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PubMed2004

Abnormal distribution and hyperplasia of thyroid C-cells in PTEN-associated tumor syndromes.

INTRODUCTION: Cowden's disease (CD) and Bannayan-Ruvalcaba-Riley syndrome (BRRS) are allelic disorders characterized by multiple hamartomatous overgrowths of the thyroid, breast, skin, and gastrointestinal tract, and an increased risk of developing benign and malignant tumors of the breast and thyroid gland, secondary to germline point mutations in the PTEN gene. In contrast to thyroid epithelial lesions, abnormalities of the C-cells are currently not considered part of the spectrum of manifestations seen in PTEN-associated syndromes. METHODS: The thyroid glands from two patients with overlapping CD/BRRS phenotypes, and with distinct PTEN mutations, were entirely submitted for histopathological examination, calcitonin immunostaining and C-cell mapping. RESULTS: Multiple follicular adenomas and adenomatous nodules were present in the thyroid glands from both patients. A microscopic focus of papillary carcinoma was also present in one gland. C-cell hyperplasia was documented in both cases by calcitonin immunostaining. CONCLUSIONS: PTEN-associated tumor syndromes should be considered in the differential diagnosis of C-cell hyperplasia of the thyroid.

Adenocarcinoma, Follicular↗
PubMed2002

Common treatment of polycystic ovarian syndrome and major depressive disorder: case report and review.

We present the case of a young woman with treatment-resistant major depression, who presented to the Mood Disorders Clinic with a Hamilton Psychiatric Rating Scale for Depression (HAM-D-21) score of 28, after a year-long treatment with Effexor-XR. The patient also had untreated Polycystic Ovarian Syndrome (PCOS). The resolution of her depressive symptoms resulted from the treatment for PCOS with metformin and spironolactone. The patient remained euthymic 5 months after discontinuation of the antidepressant while continuing therapy for PCOS. We briefly overview of the pertinent literature of the pathophysiology of PCOS and affective disorders, highlighting an overlap in phenotypical presentations between these two disorders. Dysregulation of the hypothalamo-pituitary axis and various end organ systems are implicated in both PCOS and affective disorders. As such, several clinical and biochemical markers are common to both disorders, namely insulin resistance, obesity, and hyperandrogenism. In addition, these metabolic abnormalities are interrelated, causing women with PCOS or affective disorders to get caught in a "vicious cycle" of hormonal dysregulation. The case report presented here illustrates how treatment of symptoms such as insulin resistance and hyperandrogenism can lead to remission of major depressive disorder and PCOS. We suggest that through treatment of underlying metabolic defects, both the mood of the patient and the metabolic condition of PCOS can be assisted.

Adult↗
PubMed2002

[Friedreich ataxia--diagnosis after a decade. Differential diagnosis of inherited spinocerebellar ataxias].

The clinical diagnosis of inherited spinocerebellar ataxias is difficult, because phenotypes frequently overlap. The authors attempt to review the different inherited ataxia syndromes, discussing the most frequent one, Friedreich-ataxia in detail. The case of a patient with Friedreich-ataxia is presented, where the genetically supported diagnosis has been made more than ten years following the onset of the symptoms, after several hospitalizations and misdiagnosis. The correct diagnosis can be established based on the Geoffroy-Harding criteria and gene mutation analysis.

Diagnosis, Differential↗
PubMedDate not supplied

[Polymorphic markers of the NO synthase genes and genetic predisposition to diabetic polyneuropathy in patients with type 1 diabetes mellitus].

The allele and genotype frequencies of polymorphic markers of NOS1, NOS2 and NOS3 genes, encoding three types of NO synthases, were compared in type 1 diabetes patients with and without diabetic polyneuropathty. 180 type 1 diabetes patients (T1DM) of Russian or Eastern Slavonic origin, living in Moscow city, were divided into two groups using non-overlapping (polar) phenotypes. 86 patients had overt DPN and T1DM duration in this group was less than 5 years (DPN+ group) and 94 patients had no clinical DPN and T1DM duration was more than 10 years (DPN- group). We have not found the significant differences of allele and genotype frequencies of polymorphic markers (CA)n of NOS1 gene, (CCTTT)n of NOS2 gene, ecNOS4a/4b and Glu298Asp of NOS3 gene that indicates that all these markers are not associated with diabetic polyneuropathty. Only in the case of (CCTTT)n marker of NOS2 gene we have found a tendency for the association of 14 allele with DPN development. The carriers of this allele have the lower risk of DPN in T1DM.

