A de novo PRPF8 pathogenic variant in transient severe hypophosphatemia with delayed puberty and growth failure.

INTRODUCTION: Childhood hypophosphatemia is a rare condition and may be caused by malabsorption, malignancies, or genetic factors. Prolonged hypophosphatemia leads to impaired growth and radiographic signs of rickets. METHODS: We performed a detailed clinical and genetic evaluation of an adolescent boy with repeatedly low plasma phosphate concentrations (below 0.60 mmol/L), and growth failure. RESULTS: At 14 years, the patient presented with decelerating growth and delayed puberty. Biochemistry showed hypophosphatemia due to increased urinary phosphate loss; kidney function and vitamin D status were normal. Radiographs showed mild metaphyseal changes. A gene panel for known genetic hypophosphatemias was negative. Trio exome analysis followed by Sanger sequencing identified a pathogenic heterozygous de novo stop gain variant in PRPF8 gene, c.5548C>T p.(Arg1850*)., in the conserved RNase H homology domain. PRPF8 encodes the pre-RNA protein 8, which has a role in RNA processing. Heterozygous PRPF8 variants have been associated with retinitis pigmentosa and neurodevelopmental disorders but not with phosphate metabolism. The patient underwent growth hormone (GH) stimulation tests which confirmed GH deficiency. Head MRI indicated partially empty sella. GH treatment was started at 15 years. Surprisingly, phosphate metabolism normalized during GH treatment, suggesting that hypophosphatemia was at least partly secondary to growth hormone deficiency. CONCLUSION: In conclusion, the evaluation of an adolescent with profound long-term hypophosphatemia revealed a pituitary developmental defect associated with a stop gain variant in PRPF8. Hypophosphatemia alleviated with GH treatment. The pathological PRPF8 variant may contribute to abnormal pituitary development; however, its role in phosphate metabolism remains uncertain.

Otologic injuries are frequent in pediatric patients with temporal bone fractures.

This retrospective study aimed to clarify the occurrence and types of otologic injuries in children and adolescents with skull fractures. Files of all patients under 18 years of age who had been diagnosed with skull fractures at a tertiary trauma centre were included. The primary outcome variable was the presence of any otologic symptom or finding. Secondary outcome variables were clinically detected and radiologically detected otologic injuries. The primary predictor variable was a temporal bone fracture. Other study variables were sex, age, mechanism of injury, traumatic brain injury, and mortality. A total of 97 patients were identified for the study. Otologic symptoms and findings were frequent (33.9%). The most common clinical findings were bleeding from the external auditory canal (18.6%) and hemotympanum (13.4%). The prevailing radiological finding was blood and/or cerebrospinal fluid in the middle ear (30.9%). Patients with fractures of temporal bone had a 29-fold risk for otologic symptoms or findings (RR 28.9, 95% CI 4.1-202.9, p < 0.001) relative to those who did not have a temporal bone fracture. Severe otologic complications, such as permanent hearing loss (6.2%), cerebrospinal fluid leak (5.2%), or facial nerve palsy (1%), were infrequent. Within the limitations of the study it seems that there is the necessity of otoscopy in all pediatric patients with blunt head trauma. In case of positive otologic findings, the patient should undergo imaging and ENT consultation.

Bisphosphonate Treatment and the Characteristics of Femoral Fractures in Children With Osteogenesis Imperfecta.

Context: The short-term benefits of bisphosphonates (BPs) are evident in the treatment of children with osteogenesis imperfecta (OI), but some concerns related to long-term effects remain. Objective: To elucidate the effect of BPs on characteristics of femoral fractures in children with OI. Design and Setting: Retrospective cohort study at a university hospital. Patients and Main Outcome Measure: The study included 93 patients with OI. We recorded fracture histories and analyzed all femoral fractures for location and fracture type using radiographs obtained at fracture diagnosis. Effects of BPs were evaluated by comparing fracture characteristics in three groups: patients (1) naive to BPs, (2) receiving ongoing BP treatment, and (3) whose treatment was discontinued. Results: In total, 127 femoral fractures occurred in 24 patients. Of the fractures, 63 (50%) occurred in patients naive to BPs, 44 (35%) during BP treatment, and 20 (16%) after treatment discontinuation. Mid or distal shaft fractures were most common (41%), followed by subtrochanteric (33%) and distal (20%) fractures. Almost all fractures were transverse (65%) or oblique (28%). The pattern of femoral fractures was similar in all three BP treatment groups (P = 0.78 for location; P = 0.35 for fracture type) and was not related to cumulative BP dose. Instead, OI type correlated with fracture characteristics, and distal location and transverse configuration were more common in the more severe types III and IV compared with type I OI. Conclusion: Characteristics of femoral fractures in children with OI are affected by OI type but not by BP exposure.

