More than meets the eye
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1 More than meets the eye Ana Paula Abreu, MD, PhD American Association of Clinical Endocrinologists New England Chapter Annual Meeting September 8, 2018
2 Disclosures No conflict of interest or significant financial relationships relevant to this presentation 2
3 HPI 45 y.o. man with history of HPV positive squamous cell carcinoma of the oropharynx admitted with nausea and worsening abdominal pain Increasing chronic fatigue (x 4 months), decreased PO intake and weight loss (30 lbs), and 3 prior admissions for abdominal pain in the last month
4 PMHx/PSHx Radiation-induced primary hypothyroidism Hypertension Depression Lactulose Medications Levothyroxine Nivolumab ( started 6 months prior to admission) HPV positive squamous cell carcinoma of the oropharynx
5 Social history Ex-smoker (quit 18 years ago, 1 ppd x 3 years) Smokes marijuana every other day Family history Mother: Hypertension Father: Non-Hodgkins lymphoma Divorced, has one adopted daughter
6 Physical Exam T 36.5 C HR BP 100/55 RR 20 SpO2 99 % RA Ht m (5' 6") Wt 59 kg (130 lb) BMI kg/m2 General: Pale, chronic ill appearing Skin: No rashes or bruises Neck: Palpable fixed mass ~ 1 cm in size along L neck Chest: Lungs CTAB, no wheeze CV: RRR, normal S1, S2, no murmurs, rubs, or gallops, no LE edema Abdomen: Generalized tenderness, non distended, no rebound, no guarding Extremities: No peripheral edema in bilateral LE Neuro: Alert, oriented to situation, no tremors Psych: Pleasant, cooperative, interactive, appropriate affect
7 Labs Reference range 4am ACTH AM: pg/ml Cortisol 6 10 AM: ug/dl 0.2 ug/dl
8 Labs Reference range 4am 1pm ACTH AM: pg/ml <5 pg/ml Cortisol 6 10 AM: ug/dl 0.2 ug/dl 1.8 ug/dl
9 Labs Cosyntropin stimulation test Reference range 4am 1pm 1:30pm 2pm ACTH AM: pg/ml <5 pg/ml Cortisol 6 10 AM: ug/dl 0.2 ug/dl 1.8 ug/dl 2.7 ug/dl 3.7 ug/dl Central adrenal insufficiency due to nivolumab induced hypophysitis
10 Immunotherapy and hypophysitis Cukier et al, Endocrine Related Cancer 2017
11 Immunotherapy and hypophysitis Cukier et al, Endocrine Related Cancer 2017
12 Pituitary MRI
13 Pituitary panel TSH 0.4 ng/dl ng/dl FT4 1.6 uiu/ml uiu/ml Prolactin 28.5 ng/ml ng/ml IGF ng/ml ng/ml ACTH <5 pg/ml AM: pg/ml Cortisol 0.2 ug/dl AM: ug/dl Central adrenal insufficiency due to nivolumab induced hypophysitis ACTH
14 Pituitary panel TSH 0.4 ng/dl ng/dl FT4 1.6 uiu/ml uiu/ml Prolactin 28.5 ng/ml ng/ml IGF ng/ml ng/ml ACTH <5 pg/ml AM: pg/ml Cortisol 0.2 ug/dl AM: ug/dl LH 36 IU/L IU/L FSH 40 IU/L IU/L Testosterone 301 ng/dl ng/dl Hypergonadotropic hypogonadism Central adrenal insufficiency due to nivolumab induced hypophysitis ACTH Gonadotropins
15 Updated history Normal pubertal development Diagnosed with low testosterone in his 20s during work up for infertility Azoospermia Erectile dysfunction, normal libido Severe dyslexia special education Anxiety and depression Suicide attempt was admitted for 5 days in a psychiatric hospital
16 Physical exam Male phenotype Bilateral gynecomastia Male external genitalia Testes 4 cc bilateral Normal male pubic hair distribution
17 Hypergonadotropic hypogonadism Learning disabilities Male phenotype Bilateral gynecomastia Klinefelter syndrome Small testes Height
18 Patient is short for his family potential Mid-parental height
19 Karyotype
20 46 XX testicular DSD 90 % SRY positive SRY - Testis-determining factor (TDF), Unequal crossing over between X and Y chromosome during meiosis in the father Translocation of SRY Results in a X chromosome containing the SRY gene 10% SRY- negative Mutations in autosomal or X chromosomal gene Duplication of SOX9 (chromosome 17q24) Duplication SOX3 (Xq26) Mutations of SF1 and WNT4
21 Karyotype + FISH
22 46 XX with SRY
23 De la Chapelle syndrome 46 XX testicular disorder of sex development (DSD) is a condition in which individuals with two X chromosomes in each cell have a male appearance De la Chapelle, Amer J Hum Genet, 1972
24 Clinically, these individuals have a male phenotype, male psychosexual identification, testes or gonads of testicular type without macroscopic or microscopic evidence of ovarian tissue, and absence of female genital organs.
25 Reproductive tract development Fertilization
26 Reproductive tract development SRY Mullen & Behringer, 2014
27 46 XX testicular disorder of sex development (DSD) XX male 1:20,000 Phenotypically there are three groups of sex-reversed 46 XX individuals Classically includes phenotypically normal XX males Males with genital ambiguities True hermaphrodites (ovotesticular disorder of sex development) both ovaries and testicles or ovotestis Skewed X-chromosome inactivation pattern in SRY positive XX male De la Chapelle, AJHG 1072 Verona et al, JCEM 2007
28 Verona et al JCEM 2007
29 Verona et al JCEM 2007
30 Verona et al JCEM 2007
31 Target height for XX Mid-parental height
32 Back to our patient Excellent response to Nivolumab, disease-free Hydrocortisone 10 mg in the morning and 5 mg in the afternoon and testosterone replacement Recovering weight
33 Take home points Hypophysitis is a common immune mediated endocrine AE in patients treated with immunotherapy treatment (PD-1, CTLA-4) Klinefelter is the most common cause of congenital hypergonadotropic hypogonadism but there are other causes that should be recognized karyotype is helpful XX male is a rare cause of gonadal dysgenesis usually caused by translocation of SRY
34 Acknowledgments Thiago Gagliano Nadine Palermo Matthew Kim Thank you!
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