Management of RANKL-mediated Disorders With Denosumab in Children and Adolescents: A Global Expert Guidance Document.

CONTEXT: Denosumab is an effective treatment for many receptor activator of nuclear factor kappa-B ligand (RANKL)-mediated disorders but there are potential safety considerations and limited data to guide its use in children and adolescents. OBJECTIVE: This document seeks to summarize the evidence and provide expert opinion on safe and appropriate use of denosumab in pediatric RANKL-mediated disorders. PARTICIPANTS: Ten experts in pediatric bone and mineral medicine from 6 countries with experience in the use of denosumab participated in the creation of this document. EVIDENCE: Data were sourced from the published literature, primarily consisting of case reports/series and review articles because of the lack of higher level evidence. Expert opinion of the authors was used substantially when no published data were available. CONCLUSION: Denosumab is an effective treatment for RANKL-mediated disorders in children and adolescents but is often not curative and, in some cases, is best used in conjunction with surgical or other medical treatments. Careful multidisciplinary planning is required to define the goals of treatment and expert oversight needed to manage the risk of mineral abnormalities. Substantive, collaborative research efforts are needed to determine optimal treatment regimens and minimize risks.

Case Report: Osteosclerotic metaphyseal dysplasia with optic nerve involvement and progressive osteonecrosis of the jaw due to a novel LRRK1 mutation.

Background: Osteosclerotic metaphyseal dysplasia (OSMD, OMIM 615198) is an extremely rare autosomal recessive osteopetrosis disorder resulting in a distinctive pattern of osteosclerosis of the metaphyseal margins of long tubular bones. To date, only thirteen cases have been reported (eight molecularly confirmed). Five homozygous sequence variants in the leucine-rich repeat kinase 1 (LRRK1) gene have been identified to cause OSMD. We present two male siblings with OSMD with a novel LRRK1 variant. Cases: The index case, now aged 6 years, was referred aged 9 months when diffuse sclerosis of the ribs and vertebral bodies, suggestive of osteopetrosis, was incidentally identified on a chest radiograph for suspected lower respiratory tract infection. Parents were consanguineous and of Pakistani origin. Further evaluation revealed developmental delay, nystagmus with bilateral optic nerve hypoplasia and severe visual impairment. Skeletal survey confirmed typical changes of OSMD, with widespread diffuse sclerosis and Erlenmeyer flask deformity of long bones. His older sibling, now aged 12 years, was 7 years at the time of referral and had similar clinical course and skeletal findings. Additionally, he had a chronic progressive osteonecrosis of the left mandible that required debridement, debulking and long-term antibiotics. Skeletal survey revealed findings similar to his sibling. Neither sibling had significant skeletal fractures or seizures. Unlike most previous reports suggesting sparing of the skull and lack of visual impairment, our patients had evidence of osteosclerosis of the cranium. Genetic screening for the common autosomal recessive and dominant pathogenic variants of osteopetrosis was negative. Whole Exome Sequencing (WES) followed by Sanger sequencing, identified a novel homozygous LRRK1 c.2506C>T p. (Gln836Ter) nonsense variant predicted to result in premature truncation of LRRK1 transcript. Conclusion: Our cases confirm the autosomal recessive inheritance and expand the spectrum of genotype and phenotype of OSMD reported in the literature. Increasing reports of LRRK1 variants in this phenotype raise the question of whether LRRK1 should be included in targeted osteopetrosis panels. Bone histology in previous cases has shown this to be an osteoclast rich form of osteopetrosis raising the possibility that haematopoietic stem cell transplantation may be an appropriate treatment modality.

Association of bone mineralization markers with dietary nutrient intake in adolescents with and without biochemical osteomalacia.

