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.

Profile of minor neurological findings after perinatal asphyxia.

AIM: To characterise the spectrum of findings in sequential neurological examinations, general movements (GM) assessment and magnetic resonance imaging (MRI) of infants with perinatal asphyxia. METHODS: The prospective cohort study of term infants with perinatal asphyxia treated at Helsinki University Hospital's neonatal units in 2016-2020 used Hammersmith Neonatal Neurological Examination (HNNE) and brain MRI at 2 weeks and Hammersmith Infant Neurological Examination (HINE) and GM assessment at 3 months of age. RESULTS: Analysis included 50 infants: 33 displaying perinatal asphyxia without hypoxic-ischaemic encephalopathy (HIE), seven with HIE1 and 10 with HIE2. Of the infants with atypical HNNE findings, 24/25 perinatal asphyxia without HIE cases, 5/6 HIE1 cases and all 10 HIE2 cases showed atypical findings in the HINE. The HINE identified atypical spontaneous movements significantly more often in infants with white matter T2 hyperintensity. CONCLUSION: In this cohort, most infants with perinatal asphyxia, with or without HIE, presented atypical neurological findings in sequential examinations. The profile of neurological findings for children with perinatal asphyxia without HIE resembled that of children with HIE. White matter T2 hyperintensity was associated with atypical spontaneous movements in the HINE and was a frequent MRI finding also in perinatal asphyxia without HIE.

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.

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.

Novel Hemizygous IL2RG p.(Pro58Ser) Mutation Impairs IL-2 Receptor Complex Expression on Lymphocytes Causing X-Linked Combined Immunodeficiency.

Hypomorphic IL2RG mutations may lead to milder phenotypes than X-SCID, named variably as atypical X-SCID or X-CID. We report an 11-year-old boy with a novel c. 172C>T;p.(Pro58Ser) mutation in IL2RG, presenting with atypical X-SCID phenotype. We also review the growing number of hypomorphic IL2RG mutations causing atypical X-SCID. We studied the patient's clinical phenotype, B, T, NK, and dendritic cell phenotypes, IL2RG and CD25 cell surface expression, and IL-2 target gene expression, STAT tyrosine phosphorylation, PBMC proliferation, and blast formation in response to IL-2 stimulation, as well as protein-protein interactions of the mutated IL2RG by BioID proximity labeling. The patient suffered from recurrent upper and lower respiratory tract infections, bronchiectasis, and reactive arthritis. His total lymphocyte counts have remained normal despite skewed T and B cells subpopulations, with very low numbers of plasmacytoid dendritic cells. Surface expression of IL2RG was reduced on his lymphocytes. This led to impaired STAT tyrosine phosphorylation in response to IL-2 and IL-21, reduced expression of IL-2 target genes in patient CD4+ T cells, and reduced cell proliferation in response to IL-2 stimulation. BioID proximity labeling showed aberrant interactions between mutated IL2RG and ER/Golgi proteins causing mislocalization of the mutated IL2RG to the ER/Golgi interface. In conclusion, IL2RG p.(Pro58Ser) causes X-CID. Failure of IL2RG plasma membrane targeting may lead to atypical X-SCID. We further identified another carrier of this mutation from newborn SCID screening, lost to closer scrutiny.

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.

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.

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.

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.

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.

The thoracic and lumbar spine in severe juvenile idiopathic arthritis: magnetic resonance imaging analysis in 50 children.

OBJECTIVE: To determine the prevalence of vertebral fractures as a complication of juvenile idiopathic arthritis (JIA). STUDY DESIGN: This cross-sectional study evaluated the prevalence and characteristics of spinal abnormalities in 50 children (aged 7.0-18.7 years) with treatment-resistant JIA by magnetic resonance imaging. Vertebral deformities, endplate irregularities, intervertebral disc involvement, spinal canal, neural foramina, and back muscles were analyzed and correlated with clinical characteristics and bone mineral density. RESULTS: Magnetic resonance imaging revealed various abnormalities in 31 patients (62%). Vertebral compression was seen in 28%, disc degeneration in 46%, protrusions in 14%, prolapses in 4%, endplate changes in 26%, and anterior vertebral corner lesions in 16%. Two patients (4%) had mild spinal canal narrowing without medullar involvement; none had neural root compression. Six patients (12%) had mild back muscle atrophy. No correlation was observed between spinal fractures or other vertebral changes and disease activity or duration, pain or bone mineral density; patients with spinal fractures tended to have a higher recent glucocorticoid exposure (P=.086). CONCLUSION: Children with severe JIA have a high prevalence of compression fractures and other vertebral, endplate, and disc abnormalities in the thoracic and lumbar spine.

Impaired bone health in inflammatory bowel disease: a case-control study in 80 pediatric patients.

Previous studies have indicated that children with inflammatory bowel disease (IBD) may not achieve optimal bone mass. We evaluated the skeletal characteristics in children and adolescents with IBD. This cross-sectional cohort study comprised 80 IBD patients (median age 14.9 years, range 5-20) with a median disease duration of 3.4 years; 51 had ulcerative colitis, 26 Crohn disease, and 3 unspecified colitis. Eighty age- and gender-matched healthy subjects served as controls. Areal bone mineral density (aBMD), body composition, and vertebral fractures (VFs) were assessed by DXA. Bone age (BA) was determined for IBD patients. Findings were correlated with disease- and treatment-related parameters and biochemistry. IBD patients had lower BA-adjusted lumbar spine and whole-body aBMD (p < 0.001 for both) and whole-body BMC adjusted for height (p = 0.02) than controls. Lean mass and fat mass Z scores did not differ between the groups, but IBD patients had lower whole-body BMC relative to muscle mass (p = 0.006). Despite vitamin D supplementation in 48 %, vitamin D deficiency was common. In IBD cumulative weight-adjusted prednisolone dose >150 mg/kg for the preceding 3 years increased the risk for low whole-body aBMD (OR = 5.5, 95 % CI 1.3-23.3, p = 0.02). VFs were found in 11 % of patients and in 3 % of controls (p = 0.02). IBD in childhood was associated with low aBMD and reduced bone mass accrual relative to muscle mass; the risk for subclinical VFs may be increased. These observations warrant careful follow-up and active preventive measures.

