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BACKGROUND We described the main features of an infant diagnosed with facial dysmorphic, language failure, intellectual disability and congenital malformations to strengthen our understanding of the disease. Currently, treatment is only rehabilitation and surgery for cleft lip and palate. CASE SUMMARY The proband was a 2-years-8-months-old girl. Familial history was negative for congenital malformations or intellectual disability. The patient had microcephaly, upward-slanting palpebral fissures, depressed nasal bridge, bulbous nose and bilateral cleft lip and palate. Brain magnetic resonance imaging showed cortical atrophy and band heterotopia. Her motor and intellectual development is delayed. A submicroscopic deletion in 11p13 involving the elongator acetyltransferase complex subunit 4 gene (ELP4) and a loss of heterozygosity in Xq25-q26.3 were detected. CONCLUSION There is no treatment for the ELP4 deletion caused by a submicroscopic 11p3 deletion. We describe a second case of deletion of the ELP4 gene without aniridia, which confirms the association between ELP4 gene with several defects and absence of this ocular defect. Additional clinical data in the deletion of the ELP4 gene as cleft palate, facial dysmorphism, and changes at level brain could be associated to this gene or be part of the effect of the recessives genes involved in the loss of heterozygosity region of Xq25-26.3.

Introduction: Duplication of 12q is characterized by craniofacial dysmorphia, growth failure, occasional brain malformations, abnormalities of the extremities, skeletal and thoracic malformations, cardiovascular defects, anogenital abnormalities like cryptorchidism, psychomotor delay, and intellectual disability. Case presentation: We describe a female patient with typical manifestations of duplication 12q and epilepsy. She had a normal 46,XX karyotype. The microarray assay exhibited a 19.35-Mb gain at 12q24.21q24.33 due to ins(21;12)(p11.2;q24.21q24.33)mat. Discussion and Conclusion: The duplicated region in the patient encompasses 219 genes, 24 considered as pathological. No relation between epilepsy and the genes reported as pathological has been reported.

Darier disease is a clinically variable rare disease with autosomal dominant inheritance caused by mutations in ATP2A2 gene. It affects skin, mucous membranes, and nails. The onset of symptoms is during adolescence and persists through adulthood, affecting quality of life. It presents papules and small malodorous keratotic yellow to brown plaques that emerge predominantly in seborrheic areas. In the present study, we describe a patient with Darier disease successfully treated with naltrexone at low doses.

Background The current study evaluated the metalloproteinases MMP-2 and MMP-9 expression in epithelial cells and the surrounding stroma in ovarian tumors and the association of MMPs with the histological subtypes, the clinical stage and the presence of steroid hormone receptors. Tumor samples were obtained from 88 patients undergoing surgical cytoreduction of primary ovarian tumors in Instituto Nacional de Cancerología, from México City. The formalin fixed and paraffin embedded samples were processed in order to demonstrate the presence of androgen receptor,estrogen receptor alpha, progesterone receptor, MMP-2,MMP-9 and collagen IV by immunohistochemistry and/or immunofluorescence. Results MMP-2 and MMP-9 were differentially expressed in the epithelium and the stroma of ovarian tumors associated to histological subtype, clinical stage and sexual steroid hormone receptor expression. Based on Cox proportional hazard regression model we demonstrated that MMP-2 located in the epithelium and the stroma are independent prognostic biomarkers for overall survival in epithelial ovarian tumors. Kaplan Meir analysis of the combination of AR (+) with MMP-2 (+) in epithelium and AR (+) with MMP-2 (−) in stroma displayed a significant reduction of survival. Conclusions The presence of MMP-2 in the stroma of the tumor was a protective factor while the presence of MMP-2 in the epithelium indicated an adverse prognosis. The presence of AR associated with MMP-2 in the tumor cells was a risk factor for overall survival in epithelial ovarian cancer.

Anterior segment dysgenesis (ASD) and Axenfeld-Rieger spectrum (ARS) are mainly due to PITX2 and FOXC1 defects, but it is difficult in some patients to differentiate among PITX2-, FOXC1-, PAX6- and CYP1B1-related disorders. Here, we set out to characterize the pathogenic variants (PV) in PITX2, FOXC1, CYP1B1 and PAX6 in nine unrelated Mexican ARS/ASD patients and in their available affected/unaffected relatives.Automated Sanger sequencing of PITX2, FOXC1, PAX6 and CYP1B1 was performed; those patients without a PV were subsequently analyzed by Multiplex Ligation-dependent Probe Amplification (MLPA) for PITX2, FOXC1 and PAX6. Missense variants were evaluated with the MutPred, Provean, PMUT, SIFT, PolyPhen-2, CUPSAT and HOPE programs.We identified three novel PV in PITX2 (NM_153427.2:c.217GA, c.233TC and c.279del) and two in FOXC1 [NM_001453.2:c.274CT (novel) and c.454TA] in five ARS patients. The previously reported FOXC1 c.367CT or p.(Gln123*) variant was identified in a patient with ASD. The ocular phenotype related to FOXC1 included aniridia, corneal opacity and early onset glaucoma, while an asymmetric ocular phenotype and aniridia were associated with PITX2. No gene rearrangements were documented by MLPA analysis, nor were any PV identified in PAX6 or CYP1B1.Heterozygous PV in the PITX2 and FOXC1 genes accounted for 66% (6/9) of the ARS/ASD cases. The absence of PAX6 or CYP1B1 abnormalities could reflect our small sample size, although their analysis could be justified in ARS/ASD patients that present with congenital glaucoma or aniridia.

