Radiotherapy-induced vascular cognitive impairment 20 years after childhood brain tumor.

BACKGROUND: Studies have established that radiotherapy for childhood brain tumors (BTs) increases the risk of cerebrovascular disease (CVD); however, it is unclear how this will affect cognitive function. This study aimed to investigate the associations between radiotherapy-induced CVD, white matter hyperintensities (WMHs), and neurocognitive outcomes in adult survivors of childhood BTs. METHODS: In a cross-sectional setting, we conducted a national cohort that included 68 radiotherapy-treated survivors of childhood BTs after a median follow-up of 20 years. Markers of CVD and WMHs were evaluated using brain MRI, and the sum of CVD-related findings was calculated. Additionally, the associations among CVD findings, WMHs, and neuropsychological test results were analyzed. RESULTS: Of the 68 childhood BT survivors, 54 (79%) were diagnosed with CVD and/or WMHs at a median age of 27 years. CVD and/or WMHs were associated with lower scores for verbal intelligence quotient, performance intelligence quotient (PIQ), executive function, memory, and visuospatial ability (P < .05). Additionally, survivors with microbleeds had greater impairments in the PIQ, processing speed, executive function, and visuospatial ability (P < .05). WMHs and CVD burden were associated with greater difficulties in memory function and visuospatial ability (P < .05). Small-vessel disease burden was associated with PIQ scores, processing speed, working memory, and visuospatial ability. CONCLUSIONS: The study results suggest that markers of radiotherapy-induced CVD, the additive effect of CVD markers, and risk factors of dementia are associated with cognitive impairment, which may suggest that the survivors are at a high risk of developing early-onset dementia.

Early disc degeneration in radiotherapy-treated childhood brain tumor survivors.

BACKGROUND: Childhood brain tumor (BT) survivors have an increased risk of treatment-related late effects, which can reduce health-related quality of life and increase morbidity. This study aimed to investigate lumbar disc degeneration in magnetic resonance imaging (MRI) in adult survivors of radiotherapy-treated childhood BT compared to age and sex-matched population controls. METHODS: In this cross-sectional comparative study, 127 survivors were identified from hospital registries. After a mean follow-up of 20.7 years (range 5-33.1), 67 survivors (mean age 28.4, range 16.2-43.5) were investigated with MRI and compared to 75 sex-matched population-based controls. Evaluated MRI phenotypes included Pfirrmann grading, , intervertebral disc protrusions, extrusions, and high-intensity-zone-lesions (HIZ). Groups were also compared for known risk factors of lumbar intervertebral disc (IVD) degeneration. RESULTS: Childhood BT survivors had higher Pfirrmann grades than controls at all lumbar levels (all p < 0.001). Lumbar disc protrusions at L4-5 (p = 0.02) and extrusions at L3-4 (p = 0.04), L4-5 (p = 0.004), and L5-S1 (p = 0.01) were significantly more common in the BT group compared to the control. The survivor cohort also had significantly more HIZ-lesons than the controls (n=13 and n=1, p=0.003). Age at diagnosis was associated with lower degree of IVD degeneration (p < 0.01). Blood pressure correlated with IVD degeneration (P < 0.05). CONCLUSIONS: Signs of early disc degeneration related to tumor treatment can be seen in the IVDs of survivors. Disc degeneration was more severe in children treated in adolescence.

Genetic spectrum of prenatally diagnosed skeletal dysplasias in a Finnish patient cohort.

OBJECTIVE: This retrospective cohort study aims to describe the genetic spectrum of fetal skeletal dysplasias detected in a Finnish patient cohort and the diagnostic yield of various analysis methods used. METHOD: A total of 121 pregnancies with prenatally suspected or diagnosed skeletal dysplasia were analyzed between 2013 and 2020. Clinical details and findings from genetic testing were collected. RESULTS: Abnormal ultrasound triggered further testing in most cases. However, there were several cases with increased nuchal translucency and/or abnormal risk ratio in the first trimester combined screening as the initial finding. Further genetic testing was performed in 84/121 (69.4%) cases. A genetic diagnosis was confirmed in 36/84 (42.9%) cases. Half of the identified cases could be attributed to a founder mutation specific to the Finnish Disease Heritage, whereas the other half consisted of a variety of other genetic defects. CONCLUSION: In our patient cohort, the overall genetic spectrum of prenatally diagnosed skeletal dysplasias was wide. However, the impact of Finnish founder mutations was considerable, suggesting that the genetic spectrum of skeletal dysplasias may differ significantly between populations. This should be taken into consideration during the diagnostic process especially as initial ultrasound findings may be unspecific and the interpretation of ultrasound features is usually difficult.

