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Differences or disorders of sex development (DSD) are a wide range of relatively rare conditions with diverse pathophysiology that most often present in the newborn or the adolescent. Given their rarity and the need for input from a range of clinical disciplines, the management of the child with a complex form of DSD may be quite complicated, and the situation is worsened by a lack of evidence for many diagnostic and interventional procedures that are undertaken. It is, therefore, not surprising that there will be variation in the management as well as the outcome of patients with this group of conditions. By working as a network of clinical and research centres it is possible that these variations can themselves be better managed and studied. Over the last decade there has been a major shift in the field of rare diseases towards greater collaboration in clinical as well as research activity, and this chapter will summarise these developments., (© 2014 S. Karger AG, Basel.)

In recent years there has been increasing interest in the non-skeletal effects of vitamin D. It has been suggested that vitamin D deficiency may influence the development of diabetes, cardiovascular dysfunction and autoimmune diseases. This review focuses on the current knowledge of the effects of vitamin D and its deficiency on cardiovascular function, glucose homeostasis and immune function, with a particular focus on children. Although, there is good evidence to show that there is an association between vitamin D deficiency and an abnormality of the above systems, there is little evidence to show that vitamin D supplementation leads to an improvement in function, especially in childhood., (© 2014 S. Karger AG, Basel.)

Using the MS registries in two MS clinics in Kuwait, we studied the demographics and clinical characteristics of multiple sclerosis (MS). Data of 736 patients (77.7% with relapsing remitting course) were analyzed. The mean age at onset and mean duration were 26.87 and 7.71 years, respectively. About 47.9% of patients had a disease duration ≤5 years. Cerebellar/brainstem and spinal manifestations were the presenting symptoms in 29.5 and 27.4%, of patients, respectively. The EDSS score was ≤3 in 72.8% of patients. We concluded that in Kuwait, the clinical characteristics of MS have important differences in terms of presentations at onset and disease progression as compared to regional cohorts., (© 2014 S. Karger AG, Basel.)

Objective: To evaluate the outcomes of patients with multiple sclerosis (MS) who were treated with natalizumab in Kuwait., Materials and Methods: A retrospective study using the MS registry to identify patients who were treated with natalizumab was conducted. Patients' demographics, clinical characteristics and treatment parameters were collected at baseline and last follow-up visit. Primary outcome was the proportion of relapse-free patients at the last follow-up while secondary outcomes were the change in the mean annual relapse rate, Expanded Disability Status Scale (EDSS) and the proportion of patients with magnetic resonance imaging (MRI) activity at the last follow-up visit. Forty-four patients were included in the study., Results: Of the 44 patients, 27 (61.4%) were females and the remaining 17 (38.6%) males. Mean age of patients and mean disease duration were 29.05 ± 7.25 and 5.71 ± 3.37 years, respectively. The mean number of natalizumab infusions was 18.14. The proportion of relapse-free patients significantly increased from 11.36 to 90.91% (p < 0.0001). The EDSS significantly improved from 4.76 to 3.15 (p < 0.0001) over the observational period. There was no significant difference between patients with EDSS <3 compared to those with EDSS ≥ 3 (p < 0.67). The proportion of patients with MRI activity was significantly reduced from 95.5 to 18.2% (p < 0.0001) at their last visit. Six patients discontinued the drug, 5 due to positive JC virus and 1 due to pregnancy., Conclusions: Natalizumab induced a suppression of disease activity and was responsible for a significant improvement in disability status in highly active MS patients., (Copyright © 2013 S. Karger AG, Basel.)

Many children with a variety of chronic diseases suffer from a variable component of chronic inflammation and often have co-existing growth retardation. The aetiology of this growth retardation may be multifactorial and in a condition such as inflammatory bowel disease it includes the effects of the disease on nutrition as well as the effect of drugs such as glucocorticoids. Growth is primarily regulated through the endocrine and paracrine component of the GH/IGF-1 axis which may be modulated by other factors such as sex steroids. There is increasing evidence that this axis may be affected in children with chronic inflammation. An improved understanding of the GH/IGF-1 axis and how it is affected in chronic inflammation will lead to an improved rationale for developing therapeutic regimens that can improve growth in those children whose growth does not improve despite optimal management of the disease. This review will illustrate these aspects by concentrating primarily on the pathophysiology of growth retardation in inflammatory bowel disease and possible interventions for improving growth., (Copyright © 2013 S. Karger AG, Basel.)

