Osteogenesis imperfecta: effecting the transition from adolescent to adult medical care.

The objective of this paper is to provide guidelines for pediatricians, adult physicians in different medical disciplines and patients' families who are planning the transition to adult care for the adolescent with osteogenesis imperfecta (OI). This observational report reflects concerns expressed by patients, their families, and involved physicians regarding the problems encountered with the transition of care. Methods for dealing with transitional issues are presented. OI is a heritable disorder of connective tissue in which fractures are the dominant clinical feature. However, OI is a systemic disorder with broad clinical variability in which there are unpredictable episodes of trauma. Coordinated team support provides the best level of care for the child with OI. This paper discusses 4 key topics related to effecting the transition from pediatric to adult care: 1) Transitioning and maintaining health, 2) Preserving or improving the level of function, 3) Assuring continuity of medical/surgical care, and 4) Re-structuring psychosocial and work-related systems. The process of transition requires active communication between the pediatric and adult team members along with a proactive approach by the patient and family. In addition, as the transition is established, the patient with OI should be encouraged to be his/her own advocate and care coordinator.

Multiple miliary osteoma cutis is a distinct disease entity: four case reports and review of the literature.

BACKGROUND: Multiple miliary osteoma cutis (MMOC) is a rare nodular skin disease characterized by tiny bone nodules which usually form on the facial skin, typically in middle age. The aetiology of this phenomenon is poorly understood. OBJECTIVES: To search for possible bone formation progenitors and to look for a possible association with mutations in the GNAS gene (encoding the G-protein α-stimulatory subunit) and related hormonal parameters in patients with MMOC. We also reviewed the literature and discuss the aetiology and pathogenesis of adult-onset primary osteomas. METHODS: We report four cases of MMOC. Histological samples were analysed for bone morphogenetic protein (BMP)-2, BMP-4 and oestrogen receptor-α known to be involved in bone formation. Endocrinological laboratory investigations and hand X-rays were performed to exclude a systemic disease. The GNAS gene was sequenced from DNA extracted from peripheral blood in all four patients and from a skin sample in one patient to exclude somatic mutations. RESULTS: Histological analyses revealed intramembranous cutaneous bone formation resembling the findings seen in GNAS gene-based osteoma cutis disorders. However, we did not find any germline or somatic GNAS gene mutations in our patients and all laboratory investigations gave normal results. BMP-2 and -4 were expressed normally in MMOC samples, but oestrogen receptor-α was not expressed. Altogether 47 MMOC cases, 41 female and six male, have been published between 1928 and 2009. Of these cases, 55% had a history of pre-existing acne and only 15% had extrafacial osteomas. CONCLUSIONS: MMOC is a rare but distinct disease entity of unknown aetiology. Histologically, the tiny nodular osteomas show intramembranous superficial ossification but the aetiology appears to be different from GNAS-related disorders. The osteomas seem to increase slowly in number after appearing in middle age.

Growth hormone deficiency in Sturge-Weber syndrome.

Sturge-Weber syndrome (SWS) is a disorder involving central nervous system abnormalities that may increase the risk of hypothalamic-pituitary dysfunction. Records of 19 patients with suspected growth hormone deficiency (GHD), identified from a registry of 1653 patients with SWS, were reviewed; nine patients with GHD were found.

Calcium acquisition rates do not support age-appropriate gains in total body bone mineral content in prepuberty and late puberty in girls with cystic fibrosis.

Few longitudinal data are available characterizing bone development in adolescents with cystic fibrosis (CF) although this is a critical time for bone mineralization. Dual energy X-ray absorptiometry (DXA) scans were obtained at 1- to 4-year intervals in 18 prepubertal and pubertal girls (age 7-18 years) with CF to determine calcium (Ca) accretion rates and changes (Delta) in total body bone mineral content (TBBMC) and lumbar spine bone mineral density (LS BMD) Z-scores. Daily Ca acquisition rates were calculated assuming TBBMC was composed of 32.2% Ca. Bone Ca accretion averaged 82 mg/day (2.05 mmol/day) [(range:-38 to +197 mg/day (-0.95 to 4.9 mmol/day)] on approximately 1,200 mg/day (30 mmol/day) Ca intakes. Estimated mean peak Ca accretion was 160 mg/day (4 mmol/day) at age 13 years; losses of bone Ca occurred in late puberty. Gains in insulin-like growth factor 1 (IGF-1) predicted Ca accretion (p<0.06). Body mass index (BMI) Z-score predicted LS BMD and TBBMC Z-score cross-sectionally but did not predict DeltaTBBMC Z-score. Changes in TBBMC Z-score paralleled Ca accretion rates with age. Bone Ca accretion in girls with CF fell below rates in healthy girls during prepuberty and late puberty despite Ca intakes approaching recommendations. IGF-1 and BMI Z-scores may identify children with CF at risk of compromised bone accretion, and more data are required to elucidate roles of lung function and glucocorticoid use in compromised bone health.

Mutations in PEX1 are the most common cause of peroxisome biogenesis disorders.