Background: Dietary intake is widely known to play a crucial role in achieving peak bone mass among children and adolescents. Unfortunately, this information is lacking among Arab adolescents, an understudied demographic that has recently been observed to have a high prevalence of abnormal mineralization markers [low serum 25(OH)D, high serum alkaline phosphatase (ALP), low calcium (Ca) and/or inorganic phosphate (Pi)] suggestive of biochemical osteomalacia (OM, defined as any 2 of the 4 parameters). In order to fill this gap, we aimed to evaluate the associations of serum markers of biochemical OM with dietary intake of macronutrients, vitamins and trace minerals. Methods: Saudi adolescents (N = 2,938, 57.8% girls), aged 12-17 years from 60 different schools in Riyadh, Saudi Arabia were included. Dietary intake of nutrients was calculated following a semi-quantitative 24 h dietary recall over 3 weekdays and 1 weekend-day using a validated food frequency questionnaire. Compliance to reference daily intake (RDI) of macronutrients, vitamins and trace minerals were calculated. Fasting blood samples were collected and circulating levels of 25(OH)D, ALP, Ca, and Pi were analyzed. Results: A total of 1819 (1,083 girls and 736 boys) adolescents provided the dietary recall data. Biochemical OM was identified in 175 (9.6%) participants (13.5% in girls, 3.9% in boys, p < 0.01) while the rest served as controls (N = 1,644). All participants had serum 25(OH)D levels <50 nmoL/L. Most participants had very low dietary intakes of Ca (median ~ 290 mg) and vitamin D (median ~ 4 µg) which are far below the RDI of 1,300 mg/day and 20 µg/day, respectively. In contrast, excess dietary intakes of Pi, Na, K, and Fe were observed in all participants. In the biochemical OM group, thiamine and protein intake were significant predictors of serum 25(OH)D, explaining 4.3% of the variance perceived (r = 0.23, adjusted r2 = 4.3%, p = 0.01). Among controls, dietary vitamin C and vitamin D explained 0.6% of the total variation in serum 25(OH)D (r = 0.09, adjusted r2 = 0.6%, p = 0.004). Conclusion: Arab adolescents do not meet the RDI for dietary Ca and vitamin D, and none have sufficient vitamin D status (25(OH)D levels >50 nmol/L) but they exceed the RDI for dietary Pi. Interpreting these data in the light of the increased prevalence of rickets in Arab countries, food fortification to optimise vitamin D and Ca intake in Saudi adolescents should be considered.

Vitamin D Deficiency in Chronic Childhood Disorders: Importance of Screening and Prevention.

Vitamin D plays a vital role in regulating calcium and phosphate metabolism and maintaining bone health. A state of prolonged or profound vitamin D deficiency (VDD) can result in rickets in children and osteomalacia in children and adults. Recent studies have demonstrated the pleiotropic action of vitamin D and identified its effects on multiple biological processes in addition to bone health. VDD is more prevalent in chronic childhood conditions such as long-standing systemic illnesses affecting the renal, liver, gastrointestinal, skin, neurologic and musculoskeletal systems. VDD superimposed on the underlying disease process and treatments that can adversely affect bone turnover can all add to the disease burden in these groups of children. The current review outlines the causes and mechanisms underlying poor bone health in certain groups of children and young people with chronic diseases with an emphasis on the proactive screening and treatment of VDD.

Nutritional rickets presenting with developmental regression: a rare presentation of rickets.

Rickets is a disorder of defective mineralisation of the growth plate. Vitamin D deficiency remains the leading cause of nutritional rickets worldwide.We present the case of a 3.5-year-old breastfed boy who presented with dental abscess when a history of developmental regression was noted. Clinical assessment revealed hypotonia, poor growth and stunting. Biochemistry identified hypocalcaemia (1.63mmol/L, [normal range (NR) 2.2-2.7mmol/L]), severe vitamin D deficiency (25hydroxyvitamin D 5.3nmol/L, [NR > 50nmol/L]) with secondary hyperparathyroidism (Parathormone 159pmol/L, [NR 1.6-7.5pmol/L]) and rickets on radiographs. Growth failure screening suggested hypopituitarism with central hypothyroidism and low IGF1 at baseline, however, dynamic tests confirmed normal axis. Management included nasogastric nutritional rehabilitation, cholecalciferol and calcium supplementation and physiotherapy. A good biochemical response in all parameters was observed within 3 weeks and reversal of developmental regression by 3 months from treatment. Developmental regression as a presentation of nutritional rickets is rare and requires a high index of suspicion.

