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Results for “Phenotypic variability”

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PubMed1998

Variable phenotype of familial adenomatous polyposis in pedigrees with 3' mutation in the APC gene.

BACKGROUND: Germline mutation in the adenomatous polyposis coli (APC) gene on chromosome 5 causes familial adenomatous polyposis. "Attenuated" phenotype has been reported with mutation in the 5' end of the gene (5' to codon 158), but genotype-phenotype relations at the 3' end (3' to codon 1596) have not been described fully. AIMS: To describe and compare colorectal and extracolonic phenotypes in a case series of families with mutation in the 3' end of the APC gene. METHODS: Thirty one at risk or affected members from four families with a mutation in the APC gene located at codon 1979 or 2644 were evaluated. RESULTS: Variable intrapedigree colorectal phenotype was observed: some members at older age had oligopolyposis (fewer than one hundred colorectal adenomas) whereas other members had classic polyposis at young age. Colorectal cancer was diagnosed at older mean age (50 (7) years) in the four families than in classic FAP pedigrees (39 (14) years). Extracolonic lesions characteristic of FAP occurred with 3' APC mutations, but variability in intrapedigree and interpedigree extracolonic phenotype and dissociation of severity of extracolonic manifestations from number of colorectal polyps was noted. CONCLUSIONS: Families with 3' mutations of the APC gene exhibit variable intrapedigree phenotype similar to the heterogeneity noted in families with proximal 5' mutations. Genotyping of FAP and oligopolyposis pedigrees can guide appropriate surveillance of the upper and lower gastrointestinal tract in affected members.

Adenomatous Polyposis Coli↗

PubMed1980

Embryonic testicular regression syndrome: variable phenotypic expression in siblings.

Two 46,XY agonadal siblings with variable degrees of sexual ambiguity are described. The eldest child is a phenotypic male with micropenis. The younger patient, a phenotypic female with slight fusion of the genital folds and absent müllerian ducts, conforms to the criteria usually accepted for the diagnosis of true agonadism. Coexistence of anorchia and true agonadism in the same sibship supports the hypothesis, suggested by others, that both disorders are related and are due to the regression of the embryonic testes.

Child↗

PubMed2000

Autosomal dominant hemolytic uremic syndrome: variable phenotypes and transplant results.

Autosomal dominant hemolytic uremic syndrome (ADHUS) is a rare disorder with a poor prognosis that was considered to present mainly in adults. Recurrent episodes of ADHUS were also thought to be uncommon. However, increasing reports suggest that children are often affected, that recurrent episodes may occur pretransplantation, and that post-transplant recurrences occur in about 50% of cases. We describe the occurrence of ADHUS in two unrelated families with different outcomes. It is apparent that there are several types of ADHUS (with and without serum complement abnormalities) and that there may be variable expression of the phenotype. There was variable penetration of HUS in four (possibly five) adults and two children in four generations of one kindred. There was also one definite unaffected carrier. Two patients had successful renal transplants without recurrences; the HUS recurred in a third patient soon after transplantation. In a second family, the father had three episodes of HUS at 18, 26 and 29 years of age; his son had one episode of HUS at 5 years of age. Both recovered completely. Evaluation of these patients, previous reports, and follow-up contacts of previous reports suggests that post-transplant recurrence of ADHUS is more common than previously reported and may not be prevented by prior nephrectomy of native kidneys.

Adult↗

PubMed1988

Leukemic cell maturation: phenotypic variability and oncogene expression in HL60 cells: a review.

Leukemic cells in vitro and in vivo demonstrate an unstable phenotype. We have observed in HL60 cells maintained in culture over long periods of time such phenomena as emergence of drug resistance, oncogene amplification, loss of granulocyte and monocyte lineage markers, and alteration in cell growth parameters. As summarized in this report, a comprehensive review of the literature on HL60 cells shows a wide diversity of phenotype for these cells. We have developed and acquired from other laboratories a series of HL60 sublines with varying phenotypic characteristics. The time in continuous log phase culture for HL60 cells (passage 13 ATCC, Rockville MD) to undergo phenotypic drift from a heavily granulated promyelocytic cell to a more undifferentiated agranular blast form on four occasions varied from 3 to 18 months. The actual loss of promyelocytic phenotype occurred rapidly (within less than 1 month) following a variable period of apparent stable phenotype, The change in morphology was invariably accompanied by decreased sensitivity to ARA-c (5- to 20-fold increase in LD50 and dose necessary to induce NSE positive cells). The c-myc gene is variably amplified in sublines of HL60 cells. The expression of c-myc primarily reflects alterations in cell cycle kinetics and was not found to be correlated with a switch between proliferation and maturation. These results suggest that phenotypic drift may be due to loss of response to regulatory signals that affect the expression of a number of cellular genes.

