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G6PC3 deficiency is a monogenic immunometabolic disorder that causes syndromic congenital neutropenia. Patients display heterogeneous extra-hematological manifestations, contributing to delayed diagnosis. Here, we investigated the origin and functional consequence of the G6PC3 c.210delC variant found in patients of Mexican origin. Based on the shared haplotypes amongst carriers of the c.210delC mutation, we estimated that this variant originated from a founder effect in a common ancestor. Furthermore, by ancestry analysis, we concluded that it originated in the indigenous Mexican population. At the protein level, we showed that this frameshift mutation leads to an aberrant protein expression in overexpression and patient-derived cells. G6PC3 pathology is driven by the intracellular accumulation of the metabolite 1,5-anhydroglucitol-6-phosphate (1,5-AG6P) that inhibits glycolysis. We characterized how the variant c.210delC impacts glycolysis by performing extracellular flux assays on patient-derived cells. When treated with 1,5-anhydroglucitol (1,5-AG), the precursor to 1,5-AG6P, patient-derived cells exhibited markedly reduced engagement of glycolysis. Finally, we compared the clinical presentation of patients with the mutation c.210delC and all other G6PC3 deficient patients reported in the literature to date, and we found that c.210delC carriers display all prominent clinical features observed in prior G6PC3 deficient patients. In conclusion, G6PC3 c.210delC is a loss-of-function mutation that arose from a founder effect in the indigenous Mexican population. These findings may facilitate the diagnosis of additional patients in this geographical area. Moreover, the in vitro 1,5-AG-dependent functional assay used in our study could be employed to assess the pathogenicity of additional G6PC3 variants., Competing Interests: Competing Interests The authors declare that they have no relevant conflicts of interest. Additional Declarations: No competing interests reported.

Background: Autosomal dominant tricho-rhino-phalangeal syndrome I (TRPS I) is due to mutations in the TRPS1 gene. Tricho-rhino-phalangeal syndrome I is characterized by peculiar face and skeletal anomalies. Cone-shaped epiphyses are the characteristic radiographic findings., Objective: To describe 2 families with TRPS I and 2 novel mutations in the TRPS1 gene., Patients: The study included 2 nonrelated families with TRPS I. All exons of the TRPS1 gene were analyzed from genomic DNA., Results: The TRPS1 gene mutation analysis showed in family 1 the c.978C>A nonsense mutation within exon 4 and in family 2 the c.164A>C missense mutation within exon 3., Conclusions: We found 2 families with TRPS1 caused by 2 novel mutations in the TRPS gene, particularly a missense mutation in exon 3, outside the GATA zinc finger domain, that leads a mild TRPS phenotype. Our data show a higher genotypic spectrum in the TRPS I and demonstrate that mutations in the amino terminus of the transcription factor result in TRPS I syndrome.

Objectives: To identify preferential associations between oral clefts (CL = cleft lip only, CLP = cleft lip with cleft palate, CP = cleft palate) and nonoral cleft anomalies, to interpret them on clinical grounds, and, based on the patterns of associated defects, to establish whether CL and CLP are different conditions., Design and Settings: Included were 1416 cleft cases (CL = 131, CLP = 565, CP = 720), among 8304 live- and stillborn infants with multiple congenital anomalies, from 6,559,028 births reported to the International Clearinghouse for Birth Defects Surveillance and Research by 15 registries between 1994 and 2004. Rates of associated anomalies were established, and multinomial logistic regressions applied to identify significant associations., Results: Positive associations with clefts were observed for only a few defects, among which anencephaly, encephaloceles, club feet, and ear anomalies were the most outstanding. Anomalies negatively associated with clefts included congenital heart defects, VATER complex (vertebral defects, imperforate anus, tracheoesophageal fistula, and radial and renal dysplasia), and spina bifida., Conclusion: The strong association between all types of clefts and anencephaly seems to be attributable to cases with disruptions; the association between CP and club feet seems to be attributable to conditions with fetal akinesia. Some negative associations may depend on methodologic factors, while others, such as clefts with VATER components or clefts with spina bifida, may depend on biological factors. The different patterns of defects associated with CL and CLP, indicating different underlying mechanisms, suggest that CL and CLP reflect more than just variable degrees of severity, and that distinct pathways might be involved.