Diabetes Mellitus, Type 1↗
PubMed1994

Molecular genetics of hereditary ataxias.

The hereditary ataxias are a very heterogeneous group of disorders characterized by cerebellar dysfunction that can be either isolated or accompanied by other neurological manifestations. The classification of the hereditary ataxias based on clinical or histopathological findings has been difficult because of the significant overlap of phenotypes among the various genotypes. The patterns of inheritance observed in ataxias include autosomal dominant, autosomal recessive and X-linked. Friedreich's ataxia, the most frequent form among the recessive ataxias, has been mapped to the long arm of chromosome 9 based on close linkage to the markers D9S5 and D9S15. This close linkage allows the use of these two DNA markers for prenatal diagnosis in families with one affected offspring. In the past year, significant research progress has been accomplished by applying molecular genetic studies to the dominantly inherited spinocerebellar ataxias. Spinocerebellar ataxia type 1 (SCA1), which maps to the short arm of chromosome 6, has been found to be caused by expansion of an unstable trinucleotide (CAG) repeat. This mutational mechanism explains the presence of the clinical phenomenon of anticipation in some families with SCA1. The finding of an unstable repeat in SCA1 will facilitate the diagnosis of SCA1 in familial and isolated cases and will allow preclinical and prenatal diagnosis in families with this disease. In addition to the cloning of the SCA1 gene, two dominantly inherited ataxias have been genetically mapped: SCA2, to the long arm of chromosome 12, and Machado-Joseph disease (MJD), to the long arm of chromosome 14. Given that anticipation has been observed in patients with SCA2 and MJD, it is likely that trinucleotide repeat expansion could be a common mechanism involved in all the spinocerebellar ataxias. Last, significant research progress has been accomplished in the field of hereditary ataxias associated with DNA repair defects which should facilitate our understanding of mechanisms involved in cerebellar degeneration.

Ataxia↗
PubMed1976

Multivariate classification of human populations. I. Allocation of Yanomama indians to villages.

A set of 12 anthropometric measures and six genetic traits, available for 520 Yanomama Indians from 19 villages in nine clusters, were used to allocate individuals to villages. On the basis of anthropometrics alone, 36% of the individuals were allocated to the right village and 60% to the right cluster. On the basis of genetic traits alone, 16% were allocated to the right village and 26% to the right cluster. A combination of all 18 characters yielded 41% allocation to the right village and 63% to the right cluster. Of the 924 possible combinations of six anthropometric measures, only one provided poorer resolution than did the six genetic traits. We explain the better resolution of the anthropometric traits by noting that the anthropometric traits are not totally heritable and that genetic traits are not continuously distributed. Randomization studies indicated that all of the observed correct-allocation fractions are far in excess of random expectation. We infer that the village phenotype distributions overlap only partially, and that they represent real and substantial population differentiation.

Alleles↗
PubMed2001

Hamartoma and lentiginosis syndromes: clinical and molecular aspects.

The classic hamartoma syndromes and the related conditions discussed in this chapter show varying degrees of phenotypic and genetic overlap. Knowledge of the susceptibility genes underlying their phenotypes has provided additional information for the classification of these syndromes. Germline PTEN mutations appear to cause both CS and BRR. These two syndromes are therefore likely to be different manifestations of a single disease with variable expression. It has been suggested that PTEN mutation-positive CS and BRR should be grouped as a single entity for clinical purposes and classified as the 'PTEN hamartoma-tumour syndrome' [111]. Germline PTEN mutations are unlikely to cause JPS. However, germline SMAD4 mutation, especially a well-described 4-bp deletion, can be used to confirm a clinical diagnosis of JPS. Like the hamartoma syndromes, the lentiginoses also show substantial clinical overlap; it remains to be seen whether this is reflected in the molecular pathways that are involved in the pathogenesis of these syndromes. Given that the degree and type of cancer susceptibility between the hamartoma and lentiginosis syndromes is different, clarification of these syndromes at the molecular level is predicted to allow directed cancer surveillance. The molecular story is still evolving with regards to aspects of genetic heterogeneity, signalling pathways and the manner in which these hamartoma genes function in the development of their respective syndromes. It is likely that in all of these syndromes, tumours develop against a background created by loss of the growth-suppressive function of their susceptibility gene via mechanisms including disruption of the cell cycle and the activation of anti-apoptotic pathways.

