A highly specific coding system for structural chromosomal alterations.

The Spanish Collaborative Study of Congenital Malformations (ECEMC, from the name in Spanish) has developed a very simple and highly specific coding system for structural chromosomal alterations. Such a coding system would be of value at present due to the dramatic increase in the diagnosis of submicroscopic chromosomal deletions and duplications through molecular techniques. In summary, our new coding system allows the characterization of: (a) the type of structural anomaly; (b) the chromosome affected; (c) if the alteration affects the short or/and the long arm, and (d) if it is a non-pure dicentric, a non-pure isochromosome, or if it affects several chromosomes. We show the distribution of 276 newborn patients with these types of chromosomal alterations using their corresponding codes according to our system. We consider that our approach may be useful not only for other registries, but also for laboratories performing these studies to store their results on case series. Therefore, the aim of this article is to describe this coding system and to offer the opportunity for this coding to be applied by others. Moreover, as this is a SYSTEM, rather than a fixed code, it can be implemented with the necessary modifications to include the specific objectives of each program.

Thanatophoric dysplasia type II with encephalocele and semilobar holoprosencephaly: Insights into its pathogenesis.

Thanatophoric dysplasia (TD) is a lethal form of short-limb skeletal dysplasia that is associated with macrocephaly, and variably cloverleaf skull. Two types of TD are clinically recognized, TD1 and TD2, mainly distinguished by their radiographic characteristics. The differences between the two are principally observed in the femur, which appears curved in TD1, while it remains straight but with a proximal medial spike in TD2, and are a less severe overall affectation in TD2. Both types of TD are caused by mutations in different functional domains of the FGFR3 gene. However, whereas several mutations in the different domains of FGFR3 cause TD1, the K650E mutation involving the change of a lysine to glutamic acid ("Lys650Glu") has been found in all TD2 cases to date. Here we describe a newborn infant with TD2 associated with brain defects that have either been infrequently observed (encephalocele) or not hitherto described (holoprosencephaly). Based on recent studies, we consider encephaloceles described in TD to be pseudoencephaloceles, since they are secondary to the intracranial pressure generated by severe hydrocephaly and to severe cranial structural anomalies. Finally, to analyze the mechanisms of holoprosencephaly observed in the case described here, we include a concise review on the current understanding of how FGFs and their receptors are expressed in the rostral signaling center (particularly Fgf8). In addition, we evaluated recent observations that FGF ligands and receptors (including FGFR3) act in concert to organize the whole telencephalon activity, rather than independently patterning different areas.

Subtelomeric deletion of 12p: Description of a third case and review.

Only 12 cases with a cytogenetically visible deletion of the short arm of chromosome 12 (12p) have been reported so far. The difference in clinical features observed in these patients indicates that there is no distinct phenotype associated with this short arm deletion, although the existence of a del(12p) syndrome was previously suggested. Besides those 12 reports, only two patients have been described with a subtelomeric 12p deletion; both present in the same family in which the son showed a mild phenotype of moderate mental retardation and behavioral problems and his carrier mother had no apparent phenotype. In this article, we describe the third known patient with a subtelomeric 12p deletion in a young boy with mental retardation and microcephaly, and review the literature.

[Chromosome 9P deletion: Gonadal dysgenesis associated with mental retardation and hypoplasia of the corpus callosum: A contiguous gene syndrome?]. / Deleción 9p-. Disgenesia gonadal asociada a retraso mental e hipoplasia del cuerpo calloso. ¿Síndrome de genes contiguos?

BACKGROUND: Many genes are involved in testicular differentiation. The alterations of these genes are responsible for sexual differentiation disorders with 46 XY karyotype. CASE: We report the case of a newborn who had an interscrotal hypospadias, palpable gonads and hypoplastic penis. Karyotype 46 XY. Abdominal ultrasound revealed testes and absence of Müllerian remnants. There was a good response to the short gonadotrophin test. At one year he had signs of psychomotor retardation and hypotonia. The magnetic resonance revealed frontal-temporal atrophy and a decrease in the corpus callosum. Testicular biopsy was compatible with gonadal dysgenesis. A preoperative cystography showed a vaginal remnant. Due to the presence of a sexual differentiation disorder, psychomotor retardation and facial dysmorphism, we requested a high-resolution karyotype: deletion 46, XY, del (9p) (p23-pter). Ish tel (9p-). DISCUSSION: Many genes are involved in testicular differentiation, some of which also affect the development of other tissues. In the short arm of chromosome 9, two genes, DMRT1 and DMRT2, are involved in sexual differentiation. Their alterations have also been described as causing mental retardation. In the evaluation of 46,XY disorders of sex differentiation, the accompanying signs are very important for guiding the genetic study.