The peroxisome biogenesis disorders (PBDs) are a group of lethal autosomal-recessive diseases caused by defects in peroxisomal matrix protein import, with the concomitant loss of multiple peroxisomal enzyme activities. Ten complementation groups (CGs) have been identified for the PBDs, with CG1 accounting for 51% of all PBD patients. We identified the human orthologue of yeast PEX1, a gene required for peroxisomal matrix protein import. Expression of human PEX1 restored peroxisomal protein import in fibroblasts from 30 CG1 patients, and PEX1 mutations were detected in multiple CG1 probands. A common PEX1 allele, G843D, is present in approximately half of CG1 patients and has a deleterious effect on PEX1 activity. Phenotypic analysis of PEX1-deficient cells revealed severe defects in peroxisomal matrix protein import and destabilization of PEX5, the receptor for the type-1 peroxisomal targetting signal, even though peroxisomes were present in these cells and capable of importing peroxisomal membrane proteins. These data demonstrate an important role for PEX1 in peroxisome biogenesis and suggest that mutations in this gene are the most common cause of the PBDs.

NVL: a new member of the AAA family of ATPases localized to the nucleus.

We report the cloning of NVL, a newly recognized human gene that encodes an approximately 110-kDa nuclear protein designated NVLp (nuclear VCP-like protein), which is a member of a rapidly growing family of ATP-binding proteins recently denoted the AAA family (ATPases associated with diverse cellular activities) (W. H. Kunau et al., 1993, Biochimie 75:209-224). NVL was isolated by degenerate PCR using oligonucleotides corresponding to the yeast PEX1 gene, which is necessary for peroxisomal biogenesis. Two cDNAs, designated NVL.1 and NVL.2, may represent alternatively spliced forms of a single gene that maps to chromosome 1q41-q42.2. NVL has greatest similarity to the VCP subfamily of AAA proteins, is widely expressed, and encodes a nuclear protein with two highly similar ATP-binding domains. We speculate that NVLp is involved in an ATP-dependent nuclear process.

Isolation and characterization of rat and human cDNAs encoding a novel putative peroxisomal enoyl-CoA hydratase.

We have used a PCR-based subtractive hybridization method to identify upregulated cDNAs in the livers of rats treated with a peroxisome proliferator [clofibrate or di(2-ethylhexyl) phthalate]. After four rounds of subtractive hybridization 62 differentially hybridizing clones were partially sequenced and analyzed by sequence homology searching. Of 62, 49 were identical to 14 different upregulated rat sequences in the databank (mostly genes encoding microsomal or peroxisomal enzymes), 4 of 62 were fragments of three previously unknown genes, and 9 of 62 were false positives. Two of the unknown fragments hybridized to a single novel cDNA that was found to be more than 20-fold induced by both peroxisome proliferators. The 36-kDa predicted protein product of this cDNA shows a high degree of sequence homology to enoyl-CoA hydratases of several different species and has a C-terminal peroxisomal targeting sequence. An epitope-tagged protein product of a full-length cDNA was targeted to peroxisomes in a human cell line. We named this gene, which encodes an apparent peroxisomal enoyl-CoA hydratase, ECH1. We have also identified human ECH1 cDNA and mapped its structural gene to 19q13, 3' to the ryanodine receptor, by hybridization to somatic cell hybrid DNA and chromosome 19-specific cosmid arrays. Possible roles for the ECH1 protein product in peroxisomal beta-oxidation are discussed.

Expression of a type I insulin-like growth factor receptor with low affinity for insulin-like growth factor II.

We investigated the binding properties of the type I insulin-like growth factor (IGF) receptor expressed in NIH-3T3 fibroblasts transfected with a human type I receptor cDNA. Cell surface receptors bound IGF-I with KD = 1 nM as predicted. Although recent studies have suggested that IGF-I and IGF-II bind to type I receptors with near-equal affinity, the receptors in this system bound IGF-II with much lower affinity (KD = 15-20 nM). When type I receptors from the transfected cells were solubilized and immunopurified, however, both 125I-IGF-I and 125I-IGF-II bound to the purified receptors with extremely high and relatively similar affinities (KD = 8 and 17 pM respectively). Thus the immunopurified receptors had higher affinity but lower specificity for the two ligands. The monoclonal antibody alpha IR-3 effectively inhibited IGF-I binding to cell surface receptors (75 +/- 10%), but did not inhibit IGF-II binding. In the purified receptor assay, alpha IR-3 also inhibited IGF-I binding more effectively than IGF-II binding (38 +/- 7% versus 10 +/- 4%). We conclude that the products of this cDNA can account for the binding patterns that we previously observed in receptors immunopurified from human placenta. The differential effect of alpha IR-3 on IGF-I versus IGF-II raises the possibility that these homologous growth factors bind to immunologically distinct epitopes on the type I receptor.

Twenty-nail dystrophy associated with hematologic abnormalities.

This report describes a 15 1/2 year old white male with twenty-nail dystrophy who has had recurrent episodes of immune thrombocytopenic purpura, autoimmune hemolytic anemia, and mild depression of immunoglobulin levels. The concurrence of these events suggests that each shares a common pathophysiologic mechanism, possibly an autoimmune process.