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

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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

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 History- as mentioned  ROS- amenorrhea for 4 months  Examination  Well appearing teenager  Normal height, normal BMI  Normal visual fields  Normal exam

Brief period of water deprivation

 Serum osm-304 mOsm/kg  Urine Osm-54 mOsm/kg

=DIABETES INSIPIDUS

 After DDAVP- urine osm-726 mOsm/kg

CENTRAL DIABETES INSIPIDUS (CDI)

 Imaging  Rule out anterior pituitary deficiency  Cortisol was low- ACTH stimulation test-peak-5.3

mcg/dL

 Thyroid normal  LH, FSH and estradiol normal follicular range  Growth factors- IGF1 low, IGFBP3 WNL  Prolactin-55 ng/mL

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 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  Impairment of the inhibitory effect of

dopamine on lactotropes

 Pituitary stalk thickening  Anterior pituitary involvement

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

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



“Idiopathic" central diabetes insipidus warrants close follow-up

• 

2000 French study-Natural history of 25 ‘idiopathic‘ central DI with PST



In the first 3 years of follow-up- 4 had germinoma

Mootha SL1, Barkovich AJ, Grumbach MM, Edwards MS, Gitelman SE, Kaplan SL, Conte FA. Idiopathic 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

 85 patients with DI  Median age 7.5 years  Endocrine tests and neuroimaging  6 mo x2 years  Annually for 3 years  Reassessed after adult height achievement ~10 years 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

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 Twenty-four patients (28.2%) at the time of

presentation

 8 LCH  2 germinomas  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

 61 (71.8%) patients with idiopathic DI  11 (13.0%) received a specific diagnosis

 7 - germinoma  4 - LCH

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

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

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

 Germ cell tumors  Langerhan cell histiocytosis  Autoimmune – lymphocytic infundibulo

hypophysitis

 Idiopathic



Vasopressin-cell autoantibodies (AVPc-Abs)



AVPc-Abs were found in 15 patients (75%),

 9 with idiopathic CDI  4 with LCH  2 with germinoma



AVPc-Abs –not specific



Not available, not done

Maghnie M1, Ghirardello S, De Bellis A, et al. Idiopathic central diabetes insipidus in children and young adults is commonly associated with vasopressin-cell antibodies and markers of autoimmunity. Clin Endocrinol (Oxf). 2006 Oct;65(4):470-8.

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 LCH  Skeletal survey/bone scans  Germ cell tumors- tumor markers  Serum and CSF

 human chorionic gonadotropin  alpha-fetoprotein



CONSIDER



MRI criteria

 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



RISK



Cause further anterior pituitary deficits



Rarely an early germinoma can be misdiagnosed as hypophysitis – inflammatory lymphocytic reaction Nathan J. Robison et al: Predictors of Neoplastic Disease in Children With Isolated Pituitary Stalk Thickening. Pediatr Blood Cancer 2013;60:1630  Imaging every 6 months during the first 2 years

(with high suspicion of germinoma, can be ~3 months)

 Annual imaging for another year  Year 3-5 and longer, continue clinical follow up 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  PST >6.5 mm  Tumor markers serum and CSF were negative  Skeletal survey was normal  Anterior pituitary

 Hypoadrenalism  GH insufficiency  Secondary amenorrhea-most likely hypogonadism

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 Hormone replacement  Desmopressin  Hydrocortisone  Birth control pills  Right endonasal transphenoidal biopsy

pituitary stalk

 Pituitary stalk biopsy results:  ‘Section show a mixed chronic inflammatory infiltrate

comprised of small lymphocytes, macrophages, and numerous eosinophils. A subset of the cells show crescent shaped nuclei with open chromatin and prominent nuclear folds. Immunohistochemical stains show that the atypical cells are positive for CD1a, S- 100, and CD68. The findings confirm the diagnosis of Langerhans’ cell histiocytosis.’