A novel splice mutation in PLS3 causes X-linked early onset low-turnover osteoporosis.

Genetic factors play an important role in the development of osteoporosis. Several monogenic forms of osteoporosis have been recognized, most recently an X-chromosomal form resulting from mutations in the gene encoding plastin 3 (PLS3). PLS3 is a protein involved in actin bundle formation in the cytoskeleton. We present a large family with early onset osteoporosis and X-linked inheritance. Phenotyping was performed on 19 family members and whole-exome sequencing on 7 family members (5 with a diagnosis of early onset osteoporosis and 2 with normal bone parameters). Osteoporosis had its onset in childhood and was characterized by recurrent peripheral fractures, low bone mineral density (BMD), vertebral compression fractures, and significant height loss in adulthood. Males were in general more severely affected than females. Bone histomorphometry findings in 4 males and 1 female showed severe trabecular osteoporosis, low amount of osteoid, and decreased mineral apposition rate, indicating impaired bone formation; resorption parameters were increased in some. All affected subjects shared a single base substitution (c.73-24T > A) in intron 2 of PLS3 on Xq23. The mutation, confirmed by Sanger sequencing, segregated according to the skeletal phenotype. The mutation introduces a new acceptor splice site with a predicted splice score of 0.99 and, thereby, as confirmed by cDNA sequencing, induces the insertion of 22 bases between exons 2 and 3, causing a frameshift and premature termination of mRNA translation (p.Asp25Alafs*17). The mutation affects the first N-terminal calcium-binding EF-hand domain and abolishes all calcium- and actin-binding domains of the protein. Our results confirm the role of PLS3 mutations in early onset osteoporosis. The mechanism whereby PLS3 affects bone health is unclear, but it may be linked to osteocyte dendrite function and skeletal mechanosensing. Future studies are needed to elucidate the role of PLS3 in osteoporosis and to define optimal treatment.

Pediatric solid organ transplantation and osteoporosis: a descriptive study on bone histomorphometric findings.

BACKGROUND: Organ transplantation may lead to secondary osteoporosis in children. This study characterized bone histomorphometric findings in pediatric solid organ transplant recipients who were assessed for suspected secondary osteoporosis. METHODS: Iliac crest biopsies were obtained from 19 children (7.6-18.8 years, 11 male) who had undergone kidney (n = 6), liver (n = 9), or heart (n = 4) transplantation a median 4.6 years (range 0.6-16.3 years) earlier. All patients had received oral glucocorticoids at the time of the biopsy. RESULTS: Of the 19 patients, 21 % had sustained peripheral fractures and 58 % vertebral compression fractures. Nine children (47 %) had a lumbar spine BMD Z-score below -2.0. Histomorphometric analyses showed low trabecular bone volume (< -1.0 SD) in 6 children (32 %) and decreased trabecular thickness in 14 children (74 %). Seven children (37 %) had high bone turnover at biopsy, and low turnover was found in 6 children (32 %), 1 of whom had adynamic bone disease. CONCLUSIONS: There was a great heterogeneity in the histological findings in different transplant groups, and the results were unpredictable using non-invasive methods. The observed changes in bone quality (i.e. abnormal turnover rate, thin trabeculae) rather than the actual loss of trabecular bone, might explain the increased fracture risk in pediatric solid organ transplant recipients.

Increased heterogeneity of bone matrix mineralization in pediatric patients prone to fractures: a biopsy study.