Cell Differentiation↗

PubMed2002

Saethre-Chotzen syndrome: notable intrafamilial phenotypic variability in a large family with Q28X TWIST mutation.

Saethre-Chotzen syndrome is an autosomal dominant disease characterized by craniosynostosis, ptosis, and limb and external ear abnormalities. Variable expressivity is a well-known phenomenon in this disorder. A large Indian family has been recently identified as carrying a nonsense TWIST mutation (Q28 X) in 17 members, of whom 16 were examined in detail. Only 4 (25%) of the patients showed patent craniostenosis, namely, oxycephaly. The penetrance of craniosynostosis in this family is lower than previously reported in the literature. Fifteen patients (93%) had moderate to severe ptosis. Minor limb and external ear abnormalities were present in most patients. Eyelid features were the hallmark of the disease for 12 members of the family, suggesting that mutations in TWIST may lead to a phenotype with mainly palpebral features and no craniostenosis. The clinical analysis of this large family clearly illustrates the significant variable expressivity, probably related to haploinsufficiency because of the TWIST mutation. This phenotypic variability remains unclear but could be the result of modifier genes and/or genetic background effect, as noticed previously in the transgenic twist-null heterozygous mice.

Acrocephalosyndactylia↗

PubMed2004

Four new cases of congenital secondary hypothyroidism due to a splice site mutation in the thyrotropin-beta gene: phenotypic variability and founder effect.

Isolated TSH deficiency is a rare cause of congenital hypothyroidism. We here report four children from two consanguineous Turkish families with isolated TSH deficiency. Affected children who were screened at newborn age had an unremarkable TSH result and a low serum TSH level at diagnosis. Age at diagnosis and clinical phenotype were variable. All affected children carried an identical homozygous splice site mutation (IVS2 + 5 G--> A) in the TSHbeta gene. This mutation leads to skipping of exon 2 and a loss of the translational start codon without ability to produce a TSH-like protein. However, using specific monoclonal antibodies, we detected a very low concentration of authentic, heterodimeric TSH in serum, indicating the production of a small amount of correctly spliced TSH mRNA. By genotyping all family members with polymorphic markers at the TSHbeta locus, we show that the mutation arose on a common ancestral haplotype in three unrelated Turkish families indicating a founder mutation in the Turkish population. These results suggest that this TSHbeta mutation is among the more common TSHbeta gene mutations and stress the need for a biochemical and molecular genetic workup in children with symptoms suggestive of congenital hypothyroidism, even when the neonatal TSH screening is normal.

Adenine↗

PubMed2001

Proximal myotonic myopathy and proximal myotonic dystrophy: two different entities? The phenotypic variability of proximal myotonic syndromes.

Multisystemic myotonic myopathies are characterised by a variable pattern of symptoms and signs and a variable degree of disease severity. Proximal myotonic dystrophy has been described as an entity distinct from proximal myotonic myopathy because of severe proximal muscle weakness and dystrophic changes on magnetic reasonace imaging and on muscle histopathology. We describe two siblings, one of them presenting with a proximal myotonic myopathy phenotype, the other with a proximal myotonic dystrophy-like phenotype. The variability of disease expression in these two siblings suggests that a proximal myotonic dystrophy-like variant may occur in proximal myotonic myopathy.

Biopsy↗

PubMed1998

Phenotypic variability in familial combined pituitary hormone deficiency caused by a PROP1 gene mutation resulting in the substitution of Arg-->Cys at codon 120 (R120C).

