Genotypes and Haplotypes in the AXIN2 and TCF7L2 Genes are Associated With Susceptibility and With Clinicopathological Characteristics in Breast Cancer Patients.

Background: Breast cancer is a multifactorial disease whose genetic susceptibility is related to polymorphic variants of cell proliferation and migration pathways. Variants in AXIN2 and TCF7L2 in the Wnt-ß catenin pathway have been associated with different types of cancer; however, little is known about its role in breast cancer. This study tests the hypothesis of links between AXIN2 rs1133683 and rs2240308, and TCF7L2 rs7903146 and rs12255372 variants in breast cancer. Methods: Peripheral blood samples were obtained from 404 women (202 patients and 202 control females). The polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methodology was used to identify the gene variants. Results: The AXIN2 rs2240308 (C > T), and TCF7L2 rs7903146 (C > T) and rs12255372 (G > T) variants were associated with breast cancer and with age, TNM stage, and histologic-molecular subtype (p = 0.001). Likewise, the haplotype T-T in the TCF7L2 gene (rs7903146-rs12253372) was significantly related with breast cancer (OR = 2.66, 95%, CI = 1.64-4.30, p = 0.001). Conclusion: Our data show a link between AXIN2 rs2240308 and TCF7L2 rs7903146 and rs12255372 variants in breast cancer, and speculate this may be important in pathogenesis.

Evolución y genómica del cerebro humano / Evolution and genomics of the human brain

La mayor parte de los seres vivos son capaces de realizar acciones que pueden ser consideradas inteligentes o al menos el resultado de un proceso de reacción adecuado ante las circunstancias cambiantes de su medio ambiente. Sin embargo, la inteligencia o los procesos intelectuales que desarrollan los seres humanos son enormemente superiores a los que logran los organismos de cualquier otra especie. El cerebro humano adulto es un órgano sumamente complejo: pesa aproximadamente 1.500g, lo que representa solo el 2% del peso corporal pero consume igual cantidad de energía que todo el músculo esquelético en reposo. Aunque el cerebro humano presenta una estructura típicamente primate, revela algunas características que lo distinguen y lo individualizan plenamente. El proceso de evolución y humanización del cerebro del Homo sapiens (H. sapiens) lo convirtió en un órgano único y diferente, alcanzando el mayor tamaño relativo entre todas las especies, pero además le permitió una reorganización estructural de tejidos y circuitos en segmentos y regiones específicas. Esto explica las notables capacidades cognitivas del hombre moderno, en comparación no solo con otros miembros de su género, sino con otros miembros más antiguos de su propia especie. La evolución del cerebro requirió la coexistencia de 2 mecanismos de adaptación. El primero involucra cambios genéticos que ocurren a nivel de especies y el segundo ocurre a nivel individual e involucra cambios en la organización de la cromatina o cambios epigenéticos. Entre los mecanismos genéticos se encuentran: a) cambios en regiones genéticas codificantes que conducen a cambios en la secuencia y actividad de proteínas existentes; b) los procesos de duplicación y deleción de genes previamente existentes; c) cambios en la expresión génica a través de modificaciones en las secuencias reguladoras de diferentes genes, y d) síntesis de ARNs no codificantes. Finalmente, en esta revisión se describen algunas de las más importantes diferencias cromosómicas reportadas entre humanos y grandes simios, que también han contribuido al proceso de evolución y humanización del cerebro del H. sapiens

Most living beings are able to perform actions that can be considered intelligent or, at the very least, the result of an appropriate reaction to changing circumstances in their environment. However, the intelligence or intellectual processes of humans are vastly superior to those achieved by all other species. The adult human brain is a highly complex organ weighing approximately 1500g, which accounts for only 2% of the total body weight but consumes an amount of energy equal to that required by all skeletal muscle at rest. Although the human brain displays a typical primate structure, it can be identified by its specific distinguishing features.The process of evolution and humanisation of the Homo sapiens brain resulted in a unique and distinct organ with the largest relative volume of any animal species. It also permitted structural reorganization of tissues and circuits in specific segments and regions. These steps explain the remarkable cognitive abilities of modern humans compared not only with other species in our genus, but also with older members of our own species. Brain evolution required the coexistence of two adaptation mechanisms. The first involves genetic changes that occur at the species level, and the second occurs at the individual level and involves changes in chromatin organisation or epigenetic changes. The genetic mechanisms include: a) genetic changes in coding regions that lead to changes in the sequence and activity of existing proteins; b) duplication and deletion of previously existing genes; c) changes in gene expression through changes in the regulatory sequences of different genes; and d) synthesis of non-coding RNAs. Lastly, this review describes some of the main documented chromosomal differences between humans and great apes. These differences have also contributed to the evolution and humanisation process of the H. sapiens brain

Evolution and genomics of the human brain. / Evolución y genómica del cerebro humano.