Idiopathic osteoporosis (IOP) in children is characterized by fragility fractures and/or low bone mineral density in otherwise healthy individuals. The aim of the present work was to measure bone mineralization density distribution (BMDD) based on quantitative backscattered electron imaging (qBEI) in children with suspected IOP. Entire cross-sectional areas of transiliac bone biopsy samples from children (n = 24, 17 boys; aged 6.7-16.6 years) with a history of fractures (n = 14 with at least one vertebral fracture) were analyzed for cancellous (Cn) and cortical (Ct) BMDD. Outcomes were compared with normal reference BMDD data and correlated with the patients' clinical characteristics and bone histomorphometry findings. The subjects had similar average degree but significantly higher heterogeneity of mineralization in both Cn and Ct bone (Cn.CaWidth +23%, Ct.CaWidth +15%, p < 0.001 and p = 0.002, respectively), together with higher percentages of low mineralized cancellous (Cn.CaLow +35%, p < 0.001) and highly mineralized cortical bone areas (Ct.CaHigh +82%, p = 0.032). Ct.CaWidth and Ct.CaLow were positively correlated with mineralizing surface per bone surface (MS/BS; a primary histomorphometric determinant of bone formation) and with serum bone turnover markers (all p < 0.05). The correlations of the mineralization heterogeneity with histomorphometric and serum bone turnover indices suggest that an enhanced variation in bone turnover/formation contributes to the increased heterogeneity of mineralization. However, it remains unclear whether the latter is cause for, or the response to the increased bone fragility in these children with suspected IOP.

Impaired bone health and asymptomatic vertebral compressions in fracture-prone children: a case-control study.

Frequent fractures in children may be a sign of impaired bone health, but it remains unestablished when and how fracture-prone children should be assessed. This prospective study elucidated skeletal characteristics and predisposing factors in children with recurrent fractures. Findings were used to establish guidelines for screening. During a 12-month period we recorded fracture history for all children (n = 1412) treated for an acute fracture at a large university hospital. All apparently healthy children over 4 years of age, who had sustained: (1) at least one vertebral fracture; (2) two long-bone fractures before age 10 years; or (3) three long-bone fractures before age 16 years, were recruited. They underwent dual-energy X-ray absorptiometry (DXA), laboratory tests, and spinal radiography. Information regarding family history and lifestyle factors were collected. Findings were compared with healthy controls. Sixty-six fracture-prone children (44 males, mean age 10.7 years; 5% of all children with fractures) were identified. Altogether, they had sustained 183 long-bone fractures (median 3, range 0­7); 11 children had sustained vertebral fracture(s). Patients had significantly lower bone mineral density (BMD) at lumbar spine (p < 0.001), hip (p = 0.007), and whole body (p < 0.001) than the controls; only 5 children (8%) had a BMD Z-score < −2.0. Asymptomatic vertebral compressions were prevalent, especially in those under 10 years of age. Hypercalciuria (11%) and hyperphosphaturia (22%) were significantly more prevalent than in controls. Serum concentration of 25-hydroxyvitamin D (S-25OHD) was below 50 nmol/L in 55%; low levels were associated with low BMD and vertebral compressions. The fracture-prone children had lower calcium intake, less physical activity, and more often had siblings with fractures than the controls. The findings suggest that a thorough pediatric evaluation, including DXA and spinal radiography, is often indicated already after a second significant low-energy fracture in children, in order to detect potentially preventable adverse lifestyle factors and nutritional deficits and to identify those with compromised overall bone health.

Prevalence and natural course of craniocervical junction anomalies during growth in patients with osteogenesis imperfecta.

Pathology in the craniocervical junction is a serious complication of osteogenesis imperfecta (OI). Our aim was to analyze the prevalence and natural course of craniocervical junction anomalies in patients with OI during growth. In a one-center retrospective study, we analyzed lateral skull radiographs and midsagittal magnetic resonance images of 76 patients with either type I, III, or IV OI. The material included longitudinal series of 31 patients. In total, 150 patient images taken at ages 0 to 39 years were analyzed and compared with age-matched control data. Craniocervical anomalies were observed in 37% of patients and in all OI types studied. Of the three types of anomalies, basilar invagination was seen in 13%, basilar impression in 15%, and platybasia in 29% of the patients. From those with an abnormal finding, 44% displayed more than one type of anomaly. At a group level, we found no evidence of progression of craniocervical junction pathology with age. We provide longitudinal and cross-sectional data on craniocervical junction dimensions in growing patients with OI and, based on those, suggest a radiological management strategy for diagnosis of cranial base pathology. A higher risk of having any of the pathological conditions was associated with a lower height Z-score. Careful follow-up of cranial base anomalies particularly in subjects with OI and severe growth failure is warranted.

Cerebroretinal microangiopathy with calcifications and cysts: characterization of the skeletal phenotype.

