Visual Diagnosis: Endocrine Joseph A Zenel, MD Sanford School of Medicine, University of South Dakota June 2016
17-year-old with right flank pain T 37.9º C (100.2º F) P 115 R 20 BP 153/94 Ht 148 cm < 3rd percentile Wt 88.5 kg (198 lb) 95th percentile
Truncal obesity Moon facies Muscle wasting Purple striae Easy bruising Hirsuitism Hypertension Decreased growth rate Delayed skeletal maturation Glycosuria Osteoporosis Serum, urine adrenocorticoids Serum potassium Lymphopenia Cushingoid Features
Cushing Syndrome Glucocorticoid excess Cushing Disease Excessive ACTH secretion from pituitary Cushing Syndrome Excessive secretion of adrenal steroids (adenoma, carcinoma, multinodular hyperplasia) Ectopic ACTH syndrome (ex. lung cancer) Iatrogenic Cushing Syndrome Exogenous source (drugs - ACTH, cortisol)
Cushing Syndrome Adults: ACTH Dependent 80% ACTH Independent (20%) Rare in children - 10/1,000,000 If Cushing Syndrome appears: > 7 years of age - Pituitary ACTH over secretion < 7 years of age - Adrenal tumors predominate
DDX: Cushing Syndrome Obesity Hypothyroidism Hypothalamic pathology Obesity vs Cushingoid Obesity Limbs and trunk affected Striae pink in color Cushingoid Obesity central Thin limbs Striae purple in color
Pituitary microadenoma signal left aspect of pituitary
Cushing Syndrome Appearance gradual, over years Hard to diagnose early in course Suspect Cushing Syndrome in any overweight child who stops growing With dietary obesity, child grows rapidly and is tall for age
DX: Cushing Syndrome Dexamethasone suppression test Low dose, high dose Obesity or other non-cushing disorder Low dose suppresses cortisol, ACTH Adrenal tumor or ectopic source Low and high dose do not suppress Pituitary tumor High dose suppresses, low dose does not
13-year-old female with short stature Ht 150 cm 59 in < 10%, > 5% 50% for 12-year-old Wt 38.8 kg 86 lb 10% 50% for 11.5-year-old
Findings Tanned complexion Blue spots on tongue Dark scar Mild telorism Breasts Tanner II No axillary or pubic hair Mild cubitus valgus Short 4th, 5th metacarpals
Constitutional Delay? Adult height prediction Calculate mean adult height (mother and father) Male: add 6.5 cm Female: subtract 6.5 cm Father 5 ft 5 in (<5%) PGM 5 ft (<5%) Patient (<10%)
Growth Chart If Ht > Wt: Suspect endocrine etiology If Wt > Ht: Suspect poor calorie intake Suspect calories expenditure Suspect calorie elimination
DDX: Acquired Short Stature Hypothyroidism IGF deficiency Turner syndrome Short, irregular menses, broad neck, short metacarpals But tall in childhood, early puberty, fused epiphyses Pseudohypoparathyroidism Obese, round facies, mental retardation, short metacarpals Hypocalcemia with high PTH levels Autosomal dominant
Increased Pigmentation Tanning Pregnancy Adrenal insufficiency Primary (No cortisol) Secondary (Loss of ACTH stimulation)
Laboratory Chromosome analysis Normal TSH, Free T4 Normal ACTH 3123 (9-52 pg/dl) Cortisol < 1 (8-23 g/dl) PTH 18 (10-65 pg/ml) Calcium 9.8 (8.5-10.5 mg/dl) Phosphorus 4.4 (2.5-5.0 mg/dl)
Adrenal Insufficiency Shulman, Pediatr 2007 Primary (Congenital) Glucocorticoid deficiency always Mineralocorticoid deficiency frequently Secondary (Acquired) Lack of CRH (hypothalamus) or ACTH (pituatary) Mineralocorticoids preserved
Acute Adrenal Insufficiency Nausea/vomiting Diarrhea Abdominal pain Fever Dehydration Weakness Hypotonia Shock Confusion Coma
Chronic Adrenal Insufficiency Fatigue Salt appetite Hypotension Vomiting Failure to gain weight Weight loss Dehydration Tanning
Glucocorticoid Deficiency Weakness, fatigue, anorexia, FTT, abdominal pain Decreased axillary and pubic hair Hypoglycemia Increased pigmentation: Sun-exposed skin, scars and freckles Flexor surfaces of knees, elbows, knuckles Mucous membranes (tongue, buccal mucosa)
Increased Pigmentation Cortisol causes CRH CRH causes Proopiomelanocortin (POMC) release POMC proteolysis leads to ACTH production Melanocyte-stimulating hormone (MSH) Melanin
Mineralocorticoid Deficiency Decreased aldosterone Hyponatremia Hyperkalemia Hypotension Cardiac dysrhythmias Increased renin level Decreased androgens
