Trisomy of the short arm of chromosome 5 due to a de novo inversion and duplication (5)(p15.3 p13.3).

Partial trisomies of the short arm of chromosome 5 are uncommon. The first description was made by Lejeune et al., in 1964. It has been suggested that the critical region for 5p trisomy syndrome lies between 5p10 and 5p13. We report on a Mexican girl who developed severe mental retardation and generalized tonic clonic seizures at age 1 year. On physical examination at age 5 years, she had macrodolichocephaly, upslanted palpebral fissures, bilateral inner epicanthic folds, low nasal root, and malformed ears with posterior rotation which are clinical characteristics of 5p trisomy syndrome. The cytogenetic study with G bands and FISH with painting for chromosome 5 and with the cri-du-chat 5p15 unique sequence probe showed a duplication and inversion of 5p [46,XX, dup(5)(p15.3 p13.3)] which overlaps with the critical region for 5p trisomy syndrome. Our patient shares clinical characteristics with the patients described in the literature with involvement of this critical region. Both parents have normal karyotypes indicating the rearrangement is de novo. Only one patient has been reported in the literature with the same cytogenetic rearrangement as our patient, but this patient had a different phenotype. Since they only performed conventional cytogenetics and we performed FISH to confirm the diagnosis, the differences in the phenotypes could be explained by the presence of other genes involved in the rearrangement. The combined use of conventional and molecular cytogenetics in this case allows a more precise diagnosis and furthers knowledge in phenotype/genotype correlation.

Liver fibrocystic disease and polydactyly: proposal of a new syndrome.

Liver fibrocystic disease (LFCD), characterized by dilatation of the intrahepatic bile ducts and variable degree of fibrosis, can be present alone or as part of many syndromes, such as Bardet-Biedl syndrome (BBS), Meckel syndrome, Jeune asphyxiating thoracic dysplasia, and Fraser-Jequier-Chen syndrome. We report two cases of LFCD and polydactyly with features similar, but not diagnostic of, BBS. Patient 1 was an 18-month-old boy with mental retardation, polydactyly, chronic renal failure, convergent strabismus, and hepatic fibrosis. Patient 2 was a male neonate with LFCD and polydactyly. Their manifestations could not be diagnosed as any of the previous mentioned entities. Difficulties in the early diagnosis of BBS have been previously reported and this could explain the clinical variability and heterogeneity of manifestations at the time of diagnosis. On the other hand, the existence of liver abnormalities in association with BBS has been previously described, but is rare. Our patients' malformations might represent a new entity where autosomal recessive inheritance is probable, but other patterns cannot be ruled out.

Cloverleaf skull and multiple congenital anomalies in a girl exposed to cocaine in utero: case report and review of the literature.

The case of a girl with cloverleaf skull (CLS) and multiple congenital anomalies is reported. Both parents have a history of drug use. Maternal cocaine abuse during the first trimester of pregnancy was obvious, and other drugs, such as marihuana and alcohol, were also taken by the mother. Many central nervous system malformations have been reported in association with cocaine abuse, the most severe being midline defects and neural tube defects. To our knowledge this is the first case reported of CLS anomaly associated with drug exposure. We also describe other anomalies not previously reported in association with CLS.

Molecular diagnosis of the fragile X and FRAXE syndromes in patients with mental retardation of unknown cause in Mexico.

The fragile X syndrome (Fra-X) is the most common cause of inherited mental retardation with X-linked semi-dominant inheritance. The prevalence of Fra-X in the Mexican population is unknown. The aim of this population screening study was to determine if Fra-X or FRAXE mutations are the cause of a number of cases of mental retardation in a sample of Mexican children with mental retardation of unknown cause (MRUC) and to stress the importance of performing molecular analysis of the FMR-1 gene in all patients with MRUC. We report here the direct analysis of CGG and GCC repeats within the FMR-1 and FMR-2 genes, respectively, in 62 unrelated patients with MRUC. Two male index cases had the CGG expansion, although they did not express the Xq27.3 fragile site cytogenetically. Fra-X diagnosis was highly suspected on a clinical basis in one of the patients, but not in the other. Both mothers were found to be premutation carriers. The molecular studies of FMR-1 showed that the proportion of MRUC patients with Fra-X is 3.2%. This frequency was not significantly different to that reported in most populations. As reported in other series, no patients with FRAXE were found in our sample. Our findings confirm that the molecular analysis of the FMR-1 gene is necessary in MRUC patients to achieve unequivocal diagnosis of fragile X syndrome, carrier premutation detection and for accurate genetic counseling.