Chromosome Mapping↗
PubMed2005

Distal myopathies.

PURPOSE OF REVIEW: The distal myopathies are a heterogeneous group of disorders that pose a challenge to both the clinician and geneticist. This article summarizes the findings of recent clinical, genetic and molecular studies and the current diagnostic approach to this group of patients. RECENT FINDINGS: Publications over the past 5 years describe a number of new clinical phenotypes and genetic loci and further emphasize the overlap in clinical phenotype between a number of these disorders and between the distal and limb girdle myopathies and hereditary inclusion body myopathies. Recent studies have led to the identification of the genes and mutations responsible for early onset (Laing) myopathy and tibial (Udd) myopathy, and for distal myopathy with rimmed vacuoles (Nonaka), which has been shown to be allelic with quadriceps sparing hereditary inclusion body myopathy (IBM2), and have elucidated the underlying pathogenetic mechanisms in these conditions. New diagnostic approaches using magnetic resonance imaging, and a blood-based assay for dysferlin deficiency, have also been reported. SUMMARY: These findings have important implications for future genetic linkage and gene expression studies and for the diagnostic approach to patients with a distal myopathy phenotype. They also hold promise for the eventual development of therapies for this group of disorders.

Distal Myopathies↗
PubMed2004

The development of prosocial behaviour in children and adolescents: a twin study.

BACKGROUND: Childhood psychopathology is associated with both high and low levels of prosocial behaviour. It has been proposed that the development of prosocial behaviour shows emerging and consolidating individual differences as children grow older. The influences on these individual differences have not previously been examined in children and adolescents using multiple raters in a genetically informative design. METHODS: Twin data from 682 families based on parent and teacher reports were used to examine the genetic and environmental influences on prosocial behaviour in 5-16-year-olds. Effects of sex, age and rater were examined. RESULTS: There were no significant differences in the magnitude of genetic and environmental influence on male and female prosocial behaviour. Declining common environment and increasing genetic influences were seen with age. This emerged as a trend in parent data and reached statistical significance in teacher data. When parent and teacher data were examined together in a rater bias model significant bias acting on the parent ratings emerged, in keeping with previous discrepancies between parental and observational measures. There was overlap in the phenotype rated by parents and teachers, with a highly heritable common underlying phenotype. CONCLUSIONS: The influences on the distribution of prosocial behaviour in children and adolescents show declining shared environmental and increasing genetic influences with age. Parental assessments of prosocial behaviour show significantly higher scores than teacher reports and whilst there is overlap in the phenotype rated by parents and teachers, parents show significant bias in their ratings.

Adolescent↗
PubMed2002

De novo GLI3 mutation in acrocallosal syndrome: broadening the phenotypic spectrum of GLI3 defects and overlap with murine models.

Acrocallosal syndrome (ACS) is characterised by postaxial polydactyly, hallux duplication, macrocephaly, and absence of the corpus callosum, usually with severe developmental delay. The condition overlaps with Greig cephalopolysyndactyly syndrome (GCPS), an autosomal dominant disorder that results from mutations in the GLI3 gene. Here we report a child with agenesis of the corpus callosum and severe retardation, both cardinal features of ACS and rare in GCPS, who has a mutation in GLI3. Since others have excluded GLI3 in ACS, we suggest that ACS may represent a heterogeneous group of disorders that, in some cases, may result from a mutation in GLI3 and represent a severe, allelic form of GCPS. The finding is important for counselling families with suspected ACS.

Abnormalities, Multiple↗
PubMed2002

Craniofacial anomalies, deafness, brachydactyly, short stature, and moderate mental retardation due to a cryptic 6p;11q translocation.

Monozygotic twin brothers are described who share clinical features which include: moderate mental retardation, short stature, macrocephaly, frontal bossing, ptosis, low-set ears, brachydactyly, 5th fingers clinodactyly, single palmar creases, cryptorchidism, and prelingual sensorineural deafness. One of the twins presented with mild cardiac dilatation and died at age 3(1/2) from cardiac arrest during an episode of acute respiratory infection. While chromosome analyses performed for both twins on peripheral blood showed apparently normal karyotypes, screening for all telomeric regions on the surviving propositus revealed a combination of partial 6p trisomy and partial 11q monosomy. A balanced reciprocal translocation was found in the father. The phenotype of the twins is most likely related to this cryptic chromosomal rearrangement. The fact that the phenotype in this family partially overlaps with some previously reported phenotypes is discussed.

