Peter J Simm

Children's Hospital at Westmead, Sydney, New South Wales, Australia

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Publications (15)40.66 Total impact

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    ABSTRACT: Compound heterozygous and homozygous (comp/hom) mutations in solute carrier family 34, member 3 (SLC34A3), the gene encoding the sodium (Na(+))-dependent phosphate cotransporter 2c (NPT2c), cause hereditary hypophosphatemic rickets with hypercalciuria (HHRH), a disorder characterized by renal phosphate wasting resulting in hypophosphatemia, correspondingly elevated 1,25(OH)2 vitamin D levels, hypercalciuria, and rickets/osteomalacia. Similar, albeit less severe, biochemical changes are observed in heterozygous (het) carriers and indistinguishable from those changes encountered in idiopathic hypercalciuria (IH). Here, we report a review of clinical and laboratory records of 133 individuals from 27 kindreds, including 5 previously unreported HHRH kindreds and two cases with IH, in which known and novel SLC34A3 mutations (c.1357delTTC [p.F453del]; c.G1369A [p.G457S]; c.367delC) were identified. Individuals with mutations affecting both SLC34A3 alleles had a significantly increased risk of kidney stone formation or medullary nephrocalcinosis, namely 46% compared with 6% observed in healthy family members carrying only the wild-type SLC34A3 allele (P=0.005) or 5.64% in the general population (P<0.001). Renal calcifications were also more frequent in het carriers (16%; P=0.003 compared with the general population) and were more likely to occur in comp/hom and het individuals with decreased serum phosphate (odds ratio [OR], 0.75, 95% confidence interval [95% CI], 0.59 to 0.96; P=0.02), decreased tubular reabsorption of phosphate (OR, 0.41; 95% CI, 0.23 to 0.72; P=0.002), and increased serum 1,25(OH)2 vitamin D (OR, 1.22; 95% CI, 1.05 to 1.41; P=0.008). Additional studies are needed to determine whether these biochemical parameters are independent of genotype and can guide therapy to prevent nephrocalcinosis, nephrolithiasis, and potentially, CKD.
    Journal of the American Society of Nephrology 04/2014; · 8.99 Impact Factor
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    ABSTRACT: To determine the incidence of and factors associated with vitamin D deficiency rickets in Australian children. 18-month questionnaire-based prospective observational study, using Australian Paediatric Surveillance Unit (APSU) data. Australian paediatricians and child health workers, January 2006 - July 2007. Children aged ≤ 15 years with vitamin D deficiency rickets (25-hydroxyvitamin D [25OHD] ≤ 50 nmol/L, and elevated alkaline phosphatase levels [> 229 IU/L] and/or radiological rickets). Incidence of vitamin D deficiency rickets. Description of demographics, clinical presentation, identification and further analysis of overrepresented groups, and treatment regimens compared with best-practice guidelines. We identified 398 children with vitamin D deficiency (55% male; median age, 6.3 years [range, 0.2-15 years]). The overall incidence in children ≤ 15 years of age in Australia was 4.9/100 000/year. All had a low 25OHD level (median, 28 nmol/L [range, 5-50 nmol]) and an elevated alkaline phosphatase level (median, 407 IU/L [range, 229-5443 IU/L]), and 48 (12%) were hypocalcaemic. Ninety-five children had wrist x-rays, of whom 67 (71%) had rachitic changes. Most (98%) had dark or intermediate skin colour and 18% of girls were partially or completely veiled. Most children were born in Africa (252; 63%) and 75% of children were refugees. Duration of exclusive breastfeeding was inversely related to serum vitamin D levels in children < 3 years of age. Empirical vitamin D treatment was given to 4% of children before diagnosis. Vitamin D deficiency rickets is a significant problem in Australia among known high-risk groups. Public health campaigns to prevent, identify and tre@vitamin D deficiency, especially in high-risk groups, are essential.
    The Medical journal of Australia 04/2012; 196(7):466-8. · 2.85 Impact Factor
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    ABSTRACT: There are limited data on the use of bisphosphonate therapy for secondary osteoporoses in childhood, and no previous reports of the use of zoledronic acid in this group. We report 20 children with a variety of underlying primary diagnoses with associated secondary osteoporosis, who were treated with 3 monthly zoledronic acid for 2 years (annualised dose 0.1mg/kg/year). There was a significant improvement in lumbar spine (by 1.88 SD±1.24 over first 12 months, p<0.001) and total bone mineral density as assessed by dual energy absorptiometry (DXA) scans, with a similar increase in bone mineral content for lean tissue mass (mean increase 1.34 SD in first 12 months, p<0.001). Bone turnover was reduced with a suppression of both osteocalcin and alkaline phosphatase in the first 12 months of treatment. Skeletal architecture was improved, with increased second metacarpal cortical thickness from 2.44mm to 2.72mm (p<0.001) and improved vertebral morphometry, with 7 patients who had vertebral wedging at baseline showing improved anterior (p=0.017) and middle (p=0.001) vertebral height ratios. Aside from well reported transient side effects with the first dose, there were no adverse effects reported. No adverse effects on anthropometric parameters were seen over the course of the study. Despite all patients having sustained fragility fractures prior to treatment, no fractures were reported during the study period. Further evidence is required to confirm efficacy, with long term follow up required to assess the impact of treatment on fracture risk.