Establishing the Prevalence of Osteomalacia in Arab Adolescents Using Biochemical Markers of Bone Health.

Nutrition-acquired osteomalacia is a bone mineralization disorder associated with dietary calcium and/or solar vitamin D deficiency, risk factors considered common in the Middle Eastern region. Establishing less invasive, cheap, and widely available diagnostic markers for this underdiagnosed entity is essential, in particular for screening in high-risk groups. This study assessed the prevalence of biochemical osteomalacia in Arab adolescents. In this cross-sectional study performed between September 2019 and March 2021, adolescents aged 12−17 years from 60 different secondary and preparatory year schools in Riyadh, Saudi Arabia were included. Anthropometrics and fasting blood samples were collected. Biochemical osteomalacia was defined as any two of the following four serum markers of hypomineralization, namely low 25 hydroxyvitamin D (25OHD < 30 nmol/L), high alkaline phosphatase (ALP), low calcium (Ca), and/or inorganic phosphorous (Pi). A total of 2938 Arab adolescents [1697 girls; mean age (years) 14.8 ± 1.8; 1241 boys; mean age 15.1 ± 1.6] were recruited. Vitamin D deficiency was noted in 56.2% (n = 953) of girls and 27.1% (n = 336) of boys (p < 0.001). The overall prevalence of biochemical osteomalacia was 10.0% (n = 295/2938) and was higher in girls than boys (14.7% vs. 3.6%, p < 0.001). The prevalence of low serum Ca and/or Pi was also higher in girls than in boys (24.2% vs. 12.5%, respectively, p < 0.001), as well as elevated ALP (5.1% vs. 1.5%, p < 0.001). Overall, girls were 4.6 times (95% CI 3.3−6.4) more likely to have biochemical osteomalacia than boys. Screening of apparently healthy Arab adolescents revealed a high prevalence of deranged mineralization markers suggestive of biochemical osteomalacia, which was significantly more common in girls than boys and was likely associated with Arab traditional clothing and diet. The proposed combination of typically altered mineralization markers for the diagnosis of osteomalacia is, at best, suggestive until further comparisons with established diagnostic tools (histological analysis of bone biopsies) are conducted.

The burden of vitamin D deficiency in household members of children presenting with symptomatic vitamin D deficiency.

Background: Micronutrient deficiencies are common among household/family members due to shared lifestyle and dietary habits. The extent of biochemical abnormalities in household members of children presenting with symptomatic vitamin D deficiency remains unknown. Aim: Investigate the prevalence of vitamin D deficiency and biochemical osteomalacia in the mothers and siblings of children presenting with symptomatic vitamin D deficiency. Methods: All mothers and sibling of children referred to a single tertiary endocrine centre between January 2018 and December 2021, with symptomatic vitamin D deficiency were investigated prospectively for vitamin D deficiency [defined as 25 hydroxyvitamin D (25OHD) < 30nmol/L] and biochemical osteomalacia [vitamin D deficiency and elevated alkaline phosphatase (ALP) and/or parathormone (PTH)] as per clinical guidelines. Reults: Ninety-seven family members (68 siblings and 29 mothers) of 29 index cases (median age 1.7 years, 55.5% male) were investigated. The majority (65.5%, n=19) were of Asian ethnic background. The mean (SD) 25OHD levels of the index, maternal and sibling cohorts were 15 (10), 15 (7) and 20 (10) nmol/L respectively. Vitamin D deficiency was noted in 93% of the maternal and 79% of the sibling cohorts. Biochemical osteomalacia was present in 72% of the maternal and 79% of the sibling cohorts. Mothers of infants had significantly lower mean 25OHD levels compared to mothers of older children [11 (n=12) vs 18 nmol/L (n=17) respectively, p=0.006)], most of whom were symptomatic (66.6%, n=8/12). None of the mothers had hypocalcaemia. Among the 10% (n=7) of the siblings with hypocalcaemia, 86% (n=6/7) had concurrent dietary calcium deficiency and 71.4% (n= 5/7) reported symptoms in retrospect. Hypocalcaemic siblings had significantly lower 25OHD (7 vs 15 nmol/L, p<0.001), higher PTH (175 vs 58 ng/L, p<0.001) and ALP (846 vs 318 IU/L, p<0.001), respectively compared to normocalcaemic siblings. Conclusions: In view of the substantial morbidity uncovered in household/family members of children diagnosed with symptomatic vitamin D deficiency, we recommend universal supplementation of all risk groups. Biochemical testing and treatment is indicated to replenish stores only in those at highest risk such as mothers of infants, individuals with concurrent dietary calcium deficiency and those with clinical symptoms.

