10/13/2016 Swati Banerjee MBBS; MD; MRCP Associate Clinical - PDF document

10/13/2016 Swati Banerjee MBBS; MD; MRCP Associate Clinical Professor Pediatrics, UCSF- Fresno Division of Pediatric Endocrinology Valley Children’s Healthcare  16-year-old female with a 2 month h/o of increasing polyuria and polydipsia  Blood sugar done by PCP was WNL  Random urine showed a low specific gravity  Diabetes insipidus suspected and referred to endocrinology 1

10/13/2016 Brief period of water deprivation  History- as mentioned  ROS- amenorrhea for 4 months  Serum osm-304 mOsm/kg  Examination  Urine Osm-54 mOsm/kg  Well appearing teenager =DIABETES INSIPIDUS  Normal height, normal BMI  Normal visual fields  After DDAVP- urine osm-726 mOsm/kg  Normal exam CENTRAL DIABETES INSIPIDUS (CDI)  Cortisol was low- ACTH stimulation test-peak-5.3  Imaging mcg/dL  Thyroid normal  Rule out anterior pituitary deficiency  LH, FSH and estradiol normal follicular range  Growth factors- IGF1 low, IGFBP3 WNL  Prolactin-55 ng/mL 2

10/13/2016  Posterior pituitary bright spot absent  6 x 7 x 8 mm enhancement involving the pituitary infundibulum  Normal pituitary stalk measurement <2.6 mm) Barkovich and Raybaud; Pediatric Neuroimaging: 2012; Lippincott Williams and Wilkins  Compression of the pituitary stalk  Pituitary stalk thickening  Impairment of the inhibitory effect of  Anterior pituitary involvement dopamine on lactotropes 3

10/13/2016 Congenital midline CNS malformations  Genetic defects in vasopressin synthesis  Post trauma  Post surgical  Post infectious  Tumors- craniopharyngiomas  Germinoma  Langerhans cell histiocytosis (LCH)  Autoimmune  Idiopathic  Di Iorgi N1, Napoli F, Allegri AE, Olivieri I, Bertelli E, Gallizia A, Rossi A, Maghnie M. Diabetes insipidus- diagnosis and management. Horm Res Paediatr. 2012;77(2):69-84 1997 UCSF- 9 children with idiopathic CDI aged 2 yr -18 yr , follow up MRI  Biopsy done with progression of pituitary stalk thickening over 3-14 months  Biopsy 7/9- germinoma in 6 patients and inflammatory cells in 1  85 patients with DI  “Idiopathic" central diabetes insipidus warrants close follow-up   Median age 7.5 years --------------------------------------------------------------------------------------------------- 2000 French study-Natural history of 25 ‘idiopathic‘ central DI with PST   Endocrine tests and neuroimaging In the first 3 years of follow-up- 4 had germinoma   6 mo x2 years  Annually for 3 years Mootha SL1, Barkovich AJ, Grumbach MM, Edwards MS, Gitelman SE, Kaplan SL, Conte FA. Idiopathic  Reassessed after adult height achievement ~10 years hypothalamic diabetes insipidus, pituitary stalk thickening, and the occult intracranial germinoma in children and adolescents. J Clin Endocrinol Metab. 1997 May;82(5):1362-7 Czernichow P1, Garel C, Léger J. Thickened pituitary stalk on magnetic resonance imaging in children with central diabetes insipidus. Horm Res. 2000;53 Suppl 3:61-4 Di Iorgi N, Allegri AE, Napoli F, et al. Central diabetes insipidus in children and young adults: etiological diagnosis and long-term outcome of idiopathic cases. J Clin Endocrinol Metab 2014;99:1264 4

10/13/2016  Twenty-four patients (28.2%) at the time of  61 (71.8%) patients with idiopathic DI presentation  8 LCH  11 (13.0%) received a specific diagnosis  2 germinomas  7 - germinoma  4 - LCH  6 craniopharyngiomas  3 midline defects  3 familial autosomal dominant DI  2 had post-traumatic CDI Di Iorgi N, Allegri AE, Napoli F, et al. Central diabetes insipidus in children and young adults: etiological diagnosis and long-term outcome of idiopathic cases. J Clin Endocrinol Metab 2014;99:1264 Di Iorgi N, Allegri AE, Napoli F, et al. Central diabetes insipidus in children and young adults: etiological diagnosis and long-term outcome of idiopathic cases. J Clin Endocrinol Metab 2014;99:1264 The remaining 43 patients (50.2%) ‘ idiopathic CDI’ patients followed for a median 10 years normal (1.0–3.0 mm)  minimal increases (3.1–3.9 mm)  with moderate enlargement (4.0–6.5 mm).  3 (2minimal, 1 moderate PST) developed LCH  1 (minimal PST) developed Hodgkin’s Lymphoma  Di Iorgi N, Allegri AE, Napoli F, et al. Central diabetes insipidus in children and young adults: etiological diagnosis and long-term outcome of idiopathic cases. J Clin Endocrinol Metab 2014;99:1264 5