Background: Puberty is thought to be commonly affected in adolescents with inflammatory bowel disease (IBD)., Aims: To determine the impact of Crohn's disease (CD) and ulcerative colitis (UC) on the pubertal growth spurt., Methods: Retrospective study of 30 boys with CD (CD-M), 11 girls with CD (CD-F), 14 boys with UC (UC-M) and 12 girls with UC (UC-F). Pubertal growth was assessed by calculating peak height velocity SDS (PHV SDS), height SDS at diagnosis (Ht(Diag)) and height SDS at PHV (Ht(PHV)) and age at PHV (Age(PHV)). Systemic markers of disease activity were also collected., Results: Altered parameters of pubertal growth were observed in the CD groups compared to the normal population: in the CD-M group, median Ht(Diag) was -0.56 (p = 0.001) and median Age(PHV) was 14.45 years (p = 0.004), and in the CD-F group, median Ht(Diag) was -1.14 (p = 0.007) and Ht(PHV) was -0.79 (p = 0.039). Individually, 8/30 CD-M cases had one or more parameter affected: 2 boys had Ht(Diag )<-2, 3 boys had Ht(PHV) <-2, 2 boys had an Age(PHV) >2 years above population mean, and 2 boys had a PHV SDS <-2. In the whole group, Age(PHV) showed an association with erythrocyte sedimentation rate (r = 0.4; p = 0.005) and an inverse association with BMI (r = 0.4; p = 0.001)., Conclusion: Disorders of pubertal growth are more likely to occur in CD and, particularly, in boys., (Copyright © 2011 S. Karger AG, Basel.)

Background: pubertal delay and growth retardation are common in children with inflammatory bowel disease (IBD)., Aims: To assess pubertal status and growth in a group of boys with IBD undergoing testosterone therapy for pubertal induction., Methods: retrospective study of height, weight and pubertal status in 8 boys with IBD before and after testosterone therapy. Height velocity (HV) over the 6 months before each assessment was converted to standard deviation score. Markers of disease activity and concomitant medication were recorded. Response was based on an advance in pubertal status and a greater than 50% increase in HV., Results: eight boys with IBD, median age 14.8 years, had pubertal induction using either monthly injections of 50 mg Sustanon or daily 2.5/5 mg Andropatch. Seven boys showed an advance of pubertal status. Six boys had a greater than 50% increase in HV; median HV at T0 was 1.6 cm/year (0, 5) compared with 6.9 cm/year (1, 11.7) at T6 (p = 0.005). C-reactive protein during testosterone therapy had a significant association with HV at T6 (r = -0.786; p = 0.021)., Conclusion: in most cases, testosterone therapy in boys with IBD and delayed growth and puberty is associated with an advance in pubertal status and an improvement in growth., (2010 S. Karger AG, Basel.)

Background: Growth disorders are commonly observed in children with chronic inflammatory disease. It is likely that these disorders are mediated by a combination of factors, including the disease process and its treatment (with drugs such as glucocorticoids [GCs]). These factors affect the growth hormone-insulin-like growth factor I (IGF-I) axis, which is crucial for promoting linear growth at the level of the growth plate. Recent advances in our knowledge of the effects of GCs and proinflammatory cytokines on the growth plate have led to an improved understanding of the biological rationale for the use of growth-promoting therapy in children with chronic inflammatory disease and concurrent growth retardation., Conclusions: Both GCs and proinflammatory cytokines can adversely affect a number of components of growth plate chondrogenesis, and these effects can be ameliorated by raising local IGF-I exposure. However, this intervention does not lead to complete normalization of the growth plate. In children with chronic inflammation, the cornerstone of improving growth remains the judicious use of GCs while ensuring effective control of the disease process., (Copyright 2009 S. Karger AG, Basel.)