Nutritional rickets & osteomalacia: A practical approach to management.

Defective mineralization of the growth plate and preformed osteoid result in rickets and osteomalacia, respectively. The leading cause of rickets worldwide is solar vitamin D deficiency and/or dietary calcium deficiency collectively termed as nutritional rickets. Vitamin D deficiency predominates in high-latitude countries in at-risk groups (dark skin, reduced sun exposure, infants and pregnant and lactating women) but is emerging in some tropical countries due to sun avoidance behaviour. Calcium deficiency predominates in tropical countries, especially in the malnourished population. Nutritional rickets can have devastating health consequences beyond bony deformities (swollen wrist and ankle joints, rachitic rosary, soft skull, stunting and bowing) and include life-threatening hypocalcaemic complications of seizures and, in infancy, heart failure due to dilated cardiomyopathy. In children, diagnosis of rickets (always associated with osteomalacia) is confirmed on radiographs (cupping and flaring of metaphyses) and should be suspected in high risk individuals with the above clinical manifestations in the presence of abnormal blood biochemistry (high alkaline phosphatase and parathyroid hormone, low 25-hydroxyvitamin D and calcium and/or low phosphate). In adults or adolescents with closed growth plates, osteomalacia presents with non-specific symptoms (fatigue, malaise and muscle weakness) and abnormal blood biochemistry, but only in extreme cases, it is associated with radiographic findings of Looser's zone fractures. Bone biopsies could confirm osteomalacia at earlier disease stages, for definitive diagnosis. Treatment includes high-dose cholecalciferol or ergocalciferol daily for a minimum of 12 wk or stoss therapy in exceptional circumstances, each followed by lifelong maintenance supplementation. In addition, adequate calcium intake through diet or supplementation should be ensured. Preventative approaches should be tailored to the population needs and incorporate multiple strategies including targeted vitamin D supplementation of at-risk groups and food fortification with vitamin D and/or calcium. Economically, food fortification is certainly the most cost-effective way forward.

Tissue non-specific alkaline phosphatase activity and mineralization capacity of bi-allelic mutations from severe perinatal and asymptomatic hypophosphatasia phenotypes: Results from an in vitro mutagenesis model.

BACKGROUND: Hypophosphatasia (HPP) is an inherited metabolic bone disease characterized by reduced mineralization due to mutations in the tissue non-specific alkaline phosphatase (ALPL) gene. HPP is clinically variable with extensive allelic heterogeneity in the ALPL gene. We report the findings of in vitro functional studies following site-directed mutagenesis in bi-allelic mutations causing extreme clinical phenotypes; severe perinatal and asymptomatic HPP. AIMS: Elucidate genotype-phenotype correlation using in vitro functional studies and 3 dimensional (3D) ALP modelling. METHODS: Clinical, biochemical and radiological features were recorded in two children with extreme HPP phenotypes: Subject 1 (S1): Perinatal HPP with compound heterozygous mutations (c.110T>C; c.532T>C); Subject 2 (S2): asymptomatic with homozygous missense mutation (c.715G>T). Plasmids created for mutants 1 c.110T>C (L37P), 2 c.532T>C (Y178H) and 3 c.715G>T (D239Y) using in vitro mutagenesis were transfected into human osteosarcoma (U2OS) cells and compared to wildtype (WT) and mock cDNA. ALP activity was measured using enzyme kinetics with p-nitrophenylphosphate. Mineral deposition was evaluated photometrically with Alizarin Red S staining after culture with mineralization medium. Western blot analysis was performed to identify the mature type protein expression (80 kDa). Mutations were located on a 3D ALP model. Co-transfection was performed to identify dominant negative effect of the mutants. RESULTS: Phenotype: S1, had typical perinatal HPP phenotype at birth; extremely under-mineralized bones and pulmonary hypoplasia. S2, diagnosed incidentally by laboratory tests at 4 years, had normal growth, development, dentition and radiology. All S2's siblings (3 homozygous, 1 heterozygous) were asymptomatic. All subjects had typical biochemical features of HPP (low ALP, high serum pyridoxal-5'-phosphate), except the heterozygous sibling (normal ALP). Functional assay: Mutants 1 and 2 demonstrated negligible ALP activity and mineralization was 7.9% and 9.3% of WT, respectively. Mutant 3 demonstrated about 50% ALP activity and 15.5% mineralization of WT. On Western blot analysis, mutants 1 and 2 were detected as faint bands indicating reduced expression and mutant 3 was expressed as mature form protein with 50% of WT expression. Mutant 1 was located near the Glycosylphosphatidylinositol anchor, 2 at the core structure of the ALP protein and 3 at the periphery of the protein structure. Co-transfection did not reveal a dominant negative effect in any of the mutants. CONCLUSION: Our findings expand the current knowledge of functional effect of individual mutations and the importance of their location in the ALP structure.

