Interstitial deletions at 6q14.1q15 associated with developmental delay and a marfanoid phenotype.

There are a number of reports of interstitial deletions of the long arm of chromosome 6 that have developmental delay and obesity suggesting that this is a distinct phenotype almost like Prader-Willi syndrome. Here we report a patient with a similar deletion but a strikingly different phenotype, one more in keeping with Marfan syndrome, although he does not fulfil the criteria for that syndrome. Array comparative genomic hybridization was performed to investigate a patient with a striking phenotype. This revealed an interstitial deletion of 6q14.1q15. Parental FISH studies were normal, indicating that this is a de novo deletion. Our patient has a completely different phenotype compared to other patients reported to have similar deletions. The common feature is developmental delay, but the body features are quite different in that our patient is tall, strikingly thin with pectus excavatum, scoliosis, skin striae, arachnodactyly, pes planus, cataracts, and a high-arched palate. This contrasts with other patients who have a similar deletion but have short stature and obesity. 6q14.1q15 interstitial deletions can have a very variable phenotype and do not necessarily conform to a clinical recognizable microdeletion syndrome caused by haploinsufficiency of dosage-sensitive genes in that region as proposed by others.

Co-occurrence of Joubert syndrome and Jeune asphyxiating thoracic dystrophy.

Ciliary disorders share typical features, such as polydactyly, renal and biliary cystic dysplasia, and retinitis pigmentosa, which often overlap across diagnostic entities. We report on two siblings of consanguineous parents and two unrelated children, both of unrelated parents, with co-occurrence of Joubert syndrome and Jeune asphyxiating thoracic dystrophy, an association that adds to the observation of common final patterns of malformations in ciliary disorders. Using homozygosity mapping in the siblings, we were able to exclude all known genes/loci for both syndromes except for INVS, AHI1, and three genes from the previously described Jeune locus at 15q13. No pathogenic variants were found in these genes by direct sequencing. In the third child reported, sequencing of RPGRIP1L, ARL13B, AHI1, TMEM67, OFD1, CC2D2A, and deletion analysis of NPHP1 showed no mutations. Although this study failed to identify a mutation in the patients tested, the co-occurrence of Joubert and Jeune syndromes is likely to represent a distinct entity caused by mutations in a yet to be discovered gene. The mechanisms by which certain organ systems are affected more than others in the spectrum of ciliary diseases remain largely unknown.

FOXL2 copy number changes in the molecular pathogenesis of BPES: unique cohort of 17 deletions.

Blepharophimosis Syndrome (BPES) is an autosomal dominant developmental disorder of the eyelids with or without ovarian dysfunction caused by FOXL2 mutations. Overall, FOXL2deletions represent 12% of all genetic defects in BPES. Here, we have identified and characterized 16 new and one known FOXL2 deletion combining multiplex ligation-dependent probe amplification (MLPA), custom-made quantitative PCR (qPCR) and/or microarray-based copy number screening. The deletion breakpoints could be localized for 13 out of 17 deletions. The deletion size is highly variable (29.8 kb - 11.5 Mb), indicating absence of a recombination hotspot. Although the heterogeneity of their size and breakpoints is not reflected in the uniform BPES phenotype, there is considerable phenotypic variability regarding associated clinical findings including psychomotor retardation (8/17), microcephaly (6/17), and subtle skeletal features (2/17). In addition, in all females in whom ovarian function could be assessed, FOXL2 deletions proved to be associated with variable degrees of ovarian dysfunction. In conclusion, we present the largest series of BPES patients with FOXL2 deletions and standardized phenotyping reported so far. Our genotype-phenotype data can be useful for providing a prognosis (i.e. occurrence of associated features) in newborns with BPES carrying a FOXL2 deletion.

Bowen-Conradi syndrome: a clinical and genetic study.

The purpose of the study was to delineate the anomalies and the natural life history of persons with the Bowen-Conradi syndrome [Bowen and Conradi 1976: Birth Defects: Orig Artic Ser XII(6):101-108]. We ascertained 39 cases and personally examined almost all. For those who were not seen, their clinical record were scrutinized. Pedigree analysis of all 39 was done and kinship coefficients computed. The birth prevalence was estimated to be 1/355 live births.