Most living beings are able to perform actions that can be considered intelligent or, at the very least, the result of an appropriate reaction to changing circumstances in their environment. However, the intelligence or intellectual processes of humans are vastly superior to those achieved by all other species. The adult human brain is a highly complex organ weighing approximately 1500g, which accounts for only 2% of the total body weight but consumes an amount of energy equal to that required by all skeletal muscle at rest. Although the human brain displays a typical primate structure, it can be identified by its specific distinguishing features. The process of evolution and humanisation of the Homo sapiens brain resulted in a unique and distinct organ with the largest relative volume of any animal species. It also permitted structural reorganization of tissues and circuits in specific segments and regions. These steps explain the remarkable cognitive abilities of modern humans compared not only with other species in our genus, but also with older members of our own species. Brain evolution required the coexistence of two adaptation mechanisms. The first involves genetic changes that occur at the species level, and the second occurs at the individual level and involves changes in chromatin organisation or epigenetic changes. The genetic mechanisms include: a) genetic changes in coding regions that lead to changes in the sequence and activity of existing proteins; b) duplication and deletion of previously existing genes; c) changes in gene expression through changes in the regulatory sequences of different genes; and d) synthesis of non-coding RNAs. Lastly, this review describes some of the main documented chromosomal differences between humans and great apes. These differences have also contributed to the evolution and humanisation process of the H. sapiens brain.

Protective role of +294 T/C (rs2016520) polymorphism of PPARD in Mexican patients with colorectal cancer.

PPARD encodes for peroxisome proliferator-activated receptor delta, which plays a significant role in controlling lipid metabolism, atherosclerosis, inflammation, cancer growth, progression, and apoptosis. Accumulated evidence suggests that the polymorphism rs2016520 in PPARD is associated with lipid metabolism, obesity, metabolic syndrome, and type 2 diabetes mellitus. The aim of this study was to determine whether the single nucleotide polymorphism +294T/C (rs2016520) in PPARD is associated with colorectal cancer (CRC) in the Mexican population. Genomic DNA from 178 CRC patients and 97 healthy blood donors was analyzed. The polymorphism was identified by the polymerase chain reaction-restriction fragment length polymorphism method. Results demonstrated that patients with the T/C genotype for the +294T/C (rs2016520) polymorphism present a protective role against CRC [odds ratio (OR) = 0.39; 95% confidence interval (CI) = 0.22-0.69; P = 0.0008]. This association was also evident for the T/C genotype in the stratified analysis by tumor-node-metastasis stages I+II (OR = 0.26, P = 0.0332) and III+IV (OR = 0.44, P = 0.0067). However, in the stratified analysis by tumor location, we observed an increased risk of rectal cancer (OR = 7.57, P = 0.0403) vs colon cancer (OR = 4.87, P = 0.234) in patients carrying the C/C genotype and under the dominant and recessive models of inheritance. In conclusion, for the first time, the association between the +294T/C (rs2016520) polymorphism and colorectal cancer has been studied in Mexican patients. Our results reveal that variations in PPARD may play a significant role in genetic susceptibility to colorectal cancer.

