Newborn Screening for X-Linked Adrenoleukodystrophy in Nebraska: Initial Experiences and Challenges.

X-linked adrenoleukodystrophy (X-ALD) is a neurodegenerative disease caused by pathogenic variants in ABCD1 resulting in defective peroxisomal oxidation of very long-chain fatty acids. Most male patients develop adrenal insufficiency and one of two neurologic phenotypes: a rapidly progressive demyelinating disease in mid-childhood (childhood cerebral X-ALD, ccALD) or an adult-onset spastic paraparesis (adrenomyeloneuropathy, AMN). The neurodegenerative course of ccALD can be halted if patients are treated with hematopoietic stem cell transplantation at the earliest onset of white matter disease. Newborn screening for X-ALD can be accomplished by measuring C26:0-lysophosphatidylcholine in dried blood spots. In Nebraska, X-ALD newborn screening was instituted in July 2018. Over a period of 3.3 years, 82,920 newborns were screened with 13 positive infants detected (4 males, 9 females), giving a birth prevalence of 1:10,583 in males and 1:4510 in females. All positive newborns had DNA variants in ABCD1. Lack of genotype-phenotype correlations, absence of predictive biomarkers for ccALD or AMN, and a high proportion of ABCD1 variants of uncertain significance are unique challenges in counseling families. Surveillance testing for adrenal and neurologic disease in presymptomatic X-ALD males will improve survival and overall quality of life.

The iron-sulphur cluster in human DNA2 is required for all biochemical activities of DNA2.

The nuclease/helicase DNA2 plays important roles in DNA replication, repair and processing of stalled replication forks. DNA2 contains an iron-sulphur (FeS) cluster, conserved in eukaryotes and in a related bacterial nuclease. FeS clusters in DNA maintenance proteins are required for structural integrity and/or act as redox-sensors. Here, we demonstrate that loss of the FeS cluster affects binding of human DNA2 to specific DNA substrates, likely through a conformational change that distorts the central DNA binding tunnel. Moreover, we show that the FeS cluster is required for DNA2's nuclease, helicase and ATPase activities. Our data also establish that oxidation of DNA2 impairs DNA binding in vitro, an effect that is reversible upon reduction. Unexpectedly, though, this redox-regulation is independent of the presence of the FeS cluster. Together, our study establishes an important structural role for the FeS cluster in human DNA2 and discovers a redox-regulatory mechanism to control DNA binding.

Disruption of CTNND2, encoding delta-catenin, causes a penetrant attention deficit disorder and myopia.

Attention deficit hyperactivity disorder (ADHD) is a common and highly heritable neurodevelopmental disorder with poorly understood pathophysiology and genetic mechanisms. A balanced chromosomal translocation interrupts CTNND2 in several members of a family with profound attentional deficit and myopia, and disruption of the gene was found in a separate unrelated individual with ADHD and myopia. CTNND2 encodes a brain-specific member of the adherens junction complex essential for postsynaptic and dendritic development, a site of potential pathophysiology in attentional disorders. Therefore, we propose that the severe and highly penetrant nature of the ADHD phenotype in affected individuals identifies CTNND2 as a potential gateway to ADHD pathophysiology similar to the DISC1 translocation in psychosis or AUTS2 in autism.

PIGQ glycosylphosphatidylinositol-anchored protein deficiency: Characterizing the phenotype.

PIGQ (OMIM *605754) encodes phosphatidylinositol glycan biosynthesis class Q (PIGQ) and is required for proper functioning of an N-acetylglucosamine transferase complex in a similar manner to the more established PIGA, PIGC, and PIGH. There are two previous patients reported with homozygous and apparently deleterious PIGQ mutations. Here, we provide the first detailed clinical report of a patient with heterozygous deleterious mutations associated with glycosylphosphatidylinositol-anchored protein (GPI-AP) biosynthesis deficiency. Our patient died at 10 months of age. The rare skeletal findings in this disorder expand the differential diagnosis of long bone radiolucent lesions and sphenoid wing dysplasia. This clinical report describes a new and rare disorder-PIGQ GPI-AP biosynthesis deficiency syndrome.

Structural brain anomalies in patients with FOXG1 syndrome and in Foxg1+/- mice.

