Cesarean delivery is not associated with decreased at-birth fracture rates in osteogenesis imperfecta.

PURPOSE: Osteogenesis imperfecta (OI) predisposes to recurrent fractures. Patients with the moderate to severe forms of OI present with antenatal fractures, and the mode of delivery that would be safest for the fetus is not known. METHODS: We conducted systematic analyses of the largest cohort of individuals with OI (n = 540) enrolled to date in the OI Linked Clinical Research Centers. Self-reported at-birth fracture rates were compared among individuals with OI types I, III, and IV. Multivariate analyses utilizing backward-elimination logistic regression model building were performed to assess the effect of multiple covariates, including method of delivery, on fracture-related outcomes. RESULTS: When accounting for other covariates, at-birth fracture rates did not differ based on whether delivery was by vaginal route or by cesarean delivery (CD). Increased birth weight conferred higher risk for fractures irrespective of the delivery method. In utero fracture, maternal history of OI, and breech presentation were strong predictors for choosing CD. CONCLUSION: Our study, the largest to analyze the effect of various factors on at-birth fracture rates in OI, shows that CD is not associated with decreased fracture rate. With the limitation that the fracture data were self-reported in this cohort, these results suggest that CD should be performed only for other maternal or fetal indications, not for the sole purpose of fracture prevention in OI.Genet Med 18 6, 570-576.

A cross-sectional multicenter study of osteogenesis imperfecta in North America - results from the linked clinical research centers.

Osteogenesis imperfecta (OI) is the most common skeletal dysplasia that predisposes to recurrent fractures and bone deformities. In spite of significant advances in understanding the genetic basis of OI, there have been no large-scale natural history studies. To better understand the natural history and improve the care of patients, a network of Linked Clinical Research Centers (LCRC) was established. Subjects with OI were enrolled in a longitudinal study, and in this report, we present cross-sectional data on the largest cohort of OI subjects (n = 544). OI type III subjects had higher prevalence of dentinogenesis imperfecta, severe scoliosis, and long bone deformities as compared to those with OI types I and IV. Whereas the mean lumbar spine area bone mineral density (LS aBMD) was low across all OI subtypes, those with more severe forms had lower bone mass. Molecular testing may help predict the subtype in type I collagen-related OI. Analysis of such well-collected and unbiased data in OI can not only help answering questions that are relevant to patient care but also foster hypothesis-driven research, especially in the context of 'phenotypic expansion' driven by next-generation sequencing.

Research challenges in central nervous system manifestations of inborn errors of metabolism.

The Research Challenges in CNS Manifestations of Inborn Errors of Metabolism workshop was designed to address challenges in translating potential therapies for these rare disorders, and to highlight novel therapeutic strategies and innovative approaches to CNS delivery, assessment of effects and directions for the future in the treatment of these diseases. Therapies for the brain in inborn errors represent some of the greatest challenges to translational research due to the special properties of the brain, and of inborn errors themselves. This review covers the proceedings of this workshop as submitted by participants. Scientific, ethical and regulatory issues are discussed, along with ways to measure outcomes and the conduct of clinical trials. Participants included regulatory and funding agencies, clinicians, scientists, industry and advocacy groups.

The role of evidence-based medicine and clinical trials in rare genetic disorders.

The drive to empirically evaluate and analyze tools for the screening, diagnosis, management and monitoring of disease captured by the phrase 'evidence-based medicine (EBM)' has firmly entrenched itself as part of standard clinical care. However, rare genetic disorders, by their very nature, challenge the generation and application of EBM. This review presents many of the challenges encountered in applying EBM to rare genetic disorders, highlighting areas of recent emphasis in establishing multi-institutional collaborative research networks and in the systematic evaluation of developing therapies. Resources for identifying EBM tools for the practitioner are discussed, and the features and limitations of such resources are presented. Although the application of EBM to rare genetic disorders has definite limitations, a foundation has been established, and ongoing efforts seeking to systematically summarize and critically evaluate available evidence will continue to help identify the most effective tools for screening, diagnosis, management, and monitoring.

Correlates of language impairment in children with galactosaemia.