Background: Holoprosencephaly (HPE) is a developmental field defect of the brain that results in incomplete separation of the cerebral hemispheres that includes less severe phenotypes, such as arhinencephaly and single median maxillary central incisor. Information on the epidemiology of HPE is limited, both because few population-based studies have been reported, and because small studies must observe a greater number of years in order to accumulate sufficient numbers of births for a reliable estimate., Methods: We collected data from 2000 through 2004 from 24 of the 46 Birth Defects Registry Members of the International Clearinghouse for Birth Defects Surveillance and Research. This study is based on more than 7 million births in various areas from North and South America, Europe, and Australia., Results: A total of 963 HPE cases were registered, yielding an overall prevalence of 1.31 per 10,000 births. Because the estimate was heterogeneous, possible causes of variations among populations were analyzed: random variation, under-reporting and over-reporting bias, variation in proportion of termination of pregnancies among all registered cases and real differences among populations., Conclusions: The data do not suggest large differences in total prevalence of HPE among the studied populations that would be useful to generate etiological hypotheses., (Copyright 2008 Wiley-Liss, Inc.)

Our objective was to evaluate the frequency and type of malformations associated with gastroschisis in a large pool of international data, to identify malformation patterns, and to evaluate the role of maternal age in non-isolated cases. Case-by-case information from 24 registries, all members of the International Clearinghouse for Birth Defects Surveillance and Research (ICBDSR), were evaluated. After the exclusion of other abdominal wall defects cases were classified as: (a) isolated; (b) recognizable syndrome, chromosomal or not; (c) multiple congenital anomalies (MCA). Our results showed that out of 3,322 total cases 469 non-isolated cases were registered (14.1%): 41 chromosomal syndromes, 24 other syndromes, and 404 MCA. Among MCA four groups of anomalies were most frequent: CNS (4.5%), cardio-vascular (2.5%), limb (2.2%), and kidney anomalies (1.9%). No similar patterns emerged except two patterns resembling limb-body wall complex and OEIS. In both of them the gastroschisis could be however misclassified. Chromosomal trisomies and possibly non-syndromic MCA are associated with an older maternal age more than isolated cases. On consideration of our data and the most valid studies published in the literature, the best estimate of the proportion of gastroschisis associated with major unrelated defects is about 10%, with a few cases associated to recognizable syndromes. Recognized syndromes with gastroschisis seem to be so exceptional that the well documented and validated cases are worth being published as interesting case report. An appropriate case definition in etiological studies should include only isolated gastroschisis after an appropriate definition of isolated and non-isolated cases and a thorough case-by-case review.

Dieker and Opitz in 1969 described the simultaneous occurrence of limb deficiencies (LDs) and renal anomalies (RAs) in three patients. Curran and Curran introduced in 1972 the term "acrorenal syndrome." Since then, the term "acrorenal syndrome" is used occasionally, but a well-circumscribed definition has never been established. On the other hand, the concept of an acrorenal polytopic developmental field defect was postulated by Opitz and others to explain the association between RAs and LDs. We undertook this study to investigate whether this acrorenal "syndrome" could be identified in a large group of cases with congenital RAs and a limb deficiency. Eleven birth defect registries that are part of the International Clearinghouse for Birth Defects Monitoring (i.e., registries of ICBDMS in Finland, France [Paris and Strasbourg], Israel, Italy [IPIMC and Emilia Romagna], Mexico, Northern Netherlands, South America, Spain, and the United States [Atlanta]) provided data on 815 infants who had a LD and at least one other major congenital anomaly. These 815 cases were ascertained among 5,163,958 births. We selected the 197 cases who had both a limb deficiency and a renal or urinary tract anomaly. In about 50% of these cases a diagnosis or a recognized phenotype was reported, with chromosomal aberrations and VACTERL being most frequent. In the group with no diagnosis or recognized phenotype (95 cases), we looked for (a) clustering of specific types of LDs and RAs, and (b) for clustering of associated anomalies, in order to find evidence for and be able to define better the term "acrorenal syndrome." Our data suggest that an association exists between LDs and RAs, possibly explained by the concept of the acrorenal polytopic developmental field defect. However, our dataset does not yield evidence for the existence of one distinct "syndrome," defined as a pattern of causally related multiple anomalies. Therefore, use of the term "acrorenal syndrome" should be avoided., (Copyright 2004 Wiley-Liss, Inc.)