A Novel Osteochondrodysplasia With Empty Sella Associates With a TBX2 Variant.

Skeletal dysplasias comprise a heterogenous group of developmental disorders of skeletal and cartilaginous tissues. Several different forms have been described and the full spectrum of their clinical manifestations and underlying genetic causes are still incompletely understood. We report a three-generation Finnish family with an unusual, autosomal dominant form of osteochondrodysplasia and an empty sella. Affected individuals (age range 24-44 years) exhibit unusual codfish-shaped vertebrae, severe early-onset and debilitating osteoarthritis and an empty sella without endocrine abnormalities. Clinical characteristics also include mild dysmorphic features, reduced sitting height ratio, and obesity. Whole-exome sequencing excluded known skeletal dysplasias and identified a novel heterozygous missense mutation c.899C>T (p.Thr300Met) in TBX2, confirmed by Sanger sequencing. TBX2 is important for development of the skeleton and the brain and three prior reports have described variations in TBX2 in patients portraying a complex phenotype with vertebral anomalies, craniofacial dysmorphism and endocrine dysfunctions. Our mutation lies near a previously reported disease-causing variant and is predicted pathogenic with deleterious effects on protein function. Our findings expand the current spectrum of skeletal dysplasias, support the association of TBX2 mutations with skeletal dysplasia and suggest a role for TBX2 in development of the spinal and craniofacial structures and the pituitary gland.

A family with partially penetrant multicentric carpotarsal osteolysis due to gonadal mosaicism: First reported case.

Multicentric carpotarsal osteolysis (MCTO) is an autosomal dominant condition characterized by carpal-tarsal abnormalities; over half of affected individuals also develop renal disease. MCTO is caused by mutations of MAFB; however, there is no clear phenotype-genotype correlation. We describe the first reported family of variable MCTO phenotype due to mosaicism: the proband had classical skeletal features and renal involvement due to focal segmental glomerulosclerosis (FSGS), and the father had profound renal impairment due to FSGS, necessitating kidney transplantation. Mosaicism was first suspected in this family due to unequal allele ratios in the sequencing chromatograph of the initial blood sample of proband's father and confirmed by sequencing DNA extracted from the father's hair, collected from different bodily parts. This case highlights the need for a high index of clinical suspicion to detect low-level parental mosaicism, as well as a potential role for MAFB mutation screening in individuals with isolated FSGS.

Pulmonary Follow-Up Imaging in Cartilage-Hair Hypoplasia: a Prospective Cohort Study.

Cartilage-hair hypoplasia is a syndromic immunodeficiency with short stature, chondrodysplasia, and variable degree of immune dysfunction. Patients with cartilage-hair hypoplasia are prone to recurrent respiratory tract infections, and the prevalence of bronchiectasis ranges from 29 to 52%. Pulmonary complications contribute significantly to the mortality; therefore, regular lung imaging is essential. However, the optimal schedule for repeated lung imaging remains unestablished. We determined the rate and correlates of progression of structural lung changes in a prospectively followed cohort of 16 patients with cartilage-hair hypoplasia. We analyzed clinical, laboratory, and pulmonary functional testing data and performed lung magnetic resonance imaging at a median interval of 6.8 years since previous imaging. Imaging findings remained identical or improved due to disappearance of inflammatory changes in all evaluated patients. Patients with subtle signs of bronchiectasis on imaging tended to have low immunoglobulin M levels, as well as suffered from pneumonia during the follow-up. In conclusion, our results suggest slow if any development of bronchiectasis in selected subjects with cartilage-hair hypoplasia.

Iron overload after allogeneic stem cell transplantation in children with acute lymphoblastic leukemia.