Non-invasive procedures for prenatal diagnosis are the most frequently used methods in the first trimester of pregnancy in pregnant women under 35 years of age because they do not involve risk of pregnancy loss; however, they are not considered to be a definitive diagnosis method. During the first trimester the duo test (PAPP-A and free βhGC), cell-free fetal DNA in maternal blood and structural ultrasound scans are the principal tools used; the quadruple marker test (αFP, E3, β-hCG, inhibin A) is used in the second trimester. However, the definitive diagnosis is performed by cytogenetic analysis through amniocentesis. Methods Thirty women, under 35 years of age with high-risk pregnancy, were studied with duo test and structural ultrasound in the first trimester and amniocentesis in weeks 15–18. Results Only five duo tests were positive: three showed risk of trisomy 18 and one of Turner syndrome, they all corroborated with the cytogenetic study; the fifth showed a risk of Down's syndrome, however it was a chromosomally normal product. Three patients with a negative duo test cytogenetically detected with karyotypes with structural abnormalities, which were: deletion of the short arm of chromosome 18 [46,XY, del(18)(p11)], Robertsonian translocation between chromosome 13 and 14 [45,XY, rob(13:14)] and a chromosome derived from X [46,X, der(X)]. The duo test is a very useful tool for the diagnosis of numerical chromosome abnormalities, but not for detecting structural chromosome aberrations. However, it is essential to perform amniocentesis to definitively rule out chromosomal aberrations in products of conception.

Background Sensorineural hearing loss (SNHL) is a clinically and genetically heterogeneous disease. In some populations, c.365delG mutation in the GJB2 gene represents the most frequent cause of hereditary SNHL. The great diversity of mutations in the GJB2 gene worldwide highlights the participation of ethnic background in SNHL. Objective To describe the presence of homozygous c.del35G mutation in the GJB2 gene in a Mexican family with SNHL. Materials and methods A Mexican family with SNHL was included in the study. Analysis of the GJB2 gene was performed through whole exome sequencing (WES) and DNA direct sequencing analysis in all members of the family and in 100 normal controls Results Affected sibs showed the homozygous c.del35G mutation in the GJB2 gene. Parents of the families were heterozygous for the molecular defect and had normal audition. Conclusion We describe a homozygous c.del35G mutation in the GJB2 gene through WES analysis, a homozygous mutation with a very low occurrence in Mexican population.

Background Cytochrome P450 2C9 (CYP2C9) is an important enzyme in the metabolism of many drugs, including NSAIDs, antidepressants and anticoagulants. In vitro and in vivo studies have demonstrated that CYP2C9 polymorphisms modify the activity of the enzyme and subsequently the metabolism of different drugs. Objective To characterize the diclofenac pharmacokinetics in healthy subjects with the wild type form of CYP2C9 genotype. Methods Twenty five healthy women were included in the study; a single dose of diclofenac (50 mg) was administered orally. Pharmacokinetic analyses at 12 different times were performed. DNA was extracted from peripheral blood and analyzed through direct sequencing. The CYP2C9*1/*1 allele was found in all subjects. Using the AUC 0-inf parameter, we classified the 25 volunteers as poor, intermediate and extensive metabolizer (2285.421/3217.442/4637.450, respectively). We detected statistical significant differences between the groups, especially between poor metabolizers versus intermediate and extensive metabolizers. Conclusions This data indicate that CYP2C9 is not the only enzyme responsible of the metabolism of diclofenac, so it is important to analyze other cytochromes and their variants potentially involved in the metabolism of this drug.

Mitochondria both produce the energy of the cell as ATP via respiration and regulate cellular metabolism. Accordingly, any deletion or mutation in the mitochondrial DNA (mtDNA) may result in a disease. One of these diseases is Kearns Sayre syndrome (KSS), described for the first time in 1958, where different large-scale deletions of different sizes and at different positions have been reported in the mitochondrial genome of patients with similar clinical symptoms. In this study, sequences of the mitochondrial genome of three patients with clinic features of KSS were analyzed. Our results revealed the position, heteroplasmy percentage, size of deletions, and their haplogroups. Two patients contained deletions reported previously and one patient showed a new deletion not reported previously. These results display for the first time a systematic analysis of mtDNA variants in the whole mtDNA genome of patients with KSS to help to understand their association with the disease.

Craniofrontonasal syndrome (CFNS) is a rare genetic entity with X-linked dominant inheritance. CFNS is due to mutations in the Ephrin-B1 (EFNB1) gene. It is characterized by brachycephaly, frontonasal dysplasia, palate/lip defects, dental malocclusion, short neck, split nails, syndactyly, toe and finger defects, and minor skeletal defects. Intelligence is usually unaffected. CFNS exhibits unexpected manifestations between males and females as the latter are more affected. Cellular or metabolic interference due to X inactivation explains the more severe phenotype in heterozygous females. One family with several members affected with CFNS and 100 healthy controls were examined. DNA from leukocytes was isolated to analyze the EFNB1 gene. We did molecular modeling to assess the impact of the mutation on the EFNB1-encoded protein. DNA sequencing analysis of the EFNB1 gene of the affected members showed the heterozygous missense mutation c.451G>A in the EFNB1 gene (GRcH38, chrX: 68,839,708; GERP score in hg38 of 9.961). This transition mutation resulted in the substitution of Gly at position 151 by Ser. Analysis of the healthy members of the family and 100 unrelated controls showed a normal sequence of the EFNB1 gene. Phenotypes of the patients in this family differ from the classical CFNS due to the decreased size of sulci and fissures, subarachnoid space and ventricles, and the absence of a cleft lip/palate.