10/13/2016 79 children with CDI, median age 7.0 years and median  duration of follow-up was 7.6 years 61% had anterior pituitary hormone deficits, even higher  with LCH Most frequent abnormality was GHD  Followed by hypothyroidism, hypogonadism and adrenal  insufficiency Maghnie M, Cosi G, Genovese E, et al. Central diabetes Insipidus in children and young adults. N Engl J Med 2000;343:998-1007 Vasopressin-cell autoantibodies (AVPc-Abs)  AVPc-Abs were found in 15 patients (75%),   Germ cell tumors  9 with idiopathic CDI  4 with LCH  2 with germinoma  Langerhan cell histiocytosis AVPc-Abs –not specific   Autoimmune – lymphocytic infundibulo hypophysitis Not available, not done  Maghnie M1, Ghirardello S, De Bellis A, et al. Idiopathic central diabetes insipidus in  Idiopathic children and young adults is commonly associated with vasopressin-cell antibodies and markers of autoimmunity. Clin Endocrinol (Oxf). 2006 Oct;65(4):470-8. 6

10/13/2016  LCH CONSIDER  MRI criteria   Skeletal survey/bone scans  Enlargement of the pituitary stalk lesion (>4 mm) (>6.5 mm)  Progressive enlargement of pituitary stalk  Enlargement of the anterior pituitary gland  Third ventricle involvement Anterior pituitary involvement   Germ cell tumors- tumor markers RISK   Serum and CSF Cause further anterior pituitary deficits  Rarely an early germinoma can be misdiagnosed as hypophysitis –   human chorionic gonadotropin inflammatory lymphocytic reaction  alpha-fetoprotein Nathan J. Robison et al: Predictors of Neoplastic Disease in Children With Isolated Pituitary Stalk Thickening. Pediatr Blood Cancer 2013;60:1630  PST >6.5 mm  Imaging every 6 months during the first 2 years (with high suspicion of germinoma, can be ~3  Tumor markers serum and CSF were negative months)  Skeletal survey was normal  Annual imaging for another year  Anterior pituitary  Hypoadrenalism  Year 3-5 and longer, continue clinical follow up  GH insufficiency  Secondary amenorrhea-most likely hypogonadism Di Iorgi N, Morana G, Maghnie M.Pituitary stalk thickening on MRI when is the best time to re-scan and how long should we continue re scanning for? Clin Endocrinol (Oxf). 2015 Oct;83(4):449 7

10/13/2016  Hormone replacement  Pituitary stalk biopsy results:  ‘ Section show a mixed chronic inflammatory infiltrate comprised of small lymphocytes, macrophages, and  Desmopressin numerous eosinophils. A subset of the cells show crescent shaped nuclei with open chromatin and  Hydrocortisone prominent nuclear folds. Immunohistochemical stains show that the atypical cells are positive for CD1a, S-  Birth control pills 100, and CD68. The findings confirm the diagnosis of Langerhans’ cell histiocytosis.’  Right endonasal transphenoidal biopsy pituitary stalk  Multi system disorder  Previously cell of origin was thought to be epidermal Langerhans cells  Recurrent otitis media, skin lesions, bone lesions, pulmonary involvement, or liver disease  Cell-specific gene expression profiling suggest that  LCH-related CDI can occur as a single organ localization LCH arises from bone marrow–derived immature at the level of pituitary/pituitary stalk myeloid dendritic cells  Growth hormone deficiency (GHD) is the most frequent additional deficit  Precursor myeloid cells acquire somatic mutations that activate the MAPK pathway Marchand I, Barkaoui MA, Garel C, Polak M, Donadieu J; Writing committee. Central diabetes insipidus as the inaugural manifestation of Langerhan cell histiocytosis: natural history and medical evaluation of 26 children and adolescents. J Clin Endocrinol Metab. 2011 Sep;96(9):E1352-60 8

10/13/2016  Antineoplastic chemotherapy for LCH  vinblastine/prednisone  completed  Panhypopituitarism  Multiple hormone replacement 9

10/13/2016  4 year old and a 7-year-old female  Breast development, otherwise normal Part 2  Any onset of pubertal changes prior to the age of 8 years in a girl is considered precocious  Both girls had precocious onset of puberty  Tanner 3 breasts  Tanner 2 pubic hair  Bone age advanced  GnRH stimulation test  LH elevated  Estradiol elevated 10