 Previously cell of origin was thought to be epidermal

Langerhans cells

 Cell-specific gene expression profiling suggest that

LCH arises from bone marrow–derived immature myeloid dendritic cells

 Precursor myeloid cells acquire somatic mutations that

activate the MAPK pathway

 Multi system disorder  Recurrent otitis media, skin lesions, bone lesions,

pulmonary involvement, or liver disease

 LCH-related CDI can occur as a single organ localization

at the level of pituitary/pituitary stalk

 Growth hormone deficiency (GHD) is the most frequent

additional deficit

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

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 Antineoplastic chemotherapy for LCH  vinblastine/prednisone  completed  Panhypopituitarism  Multiple hormone replacement

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Part 2

 4 year old and a 7-year-old female  Breast development, otherwise normal  Any onset of pubertal changes prior to the age

• f 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

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 Tanner 3 breasts  Tanner 2 pubic hair  Baseline LH and estradiol were prepubertal



Patient lost to follow-up for 2 years

 Came back at age 9 years  Puberty had progressed, patient was also seeing

neurology for migraines

 Hormonal profile – pubertal LH and FSH  Advanced bone age

 GnRH secretory activity is low  Gradual increase in GnRH pulsatility  Rise in sex steroids  What initiates this process?  It has been proposed that a ‘pulse generator’

stimulates GnRH neurons

 Kisspeptin is a hypothalamic neuropeptide  Acts via GPR54, a G-protein coupled receptor

located on GnRH neurons

 Kisspeptin and its receptor GPR 54 play key roles

in establishing the onset, tempo and pace of puberty

Seminara SB: Mechanisms of Disease: the first kiss-a crucial role for kisspeptin 1 and its receptor, G-protein-coupled receptor 54, in puberty and reproduction. Nat Clin Pract Endocrinol Metab. 2006 Jun;2(6):328-34

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

The kiss1 gene was originally identified by scientists in Hershey, PA



It was dubbed kiss1 in honor

• f another product of

Hershey… GONADARCHE: GONAD+ (GREEK) ARKHĒ, BEGINNING (FROM ARKHEIN, TO BEGIN)

 Multifactorial  Genetically determined  Ethnicity  The growth hormone/insulin-like growth factor

system, thyroid hormones

 Nutrition

 Leptin appears to be an important link between nutrition

and reproductive competence

 The attainment of a critical threshold appears to signal that

nutritional stores are sufficient

 Permissive effect on the GnRH pulse generator Frisch R. Body fat, puberty, and fertility. Biol Rev Camb Philos Soc. 1984;59:161–188 Rosenfield RL, Lipton RB, Drum ML. Thelarche, pubarche, and menarche attainment in children with normal and elevated body mass index. Pediatrics. 2009;123:84–88

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

Com plex interplay of num erous neural signals



CRCT1 : the creb1-regulated transcription coactivator-1 (crct1) mediates leptin effects on the kiss1 system at the hypothalamus



MTOR: recent evidence also that another hypothalamic signal through MTOR (mammalian target of rapamycin) is also involved in the control of puberty onset, at least partially, via modulation of kiss1 expression

Roa J, et al Metabolic control of puberty onset: new players, new mechanisms . Mol Cell Endocrinol. 2010 Aug 5;324(1-2):87-94.

A functional or anatom ical disruption of this com plex signaling cascade m ay result in an early and precocious onset of puberty  Children with neurological disorders  Hydrocephalus , myelomeningocele

 Tumors Work up of CPP requires CNS im aging

 Idiopathic

 Hypothalamic hamartomas  Tumors located in the vicinity of the hypothalamus

• r optic nerves

 Low grade gliomas- juvenile pilocytic astrocytomas  Gliomas in the optic pathway associated with NF1  Tumors that cause obstructive hydrocephalus  Ependymomas  Pineal tumors  Craniopharyngiomas

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 Non neoplastic developmental lesion  Histologically normal, neuron and glial cell

mass is present in an ectopic location-at the base of the 3rd ventricle

 Isointense on MRI  Triggers puberty  ectopic production of GnRH  secretion of glial factors such as transforming growth

factor-  which stimulates GnRH

 For CPP- no surgical intervention is needed Jung H, Ojeda SR.Pathogenesis of precocious puberty in hypothalamic

• hamartoma. Horm Res. 2002;57 Suppl 2:31-4.

 Mechanism of treatment  (The pubertal process needs pulsatile GnRH

release)

 ‘Continuous’ or non pulsatile GnRH is inhibitory

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 Leuprolide– IM inj Q month or Q 3 months  Histrelin implants –last for 1 year  Treated till reaches pubertal age

Further work up - Normal!

