Catherine J. Owen

Diagnosis and Management of Polyendocrinopathy Syndromes

The autoimmune polyendocrinopathy syndromes are variable in presentation and can be challenging to diagnose and manage. Diagnosis of the type 1 autoimmune polyendocrinopathy syndrome can be difficult at an early age when often only one manifestation is present, and it may take years for others to appear. Increased awareness of polyendocrinopathy syndromes, combined with analysis of specific autoantibodies and molecular genetics, should help earlier diagnosis of these conditions and prevent serious complications. Further definition of susceptibility genes and autoantigens, as well as a better understanding of the pathogenesis, is required to improve the diagnosis and management of these patients.

No association of the codon 55 methionine to valine polymorphism in the SUMO4 gene with Graves’ disease

Objective  A functional polymorphism at codon 55 of the small ubiquitin‐like modifier‐4 (SUMO4) gene (methionine to valine; M55V) has recently been associated with type 1 diabetes mellitus (T1D). We aimed to establish whether this locus also contributes towards the genetic susceptibility to Graves’ disease (GD) and autoimmune Addisons disease.

Prophylactic oral bisphosphonate therapy in duchenne muscular dystrophy.

We assessed prophylactic use of bisphosphonate (BP) in Duchenne muscular dystrophy (DMD) patients on glucocorticoid (GC) therapy.

Testosterone Treatment of Pubertal Delay in Duchenne Muscular Dystrophy

BACKGROUND The outlook for adolescents with Duchenne muscular dystrophy (DMD) has improved greatly as a result of corticosteroid use, but treatment will compromise growth and delay puberty. Whether exogenous testosterone can promote growth, development, and skeletal health is unclear. METHODS We collected data retrospectively on growth and pubertal response in 14 adolescents with DMD who were treated with testosterone between 2008 and 2014. RESULTS A total of 14 boys were treated at a median age of 14.5 years. Eight have finished treatment after a mean age of 3.1 years and the feedback from families was generally positive. The mean testicular volume pretreatment was 2.4 and 3.9 mL posttreatment. The mean baseline testosterone concentrations were < 1.0 and 5.4 nmol/L postintervention. Median height velocity increased from 0.45 cm/y before treatment to 3.6 cm/y after the treatment. The mean height gain was 14.2 cm. CONCLUSIONS A broad range of testosterone preparations was used. Testosterone was generally well-liked, but side effects were experienced by some patients and the pubertal growth increment appears to be compromised. Few subjects had adult endogenous testosterone levels posttreatment. Controlled studies are required to determine the most appropriate treatment regimen and the precise impact of testosterone on key outcomes, such as muscle function and bone integrity. Clinicians will then be better placed to advise families about likely benefits and risks.

Discordance for X-Linked hypophosphataemic rickets in identical twin girls

Background: We report monozygotic twin girls with a family history consistent with X-linked hypophosphataemic rickets (XLH). One twin had a skeletal and biochemical phenotype consistent with XLH, whilst the second twin appeared normal. Complete non-penetrance in XLH has not been previously reported and our aim was to explore potential reasons for this. Methods: Serum and urine biochemistry were analysed at regular intervals. Microsatellite analysis was performed to confirm monozygosity and bi-parental inheritance of the X chromosome. The X chromosome inactivation pattern was studied in peripheral blood. Exons of the paternal PHEX and FGF23 genes were sequenced. Results: Biochemistry was persistently abnormal in the slow-growing twin 1 and normal in twin 2 who has grown normally. Maximal tubular phosphate reabsorption was 0.68 mmol/l in twin 1 and 1.64 mmol/l in twin 2 at 10.8 years of age (normal 1.15–2.58 mmol/l). Microsatellite analysis confirmed monozygosity and the X chromosome inactivation pattern was random. These studies also excluded uniparental isodisomy. The exon sequence of paternal PHEX and FGF23 genes was normal. Conclusions: Discordant X inactivation is a well-recognised phenomenon in identical twins, and we suspect that non-random expression of the normal PHEX gene in critical tissues is the most likely explanation for non-penetrance.

Bisphosphonate use in Duchenne Muscular Dystrophy – why, when to start and when to stop?

ABSTRACT Introduction: Long term use of glucocorticoids has dramatically improved the disease course in Duchenne Muscular Dystrophy (DMD) and patients are now frequently surviving into their thirties. However, there are significant side-effects associated with chronic glucocorticoid administration, including a reduction in bone mineral content. The resultant osteoporosis, which predisposes to fragility fractures of both long bones and vertebrae, is a major cause for concern. There is a wide variation in clinical practice regarding the use of bisphosphonates (BP) as a means of preserving skeletal integrity in this patient group. Areas covered: This review describes the rationale and evidence for use of BP in DMD, and discusses the main side-effects and limitations of their use. It will introduce the controversial concept of a bisphosphonate holiday (a break in BP therapy after a prolonged period of use) and then summarise the potential strategies for monitoring bone health when BP is stopped. It will highlight evidence from adult studies and discuss the paucity of knowledge relating to the growing skeleton. Expert Opinion: Bisphosphonates are currently the most effective therapy for steroid-induced osteoporosis in DMD but the side-effects and consequences of their long term use remain a concern. The impact of a BP holiday on the developing skeleton is unknown and further controlled studies in children are required.