Background: Late presentation of congenital adrenal hyperplasia as a 46,XX disorder of sex development due to 11-beta hydroxylase deficiency is uncommon. Such a case raises issues regarding appropriate investigation and management., Case History: A 5-year-old boy who had recently moved to the United Kingdom presented at the endocrinology clinic with recurrent abdominal pain. He was normotensive and had a history of ambiguous genitalia since birth, a relatively small penis, bilateral cryptorchidism and pubic hair. A systematic workup revealed low anti-Mullerian hormone levels for age and sex and elevated serum testosterone, androstenedione and deoxycortisol levels. A urinary steroid profile confirmed a diagnosis of 11-beta hydroxylase deficiency. The child's karyotype was 46,XX. Further genetic analysis revealed a compound heterozygote mutation in the CYP11B1 gene. Ultrasound scan showed evidence of Mullerian structures and accumulation of menstrual blood in the vagina (haematocolpos). Following discussion at a multidisciplinary clinic, the patient did not undergo sex reassignment and subsequently proceeded to surgery for removal of the Mullerian structures., Conclusions: This case emphasizes the importance of a systematic approach to investigation of older children presenting with apparent male undermasculinisation. It also raises important issues about gender reassignment in mid-childhood and the indications for removal of Mullerian organs in a 46,XX boy., (Copyright 2009 S. Karger AG, Basel.)

Secondary osteoporosis is more difficult to define in children than in adults but clearer definitions have recently been provided by the International Society for Clinical Densitometry. Whereas in adults, osteoporosis is defined on the basis of reduced bone density on scanning, in children the definition requires additional clinical parameters to be fulfilled. Secondary osteoporosis may arise either as a result of the effects of underlying disease or as a result of the treatment of such diseases (e.g. with glucocorticoids). The normal balance of bone formation and removal, both by bone modelling and remodelling, is disturbed in such a way as to alter the normal accumulation of bone that occurs during childhood. A multitude of intrinsic and extrinsic factors contributes to these processes. The underlying principles of treatment of secondary osteoporosis is, where possible, to remove the underlying cause. Where this is not possible, minimising the effects of treatment with drugs that adversely effect bone may be sufficient to eliminate any deterioration in bone quality. If this is not possible, the use of bone sparing drugs such as the bisphosphonates may be necessary whilst ensuring that attention is paid to optimising calcium and vitamin D intake and encouraging exercise and mobility., (Copyright (c) 2009 S. Karger AG, Basel.)

Introduction: There is a scarcity of data on height as well as bone densitometry in humans with NOGGIN mutations., Methods: In 2 families with symphalangism, anthropometry, bone densitometry and genetic analysis of the NOGGIN gene were performed., Results: In family A, the height standard deviation scores of the affected father and son were -0.4 and 3.5, respectively. In family B, the height standard deviation scores of the affected father, twin daughters and another daughter were 1.7, 1.8, 2.4 and 1.8, respectively. In the children, percentage predicted bone mineral content (BMC) for height at the appendicular sites (total femur, femoral neck) was lower than at an axial site lumbar spine. In the 2 fathers, median bone mineral density at total femur and femoral neck was -0.3 standard deviation scores (-0.7, 0.2) and at lumbar spine the scores were -0.4 and 0.9. The children had median tibial and radial speed of sound velocities of -2.1 (-0.9 to -6.4) and -1.4 (-0.2 to -4.9), respectively. DNA analysis revealed a novel missense mutation in family A and family B, resulting in a Met190Val substitution and a Pro42Arg substitution, respectively., Conclusion: Heterozygous gene mutations in NOGGIN are associated with tall stature in children but not necessarily in adults. The appendicular BMC and speed of sound may be low in affected children but normalises by adulthood. However, axial BMC seems normal in childhood and is high in adulthood., ((c) 2008 S. Karger AG, Basel)