Congenital cataract, an important cause of reversible blindness, is due to several causes including Mendelian inheritance. Thirty percent of cataracts are hereditary with participation of the gamma crystallin genes. Clinical and genetic heterogeneity is observed in patients with gene mutations and congenital cataract; about 40 genetic loci have been associated with hereditary cataract. In this study, we identified the underlying genetic cause of an autosomal dominant pulverulent cataract (ADPC) in a large Mexican family. Twenty-one affected patients and 20 healthy members of a family with ADPC were included. Genomic DNA was analyzed by whole exome sequencing in the proband, a normal daughter, and in an affected son, whereas DNA Sanger sequencing was performed in all members of the family. After the bioinformatics analysis, all samples were genotyped using Sanger sequencing to eliminate variants that do not cosegregate with the cataract. We observed a perfect cosegregation of a nonsense mutation c.475C>T (p.Q155*) in exon 6 of the CRYBB2 gene with ADPC. We calculated a logarithm of the odds score of 5.5. This mutation was not detected in healthy members of the family and in 100 normal controls. This is the first Mexican family with ADPC associated with a p.Q155* mutation. Interestingly, this specific mutation in the CRYBB2 gene seems to be exclusively associated with pulverulent/cerulean cataract (with some clinical variability) independent of the population's genetic background.

Introduction and Objectives: Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in children and it is more prevalent in Hispanic males. The gender differences can be explained by body fat distribution, lifestyle, or sex hormone metabolism. We evaluated anthropometric and metabolic differences by gender in children with and without NAFLD. Methods: We included 194 participants (eutrophic, overweight, and individuals with obesity). The presence of NAFLD was determined using ultrasonography, and we evaluated the association between this disease with metabolic and anthropometric variables by gender. Results: The mean age was 10.64 ± 2.54 years. The frequency of NAFLD in boys was 24.51% and in girls was 11.96% (OR = 2.39; 95%CI = 1.10–5.19; p = 0.025). For girls, NAFLD was significantly associated with triglycerides (p = 0.012), homeostatic model assessment of insulin resistance (HOMA-IR) (p = 0.048), and the visceral adiposity index (VAI) (p = 0.024). The variables related to NAFLD in a gender-specific manner were body mass index (BMI) (p = 0.001), waist circumference (WC) (p

The proband in this study was a 4-year-old Mexican girl with Blau syndrome. She and her affected family members had skin rash and arthritis but no uveitis. Exome sequencing and DNA direct sequencing from blood samples revealed a novel nucleotide-binding oligomerization domain-containing protein 2 gene mutation in the affected family members. This study is the first report of a Mexican family with Blau syndrome showing good infliximab treatment response. The novel mutation in the nucleotide-binding oligomerization domain-containing protein 2 gene (c.1808A>G) enriches the mutation spectrum in Blau syndrome. This family represents one of the few cases of autosomal Blau syndrome with no uveitis; because of phenotype variability, it is important to recognize Blau syndrome's clinical spectrum and recommend genetic consultation.

Rearrangements of the distal region of 9p are important chromosome imbalances in human beings. Trisomy 9p is the fourth most frequent chromosome anomaly and is a clinically recognizable syndrome. Kleefstra syndrome, previously named 9q subtelomeric deletion syndrome, is either caused by a submicroscopic deletion in 9q34.3 or an intragenic mutation of EHMT1. We report a Mexican male patient with abnormal development, dysmorphism, systemic anomalies and a complex chromosomal rearrangement (CCR). GTG-banding revealed a 46,XY,add(9)(q34.3) karyotype, whereas array analysis resulted in arr[hg19] 9p24.3p23(203,861-11,842,172)×3, 9q34.3(138,959,881-139,753,294)×3, 9q34.3(139,784,913-141,020,389)×1. Array and karyotype analyses were normal in both parents. Partial duplication of 9p is one of the most commonly detected autosomal structural abnormalities in liveborn infants. A microdeletion in 9q34.3 corresponds to Kleefstra syndrome, whereas a microduplication in 9q34.3 shows a great clinical variability. Here, we present a CCR in a patient with multiple congenital anomalies who represents the first case with partial 9p trisomy, partial 9q trisomy and partial 9q monosomy.

Background Hereditary sensorineural hearing loss (SNHL) is a genetically heterogeneous disorder worldwide. Mutations in the GJB2 gene are a frequent cause of hereditary SNHL. There is a prevalence of certain mutations in various populations which suggests that specific mutations may be influenced by ethnic background. Objective To analyze the prevalence of GJB2 , GJB6 mutations in several geographic areas of Mexico in patients with hereditary SNHL. Materials and methods One hundred and forty Mexican unrelated propositi with prelingual SNHL were included in the study. All patients had three previous generations born in Mexico and belonged to no specific ethnic group. Analyses of the GJB2 and GJB6 genes and mt.1555A Results Twenty-three homozygous mutations, 57 heterozygous mutations, 1 double heterozygous ( GJB2 / GJB6 ) and 59 wild-type genotypes in the GJB2 gene were observed. Three patients had the homozygous c.del35 mutation whereas 26 patients were heterozygous for this gene defect. Only one patient with the GJB6 gene deletion was present (it includes the double heterozygous GJB2 / GJB6 ). The mt.1555A > G mutation was not detected. Conclusion We found a great variety of mutations depending on the analyzed region in patients with SNHL; 57.86% of patients had affection in one or two alleles in GJB2 or GJB6 genes whereas 42.14% were wild-type. In some cases, allele distribution depended on region. Molecular studies of more genes involved in hereditary non-syndromic SNHL are required to completely confirm the molecular basis of hearing loss in Mexican population.

Microdeletions of the long arm of chromosome 13 lead to a characteristic facial appearance with systemic affection; 13q deletion shows a wide phenotypic spectrum that varies with respect to the location and size of the deletion region. The main clinical features are mental retardation, growth retardation, craniofacial dysmorphy and various congenital defects. In the present study we describe the case of an adult female of Mexican origin with microcephaly, facial dysmorphism, short stature, hand anomalies and normal intelligence associated with a de novo 13q31.3-q32.1 microdeletion that involved several genes including the MIR17HG and the GPC5 genes.