In humans, unpaired organs are placed in a highly ordered pattern along the left-right axis. As indicated by animal studies, a cascade of signaling molecules establish left-right asymmetry in the developing embryo. Some of the same genes are involved also in limb patterning. To provide a better insight into the connection between these processes in humans, we analysed the symmetry of limb deficiencies among infants with multiple congenital anomalies. The study was based on data collected by the International Clearinghouse for Birth Defects Monitoring Systems (ICBDMS). Registries of the ICBDMS provided information on infants who, in addition to a limb deficiency, also had at least one major congenital anomaly in other organ systems. We reviewed 815 such cases of which 149 cases (18.3 %) were syndromic and 666 (81.7 %) were nonsyndromic. The comparisons were made within the associated limb deficiencies, considering the information on symmetry, using a comparison group with malformations associated not involved in the index association. Among the non-syndromic cases, the left-right distribution of limb deficiencies did not differ appreciably between limb deficiency subtypes (e.g., preaxial, transverse, longitudinal). The left-right distribution of limb anomalies did not differ among most types of non-limb anomalies, though a predominance of left-sided limb deficiencies was observed in the presence of severe genital defects - odds ratio [OR], 2.6; 95 % CI, 1.1-6.4). Limb deficiencies (LDs) were more often unilateral than bilateral when accompanied by gastroschisis (OR, 0.1) or axial skeletal defects (OR, 0.5). On the contrary, LDs were more often bilateral than unilateral when associated with cleft lip with or without cleft palate (OR, 3.9) or micrognathia (OR, 2.6). Specifically, we found an association between bilateral preaxial deficiencies and cleft lip, bilateral amelia with gastroschisis and urinary tract anomalies, and bilateral transverse deficiencies and gastroschisis and axial skeleton defects. Of 149 syndromic cases, 62 (41.6 %) were diagnosed as trisomy 18. Out of the 30 cases of trisomy 18 with known laterality, 20 cases were bilateral. In the remainder the right and left sides were equally affected. Also, in most cases (74.4 %) only the upper limbs were involved. In conclusion the left-right distribution of limb deficiencies among some non-limb anomalies may suggest a relationship between the development of the limb and the left-right axis of the embryo.

Although limb defects associated with other congenital anomalies are rarely studied, they may provide insights into limb development that may be useful for etiologic studies and public health monitoring. We pooled data from 11 birth defect registries that are part of the International Clearinghouse for Birth Defects Monitoring Systems. We identified 666 infants, born from 1983 through 1993, who had a non-syndromal limb defect plus at least one other major malformation (rate 12.9/100,000 population). We used observed/expected ratios and log-linear models to detect association patterns. We found that specific limb defects occurred with relatively distinct sets of malformations. Preaxial limb defects occurred more frequently with microtia, esophageal atresia, anorectal atresia, heart defects, unilateral kidney dysgenesis, and some axial skeleton defects; postaxial defects with hypospadias; transverse defects with craniofacial defects, micrognathia, ring constrictions, and muscular defects; intercalary defects with omphalocele; split hand/foot with encephalocele; and amelia with anorectal atresia, omphalocele, severe genitalia defects, unilateral kidney dysgenesis, gastroschisis, and ring constriction. Log-linear modeling identified higher order associations among some of these same malformations., (Copyright 2000 Wiley-Liss, Inc.)

Objective: To describe two brothers with hypopituitarism who had been born by breech delivery and to discuss whether this condition corresponds to a familial form or to a pituitary stalk section as a result of the breech delivery., Methods: We present the clinical, biochemical, and magnetic resonance imaging (MRI) characteristics of two Mexican brothers, 19 and 21 years old, with hypopituitarism and a history of breech delivery., Results: Physical examination of both patients showed short stature with normal body proportions, an obviously younger appearance than that expected for their chronologic age, high-pitched voice, irregularly positioned teeth, no axillary or pubic hair, and prepubertal genitalia. Biochemical testing showed low thyroxine and free thyroxine values with inadequate or normal thyrotropin, low basal testosterone, and mildly increased serum prolactin levels. Stimulation tests showed a normal and a delayed thyrotropin response to thyrotropin-releasing hormone, subnormal serum cortisol, considerably blunted growth hormone (GH) response to insulin-induced hypoglycemia, and absence of GH response to GH-releasing hormone in both cases. MRI showed an ectopic neuropituitary gland. In case 1, a caudal portion of a very thin pituitary stalk was observed, suggesting the preservation of a vascular component of the stalk. Because both parents of these brothers shared the major histocompatibility complex haplotype HLA-A*2301, B*3501, DRB1*0407, DQA1*03, DQB1*0201, consanguinity was suggested., Conclusion: The phenotype of these patients differs from that described in families with POU1F1 (Pit-1) and PROP1 mutations. These cases are most likely related to an autosomal recessive gene mutation that warrants further research. To our knowledge, this is the first report of hypopituitarism in two brothers born by breech delivery.