Cerebral cysts and calcifications with leukoencephalopathy and retinal vascular abnormalities are diagnostic hallmarks of cerebroretinal microangiopathy with calcifications and cysts (CRMCC). Previous studies have suggested that skeletal involvement is also common, but its characteristics remain unknown. This study aimed to assess the skeletal phenotype in CRMCC. All Finnish patients with features consistent with CRMCC and for whom radiographs were available were included. Clinical information pertinent to the skeletal phenotype was collected from hospital records, and all plain radiographs were reviewed for skeletal features. Bone mineral density (BMD) was measured by DXA. In one patient, bone biopsies were obtained for bone histology and histomorphometric analyses. The LRP5 gene was analyzed for mutations by direct sequencing. Our results show that the skeletal phenotype in CRMCC includes (1) compromised longitudinal growth pre- and postnatally, (2) generalized osteopenia or early onset low turnover osteoporosis with fragility fractures, and (3) metaphyseal abnormalities that may lead to limb deformities such as short femoral neck or genua valga. DXA measurements in three patients showed low BMD, and bone biopsies in the fourth patient with pathological fractures and impaired fracture healing showed low-turnover osteoporosis, with reduced osteoclast and osteoblast activity. Direct sequencing of all LRP5 coding exons and exon-intron boundaries in six patients with CRMCC revealed no putative mutations. We conclude that the CRMCC-associated bone disease is characterized by low BMD and pathological fractures with delayed healing, metaphyseal changes, and short stature pre- and postnatally. LRP5 is not a disease-causing gene in CRMCC.

Altered bone composition in children with vertebral fracture.

Primary osteoporosis in children often leads to vertebral fractures, but it remains unknown whether these fractures associate with changes in bone composition. This study aimed to determine the differences in bone composition in fracture-prone children with and without vertebral fractures, as assessed by Fourier transform infrared spectroscopic imaging (FTIRI) and bone histomorphometry. Iliac crest bone biopsies (n = 24) were obtained from children who were suspected of primary osteoporosis based on evidence from the fracture history and/or low bone mineral density (BMD) by dual-energy X-ray absorptiometry. Vertebral morphology was determined by radiography. Bone biopsies were analyzed using histomorphometry and FTIRI. Phosphate-to-amide I, carbonate-to-phosphate, carbonate-to-amide I, and cross-link ratio (collagen maturity) were calculated. Children with (n = 14) and without (n = 10) vertebral fracture were compared. Low cancellous bone volume (BV/TV) was detected by histomorphometry in 36% of the children with vertebral fracture, and bone turnover rate was abnormal in 64% of them. Children with vertebral fractures had lower carbonate-to-phosphate ratios (p < .05) and higher collagen maturity (p < .05) than children without vertebral fracture. The children with low BV/TV in biopsy showed lower carbonate-to-amide I ratios (p < .05) than the children with normal bone volume. This study showed changes in bone composition among fracture-prone children who had sustained a vertebral fracture. The observed changes in bone composition in these children may contribute to their greater propensity to sustain vertebral fractures.

Bone biopsy findings and correlation with clinical, radiological, and biochemical parameters in children with fractures.

In children the diagnosis of osteoporosis is based on fracture history and DXA-derived BMD. Bone biopsy is an invasive but accurate method for studying bone characteristics. In this study we evaluated bone biopsy findings and their correlation with noninvasive measures of bone health. Transiliac bone biopsy was performed on 24 consecutive children (17 boys, median age 12 years, range 6 to 16 years) evaluated for suspected primary osteoporosis. Biopsy findings were compared with normative data and correlated with clinical, radiological, biochemical, and densitometric findings. The patients had sustained altogether 64 nonvertebral fractures (median 2.5) from low- or moderate-energy traumas, and 14 patients (58%) had vertebral fractures. The median lumbar spine BMD Z-score was -1.2 (range -3.1 to +1.0). Hypovitaminosis D was present in 58%. Histomorphometry showed low bone volume in 7 patients and normal bone volume in 17. Bone turnover was high in 7, low in 7, and normal in 10 patients. Histomorphometric findings correlated poorly with fracture history, serum bone turnover markers, and DXA findings. Vitamin D deficiency and low lumbar BMD were associated with high bone turnover in the biopsy. These findings underscore the difficulties in diagnosing pediatric osteoporosis. Bone histomorphometry gives additional information and may be useful when considering bisphosphonate treatment in children with suspected primary osteoporosis.

Decreasing incidence and changing pattern of childhood fractures: A population-based study.