Red blood cell transfusions are an essential part of supporting care in leukemia treatment. We examined the prevalence of iron overload and its effects on organ function and childhood growth in pediatric patients after allogeneic HSCT for acute lymphoblastic leukemia. Twenty-three patients were included (median age 12.6, range 7.5-21.4 years). Body iron load was determined using laboratory tests, hepatic and cardiac MRI, and by calculating iron received from transfusions. We performed multivariate analysis to determine association of body iron load with liver enzymes, cardiac function, insulin resistance, and growth. Median plasma ferritin was 344 (range 40-3235) ng/mL and exceeded 1000 ng/mL in three patients (13%). In MRI, 11 patients (48%) had hepatic iron overload and 1 patient (4%) myocardial iron overload. In cardiac MRI, 8 patients (35%) had significant but subclinical decrease in ejection fraction (median z-score -1.7, range -3.1-0.14), but cardiac function did not associate with iron status. Alanine transaminase associated with transfused iron per time unit (P = .001) after the median follow-up of 4.5 years. No correlation was found between iron load and growth or insulin resistance. Iron overload is common in children transplanted for ALL, but iron overload associated organ dysfunction is not present at early age. We recommend evaluation of iron load for all patients at least once during follow-up after transplantation.

Radiation-induced accelerated aging of the brain vasculature in young adult survivors of childhood brain tumors.

BACKGROUND: Cranial radiotherapy may damage the cerebral vasculature. The aim of this study was to understand the prevalence and risk factors of cerebrovascular disease (CVD) and white matter hyperintensities (WMHs) in childhood brain tumors (CBT) survivors treated with radiotherapy. METHODS: Seventy CBT survivors who received radiotherapy were enrolled in a cross-sectional study at a median 20 years after radiotherapy cessation. The prevalence of and risk factors for CVD were investigated using MRI, MRA, and laboratory testing. Tumors, their treatment, and stroke-related data were retrieved from patients' files. RESULTS: Forty-four individuals (63%) had CVD at a median age of 27 years (range, 16-43 years). The prevalence rates at 20 years for CVD, small-vessel disease, and large-vessel disease were 52%, 38%, and 16%, respectively. Ischemic infarcts were diagnosed in 6 survivors, and cerebral hemorrhage in 2. Lacunar infarcts were present in 7, periventricular or deep WMHs in 34 (49%), and mineralizing microangiopathy in 21 (30%) survivors. Multiple pathologies were detected in 44% of the participants, and most lesions were located in a high-dose radiation area. Higher blood pressure was associated with CVD and a presence of WMHs. Higher cholesterol levels increased the risk of ischemic infarcts and WMHs, and lower levels of high-density lipoprotein and higher waist circumference increased the risk of lacunar infarcts. CONCLUSIONS: Treating CBTs with radiotherapy increases the risk of early CVD and WMHs in young adult survivors. These results suggest an urgent need for investigating CVD prevention in CBT patients.

Radiation-Induced Meningiomas After Childhood Brain Tumor: A Magnetic Resonance Imaging Screening Study.

Purpose: Childhood brain tumors (CBTs) and their treatment increase the risk of secondary neoplasms (SNs). We studied the incidence of secondary craniospinal tumors with magnetic resonance imaging (MRI) screening in a national cohort of survivors of CBT treated with radiotherapy, and we analyzed the Finnish Cancer Registry (FCR) data on SNs in survivors of CBT with radiotherapy registered as a part of the primary tumor treatment. Methods: A total of 73 survivors of CBT participated in the MRI study (mean follow-up of 19 ± 6.2 years). The incidence of SNs in a cohort of CBT patients (N = 569) was retrieved from the FCR (mean follow-up of 11 ± 12.9 years). Brain tumors were diagnosed at age ≤16 years between the years 1970 and 2008 in the clinical study and the years 1963 and 2010 in the FCR population. Results: Secondary brain tumors, meningiomas in all and schwannoma in one, were found in 6 of the 73 (8.2%) survivors with a mean of 23 ± 4.3 years after the diagnosis of the primary tumor. The cumulative incidence was 10.2% (95% confidence interval [CI] 3.9-25.1) in 25 years of follow-up. In the FCR data, the 25-year cumulative incidence of SNs was 2.4% (95% CI 1.3-4.1); only two brain tumors, no meningiomas, were registered. Conclusion: Survivors of CBT treated with radiotherapy have a high incidence of meningiomas, which are rarely registered in the FCR.