    Bone 07/2011; 49(5):939-43. · 3.82 Impact Factor
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    ABSTRACT: While oestrogen is recognized to play a key role in regulating growth, particularly in relation to epiphyseal fusion, the mechanisms that mediate its effects are still unclear. We utilized an in vitro model of chondrogenesis, the RCJ3.1C5.18 cell line, to explore the effect of oestrogen on this process. We demonstrated the presence of oestrogen receptors (ER) α and β in these cells, with increased abundance of both receptor sub-types evident as the cells differentiated. ERα localized to the nucleus, suggesting it was signalling by genomic pathways, while ERβ was seen predominantly in the cytoplasm, suggesting it may be utilizing non-genomic signalling. While exogenous oestrogen had no effect on proliferation or differentiation, we found some evidence for the endogenous production of oestrogen (intracrinology), as suggested by the expression of aromatase in these cells. Selective ERα blockade with methyl piperidinopyrazole (MPP) led to a significant reduction in both proliferation and differentiation, while ERβ blockade with R,R tetrahydrochrysene (THC) led to an increase in these parameters. This is in keeping with results from mouse knockout models suggesting that unopposed ERβ signalling leads to an inhibition of skeletal growth. Our results are further evidence for the importance of differential ER signalling in regulating chondrogenesis. Future studies examining in vivo effects of these agents are required to extrapolate these findings to a mammalian model.
    Endocrine 05/2011; 40(1):27-34. · 1.42 Impact Factor
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    ABSTRACT: Aromatase inhibitors have been increasingly used in boys with growth retardation to prolong the duration of growth and increase final height. Multiple important roles of oestrogen in males point to potential adverse effects of this strategy. Although the deleterious effects of aromatase deficiency in early childhood and adulthood are well documented, there is limited information about the potential long-term adverse effects of peripubertal aromatase inhibition. To address this issue, we evaluated short-term and long-term effects of peripubertal aromatase inhibition in an animal model. Peripubertal male Wistar rats were treated with aromatase inhibitor letrozole or placebo and followed until adulthood. Letrozole treatment caused sustained reduction in bone strength and alteration in skeletal geometry, lowering of IGF1 levels, inhibition of growth resulting in significantly lower weight and length of treated animals and development of focal prostatic hyperplasia. Our observation of adverse long-term effects after peripubertal male rats were exposed to aromatase inhibitors highlights the need for further characterisation of long-term adverse effects of aromatase inhibitors in peripubertal boys before further widespread use is accepted. Furthermore, this suggests the need to develop more selective oestrogen inhibition strategies in order to inhibit oestrogen action on the growth plate, while beneficial effects in other tissues are preserved.
    Journal of Endocrinology 10/2010; 207(1):27-34. · 4.06 Impact Factor
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    ABSTRACT: Complex regional pain syndrome (CRPS) is a disorder that can cause significant functional morbidity. While it usually presents in adulthood, it has also been reported in children. Multiple treatment modalities have been reported with mixed success. Bisphosphonate therapy has been shown to be effective in adult patients, but there are limited data in children. We report the successful use of intravenous pamidronate therapy in diminishing pain, improving function, and restoring bone mass in an 11-year-old girl with CRPS of her left lower limb following a tibial fracture. Previous treatment with intense physiotherapy and regional sympathetic blockade had not improved her symptoms. Pain improved within weeks of the first pamidronate infusion, with subsequent improvement in function. The benefit in pain reduction and function was sustained during the 2-year treatment regime. Improvement in bone mass and density was demonstrated by dual-energy X-ray absorptiometry (DXA) and peripheral quantitative computerised tomography (pQCT). pQCT scans showed marked improvement in bone size and geometry and muscle bulk on the affected side. No adverse affects were reported. We conclude that intravenous pamidronate was associated with reduced pain, a return of function, and recovery of bone and muscle parameters in a child with CRPS. Before definitive conclusions can be drawn, a randomised controlled trial similar to those undertaken in adults previously is required to fully validate this approach.
    Bone 12/2009; 46(4):885-8. · 3.82 Impact Factor
  • Article: Reply.
    The Journal of pediatrics 02/2009; 154(1):155. · 4.02 Impact Factor