 Headaches  No other symptoms or signs  Formal vision evaluation normal  Prolactin, thyroid, growth factors and cortisol

were all normal

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 3-6% of all brain tumors in children  It is diagnosed most often between the ages of 5 and 14

yrs, (2nd peak ~ 5th and 6th decades)

 Suprasellar tumor arising from ectodermal remnants of

Rathke cleft

 Solid epithelial cells and cystic component  Dark, oily fluid  Raised ICP

 Headaches, vomiting

 Vision changes  Hypopituitarism

 DI  Growth failure  Delayed puberty

 Precocious puberty  ‘Benign’ histological appearance  10-year overall survival rates of 90%  Traditionally, surgical excision is the treatment of

choice

 Unfavorable long term prognosis with significant

QUALITY OF LIFE ISSUES

 Due to tumor but also due to the treatment

 There is no consensus on the optimal treatment

for newly diagnosed craniopharyngioma

 Treatment is individualized on the basis of

factors that include the following:

 Tumor size  Tumor location  Potential short-term and long-term toxicity of

treatment

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1.Radical surgery with or without radiation therapy 2.Subtotal resection with radiation therapy 3.Primary cyst drainage Gross-total resection is technically challenging because the tumor is surrounded by vital structures

 optic nerves and chiasm  the carotid artery and its branches  3rd cranial nerve  the hypothalamus  Attached to the pituitary stalk

Clark AJ, Cage TA, Aranda D, Parsa AT, Auguste KI, Gupta N. Treatment-related morbidity and the management of pediatric craniopharyngioma: a systematic review: J Neurosurg Pediatr. 2012 Oct;10(4):293-301  Endocrine disorders accompanying resection are

considered inevitable

 Further vision loss  Hypothalamic involvement

 loss of neurovegetative homeostasis  hyperphagia/obesity  behavioral disorders  impairment in cognition, memory and executive

functioning

Karavitaki N1, Brufani C, Warner JT, Adams CB, Richards P, Ansorge O, Shine B, Turner HE, Wass JA. Craniopharyngiomas in children and adults: systematic analysis of 121 cases with long-term follow-up. Clin Endocrinol (Oxf). 2005 Apr;62(4):397-409 Özyurt J, Thiel CM, Lorenzen A, et al.: Neuropsychological outcome in patients with childhood craniopharyngioma and hypothalamic involvement. J Pediatr 164 (4): 876-881.e4, 2014. 

The goal of limited surgery is to

 establish a diagnosis  drain any cysts  and decompress the optic nerves



No attempt is made to remove tumor from the pituitary stalk or hypothalamus



The surgical procedure is often followed by radiation therapy



A systematic review of 109 studies found that subtotal resection plus radiation therapy had tumor control similar to those for gross- total resection

Clark AJ, Cage TA, Aranda D, et al.: A systematic review of the results of surgery and radiotherapy

• n tumor control for pediatric craniopharyngioma. Childs Nerv Syst 29 (2): 231-8, 2013.

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 Endocrine effects  Vasculopathies  Neurocognitive side effects (<7 years of age and with

larger tumors)

 Subsequent neoplasms Kiehna EN, Merchant TE: Radiation therapy for pediatric craniopharyngioma. Neurosurg Focus 28 (4): E10, 2010

Recurrence of craniopharyngioma occurs in approximately 35% of patients regardless of primary therapy Treatment options

• 1. Surgery
• 2. Radiation therapy
• 3. Intracavitary instillation of

 radioactive P-32, Yttrium-99, bleomycin  interferon-α

• 4. Systemic interferon α

Yang I, Sughrue ME, Rutkowski MJ, et al.: Craniopharyngioma: a comparison of tumor control with various treatment strategies. Neurosurg Focus 28 (4): E5, 2010.  Has an effect on squamous cells which line the cysts  Mechanism may be through FAS-mediated

apoptotic pathway

 A number of series have been published on its use,

with reduction in cyst size in up to 80% of patients

 Side effects consist of arthralgia, fatigue, fevers and

• ccasionally new endocrine deficits

Yeung JT, Pollack IF, Panigrahy A, et al.: Pegylated interferon-α-2b for children with recurrent craniopharyngioma. J Neurosurg Pediatr 2012; 10 (6):498503, 2012.