For a number of reasons there is a need to explore reliable non-invasive methods for assessing bone health in neonates and young infants. Epidemiological studies suggest that early events in life may predispose the adult to degenerative diseases such as osteoporosis. Preterm infants have an increased risk of low bone mass because of limited bone mass accretion in utero and a greater need for bone nutrients. Despite improvements in neonatal care fractures still occur. The diagnosis of osteopaenia of prematurity remains difficult as there is no screening test which is both sensitive and specific. Biochemical indices are non-diagnostic, and plain X-rays in the absence of fractures are poor at diagnosing bone disease. Although dual energy X-ray absorptiometry is increasingly used to assess bone mineral status in newborn infants, the size and immobility of the scanner, the length of time to perform the scan and use of ionising radiation make it unsuitable for routine use in the setting of the fragile very low birth weight infant. Quantitative ultrasound (QUS) was first developed in 1984, as a non-ionising, portable and low cost method of assessing bone health. The measurements obtained from QUS are thought to be related not only to the mineral density of the bone but also to reflect parameters of bone quality and strength. Preliminary studies suggest that this technique may be a useful method of assessing changes in bone health in preterm infants, but the data need to be interpreted carefully. This review will concentrate on the methodology of QUS and the studies that have already been performed in neonates.

To investigate any association between changes in lower leg length (LLL) and urinary growth hormone (uGH) excretion, 4 prepubertal children supplied daily 12-hour overnight urine samples and had daily knemometry performed for 4 weeks. The mean daily and weekly LLL velocity (LLLV) of the group was (0.08 mm/day (95% CI 0.01-0.18) and 0.52 mm/week (range 0.38-0.78), respectively. The mean uGH excretion was 8.9 ng/l (CI 3.7-13.3), and the mean intrasubject coefficient of variation of uGH was 55% (range 32-93). The tallest subject who also had the highest LLLV excreted the least amount of uGH (mean 3.7 ng/l, CI 2.9-4.5). No temporal relationship was evident between daily uGH excretion and LLLV. There was no evidence of any association between amount of uGH excreted and LLLV. There remains some doubt on the usefulness of uGH measurement as the sole predictor of normal GH production.

In order to study the short-to medium-term effects of cytotoxic chemotherapy (CT) for acute lymphoblastic leukaemia (ALL) on growth in prepubertal children, a prospective study of weight (Wt), height (Ht), sitting height (SH) and body mass index (BMI) was performed in 31 children receiving intensive CT for ALL. Two pubertal children, 1 child with Down's syndrome and 3 children who had cranial irradiation were excluded from the analysis. Monthly measurements were presented as change in standard deviation scores from baseline (delta SDS). The median age at diagnosis was 4.4 years (range, 1.1-14). The median duration of study per subject was 18 months (3-24). The median delta SDS-Ht reached a nadir of -0.35 at 6 months after the start of CT (p = 0.001, Wilcoxon signed rank test); the median delta SDS-SH was -0.55 at 3 months (p = 0.02); the median delta SDS-Wt and delta SDS-BMI increased at 2 months to 0.15 (p = 0.03) and 0.5 (p = 0.002), respectively. The median delta SDS-BMI was also elevated at 10 months (0.75, p = 0.01) reflecting the relative delay in recovery of Ht-SDS in comparison to Wt-SDS. The median SH:Ht ratio, a measure of disproportion, was reduced at 3 months (delta SH:Ht ratio, -0.01, p = 0.009). No significant changes in Ht-SDS, BMI-SDS or SH:Ht from baseline were evident at the end of the CT. Cytotoxic CT for ALL in childhood has a significant adverse effect on growth, but there is some evidence for recovery before the end of CT.

Three studies to evaluate procollagen type I C-terminal propeptide, type I collagen cross-linked telopeptide and bone alkaline phosphatase (BALP) in the assessment of bone turnover and growth in children are presented. (1) In 50 short normal children treated with placebo or growth hormone, delta BALP after 3 months of treatment was highly correlated with height velocity response after 1 year (r = 0.67, p < 0.0001). (2) In 12 children with acute lymphoblastic leukaemia, marked changes in collagen peptides, BALP, and lower leg length velocity were seen during the first 6 months of chemotherapy. Suppression occurred during induction and the two intensification phases, with catch-up during the intervening phase (paired t-tests, p < 0.001). (3) Fourteen babies (birthweight < 1,500 g) treated with high-dose dexamethasone for bronchopulmonary dysplasia were compared with 25 non-steroid-treated babies < 1,500 g. Both collagen peptides decreased rapidly and dramatically (mean decreases 41-68%) after dexamethasone was started, accompanied by weight loss and lower leg shrinkage and followed by recovery during steroid weaning.