Ataxia-pancytopenia syndrome.

We report on a Mexican girl who developed cerebellar ataxia at age 3 years and pancytopenia at age 13 years. Cerebral computed tomography scan and magnetic resonance imaging showed evidence of severe cerebellar atrophy. Telangiectasias were not present; immunoglobulins and alpha-fetoprotein levels were normal. Cytogenetic studies showed no evidence of spontaneous chromosome aberrations, a normal rate of diepoxybutane (DEB) and mitomycin C (MMC)-induced chromosome aberrations, but an increased response to bleomycin. The phenotype support the diagnosis of ataxia-pancytopenia syndrome, although monosomy of chromosome 7 was not found in bone marrow. The cytogenetic studies suggest that this may be a chromosomal instability disorder.

[Intermediate moisture food for elder people based on a legume: soybeans, mixture with calcium]. / Alimentos de humedad intermedia para ancianos en base a extrusado de maíz: soja, adicionado con calcio.

An intermediate moisture food (IMF), has been developed in our laboratory for elder people, over 60 years. The IMF is based on a cereal: legume mixture with calcium and flavour, it supplies proteins, carbohydrates and vegetable oils; as well as, high energetic density (3.22 cal/g) and covers up to 51% of calcium needed. It can be easily consumed as a tasty and soft food. It has a water activity of 0.80, for it can be stored at room conditions. It is very likely that IMF becomes a good alternative to improve and vary elder peoples diet.

[A supplementary sportmen food formulation and characterization]. / Formulación y caracterización de un alimento suplementario para deportistas.

A supplementary sportman food, based on corn:soy extruded blend, freeze-dried egg albumen and protein soy isolate, was developed. The resulting powder was subject to physico-chemical, functional, nutritional and sensorial test and then compared with a commercial food that was used as reference. Chemical and biological analysis of both foods revealed lower protein content in the formulated food (65%) than the commercial product (90%) although NPR values are larger in product showed (4.86) that than the observed in the second (4.03). On the other hand RNPR values of teh developed product also presented higher values than the commercial (Prot 90) (83.76 and 69.48 respectively). Casein was used as standard. Digestibility results were similar (93.65 and 95.7 for formulated and commercial products respectively). The absence of ureasic, antitryptic or hemagglutinating activity of the formulated product are also reported. Physico-chemical analysis shown that available lysine values are larger for the formulated product (15 g/16 g nitrogen) than those for the commercial food (7.80). Peroxide content was always very small (1.37 meq/kg) and in all cases micotoxine assay, for raw materials, was always negative. A comparison of other properties, such as colour, WAI, WSI and aw for both products, is also presented. Flow behavior of water, milk and orange juice suspensions showed pseudoplastic behavior on both products. Sedimentation experiments minutes revealed stability of suspensions without phase separation during the first 30 minutes. Sensorial analysis have shown that developed product received 78.5% acceptability and 100% preference.

High frequency of de novo deletions in Mexican Duchenne and Becker muscular dystrophy patients. Implications for genetic counseling.

Duchenne muscular dystrophy (DMD) is the most common lethal hereditary neuromuscular disease. As there is no effective treatment, accurate carrier detection is essential for genetic counseling and prevention. Although linkage analysis has been widely used for this purpose, being an indirect analysis it has several limitations. Using linkage analysis for carrier detection, we found serious limitations, mainly because 82.9% of all proposita were isolated cases. We used quantitative polymerase chain reaction for direct carrier detection in families with exon deletions and found a higher than expected frequency of de novo deletions (62.2%). Furthermore, only 20.7% of the mothers of isolated deletion DMD/Becker muscular dystrophy (BMD) patients were found to be carriers. This result suggests that the Mexican population has a high frequency of de novo DMD mutations.