Fractures are common in children, and some studies suggest an increasing incidence. Data on population-based long-term trends are scarce. In order to establish fracture incidence and epidemiologic patterns, we carried out a population-based study in Helsinki, Finland. All fractures in children aged 0 to 15 years were recorded from public health care institutions during a 12-month period in 2005. Details regarding patient demographics, fracture site, and trauma mechanism were collected. All fractures were confirmed from radiographs. Similar data from 1967, 1978, and 1983 were used for comparison. In 2005, altogether 1396 fractures were recorded, 63% in boys. The overall fracture incidence was 163 per 10,000. Causative injuries consisted of mainly falls when running or walking or from heights less than 1.5 m. Fracture incidence peaked at 10 years in girls and 14 years in boys. An increase in fracture incidence was seen from 1967 to 1983 (24%, p < .0001), but a significant decrease (18%, p < .0001) was seen from 1983 to 2005. This reduction was largest in children between the ages of 10 and 13 years. Despite the overall decrease and marked decrease in hand (-39%, p < .0001) and foot (-48%, p < .0001) fractures, the incidence of forearm and upper arm fractures increased significantly by 31% (p < .0001) and 39% (p = .021), respectively. Based on these findings, the overall incidence of childhood fractures has decreased significantly during the last two decades. Concurrently, the incidence of forearm and upper arm fractures has increased by one-third. The reasons for these epidemiologic changes remain to be elucidated in future studies.

Low-density lipoprotein receptor-related protein 5 (LRP5) variation in fracture prone children.

OBJECTIVE: Recent studies have confirmed that the low-density lipoprotein receptor-related protein 5 gene (LRP5), plays a role in bone mass accrual and in susceptibility to osteoporotic fractures in adults. This study evaluated whether LRP5 variation is implicated in childhood fractures. PATIENTS AND METHODS: During an epidemiological study on childhood fractures, comprising 1390 consecutive Finnish children with an acute fracture, we recruited fracture-prone 4-16 years old children, who had a history of at least two low-energy long bone fractures before age 10 years or three low-energy long bone fractures before age 16 years, and/or at least one low-energy vertebral compression fracture. A total of 72 (5.2%) children fulfilled these inclusion criteria; DNA samples were obtained for 66 of them. All 23 exons and exon-intron boundaries of the LRP5 gene were sequenced; the identified variants were analyzed in 235 healthy Finnish control samples. RESULTS: Sequencing revealed 15 coding region missense or silent variants with unknown functional consequences. No obvious loss-of-function mutations such as deletions, insertions, or changes resulting in premature termination codon or altered splicing were identified. Phenotyping of the proband and parents, and genotyping of the parents, in 9 families with novel or rare variants showed no obvious correlation between any of the LRP5 variants and fractures. CONCLUSIONS: Our study shows that in children LRP5 mutations are not a common cause of increased fractures. The observed rare LRP5 variants may together with unfavorable environmental and other genetic factors contribute to childhood fractures, but further studies are needed to confirm their functional significance and biological pathways through which this may occur. Our findings suggest that systematic LRP5 screening is not indicated in children with recurrent fractures.

Injuries as a result of treatment of tibial fractures in children: Claims for compensation submitted to the Patient Insurance Center in Finland.

BACKGROUND AND PURPOSE: Tibial fractures comprise 10% of all fractures in children. To our knowledge there have been no previous reports of treatment injuries in these fractures. We analyzed compensation claims concerning treatment of these fractures in Finland. We used this information to determine preventable causes of treatment injuries. MATERIAL AND METHODS: In Finland, the Patient Insurance Center (PIC) provides financial compensation for patients who have sustained an injury in connection with medical treatment or operation. We retrospectively analyzed all claims for compensation arising from treatment of tibial fractures in children that had been received by the PIC between 1997 and 2004. The mode of treatment, complications, and permanent sequelae were assessed. We also estimated the number of avoidable treatment injuries. RESULTS AND INTERPRETATION: The PIC received 50 claims for compensation during the 8-year study period. The claims were based on the following issues: pain, incorrect diagnosis and treatment, permanent disability, extra treatment expenses, inappropriate behavior of the medical personnel, and loss of income of the parents. 35/50 claims had received compensation, of which 32 were related to the treatment and 3 to infections. The treatment injuries that had led to compensation comprised a delay in diagnosis and treatment in 15 patients, inappropriate casting in 9, inappropriate operative treatment in 5, and other causes in 3 patients. An unsatisfactory standard of treatment and missed diagnosis were the most common reasons for compensation. In restrospect, all but 1 of the 35 injuries that had led to compensation were considered to be avoidable.

Shwachman-Diamond syndrome is associated with low-turnover osteoporosis.