A small and active ring X chromosome in a female with features of Kabuki syndrome.

A ring X chromosome is found in about 6% of patients with Turner syndrome (TS), often with mosaicism for a 45,X cell line. Patients with this karyotype are reported to have a higher incidence of a more severe phenotype including mental retardation. In fact, some studies have shown a correlation between this severity and the presence or absence of an intact and functional X inactivation center (XIST). However, the phenotype of the individuals with r(X) cannot be entirely defined in terms of their X-inactivation patterns. Nevertheless, a small group of these patients have been described to manifest clinical features reminiscent of the Kabuki syndrome. Here we present a female patient with clinical features resembling Kabuki syndrome and a mos 45,X/46,X,r(X) karyotype. Methylation analyses of polymorphic alleles of the androgen receptor gene showed that both alleles were unmethylated suggesting an active ring chromosome. A specific X chromosome array CGH was performed estimating the size of the ring to be 17 Mb, lacking the XIST gene, and including some genes with possible implications in the phenotype of the patient.

The biochemical structure and function of methylenetetrahydrofolate reductase provide the rationale to interpret the epidemiological results on the risk for infants with Down syndrome.

Studies on the structure of the methylenetetrahydrofolate reductase (MTHFR) gene and the mechanisms by which folate may reduce homocysteine levels in bacteria and in humans have provided a rationale to understand the conflicting epidemiological observations between the studies on the 677C-T and 1298A-C MTHFR polymorphic variants, and the risk of having an infant with Down syndrome (DS). However, three of the combined genotypes (CTCC, TTAC, and TTCC) are very infrequent in the human population. In fact, these three rare genotypes were only observed in two of the eight epidemiological studies that analyzed these genotype combinations and the risk of DS. In a study of the Indian population these three genotypes were identified in mothers of DS children but not in control mothers demonstrating a statistically significant increase in the risk of giving birth to DS infants. Conversely, the CTCC and TTAC genotypes were only observed in control mothers and not in mothers of DS infants in the Spanish study, while the TTCC genotype was not observed in any Spanish mother analyzed. These results were not related to the frequency of the T allele, since this was lower in the Indian population (21.4% among case mothers and 12.4% in control mothers) than in the Spanish population (33.9%). At present, several important biological aspects on the Hcy cycle are known, including: (a) the biochemical structure and function of the MTHFR enzyme, (b) the biological basis for the effect of the different 677C-T and 1298A-C MTHFR genotype combinations on Hcy levels, (c) that folate is not synthesized by the organism that obtained it from the diet, (d) that TT homozygotes will be at particular risk when their folate status is low because the mutant enzyme requires much higher levels of folate than the physiological one to stabilize the binding of flavin-adenosine-dinucleotide (FAD), (e) that the release of flavin is prevented by increasing the levels of folate, and (f) that the cystathionine-beta-synthase gene is located on chromosome 21. Together, these facts suggest that destabilization of the Hcy cycle in function of the levels of S-adenosylmethionine (SAM), may be modified by some embryonic and maternal genotypes, as well as by maternal nutritional status and life style. This may also influence the probability that some embryos survive to birth, but in different way for those with and without trisomy 21, as is discussed in this article.

Two new patients bearing mutations in the fukutin gene confirm the relevance of this gene in Walker-Warburg syndrome.

Walker-Warburg syndrome (WWS) is an autosomal recessive disorder characterized by congenital muscular dystrophy, brain malformations and structural abnormalities of the eye. We have studied two WWS patients born to non-consanguineous parents, and in both cases, we identified mutations in the fukutin gene responsible for this syndrome. One of the patients carries a homozygous-single nucleotide insertion that produces a frameshift, being this the first time that this insertion has been described in homozygosis and causing a WWS phenotype. The other patient carries two novel mutations, one being a point mutation that produces an amino acid substitution, while the other is a deletion in the 3'UTR that affects the polyadenylation signal of the fukutin gene. This deletion would probably result in the complete loss of the fukutin transcripts from this allele. This is the first time a mutation localized outside of the fukutin coding region has been identified as a cause of WWS.

Small supernumerary chromosome marker generating complete and pure trisomy 18p, characterized by molecular cytogenetic techniques and review.