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.

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.

Poor aEEG background recovery after perinatal hypoxic ischemic encephalopathy predicts postneonatal epilepsy by age 4 years.

OBJECTIVE: This study evaluated the accuracy of neonatal amplitude-integrated electroencephalography (aEEG) brain monitoring for predicting development of postneonatal epilepsy after perinatal hypoxic ischemic encephalopathy (HIE). METHODS: We studied a population-based cohort of 85 consecutive neonates with moderate-to-severe HIE that had aEEG started <12 hours postnatally. We marked electrographic seizures and graded each hour of the aEEG background as inactive, burst-suppression, or continuous without or with sleep cycling. These aEEG parameters were compared to outcome at 4-years age (deceased, epilepsy, cerebral palsy without epilepsy, favorable), which was available for 80 children. RESULTS: At group level, total seizure burden (p = 0.003), maximum hourly seizure burden (p = 0.007), and aEEG background recovery (p < 0.001) were all significantly associated with outcome. At individual level six children developed epilepsy, and the most accurate predictors for later epilepsy were inactive aEEG at 24 hours (accuracy 97%, positive predictive value 100%, two false negatives) and inactive aEEG at the onset of seizures (accuracy 97%, sensitivity of 100%, one false positive). CONCLUSIONS: At individual level aEEG background recovery was a better predictor for later epilepsy than neonatal seizures, although both were associated with epilepsy at group level. SIGNIFICANCE: Poor aEEG background recovery predicts development of epilepsy after perinatal HIE at individual level.

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.

Towards multimodal brain monitoring in asphyxiated newborns with amplitude-integrated EEG and simultaneous somatosensory evoked potentials.

BACKGROUND: Somatosensory evoked potentials (SEPs) offer an additional bedside tool for outcome prediction after perinatal asphyxia. AIMS: To assess the reliability of SEPs recorded with bifrontoparietal amplitude-integrated electroencephalography (aEEG) brain monitoring setup for outcome prediction in asphyxiated newborns undergoing therapeutic hypothermia. STUDY DESIGN: Retrospective observational single-center study. SUBJECTS: 27 consecutive asphyxiated full- or near-term newborns (25 under hypothermia) that underwent median nerve aEEG-SEPs as part of their clinical evaluation at the neonatal intensive care unit of Helsinki University Hospital. OUTCOME MEASURES: aEEG-SEP classification (present, absent or unreliable) was compared to classification of SEPs recorded with a full EEG montage (EEG-SEP), and outcome determined from medical records at approximately 12-months-age. Unfavorable outcome included death, cerebral palsy, or severe epilepsy. RESULTS: The aEEG-SEP and EEG-SEP classifications were concordant in 21 of the 22 newborns with both recordings available. All five newborns with bilaterally absent aEEG-SEPs had absent EEG-SEPs and the four with outcome information available had an unfavorable outcome (one was lost to follow-up). Of the newborns with aEEG-SEPs present, all with follow-up exams available had bilaterally present EEG-SEPs and a favorable outcome (one was lost to follow-up). One newborn with unilaterally absent aEEG-SEP at 25 h of age had bilaterally present EEG-SEPs on the next day, and a favorable outcome. CONCLUSIONS: aEEG-SEPs recorded during therapeutic hypothermia on the first postnatal days are reliable for assessing brain injury severity. Adding SEP into routine aEEG brain monitoring offers an additional tool for very early outcome prediction after birth asphyxia.

Low density lipoprotein receptor-related protein 5 (LRP5) mutations and osteoporosis, impaired glucose metabolism and hypercholesterolaemia.

OBJECTIVE: Mutations in the low-density lipoprotein receptor-related protein 5 gene (LRP5) underlie osteoporosis-pseudoglioma syndrome. Animal models implicate a role for LRP5 in lipid and glucose homeostasis. The objective was to evaluate metabolic consequences of LRP5 mutations in humans. DESIGN AND PATIENTS: Thirteen Finnish individuals with homozygous or heterozygous LRP5 mutations were assessed for bone health, glucose and lipid metabolism, and for serum serotonin concentration. Results were compared with findings in family members without mutations. MEASUREMENTS: Bone mineral density (BMD), vertebral morphology, oral and intravenous glucose tolerance tests, lipid profile and serum serotonin concentrations. RESULTS: Two individuals were homozygous for R570W, one compound heterozygous for R570W and R1036Q, and 10 were heterozygous (six for R570W, three for R1036Q and one for R925C). Subjects with two LRP5 mutations had multiple spinal fractures and low BMD. Subjects with one mutation had significantly lower median lumbar spine (P = 0.004) and femoral neck (P = 0.005) BMD Z-scores, and more often vertebral fractures than the 18 individuals without mutations. Of the 12 subjects with LRP5 mutation six had diabetes and one had impaired glucose tolerance. Intravenous glucose tolerance tests suggested impaired beta-cell function; no insulin resistance was observed. Prevalence of hypercholesterolaemia was similar in mutation positive and negative subjects. Serum serotonin concentrations showed a trend towards higher concentrations in subjects with LRP5 mutation. CONCLUSIONS: We found high prevalence of osteoporosis and abnormal glucose metabolism in subjects with LRP5 mutation(s). Further studies are needed to establish the role of LRP5 in glucose and lipid metabolism.