Mecanismos epigenéticos en el desarrollo de la memoria y su implicación en algunas enfermedades neurológicas / Epigenetic mechanisms in the development of memory and their involvement in certain neurological diseases

Introducción: Hoy en día se acepta que el sistema nervioso central adulto posee una enorme flexibilidad morfofuncional que le permite realizar procesos de remodelación estructural aún después de haber alcanzado su desarrollo y maduración. Además del enorme número de genes que participan en el desarrollo de la memoria, los diferentes mecanismos epigenéticos conocidos también han sido involucrados en procesos de modificación neuronal normal y patológica y, por ende, en los mecanismos de desarrollo de la memoria. Desarrollo: Este trabajo fue llevado a cabo a través de una sistemática revisión de las bases de datos de publicaciones biomédicas sobre los aspectos genéticos y epigenéticos que participan en la función sináptica y la memoria. Conclusiones: La activación de la expresión génica, en respuesta a estímulos extrínsecos, ocurre también en células nerviosas diferenciadas. La actividad neuronal induce formas específicas de plasticidad sináptica que permiten la formación y almacenamiento de la memoria a largo plazo. Los mecanismos epigenéticos tienen un papel crucial en los procesos de modificación sináptica y en la formación y desarrollo de la memoria. Alteraciones en estos mecanismos producen déficit cognitivo y de memoria en padecimientos neurodegenerativos (enfermedad de Alzheimer y Huntington) así como en trastornos del desarrollo neurológico (síndrome de Rett, X-frágil y esquizofrenia). Los resultados obtenidos en diferentes modelos muestran, sin embargo, un escenario promisorio con tratamientos potenciales para algunos de estos padecimientos

Introduction: Today, scientists accept that the central nervous system of an adult possesses considerable morphological and functional flexibility, allowing it to perform structural remodelling processes even after the individual is fully developed and mature. In addition to the vast number of genes participating in the development of memory, different known epigenetic mechanisms are involved in normal and pathological modifications to neurons and therefore also affect the mechanisms of memory development. Development: This study entailed a systematic review of biomedical article databases in search of genetic and epigenetic factors that participate in synaptic function and memory. Conclusions: The activation of gene expression in response to external stimuli also occurs in differentiated nerve cells. Neural activity induces specific forms of synaptic plasticity that permit the creation and storage of long-term memory. Epigenetic mechanisms play a key role in synaptic modification processes and in the creation and development of memory. Changes in these mechanisms result in the cognitive and memory impairment seen in neurodegenerative diseases (Alzheimer disease, Huntington disease) and in neurodevelopmental disorders (Rett syndrome, fragile X, and schizophrenia). Nevertheless, results obtained from different models are promising and point to potential treatments for some of these diseases

TCF7L2 and CCND1 polymorphisms and its association with colorectal cancer in Mexican patients.

Accumulative evidence suggests that alterations due to mutations or genetic polymorphisms in the TCF7L2 and CCND1 genes, which are components of the Wnt signaling pathway, contributes to carcinogenesis. The present study was designated to clarify whether common single nucleotide polymorphisms (SNPs) of the transcription factor 7- like 2 (TCF7L2) and cyclin D1 (CCND1) genes are associated with colorectal cancer risk in Mexican patients. A case-control study including 197 colorectal cancer patients and 100 healthy subjects was conducted in a Mexican population. Identification of polymorphisms was made by the polymerase chain reaction-restriction fragment length polymorphism methodology. The association was calculated by the odds ratio (OR) test. The results demonstrate that patients with the T/T genotype for the rs12255372 polymorphism of the TCF7L2 gene present an increased colorectal cancer risk (OR=2.64, P=0.0236). Also, the risk analysis for Tumor-Nodule-Metastasis (TNM) stage and tumor location showed association with this polymorphism under the over-dominant model of inheritance (OR=1.75, P=0.0440). A similar relation was observed for the genotype T/T of the rs7903146 polymorphism and the rectal location of cancer (OR=7.57, P=0.0403). For the rs603965 polymorphism of the CCND1 gene, we observed a protection effect for the colon cancer location under the dominant model (OR=0.49, P=0.0477). These results reveal a significant role of the analyzed polymorphisms in the TCF7L2 and CCND1 genes on the susceptibility or protection for developing colorectal cancer in the Mexican population.

Epigenetic mechanisms in the development of memory and their involvement in certain neurological diseases. / Mecanismos epigenéticos en el desarrollo de la memoria y su implicación en algunas enfermedades neurológicas.