Data provided by nine registries based in European and Latin America countries were analyzed to assess whether there is an excess of malformations in twins compared to singletons. Specific congenital malformations were coded according to the ninth revision of the International Classification of Diseases (ICD). Malformation rates and rate ratios (RR) for twins compared to singletons were calculated for each registry, and the homogeneity of the RRs was tested using the test of Breslow and Day. If departure from homogeneity in the different registries was not significant, registry-adjusted RRs with 95% confidence intervals were calculated. Overall, among 260,865 twins, 5,572 malformations were reported. A total of 101 different types of malformations or groups of defects was identified, and a homogeneous estimate of the RRs among registries was found for 91.1% of the malformations. Thirty-nine of the 92 malformations with homogeneous estimates of RRs were more common in twins than in singletons. For the remaining nine malformations, heterogeneous estimates of RRs were obtained. This study confirms the majority of already known associations and further identifies previously unreported malformations associated with twins. In conclusion, there is an excess of malformations in twins compared with singletons, and all anatomical sites are involved. The number of specific malformations associated with twins is higher than that previously reported in smaller studies.

Total trisomy 9 is a rare disorder with most patients dying before age 4 months. Herein, we report a 9-year-old girl with mental retardation, short stature, a peculiar face and other minor defects, who was diagnosed as having an unbalanced de novo X-autosome translocation with a 46,X,der(9)t(X;9)(q12;q32) karyotype resulting in almost a full trisomy 9(pter-->q32) and a partial monosomy X(q12-->pter). The clinical findings of our patient, almost exclusively resemble those of trisomy 9p and the Ullrich-Turner syndromes and has few manifestations of 9q trisomy. BrdU replication studies by Giemsa staining showed an earlier replication of 9p in the translocated chromosome, but a marked late-replication pattern for almost the complete 9q arm involved in the translocation. FISH studies confirmed the presence of three 9 centromeres, excluded the presence of the X centromere signal in the rearranged chromosome, and showed that both Xq telomeric sequences were present. BrdU replication studies by FISH showed an usual pattern of striking late-replication around the XIC of the derivative chromosome, but early replication of the chromosome 9p segment and distal Xq.

A case study describing an accident in Mexico caused by failure to de-energize an x-ray spectrometer prior to repair is presented. The evolution, medical management, and outcome of the radiation injury to the hand are briefly reviewed. A discussion follows, with radiation injury and thermal burns compared and contrasted. The anatomy and physiology of thick skin and the vascular system of the hand are reviewed so that the reader will have a better understanding of the role of vascular injury in the pathological process that leads to tissue atrophy and radiation necrosis. Hyperbaric oxygen therapy, sympathectomy, and other techniques for improving circulation in involved areas are reviewed.

Background and Objective: Male pseudohermaphroditism due to 5 alpha-reductase deficiency was originally described in 1974. Recently, 5 alpha-reductase Type 2 gene defects have been found generally to be due to point mutations within the 5 exons of the 5 alpha-reductase-2 gene. In this report, we describe the molecular study of patients with 5 alpha-reductase deficiency., Design: Previously diagnosed patients with 5 alpha-reductase deficiency were sampled in order to perform molecular studies., Patients: Eight 5 alpha-reductase deficient individuals from 6 unrelated families., Measurements: Single-strand conformational polymorphism and DNA sequencing were performed after polymerase chain reaction amplification of each of the 5 exons of the gene., Results: Five different missense mutations were found. In 4 patients a cytosine to guanine substitution was observed at codon 212 in exon 4. Two siblings presented a cytosine to adenine substitution at codon 207 in exon 4. Another patient exhibited a guanine to adenine substitution at codon 34 in exon 1, whilst one individual presented 2 mutations: a guanine to adenine substitution at codon 115 in exon 2 and a guanine to adenine substitution at codon 203 in exon 4 (previously undescribed mutation)., Conclusions: The presence of the same mutation in 4 patients from 3 families indicates the increased prevalence of this mutation in a particular ethnic group, suggesting a common ancestry for the gene defect in these patients. The existence of hot spots is supported by the mutations in codons 34 and 207 which have also been found in other ethnic groups. Interestingly, the patient who presented 2 different mutations, one of them previously undescribed, was reared as a male and exhibited a more masculine phenotype. Further studies in patients with this and other mutations will be needed to verify genotype-phenotype correlation.

