Visual Diagnosis: Endocrine. Joseph A Zenel, MD Sanford School of Medicine, University of South Dakota June 2016

Transcription

1 Visual Diagnosis: Endocrine Joseph A Zenel, MD Sanford School of Medicine, University of South Dakota June 2016

2 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

3 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

4 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)

5 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

6 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

7 Pituitary microadenoma signal left aspect of pituitary

8 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

9 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

10 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

11 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

12 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%)

13 Growth Chart If Ht > Wt: Suspect endocrine etiology If Wt > Ht: Suspect poor calorie intake Suspect calories expenditure Suspect calorie elimination

14 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

15 Increased Pigmentation Tanning Pregnancy Adrenal insufficiency Primary (No cortisol) Secondary (Loss of ACTH stimulation)

16 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 ( mg/dl) Phosphorus 4.4 ( mg/dl)

17 Adrenal Insufficiency Shulman, Pediatr 2007 Primary (Congenital) Glucocorticoid deficiency always Mineralocorticoid deficiency frequently Secondary (Acquired) Lack of CRH (hypothalamus) or ACTH (pituatary) Mineralocorticoids preserved

18 Acute Adrenal Insufficiency Nausea/vomiting Diarrhea Abdominal pain Fever Dehydration Weakness Hypotonia Shock Confusion Coma

19 Chronic Adrenal Insufficiency Fatigue Salt appetite Hypotension Vomiting Failure to gain weight Weight loss Dehydration Tanning

20 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)

21 Increased Pigmentation Cortisol causes CRH CRH causes Proopiomelanocortin (POMC) release POMC proteolysis leads to ACTH production Melanocyte-stimulating hormone (MSH) Melanin

22 Mineralocorticoid Deficiency Decreased aldosterone Hyponatremia Hyperkalemia Hypotension Cardiac dysrhythmias Increased renin level Decreased androgens

23 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

24 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

25 Lab Dx Primary Adrenal Insufficiency Decreased sodium Decreased bicarbonate Decreased serum ph Central Adrenal Insufficiency Mildly decreased sodium

26 Adrenal Insufficiency: Lab Dx ACTH stimulation test Baseline ACTH level Urinary free cortisol low Urinary 17-hydroxycorticosteroid low

27 Na 140 K 4.1 Renin 178 ( 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

28 Treatment Hydrocortisone BID, with stress doses Decreased skin pigmentation Increased: Energy Exercise Pubic hair

29 13-year-old male presents for routine care Always short Moved from Philippines one month ago

30 Ht & Wt Ht cm 43 in << 3rd percentile 50% for 5-year-old Wt 18.6 kg 38 lb << 3rd percentile 50% for 5-year-old

31 DDX: Growth Retardation Primary growth abnormalities Osteochondroplasias Chromosomal abnormalities IUGR Genetic short stature Secondary growth disorders Malnutrition Chronic diseases Endocrine diseases

32 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

33 Secondary Growth Disorders Malnutrition Chronic disease Endocrine TH and IGF-1 are major mediators of growth Constitutional delay of growth

34 Secondary Growth Disorders Endocrine Hypothyroidism Cushing syndrome Pseudohypoparathyroidism Rickets IGF deficiency Hypothalamic dysfunction Pituitary GH deficiency GH insensitivity

35 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

36 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

37 Laboratory Lytes, BUN, creatinine normal TSH 1.4 ( uiu/ml) Free T4 1.0 ( ng/dl) IGF ( ng/ml) IGFBP ( mg/l) GH < 0.1 (< 9.1 ng/ml) Bone age: male, 13 years

38 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

39 DX: Empty Sella Syndrome Ectopic neurohypophysis Absent infundibulum Absent anterior pituitary Treated with: Gonadotropin L-thyroxin Cortef

40 Growth Failure (< 2-3 SD) Consensus Statement, J Clin Endocrinol Metab. November 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

41 Genetic Workup: Short Stature Bang et al. Clin Endocrinol 2012

42 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

43 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

44 12-month-old male with growth failure Coarse Facies 7.69 kg <<< 5% 50% 6 mos Ht and HC << 5% 50% 4 mos

45 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

46 Hypothyroidism: Low T 4 Developmental delay Hair loss Weakness Hypotonia? Myxedema

47 Myxedema Relatively hard edema of subcutaneous tissue with: Somnolence Slow mentation Hair loss Hoarseness Weakness

48 Acquired Hypothyroidism Most common cause: chronic lymphocytic thyroiditis (Hashimoto s) Ectopic or hypoplastic thyroid gland May be euthyroid at birth Develop hypothyroidism during childhood

49 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

50 Acquired Hypothyroidism: Rare Causes Iodine deficiency Thyrotropin deficiency TH resistance Cystinosis Goitrogens

51 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

52 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

53 Increased Facial Hair 14-year-old female complains of increased facial hair

54 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

55 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

56 Virilization Hirsutism with other signs of androgen excess: Frontotemporal balding Acne Deepening of voice Clitoral hypertrophy Increased muscle mass

57 Causes: Hirsutism Excess androgen production Relative androgen excess Decreased binding globulin Excess end-organ response Patient perception

58 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

59 DDX: Hirsutism Other Obesity Hypothyroidism Hyperprolactinemia Cushing syndrome Pregnancy Drugs Androgens OCP Minoxidil Diazoxide

60 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

61 Androgens Ovary Testosterone Androstenedione DHEA Adrenal Androstenedione DHEA DHEA-S

62 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

63 Sertoli-Leydig-cell tumor Rare, <1% Ovarian tumors Average age 25 years Alam, Indian J Pathol Micro % virilization 50% abdominal mass 50% No endocrine symptoms Some present with estrogenization

64 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

65 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