Microtia: a clinical and genetic study at the National Institute of Pediatrics in Mexico City.

BACKGROUND: Microtia is a malformation of the ear with extreme variability of expression. It is generally seen as an isolated malformation. However, some authors consider it to be a minimal manifestation of the oculo-auriculo-vertebral spectrum (OAVS), where, in addition, there are facial, vertebral, and renal abnormalities, among others. METHODS: A total of 145 pediatric patients with unilateral or bilateral microtia not considered as part of a syndrome were studied. All patients were subjected to an intentional clinical examination, a familial history, and radiographic imaging studies for ruling out associated malformations. Patients were classified into two groups: group 1 (60%), with isolated microtia; and group 2 (40%), considered as OAVS, with microtia associated with hemifacial skeletal microsomia, vertebral and/or renal malformations. RESULTS: No significant differences were found between the groups when the following variables were compared: gender; presence of unilateral or bilateral microtia; atretic external auditory canal; presence of preauricular tags; hearing loss of any type, and affection of the seventh cranial nerve, as well as associated malformations of other organs or systems. There were significant differences in relation to the presence of soft-tissue hemifacial microsomia, more frequently seen in patients with OAVS, because the majority of these patients had bone microsomia. Over 66% of the cases were sporadic and the rest were familiar. In 28.3% of the cases, the history suggested an autosomal-dominant inheritance pattern, and in 5.5%, an autosomal-recessive inheritance pattern, although in some familial cases, multifactorial inheritance could not be ignored. Some members in several families had isolated microtia, and others had mild characteristic manifestations of OAVS. CONCLUSIONS: Our results support the hypothesis that isolated microtia is a minimal expression of OAVS. Therefore, it is recommended that patients with microtia be subjected to intentional studies that search for malformations and physical examinations of first-degree relatives for adequate genetic counseling and management.

[Detection of aneuploidies using in situ hybridization in cells of the oral mucosa]. / Detección de aneuploidías por hibridación in situ en células de mucosa oral.

Aneuploidies have been traditionally diagnosed by chromosome analysis, however this method may be difficult to perform in certain cellular types or in severely ill patients. With the fluorescence in situ hybridization (FISH) technique it is possible to identify the number of specific chromosomes in interphase cells. In the present study we analyzed exfoliated epithelial cells from the oral mucosa of 15 patients with trisomy 21, and in six patients with mosaicism; five normal subjects were included for comparison. To allow the probe to reach its target DNA we first treated the keratin-surrounded membrane with pepsin during 20 minutes. In the 15 cases of trisomy 21, the cells showed five fluorescent signals indicating the presence of three chromosomes 21 and two 13, while the normal subjects showed four signals. In one girl with Turner syndrome and a karyotype 46,X+mar, the FISH analysis in 1000 cells revealed that the marker derived from chromosome X and there was a mosaicism 45,X/46,X,r(X). In the other patients with mosaicisms, we observed variations in the proportions of cells but the differences were not significant. In conclusion, interphase FISH on buccal cells showed to be a rapid, effective and non-invasive method for the diagnosis of chromosome aberrations, particularly when the cytogenetic study on lymphocytes is difficult to perform.

[Fluorescence in situ hybridization in 6 patients with alterations of chromosome 18 and in 7 with marker chromosomes]. / Hibridación in situ con fluorescencia en seis pacientes con alteraciones del cromosoma 18 y en siete con cromosomas marcadores.

The purpose of the present study was to use the FISH method to establish the origin of chromosome aberrations currently unidentifiable by routine banding procedures. It was done in 13 cases with structurally rearranged chromosomes, seven of them with non-satellited marker chromosomes; in two of the latter an isochromosome 18p was identified which was consistent with a clinical picture of a tetrasomy 18p. FISH with chromosome-specific painting probes showed a deletion 18q in a girl with a cytogenetically balanced t(8;18). Two patients with deletions and two with 18 ring chromosomes were studied using a telomeric probe: both deletions had telomeric integrity and telomeric material was not present in the 18 rings. In a patient with an abnormal chromosome 18, the FISH analysis confirmed a pericentric inversion. We conclude from these results that FISH can provide a rapid and unequivocal cytogenetic diagnosis, which may improve genetic counseling.