Spot the silent sufferers: A call for clinical diagnostic criteria for solar and nutritional osteomalacia.

Osteomalacia and rickets result from defective mineralization when the body is deprived of calcium. Globally, the main cause of osteomalacia is a lack of mineral supply for bone modeling and remodeling due to solar vitamin D and/or dietary calcium deficiency. Osteomalacia occurs when existing bone is replaced by unmineralized bone matrix (osteoid) during remodeling in children and adults, or when newly formed bone is not mineralized in time during modeling in children. Rickets occurs when hypomineralization affects the epiphyseal growth plate chondrocytes and adjacent bone metaphysis in growing children. Hence, osteomalacia co-exists with rickets in growing children. Several reports in the last decade highlight the resurgence of so-called "nutritional" rickets in the dark-skinned population living in high-income countries. However, very few studies have ever explored the hidden iceberg of nutritional osteomalacia in the population. Rickets presents with hypocalcaemic (seizures, tetany, cardiomyopathy), or hypophosphataemic complications (leg bowing, knock knees, rachitic rosary, muscle weakness) and is diagnosed on radiographs (cupping and fraying of metaphyses). In contrast, osteomalacia lacks distinctive, non-invasive diagnostic laboratory or imaging criteria and the clinical presentation is non-specific (general fatigue, malaise, muscle weakness and pain). Hence, osteomalacia remains largely undiagnosed, as a hidden disease in millions of dark-skinned people who are at greatest risk. Radiographs may demonstrate Looser's zone fractures in those most severely affected, however to date, osteomalacia remains a histological diagnosis requiring a bone biopsy. Biochemical features of high serum alkaline phosphatase (ALP), high parathyroid hormone (PTH) with or without low 25 hydroxyvitamin D (25OHD) concentrations are common to both rickets and osteomalacia. Here, we propose non-invasive diagnostic criteria for osteomalacia. We recommend a diagnosis of osteomalacia in the presence of high ALP, high PTH, low dietary calcium intake (<300 mg/day) and/or low serum 25OHD (<30 nmol/L). Presence of clinical symptoms (as above) or Looser's zone fractures should be used to reaffirm the diagnosis. We call for further studies to explore the true prevalence of nutritional osteomalacia in various populations, specifically the Black and Asian ethnic groups, in order to identify the hidden disease burden and inform public health policies for vitamin D/calcium supplementation and food fortification.

Cardiac, bone and growth plate manifestations in hypocalcemic infants: revealing the hidden body of the vitamin D deficiency iceberg.