PURPOSE: This study describes risk factors associated with language impairment in children with classic galactosaemia. METHOD: Thirty-three 4-16-year-old participants with classic galactosaemia and a history of speech sound disorders completed a battery of cognitive and language measures and their parents completed a family history questionnaire. RESULTS: Nine of the sixteen (56%) participants with typical cognitive development and 15 of the 17 (88%) with borderline-low cognitive development had language impairments. Participants with typical cognitive development more often had an expressive language disorder, whereas those with borderline-low cognitive development more often had a mixed receptive-expressive language disorder. Participants with Q188R/Q188R genotypes had increased risk for both cognitive and language impairments. The IQs of younger siblings who did not consume milk postnatally were 10-56 points higher than the IQs of their older siblings with galactosaemia who had consumed milk postnatally. However, 4 of 5 younger siblings who were lactose-restricted from birth had language impairments. Typically-reported risk factors for language disorder, including parental history of speech/learning problems and low parental education level, were not significantly associated with cognitive or language impairments in the present sample of children with galactosaemia. CONCLUSIONS: Children with galactosaemia and speech disorders have a 4-6 times greater risk for language impairment than children with early speech disorders of unknown origin. Early dietary lactose may increase the risk for cognitive and language impairments; however, the lack of significant associations of language impairment with days of milk consumption, and other familial and educational risk factors, is consistent with prenatal causation.

A novel mutation in medium chain acyl-CoA dehydrogenase causes sudden neonatal death.

Medium chain acyl-CoA dehydrogenase (MCAD) deficiency is the most common known genetic disorder of fatty acid oxidation. Most (approximately 80%) cases are homozygous for a single mutation: A to G replacement at nucleotide 985 (A985G). MCAD deficiency typically presents in the second year of life as hypoketotic hypoglycemia associated with fasting and may progress to liver failure, coma, and death. Prompt diagnosis and management may prevent long-term sequelae. MCAD deficiency was verified by analysis of urinary acylglycine and serum acylcarnitine species from two neonates referred for diagnosis. Full-length cDNA and MCAD exon 7 and 11 genomic clones were prepared for sequence analysis. Normal and mutant cDNAs were expressed in bacteria, and enzymatic activity was assayed by the ferricenium hexaflurophosphate method. Four compound heterozygote individuals from two unrelated families with A985G on one allele and a novel G to A mutation at nucleotide 583 (G583A) as the second mutant allele presented with MCAD deficiency in the first week of life. The expressed G583A mutant protein lacks enzymatic activity. This novel mutation, G583A, is associated with severe MCAD deficiency causing hypoglycemia or sudden, unexpected neonatal death. This previously unrecognized phenotype of MCAD deficiency may contribute significantly to preventable infant deaths.

Deletion of a single mevalonate kinase (Mvk) allele yields a murine model of hyper-IgD syndrome.

In the current study our objective was to develop a murine model of human hyper-IgD syndrome (HIDS) and severe mevalonic aciduria (MA), autoinflammatory disorders associated with mevalonate kinase deficiency (MKD). Deletion of one Mvk allele (Mvk (+/-)) yielded viable mice with significantly reduced liver Mvk enzyme activity; multiple matings failed to produce Mvk (-/-) mice. Cholesterol levels in tissues and blood, and isoprene end-products (ubiquinone, dolichol) in tissues were normal in Mvk (+/-) mice; conversely, mevalonate concentrations were increased in spleen, heart, and kidney yet normal in brain and liver. While the trend was for higher IgA levels in Mvk (+/-) sera, IgD levels were significantly increased (9-12-fold) in comparison to Mvk (+/+) littermates, in both young (<15 weeks) and older (>15 weeks) mice. Mvk (+/-) animals manifested increased serum TNF-alpha as compared to wild-type littermates, but due to wide variation in levels between individual Mvk (+/-) mice the difference in means was not statistically significant. Mvk (+/-) mice represent the first animal model of HIDS, and should prove useful for examining pathophysiology associated with this disorder.

Klippel-Trenaunay-Weber syndrome associated with a 5:11 balanced translocation.

We report on a case of Klippel-Trenaunay Weber syndrome (KTWS) associated with a reciprocal translocation [46,XX,t (5;11) (q13.3;p15.1)]. The patient has developmental delay and minor anomalies in addition to classic findings of KTWS. These data support the notion that Klippel-Trenaunay-Weber syndrome may be due to a single gene defect and suggests the possible localization of a Klippel-Trenaunay-Weber gene(s) to 5q or 11p.