As pituitary function depends on the integrity of the hypothalamic-pituitary axis, any defect in the development and organogenesis of this gland may account for a form of combined pituitary hormone deficiency (CPHD). A mutation in a novel, tissue-specific, paired-like homeodomain transcription factor, termed Prophet of Pit-1 (PROP1), has been identified as causing the Ames dwarf (df) mouse phenotype, and thereafter, different PROP1 gene alterations have been found in humans with CPHD. We report on the follow-up of two consanguineous families (n = 12), with five subjects affected with CPHD (three males and two females) caused by the same nucleotide C to T transition, resulting in the substitution of Arg-->Cys in PROP1 at codon 120. Importantly, there is a variability of phenotype, even among patients with the same mutation. The age at diagnosis was dependent on the severity of symptoms, ranging from 9 months to 8 yr. Although in one patient TSH deficiency was the first symptom of the disorder, all patients became symptomatic by exhibiting severe growth retardation and failure to thrive, which was mainly caused by GH deficiency (n = 4). The secretion of the pituitary-derived hormones (GH, PRL, TSH, LH, and FSH) declined gradually with age, following a different pattern in each individual; therefore, the deficiencies developed over a variable period of time. All of the subjects entered puberty spontaneously, and the two females also experienced menarche and periods before a replacement therapy was necessary.

Adrenocorticotropic Hormone↗

PubMed2006

Molecular cytogenetic analysis of a familial interstitial deletion Xp22.2-22.3 with a highly variable phenotype in female carriers.

We describe a familial interstitial deletion of 7.7-Mb involving Xp22.2-22.3. The deletion was transmitted from an asymptomatic mother to her two children with severe developmental delay, no speech development and autistic behavior. Assessment of the deletion boundaries by FISH and PCR analyses indicated that the deletions encompasses 27 genes. Several of these genes are associated with known disorders, like KAL1 (Kallmann syndrome), steroid sulfatase (STS) (X-linked ichtyosis), and arylsulfatase E (ARSE) (chondrodysplasia punctata). The deletion also includes all four VCX genes (VCX-A, VCX-B1, VCX-B, and VCX-C) and the neuroligin 4 (NLGN4) gene. VCX-A deficiency has been shown previously to be associated with mental retardation and NLGN4 mutations lead to mental retardation in conjunction with autism. Functional deficiency of both MRX genes, VCX-A and NLGN4, are most likely associated with the impaired cognitive development of the patients described here. The phenotype associated with the Xp deletion was highly variable in female carriers and might be attributed to unfavorable X inactivation. However, all the 27 genes included in the deleted interval escape X inactivation and are expressed at variable levels from the normal X chromosome. Thus, the overall X inactivation pattern and inter-individual expression variability of the genes in distal Xp might be determinants of the phenotype associated with the deletion.

Abnormalities, Multiple↗

PubMed2000

Char syndrome: a new family and review of the literature emphasising the presence of symphalangism and the variable phenotype.

We report a family of three affected individuals with the facial features of Char syndrome. The family also demonstrates symphalangism of the distal interphalangeal joints of the fifth fingers, extending the digital phenotype seen in this condition. We review the features of previously reported patients and emphasise the variability in the phenotype of Char syndrome.

Adult↗

PubMed1999

[Non-classical 21-hydroxylase deficiency: clinico-hormonal discrepancies and intrafamilial phenotypic variability].

BACKGROUND: We report here two families illustrating the intrafamilial phenotypic variety of the non-classical 21-hydroxylase deficiency and other discrepancies between clinical and hormonal data. PATIENTS, METHODS AND RESULTS: The index case in the first family had a mild hirsutism which appeared peripuberally and basal 17-hydroxyprogesterone over the measurement limit. One of her sister, without hair excess, had the same biochemical abnormality. The index case in the second family was detected at five years because of early appearance of public hair and basal 17-hydroxyprogesterone over the measurement limit. One of her siblings, a 16-year old girl, was also diagnosed of mild hirsutism and increased levels of basal and post-stimulation 17-hydroxyprogesterone. CONCLUSIONS: The association of marked biochemical abnormalities with scarce or no clinical expression in the first family and the different presentation form of both cases in the second family suggest that there is something else than the mutation in the CYP 21B gene in the non-classic deficiency of 21-hydroxylase.

17-alpha-Hydroxyprogesterone↗

PubMed2006

Defining constant versus variable phenotypic features of women with polycystic ovary syndrome using different ethnic groups and populations.