INTRODUCTION: Shwachman-Diamond syndrome (SDS) is an autosomal recessive disorder characterized by exocrine pancreatic insufficiency and bone marrow dysfunction. These result in malabsorption and hematological abnormalities. A skeletal dysplasia is also an integral feature of SDS. The present study assessed prevalence and determinants of osteopenia and osteoporosis in patients with SDS and disease-causing mutations in the SBDS gene. MATERIALS AND METHODS: Eleven patients (8 males) aged from 5 to 37 years (median 16.7 years) with a genetically confirmed diagnosis of SDS were assessed for fracture history, bone mineral content (BMC), lean tissue mass (LTM) and bone mineral density (BMD) (Hologic Discovery A), osteoporotic vertebral changes, and for blood biochemistry and hematological parameters. Iliac crest bone biopsies were obtained from four patients for histology and histomorphometry. RESULTS: The main findings were: (1) markedly reduced BMD Z-scores at the lumbar spine (median -2.1, range -4.4 to -0.8), proximal femur (median -1.3, range -2.2 to -0.7) and, whole body (median -1.0, range -2.8 to +0.6), and reduced Z-scores for height-adjusted BMC/LTM ratio (median -0.9, range -3.6 to +1.1); (2) vertebral compression fractures in three patients; and (3) blood biochemistry suggestive of mild vitamin D and vitamin K deficiency. Bone biopsies in four patients showed significant low-turnover osteoporosis with reduced trabecular bone volume, low numbers of osteoclasts and osteoblasts, and reduced amount of osteoid. CONCLUSIONS: The results suggest that in addition to the skeletal dysplasia, SDS is associated with a more generalized bone disease characterized by low bone mass, low bone turnover and by vertebral fragility fractures. Osteoporosis may result from a primary defect in bone metabolism, and could be related to the bone marrow dysfunction and neutropenia.

Bone densitometry in the diagnosis of vertebral fractures in children: accuracy of vertebral fracture assessment.

BACKGROUND: DXA scanner derived images of the spine are used for vertebral fracture detection in adults. It is unknown whether the method could be used in pediatrics. This study evaluated the diagnostic accuracy of DXA images in vertebral fracture assessment (VFA) in children. METHODS: The study included 65 children (37 males; median age 12.1 years) with primary or secondary osteoporosis. Data on clinical history were collected from hospital records. Patients were assessed for spinal compression fractures by standard spinal radiographs and by bone densitometry (Hologic Discovery A) derived VFA images. The visibility and morphology of each vertebra in VFA images was assessed by two readers and by a semi-computerized software developed for the DXA scanner. The findings were compared with those in spinal radiographs and correlated with clinical parameters. RESULTS: The visibility of vertebrae in VFA images was good in T8-L4 but compromised in the upper thoracic region (T4-T7) and was constantly inferior to that in standard radiographs. A total of 25 vertebral fractures were diagnosed in radiographs, but only 9 (36%) of these also in VFA images. The semi-computerized software could not accurately detect vertebrae in most of the children; accuracy increased with increasing age, height and BMD but was not sufficient to detect vertebral fractures. CONCLUSIONS: The utility of DXA scanner derived images of the spine in vertebral fracture detection in children is limited by compromised visibility and poor diagnostic accuracy. The semi-computerized software is not suitable for pediatric use. These limitations should be kept in mind when assessing pediatric patients for osteoporosis.

Bone biopsy and densitometry findings in a child with Camurati-Engelmann disease.

Progressive diaphyseal dysplasia (MIM 131300), also known as Camurati-Engelmann disease (CED), is a rare autosomal dominant craniotubular dysplasia caused by mutations in the transforming growth factor beta1 (TGF-beta1) gene. Radiographs of the long bones of a 9-year-old boy presenting with waddling gait, muscular weakness, underweight, and severe skeletal pain showed symmetric diaphyseal cortical thickening pathognomonic for CED. The diagnosis was verified by detecting a mutation in exon 4 of the TGF-beta1 gene. Full body bone mineral densitometry studies performed before treatment with prednisolone were indicative for osteoporosis (Z-scores for the lumbar spine and femoral neck -2.3 and -3.2, respectively). A transiliac bone biopsy showed markedly reduced trabecular bone volume. Oral prednisolone was initiated, and subsequently, pamidronate infusions were commenced in an attempt to prevent progression of osteoporosis. To our knowledge, this is the first time bone biopsy and bone mineral densitometry studies have been performed and bisphosphonate treatment evaluated in a child with CED.