兒童內分泌疾病與遺傳代謝疾病 小兒科 蔡孟哲

兒童內分泌疾病 糖 尿 病 急 性 併 發 症 低 血 糖 症 肥胖症 性早熟、晚熟 腦下垂體低能症 先天性腎上腺增生症與腎 上 腺 危 症 血 鈣、副甲狀腺 與維生素D 甲狀腺疾病

腦下垂體低能症(Panhypopituitarism) Congenital: Idiopathic combined pituitary hormone deficiency (CPHD) Non-syndromic genetic CPHD Syndromic CPHD: septo-optic dysplasia, holoprosencephaly Acquired: Infiltrative disease Infectious disease: T.B. hypophysitis Inflammatory disease Hydrocephalus Trauma Hemorrhage/ischemia Radiation Autoimmune disease

腦下垂體低能症的臨床表現 GH-related: ACTH-related: TSH-related: GnRH-related: Growth failure, frontal bossing, truncal obesity, mid-facial hypoplasia, delayed dentition ACTH-related: Lethargy, apnea, jitteriness, seizure, hypotension, fever TSH-related: Prolonged neonatal jaundice, temperature instability GnRH-related: Undescended testes, microphallus Absent, delayed or arrested puberty, infertility ADH-related: Diabetes insipitus Others: Hypoglycemia, electrolytes imbalance

腦下垂體低能症的處理 Check serum Na, K, osmo, Glucose Check GH, ACTH, cortisol, TSH, T3, T4, IGF-1 Check estrogen, testosterone, LH, FSH if the patient is beyond pubertal age Hormone supplement: Cortisone 10-20 mg/m2/day L-thyroxine: 10-15 ug/kg/day for neonate; 4 ug/kg/day for children; 2 ug/kg/day for adult Growth hormone needs specifically endocrinologic consultation Sex hormone needs specifically endocrinologic consultation

先天性腎上腺增生症與腎 上 腺 危 症 (Congenital adrenal hyperplasia and adrenal crisis) Glucocorticoid deficiency: Impaired metabolism and glucose homeostasis Anorexia, apathy, nausea, hypoglycemia, hypotension, fever Mineralocorticoid deficiency: Impaired Na reabsorption and K excretion Osmotic diuresis, hyponatremia, hyperkalemia

腎上腺危症之原因 Primary (Addison disease) Secondary (pituitary lesion) Hyperpigmentation due to elevated ACTH Usually severe adrenal crisis Secondary (pituitary lesion) Isolated vs. combined; congenital vs. acquired Usually mild electrolytes problem but variable clinical presentation Tertiary (hypothalamus lesion) Responsive to CRH

原發性腎上腺功能低下 Congenital: Acquired: 先天性腎上腺增生症 (CAH): 21-hydroxylase deficiecy (most common)> 90% of CAH 先天性腎上腺發育不良 (adrenal hypoplasia congenita) Adrenoleukodystrophy Acquired: Autoimmune adrenalitis Infection Hemorrhage

先天性腎上腺增生症(CAH) : 7 d/o, 女性假陰陽人, 嘔吐, 體重減輕, 低血鈉, 高血鉀

先天性腎上腺增生症的臨床處置 Check 17-OHP, cortisol, ACTH, testosterone, aldosterone, renin Monitor: glucose, electrolytes, BUN/Cr Treatment: Fluid supplement: 20 ml/kg bolus of D5W/NS or colloid, then NS 200 ml/kg/day for <10 kg Hypoglycemia: 0.5-1g/kg/dose of D50W and D10W Steroid replacement: Hydrocortisone 50mg/m2/dose IV q6hrs (acute stage); cortisone 5-10mg/m2/day (mainenance) Fludrocortisone 50-100 mg/day (maintenance) Surgical intervention for external genitalia

血 鈣、副甲狀腺 與維生素D Neonatal hypocalcemia/hypercalcemia Maternal factor Perinatal factor Rickets of prematuriy Formula contents Childhood hypocalcemia Hypoparathyroidism Pseudohypoparathyroidism Hypomagnesmia Hypo-vitaminosis/rickets Renal failure Genetic disease: mitochondrial diseases, DiGeorge sundrome Autoimmune disease: APS type 1 Childhood hypercalcemia Hyperparathyroidism Neoplasm: MEN1, MEN2A Hyervitaminosis D Inflammatory disease: sarcoidosis Genetic disease: Williams syndrome Immobilization Malignancy