Abnormalities, Multiple↗
PubMed1993

Isolation, culture, and transplantation of rat hepatocytic precursor (stem-like) cells.

From a review of past studies and the report of new studies from our laboratory, this article provides strong evidence to show that WB-F344 (WB) rat liver epithelial cells are stem-like precursor cells for hepatocytes. WB cells are structurally and phenotypically simple epithelial cells that were isolated from the liver of an adult male Fischer 344 rat, under conditions that excluded their origin from hepatocytes in vivo. WB cells express a phenotypic repertory that overlaps, but is distinct from, that of both hepatocytes and bile duct epithelial cells. The complex phenotype of WB cells is compatible with their being embryonic or undifferentiated variants of either hepatocytes or bile duct epithelial cells. When WB cells are tagged genetically with genes for bacterial beta-galactosidase and neomycin resistance (BAG2-WB), they and their progeny can be distinguished from parental WB cells and hepatocytes by the expression of these gene products. Progeny of BAG2-WB cells that were transplanted into the liver parenchyma of syngeneic rats integrated into hepatic plates and acquired the morphological and functional attributes of adjacent host hepatocytes; the progeny of BAG2-WB cells in the liver express albumin, tyrosine aminotransferase, alpha-1-antitrypsin, and transferrin. We also demonstrate that progeny of BAG2-WB cells can be recovered from livers into which they have been transplanted, which may allow the elucidation of alterations in gene expression that accompany their differentiation.

Animals↗
PubMed2001

Heterogeneity within tissue-specific macrophage and dendritic cell populations during cutaneous inflammation in atopic dermatitis.

BACKGROUND: Macrophages and dendritic cells may play a role in chronicity of atopic dermatitis (AD); however, so far only limited data are documented on the distribution of these cells in the skin during cutaneous inflammation. OBJECTIVES: To gain better insight into the presence and distribution of macrophage and dendritic cell (sub)populations in acutely and chronically inflamed skin of AD patients. METHODS: Chronic inflammatory reactions were studied in lesional AD skin biopsies; the atopy patch test was used as a model for the initiation of AD lesions, representing acute inflammation. To determine the number and phenotype of different dermal macrophage and dendritic cell populations immunohistochemistry and digital imaging were used. RESULTS: There was an increase in macrophage numbers in acutely and chronically inflamed AD skin, whereas absolute dendritic cell numbers were unchanged, compared with non-lesional AD skin. Furthermore, phenotypically heterogeneous and overlapping macrophage and dendritic cell populations were present in inflamed AD skin. The classic macrophage marker CD68 and prototypic dendritic cell marker CD1a could bind to the same cell subpopulation in the dermis of inflamed AD skin. Mannose receptors were expressed mainly by macrophages in inflamed AD skin. CONCLUSIONS: In this study we observed changes in macrophage number and phenotype during cutaneous inflammation in AD. Dendritic cell numbers did not change; however, phenotypically dendritic cell and macrophage subpopulations showed increasing overlap during inflammation in AD skin. We show for the first time that within tissue-specific macrophage populations further subpopulations are present, and that monocyte-derived cells may express markers for both dendritic cells and macrophages. Our results point to the existence of a heterogeneous pool of macrophage/dendritic cell-like cells, from which subpopulations of dermal macrophages and dendritic cells arise.

Acute Disease↗
PubMedDate not supplied

Interstitial 6q duplication in an adult male without growth delay or severe mental retardation.

We report on a 28 year-old male with peculiar facies, distal joint contractures and other multiple congenital anomalies. Cytogenetic analysis by G banding revealed a distal tandem interstitial duplication of the long arm of chromosome q6, dup.(6)(6q24.2-->q26). This chromosome abnormality was confirmed by fluorescence in situ hybridization with total chromosome 6 painting. This is probably the second documented case of 6q duplication without growth retardation or severe psychomotor retardation. The clinical findings in our patient are similar to that of whistling face syndrome (WFS) and, in fact, he was diagnosed with WFS as a child. The literature were reviewed and the phenotypic features of this patient were compared with those previously reported for both duplication 6q and whistling face syndromes. There is a significant overlap between the phenotypes of these two syndromes. Careful evaluation of the terminal end of the 6q in cases suggestive of WFS might be warranted.