INTRODUCTION: Today, scientists accept that the central nervous system of an adult possesses considerable morphological and functional flexibility, allowing it to perform structural remodelling processes even after the individual is fully developed and mature. In addition to the vast number of genes participating in the development of memory, different known epigenetic mechanisms are involved in normal and pathological modifications to neurons and therefore also affect the mechanisms of memory development. DEVELOPMENT: This study entailed a systematic review of biomedical article databases in search of genetic and epigenetic factors that participate in synaptic function and memory. CONCLUSIONS: The activation of gene expression in response to external stimuli also occurs in differentiated nerve cells. Neural activity induces specific forms of synaptic plasticity that permit the creation and storage of long-term memory. Epigenetic mechanisms play a key role in synaptic modification processes and in the creation and development of memory. Changes in these mechanisms result in the cognitive and memory impairment seen in neurodegenerative diseases (Alzheimer disease, Huntington disease) and in neurodevelopmental disorders (Rett syndrome, fragile X, and schizophrenia). Nevertheless, results obtained from different models are promising and point to potential treatments for some of these diseases.

Neuhauser syndrome: a rare association of megalocornea and mental retardation. Review of the literature and further phenotype delineation.

Megalocornea can be observed as an isolated abnormality that is inherited by an X-linked mechanism, or it can be associated with other entities. Megalocornea-mental retardation syndrome, also known as Neuhauser syndrome, is a rare autosomal recessive congenital disorder that presents with megalocornea, mental retardation, hypotonia, and facial dysmorphism, among other signs. With the report of this new case, and after an extensive review of the literature, we attempt to delineate the Neuhauser syndrome phenotype.

Variegated-like mosaicism and ring syndrome in a r(4) boy. Appraisal of 38 patients with a fairly complete ring 4.

A 13-month-old boy with normal development and growth failure of prenatal onset but no other physical stigmata had a 46,XY,r(4)(p1 6.3q35).ish (4psubtel-, WHS1+, 4qsubtel+, pantel-) de novo karyotype. The analysis of 50-106 metaphases from each of four lymphocyte cultures (three of 72 h including one without colchicine and one of 96 h) revealed a dynamic mosaicism in 22-36% of cells. We did not observe a normal cell line. Hypoploidies (excluding ring losses) were observed in 2-7% of metaphases from colchicine-arrested cultures whereas tetraploidies were observed in 2-12% of metaphases from all four lymphocyte cultures. Further FISH studies were carried out on interphase nuclei from uncultured buccal cells and lymphocytes using two alphoid (CEP 1 and 9), a dual CEP X/SRY, and (in the former only) a subtel 4p probes. We scored 70-131 nuclei per assay and found apparent heteroploidies in approximately 1-47% of cells for CEP 1, CEP 9, subtel 4p, and SRY but not for CEP X. The patient's phenotype was typical of the ring syndrome and comparable to 9/37 previous r(4) cases. Moreover, all 38 patients were alive at the time of reporting and none has developed cancer. The 2-7% rate of hypodiploid cells in colchicine-arrested cultures and the approximately 1-47% rate of apparent heteroploidies in nuclei of uncultured cells evoke the in vitro and in vivo findings in patients with mosaic variegated aneuploidy (MVA). We conclude that our observation highlights the clinical and cytogenetical overlapping between the ring syndrome and the MVA syndrome; the crucial difference is the high risk of cancer related to BUB1B mutations in the latter.

XRCC1 polymorphisms and haplotypes in Mexican patients with acute lymphoblastic leukemia.

We examined the influence of the Arg194Trp, Arg280His, and Arg399Gln polymorphisms of XRCC1 (X-ray repair cross-complementing group 1) on the development of childhood acute lymphoblastic leukemia (ALL) in 120 ALL patients and 120 controls in Mexico. All of them were genotyped for these polymorphisms, using polymerase chain reaction. No significant differences in allele and genotype frequencies for any polymorphism were observed between patients and controls. Estimation of haplotypes showed the eight expected haplotypes (A-H), seven of which were found in both patients and controls; haplotype A (Arg-Arg-Arg) was the most common, whereas haplotypes F and G were absent in patients and controls, respectively. Haplotype B (Trp-Arg-Arg) was found to be associated with an increased risk of ALL (odds ratio (OR) = 1.95, 95% confidence interval (CI) = 1.13-3.37; P = 0.016), particularly in males (OR = 2.65, 95%CI = 1.25-5.63; P = 0.01). Individually, the 194Trp, 280His, and 399Gln alleles were not associated with significantly increased risk for ALL in these Mexican children.

