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Pediatric Cushing’s Syndrome and bone development

Pediatric Cushing’s Syndrome and bone development. Accesion 112110. Conan. 4-5 mo MI Australian Shepherd presents for recent onset of murmur

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Pediatric Cushing’s Syndrome and bone development

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  1. Pediatric Cushing’s Syndrome and bone development Accesion 112110

  2. Conan • 4-5 mo MI Australian Shepherd presents for recent onset of murmur • Hx: Chronic recurrent fevers, musculoskeletal pain, lethargy, has been on Prednisone 1 mg/kg BID chronically, recently up to 2 mg/kg BID, several doses of Clavamox. Intermittent episodes of dyspnea and cyanosis, and subcutaneous abcessation • PE: small stature, small testes, carpal hyperextension, shoulder and stifle effusion, pain on flexion and extension of multiple joints • Echo: Moderate MR with HCM; dynamic LVOT obstruction d/t MV displacement, either dysplastic valve or secondary to HCM • Chemistry: low Creat, high Phos*, low norm Alb, mild high ALP*, Low Amy* (*could be artifactual d/t hemolysis) • CBC: PLT=943, PCV=37, PMN=1.643, Lymph-0.091, Mono=7.121 • Arthrocentesis: Mild chronic inflammation (large mononuclear)

  3. Radiographs

  4. Juvenile hyperadrenocorticism-veterinary sources1,2 • Hyperadrenocorticism is a differential for a pediatric growth failure resulting in small stature and good body condition • Partly through inhibition of GH release • Retarded growth and delayed growth plate closure may occur in young dogs • Osteopenia is attributable to decreased bone formation, bone resorption is apparently normal • Spontaneous fractures, increased prevalence of IVDD has also been reported

  5. Signs and symptoms of pediatric Cushing’s Syndrome-CS3 • Weight gain and growth failure: reduction in height SDS with increased BMI SDS • Hypertension • Osteoporosis • Abnormal pubertal development • Hirsuitism and virilization (excessive hair growth for level of gonadal and breast development) • Hypertension

  6. Pediatric Cushing’s Syndrome and bone disease • Guyton: osteoporosis with Cushing’s syndrome d/t : • decreased deposition of protein throughout the body; increased catabolism of protein • Depression on osteoblastic activity • Cushing’s syndrome in children can result in severe loss in bone mineral density7 • Bone loss more severe in primary adrenal Cushing’s syndrome than PDH

  7. Skeletal maturation at diagnosis of pediatric Cushing’s disease • Children with Cushing’s syndrome present with obesity and decreased linear growth, renal stones (increased calciuria), gonadal dysfunction (especially males) • 75-80% of pediatric Cushing’s syndrome is caused by ACTH-secreting pituitary corticotroph adenoma • Delay in skeletal growth due to decreases in GH and d/t direct effects on the growth plate by glucocorticoids • Down-regulation of hypothalamic-pituitary-gonadal axis: delay in puberty • Bone age delay =difference between chronological age and bone age; • present in most cases reviewed • correlated negatively with height and positively with duration of syndrome

  8. Pathophysiology • Bone age delay • may not be present in puberty, but is commonly delayed in prepubertal population • ACTH stimulation may cause upregulation of adrenal androgen secretion, may accelerate linear growth and skeletal maturation • In vivo, patients may have GH deficiency, IGF_1 levels may be normal, • both have been shown to be suppressed by glucocorticoids in rats, effects may also be due to downregulation of GH binding proteins • Downregulation of vascular endothelial growth factor production • Lead to disruption of normal invasion of blood vessels in the growth plate with disturbance of endochondral ossification and growth • Reduction of number and function of mature osteoblast cells • Stimulation and prolongation osteoclast formation, activity and survival

  9. Pediatric Cushing’s syndrome-Outcome • Subnormal growth rate and short stature reported even after transsphenoidal surgery and radiation therapy • Measurements for GH deficiency and replacement if present has resulted in acceptable growth • Many patients remain obese, with elevated BMI post cure • BMD, bone mineral density, is often, but not always, reduced in children after cure; possible risk for longterm osteoporosis

  10. References • Ihle SL. Failure to Grow. In Textbook of Veterinary Internal Medicine. Ettinger and Feldman. Elselvier Saunders, St. Louis, 2005. pp 80-83. • Johnson KA, Watson ADJ. Skeletal Diseases. In Textbook of Veterinary Internal Medicine. Ettinger and Feldman. Elselvier Saunders, St. Louis, 2005. pp 80-83. • Chan LF, et al. Pediatric Cushing’s Syndrome: Clinical Features, Diagnosis, and Treatment. Arq Bras EndocrinolMetab 2007;51/8:1261-1271 • Guyton AC, Hall JE. Parathyroid Hormone, Calcitonin, Calcium and Phosphate Metabolism, Vitamin D, Bone, and Teeth. In Textbook of Medical Physiology. W. B. Saunders. Philadelphia, 2000. pp 899-915. • Newell-Price J, Bertagna X, Grossman AB, Nieman LK. Cushing’s Syndrome. Lancet 2006; 367: 1605–17. • Peters CJ, et al. Factors Influencing Skeletal Matruation at Diagnosis of Paediatric Cushing’s Disease. Horm Res 2007;68:231–235. • Leong GM, et al. The effect of Cushing’s Disease on Bone Mineral Density, Body Composition, Growth and Puberty: A Report of an Identical Adolescent Twin Pair. J ClinEndocrinolMetab 1996; 81: 1905-1911.

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