Syndrome of coronal craniosynostosis, Klippel-Feil anomaly, and sprengel shoulder with and without Pro250Arg mutation in the FGFR3 gene.

A unique Pro250Arg point mutation in fibroblast growth factor receptor 3 (FGFR3) was initially reported by Bellus et al. [1996: Nat Genet 14:174-176] and the phenotype subsequently by Muenke et al. [1997: Am J Hum Genet 60:555-564], Reardon et al. [1997: J Med Genet 34:632-636], and Graham et al. [1998: Am J Med Genet 77:322-329]. These authors emphasized the pleiotropic nature of this form of coronal craniosynostosis, including brachydactyly with carpal and/or tarsal coalitions, with other anomalies at lower frequency. We report on a family with autosomal dominant coronal synostosis, segmentation and fusion anomalies of the vertebra and ribs, and Sprengel shoulder due to the Pro250Arg mutation. We also report a single case with an identical phenotype without the mutation.

Mutations in the novel protocadherin PCDH15 cause Usher syndrome type 1F.

We have determined the molecular basis for Usher syndrome type 1F (USH1F) in two families segregating for this type of syndromic deafness. By fluorescence in situ hybridization, we placed the human homolog of the mouse protocadherin Pcdh15 in the linkage interval defined by the USH1F locus. We determined the genomic structure of this novel protocadherin, and found a single-base deletion in exon 10 in one USH1F family and a nonsense mutation in exon 2 in the second. Consistent with the phenotypes observed in these families, we demonstrated expression of PCDH15 in the retina and cochlea by RT-PCR and immunohistochemistry. This report shows that protocadherins are essential for maintenance of normal retinal and cochlear function.

Completeness and accuracy of the birth registry data on congenital anomalies in Alberta, Canada.

Vital statistics and other administrative data are becoming an increasingly important source for epidemiologic research and surveillance. This study, the first in Canada, evaluated the usefulness of birth registry data on congenital anomalies in Alberta. We compared the number of birth defects recorded in the birth registry with the number collected through the Alberta Congenital Anomalies Surveillance System (ACASS) between 1985 and 1996. In addition, records of 3,881 (99.9 %) babies with (a) birth defect(s) from the ACASS during 1994--1996 were matched to the birth registry by deterministic linkage. Of these, 2,969 babies had single anomalies that were used for validity analysis. The anomalies were grouped by those within International Classification of Disease (ICD) ICD-9 Section XIV (ICD-9=740.0-759.9) and those outside the Section XIV. For those within Section XIV, 24 summary diagnostic categories were examined. As shown, the total case count from the birth registry was on average about 3 % lower than that from the ACASS between 1985 and 1996. The validity of diagnostic categories is high for the 24 categories examined, with an overall agreement of between 80 % and 100 %. The sensitivity, positive predictive value, and kappa are also high for all these anomalies combined during 1994 and 1996, showing 95.7 %, 99.8, and 0.81 respectively.

Two brothers with severe developmental delay, growth retardation and unusual appearance.

We report on two brothers with short stature, severe developmental delay and unusual appearance. Several conditions including the Russell-Silver, Dubowitz, Floating-Harbour and Cockayne syndromes were considered in the differential diagnosis, but subsequently rejected. These two cases are likely to represent a new autosomal recessive or X-linked recessive syndrome.

Association between congenital foot anomalies and gestational age at amniocentesis.

OBJECTIVES: Our objectives were to confirm the reported association between early amniocentesis and congenital foot anomalies as well as to report, for the first time, on the outcome of amniocenteses performed during the 13th and 14th weeks of gestation. METHODS: We conducted a triple cohort retrospective study of 4457 amniocenteses. Cohort definitions: early amniocentesis (EA), 11 weeks and 0/7 days to 12 weeks to 6/7 days; early midtrimester amniocentesis (EMA), 13 weeks and 0/7 days to 14 weeks and 6/7 days; and midtrimester amniocentesis (MA), 15 weeks and 0/7 days to 19 weeks and 6/7 days. Outcome measures were obtained by searching the Alberta Congenital Anomalies Surveillance System (ACASS) database for children born with foot anomalies represented by International Classification of Diseases version 9 (ICD-9) codes 754.5, 754.6 and 754.7. RESULTS: Incidences of congenital foot anomalies were: EA 11/980 (1.1%), EMA 11/2515 (0.4%), and MA 1/962 (0.1%). There is a significant difference between the EA and EMA cohorts (p=0.019) and between the EA and MA cohorts (p=0.003); however, these data suggest there is no difference between EMA and MA cohorts (p=0.11). CONCLUSIONS: Our incidence of congenital foot anomalies of 1.1% for women who underwent EA is similar to previously reported data, which further validates this association; however, our data also suggest that the foot anomaly risk may be limited to amniocenteses performed before the 13th week of gestation.