Cholesterol supplementation with egg yolk increases plasma cholesterol and decreases plasma 7-dehydrocholesterol in Smith-Lemli-Opitz syndrome.

Smith-Lemli-Opitz syndrome (SLOS), an autosomal recessive condition comprising multiple malformations, mental retardation, and growth failure, results from reduced activity of the final enzyme in cholesterol biosynthesis, 7-dehydrocholesterol Delta(7)-reductase (DHCR7). Reduced plasma and tissue cholesterol concentrations and accumulation of cholesterol precursors including 7-dehydrocholesterol (7-DHC) are characteristic biochemical abnormalities. While it is still unclear what role these potentially toxic precursors have in the pathogenesis of this disorder, the accumulation of 7-DHC in the brain has been associated with impaired learning in rats and oxidized 7-DHC has been shown to induce growth retardation in cultured rat embryos. We hypothesized that supplemental dietary cholesterol would increase plasma cholesterol levels and suppress synthesis of 7-DHC and other abnormal sterols in individuals with SLOS. After baseline sterol levels were obtained, patients were provided supplemental cholesterol as egg yolk. Plasma sterols were analyzed by capillary-column gas chromatography over time in four children with SLOS. When evaluated at 4-8 weeks after the initiation of cholesterol supplementation, there was a marked increase in mean plasma cholesterol, from 53 mg/dl to 82 mg/dl. While the percent of total sterols as 7-DHC decreased from 15% to 10%, there was no change in total plasma 7-DHC levels. However, when evaluated 35-90 weeks after the institution of cholesterol supplementation, mean plasma 7-DHC decreased, from 11.3 mg/dl to 3.5 mg/dl (-67%, P < 0.05), along with an increase in mean plasma cholesterol from 53 mg/dl to 114 mg/dl (+116%, P < 0.05). These results support the hypothesis that over time dietary cholesterol supplementation from egg yolk increases the plasma cholesterol levels and decreases levels of 7-DHC which may be toxic. These data have important therapeutic implications in the management of SLOS.

Bilateral radial ray hypoplasia with multiple epiphyseal dysplasia.

We describe a 5-4/12-year-old girl with the unique combination of bilateral radial ray hypoplasia and multiple epiphyseal dysplasia (MED). Radial ray hypoplasia was diagnosed at birth. MED was documented at age 4-3/12 years when she presented with leg pain and short stature and was found to have femoral anteversion and tibial torsion giving rise to severe genu valgum deformity and intoeing. She has no facial anomalies and is developmentally normal. Family history is unremarkable and chromosomal analysis was normal. Investigation of mineral metabolism showed idiopathic hypercalciuria. Surgical lengthening of her severely hypoplastic left radius at age 19 months was successful. Bilateral femoral and tibial osteotomies at age 5-4/12 years corrected her lower limb deformities. This combination of two distinctive but rare skeletal abnormalities may represent a new syndrome.

Eye findings in 8 children and a spontaneously aborted fetus with RSH/Smith-Lemli-Opitz syndrome.

We evaluate the ophthalmologic findings in 8 children with RSH/Smith-Lemli-Opitz syndrome (SLOS) and document abnormal concentrations of cholesterol and cholesterol precursors in the ocular tissues in a case of SLOS. The most common ophthalmologic finding was blepharoptosis, which was found in 6 of 8 patients, with the severity ranging from mild to moderate. None of the patients in the present study demonstrated cataracts; none had amblyopia from blepharoptosis. One patient had a right hypertropia with overaction of the inferior oblique muscle. This patient also had optic atrophy and a second patient had bilateral optic nerve hypoplasia. The importance of these findings to the visual function remains to be defined. Sterol analysis from ocular tissues of an aborted fetus with SLOS showed increased 7- and 8-dehydrocholesterol and a low cholesterol concentration in the retinal pigment epithelium, lens, cornea, and sclera. Routine ophthalmologic examination is indicated in SLOS because of the high incidence of abnormalities, most likely due to the abnormal synthesis of cholesterol and cholesterol precursors in the ocular tissues of these patients, as evidenced by sterol analysis of the ocular tissues in a case of SLOS.