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    ABSTRACT: Estrogen plays a key role in the regulation of growth in both genders, via its stimulation of the pubertal growth spurt and mediation of epiphyseal fusion. Mouse knockout models suggest a differential effect of oestrogen receptor (ER) alpha and beta on the growth plate, with ER beta possibly being more important in regulating epiphyseal fusion. Epiphyseal fusion may also depend on growth plate senescence, which is regulated by oestrogen. While molecular mechanisms for oestrogen's actions remain unclear, local production of oestrogen may be important for growth. Aromatase inhibitors appear to be effective in improving final height outcome in short stature, however long term safety data is lacking particularly in regards to reproductive function. Future studies are required to further understand the mechanisms by which ER alpha and ER beta affect growth plate function, while longer term studies of aromatase inhibitor usage, preferably utilising animal models, are required to verify the safety of these compounds.
    Pediatric endocrinology reviews: PER 10/2008; 6(1):32-41.
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    ABSTRACT: To test the safety and efficacy of biphosphonates in chronic recurrent multifocal osteomyelitis (CRMO). Five patients with CRMO, all of whom had ongoing pain and loss of function despite conventional treatment with non-steroidal anti-inflammatory agents, were treated with pamidronate (1 mg/kg/dose with a dosing frequency of 2 to 4 monthly for a total treatment duration of 12 to 42 months). Pain decreased after the first infusion for 4 of 5 patients, with symptomatic improvement maintained with time. Significant improvement was seen in radiological lesions for these 4 patients. Bisphosphonates appear to be a useful and safe adjunctive treatment in CRMO when simple therapies such as anti-inflammatory agents fail to control symptoms or cases in which lesion expansion continues.
    The Journal of pediatrics 05/2008; 152(4):571-5. · 4.02 Impact Factor
  • Peter J Simm, Margaret R Zacharin
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    ABSTRACT: 11 beta-Hydroxylase deficiency is a rare form of congenital adrenal hyperplasia, resulting in virilization, glucocorticoid deficiency and hypertension. There have been no previous reports in the literature of a successful pregnancy in a severely affected female. We report the first successful pregnancy resulting in a live birth for a female with 11 beta-hydroxylase deficiency and outline management issues from preconception to successful birth. We also report 2 novel mutations in the CYP11B1 gene leading to 11 beta-hydroxylase deficiency.
    Hormone Research 02/2007; 68(6):294-7. · 2.48 Impact Factor
  • P J Simm, M R Zacharin
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    ABSTRACT: To describe psychosocial morbidity in a cohort of young males with hypogonadism due to Klinefelter syndrome, to document the effect of androgen replacement on behaviour, to underline issues confronting clinicians involved in treatment of this condition and to demonstrate a need for a structured program for prospective intervention for this group. We also compare this group to young men with hypogonadotrophic hypogonadism. A retrospective audit of patients with Klinefelter and Kallmann syndromes, presenting for medical assessment from 1994-2004. Postpubertal males with Klinefelter syndrome (n = 32) and Kallmann syndrome (n = 19) were audited by chart review for psychosocial comorbidities, pubertal management, and the need for exogenous testosterone. Seventeen of 32 postpubertal patients with Klinefelter syndrome required testosterone therapy while 11 were documented to have serum testosterone in the normal adult range. All patients with Kallmann syndrome required long term testosterone treatment. Significant psychosocial and behavioural problems were present in 22/32 of patients with Klinefelter syndrome, including seven who were testosterone replete, with an identifiable pattern of disorder, including marked lack of insight, poor judgement and impaired ability to learn from adverse experience. Use of long term replacement testosterone treatment reduced episodes of behavioural indiscretion. Of those patients with Kallmann syndrome, 5/19 reported mild depressive symptoms only, all resolving with testosterone replacement. Inadequately treated hypogonadism in Klinefelter syndrome increases recognized psychosocial morbidity. There is a need for prospectively planned and timed support for young men with Klinefelter syndrome, to ameliorate current poor psychosocial outcomes.
    Journal of pediatric endocrinology & metabolism: JPEM 05/2006; 19(4):499-505. · 0.75 Impact Factor
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    ABSTRACT: We report a case of an adolescent girl treated with high-dose oral steroids for prolonged coughing thought to be secondary to unstable asthma. Iatrogenic adrenal suppression led to clinical appearance of Cushing syndrome and associated bilateral early post-capsular cataracts, slowing of growth velocity and osteopenia. After weaning off steroids, there was a spontaneous increase in aeral lumbar bone mineral density and also catch-up growth evident over a 5-year period.
    Journal of Paediatrics and Child Health 01/2006; 42(1-2):68-9. · 1.25 Impact Factor