血鈣異常 Normal range: 8.8 to 10.3 mg/dl Corrected [Ca]   =   Measured total [Ca]  +  (0.8  x  (4.5  -  [alb])) Presentations: seizure , nausea, parethesia, agitation, weakness/ tetanus, abnormal QT interval Measurements: Serum Ca, P, Mg, ALK-P, Cr, iPTH, VitD Urine Ca, P, Cr

鑑別診斷

臨床案例 一個月大男嬰, 張力較低,偶爾發紺,有一心雜音 心臟超音波診斷為mild pulmonary stenosis Ca: 5.6 mg/dl, P: 6.1 mg/dl, iPTH 20 pg; Cr 0.48 mg/dL; Na 134 mmol/L; K 7.4 mmol/L; Cl 105 mmol/L; Mg 3.2 mmol/L; ALK-P 210 U/L; Alb 5.0 g/dL; iPTH 20 pg/mL 還需要做哪些檢查? 可能診斷是?

臨床處置 Hypocalcemia Hypercalcemia Calcium gluconate 10% IV: 2ml/kg/dose at 5-10 mins Correct Magnesium level Give calcitriol if hypovitaminosis or hypoparathyroidism Hypercalcemia IVF hydration Calcitonin, bisphosphonate, prednisolone

Vitamine D 24,25(OH)2D3 ↑p ↑ Ca 1,25(OH)2D3 Liver D3 25OHD3 Kidney PTH ↑ 1,25(OH)2D3

佝僂症 (Rickets)

佝僂症的原因 Prematurity of rickets Calcium deficiency rickets Vitamin D deficiency rickets: < 25-30 ng/ml Vitamin D dependent rickets Type 1: low 1,25(OH)2D3 Type 2: hereditary vitamin D resistant rickets (HVDRR) With normal VitD receptor Hypophosphatemic rickets X-linked dominant Autosomal dominant Autosomal recessive

甲狀腺疾病 甲狀腺低下 (Hypothyroidism) 甲狀腺亢進 (Hyperthyroidism) Congenital vs. acquired Primary vs. secondary vs. tertiary 甲狀腺亢進 (Hyperthyroidism) Auto-immune vs. allo-immune

先天性甲狀腺低下(Congenital hypothyroidism) Presentations: Lethargy, hypotonia, jaundice, delayed umbilical detachment, large tongue, short stature, retardation Primary: elevated TSH Thyroid dysgenesis: ectopic or absent thyroid; 85% Dyshormonogenesis: present thyroids; 10-15% Transient: idiopathic or maternal thyroid disease Secondary or tertiary: Isolated or syndromic pituitary lesion

先天性甲狀腺低下治療原則 Treatment targets: Treatment dose: Levothyroxine T4 within age-specific range TSH < 10 Treatment dose: Levothyroxine 10-15 mcg/kg/day for newborn 8-10 mcg/kg/day for children 5-8 mcg/kg/day for adolescent onward Treatment duration 1st trial of discontinuation at 3 y/o Unsuccessful  lifelong supplementation

自體免疫甲狀腺疾病 Hypothyroidism Hyperthyroidism Association: Hashimoto’s disease (goitrous) vs. primary myxedema Family preponderance: anti-microsomal Ab (+); anti- thyroiglobulin Ab (+) Tx: levothyroxine supplement Hyperthyroidism Graves’ disease vs. hashitoxicosis Family preponderance: anti-TSHR Ab (+) Tx: Methimazole or propriouracil Association: Autoimmune disease, type I DM, adrenalitis, vitiligo, myathenia gravis…

自體免疫甲狀腺疾病治療原則 Hypothyroidism Hyperthyroidism Tx: Levothyrpoxine 5-10 ug/kg Monitor: TSH < 10 Hyperthyroidism Monitor: T4 or fT4 within normal range Anti-thyroid drugs Methimazole (MMI) 0.5 mg/kg/day Propylthiouracil (PTU) 5mg/kg/day Anti-arrthymic drugs: Inderal 0.5-2 mg/kg/day Steroids: prednisolone 1-2 mg/kg/day Others: lugol solution, surgery, radio-isotope