OBJECTIVE: FOXG1 syndrome is a rare neurodevelopmental disorder associated with heterozygous FOXG1 variants or chromosomal microaberrations in 14q12. The study aimed at assessing the scope of structural cerebral anomalies revealed by neuroimaging to delineate the genotype and neuroimaging phenotype associations. METHODS: We compiled 34 patients with a heterozygous (likely) pathogenic FOXG1 variant. Qualitative assessment of cerebral anomalies was performed by standardized re-analysis of all 34 MRI data sets. Statistical analysis of genetic, clinical and neuroimaging data were performed. We quantified clinical and neuroimaging phenotypes using severity scores. Telencephalic phenotypes of adult Foxg1+/- mice were examined using immunohistological stainings followed by quantitative evaluation of structural anomalies. RESULTS: Characteristic neuroimaging features included corpus callosum anomalies (82%), thickening of the fornix (74%), simplified gyral pattern (56%), enlargement of inner CSF spaces (44%), hypoplasia of basal ganglia (38%), and hypoplasia of frontal lobes (29%). We observed a marked, filiform thinning of the rostrum as recurrent highly typical pattern of corpus callosum anomaly in combination with distinct thickening of the fornix as a characteristic feature. Thickening of the fornices was not reported previously in FOXG1 syndrome. Simplified gyral pattern occurred significantly more frequently in patients with early truncating variants. Higher clinical severity scores were significantly associated with higher neuroimaging severity scores. Modeling of Foxg1 heterozygosity in mouse brain recapitulated the associated abnormal cerebral morphology phenotypes, including the striking enlargement of the fornix. INTERPRETATION: Combination of specific corpus callosum anomalies with simplified gyral pattern and hyperplasia of the fornices is highly characteristic for FOXG1 syndrome.

Novel PLP1 Mutations Identified With Next-Generation Sequencing Expand the Spectrum of PLP1-Associated Leukodystrophy Clinical Phenotypes.

Next-generation sequencing was performed for 2 families with an undiagnosed neurologic disease. Analysis revealed X-linked mutations in the proteolipid protein 1 (PLP1) gene, which is associated with X-linked Pelizaeus-Merzbacher disease and Spastic Paraplegia type 2. In family A, the novel PLP1 missense mutation c.617T>A (p.M206K) was hemizygous in the 2 affected male children and heterozygous in the mother. In family B, the novel de novoPLP1 frameshift mutation c.359_369del (p.G120fs) was hemizygous in the affected male child. Although PLP1 mutations have been reported to cause an increasingly wide range of phenotypes inclusive of the dystonia, spastic paraparesis, motor neuronopathy, and leukodystrophy observed in our patients, atypical features included the cerebrospinal fluid deficiency of neurotransmitter and pterin metabolites and the delayed appearance of myelin abnormalities on neuroimaging studies. Next-generation sequencing studies provided a diagnosis for these families with complex leukodystrophy disease phenotypes, which expanded the spectrum of PLP1-associated leukodystrophy clinical phenotypes.

FOXG1 syndrome: genotype-phenotype association in 83 patients with FOXG1 variants.

PurposeThe study aimed at widening the clinical and genetic spectrum and assessing genotype-phenotype associations in FOXG1 syndrome due to FOXG1 variants.MethodsWe compiled 30 new and 53 reported patients with a heterozygous pathogenic or likely pathogenic variant in FOXG1. We grouped patients according to type and location of the variant. Statistical analysis of molecular and clinical data was performed using Fisher's exact test and a nonparametric multivariate test.ResultsAmong the 30 new patients, we identified 19 novel FOXG1 variants. Among the total group of 83 patients, there were 54 variants: 20 frameshift (37%), 17 missense (31%), 15 nonsense (28%), and 2 in-frame variants (4%). Frameshift and nonsense variants are distributed over all FOXG1 protein domains; missense variants cluster within the conserved forkhead domain. We found a higher phenotypic variability than previously described. Genotype-phenotype association revealed significant differences in psychomotor development and neurological features between FOXG1 genotype groups. More severe phenotypes were associated with truncating FOXG1 variants in the N-terminal domain and the forkhead domain (except conserved site 1) and milder phenotypes with missense variants in the forkhead conserved site 1.ConclusionsThese data may serve for improved interpretation of new FOXG1 sequence variants and well-founded genetic counseling.

Capture-based high-coverage NGS: a powerful tool to uncover a wide spectrum of mutation types.

