Clinical, molecular and biochemical characterization of nine Spanish families with Conradi-Hünermann-Happle syndrome: new insights into X-linked dominant chondrodysplasia punctata with a comprehensive review of the literature.

BACKGROUND: Conradi-Hünermann-Happle syndrome (CDPX2, OMIM 302960) is an inherited X-linked dominant variant of chondrodysplasia punctata which primarily affects the skin, bones and eyes. CDPX2 results from mutations in EBP (emopamil binding protein), and presents with increased levels of sterol precursors 8(9)-cholesterol and 8-dehydrocholesterol. OBJECTIVES: To expand the understanding of CDPX2, clinically, biochemically and genetically. METHODS: We present one of the largest series reported to date, including 13 female patients belonging to nine Spanish families. Patients were studied biochemically using gas chromatography-mass spectrometry, genetically using polymerase chain reaction and in their methylation status using the HUMARA assay. RESULTS: In our cases, there was a clear relationship between abnormal sterol profile and the EBP gene mutation. We describe three novel mutations in the EBP gene. EBP mutations were inherited in three out of nine families and were sporadic in the remaining cases. CONCLUSIONS: No clear genotype-phenotype correlation was found. Patients' biochemical profiles did not reveal a relationship between sterol profiles and severity of disease. A skewed X-chromosome inactivation may explain the clinical phenotype in CDPX2 in some familial cases.

[Molecular diagnosis of adult dominant polycystic kidney disease in the Canary Islands]. / Diagnóstico molecular de la Poliquistosis Renal Autosómica Dominante en la Comunidad Autónoma de Canarias.

Adult dominant polycystic kidney disease is an hereditary condition responsible for 6% of end-stage renal failure in Spain. Two genes were located in chromosomes 16 and 4 as related to this age-dependent disease in the 90s (PKD1 and PKD2). The diagnosis can be easily achieved by sonographic study, but molecular analysis by means of linkage analysis has the advantage of an early diagnosis in asymptomatic genetic carriers, with a view to the preventive follow-up of these subjects and genetic counselling. In this paper we present the results of molecular analysis of 30 families with Adult Dominant Polycystic Kidney Disease (from the province of Las Palmas Spain), carried out linkage analysis with two series of microsatellite markers located within or in the vicinity ofPKD1 (D16S521, KG8, AC2.5, CW2, SM7) and PKD2 (D4S1538, D4S1534, D4S423,D4S414) genes. The objectives of the study were: first, to verify the informativeness, and therefore, the usefulness of these markers for family studies in our population; and second,to assess the sensitivity and specificity of the genetic analysis in our population. Most of the markers showed a high heterozygosity, comparable to data in other studies. Considering the alleles of the different markers together in a chromosome as an haplotype increased the informativeness of the markers, and allowed the unequivocal identification of genetic data in 97.7% of patients and 88.7% of healthy subjects. The sensitivity and specificity of the genetic analysis were 90.7% (CI 95%: 85.7-95.7) and 86.8% (CI 95%: 80.6-93.0), respectively.

[Paroxysmal stereotypy-tic-dystonia syndrome]. / Síndrome de estereotipias tics distonía paroxística.

CASE REPORTS: We report the cases of four males from four different families, who presented paroxysmal episodes from the 1st 2nd year. These episodes were characterised by asymmetrical bilateral dystonia of the upper limbs, predominantly in both hands, and were associated with orofacial dyskinesias, stereotipies (jumping, arm flapping, etc.), facial tics and, occasionally, phonic tics. Consciousness is not affected in any of the cases. These movements are triggered in situations where the patient is relaxed or excited. They occur daily and last from a few seconds to 30 minutes. Between the bouts, they remain asymptomatic. Family cases suggest it is inherited by autosomal dominant transmission, perhaps linked to the X chromosome; in addition, two cases are sporadic. In the only adult, the movements progress to a series of rhythmic bilateral dystonic myoclonias and facial tics dyskinesias. All the studies carried out, EEG, hemogram, biochemical analysis, neuroimaging, copper and ceruloplasmin levels, were normal. CONCLUSIONS: 1. We report a non epileptic paroxysmal disorder originating in the extrapyramidal tracts with its own characteristics, with onset during early childhood, which is associated with stereotipies, tics and dystonia; 2. It occurs predominantly in males; 3. It is inherited by autosomal dominant transmission, or perhaps sex linked autosomal dominant inheritance, and there are also sporadic cases; 4. The range of clinical features is very wide and includes cases in which there are few symptoms to others where the extent and gravity of the disorder is very significant.

[Familial Pitt-Rogers-Danks: two new cases]. / Síndrome de Pitt-Rogers-Danks familiar: dos nuevos casos.

INTRODUCTION AND CLINICAL CASES: The Pitt Rogers Danks syndrome is characterized by prenatal and postnatal retardation of growth, mental retardation, microcephaly, convulsions and a peculiar facies. It is believed to represent a clinical variant of the Wolf Hirschhorn syndrome, since there is a deletion in the 4p16.3 region in both syndromes. We report two cases in the same family caused by maternal mal segregation of a 4:8 balanced translocation. We describe the clinical characteristics, investigations done and a review of the literature.

Detection of the fragile X syndrome protein for the evaluation of FMR1 intermediate alleles.

Molecular screening programs in mentally retarded individuals have been performed in several populations worldwide. One finding has been an excess of FMR1 intermediate alleles in a population with learning difficulties. However, other published reports with similar characteristics did not corroborate those previous results. In order to contribute additional data from our population, we studied 563 patients affected with nonspecific mental retardation (MRX) that did not present a CGG expansion in the FMR1 gene and 208 individuals as a control population. Forty MRX patients presented alleles within the intermediate range. Among them, one case showed a pattern of expression of the FMR1 protein (FMRP) concordant with a fragile X syndrome case with an intermediate allele/full mutation mosaicism, although it was not detected by Southern blot analysis. Statistical analysis was performed again showing no statistically significant difference regarding the intermediate allele frequency in the MRX and control populations. This finding is in agreement with the hypothesis that the incidence of intermediate FMR1 alleles in MRX populations does not seem to be higher than in control populations, and it emphasizes the importance of FMRP detection as a diagnostic tool for fragile X syndrome.