 Large cysts encroaching on very vital structures  Various options discussed with family  Decided on initial trial of systemic interferon, to

be followed by surgery/radiation

 Pegylated interferon-α-2b weekly injections

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 Not yet 3 months – no follow up MRI yet  So far minimal side effects with injections  No new endocrine problems  Visual fields normal  Headaches have resolved

• Dr. Fred Laningham

Pediatric Neuro Radiologist Valley Childrens Hospital

• Dr. David Samuel

Pediatric Neurooncologist Valley Childrens Hospital

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• 1. Barkovich and Raybaud. Pediatric Neuroimaging 2012: Published by Lippincott

Williams and Wilkins

• 2. 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

• 3. Mootha SL1, Barkovich AJ, Grumbach MM, Edwards MS, Gitelman SE, Kaplan SL,

Conte FA. Idiopathic 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.

• 4. 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.

• 5. 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

• 6. Nathan J. Robison et al: Predictors of Neoplastic Disease in Children With Isolated

Pituitary Stalk Thickening. Pediatr Blood Cancer 2013;60:1630

• 7. Maghnie M, Cosi G, Genovese E, et al. Central diabetes Insipidus in children and

young adults. N Engl J Med 2000;343:998-1007

• 8. 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

• 9. Maghnie M1, Ghirardello S, De Bellis A, di Iorgi N, Ambrosini L, Secco A, De Amici

M, Tinelli C, Bellastella A, Lorini R. Idiopathic central diabetes insipidus in children and young adults is commonly associated with vasopressin-cell antibodies and markers of autoimmunity. Clin Endocrinol (Oxf). 2006 Oct;65(4):470-8.

• 10. Marchand I, Barkaoui MA, Garel C, Polak M, Donadieu J; Writing

committee.Central diabetes insipidus as the inaugural manifestation of Langerhan cell histiocytosis: naturalhistory and medical evaluation of 26 children and

• adolescents. J Clin Endocrinol Metab. 2011 Sep;96(9):E1352-60
• 11. Seminara SB: Mechanisms of Disease: the first kiss-a crucial role for kisspeptin1 and

its receptor, G-protein-coupled receptor 54, in puberty and reproduction. Nat Clin Pract Endocrinol Metab. 2006 Jun;2(6):328-34

• 12. Rosenfield RL, Lipton RB, Drum ML. Thelarche, pubarche, and menarche attainment

in children with normal and elevatedbody mass index. Pediatrics. 2009;123:84–88

• 13. Roa J, et al Metabolic control of puberty onset: new players, new mechanisms . Mol

Cell Endocrinol. 2010 Aug 5;324(1-2):87-94.

• 14. Jung H, Ojeda SR.Pathogenesis of precocious puberty in hypothalamic hamartoma.

Horm Res. 2002;57 Suppl 2:31-4.

• 15. Winkfield KM, Tsai HK, Yao X, et al.: Long-term clinical outcomes following

treatment of childhood craniopharyngioma. Pediatr Blood Cancer 56 (7): 1120-6, 2011.

• 16. Özyurt J, Thiel CM, Lorenzen A, et al.: Neuropsychological outcome in patients with

childhood craniopharyngioma and hypothalamic involvement. J Pediatr 164 (4): 876-881.e4, 2014.

• 17. Clark AJ, Cage TA, Aranda D, Parsa AT, Auguste KI, Gupta N. Treatment-related

morbidity and the management of pediatric craniopharyngioma: a systematic review: J Neurosurg Pediatr. 2012 Oct;10(4):293-301

• 18. Clark AJ, Cage TA, Aranda D, Parsa AT, Sun PP, Auguste KI, Gupta N. A systematic

review of the results of surgery and radiotherapy on tumor control for pediatric

• craniopharyngioma. Childs Nerv Syst 29 (2): 231-8, 2013.
• 19. Kiehna EN, Merchant TE: Radiation therapy for pediatric craniopharyngioma.

Neurosurg Focus 28 (4): E10, 2010

• 20. Karavitaki N1, Brufani C, Warner JT, Adams CB, Richards P, Ansorge O, Shine B,

Turner HE, Wass JA.Craniopharyngiomas in children and adults: systematic analysis of 121 cases with long-term follow-up. Clin Endocrinol (Oxf). 2005 Apr;62(4):397-409

• 21. Yang I, Sughrue ME, Rutkowski MJ, et al.: Craniopharyngioma: a comparison of

tumorcontrol with various treatment strategies. Neurosurg Focus 28 (4): E5, 2010.

• 22. Yeung JT, Pollack IF, Panigrahy A, et al.: Pegylated interferon-α-2b for children with

recurrent craniopharyngioma. J Neurosurg Pediatr. 2012: 10 (6):498-503