Recessive multiple epiphyseal dysplasia - Clinical characteristics caused by rare compound heterozygous SLC26A2 genotypes.

Pathogenic sequence variants in the solute carrier family 26 member 2 (SLC26A2) gene result in lethal (achondrogenesis Ib and atelosteogenesis II) and non-lethal (diastrophic dysplasia and recessive multiple epiphyseal dysplasia, rMED) chondrodysplasias. We report on two new patients with rMED and very rare compound heterozygous mutation combinations in non-consanguineous families. Patient I presented in childhood with waddling gait and joint stiffness. Radiographs showed epiphyseal changes, bilateral coxa plana-deformity and knee valgus deformity, for which he underwent surgeries. At present 33 years his height is 165 cm. Patient II presented with cleft palate, small jaw, short limbs, underdeveloped thumbs and on radiographs, cervical kyphosis with an underdeveloped C4. He also developed severe scoliosis but has grown at -2.9 SD curve. Molecular analysis revealed that patient I is heterozygous for two known pathogenic variants in SLC26A2, a splice site variant c.-26+2T > C and a missense variant c.1957T > A (p.Cys653Ser), while patient II is compound heterozygous for missense variants c.835C > T (p.Arg279Trp) and c.1535C > A (p.Thr512Lys). These patients further elucidate the variability of the phenotypic and genetic presentations of rMED.

Late vertebral side effects in long-term survivors of irradiated childhood brain tumor.

PURPOSE: Long-term side effects of the treatments are common in survivors of irradiated pediatric brain tumors. Ionizing radiation in combination with surgery and chemotherapy during childhood may reduce vertebral height and bone mineral density (BMD), and cause growth failure. The aim of this study was to evaluate the late consequences of tumor treatments on vertebrae in survivors of childhood brain tumors. METHODS: 72 adult survivors (mean age 27.8 years, standard deviation 6.7) of irradiated childhood brain tumor were studied by spinal magnetic resonance imaging (MRI) for vertebral abnormalities from the national cohort of Finland. Patients were treated in five university hospitals in Finland between the years 1970 and 2008. Subject height and weight were measured and body mass index (BMI) was calculated. The morphology and height/depth ratio of the vertebrae in the middle of the kyphotic thoracic curvature (Th8) and lumbar lordosis (L3) were examined. Vertebrae were analyzed by Genant's semiquantative (SQ) method and spinal deformity index (SDI) was calculated. BMD was measured by using dual X-ray absorptiometry. RESULTS: 4.2% (3/72) of the patients had undiagnosed asymptomatic vertebral fracture and 5.6% (4/72) of patients had radiation-induced decreased vertebral body height. Male patients had flatter vertebrae compared with females. Patient age at the time of irradiation, BMI and irradiation area correlated to vertebral morphology differentially in males and females. BMD had no association with the vertebral shape. Patients who had received craniospinal irradiation were shorter than the general population. CONCLUSION: Childhood brain tumor survivors had a high number of vertebral abnormalities in young adulthood. Irradiation was associated with abnormal vertebral morphology and compromised final height. Male gender may predispose vertebrae to the side effects of irradiation.

Impaired growth and intracranial calcifications in autosomal dominant hypocalcemia caused by a GNA11 mutation.

OBJECTIVE: Autosomal dominant hypocalcemia (ADH) is characterized by hypocalcemia and inappropriately low PTH concentrations. ADH type 1 is caused by activating mutations in the calcium-sensing receptor (CASR), a G-protein-coupled receptor signaling through α11 (Gα11) and αq (Gαq) subunits. Heterozygous activating mutations in GNA11, the gene encoding Gα11, underlie ADH type 2. This study describes disease characteristics in a family with ADH caused by a gain-of-function mutation in GNA11. DESIGN: A three-generation family with seven members (3 adults, 4 children) presenting with ADH. METHODS: Biochemical parameters of calcium metabolism, clinical, genetic and brain imaging findings were analyzed. RESULTS: Sanger sequencing revealed a heterozygous GNA11 missense mutation (c.1018G>A, p.V340M) in all seven hypocalcemic subjects, but not in the healthy family members (n=4). The adult patients showed clinical symptoms of hypocalcemia, while the children were asymptomatic. Plasma ionized calcium ranged from 0.95 to 1.14mmol/L, yet plasma PTH was inappropriately low for the degree of hypocalcemia. Serum 25OHD was normal. Despite hypocalcemia 1,25(OH)2D and urinary calcium excretion were inappropriately in the reference range. None of the patients had nephrocalcinosis. Two adults and one child (of the two MRI scanned children) had distinct intracranial calcifications. All affected subjects had short stature (height s.d. scores ranging from -3.4 to -2.3 vs -0.5 in the unaffected children). CONCLUSIONS: The identified GNA11 mutation results in biochemical abnormalities typical for ADH. Additional features, including short stature and early intracranial calcifications, cosegregated with the mutation. These findings may indicate a wider role for Gα11 signaling besides calcium regulation.