Adrenal Insufficiency Most Common Causes Hereditary enzymatic defects (CAH) Loss of adrenal function Autoimmune destruction (Addison disease) Central adrenal insufficiency Following intracranial tumor Rx Congenital midline defects associated with optic nerve hypoplasia Septo-optic dysplasia
Adrenal Insufficiency: Rare Causes Infection TB, fungal (AIDS) Adrenal destruction Tumor, calcification, hemorrhage Familial autoimmune Addison Hypoparathyroidism, candidiasis, hypothyroidism, pernicious anemia, hypogonadism, DM Exogenous corticosteroids Adrenoleukodystrophy Behavior changes, poor school performance, dysarthria, dementia Hereditary unresponsiveness to ACTH No mineralocorticoid deficiency Very rare Both sex-linked, autosomal recessive forms described
Lab Dx Primary Adrenal Insufficiency Decreased sodium Decreased bicarbonate Decreased serum ph Central Adrenal Insufficiency Mildly decreased sodium
Adrenal Insufficiency: Lab Dx ACTH stimulation test Baseline ACTH level Urinary free cortisol low Urinary 17-hydroxycorticosteroid low
Na 140 K 4.1 Renin 178 (50-330 ng/dl/hr) Patient Laboratory Normal levels: 17 - OHP, DHEAS, Testosterone, Androstenedione Adrenal antibodies < 1:4 DX: Isolated Glucocorticoid Deficiency Mutation in coding for ACTH receptor Not associated with salt wasting
Treatment Hydrocortisone BID, with stress doses Decreased skin pigmentation Increased: Energy Exercise Pubic hair
13-year-old male presents for routine care Always short Moved from Philippines one month ago
Ht & Wt Ht 107.3 cm 43 in << 3rd percentile 50% for 5-year-old Wt 18.6 kg 38 lb << 3rd percentile 50% for 5-year-old
DDX: Growth Retardation Primary growth abnormalities Osteochondroplasias Chromosomal abnormalities IUGR Genetic short stature Secondary growth disorders Malnutrition Chronic diseases Endocrine diseases
Primary Growth Abnormalities Osteochondroplasias Achondroplasia (1:26,000; autosomal dominant) Hypochondroplasia Chromosomal abnormalities Trisomy 21, Turners XO IUGR GH independent IGF dependent Achondroplasia Megalocephaly Rhizomelia
Secondary Growth Disorders Malnutrition Chronic disease Endocrine TH and IGF-1 are major mediators of growth Constitutional delay of growth
Secondary Growth Disorders Endocrine Hypothyroidism Cushing syndrome Pseudohypoparathyroidism Rickets IGF deficiency Hypothalamic dysfunction Pituitary GH deficiency GH insensitivity
Hypothyroidism Endocrine Delayed growth, maturation, bone age Cushing syndrome Pseudohypoparathyroidism Obese, round facies, mental retardation, short metacarpals Rickets Frontal bossing, bowing of legs, rachitic rosary
Hypothalamic dysfunction Genetic abnormalities Congenital malformation (Septo-optic dysplasia) Trauma, infection, tumor Pituitary GH deficiency Genetic abnormality in GH production Congenital absence/hypoplasia of ant pituitary Craniopharyngioma Psychosocial dwarfism GH insensitivity GH receptor deficiency Antibody to GH IGF Deficiency
Laboratory Lytes, BUN, creatinine normal TSH 1.4 (0.28-5.00 uiu/ml) Free T4 1.0 (0.7-1.8 ng/dl) IGF-1 9.0 (202-957 ng/ml) IGFBP-3 0.8 (2.1-6.2 mg/l) GH < 0.1 (< 9.1 ng/ml) Bone age: male, 13 years
Bone Age Left hand and wrist Skeletal maturation compared with normal age-related standards Bone age correlates well with pubertal stage Bone age = true age in familial short stature Affected by thyroxin, GH, sex steroids
DX: Empty Sella Syndrome Ectopic neurohypophysis Absent infundibulum Absent anterior pituitary Treated with: Gonadotropin L-thyroxin Cortef
Growth Failure (< 2-3 SD) Consensus Statement, J Clin Endocrinol Metab. November 2008 1. Check CBC, ESR, lytes, creatinine, Calcium, Phosphate, TSH, Free T 4 bone age, IGF-1 - IGFBP-3 if child <3 years 2. If normal height velocity and no bone age delay, no IGF-1 3. If IGF-1 low, refer to endocrinologist GH stimulation test
Genetic Workup: Short Stature Bang et al. Clin Endocrinol 2012
Growth Hormone Indications Growth hormone deficiency Idiopathic short stature (>2SD below predicted) SGA SHOX Deficiency Short stature homeobox containing gene deficiency FDA Approved Turner syndrome Noonan syndrome Prader-Willi syndrome Chronic renal insufficiencyshort Bowel Syndrome