CONTEXT: The phenotype of women with polycystic ovary syndrome (PCOS) is variable, depending on the ethnic background. OBJECTIVE: The phenotypes of women with PCOS in Iceland and Boston were compared. DESIGN: The study was observational with a parallel design. SETTING: Subjects were studied in an outpatient setting. PATIENTS: Women, aged 18-45 yr, with PCOS defined by hyperandrogenism and fewer than nine menses per year, were examined in Iceland (n = 105) and Boston (n = 262). INTERVENTION: PCOS subjects underwent a physical exam, fasting blood samples for androgens, gonadotropins, metabolic parameters, and a transvaginal ultrasound. MAIN OUTCOME MEASURES: The phenotype of women with PCOS was compared between Caucasian women in Iceland and Boston and among Caucasian, African-American, Hispanic, and Asian women in Boston. RESULTS: Androstenedione (4.0 +/- 1.3 vs. 3.5 +/- 1.2 ng/ml; P < 0.01) was higher and testosterone (54.0 +/- 25.7 vs. 66.2 +/- 35.6 ng/dl; P < 0.01), LH (23.1 +/- 15.8 vs. 27.6 +/- 16.2 IU/liter; P < 0.05), and Ferriman Gallwey score were lower (7.1 +/- 6.0 vs. 15.4 +/- 8.5; P < 0.001) in Caucasian Icelandic compared with Boston women with PCOS. There were no differences in fasting blood glucose, insulin, or homeostasis model assessment in body mass index-matched Caucasian subjects from Iceland or Boston or in different ethnic groups in Boston. Polycystic ovary morphology was demonstrated in 93-100% of women with PCOS in all ethnic groups. CONCLUSIONS: The data demonstrate differences in the reproductive features of PCOS without differences in glucose and insulin in body mass index-matched populations. These studies also suggest that measuring androstenedione is important for the documentation of hyperandrogenism in Icelandic women. Finally, polycystic ovary morphology by ultrasound is an almost universal finding in women with PCOS as defined by hyperandrogenism and irregular menses.

Adolescent↗

PubMed2000

Phenotypic variability and origins of mutations in the gene encoding 3beta-hydroxysteroid dehydrogenase type II.

Mutations in HSD3B2, the gene for 3beta-hydroxysteroid dehydrogenase type II (3beta-HSD II) have been detected and activities analysed through the in vitro expression of mutant cDNAs. Two full sibs with male pseudohermaphroditism were found to be double heterozygotes: N100S/266DeltaA. This genotype leads to the most profound loss of 3beta-HSD II enzyme activity (1.3% of normal) described to date in cases without severe salt-loss. One sib (N100S/266DeltaA) is the first reported male case of type II deficiency affected with premature adrenarche. Three apparently independent kindreds had propositi affected with the HSD3B2 mutation A82T/A82T, which is associated with a non salt-losing phenotype with variable expressivity in females. These three families had the same extended HSD3B haplotype and are likely to have inherited the same ancestral mutation. The significance of this finding is discussed in the light of the presence of A82T mutation at a homologous position in pseudogene varphi5 that is present in the HSD3B cluster.

3-Hydroxysteroid Dehydrogenases↗

PubMed2004

Phenotypic variability in Angelman syndrome: comparison among different deletion classes and between deletion and UPD subjects.

Angelman syndrome (AS) can result from either a 15q11-q13 deletion (del), paternal uniparental disomy (UPD), imprinting, or UBE3A mutations. Here, we describe the phenotypic and behavioral variability detected in 49 patients with different classes of deletions and nine patients with UPD. Diagnosis was made by methylation pattern analysis of exon 1 of the SNRPN-SNURF gene and by microsatellite profiling of loci within and outside the 15q11-q13 region. There were no major phenotypic differences between the two main classes (BP1-BP3; BP2-BP3) of AS deletion patients, except for the absence of vocalization, more prevalent in patients with BP1-BP3 deletions, and for the age of sitting without support, which was lower in patients with BP2-BP3 deletions. Our data suggest that gene deletions (NIPA1, NIPA2, CYF1P1, GCP5) mapped to the region between breakpoints BP1 and BP2 may be involved in the severity of speech impairment, since all BP1-BP3 deletion patients showed complete absence of vocalization, while 38.1% of the BP2-BP3 deletion patients were able to pronounce syllabic sounds, with doubtful meaning. Compared to UPD patients, deletion patients presented a higher incidence of swallowing disorders (73.9% del x 22.2% UPD) and hypotonia (73.3% del x 28.57% UPD). In addition, children with UPD showed better physical growth, fewer or no seizures, a lower incidence of microcephaly, less ataxia and higher cognitive skills. As a consequence of their milder or less typical phenotype, AS may remain undiagnosed, leading to an overall underdiagnosis of the disease.