  • Peter J Simm, George A Werther
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    ABSTRACT: While many children presenting with apparent disorders of growth will be short or tall children growing normally, it is important to identify those children who have an underlying pathological cause. Parental expectation and anxiety will often accompany growth issues and this needs to be addressed. The article aims to assist the clinician in distinguishing pathological short stature from normal variants, and to guide in the management of normal variants and common pathologies. Pathological short stature can be distinguished from normal variants by careful history and examination followed by accurate assessment of the growth parameters of height, weight, body proportions and growth velocity, and judicious use of investigations. Growth is a dynamic process that requires multiple measurements over time. If the patient has a nonpathological cause of short stature, explanation and reassurance are critical--for both the parents and child--to feel supported and comfortable with their height outcome.
    Australian family physician 10/2005; 34(9):731-7. · 0.71 Impact Factor
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    ABSTRACT: Primary adrenal insufficiency occurring in childhood and adolescence is due to abnormalities of gland development, gland responsiveness, and steroid biosynthesis or target organ response. Causes include autoimmune Addison's disease, tuberculosis, HIV, adrenoleukodystrophy, adrenal hypoplasia congenita and syndromes including triple A and IMAGe. We aimed to define the causes of adrenal insufficiency for a cohort of children in Melbourne. We reviewed the frequency and variety of presentation of primary adrenal insufficiency to the Royal Children's Hospital over the past 10 years through an audit of patient records, collating demographic information, presentation and investigations. Sixteen cases (13 male, 3 female) of primary adrenal insufficiency were diagnosed at this hospital between January 1993 and July 2003. Median age at presentation was 7.7 years (range: birth to 14.8 years). Symptoms at presentation included weakness, increased pigmentation, abdominal pain, nausea, developmental delay or a reduction in school performance. Four patients presented with adrenal crisis. Median adrenocorticotrophic hormone (ACTH) at diagnosis was 246 pmol/L (range 30-969 pmol/L). Autoantibodies were positive in five patients. Five patients had elevation of very long chain fatty acids. Five patients were diagnosed with autoimmune adrenal insufficiency, five with adrenal hypoplasia congenita, five with adrenoleukodystrophy and one with IMAGe syndrome. A high index of suspicion results in earlier detection and possible prevention of adrenal crisis with a reduction in associated morbidities. Definitive diagnosis is now possible for almost all cases of primary adrenal insufficiency using technologies for screening autoimmunity, adrenoleukodystrophy (ALD) and genetic screening.
    Journal of Paediatrics and Child Health 12/2004; 40(11):596-9. · 1.25 Impact Factor
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    ABSTRACT: : Aneurysmal bone cysts (ABCs) in the sacrum pose a management challenge as their location usually means that surgical excision is not possible. Strategies such as embolization have been used previously but have the potential for significant side effects. We report the successful use of bisphosphonate treatment (zoledronic acid) in an 8-year-old boy who presented with an ABC that did not respond to embolization. : The patient presented with pain and progressive limp. After radiologic and histologic confirmation of the diagnosis, embolization therapy was trialed, which was unsuccessful. At this point, he had severe pain and extremely limited mobility, requiring the use of a wheelchair. His ability to lie flat or sit erect was limited by the pain. Zoledronic acid therapy was subsequently commenced at 0.04 mg/kg per dose by intravenous infusion, at 4 monthly intervals, for a total of 2 years (7 doses). : The infusions were well tolerated, with rapid reduction in pain and resolution of previously severe immobility, from being bed and chair bound at baseline to normal independent ambulation over several months. This was associated with marked radiologic improvement. We postulate that the effect of treatment is a combination of the anti-inflammatory effect of zoledronic acid and the antiresorptive effect of osteoclast inhibition. : We conclude that bisphosphonates should be considered as possible second-line agents for ABCs. Further, study of a larger cohort would help to establish their efficacy in this setting. : Level IV (case report, no comparator/control arm).
    Journal of pediatric orthopedics 33(5):e61-4. · 1.23 Impact Factor

Publication Stats

83 Citations
40.66 Total Impact Points

Institutions

  • 2009–2011
    • Children's Hospital at Westmead
      • • Institute of Endocrinology and Diabetes
      • • Children's Hospital at Westmead Clinical School
      Sydney, New South Wales, Australia
  • 2007–2011
    • Royal Melbourne Hospital
      Melbourne, Victoria, Australia
  • 2004–2010
    • The Royal Children's Hospital
      • Department of Endocrinology and Diabetes
      Melbourne, Victoria, Australia