Congenital anomalies ascertained by two record systems run in parallel in the Canadian Province of Alberta.

To assess the quality and appropriateness of Canadian Congenital Anomalies Surveillance System (CCASS), a system based on routine hospital admission/separation records, we compared the congenital anomalies ascertained by CCASS for the period of January 1, 1990 to December 31, 1993 in the province of Alberta with corresponding figures obtained from Alberta Congenital Anomalies Surveillance System (ACASS), a specific-purpose surveillance program collecting information on congenital anomalies from multiple sources with mechanisms to evaluate diagnosis. Rates of congenital anomalies estimated by CCASS tended to be higher. Agreement between CCASS and ACASS depended on diagnosis: for the International Clearinghouse for Birth Defects Monitoring System standard categories of congenital anomalies (except for anomalies of abdominal wall), agreement usually exceeded 50%; for less clear-cut diagnoses, it was well below 50%. We conclude that routine medical records can be used for surveillance purposes for major congenital anomalies with clear-cut diagnosis.

Incidence of inborn errors of metabolism in British Columbia, 1969-1996.

OBJECTIVE: To determine how many children with specific types of inborn errors of metabolism are born each year in British Columbia, Canada. This population provides a relatively unique setting for collection of accurate and uniform incidence data because the diagnoses are all made through one laboratory in a population with universal access to government-funded medical care. METHODOLOGY: We used the records of the Biochemical Diseases Laboratory, Children's Hospital, Vancouver (the central referral point for all metabolic diagnoses in British Columbia) to identify all patients diagnosed with the metabolic diseases defined below. We obtained incidence figures by including only the children diagnosed with the diseases covered in this article who were confirmed as having been born within the province for the years 1969 to 1996. The diseases covered were diseases of amino acids, organic acids, the urea cycle, galactosemia, primary lactic acidoses, glycogen storage diseases, lysosomal storage diseases, and diseases involving specifically peroxisomal and mitochondrial respiratory chain dysfunction. Because the technology needed for diagnosis of specific disease groups was in place at different times our data for the different disease groups correspond to different time frames. We have also adjusted the time frames used to allow for the likelihood that some diseases may not come to medical attention for some time after birth. For instance the incidence of amino acid diseases was assessed throughout the whole of this time frame but the incidence of peroxisomal diseases was restricted to 1984 to 1996 because this was the time frame during which the technology needed for diagnosis was in place and reliable. Most disease group statistics included at least 400 000 births. RESULTS: The overall minimum incidence of the metabolic diseases surveyed in children born in British Columbia is approximately 40 cases per 100 000 live births. This includes phenylketonuria (PKU) and galactosemia which are detected by a newborn screening program. Metabolic diseases, which were not screened for at birth, ie, those with PKU and galactosemia subtracted from the total, have a minimal incidence of approximately 30 cases per 100 000 live births. This diagnostic dilemma group would present to pediatricians for diagnosis. Not all metabolic diseases have been surveyed and our data are restricted to the following metabolic disease groups. Approximately 24 children per 100 000 births (approximately 60% of the total disease groups surveyed) have a disease involving amino acids (including PKU), organic acids, primary lactic acidosis, galactosemia, or a urea cycle disease. These children all have metabolic diseases involving small molecules. Approximately 2.3 children per 100 000 births ( approximately 5%) have some form of glycogen storage disease. Approximately 8 per 100 000 births (20%) have a lysosomal storage disease; approximately 3 per 100 000 births (7%-8%) have a respiratory chain-based, mitochondrial disease and approximately 3 to 4 per 100 000 (7%-8%) of births have a peroxisomal disease. The diseases involving subcellular organelles represent approximately half of the diagnostic dilemma group. The incidence of each of the specific diseases diagnosed, including apparently rare diseases such as nonketotic hyperglycinemia, is to be found in the text. The metabolic diseases reported in this survey represent over 10% of the total number of single gene disorders in our population. CONCLUSIONS: Our data provide a good estimate of metabolic disease incidence, for the disease groups surveyed, in a predominantly Caucasian population. Incidence data for metabolic diseases are hard to collect because in very few centers are diagnoses centralized for a population with uniform access to modern health care and this has been the case for our population during the course of the study. (ABSTRACT TRUNCATED)

Characterization of an interstitial deletion del(13)(q22q32) using microdissection and sequential FISH and G-banding.