Familial Constitutional Delay Bone age Nl Bone age Delay Family Ht Short Family Ht Nl Puberty onset Nl Puberty onset Delay Ultimate Ht Short Ultimate Ht Tall, Nl
12-month-old male with growth failure Coarse Facies 7.69 kg <<< 5% 50% 6 mos Ht and HC << 5% 50% 4 mos
Hypothyroidism Congenital, Acquired Bradycardia (P 75) Hypothermia T 35.7 C (96.3 F) Macroglossia Umbilical hernia, protuberant abdomen Short stature, bone delay, no organomegaly
Hypothyroidism: Low T 4 Developmental delay Hair loss Weakness Hypotonia? Myxedema
Myxedema Relatively hard edema of subcutaneous tissue with: Somnolence Slow mentation Hair loss Hoarseness Weakness
Acquired Hypothyroidism Most common cause: chronic lymphocytic thyroiditis (Hashimoto s) Ectopic or hypoplastic thyroid gland May be euthyroid at birth Develop hypothyroidism during childhood
Chronic Lymphocytic Thyroiditis Females 3 > males Associated with other autoimmune diseases incidence in Down, Turner and Noonan syndrome At risk for Addison disease, DM type I Antimicrosomal Ab
Acquired Hypothyroidism: Rare Causes Iodine deficiency Thyrotropin deficiency TH resistance Cystinosis Goitrogens
Laboratory: TSH, free T 4 If TSH and free T 4 Primary hypothyroidism If TSH nl and free T 4 Secondary/tertiary hypothyroidism Pituitary test, head MRI If TSH and free T 4 normal Subclinical or compensated hypothyroidism TSH single best test to diagnose, monitor thyroid disease
Congenital Hypothyroidism LaFranchi, Pediatr Endocrinol Metab 2007 Transplacental passage of maternal thyroid hormone offers some protection Serum half-life 6 days Neonatal T4 falls 2-3 weeks Need replacement during this crucial time or risk losing 5-20 IQ points
Increased Facial Hair 14-year-old female complains of increased facial hair
History Thelarche, pubarche at 11 years of age Menarche at 12 years of age Menstruation every 4-8 weeks Tallest in class Always had deep voice Clitoral enlargement 2.5 cm length
Hirsutism Excess terminal hair in adult male-pattern In a female Hair in androgen-sensitive areas of skin: Upper lip Chin Sideburns Upper arms Chest (periareolar) Upper pubic triangle Thighs Intergluteal folds
Virilization Hirsutism with other signs of androgen excess: Frontotemporal balding Acne Deepening of voice Clitoral hypertrophy Increased muscle mass
Causes: Hirsutism Excess androgen production Relative androgen excess Decreased binding globulin Excess end-organ response Patient perception
DDX: Hirsutism Polycystic ovarian syndrome (PCOS) Menstrual irregularity, acne, acanthosis nigricans, obesity Nl or Testosterone, nl DHEA-S, nl 17 - OHP Nl or LH, nl FSH Mild or non-classic CAH 17 - OHP, Testosterone 17 -hydoxylase deficiency Idiopathic Nl or slightly androgen levels
DDX: Hirsutism Other Obesity Hypothyroidism Hyperprolactinemia Cushing syndrome Pregnancy Drugs Androgens OCP Minoxidil Diazoxide
DDX: Virilization Exogenous androgen Androgen producing tumor (Testosterone > 200 ng/dl) Adrenal gland Testosterone, DHEA-S (> 800 ng/dl) Ovary Testosterone, nl DHEA-S Disorders of sexual differentiation
Androgens Ovary Testosterone Androstenedione DHEA Adrenal Androstenedione DHEA DHEA-S
Laboratory Testosterone DHEA-S 17-OHP FSH LH 5 Normal Normal 2 Normal Low Normal Chromosome 46, xx DX: Ovarian Tumor Sertoli-Leydig-cell tumor Sex cord stromal tumor
Sertoli-Leydig-cell tumor Rare, <1% Ovarian tumors Average age 25 years Alam, Indian J Pathol Micro 2009 40% virilization 50% abdominal mass 50% No endocrine symptoms Some present with estrogenization
Hirsutism Laboratory Total & free testosterone DHEA-S Distinguish adrenal from ovary disease 17 - OHP 17 -hydroxylase deficiency (r/o CAH) Free T 4 TSH Prolactin
Visual Diagnosis: Endocrinology I will check T 4, lytes, BUN, creatinine, bone age, IGF-1 in a child with growth failure I will consider Cushing syndrome in an obese child who has stopped growing. I will consider hypothyroidism in an infant with developmental delay and weakness even if newborn screen was negative for congenital hypothyroidism