Metronomic therapy can increase quality of life during paediatric palliative cancer care, but careful patient selection is essential.

AIM: Children with refractory or high-risk malignancies frequently suffer from poor quality of life during palliative care. This study explored the effect of metronomic drug administration on survival and quality of life in paediatric patients with various refractory or high-risk tumours. METHODS: We treated 17 patients with a maintenance therapy that consisted of metronomic thalidomide, etoposide and celecoxib. The endpoints of the study were overall and progression-free survival, changes in the Karnofsky-Lansky scores from baseline to the end of the study therapy and radiological responses. RESULTS: The median overall survival after the start of the study therapy was 6.2 months (range 2.0-57.7), and the six-, 12- and 24-month survival rates were 59%, 18% and 18%, respectively. The median progression-free survival was 3.2 months (range 0.3-17.8). The Karnofsky-Lansky scores increased significantly during the study therapy (p = 0.02), with 35% of the patients having a transient improvement in their clinical status. Radiologically, one partial response and two disease stabilisations were encountered. Grade III-V adverse events occurred in 76% of the patients. CONCLUSION: Metronomic therapy may increase the quality of life during palliative care for childhood cancer, but requires careful patient selection to minimise the risk of serious adverse events.

Bone marrow fat unsaturation in young adults is not affected by present or childhood obesity, but increases with age: A pilot study.

OBJECTIVES: Obesity increases bone marrow fat (BMF) content. The association between early obesity and bone marrow fatty acid composition is unknown. We measured BMF unsaturation index (UI) in normal-weight and overweight young adults with a known weight status in early childhood and tested the relationship between BMF UI and exercise history, glycemic state, and other clinical characteristics. METHODS: The study included 18 normal-weight (BMI <25 kg/m(2); 2 males, 16 females) and 17 overweight (BMI ≥25 kg/m(2); 9 males, 8 females) young adults aged 15-27 years. BMF UI was assessed with magnetic resonance proton spectroscopy optimized to reduce water interference. Exercise information was obtained with a pedometer accompanied with the history of recent physical activity. Blood samples (insulin, glucose, HbA1c) and body characteristics (BMI, waist-to-hip ratio, body fat composition) were assessed. RESULTS: BMF UI was not affected by obesity at the time of study or before age 7 years. BMF UI increased with age in normal-weight and overweight subjects (R=0.408, p=0.015) but did not associate with gender, physical activity or body fat composition; a suggestive association was observed with glucose (R=-0.289, p=0.10). CONCLUSIONS: The association of BMF UI with age in early adulthood may represent normal maturation of bone marrow. There was a trend toward an association with blood glucose, warranting further studies.

Compromised peak bone mass in patients with inflammatory bowel disease--a prospective study.

OBJECTIVE: To evaluate peak bone mass attainment in children and adolescents with inflammatory bowel disease and to identify risk factors for suboptimal bone mass attainment. STUDY DESIGN: We conducted a prospective follow-up study of 47 children and adolescents (24 males) with ulcerative colitis (n = 30) or Crohn's disease (n = 17). They were assessed for lumbar spine areal bone mineral density (aBMD) and for height-adjusted whole body less head bone mineral content (BMC); the values were corrected for bone age. RESULTS: Altogether, 73% of the patients had completed pubertal development after the median follow-up time of over 5 years. Despite clinical inactivity of the disease in 70% of the patients at the follow-up visit, BMD or BMC Z-scores improved in none of the measurement sites. Lumbar spine aBMD Z-scores (mean difference [95% CI], -0.47 [-0.92 to -0.03]; P = .04) and whole body less head BMC height- and bone age-adjusted Z-scores (-0.52 [-1.01 to -0.02]; P = .04) decreased in patients who were pubertal at baseline and completed their pubertal development during the follow-up. Postpubertal patients had lower aBMD and BMC Z-scores in comparison with prepubertal and pubertal patients. Low lumbar spine aBMD (Z-score < -1.0) was associated with completed pubertal development, underweight, and greater lifetime cumulative weight-adjusted prednisolone dose. Vertebral fractures were detected in 3 patients (6%). One-fourth of the patients had insufficient serum 25-hydroxyvitamin D concentrations (<50 nmol/L). CONCLUSIONS: The longitudinal follow-up over the pubertal years shows that inflammatory bowel disease poses a significant threat for bone health. The suboptimal peak bone mass attainment may have life-long consequences.