Background Haematologic malignancies are generated by alterations in haematopoietic stem cells. Chromosomal rearrangements are present in >50% of patients and are useful as diagnostic and prognostic factors. Objective In this study we describe the cytogenetic characteristics observed in patients with haematological malignancies in the Genetics Department during the period 2000–2014. Material and Methods The karyotype was performed on bone marrow (85%) and peripheral blood (15%) with conventional techniques in 9717 samples. Results The average age was 40 years (range 0.3–95) and the male/female distribution was 50.5%/49.5%. 352 cases (3.6%) were paediatric with a male/female distribution of 59/41%. The diagnosis was: acute leukaemia 4445 (45.7%), CML 2058 (20.4%), and MDS or some form of cytopenia 1573 (16%). Fewer than 5% of samples received were from AA, MM, CMPD, NHL, CLL, LPD and others. The distribution of acute leukaemia was: ALL 44%, AML 43% and unspecified 13%; the predominant subtypes were ALL-L2 at 50.7% and AML-M3 at 54.2%. Only 61% of the 9717 samples were processed. The karyotype was normal in 3956 (66.7%) samples, the rest (1972, 33.3%) had chromosomal abnormalities: 65% structural and 35% numerical. The changes observed most frequently were t(9;22)(q34;q11) 26%, hyperdiploidy/polyploidy 19.3%, diverse translocations 8.4%, hypodiploidy 8%, t(15;17)(q22;q12) 7.8%, and MDS-related disorders (del5q/-5/-7/+8) 7.7%. Different deletions, trisomy, monosomy and/or complex karyotype were present in smaller proportion ( Conclusions The karyotype remains useful to confirm the diagnoses, establish risk-based prognoses, and classify based on risk to patients; for example in cases with t(9;22) in CML or t(15;17) in M3.

Mucopolysaccharidosis type II (MPS II) or Hunter syndrome is an inborn error of metabolism due to lysosomal accumulation, with a recessive inheritance pattern linked to the X chromosome. It is caused by a deficiency in the activity of the lysosomal enzyme iduronate-2-sulfatase encoded by the IDS gene. Iduronate-2-sulphatase enzyme activity in plasma was measured and the IDS gene was analysed in genomic DNA by automated direct sequencing. Enzyme activity was 1.2 μmol/l/h (reference value: >2 μmol/l/h), while the molecular analysis detected the mutation c.1403G>A (p.R468Q), confirming the diagnosis of MPS II. In conclusion, since here in Mexico there are few groups dedicated to this family of diseases, we must emphasise the need to keep up to date and create expert teams of doctors and scientists specialised in inborn errors of metabolism.

Epidermolytic palmoplantar keratoderma (EPPK), an autosomal-dominant genodermatosis, is the most frequently occurring hereditary palmoplantar keratoderma. EPPK is characterized by hyperkeratosis of the palms and soles. Approximately 90% of patients present with mutations in the KRT9 gene, which encodes for keratin 9. Many of these mutations are located within the highly conserved coil 1A region of the alpha-helical rod domain of keratin 9, an important domain for keratin heterodimerization. The objective was to assess the clinical and molecular characteristics of a Mexican family with EPPK. The clinical characteristics of members of this family were analyzed. The KRT9 gene of affected members was polymerase chain reaction amplified from genomic DNA and sequenced. All affected members of the family had hyperkeratosis of the palms and soles with knuckle pads. The R163W mutation in the KRT9 gene was present in all affected individuals who were tested. Although R163W is the most frequent KRT9 mutation in patients with EPPK, only two families have been reported with knuckle pads associated with this mutation. Our findings indicate that knuckle pads can be associated with EPPK and the R163W mutation in a family with a genetic background different from that described here.

Complete monosomy mosaic of chromosome 21 is a rare disorder. The syndromic features are highly variable. This study describes a girl of Mexican origin with complete monosomy 21 in mosaicism with novel findings, including cortical atrophy, macrostomia, pectum excavatum and immune deficiencies. Parental karyotypes were normal. FISH analysis with probes from 21q22.1-q22.2 region and centromere of X DNA probe was performed on peripheral blood lymphocytes whereas 21q22.1-q22.2 and 21q, 4p, 4q subtelomeric DNA probes were tested in fibroblasts. We propose that the monosomy 21 mosaicism is the cause of the survival of children with more than 4 months of age.

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.

Background Pycnodysostosis, an autosomal recessive skeletal dysplasia, is characterized by short stature, osteosclerosis, delayed cranial suture closure, hypoplastic mandible, acro-osteolysis, hypoplastic clavicle, and dental anomalies. The disorder is caused by CTSK gene defects, a gene localized on 1q21. Purpose To describe the clinical, radiological, and molecular findings in a family with pycnodysostosis. Methods The CTSK gene was analyzed from genomic DNA in a nonconsanguinity Mexican family with 3 affected members with pycnodysostosis and 100 healthy controls. Results and Interpretation We identified the novel homozygous mutation c.908G>A within exon 8 of the CTSK gene. This missense mutation leads to the substitution of the amino acid glycine at position 303 by glutamic acid (G303E) in cathepsin K protease. No genotype/phenotype correlation was present in affected members of the family with pycnodysostosis.

Satoyoshi syndrome (SS) (OMIM 600705) is a rare multisystemic disorder of unknown etiology characterized by progressive painful intermittent muscle spasm, alopecia universalis, diarrhea, short stature, amenorrhea, and secondary skeletal abnormalities mimicking a metaphyseal chondrodysplasia. To date all reported cases have been sporadic. We describe a 26-year-old Mexican woman, a product of consanguineous parents with clinical characteristics of SS. Our patient, also showed skeletal anomalies not previously reported that seems to be a coincidental finding.