PURPOSE: Next-generation sequencing (NGS) has been widely applied to clinical diagnosis. Target-gene capture followed by deep sequencing provides unbiased enrichment of the target sequences, which not only accurately detects single-nucleotide variations (SNVs) and small insertion/deletions (indels) but also provides the opportunity for the identification of exonic copy-number variants (CNVs) and large genomic rearrangements. METHOD: Capture NGS has the ability to easily detect SNVs and small indels. However, genomic changes involving exonic deletions/duplications and chromosomal rearrangements require more careful analysis of captured NGS data. Misaligned raw sequence reads may be more than just bad data. Some mutations that are difficult to detect are filtered by the preset analytical parameters. "Loose" filtering and alignment conditions were used for thorough analysis of the misaligned NGS reads. Additionally, using an in-house algorithm, NGS coverage depth was thoroughly analyzed to detect CNVs. RESULTS: Using real examples, this report underscores the importance of the accessibility to raw sequence data and manual review of suspicious sequence regions to avoid false-negative results in the clinical application of NGS. Assessment of the NGS raw data generated by the use of loose filtering parameters identified several sequence aberrations, including large indels and genomic rearrangements. Furthermore, NGS coverage depth analysis identified homozygous and heterozygous deletions involving single or multiple exons. CONCLUSION: Our results demonstrate the power of deep NGS in the simultaneous detection of point mutations and intragenic exonic deletion in one comprehensive step.Genet Med 18 5, 513-521.

Mode of action of diterpene and characterization of related metabolites from the soft coral, Xenia elongata.

Chemical and biological investigation of the cultured marine soft coral Xenia elongata led to the isolation of two new diterpenes (2, 3). Their structures were elucidated using a combination of NMR and mass spectrometry. Biological evaluations and assessments were determined using the specific apoptosis induction assay based on genetically engineered mammalian cell line D3 deficient in Bak and Bax and derived from a mouse epithelial cell. The diterpenes induce apoptosis in low micromolar concentrations. The results indicate that the previously isolated compound (1) affects cell in a manner similar to that of HSP90 and HDAC inhibitors and in a manner opposite of PI3 kinase/mTOR inhibitors. Compound (3) inhibits selectively HDAC6 in high micromolar concentrations.

Deep-sea hydrothermal vent Epsilonproteobacteria encode a conserved and widespread nitrate reduction pathway (Nap).

Despite the frequent isolation of nitrate-respiring Epsilonproteobacteria from deep-sea hydrothermal vents, the genes coding for the nitrate reduction pathway in these organisms have not been investigated in depth. In this study we have shown that the gene cluster coding for the periplasmic nitrate reductase complex (nap) is highly conserved in chemolithoautotrophic, nitrate-reducing Epsilonproteobacteria from deep-sea hydrothermal vents. Furthermore, we have shown that the napA gene is expressed in pure cultures of vent Epsilonproteobacteria and it is highly conserved in microbial communities collected from deep-sea vents characterized by different temperature and redox regimes. The diversity of nitrate-reducing Epsilonproteobacteria was found to be higher in moderate temperature, diffuse flow vents than in high temperature black smokers or in low temperatures, substrate-associated communities. As NapA has a high affinity for nitrate compared with the membrane-bound enzyme, its occurrence in vent Epsilonproteobacteria may represent an adaptation of these organisms to the low nitrate concentrations typically found in vent fluids. Taken together, our findings indicate that nitrate reduction is widespread in vent Epsilonproteobacteria and provide insight on alternative energy metabolism in vent microorganisms. The occurrence of the nap cluster in vent, commensal and pathogenic Epsilonproteobacteria suggests that the ability of these bacteria to respire nitrate is important in habitats as different as the deep-sea vents and the human body.

Variability of disease spectrum in children with liver phosphorylase kinase deficiency caused by mutations in the PHKG2 gene.

Liver phosphorylase b kinase (PhK) deficiency (glycogen storage disease type IX), one of the most common causes of glycogen storage disease, is caused by mutations in the PHKA2, PHKB, and PHKG2 genes. Presenting symptoms include hepatomegaly, ketotic hypoglycemia, and growth delay. Clinical severity varies widely. Autosomal recessive mutations in the PHKG2 gene, which cause about 10-15% of cases, have been associated with severe symptoms including increased risk of liver cirrhosis in childhood. We have summarized the molecular, biochemical, and clinical findings in five patients, age 5-16 years, diagnosed with liver PhK deficiency caused by PHKG2 gene mutations. We have identified five novel and two previously reported mutations in the PHKG2 gene in these five patients. Clinical severity was variable among these patients. Histopathological studies were performed for four of the patients on liver biopsy samples, all of which showed signs of fibrosis but not cirrhosis. One of the patients (aged 9 years) developed a liver adenoma which later resolved. All patients are currently doing well. Their clinical symptoms have improved with age and treatment. These cases add to the current knowledge of clinical variability in patients with PHKG2 mutations. Long term studies, involving follow-up of these patients into adulthood, are needed.