Mutation analysis and description of sixteen RSH/Smith-Lemli-Opitz syndrome patients: polymerase chain reaction-based assays to simplify genotyping.

We report the clinical and molecular data of 16 patients with RSH/Smith-Lemli-Opitz syndrome (RSH/SLOS) with varying phenotypic severity, for which we have identified mutations in both alleles. RSH/SLOS is an autosomal recessive malformation syndrome caused by mutations in the gene encoding the sterol Delta(7)-reductase. This protein catalyzes the reduction of 7-dehydrocholesterol to cholesterol in the last step of cholesterol biosynthesis via the Kandutsch-Russell pathway. In addition to previously reported mutations (T93M, L109P, G147D, W151X, T154M, R242C, A247V, T289I, IVS8-1G-->C, Y408H, and E448K), we have identified six previously undescribed mutations (321G-->C, W177R, R242H, Y318N, L341P, and C444Y). We also report rapid polymerase chain reaction (PCR)-based assays developed to detect four of the recurring mutations (T93M, W151X, V326L, and R404C) and six other RSH/SLOS mutations (321G-->C, L109P, T154M, T289I, Y318N, and L341P). The purpose of this article is to correlate detailed clinical information with molecular data in order to improve our understanding of the genotype-phenotype correlation of RSH/SLOS and to report the development of PCR-based assays that will allow more rapid mutation analysis.

Corneal abnormalities in a mother and daughter with focal dermal hypoplasia (Goltz-Gorlin syndrome).

PURPOSE/METHODS: Focal dermal hypoplasia is an inherited dermatologic disorder commonly associated with skeletal and dental abnormalities. Ocular abnormalities frequently found in patients with focal dermal hypoplasia include microphthalmos, anophthalmos, and colobomas. Corneal abnormalities rarely have been described in patients with focal dermal hypoplasia. We examined a mother and daughter with focal dermal hypoplasia with distinctive corneal lesions. RESULTS/CONCLUSION: Several discrete vascularized peripheral subepithelial corneal opacifications were present bilaterally in both patients with focal dermal hypoplasia. No ocular abnormalities that would predispose to these abnormalities were found. These corneal lesions appear to represent an unusual manifestation of focal dermal hypoplasia.

Deficits in memory strategy use related to prefrontal dysfunction during early development: evidence from children with phenylketonuria.

The prefrontal cortex has been implicated in the mediation of executive processes that facilitate learning and memory. The authors hypothesized that children with prefrontal dysfunction related to phenylketonuria (PKU) would experience deficits in learning and memory because of impaired strategy use. They evaluated 23 children with PKU and 23 controls by using the California Verbal Learning Test-Children's Version (CVLT-C). General executive abilities were tested using the Stroop Color and Word Test, the Wisconsin Card Sorting Test, and phonemic and category fluency. Children with PKU, especially older children, showed poorer learning across trials and less use of semantic clustering on the CVLT-C but intact retention of previously encoded information. With the exception of phonemic fluency, deficits were not observed in general executive control. Results are discussed within the context of abnormalities in the prefrontal cortex and white matter of the brain.

Hydrops fetalis: role of the geneticist.

The causes of hydrops fetalis are myriad. As a result of the advent of routine Rh screening, most cases are not currently related to Rh incompatibility. Genetic, metabolic, chromosomal, and syndromic causes are among the most frequently identified causes of nonimmune hydrops. The importance of determining the underlying cause of hydrops becomes evident once issues such as prognosis, specific treatment, and risk of recurrence are considered. The medical geneticist is highly qualified to assist in the evaluation of hydrops. Clinical geneticists have undergone training in a primary care specialty followed by intensive training in the diagnosis, management, and counseling of individuals and families with genetic, chromosomal, or multifactorial syndromes or birth defects. This training prepares the medical geneticist well to serve as a consultant when hydrops is diagnosed. As knowledge of the molecular genetic and metabolic basis of disease increases, utilization of genetics laboratories continues to increase dramatically. In addition to examining the child to look for dysmorphic features, the clinical geneticist can assist with the laboratory evaluation by coordinating testing with the cytogeneticist, molecular geneticist, and biochemical geneticist as appropriate. Increased awareness of the role of the geneticist in the evaluation of such patients should prove helpful to the physicians caring for such patients and the patients' families.