[Diseases caused by triplet expansion]. / Enfermedades causadas por expansión de tripletes.

INTRODUCTION: Today we know of a group of mutations caused by the expansion of nucleotide triplets, which are very unstable in meiosis and mitosis. Four types of triplets have the capacity for pathogenic expansion in human beings (CGG/ GCC, CAG/GTC, CTG/GAC and GAA/CTT) and maybe located both in coding sequences (bulbospinal muscular atrophy, Huntington's disease and certain spinocerebellar ataxias) and non-coding sequences (fragile X syndrome, Friedreich's ataxia, myotonic dystrophy). Trinucleotide expansion may lead to gains or losses in gene functioning and seems to be associated to a variety of factors, some of which are directly related with the expansive process (cis-acting) and others whose interaction with the triplets helps to make them increasingly more unstable (trans-acting). Medium-sized expansions (pre-mutations), although clinically silent, do show a marked tendency to expand into complete mutations during the transition along the germinal line. The models that have been proposed to explain triplet expansion involve gene recombination and replication processes; however, they have not fully succeeded in explaining the phenomena related to mutation or phenotypic expression in these diseases. DEVELOPMENT: This work examines the most recent concepts related to the dynamic mutation processes that give rise to human diseases; it also reviews the most important clinico-biological aspects observed in those diseases. CONCLUSIONS: Dynamic mutation processes represent a new concept in the molecular biology of gene mutations. An ever increasing number of pathologies are caused by this type of DNA alterations, which, as a whole, display very interesting clinico-biological characteristics.

Enfermedades causadas por expansión de tripletes / Disease caused by Triplet expansion

Resumen. Introducción. Actualmente se conoce un grupo de mutaciones por la expansión de tripletes de nucleótidos, los cuales resultan muy inestables en meiosis y mitosis. Cuatro tipos de tripletes tienen capacidad de expansión patogénica en seres humanos (CGG/GCC, CAG/GTC, CTG/GAC y GAA/CTT) y pueden localizarse tanto en secuencias codificadoras (atrofia muscular bulboespinal, enfermedad de Huntington y algunas ataxias espinocerebelosas) como no codificadoras (síndrome X frágil, ataxia de Friedreich, distrofia miotónica). La expansión trinucleótida puede producir ganancia o pérdida de la función génica y parece asociarse a una variedad de factores, algunos directamente relacionados con el proceso expansivo (cis-actuantes) y otros cuya interacción con los tripletes contribuye a su inestabilidad (trans-actuantes). Las expansiones de tamaño intermedio (premutaciones), aunque clínicamente silentes, muestran una marcada tendencia a expandirse a mutaciones completas durante la transición por línea germinal. Los modelos propuestos para explicar la expansión de tripletes involucran los procesos de replicación y recombinación génica; sin embargo, no han logrado explicar por completo los fenómenos relacionados con la mutación o la expresión fenotípica en estas enfermedades. Desarrollo. Este trabajo examina los conceptos más recientes en relación a los procesos de mutación dinámica causantes de enfermedades humanas y revisa los más importantes aspectos clínicobiológicos observados en éstas. Conclusiones. Los procesos de mutación dinámica representan un nuevo concepto en la biología molecular de las mutaciones génicas. Un número continuamente creciente de patologías son causadas por este tipo de alteraciones en el ADN, las cuales muestran, en conjunto, características clinicobiológicas muy interesantes (AU)

Summary. Introduction. Today we know of a group of mutations caused by the expansion of nucleotide triplets, which are very unstable in meiosis and mitosis. Four types of triplets have the capacity for pathogenic expansion in human beings (CGG/ GCC, CAG/GTC, CTG/GAC and GAA/CTT) and maybe located both in coding sequences (bulbospinal muscular atrophy, Huntington’s disease and certain spinocerebellar ataxias) and non-coding sequences (fragile X syndrome, Friedreich’s ataxia, myotonic dystrophy). Trinucleotide expansion may lead to gains or losses in gene functioning and seems to be associated to a variety of factors, some of which are directly related with the expansive process (cis-acting) and others whose interaction with the triplets helps to make them increasingly more unstable (trans-acting). Medium-sized expansions (pre-mutations), although clinically silent, do show a marked tendency to expand into complete mutations during the transition along the germinal line. The models that have been proposed to explain triplet expansion involve gene recombination and replication processes; however, they have not fully succeeded in explaining the phenomena related to mutation or phenotypic expression in these diseases. Development. This work examines the most recent concepts related to the dynamic mutation processes that give rise to human diseases; it also reviews the most important clinico-biological aspects observed in those diseases. Conclusions. Dynamic mutation processes represent a new concept in the molecular biology of gene mutations. An ever increasing number of pathologies are caused by this type of DNA alterations, which, as a whole, display very interesting clinico-biological characteristics (AU)