Osteogenesis imperfecta caused by PPIB mutation with severe phenotype and congenital hearing loss.

Osteogenesis imperfecta (OI) is an inherited disorder of connective tissue typically caused by defects in either COL1A1 or COL1A2. A number of other genes causative of this disorder have been found, including PPIB, which forms one subunit of the prolyl 3-hydroxylase enzyme complex. Patients with homozygous or compound heterozygous mutations in this gene have OI with a trend toward lethal or severe phenotype. We present a Native American female with prenatal diagnosis of OI. Long bones were shortened with significant rhizomelia. At birth, fractures were present in ribs, humerii, and femurs. She had significant respiratory disease at birth, and required oxygen throughout her life. She also had recurrent pneumonias, one of which ultimately caused her death at age 16 mo. She also had significant bilateral sensorineural hearing loss. Molecular testing showed that the patient was homozygous for a single nucleotide substitution in PPIB (c. 136-2A>G). Patients with OI caused by PPIB mutations have had variable disease, but with majority of either with perinatal lethality or progressively deforming severe disease. Patients with OI due to PPIB mutation have shown some differences in phenotype. There appears to be a trend toward rhizomelic shortening and less severe bowing of the extremities, as compared to patients with comparably severe OI caused by COL1A1 or COL1A2 mutation. Congenital hearing loss may be an inconsistent feature of this condition, or may have co-occurred in our patient for unrelated reasons. Still, patients with OI caused by PPIB mutation should have appropriate early and regular management of their hearing.

Prevalence of pilomatricoma in Turner syndrome: findings from a multicenter study.

IMPORTANCE: The absence of data on the prevalence of pilomatricoma among patients with Turner syndrome served as the catalyst for this multicenter investigation. OBJECTIVES: To ascertain the prevalence of pilomatricoma among patients with Turner syndrome and to determine any association between the development of pilomatricomas and the use of exogenous hormones in patients with Turner syndrome. DESIGN: A retrospective medical record review from January 1, 2000, through January 1, 2010, was performed of all patients with Turner syndrome. Data on pilomatricomas and the use of hormone therapy were collected. SETTING: University of California-Davis Medical Center, University of Nebraska Medical Center, and The University of North Carolina at Chapel Hill. PARTICIPANTS: Patients with a diagnosis of Turner syndrome. MAIN OUTCOME MEASURES: Prevalence of concomitant pilomatricoma and diagnosis of Turner syndrome. Secondary outcome measures included the use of the exogenous hormones estrogen or recombinant human growth hormone (rhGH). RESULTS: In total, 311 patients with Turner syndrome were identified from these 3 institutions. Among them, 8 patients (2.6%) were diagnosed as having pilomatricomas. Before the development of pilomatricomas, 5 patients had been treated with rhGH but not estrogen, 1 patient had received estrogen but not rhGH, and 2 patients did not receive either therapy. CONCLUSIONS AND RELEVANCE: Although the prevalence of pilomatricoma among the general population is unknown, this study demonstrates a high prevalence (2.6%) of pilomatricomas among patients with Turner syndrome. No apparent relationship was noted among our patients or in the literature between the use of rhGH and the development of pilomatricomas.

Ammonificins C and D, hydroxyethylamine chromene derivatives from a cultured marine hydrothermal vent bacterium, Thermovibrio ammonificans.

Chemical and biological investigation of the cultured marine hydrothermal vent bacterium, Thermovibrio ammonifican led to the isolation of two hydroxyethylamine chromene derivatives, ammonificins C and D. Their structures were elucidated using combination of NMR and mass spectrometry. Absolute stereochemistry was ascertained by comparison of experimental and calculated CD spectra. Biological evaluation and assessment were determined using the patented ApopScreen cell-based screen for apoptosis-induction. Ammonificins C and D induce apoptosis in micromolar concentrations. To our knowledge, this finding is the first report of chemical compounds that induce apoptosis from the cultured deep-sea marine organism, hydrothermal vent bacterium, Thermovibrio ammonificans.

Evaluation and comparison of safety, convenience and cost of administering intravenous pamidronate infusions to children in the home and ambulatory care settings.