Renal tubular acidosis in the Silver-Russell syndrome.

Several patients with the Silver-Russell syndrome (SRS) attending our Genetics Clinic were diagnosed as having persistent metabolic acidosis. Since this abnormality has not been reported previously in the SRS, we reexamined 33 SRS patients to evaluate the frequency and type of metabolic acidosis, the clinical and laboratory findings, and the growth pattern in SRS patients with and without metabolic acidosis. Among them, 14 had a consistent decrease in HCO3- levels. Renal studies in acidotic patients showed urine pH of 5.8 and 24 h urine calcium of < 2.4 mg/kg/24 h; serum creatinine, excretion of glucose, and amino acids were normal, as were renal ultrasound and excretory urography findings. These data supported the diagnosis of renal tubular acidosis, probably type II; the patients were treated with oral bicarbonate and acidosis was corrected successfully. Clinical manifestations were similar in acidotic and non-acidotic patients. The nutritional indices at diagnosis and at last evaluation (at least 8 months after diagnosis) were abnormally low in all patients; however, acidotic patients, treated with bicarbonate, showed an improvement of nutritional status particularly in the weight/height index, although the difference between groups after follow-up did not reach statistical significance. We suggest that metabolic acidosis due to renal tubular acidosis, probably type II, may occur in children with the SRS and should be looked for and treated in all patients.

[Identification of sex chromosome markers using fluorescence in situ hybridization (FISH)]. / Identificación de cromosomas sexuales marcadores mediante hibridación in situ con fluorescencia (FISH).

From 6 to 15% of the patients with Turner syndrome have a mosaic karyotype, i.e. a 45,X cell line and another with a small sex chromosome marker of undetermined origin which may be a ring or a centric fragment. It is important to establish whether this marker chromosome derives from a Y chromosome as this implies that the patient has a high risk of developing gonadoblastoma. The objective of the present paper was to identify the origin of small sex chromosome markers using fluorescence in situ hybridization (FISH). Eight patients were studied; seven had a Turner phenotype and one had a short stature with ambiguous genitalia. In all cases karyotype in peripheral lymphocytes showed mosaicism, with one cell line that had a sex chromosome marker, and in three cases, the mosaicism was corroborated in fibroblast cultures. Biotin labeled DNA probes with complementary centromeric alpha-satellite sequences of chromosomes X and Y were used in the FISH technique. In seven patients the chromosome marker came from the X chromosome as established with the X chromosome alpha-satellite probe. In the patient with ambiguous genitalia, the marker did derive from the Y chromosome. We conclude that the FISH technique proved to be useful to establish the origin of sex chromosome markers in our laboratory.

Encephalocraniocutaneous lipomatosis: an uncommon neurocutaneous syndrome.

We describe a 2 1/2-year-old girl with encephalocraniocutaneous lipomatosis. The dysmorphologic manifestations in the skull, brain, skin, and eyes associated with a normal karyotype suggested the diagnosis of this rare neurocutaneous syndrome.

Hypomelanosis of Ito: diagnostic criteria and report of 41 cases.

We conducted a 20-year prospective review of 41 pediatric patients with a diagnosis of hypomelanosis of Ito. No evidence pointed to hereditary transmission of the disease. Associated extracutaneous pathology was mainly of the nervous and musculoskeletal systems. Three of 19 patients had chromosomal anomalies. Hypomelanosis of Ito is a clinically well-characterized syndrome in which chromosomal instability may be a component. Criteria for its presumptive and definitive diagnosis are proposed.

Anthropometric studies in five children and their mother with a severe form multiple epiphyseal dysplasia.