Summary Background X-linked ichthyosis (XLI), an inborn error of metabolism, is due to steroid sulphatase (STS) deficiency. Most patients with XLI harbour complete deletion of the STS gene and flanking sequences. The presence of low copy number repeats on either side of the STS gene seems to have a major role in the high frequency of these deletions. Some patients with XLI with terminal deletions of Xp22.3 involving marker DXS1139 and the STS gene show mental retardation (MR); VCX3A is the only gene located on this critical region. Objectives To analyse the VCX3A, VCX, VCX2 and VCX3B genes in 80 unrelated Mexican patients with XLI with normal intelligence. Methods STS activity was measured in the leucocytes using 7-[3H]-dehydroepiandrosterone sulphate as a substrate. Amplification of the regions from telomeric DXS89 to centromeric DXS1134 including both extremes of the STS and the VCX3A, VCX, VCX2 and VCX3B genes was performed using polymerase chain reaction. Results No STS activity was detected in the patients with XLI (0·00 pmol mg−1 protein h−1). We observed two different deletion patterns: the first group included 62 patients with deletion of VCX3A and VCX genes. The second group included 18 patients with breakpoints at several regions on either side of the STS gene not including the VCX3A gene. Conclusions These data indicate that more complex mechanisms, apart from possible VCX3A gene participation, are occurring in the genesis of MR in XLI, at least in the sample of Mexican patients analysed.

Jacobsen syndrome (JBS) is an uncommon contiguous gene syndrome. About 85-92% of cases have a de novo origin. Clinical variability and severity probably depend on the size of the affected region. The typical clinical features in JBS include intellectual disability, growth retardation, craniofacial dysmorphism as well as craniosynostosis, congenital heart disease, and platelet abnormalities. The proband was a 1 year/3-month-old Mexican male. Oligonucleotide-SNP array analysis using the GeneChip Human Cytoscan HD was carried out for the patient from genomic DNA. The SNP array showed a 14.2-Mb deletion in chromosome 11q23.3q25 (120,706-134,938 Mb), which involved 163 RefSeq genes in the database of genomic variation. We report a novel deletion in JBS that increases the knowledge of the variability in the mutation sites in this region and expands the spectrum of molecular and clinical defects in this syndrome.

Background: Mutations and polymorphisms have been identified in the CYP1B1 gene; while mutations that affect the conserved core structures of cytochrome P4501B1 result in primary congenital glaucoma (PCG), mutations in other regions hold the potential to define differences in estrogen metabolism. In the present study, we analyzed the CYP1B1 gene in Mexican patients with PCG and described four novel mutations. Materials and Methods: The sample included 12 nonrelated cases with PCG. Analysis of coding regions of the CYP1B1 gene was performed through PCR and DNA sequencing analysis from genomic DNA. Results and Discussion: Molecular analysis of the CYP1B1 gene showed the following molecular defects: (1) a novel single-base pair deletion within codon 370 (1454delC) that produces a substitution of leucine instead of proline and a premature stop codon 57 amino acids after the last original amino acid; this family also harbored a novel polymorphic variant of the cytochrome P4501B1 with six single-nucleotide polymorphisms (142C→G; 355G→T; 729G→C; 4326C→G; 4360C→G and 4379C→T); (2) a novel single-base pair deletion within codon 277 (1176delT) that results in a premature stop codon; (3) a novel single-base pair deletion within codon 179 (880delG) that produces a substitution of arginine instead of alanine and a premature stop codon 17 amino acids downstream from the last original amino acid, and (4) a duplication (or insertion) of ten base pairs within codon 404 (1556dupATGCCACCAC) that results in a premature stop codon 26 amino acids after the last original amino acid. We also observed in 2 nonrelated patients a deletion of 13 bp (1410_1422delGAGTGCAGGCAGA) previously reported for other populations. Conclusion: We reported four novel mutations and a novel polymorphic variant in the CYP1B1 gene in PCG in the Mexican population; it has important implications in diagnosis and genetic counseling.

Purpose: To describe the molecular defects in the Norrie disease protein (NDP) gene in two families with Norrie disease (ND). Methods: We analysed two families with ND at molecular level through polymerase chain reaction, DNA sequence analysis and GeneScan. Results: Two molecular defects found in the NDP gene were: a missense mutation (265C > G) within codon 97 that resulted in the interchange of arginine by proline, and a partial deletion in the untranslated 3′ region of exon 3 of the NDP gene. Clinical findings were more severe in the family that presented the partial deletion. We also diagnosed the carrier status of one daughter through GeneScan; this method proved to be a useful tool for establishing female carriers of ND. Conclusion: Here we report two novel mutations in the NDP gene in Mexican patients and propose that GeneScan is a viable mean of establishing ND carrier status.

Steroid sulfatase deficiency results in X-linked ichthyosis, an inborn error of metabolism in which the principal molecular defect is the complete deletion of the steroid sulfatase gene and flanking markers. Mosaicism for the steroid sulfatase gene has not yet been reported in X-linked ichthyosis. In this study we describe an X-linked ichthyosis patient with complete deletion of the steroid sulfatase gene and his mother with somatic and germinal mosaicism for this molecular defect. The family (X-linked ichthyosis patient, grandmother, mother, and sister) was analyzed through steroid sulfatase enzyme assay, polymerase chain reaction, DNA markers, and fluorescence in situ hybridization of the steroid sulfatase gene. Steroid sulfatase activity was undetectable in the X-linked ichthyosis patient, very low in the mother, and normal in the grandmother and sister. The X-linked ichthyosis patient showed a 2 Mb deletion of the steroid sulfatase gene and flanking regions from 5'DXS1139 to 3'DXF22S1. The mother showed one copy of the steroid sulfatase gene in 98.5% of oral cells and in 80% of leukocytes. The grandmother and sister showed two copies of the steroid sulfatase gene. The origin of the X chromosome with the deletion of the steroid sulfatase gene corresponded to the grandfather of the proband. We report the first case of somatic and germinal mosaicism of the steroid sulfatase gene in an X-linked ichthyosis carrier and propose DNA slippage as the most plausible mechanism in the genesis of this mosaicism.