The use of bisphosphonates in children to treat low bone mineral density has increased. Safety and efficacy of pamidronate has been previously demonstrated. However, little research has been done on pamidronate infusion in the home health setting for patients with metabolic bone disease. Data were collected via a survey to assess satisfaction and convenience of infusions. Adverse events were measured by collecting calcium levels before and after infusions. Infusion costs were estimated from the standard orders from one home health agency and our infusion center. We found no difference in the rates of hypocalcemia between the two groups. The survey results showed high satisfaction for both groups, with higher scores in the home health group for convenience and stress. Home health infusions showed lower cost and less absenteeism from school and work. Home health-based pamidronate infusion appears to be safe, less expensive, and is associated with high patient satisfaction.

Enzyme-replacement therapy in life-threatening hypophosphatasia.

BACKGROUND: Hypophosphatasia results from mutations in the gene for the tissue-nonspecific isozyme of alkaline phosphatase (TNSALP). Inorganic pyrophosphate accumulates extracellularly, leading to rickets or osteomalacia. Severely affected babies often die from respiratory insufficiency due to progressive chest deformity or have persistent bone disease. There is no approved medical therapy. ENB-0040 is a bone-targeted, recombinant human TNSALP that prevents the manifestations of hypophosphatasia in Tnsalp knockout mice. METHODS: We enrolled infants and young children with life-threatening or debilitating perinatal or infantile hypophosphatasia in a multinational, open-label study of treatment with ENB-0040. The primary objective was the healing of rickets, as assessed by means of radiographic scales. Motor and cognitive development, respiratory function, and safety were evaluated, as well as the pharmacokinetics and pharmacodynamics of ENB-0040. RESULTS: Of the 11 patients recruited, 10 completed 6 months of therapy; 9 completed 1 year. Healing of rickets at 6 months in 9 patients was accompanied by improvement in developmental milestones and pulmonary function. Elevated plasma levels of the TNSALP substrates inorganic pyrophosphate and pyridoxal 5'-phosphate diminished. Increases in serum parathyroid hormone accompanied skeletal healing, often necessitating dietary calcium supplementation. There was no evidence of hypocalcemia, ectopic calcification, or definite drug-related serious adverse events. Low titers of anti-ENB-0040 antibodies developed in four patients, with no evident clinical, biochemical, or autoimmune abnormalities at 48 weeks of treatment. CONCLUSIONS: ENB-0040, an enzyme-replacement therapy, was associated with improved findings on skeletal radiographs and improved pulmonary and physical function in infants and young children with life-threatening hypophosphatasia. (Funded by Enobia Pharma and Shriners Hospitals for Children; ClinicalTrials.gov number, NCT00744042.).

Parvibaculum hydrocarboniclasticum sp. nov., a mesophilic, alkane-oxidizing alphaproteobacterium isolated from a deep-sea hydrothermal vent on the East Pacific Rise.

An aerobic, alkane-oxidizing bacterium, designated strain EPR92(T), was isolated from hydrothermal fluids that had been collected from a deep-sea vent on the East Pacific Rise (at 9° 50' N 104° 17' W). The cells of the novel strain were Gram-staining-negative rods that measured approximately 1.4 µm in length and 0.4 µm in width. Strain EPR92(T) grew at 20-40 °C (optimum 35 °C), with1.0-5.0% (w/v) NaCl (optimum 2.5%), and at pH 4.0-8.5 (optimum pH 7.5). The generation time under optimal conditions was 63 min. Strain EPR92(T) grew aerobically in artificial seawater minimal medium with n-alkanes as sole carbon and energy sources, and also in artificial seawater medium supplemented with peptone and yeast extract. The predominant fatty acids were C(18:1)ω7c, C(19:0) cyclo ω8c, 11-methyl C(18:1)ω7c and a putative C(12:0) aldehyde. The major polar lipids were phosphatidylglycerol, diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylcholine and four unidentified aminolipids. The major respiratory quinone was Q-10 and the genomic DNA G+C content was 60.7 mol%. Phylogenetic analyses of the 16S rRNA gene showed that strain EPR92(T) belongs in the class Alphaproteobacteria and the recognized species that were most closely related to the novel strain were identified as Parvibaculum indicum P-31(T) (98.7% sequence similarity) and Parvibaculum lavamentivorans DS-1(T) (95.8%). In DNA-DNA hybridizations, the level of DNA-DNA relatedness observed between strain EPR92(T) and P. indicum P-31(T) was 47.7%, indicating that the two strains do not belong to the same species. Based on the phylogenetic, physiological, chemotaxonomic and genetic evidence, strain EPR92(T) represents a novel species within the genus Parvibaculum, for which the name Parvibaculum hydrocarboniclasticum sp. nov. is proposed. The type strain is EPR92(T) ( = DSM 23209 = JCM 16666(T)).