We report on a form of multiple epiphyseal dysplasia with striking acromelic shortness in a woman and five of her ten children. The somatometric and metacarpo-phalangeal pattern profile of the affected individual showed short limb dwarfism and shortness of all the tubular bones of the hand. Epiphyseal irregularities and shortness of the 4th metatarsal bones were outstanding. The disorder showed a dominant and probably autosomal pattern of inheritance with variability of expression. The measurement of metacarpo-phalangeal profiles allowed an objective and quantitative assessment of brachydactyly. In the family reported here, there was a clear discrepancy between the severity of shortness of hands and feet and the severity of shortness of stature. This family also illustrates the effects of a single gene in a large kindred, therefore describing the range and variability of a phenotype not otherwise available.

[Clinical and radiologic study of hereditary diseases of the femoral epiphysis]. / Estudio clínico y radiológico de las enfermedades hereditarias de la epifisis femoral.

The diseases that involve the proximal femoral epiphysis are an heterogeneous group with similar clinical characteristics, so it is important to establish a differential diagnosis to bring suitable management and genetic counseling. The present study includes 33 patients: eleven with multiple epiphyseal dysplasia (MED), five with spondylo-epiphyseal dysplasia (SED), twelve with unilateral Perthes disease (PD uni) and five with bilateral Perthes disease (PD bi). The clinical study showed that affected relatives and associated clinical manifestations were more frequent in the dysplastic patients. The somatometric profile of the 17 PD patients was within two standard deviations of the average, whereas the dysplastic patients showed short stature. In the radiological study all patients had one or both proximal femoral epiphysis affected. All the dysplastic patients had other irregular or flattened epiphysis, but only half of those with PD showed mild flattening or distal femoral epiphysis. Eight of 29 patients had a delay in bone maturity, and all patients had mild flattened vertebras. We think this study shows the importance of having sufficient clinic and radiologic criteria to establish the differential diagnosis in view of the heterogeneity of these entities.

Serum immunoglobulin G directed against porcine trypsin in pancreatic insufficient cystic fibrosis patients receiving pancreatic enzyme supplements.

Cystic fibrosis (CF) patients frequently malabsorb nutrients because of pancreatic failure. Standard therapy entails oral administration of porcine pancreatic enzymes, with meals. Porcine enzymes contain in excess of 25 potentially antigenic proteins. To evaluate antigenicity of one of these (porcine trypsin), we developed ELISA techniques capable of measuring total immunoglobulin G (IgG) and IgG directed against porcine trypsin in patient sera. Cross-sectional evaluation of sera from 12 controls and 41 CF patients showed that IgG directed against porcine trypsin was detectable in 12/17 CF patients receiving porcine enzymes (50.6 +/- 56.0 ng/ml; range 0-154.0 ng/ml), while none was detected in controls or the 26 CF subjects not receiving enzymes. In the 17 CF patients receiving enzymes, porcine trypsin binding IgG contributed 0.85 +/- 0.83% of the total IgG pool. Levels of porcine trypsin binding did not correlate with total IgG. Longitudinal evaluation was then performed in 26 CF patients, before and after commencement of enzyme therapy. Prior to commencing therapy, porcine trypsin binding IgG was undetectable in sera from 24/26 patients. Within 4.2 years of commencing therapy, 25/26 patients (96%) developed porcine trypsin binding IgG. Thus, serum IgG responses to porcine trypsin appear to be common in CF patients receiving porcine enzymes and contribute considerably to total IgG levels. Other individual enzymes in porcine extracts are likely to elicit similar antigenic response.

[Congenital multiple arthrogryposis. Clinical and genetic study]. / Artrogriposis múltiple congénita. Estudio clínico y genético.

Forty six cases of arthrogryposis multiplex congenital (AMC) were studied at the Genetic Departament of the Instituto Nacional de Pediatría (México). Three were familial cases, two of them suggesting an autosomal recessive inheritance and one probably dominant. Almost half of the patients were the product of the first pregnancy. The limbs abnormalities allowed the classification of cases in: generalized AMC (54%), lower limbs (30%), upper limbs (5%) and distal (11%). The commonest associated defects were hemangioma, round face and micrognathia. It is concluded that AMC produces severe limitations and variable degree of severity. Associated defects are common and must be explored. Although the majority are sporadic cases the pedigree may show a mendelian inheritance and genetic counseling is needed.