BACKGROUND: Whilst hypocalcemic complications from vitamin D deficiency are considered rare in high-income countries, they are highly prevalent among Black, Asian and Minority Ethnic (BAME) group with darker skin. To date, the extent of osteomalacia in such infants and their family members is unknown. Our aim was to investigate clinical, cardiac and bone histomorphometric characteristics, bone matrix mineralization in affected infants and to test family members for biochemical evidence of osteomalacia. CASE PRESENTATION: Three infants of BAME origin (aged 5-6 months) presented acutely in early-spring with cardiac arrest, respiratory arrest following seizure or severe respiratory distress, with profound hypocalcemia (serum calcium 1.22-1.96 mmol/L). All infants had dark skin and vitamin D supplementation had not been addressed during child surveillance visits. All three had severely dilated left ventricles (z-scores + 4.6 to + 6.5) with reduced ejection fraction (25-30%; normal 55-70), fractional shortening (7 to 15%; normal 29-40) and global hypokinesia, confirming hypocalcemic dilated cardiomyopathy. They all had low serum levels of 25 hydroxyvitamin D (25OHD < 15 nmol/L), and elevated parathyroid hormone (PTH; 219-482 ng/L) and alkaline phosphatase (ALP; 802-1123 IU/L), with undiagnosed rickets on radiographs. One infant died from cardiac arrest. At post-mortem examination, his growth plate showed a widened, irregular zone of hypertrophic chondrocytes. Histomorphometry and backscattered electron microscopy of a trans-iliac bone biopsy sample revealed increased osteoid thickness (+ 262% of normal) and osteoid volume/bone volume (+ 1573%), and extremely low bone mineralization density. Five of the nine tested family members had vitamin D deficiency (25OHD < 30 nmol/L), three had insufficiency (< 50 nmol/L) and 6/9 members had elevated PTH and ALP levels. CONCLUSIONS: The severe, hidden, cardiac and bone pathology described here exposes a failure of public health prevention programs, as complications from vitamin D deficiency are entirely preventable by routine supplementation. The family investigations demonstrate widespread deficiency and undiagnosed osteomalacia in ethnic risk groups and call for protective legislation.

Prevention of rickets and osteomalacia in the UK: political action overdue.

The consequences of vitamin D and dietary calcium deficiency have become a huge public health concern in the UK. The burden of disease from these deficiencies includes rickets, and hypocalcaemic seizures, dilated cardiomyopathy and mostly occult myopathy and osteomalacia. The increasing burden of the disease is intrinsically linked to ethnicity and the population demographic changes in the UK. Three facts have led to the resurfacing of the English disease: (1) the UK has no ultraviolet sunlight for at least 6 months of the year, (2) dark skin produces far less vitamin D than white skin per unit ultraviolet light exposure, and (3) non-European Union immigration over the last century. To date, the UK government demonstrates incomplete understanding of these three facts, and its failure to adjust its prevention programmes to changing demographics is endangering the health and life of UK residents with dark skin, of whom infants are the most vulnerable. Establishing accountability through the implementation of monitored antenatal and infantile supplementation programmes and mandatory food fortification is overdue.

Osteonecrosis of the Jaw and Rebound Hypercalcemia in Young People Treated With Denosumab for Giant Cell Tumor of Bone.

Context: Denosumab, an inhibitor of receptor activator of nuclear factor κ-B ligand, is an approved treatment of giant cell tumor of bone (GCTB) in adults and "skeletally mature" adolescents. Safety concerns include oversuppression of bone remodelling, with risk of osteonecrosis of the jaw (ONJ) and atypical femur fractures during treatment in adults and rebound hypercalcemia after treatment cessation in children. To date, ONJ has never been reported in children or adolescents. Objectives: To describe serious adverse effects during and following high-dose denosumab therapy in GCTB patients. Patients: Two adolescents (14 and 15 years) and a young adult (40 years) received fixed-dose denosumab for GCTB for 1.3 to 4 years (cumulative dose, 47 to 98 mg/kg), which was stopped because of development of ONJ in one adolescent and bilateral femoral cortical stress reactions in the young adult. All three patients developed rebound hypercalcemia with acute kidney injury 5.5 to 7 months after denosumab cessation. Results: The ONJ necessitated surgical debridement. Rebound hypercalcemia (serum calcium, 3.1 to 4.3 mmol/L) was unresponsive to hyperhydration alone, requiring repeated doses of calcitonin or intravenous bisphosphonate treatment. Hypercalcemia recurred in two patients within 4 weeks, with normal serum calcium profiles thereafter. All patients were naive to chemotherapy, radiotherapy, bisphosphonates, and corticosteroids and were metastases free, confirming the causative role of denosumab in these complications. Conclusion: These suppression-release effects of high-dose denosumab on bone remodeling raise questions about safety of fixed dosing and treatment duration. In young people, weight-adjusted dosing and safety monitoring during and after antiresorptive therapy is required.