Objectives: This report describes our experience with the use of an anticoagulant regimen of adjusted doses of subcutaneous heparin during pregnancy in women with cardiac valve prostheses., Background: Gravid patients with prosthetic heart valves require long-term anticoagulant therapy. To avoid the increased incidence of fetal morbidity and mortality associated with the use of coumarin agents in such patients during pregnancy, anticoagulation with subcutaneous heparin has been suggested. Controversy exists concerning the appropriate treatment of these patients., Methods: Forty pregnancies in 37 women with prosthetic heart valves were prospectively followed up. Subcutaneous heparin was administered from the 6th until the end of the 12th week and in the last 2 weeks of gestation. Heparin was given every 8 h in the first 36 cases and every 6 h in the last 4 cases, and the dose adjusted to maintain the activated partial thromboplastin time at 1.5 to 2.5 times the control level. Acenocoumarol was used at other times., Results: The incidence rate of spontaneous abortions was 37.5%; there was one neonatal death (2.5%) due to cerebral hemorrhage. No signs of coumarin-induced embryopathy were found in any of the 16 live-born infants studied by the geneticist. One mother died of gastrointestinal bleeding while receiving oral anticoagulant agents. There were two cases of fatal massive thrombosis of a mitral tilting-disk prosthesis during heparin therapy. The study was interrupted after the last of these two cases., Conclusions: The regimen of adjusted doses of subcutaneous heparin used in this study is not effective to prevent thrombosis of mechanical valve prostheses during pregnancy. The use of heparin from the 6th to the 12th week of gestation does not decrease the high incidence of fetal wastage associated with anticoagulant therapy. Coumarin agents provide adequate protection against thromboembolism during pregnancy in patients with mechanical valve prostheses.

With the use of the polymerase chain reaction (PCR), we investigated the frequency of the typical and atypical genes of the alcohol dehydrogenase 2 (ADH2) and aldehyde dehydrogenase 2 (ALDH2) loci, in a group of patients with alcoholic liver cirrhosis and two comparison groups. Contrary to what has been found in the Japanese population, there was no difference in the frequencies of these genes in the groups investigated, and we conclude that in Mexicans, the particular mutation of the ALDH2 locus which "protects" Orientals from alcoholic hepatic diseases, by making them very susceptible to alcohol and therefore discouraging its ingestion, is not present.

Epidemiologic data were analyzed for a total of 2,693 infants with esophageal atresia registered in nine congenital malformation registries around the world. The average recorded prevalence at birth was 2.6 per 10,000 births, with a significant variability among programs--and sometimes within a program--and a maximum prevalence of above 3 per 10,000 births. Clusters of infants with esophageal atresia were observed but may be random. An increasing rate was seen during the period 1965 to 1975 (Norway, South America, Sweden). The type of esophageal atresia was specified in only 439 cases, but no major differences were seen in the epidemiologic characteristics of infants with the most common type (distal fistula) and infants with other types. There was an excess of low birth weight and preterm birth, and infants with esophageal atresia had a birth weight 500 to 1,000 g less than normal infants in each gestational week. There was an excess of twins, apparently mainly or exclusively due to monozygotic twinning, but in only two pairs did both twins have esophageal atresia. There was no effect seen of maternal age, but low parity, irrespective of maternal age, was associated with an increased risk for esophageal atresia. Infant survival varied among programs and depended heavily on associated malformations. Among 1,107 sibs born before the proband and 385 born after the proband, only 25 (1.7%) had a serious malformation; three had esophageal atresia. In 57.3% of the infants with esophageal atresia, no other malformations were present, in 36.4% other major malformations were recorded, and in 6.3% there were chromosomal anomalies. The malformations present associated with esophageal atresia were analyzed: a large proportion entered the constellation sometimes called "caudal mesoderm spectrum of malformations": VATER, Potter, and caudal regression sequences.

We describe clinical, cytogenetic, endocrine, and histopathological findings in 16 patients with mixed gonadal dysgenesis (MGD). All patients except 1 presented genital ambiguity and 10 of them had Ullrich-Turner manifestations. The 45,X/46,XY karyotype was the most frequent with a predominance of 45,X cells in both peripheral lymphocytes and gonads. In all cases Müllerian and Wolffian remnants and/or derivatives were found and in some patients both Wolffian- and Müllerian-derived structures were identified on the streak or testicular side. Postpubertal patients exhibited variable degrees of virilization and all of them had hypergonadotropism coexisting with low to normal baseline serum levels of testosterone; their testicular response to human chorionic gonadotropin (HCG) in terms of testosterone secretion was also variable, ranging from minimal to almost a normal response. All prepubertal patients but 1 had normal baseline levels of pituitary gonadotropins and testosterone and their gonadal response to the HCG challenge was highly variable. With the exception of 1 case, who had a 45,X/46,XY(p-) karyotype, no correlation between the cytogenetic data and degree of external genital ambiguity and the hormonal findings was observed. Additional information on the specific structural abnormalities involving the testis-determining gene of the Y chromosome in patients with MGD is needed in order to further understand the mechanisms responsible for the wide variability characteristic of this disorder.