficiency (SCID) usually characterized by the near absence of T and NK cells, but preserved numbers of B lymphocytes (T-B+SCID). We now report a family whose JAK3 mutations are associated with the persistence of circulating T cells, resulting in previously undescribed clinical presentations, ranging from a nearly unaffected 18-year-old subject to an 8-year-old sibling with a severe lymphoproliferative disorder. Both siblings were found to be compound heterozygotes for the same deleterious JAK3 mutations: an A96G initiation start site mutation, resulting in a dysfunctional, truncated protein product and a G2775(+3)C mutation in the splice donor site sequence of intron 18, resulting in a splicing defect and a predicted premature stop. These mutations were compatible with minimal amounts of functional JAK3 expression, leading to defective cytokine-dependent signaling. Activated T cells in these patients failed to express Fas ligand (FasL) in response to IL-2, which may explain the accumulation of T cells with an activated phenotype and a skewed T cell receptor (TcR) Vbeta family distribution. We speculate that residual JAK3 activity accounted for the maturation of thymocytes, but was insufficient to sustain IL-2-mediated homeostasis of peripheral T cells via Fas/FasL interactions. These data demonstrate that the clinical spectrum of JAK3 deficiency is quite broad and includes immunodeficient patients with accumulation of activated T cells, and indicate an essential role for JAK3 in the homeostasis of peripheral T cells in humans.

Adolescent↗
PubMed2005

Variable phenotypes of enterocolitis in interleukin 10-deficient mice monoassociated with two different commensal bacteria.

BACKGROUND & AIMS: To explore the hypothesis that selective immune responses to distinct components of the intestinal microflora induce intestinal inflammation, we characterized disease kinetics and bacterial antigen-specific T-cell responses in ex germ-free interleukin 10 -/- and wild-type control mice monoassociated with Enterococcus faecalis , Escherichia coli , or Pseudomonas fluorescens . METHODS: Colitis was measured by using blinded histological scores and spontaneous interleukin 12 secretion from colonic strip culture supernatants. Interferon gamma secretion was measured from mesenteric or caudal lymph node CD4 + T cells stimulated with bacterial lysate-pulsed antigen-presenting cells. Luminal bacterial concentrations were measured by culture and quantitative polymerase chain reaction. RESULTS: Escherichia coli induced mild cecal inflammation after 3 weeks of monoassociation in interleukin 10 -/- mice. In contrast, Enterococcus faecalis-monoassociated interleukin 10 -/- mice developed distal colitis at 10-12 weeks that was progressively more severe and associated with duodenal inflammation and obstruction by 30 weeks. Neither bacterial strain induced inflammation in wild-type mice, and germ-free and Pseudomonas fluorescens-monoassociated interleukin 10 -/- mice remained disease free. CD4 + T cells from Enterococcus faecalis- or Escherichia coli-monoassociated interleukin 10 -/- mice selectively produced higher levels of interferon gamma and interleukin 4 when stimulated with antigen-presenting cells pulsed with the bacterial species that induced disease; these immune responses preceded the onset of histological inflammation in Enterococcus faecalis -monoassociated mice. Luminal bacterial concentrations did not explain regional differences in inflammation. CONCLUSIONS: Different commensal bacterial species selectively initiate immune-mediated intestinal inflammation with distinctly different kinetics and anatomic distribution in the same host.

Animals↗
PubMed2000

Somatic and germline mosaic mutations in the doublecortin gene are associated with variable phenotypes.

Mutations in the X-linked gene doublecortin lead to "double cortex" syndrome (DC) in females and to X-linked lissencephaly (XLIS) in males. Because most patients with DC and XLIS are sporadic, representing de novo doublecortin mutations, we considered that some of these patients could be somatic or germline mosaics. Among a population of 20 patients and their families, we found evidence for mosaic doublecortin mutations in 6 individuals. Germline mosaicism was identified in two unaffected women, each with two affected children. Additionally, one affected male with DC was found to be a somatic mosaic, which presumably spared him from the more severe phenotype of lissencephaly. The high rate of mosaicism indicates that there may be a significant recurrence risk for DC/XLIS in families at risk, even when the mother is unaffected.

Adult↗
PubMed2003

Mitochondrial DNA haplogroups do not play a role in the variable phenotypic presentation of the A3243G mutation.

Thirty-five mitochondrial (mt) DNAs from Spain that harbor the mutation A3243G in association with either MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes) syndrome or a wide array of disease phenotypes (ranging from diabetes and deafness to a mixture of chronic progressive external ophthalmoplegic symptoms and strokelike episodes) were studied by use of high-resolution restriction fragment length polymorphism analysis and control-region sequencing. A total of 34 different haplotypes were found, indicating that all instances of the A3243G mutation are probably due to independent mutational events. Haplotypes were distributed into 13 haplogroups whose frequencies were close to those of the general Spanish population. Moreover, there was no statistically significant difference in haplogroup distribution between patients with MELAS and those with disease phenotypes other than MELAS. Overall, these data indicate that the A3243G mutation harbors all the evolutionary features expected from a severely deleterious mtDNA mutation under strong negative selection, and they reveal that European mtDNA backgrounds do not play a substantial role in modulating the mutation's phenotypic expression.

Adult↗