Nutritional Rickets and Osteomalacia in the Twenty-first Century: Revised Concepts, Public Health, and Prevention Strategies.

PURPOSE OF REVIEW: Nutritional rickets and osteomalacia are common in dark-skinned and migrant populations. Their global incidence is rising due to changing population demographics, failing prevention policies and missing implementation strategies. The calcium deprivation spectrum has hypocalcaemic (seizures, tetany and dilated cardiomyopathy) and late hypophosphataemic (rickets, osteomalacia and muscle weakness) complications. This article reviews sustainable prevention strategies and identifies areas for future research. RECENT FINDINGS: The global rickets consensus recognises the equal contribution of vitamin D and dietary calcium in the causation of calcium deprivation and provides a three stage categorisation for sufficiency, insufficiency and deficiency. For rickets prevention, 400 IU daily is recommended for all infants from birth and 600 IU in pregnancy, alongside monitoring in antenatal and child health surveillance programmes. High-risk populations require lifelong supplementation and food fortification with vitamin D or calcium. Future research should identify the true prevalence of rickets and osteomalacia, their role in bone fragility and infant mortality, and best screening and public health prevention tools.

Hypopituitarism in children with cerebral palsy.

Poor growth and delayed puberty in children with cerebral palsy is frequently felt to be related to malnutrition. Although growth hormone deficiency is commonly described in these children, multiple pituitary hormone deficiency (MPHD) has not been previously reported. We present a series of four children with cerebral palsy who were born before 29 weeks gestation who were referred to the regional endocrinology service, three for delayed puberty and one for short stature, in whom investigations identified MPHD. All patients had a height well below -2 standard deviation score (2nd centile) at presentation and three who had MRI scans had an ectopic posterior pituitary gland. We therefore recommend that the possibility of MPHD should be considered in all children with cerebral palsy and poor growth or delayed puberty. Early diagnosis and treatment is essential to maximise growth and prevent associated morbidity and mortality.

Endocrine sequelae beyond 10 years in survivors of medulloblastoma.

INTRODUCTION: Survival following treatment of paediatric medulloblastomas has significantly improved over the past few decades, but as a consequence, late effects, particularly endocrine sequelae, have been recognized. The complete picture of late effects, however, has been limited by short duration of follow-up. AIM: To establish the evolution of endocrine sequelae in patients treated for medulloblastoma. METHODS: Single-centre analysis of medulloblastoma treatment and endocrine sequelae in patients diagnosed between 1982 and 2002. RESULTS: A total of 109 patients were treated for medulloblastoma, with various treatment modalities involving radio- and chemotherapy. Only 45 (41%) patients remained alive, and details of treatment and late effects were available for 35 (25 m). The median age at diagnosis was 8 (range 2-14) years, and the median follow-up was 18 (range 10-28) years. Growth hormone deficiency (GHD) was the most prevalent hormone deficiency (97%), followed by primary hypothyroidism (60%) and adrenocorticotrophic hormone (ACTH) deficiency (45·5%). The median time from end of treatment to loss of growth hormone was 1·7 (range 0·7-15) years, ACTH deficiency 2·9 (range 0·75-7·5) years and hypothyroidism 4·1 (range 0·7-11·4) years. Twenty-three percentage developed hypogonadism (17% primary and 6% secondary), whilst precocious puberty was seen in 20%. Endocrinopathies appeared to be more prevalent in those treated with concomitant chemotherapy and radiotherapy. CONCLUSIONS: Prevalence of endocrine sequelae in medulloblastoma survivors is high, and evolution of endocrine dysfunction can occur as late as 15 years from treatment completion; hence, long-term close monitoring of growth, puberty and gonadal function is essential.