The β adrenergic receptors (ADRB) are expressed in the ciliary body and trabecular meshwork, structures involved in aqueous humor production and outflow, respectively. ADRB are members of the adrenergic family of G-protein-coupled receptors. Topic β blockers have a good local and systemic tolerance; they reduce the aqueous humor production and eye strain blocking the ADRB of the ciliary body and interfering with adenylate cyclase. However, the ocular hypotensive response is not the same in all patients and could be mediated by the polymorphisms of the ADRB genes.Seventy-two healthy subjects were studied after treatment with topical betaxolol in both eyes. We analyzed ADRB1 and ADRB2 gene polymorphisms by PCR and automated DNA sequencing.There was statistically significant difference between baseline intraocular pressure (IOP) and final IOP of both eyes (baseline IOP 16.2 ± 1.2 - follow-up IOP 13.6 ± 2.0 (mean difference-2.5 ± 1.3, p 0.001). Gly389 had a higher baseline IOP than Arg389 (17.0 ± 1.2 mmHg versus 16.0 ± 1.2 mmHg; p = 0.02), and conversely Arg389 had a greater magnitude of response than Gly389 to betaxolol therapy (-2.9 ± 1.1 mmHg versus -0.7 ± 0.4 mmHg; p 0.001). Gln27 had a higher response than Glu27 (-2.7 ± 1.3 mmHg versus -1.9 ± 1.0; p = 0.02).Arg389 polymorphism of the ADRB1 gene and Gln27 polymorphism of the ADRB2 gene were associated with the hypotensive response to topic betaxolol in healthy Mexican volunteers.

Purpose To report discordant retinoblastoma in monozygotic twins, confirmed by GeneScan. Methods One twin presented unilateral retinoblastoma that was treated with enucleation; the other twin had no retinoblastoma. To confirm monozygosity, DNA from leukocytes was analyzed through GeneScan with highly polymorphic markers; to exclude 13q14 deletion, FISH analysis was performed in leukocytes and oral cells of both twins and their parents and in retinal tissue of the affected twin with the cDNA LSI RB1 probe. Results GeneScan analysis confirmed monozygosity. 13q14 deletion was observed in homozygous state in retinal tissue and in heterozygous state in oral cells and leukocytes of the affected twin. The nonaffected twin and parents showed no deletion of 13q14. Conclusions These data show unexpected differences in monozygotic twins that could be explained by postzygotic events in embryonic development.

X-linked ichthyosis (XLI) is an inherited disorder due to steroid sulfatase deficiency (STS). Most XLI patients (>90%) have complete deletion of the STS gene and flanking sequences. The presence of low copy number repeats (G1.3 and CRI-S232) on either side of the STS gene seems to play a role in the high frequency of these interstitial deletions. In the present study, we analyzed 80 Mexican patients with XLI and complete deletion of the STS gene. STS activity was measured in the leukocytes using 7-[3H]-dehydroepiandrosterone sulfate as a substrate. Amplification of the regions telomeric-DXS89, DXS996, DXS1139, DXS1130, 5′ STS, 3′ STS, DXS1131, DXS1133, DXS237, DXS1132, DXF22S1, DXS278, DXS1134-centromeric was performed through PCR. No STS activity was detected in the XLI patients (0.00 pmoles/mg protein/h). We observed 3 different patterns of deletion. The first two groups included 25 and 32 patients, respectively, in which homologous sequences were involved. These subjects showed the 5′ STS deletion at the sequence DXS1139, corresponding to the probe CRI-S232A2. The group of 32 patients presented the 3′ STS rupture site at the sequence DXF22S1 (probe G1.3) and the remaining 25 patients had the 3′ STS breakpoint at the sequence DXS278 (probe CRI-S232B2). The third group included 23 patients with the breakpoints at several regions on either side of the STS gene. No implication of the homologous sequences were observed in this group. These data indicate that more complex mechanisms, apart from homologous recombination, are occurring in the genesis of the breakpoints of the STS gene of XLI Mexican patients.

Summary Background & aims People with the highest risk of iron deficiency are infants, teenagers and pregnant women. Iron deficiency has negative effects on physical and psychomotor development and has high impact on the productive life and on the development of a country. The aim of this study was to determine iron state in healthy six-month-old infant Mexican patients. Methods The analysis was held in 205 subjects in an observational and descriptive study. We included infants at term with good health, no acute or chronic diseases at least in the 4 previous weeks and with any type of feeding. We evaluated the birth weight, gain weight and iron status of infants at the age of six months. Laboratory studies included blood hemoglobin (Hb), mean cell volume (MCV), red blood cell distribution width (RDW), transferrin saturation (TS) and ferritin. Results Birth weight and gain weight were acceptable in 94.1%. Iron deficiency was detected in 44.9% and anaemia secondary due to iron deficiency was present in 19.5%. Multiple linear regression analysis showed that exclusive breast-fed correlated with iron deficiency (rp = −0.167, p Conclusions High prevalence of iron deficiency and secondary anaemia, two important public health problems, were present in children during the first months of life in the analyzed sample.