The objective of this study was to delineate a chromosome 13 abnormality and establish its clinical correlation by using molecular cytogenetics procedures. A newborn boy presented with clinical findings, including mild symmetric intrauterine growth retardation (IUGR), small ears with thickened helices, a scalp lesion, short fifth fingers, missing toes, and talipes equinovarus. Routine G-banding of cultured peripheral blood cells revealed that the patient had one abnormal and shortened chromosome 13, but uncertainty remained as to whether the abnormality was the result of an interstitial deletion or a translocation. Thirteen copies of G-banded abnormal chromosomes 13 were isolated with microdissection and amplified with PCR using degenerate oligonucleotide primers. Fluorescence in situ hybridization (FISH) of the PCR product to normal metaphases showed one pair of acrocentrics hybridized, more or less uniformly, along the length of the long arm with an unhybridized gap in the distal region, indicative of an interstitial deletion. Sequential FISH and G-banding of the same chromosome preparations conclusively demonstrated that the deleted segment was 13q22-q32. Four cases of del(13)(q22q32) have been previously reported. The common findings in all five cases, including the present one, are psychomotor and growth retardation, as well as hand and foot anomalies.

Congenital autosomal dominant distal spinal muscular atrophy.

We present a father and son with congenital foot deformity. The father at age 41 years used crutches and the son at 7 years walked unaided. Both had atrophy and weakness of lower leg muscles and mild proximal and hand intrinsic weakness. Knee and ankle myotactic reflexes were absent and sensation was intact. Creatine kinase level was normal, nerve conduction studies wer normal and electromyography showed chronic neurogenic change. In both, nerve biopsies were normal and muscle biopsies showed type 1 predominance. The boy's serum hexosaminidase, spinal MRI and SMN gene were normal. This may be the first well documented example of congenital autosomal dominant distal spinal muscular atrophy affecting legs and arms.

Syndrome of multiple epiphyseal dysplasia (ribbing type) with rhizomelic shortness, cleft palate, and micrognathia in two unrelated patients.

We report on two unrelated patients with an apparently new syndrome. In each family they are the only affected members, their parents are not consanguineous, and paternal and maternal ages are not advanced. At birth each patient was noted to have a marked Robin phenotype (cleft of the secondary palate and micrognathia) plus rhizomelic shortness. Delay in the appearance of long bone epiphyses was noted and followed by small fragmented and later very flat epiphyses of all long bones. The fibulae are short and radial heads dislocated. Scoliosis and marked genu valgum developed in both. Both patients have normal intelligence, vision, and hearing. Both have mildly upward slanting palpebral fissures, broad nasal tip, and apparent hypertelorism.

Autosomal recessive, fatal infantile hypertonic muscular dystrophy among Canadian Natives.

We describe eleven mid-western Canadian aboriginal infants with a unique, progressive muscle disorder. All except one had muscle biopsy and/or autopsy. The infants were normal newborns who rapidly developed rigidity of all skeletal muscles, with early, respiratory insufficiency. Death occurred before 18 months of age. Electromyography showed increased insertion activity and profuse fibrillation potentials; motor unit potentials and interference pattern are normal until late in the course. Pathologic features include progressive, granular to powdery Z-band transformation, myofibrillar loss, and muscle regeneration. SDS-gel electrophoresis of one muscle sample revealed increased 54kDa and reduced 80kDa protein fractions. This disease differs from other conditions with Z-band alterations because of continuous muscle activity and relentless clinical progression. The clinical features, elevated serum creatine kinase, electromyographic and muscle biopsy findings suggest a dystrophic process. The recognition of this condition as an autosomal recessive disorder allows appropriate genetic counselling.