Crouzon with acanthosis nigricans. Further delineation of the syndrome.

Patients with Crouzon and acanthosis nigricans syndrome show craniofacial features similar to those observed in patients with classic Crouzon syndrome, in addition to acanthosis nigricans with peculiar characteristics. More severe physical manifestations, such as Chiari malformation, hydrocephalus, and atresia or stenosis of the choanas, which are unusual in individuals with classic Crouzon syndrome, are reported in these patients. The molecular abnormality associated with Crouzon syndrome with acanthosis nigricans (CAN) is a transition in the transmembrane domain of the FGFR3 gene that results in an Ala391Glu mutation. We describe two unrelated patients showing this mutation and compare their clinical features with those of other patients with CAN reported in the literature. In addition to craniosynostosis with crouzonoid facies and acanthosis nigricans (present in all patients), melanocytic nevi, choanal atresia or stenosis, hydrocephalus, Chiari malformations and oral abnormalities were observed in the majority of the 35 patients analyzed. Vertebral anomalies and conductive hearing loss were present with less frequency. Some characteristics considered typical of this condition (jaw cementomas, acanthomas and finger abnormalities) were absent in most of the patients.

Apert syndrome with preaxial polydactyly showing the typical mutation Ser252Trp in the FGFR2 gene.

The Apert syndrome is characterized by craniosynostosis and syndactyly of hands and feet. Although most cases are sporadic, an autosomal dominant mode of inheritance is well documented. Two mutations in the FGFR2 gene (Ser252Trp and Pro253Arg) account for most of the cases. We report a patient with a rare form of Apert syndrome with polydactyly. The proposita has turribrachycephaly. complete syndactyly of 2nd to 5th digits ("mitten hands" and cutaneous fusion of all toes). The X-rays revealed craniosynostosis of the coronal suture and preaxial polydactyly of hands and feet with distal bony fusion. Molecular analysis found a C755G transversion (Ser252Trp) in the FGFR2 gene. Only eight patients with Apert syndrome and preaxial polydactyly have been reported and this is the first case in which molecular diagnosis is available. On the basis of the molecular findings in this patient, polydactyly should be considered part of the spectrum of abnormalities in the Apert syndrome. This assertion would establish the need for a new molecular classification of the acrocephalopolysyndactylies.

High sensitivity of chemiluminescent methodology for detection of clonal CDR3 sequences in patients with acute lymphoblastic leukemia.

Detection of minimal residual disease (MRD) in patients with B-cell acute lymphoblastic leukemia (B-ALL) has been achieved using several radioactive labelling methodologies; however, limited information exists about the use of chemiluminescent labelling. Although many malignant disorders are related to cytogenetic alterations, there is not a consistent chromosomal translocation that could serve as a tumour marker for the monitoring of MRD. ALL are derived from B-lymphocytes in 80% of cases. In the early stages of their maturation, the immunoglobulin heavy chain genes (IgH) undergo rearrangements among their V, D, and J segments, giving rise to the Complementary Determining Regions (CDR). Among these, CDR3 is considered unique for each lymphocyte and used as a tumour-specific marker in B-ALL patients. In this study, the CDR3 was labelled with digoxigenin and used as a patient-specific probe to test its sensitivity for further detection of MRD. Fourteen pretreatment samples of bone marrow (BM) or peripheral blood (PB) from B-ALL patients were included. Tumour-specific probes were designed from each clonal product by elimination of the consensus sequences. Ten digoxigenin-labelled probes were hybridized with a mixture of their respective clonal DNA and the polyclonal product from a normal healthy donor, in serial dilutions from 1:1 up to 1:10(7). A sensitivity range of 1:10(3)-1:10(6) was obtained, with an average of 1:10(5). Crossed tests performed in four patients, showed right probe specificity in all cases. We propose that the design of allele-specific probes with chemiluminescent labelling, represents a reliable, sure and sensitive alternative methodology for MRD detection in patients with B-cell lymphoproliferative disorders.