Abnormalities, Multiple↗
PubMed1991

Molecular and clinical overlap of Angelman and Prader-Willi syndrome phenotypes.

The Prader-Willi (PWS) and Angelman syndromes (AS) share the same apparent cytogenetic and molecular lesions of 15q11-13 and yet exhibit distinct clinical phenotypes. The etiology of PWS or AS appears to depend on the parental origin of the aberrant chromosome 15. Substantial clinical overlap has not been reported between deletion-positive PWS and AS patients. In the present study, we report the clinical, cytogenetic, and molecular findings in three AS patients. The first patient is a mentally retarded woman with a visible deletion of 15q11-13 with typical craniofacial, behavioral, and neurologic changes of AS. This patient is hyperphagic, and she is moderately obese for her height. Her hands and feet are small. These manifestations are more characteristic of PWS and not of AS. The molecular studies showed deletions of maternal origin for five distal PWCR loci. The most proximal locus, D15S18, was not deleted. These findings are identical to those found in our third AS patient who does not have any PWS features. To the best of our knowledge, this is the first report of concurrence of hyperphagia with consequent obesity and the AS phenotype in a patient with a del 15(q11-13) of maternal origin. These clinical findings suggest that overlap in the symptoms of PWS and AS can occur. Our second AS patient presents with atypical molecular findings in that he cannot be classed into any of the three proposed sub-groups of AS patients and may be representative of a fourth sub-group of AS patients.

Chromosome Deletion↗
PubMed1996

Two temporally overlapping "delayed-rectifiers" determine the voltage-dependent potassium current phenotype in cultured hippocampal interneurons.

1. Whole cell voltage-clamp recordings were used to characterize the calcium-independent "delayed-rectifier" potassium currents of gamma-aminobutyric acid (GABA)-positive stratum radiatum-lacunosum-moleculare (st. L-M) interneurons in primary culture derived from neonate rats [postnatal day 5-7 (P5-P7)]. 2. Two distinct current phenotypes were observed, which we termed "sustained" and "slowly inactivating." Despite possessing similar voltage-dependent activation properties, current differed in their time-dependent inactivation properties and their kinetics of activation and deactivation. The phenotypes of the observed currents did not change during the time in vitro. The total current phenotype observed in any cell likely resulted from the temporal overlap of the two current components expressed in different relative proportions. 3. Externally applied 4-aminopyridine (4-AP) selectively blocked the slowly inactivating current component, by a use-dependent, but voltage-independent mechanism, suggesting that channel activation is required for 4-AP to interact with its binding site. In contrast, the sustained current component was unaffected by 4-AP. 4. Both the slowly inactivating and sustained current phenotypes were sensitive to externally applied tetraethylammonium (TEA). The IC50 of block by TEA was lower in cells expressing predominantly the sustained current components. 5. Currents recorded in the presence of internally applied TEA were of a slowly inactivating phenotype, suggesting that [TEA]i preferentially blocked the sustained current component. 6. When test pulses were preceded by a prepulse to -100 mV, a transient A-type current component was observed, but in contrast to pyramidal neurons and other interneuron types, this transient current contributed only a minor component to the total initial peak current. 7. In conclusion, two distinct, temporally overlapping potassium current phenotypes were observed on st. L-M interneurons. The overall phenotype was determined by the relative proportion of each current component. The absence of a prominent transient current suggests that the two delayed-rectifier currents play a critical role in determining the firing characteristics of these interneurons.

4-Aminopyridine↗
PubMed2003

Overlap between VACTERL and hemifacial microsomia illustrating a spectrum of malformations seen in axial mesodermal dysplasia complex (AMDC).

We describe a male infant born to consanguineous healthy parents with multiple congenital anomalies of the skeleton and internal organs. His phenotype displays an overlap between VACTERL and hemifacial microsomia (oculo-auriculo-vertebral spectrum/OAV). In addition, striking asymmetry of the malformations further supports the classification as part of the "axial mesodermal dysplasia complex" (AMDC) which is supposed to arise from disturbed mesodermal cell migration during early blastogenesis. The present case was instructive to review the continuous spectrum of AMDC related anomalies.

Abnormalities, Multiple↗