Hypoplastic anemia in cartilage-hair hypoplasia-balancing between iron overload and chelation.

OBJECTIVE: To evaluate the severity of iron overload and the success of iron chelation therapy in patients with cartilage-hair hypoplasia (CHH) and hypoplastic anemia, with particular focus on adverse effects of iron chelators. STUDY DESIGN: Four of the 23 presently surviving Finnish patients with CHH under 18 years of age are dependent on regular red blood cell transfusions. Their hospital records were reviewed for history of anemia and chelation therapy. Cumulative iron load from transfusions was calculated. Efficacy of the chelation therapy was evaluated biochemically and by liver iron content assessments. RESULTS: At the introduction of iron chelation, the patients had received on average 99 (37-151) transfusions; the mean cumulative iron overload was 4640 (800-8200) mg, the annual iron accumulation rate 0.35 (0.25-0.41) mg/kg/d, and the mean plasma ferritin was 2896 (1217-6240) µg/L. Liver iron content, determined by biopsy in 3 patients, was on average 20.0 (6.6-30.0) mg/g liver dry weight. All patients, except 1 with Hirschsprung disease, tolerated deferoxamine, deferiprone, and deferasirox therapy well, showing only mild adverse effects typical for the agents. Plasma ferritin levels and liver magnetic resonance imaging T2* of iron overload showed successful chelation. CONCLUSION: Iron chelation is well tolerated in patients with CHH, with possible exception of patients with Hirschsprung disease. Successful chelation will prepare for hematopoietic stem cell transplantation in patients with CHH with persistent transfusion dependency.

Neuroimaging and neurological findings in patients with hypochondroplasia and FGFR3 N540K mutation.

Hypochondroplasia (HCH), an autosomal dominant skeletal dysplasia caused by mutations in the FGFR3 gene, has not been commonly associated with neurological problems. Temporal lobe dysgenesis associated with epilepsy was recently described in single patients. In this retrospective study, we assessed neurological and neuroimaging aspects of 13 FGFR3 (N540K) mutation verified HCH patients in Finland. Eight patients had neurocognitive difficulties, ranging from specific learning disorder (2/13) to mild intellectual disability (5/13) or global developmental delay (1/13). Six of 13 patients had a history of seizures or epilepsy. Eight patients had undergone MRI. They all had structural abnormalities consistent with temporal lobe dysgenesis. Six patients had peritrigonal white matter reduction, and 4 had abnormally shaped lateral ventricles. We recommend a close follow-up of development in patients with HCH and a low threshold for neuroimaging.

Draft consensus guidelines for diagnosis and treatment of Shwachman-Diamond syndrome.

Shwachman-Diamond syndrome (SDS) is an autosomal recessive disorder characterized by pancreatic exocrine insufficiency and bone marrow failure, often associated with neurodevelopmental and skeletal abnormalities. Mutations in the SBDS gene have been shown to cause SDS. The purpose of this document is to provide draft guidelines for diagnosis, evaluation of organ and system abnormalities, and treatment of hematologic, pancreatic, dietary, dental, skeletal, and neurodevelopmental complications. New recommendations regarding diagnosis and management are presented, reflecting advances in understanding the genetic basis and clinical manifestations of the disease based on the consensus of experienced clinicians from Canada, Europe, and the United States. Whenever possible, evidence-based conclusions are made, but as with other rare diseases, the data on SDS are often anecdotal. The authors welcome comments from readers.

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.