Adolescent↗

PubMed2002

Broad phenotypic variability in a single pedigree with a novel 1410delC mutation in the PST domain of the PAX6 gene.

The PAX6 mutation present in an individual with aniridia was determined and phenotypic features of immediate relatives carrying the same mutation investigated. Mutation analysis revealed a novel single base deletion 1410delC in the PAX6 gene in ten affected individuals. Clinical features ranged from total aniridia to very mild anterior segment findings. Other findings included partial aniridia, iris stromal hypoplasia, keratitis, cataract, glaucoma, optic disc anomalies and foveal hypoplasia. It appears that independent modifying factors may underlie the variability of the different phenotypic features of the PAX6 mutation.

Aniridia↗

PubMed1994

Mutations in the phenylalanine hydroxylase gene: genetic determinants for the phenotypic variability of hyperphenylalaninemia.

Phenylalanine hydroxylase (PAH) deficiency is a heterogeneous disease at the phenotype level. The spectrum of clinical and metabolic phenotypes spans from the potential pathogenic disease classical phenylketonuria (PKU) to the benign condition non-PKU hyperphenylalaninemia (non-PKU HPA). This review provides an introduction to the clinical variants of PAH deficiency, and summarizes our attempts to define the disease at the molecular level and to relate mutation genotype to clinical outcome. Complete genotype determination in a large number of patients with PAH-deficient hyperphenylalaninemia demonstrates that clinical heterogeneity can be explained by a multiplicity of mutations in the PAH gene. Some combinations of mutations are associated with phenylalanine levels fluctuating around the border between PKU and non-PKU HPA. However, certain mutations seem always to cause non-PKU HPA irrespective of the mutation on the second allele and can, therefore, unambiguously be designated as being associated with the non-PKU HPA phenotype. Our results suggest that mutation analysis in newborns presenting with hyperphenylalaninemia can be used for rapid and highly efficient differential diagnosis of PAH deficiency, and for predicting the severity of the disease. These possibilities may facilitate and optimize the management of hyperphenylalaninemia and thereby improve prognosis.

Denmark↗

PubMedDate not supplied

[Genetic heterogeneity and phenotypic variability in 46,XY sex reversal].

The discordance between the chromosomic and the gonadal-phenotypic sex is known as sex reversal (XX males and XY females). We review the XY pure gonadal dysgenesis characterized by female phenotype, primary amenorrhea and absence of secondary sexual development. Bilateral streak gonads are always present in the complete form of this syndrome, while variable degrees of virilization are found in the partial forms, depending on the severity of the testicular damage. A plausible explanation for this pathology are SRY mutations that interfere with the testicular differentiation. However, only 10-15% of the patients with the complete form show SRY mutations, particularly in the HMG box. The remaining cases are probably due to mutations in different autosomal or X-linked genes which are also involved in the sex differentiation cascade. Recently, it has been shown that mutations in several genes responsible of well known genetic entities as WT1, SOX9, DSS and SF1, result in sex reversal. These findings reveal the genetic heterogeneity and clinical variability of XY sex reversal and provide the basis establishing a hierarchy of genes and their participation in the sex determination pathway.

Female↗

PubMed1995

The molecular basis for phenotypic variability of the common thalassaemias.

The thalassaemias, the commonest monogenic diseases in humans, and the first to be analysed at the molecular level, show remarkable phenotypic heterogeneity. As much of this variability can be ascribed to acquired pathology resulting from complications of the profound anaemia that accompanies these diseases, it is often difficult to define the precise relationships between different mutations and their clinical manifestations. Some progress has been made, however. In this article, what has been learnt about genotype/phenotype relationships for the two common forms of thalassaemia is summarized.

Gene Dosage↗