Small supernumerary marker chromosomes (sSMC) have been described from all human chromosomes with different sizes and shapes. However, it is difficult to know the clinical manifestations associated with them, because such knowledge depends on the size, presence of euchromatic material, degree of mosaicism and/or uniparental disomy (UPD). Pure trisomy of the whole arm of chromosome 18 (18p), has been described in only a few cases and the general consensus is that there is a mild phenotypic effect. Here we report on a newborn male presenting with an atrial septal defect and a club foot. The high resolution G-band karyotype (550-850 bands) and the molecular cytogenetic techniques revealed in all cells the presence of an sSMC, which was a complex derivative from the short arm of a chromosome 18 (18p) and a centromere of a chromosome 13/21. His healthy mother had the same sSMC in all analyzed cells. With the present case, we support the previous suggestion that this unusual chromosome trisomy 18p has little clinical repercussions.

The first 4p euchromatic variant in a healthy carrier having an unusual reproductive history.

We report on the molecular cytogenetics studies in a healthy couple who had had three pregnancies which ended in a termination of pregnancy (TOP). In two of them, prenatal sonogram showed fetal dwarfism and in the third one, a chromosome alteration was found in the amniocentesis. A previous pregnancy ended in a healthy girl. A high-resolution G-band karyotype (550-850 bands), together with Fluorescence in situ Hybridization (FISH) techniques, detected in the father a 4p interstitial euchromatic duplication. This chromosome duplication appears to be a previously undescribed euchromatic variant (EV). We discuss the possibility that the 4p paternal EV could be involved in the clinical and genetic findings of the three TOPs.

[Characteristics of neonates with and without a single umbilical artery. Analysis of two consecutive series of neonates with and without congenital defects]. / Características de los neonatos con y sin arteria umbilical única. Análisis de dos series consecutivas de recién nacidos con y sin defectos congénitos.

BACKGROUND AND OBJECTIVE: The implications of the presence of a single umbilical artery (SUA) are unknown. Although most articles are based on selected samples, they suggest a relationship between SUA and malformations. Consequently, prenatal detection of SUA causes concern, since there are no definitive guidelines that can be followed after identification of this abnormality. The objective of this study was to comparatively analyze SUA in two series of consecutive births, with and without congenital defects. PATIENTS AND METHODS: A total of 19,909 cases and 19,148 controls from the Registry of the Spanish Collaborative Study on Congenital Malformations were studied. The variables analyzed were sex, birth weight, length, occipito-frontal circumference, gestational age, prematurity, delivery by caesarean section, umbilical cord length, placental weight, survival at 72 hours, primiparity, oligohydramnios, and polyhydramnios. Calculations included relative frequency, odds ratios (OR) and 95 % confidence intervals, the chi-square test, Fisher's p-value, and Student's t-test. RESULTS: SUA was found in 2.29 % of cases and in 1.03 % of controls (p = 0.0000001). These figures showed secular variation due to improvements in prenatal diagnosis and interruption of some pregnancies. When cases with and without SUA were compared, those with SUA had lower values of somatometry at birth, umbilical cord length and gestational age and had a higher risk for oligohydramnios, polyhydramnios, caesarean section, and death in the first 72 hours. Among controls, the only differences were a shorter umbilical cord and a higher frequency of oligohydramnios among infants with SUA. CONCLUSIONS: The results suggest that certain malformations associated with SUA could cause some of the differences among cases. Shortening of the umbilical cord and oligohydramnios could be related to SUA, as these abnormalities were found in both cases and controls. Comparison of cases and controls suggests that the etiopathogenesis of SUA could differ in the two groups.

Pre-gestational maternal body mass index predicts an increased risk of congenital malformations in infants of mothers with gestational diabetes.

AIMS: The aim of the present study was to identify characteristics in women diagnosed with gestational diabetes mellitus (GDM) that could be predictive of congenital malformations in their infants. METHODS: Using data from the Spanish Collaborative Study of Congenital Malformations (ECEMC), a hospital-based case-control study and surveillance system, we assessed the relationship between a number of maternal variables, including pre-gestational body mass index (BMI), and specific congenital malformations in their infants. RESULTS: The overall risk for a selected group of congenital malformations in an infant of an obese mother with GDM compared with an obese mother with normal glucose tolerance (NGT) was 2.78 (1.38-5.55, P < 0.001). Within the group of mothers with GDM, obesity (BMI > or = 30 kg/m2) was associated with a significantly increased risk of cardiovascular defects compared with non-obese women [OR = 2.82 (1.31-7.04), P < 0.01]. In mothers with NGT, pre-gestational BMI was not associated with congenital malformations. CONCLUSION: Pre-gestational obesity is a predictive variable for congenital malformations in infants of mothers with GDM. The greater their BMI, the higher the risk for congenital malformations in their offspring. Given the blastogenic origin of the congenital defects identified, and the relationship between obesity and Type 2 diabetes, it is probable that this increased risk is as a result of previously unidentified pre-gestational diabetes mellitus (PGD). It is important that overweight and obese women planning a pregnancy be evaluated for the presence of diabetes.