Triphalangeal thumb and psychomotor retardation: a new association?

The triphalangeal thumb (TPT) is a rare malformation in which the thumb is presented as a long digit of three phalanges. We describe two brothers showing TPT and psychomotor retardation, especially in language. Difficulties in language development were also observed in children with TPT in another study. The coexistence of TPT and psychomotor retardation in those patients and in the two patients described here suggests that TPT and psychomotor retardation could be part of a syndromic association not described previously.

Detection and monitoring of clonality in peripheral blood and bone marrow of patients with B-cell lymphoproliferative disorders.

Bone marrow (BM) is accepted as the tissue of choice for the detection of monoclonal populations in leukemias and lymphomas; however, obtaining BM can be painful and traumatic for the patients. Although it is possible to detect clonality in peripheral blood (PB) samples, there are no reports comparing the results observed from BM with those from PB. Lymphoblastic leukemias and lymphomas are derived from B-lymphocytes in 80% of cases. In the early stages of their maturation, the immunoglobulin heavy chain genes (IgH) undergo rearrangements among their V, D, and J segments, giving rise to the Complementarity Determining Regions (CDR). Of these, CDR3 is unique for each lymphocyte and therefore it can be used as a tumour-specific marker in these malignant disorders. Among the 104 patients from whom we obtained pre-treatment paired samples of PB and BM, 94 (90.4%) showed concordant results. Similarly, at the end of treatment, 40 of 44 patients (90.9%) showed this concordance. During treatment only 24 patients were monitored and monoclones disappeared in 12 patients; in the other half, they persisted either partial or totally. We demonstrate that the detection and monitoring of monoclonal populations in the PB, in comparison with BM, was achieved with a statistical sensitivity of 90% and specificity of 92%.

Nine independent F9 mutations in the Mexican hemophilia B population: nonrandom recurrences of point mutation events in the human germline.

The factor IX gene (F9) is a valuable model for studying germ-line mutations. Nine mutations were detected in nine Mexican patients with hemophilia B by direct sequencing using genomic amplification with transcript sequencing (GAWTS): six single base changes, one micro-deletion, and two large deletions. Germline origins of mutations were found in three of six families with sporadic cases. Curiously, the four independent single base substitutions which were not at CpG dinucleotides occurred at only two different nucleotide positions (17,678 and 17,747) one transition and one transversion at each. The two remaining substitutions were identical changes at a CpG dinucleotide, but were determined to be independent by germline origin analysis. A statistical analysis suggests that the independent recurrence of mutations at these locations may reflect an unusual aspect of F9 mutagenesis in the Mexican population. These data raise the possibility of population-specific differences in human germline mutations.

Novel Hairless mutations in two kindreds with autosomal recessive papular atrichia.

Papular atrichia is an autosomal recessive disorder characterized clinically by the occurrence of universal congenital alopecia and disseminated papular lesions. Recently, mutations in the human hairless (HR) gene have been reported in Irish and Arab Palestinian families with papular atrichia. We have studied two further kindreds with this clinical phenotype from other ethnic backgrounds. For mutation detection the complete coding region as well as exon-intron boundaries of the HR gene were sequenced. The first family is a Mexican family with clinically typical papular atrichia. Sequencing identified a homozygous deletion of 4 bp in exon 7 (2001delCCAG) leading to a premature stop codon in exon 8. The second family is a South Tyrolian family with affected individuals showing papular atrichia and retardation of bone age during childhood. All affected individuals were identified as homozygous for an A-->G transition at nucleotide position 2909 (exon 14) leading to an amino acid change of asparagine to serine in codon 970 (Asn970Ser). These data provide further evidence for the involvement of hairless mutations in papular atrichia. In addition, these findings suggest that the hairless protein is not only involved in hair development but also in the process of ossification during development.