Phorcysia thermohydrogeniphila gen. nov., sp. nov., a thermophilic, chemolithoautotrophic, nitrate-ammonifying bacterium from a deep-sea hydrothermal vent.

A novel hyperthermophilic, anaerobic, chemolithoautotrophic bacterium, designated strain HB-8(T), was isolated from the tube of Alvinella pompejana tubeworms collected from the wall of an actively venting sulfide structure on the East Pacific Rise at 13° N. The cells were Gram-negative rods, approximately 1.0-1.5 µm long and 0.5 µm wide. Strain HB-8(T) grew between 65 and 80 °C (optimum 75 °C), 15 and 35 g NaCl l(-1) (optimum 30 g l(-1)) and pH 4.5 and 8.5 (optimum pH 6.0). Generation time under optimal conditions was 26 min. Growth occurred under chemolithoautotrophic conditions with H(2) as the energy source and CO(2) as the carbon source. Nitrate and sulfur were used as electron acceptors, with concomitant formation of ammonium or hydrogen sulfide, respectively. The presence of lactate, formate, acetate or tryptone in the culture medium inhibited growth. The G+C content of the genomic DNA was 47.8 mol%. Phylogenetic analysis of the 16S rRNA gene and of the alpha subunit of the ATP citrate lyase of strain HB-8(T) indicated that this organism formed a novel lineage within the class Aquificae, equally distant from the type strains of the type species of the three genera that represent the family Desulfurobacteriaceae: Thermovibrio ruber ED11/3LLK8(T), Balnearium lithotrophicum 17S(T) and Desulfurobacterium thermolithotrophum BSA(T). The polar lipids of strain HB-8(T) differed substantially from those of other members of the Desulfurobacteriaceae, and this bacterium produced novel quinones. On the basis of phylogenetic, physiological and chemotaxonomic characteristics, it is proposed that the organism represents a novel genus and species within the family Desulfurobacteriaceae, Phorcysia thermohydrogeniphila gen. nov., sp. nov. The type strain of Phorcysia thermohydrogeniphila is HB-8(T) ( = DSM 24425(T)  = JCM 17384(T)).

The incidence of spondylolysis and spondylolisthesis in children with osteogenesis imperfecta.

BACKGROUND: Spondylolysis and spondylolisthesis are common abnormalities of the lumbar spine. The incidence of these diagnoses is recognized in the healthy population. However, their incidence in osteogenesis imperfecta (OI) patients is less well defined. METHODS: This is a retrospective radiographic review of patients treated in the OI clinic from a single institution. Lateral radiographs were reviewed on all available patients to assess the incidence of spondylolysis and spondylolisthesis in this patient population. The morphology of the pedicle and pars interarticularis was also evaluated to identify any abnormalities or dysplasia of these structures. RESULTS: One hundred ten of the 139 patients treated in the OI clinic met the inclusion criteria for this study. Of these patients, 79% (87 of 110) were ambulatory. The overall incidence of spondylolysis in this pediatric OI population was found to be 8.2% (9 of 110) at an average age of 7.5 years. The incidence of spondylolisthesis was 10.9% (12 of 110) at an average age of 6.5 years with 75% (3 of 12) being isthmic type and 25% (3 of 12) dysplastic. The combined incidence of spondylolysis and spondylolisthesis was 19.2%. Incidentally, the pedicle length was noted to be elongated in 40.0% (44 of 110) of this OI population. CONCLUSIONS: This study found that the incidence of spondylolysis in a group of children with OI was much higher than in the normal pediatric population, which has been reported to be 2.6% to 4.0%. This incidence was also found to be higher than previously reported incidence of spondylolysis in OI patients (5.3%). The incidence of spondylolisthesis was also found to be much higher than that of the normal pediatric population (4.2%). It is important to recognize this higher incidence of these abnormalities and to anticipate future associated symptoms and potential worsening listhesis that can clinically affect the lifestyles of these children and potentially require surgical treatment. The clinical significance of these findings will necessitate long-term follow-up.