兒童遺傳代謝疾病 先天性代謝異常 (Inborn error of metabolism) 染色體異常疾病 高血氨症 (hyperammonemia) 有機酸血/尿症 (organic acidemia/aciduria) 儲積症 (storage disease) 染色體異常疾病 體染色體異常 性染色體異常 小片段染色體異常

新生兒高血氨症臨床症狀 症狀在餵食 24-72 hrs 後出現 (protein load) 神經學症狀 腸胃道症狀 其他 嗜睡, seizures, 昏迷 腸胃道症狀 噁心, 嘔吐, 肝腫大 其他 呼吸急促, 躁動不安, 低體溫

鑑別診斷 Ammonia正常值 < 35 mM/L 發生率: 1 in 30,000 live births Inborn error of metabolism  check blood on filter paper for tandem mass and urine for GC mass Systemic illness (usually < 200): 敗血症, 腦出血, 心臟病, 腸胃道阻塞

臨床處置 Nutritional support: General consideration: IV glucose 60-150 kcal/kg/day: most important Low-protein diets: 0.5-1.0 g/kg/24h IV intralipids: indicated in patients without metabolism error in lipids General consideration: If bicarbonate <10meq/L, correct accidosis Carnitine 100-200 mg/kg po tid or IV qd Treat IICP as indicated

血氨移除 Medical treatment: Na-benzoate : remove 1 mole of ammonia/mole 罕見藥物物流中心 in 2002 Na-phenylacetate : remove 2 moles of ammonia/mole Arginine : indicated in disorder of urea cycle Hemodialysis: indicated in extremely high ammonemia (> 10X) HD: highest efficiency PD: less effective. CVVHD:最適合新生兒高血氨移除

新生兒有機酸血/尿症 Clinical presentations: normal between crisis!! Excessive vomiting  dehydration Metabolic acidosis  cardiac compromise Hypoglycemia  seizure, neurotoxicity Neutropenia  infection-prone Diagnostic approach: Check blood on filter paper for tandem mass; urine for GC-mass Check enzyme level in cultured fibrobasts or leukocyes Mutational analysis

臨床處置 與高血氨症類似!!

儲積症 肝醣儲積症 (Glycogen storage disease) Ketotic hypoglycemia Lactate acidosis Variable elevation in TG, Chol, UA Hepatomegaly and hepatitis Muscle weakness: variable 溶機體疾病 (Lysosomal disorders)  neurodegenerative process 黏多醣症 (Mucopolysacharridosis) 黏多脂症 (Mucolipidosis) 神經脂質症 (Sphingolipidosis)

臨床處置 診斷流程 治療 臨床懷疑 特定代謝物質偵測 (e.g. MPS screening) 特定酵素檢測 (functional enzyme assay) 基因分析 治療 Supportive care Enzyme replacement MPS type 1, 2, 6 Gaucher Niemann-Pick C Fabry disease

染色體疾病 定義: 染色體數目或者結構異常 其他類: 數目異常: 結構異常: Chromosome instability syndrome 體染色體數目異常: 如唐氏症、愛德華氏症等 性染色體數目易常: 如透納氏症、克林菲爾德氏症等 結構異常: Deletion: 如貓哭症等 Duplication:如貓眼症等 Translocation: Balanced vs. unbalanced translocation Reciprocal translocation vs. Robersonian translocation Insertion, inversion, rings, isochromosome 其他類: Chromosome instability syndrome Microdeletion, microduplication

周邊血液染色體檢查適應症

染色體採檢補助聯

染色體基因晶片適應症 Indications: Mechanism: Clinical consideration Dysmorphic features, mental retardation, developmental delay, autism spectrum disorder, multiple congenital anomalies…more and more… Delineation of aberrant chromosome characters Mechanism: Array comparative genomic hybridization (aCGH) Probes for All the known microdeletion/duplication syndrome Pericentromeric and subtelomeric regions Clinical consideration Version of probe combination Cost and effectiveness

臨床個案 3.5 y/o boy with developmental delay Autistic behavior with mildly protruding tongue Cardiac anomaly: VSD Chromosome study: 46 XX, normal female Parents come for genetic counseling about their next pregnancy!!

染色體基因晶片

FISH

Methylation-specific multiplex ligation-dependent probe amplifacation (MLPA)

Father

Mother

Final diagnosis

結束 感謝聆聽