BACKGROUND AND OBJECTIVE Kallmann's syndrome (KS) is characterized by hypogonadotrophic hypogonadism in association with anosmia or hyposmia. This entity can be associated with X-linked ichthyosis (XLI) in a contiguous gene syndrome. Genetic defects have been demonstrated on the Xp22.3 region explaining the presence of one or both entities in affected individuals. In this report we describe the molecular findings in four patients, pertaining to a three generation family, with KS which was associated with XLI in two of them. MEASUREMENTS Enzymatic activity of steroid sulphatase was measured in leucocytes. Polymerase chain reaction of the 14 exons of the Kallmann gene (KAL) and of the 5' and 3' extremes of the steroid sulphatase gene was performed in genomic DNA. PCR products of the 14 exons of the KAL gene were purified and sequenced. RESULTS Absence of steroid sulphatase activity and a complete deletion of the STS gene were demonstrated in both patients with XLI. In all subjects, the 14 KAL gene exons amplified in a normal fashion; no mutation was documented after sequencing all exons. CONCLUSIONS Although it has been proposed recently that the X-linked form of the disease accounts for the minority of patients with Kallman's syndrome, the pedigree chart of this family demonstrates this inheritance pattern. Various possibilities are mentioned in order to explain the absence of mutation in the KAL gene. The coexistence, in this family, of Kallman's syndrome individuals and patients with Kallman's syndrome and X-linked ichthyosis is discussed.

OBJECTIVE Large terminal or interstitial deletions of the 22.3 region on the short arm of the X chromosome cause contiguous gene syndromes. Kallmann syndrome (hypogonadotrophic hypogonadism with anosmia or hyposmia) associated with X-linked ichthyosis, due to a contiguous gene syndrome, is an uncommon finding. Genetic defects have been demonstrated in the Xp22.3 region, explaining the presence of one or both entities in affected individuals. In this report we describe the molecular findings of a patient with Kallmann syndrome and X-linked ichthyosis. PATIENT A 20-year-old subject with hypogonadism, anosmia and generalized ichthyosis was studied endocrinologically, biochemically and molecularly. MEASUREMENTS Levels of LH, FSH, GH, testosterone, oestradiol and cortisol were determined basally and after specific stimulation tests. Enzymatic activity of steroid sulphatase was measured in leucocytes. Polymerase chain reaction of the 14 exons of the Kallmann gene and of the 5' and 3' extremes of the steroid sulphatase gene was performed in genomic DNA. RESULTS A partial deletion from exon 1 to exon 3 of the Kallmann gene, as well as a complete deletion of the steroid sulphatase gene were observed. CONCLUSIONS A patient bearing a contiguous gene syndrome with partial deletion of the Kallmann syndrome gene and complete deletion of the steroid sulphatase gene is described. This is the first time a mutation in the conserved cysteine-rich N-terminal region which corresponds to the whey acidic protein motif of the Kallmann gene has been characterized, thus demonstrating the importance of this specific region for the function of the gene.

Pycnodysostosis (OMIM # 265800) is an inherited lysosomal disorder due to affection of cathepsin K gene, localised to 1q21. Pycnodysostosis can present with both skeletal and extraskeletal features. The index patient presented with cardinal features of short stature, dental and digital anomalies with history of multiple fractures. He, in addition had an unreported finding of white matter hyperintensity suggesting dysmyelination on neuroimaging. Molecular analysis revealed a homozygous insertion of single nucleotide in exon 5 of the CTSK gene that produces the substitution of phenylalanine instead of leucine at position 160 of protein and a premature termination of protein synthesis due to insertion of a stop codon. This mutation (c.480_481insT), (p.L160fsX173) is a novel frameshift mutation. The index case extends the phenotypic spectrum and the list of previously reported mutations in the CTSK gene.

Purpose To describe at molecular level a family with pulverulent congenital cataract associated with a CRYGC gene mutation. Methods One family with several affected members with pulverulent congenital cataract and 230 healthy controls were examined. Genomic DNA from leukocytes was isolated to analyze the CRYGA - D cluster, CX46, CX50 and MIP genes through high-resolution melting curve and DNA sequencing. Results DNA sequencing in the affected members revealed the c.143G>A mutation (p.R48H) in exon 2 of the CRYGC gene; 230 healthy controls and ten healthy relatives were also analyzed and none of them showed the c.143G>A mutation. No other polymorphisms or mutations were found to be present. Conclusion In the present study, we described a family with pulverulent congenital cataract that segregated the c.143G>A mutation (p.R48H) in the CRYGC gene. A few mutations have been described in the CRYGC gene in autosomal dominant cataract, none of them with pulverulent cataract making clear the clinical heterogeneity of congenital cataract. This mutation has been associated with the phenotype of congenital cataract but also is considered an SNP in the NCBI data base. Our data and previous report suggest that p.R48H could be a disease-causing mutation and not an SNP.

Mutations in the WNK1/HSN2 (with-no-lysine(K)-1/ hereditary sensory neuropathy 2) gene cause autosomal recessive HSAN2 [1, 2]. HSAN2, an early onset ulceromutilating sensory neuropathy, is clinically characterized by impairment of pain, temperature, and touch sensation. Other characteristics are loss of tendon reflexes, finger ulcers, frequent amputations and virtual absence of myelinated fibers with decreased numbers of unmyelinated fibers in sural nerves [3]. The HSN2, located on 12p13.33, is a nervous systemspecific exon of WNK1 and is referred to as the WNK1/ HSN2 isoform. WNK1/HSN2 encodes a polypeptide of 434 amino acids with a high expression in dorsal root ganglia and sciatic nerves [1, 2]. Apart from HSN2 mutations, a compound heterozygous mutation in exon 6 of WNK1 and in HSN2 [2] and mutations in FAM134B (family with sequence similarity 134, member B) [4] have been identified in HSAN2 demonstrating locus heterogeneity. In the present study, we analyzed two Mexican families with HSAN2 and identified a novel mutation in the WNK1/ HSN2 gene. We evaluated four out of five patients with HSAN2 and 16 healthy members belonging to two families. Family pedigrees are described in Fig. 1 and clinical characteristics are shown in Table 1. Clinical pictures and CT are shown in Fig. 2. Both families came from Chiapas (southeast of Mexico) of distant communities (Ocosingo and San Cristobal de las Casas). Careful examination of heterozygous carriers showed no clinical manifestations. Genomic DNA was extracted from 20 family members and 150 normal controls using standard techniques [5]. The WNK1/HSN2 gene was amplified through PCR [1] and directly sequenced using an ABI Prism Genetic Analyzer (Applied Biosystems, Foster City, CA, USA.) under the supplier’s conditions. All procedures were repeated twice. All members were informed about the characteristics of the study and they agreed to participate. We identified a homozygous mutation in WNK1/HSN2 in affected members of the two HSAN2 families. This mutation is a deletion of eight nucleotides (c. 1219_1226 delTCTCAGCA, NM 213655) that causes a novel stop codon 26 nucleotides after the original stop codon (S407fsX442) (Fig. 1). This mutation was not found in 150 normal controls and healthy members of the family, so we discarded a possible polymorphism. Subjects I1, I2, and III9 from family B were heterozygous with no clinical manifestations. Several mutations in WNK1/HSN2 have been identified among several populations: in Canada E198fs207, S307fsX319, Q315X; in Italy P85fsX98, G. Pacheco-Cuellar L. M. Gonzalez-Huerta J. M. Valdes-Miranda S. A. Cuevas-Covarrubias (&) Servicio de Genetica, Hospital General de Mexico, Facultad de Medicina, Universidad Nacional Autonoma de Mexico, Dr. Balmis 148, Col. Doctores, C.P. 06726 Mexico City, DF, Mexico e-mail: sercuevas@yahoo.com; sergioa@servidor.unam.mx