Genetic syndromes mimic congenital infections.

Genetic syndromes that mimic congenital infection are important to recognize because of the associated risk of recurrence. We describe two brothers born to consanguineous parents with clinical features suggestive of intrauterine infection but with negative serologic investigations. Our observations suggest that Aicardi-Goutieres syndrome (AGS) and pseudo-TORCH syndrome likely represent the same disorder.

[De novo partial duplication of the distal segment of the long arm of chromosome 5 (q31--> qter). Report of a new case]. / Duplicación parcial de novo del segmento distal del brazo largo del cromosoma 5 (q31 --> qter).

We report a case of de novo partial duplication of the distal segment of the long arm of chromosome 5 (q31--> qter). The patient showed dysmorphic features (flat face, short and horizontal palpebral fissures, depressed and broad nasal bridge, wide nose with hypoplastic alae nasae, short and flat philtrum, high arched palate, micrognathia, anomalies of the ears), redundant adipose panniculus of the neck, proximal shortening of the limbs, flexion contractures, long and distally widened fingers, bilateral clubfoot, single umbilical artery, hypoplasia of lung and pulmonary arteries, atrial septal defect and patent ductus arteriosus. She died 23 hours after birth from respiratory failure. Chromosome analysis with high resolution GTG bands showed 46,XX,1p1, which was interpreted as a partial duplication of the distal long arm of chromosome 5 (q31--> qter). Fluorescence in situ hybridization analyses with whole chromosome painting technique for chromosome 5 proved that this extra region belonged to chromosome 5. Our case is the first to have a de novo partial duplication of this chromosome segment.

[Comparison of the epidemiological characteristics of neural tube defects classified according to failure of the different points of closure]. / Comparación de las características epidemiológicas de los defectos del tubo neural clasificados según el fallo de los distintos puntos de cierre.

OBJECTIVES: To study the epidemiological characteristics of neural tube defects (NTD) classified according to the theory of multi-site closure of the neural tube and to correlate several factors with the failure of different closure sites. MATERIAL AND METHODS: We used the data from the Spanish Collaborative Study of Congenital Malformations (ECEMC), collected from April 1976 to April 1995. During this time, 757 NTD of non-syndromic origin were diagnosed. These were classified into groups according to the failure of the point of closure and a range of variables were analyzed by comparing the different groups of NTD with each other. RESULTS AND CONCLUSIONS: Among non-syndromic NTD, 2.11 % recurred in siblings. However, the real recurrence rate in our population is 2.63 %, which corresponds with the recurrence rate observed before 1986. From this year the recurrence rate was modified by the legal possibility of abortion after prenatal diagnosis. The infants with NTD classified according to multi-site closure failure of neural tube differed in weight, mortality, maternal use of valproic acid, and maternal diabetes mellitus. While valproic acid is more specific to failure of closure sites 1 and 1 5, maternal diabetes mellitus preferentially affects failure of closure site 4. Closure site 4 is clearly genetically determined: it is frequently observed in genetic syndromes, predominantly affects females and is associated with a higher rate of maternal abortions and higher recurrence. Moreover, it is frequently observed in infants with multiple congenital anomalies and is associated with a higher rate of malformations among relatives.

Epidemiological evidence that maternal diabetes does not appear to increase the risk for Down syndrome.

In 1997, Narchi and Kulaylat, studying the incidence of Down syndrome in infants of gestational diabetic mothers, concluded that maternal diabetes increases the risk for Down syndrome, but failed to control the maternal age in their analysis. Using data from the Spanish Collaborative Study of Congenital Malformations (ECEMC), we analyzed the relationship between Down syndrome and maternal diabetes mellitus, and maternal gestational diabetes, controlling the maternal age through the pair-matching analysis, stratifying by maternal age and logistic regression analysis. The analyses show that maternal age is related either to Down syndrome as well as to both types of maternal diabetes. Thus, the overall analysis could be confounded by maternal age. Once we controlled the maternal age, the risk of maternal diabetes mellitus for Down syndrome is: odds ratio (OR) = 0.92 (0.41-2.07); P = 0.83. Controlling maternal age in gestational diabetes, the risk is OR = 1.18 (0.61-2.35); P > 0.70. Based on our results, we conclude that Down syndrome is related to maternal age, but does not seem to be related to any type of maternal diabetes.