Interhemispheric interaction during childhood: II. Children with early-treated phenylketonuria.

This study examined whether children with early-treated phenylketonuria (ETPKU) exhibited a disruption in communication between the hemispheres as a function of computational complexity (Banich & Belger, 1990; Belger & Banich, 1992, 1998) when compared to neurologically uncompromised children who were matched in age and IQ. This investigation was motivated by findings that phenylketonuria affects myelination of neurons, including those that make up the corpus callosum, the main neural conduit for interhemispheric interaction. Children performed 2 tasks: a less complex physical-identity task and a more complex name-identity task. For both tasks, we compared performance on across-hemisphere trials, which require interhemispheric interaction, and on within-hemisphere trials, in which no hemispheric interaction is required. On the more complex name-identity task, children with ETPKU exhibited less of a benefit from across-hemisphere processing than did neurologically intact children. These results suggest that the interhemispheric interaction required to complete computationally complex tasks is compromised in children with ETPKU. Such an insufficiency may explain some of the attentional deficits observed in this group of children.

A simple PCR-based assay allows detection of a common mutation, IVS8-1G-->C, in DHCR7 in Smith-Lemli-Opitz syndrome.

Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive multiple malformation disorder. A deficiency of the enzyme 7-dehydrocholesterol delta 7-reductase (DHCR7) is the primary abnormality in SLOS. The gene encoding DHCR7 has been cloned, and we have identified a mutation affecting the splice acceptor site 5' of exon 9 that occurs frequently in affected individuals. We developed a novel PCR-based assay to detect this common mutation in DHCR7. Using this assay, heterozygosity was detected for this mutation in 18 of 26 and homozygosity in 1 of 26 unrelated affected individuals. The high frequency of this mutation is suggestive of either a founder effect in our group of patients or a mutational hotspot. The simplicity and reliability of this assay will allow it to be used as a clinical test to aid in diagnosis of atypical cases, in carrier testing, in prediction of prognosis based on genotype, and in prenatal molecular genetic diagnostic testing.

Autosomal dominant transmission of acrodysostosis.

A mother and daughter with acrodysostosis are described. This documented parent-to-child transmission supports the hypothesis of autosomal dominant inheritance of acrodysostosis. The daughter exhibited many features of acrodysostosis by two months of age, demonstrating that acrodysostosis may be diagnosed in infancy.

Alendronate for the treatment of pediatric osteogenesis imperfecta: a randomized placebo-controlled study.

CONTEXT: Information on the use of oral bisphosphonate agents to treat pediatric osteogenesis imperfecta (OI) is limited. OBJECTIVE: The objective of the investigation was to study the efficacy and safety of daily oral alendronate (ALN) in children with OI. DESIGN AND PARTICIPANTS: We conducted a multicenter, double-blind, randomized, placebo-controlled study. One hundred thirty-nine children (aged 4-19 yr) with type I, III, or IV OI were randomized to either placebo (n = 30) or ALN (n = 109) for 2 yr. ALN doses were 5 mg/d in children less than 40 kg and 10 mg/d for those 40 kg and greater. MAIN OUTCOME MEASURES: Spine areal bone mineral density (BMD) z-score, urinary N-telopeptide of collagen type I, extremity fracture incidence, vertebral area, iliac cortical width, bone pain, physical activity, and safety parameters were measured. RESULTS: ALN increased spine areal BMD by 51% vs. a 12% increase with placebo (P < 0.001); the mean spine areal BMD z-score increased significantly from -4.6 to -3.3 (P < 0.001) with ALN, whereas the change in the placebo group (from -4.6 to -4.5) was insignificant. Urinary N-telopeptide of collagen type I decreased by 62% in the ALN-treated group, compared with 32% with placebo (P < 0.001). Long-bone fracture incidence, average midline vertebral height, iliac cortical width, bone pain, and physical activity were similar between groups. The incidences of clinical and laboratory adverse experiences were also similar between the treatment and placebo groups. CONCLUSIONS: Oral ALN for 2 yr in pediatric patients with OI significantly decreased bone turnover and increased spine areal BMD but was not associated with improved fracture outcomes.