X-linked ichthyosis is an inherited disorder due to steroid sulfatase deficiency. It is clinically characterized by dark, adhesive, and regular scales of the skin. Most X-linked ichthyosis patients present large deletions of the STS gene and flanking markers; a minority show a point mutation or partial deletion of the STS gene. In this study we analyzed the STS gene in a family with simultaneous occurrence of X-linked ichthyosis and ichthyosis vulgaris. X-linked ichthyosis diagnosis was confirmed through steroid sulfatase assay in leukocytes using 7-[ 3 H]-dehydroepiandrosterone sulfate as a substrate. Exons 1, 2, 5, and 6–10, and the 5′ flanking markers DXS1130, DXS1139, and DXS996 of the STS gene were analyzed by polymerase chain reaction. X-linked ichthyosis patients of the family (n = 4 males) had undetectable levels of STS activity (0.00 pmol per mg protein per h). The DNA analysis showed that only exons 6–10 and the 5′ flanking markers of the STS gene were present. We report the first partial deletion of the STS gene spanning exons 1–5 in X-linked ichthyosis patients.

X-linked ichthyosis (XLI) is an inborn error of metabolism due to steroid sulfatase (STS) deficiency. STS assay and FISH are useful in diagnosing carrier status of XLI. Biochemical analysis appears to indicate that most sporadic cases are inherited. Since this method does not seem to be completely reliable in recognizing XLI-carriers, the aim of the present study was to corroborate by FISH whether or not most sporadic cases of XLI had de novo mutations. XLI patients were classified through STS assay and PCR amplification of 5'-3' ends of the STS gene. XLI patients had undetectable levels of STS activity and complete deletion of the STS gene. Patients' mothers were studied through STS assay and FISH. Nine out of 12 mothers presented an STS activity compatible with XLI-carrier state. These mothers also had only one copy of the STS gene, indicating that they carry the primary gene defect. One mother had normal STS activity but only one copy of the STS gene. This data corroborated that most sporadic cases do not represent de novo mutations, and that FISH must be included in the analysis of mothers of sporadic cases when they present with normal STS activity, in order to correctly diagnose the XLI carrier state.

Objective. To describe the case of a pregnant woman and her fetus with Noonan syndrome (NS) whom were diagnosed through ultrasonography 3D and molecular analysis of the PTPN11 gene.Study design. Case report.Results. We detected in a pregnant woman and her child the G

X-linked ichthyosis is an inherited disease due to steroid sulfatase deficiency. Onset is at birth or early after birth with dark, regular, and adherent scales of skin. Approximately 85%-90% of X-linked ichthyosis patients have large deletions of the STS gene and flanking sequences. Three patients have been identified with partial deletions of the gene. Two deletions have been found at the 3′ extreme and the other one implicating exons 2–5. This study describes a novel partial deletion of the STS gene in an X-linked ichthyosis patient. The subject was classified through steroid sulfatase assay in leukocytes using 7-[ 3 H]-dehydroepiandrosterone sulfate as a substrate. Exons 1, 2, 5, and 7–10, and 3′ flanking sequences DXS1131, DXS1133, DXS237, DXS1132, DXF22S1, and DXS278 of the STS gene were analyzed through polymerase chain reaction. The DNA analysis showed that exon 1 and 3′ flanking sequences from DXS237 to DXS278 were present. In this study we report the fourth partial deletion of the STS gene and the first spanning exons 2–10 in X-linked ichthyosis patients.

A 70-year-old male presented with very large, thick, tightly adherent, dark-brown scales on the front of his lower extremities. His face, neck, back, abdomen, upper extremities, flexural areas, palms and soles as well as hair and nails were not involved. Family history was negative for similar lesions. Otherwise, the patient had a normal development. Onset of symptoms occurred during childhood with scales on lower extremities with no more additional features. Treatment included emollients exclusively with partial and temporary remission of cutaneous lesions. Recently, the patient had not received topical or systemic medical treatment. Laboratory investigations were within normal limits. The patient had undetectable levels of STS activity when compared with normal control (0.00 pmol mg(-1) protein h(-1)) which confirmed the diagnosis of X-linked ichthyosis (XLI) . PCR analysis showed deletion of the STS gene, markers DXS1139 and DXF22S1and the 5' end of the VCX3A gene. The patient had scales present on lower extremities only with no medical treatment that corresponded to an unusual clinical manifestation of XLI. Clinical manifestations of XLI are due to a great variety of environmental, genetic and individual factors that should be considered in XLI diagnosis.