儿科学教学课件：12-Congenital Hypothyroidism

(Cretinism)Congenital HypothyroidismLearning objectivesYou should know:The clinical features of congenital hypothyroidism in neonates and childrenBe able to discuss the diagnosis and managementMajor contentsOverview of congenital hypothroidismEtiologyClinical manifestationLaboratory examination Diagnosis and differential diagnosisTreatment Abbreviation CH congenital hypothyroidismTRH thyrotropin-releasing hormoneTSH thyrotropic-stimulating hormoneT4 thyroxineT3 triiodothyronineMIT monoiodotyrosine(单碘酪氨酸）单碘酪氨酸）DIT diiodotyrosine（双碘酪氨酸）（双碘酪氨酸）TG thyroglobulinTBG thyroxine-binding globulinTH thyroid hormone OverviewHypothyroidism Congenital hypothyroidism acquired hypothyroidism Iodine deficiency Autoimmune disease Hashimoto thyroiditisOverviewHypothyroidism Congenital hypothyroidism acquired hypothyroidism Iodine deficiency Autoimmune disease Hashimoto thyroiditisOverviewCongenital Hypothyroidism(CH)is common disease of pediatric endocrinology.Congenital factors cause the insufficiency of thyroid hormone,which result in the low metabolism,growth retardation,and mental impairment.The onset during inborn or newborn period,will lead to irreversible mental impairment.CH is one of preventable causes of mental retardation,early treatment will improve the prognosis thoroughly.Incidence 1 in 4000 live births(in America and Europe)Females:Male is 2:1In China:Incidence of Congenital hypothyroidism（From the neonatal screening):1 in 3624 -the nationwide neonatal screening from clinical examination center of Health Bureau in 1999 ClassificationSporadical CHMajority CH patients are sporadical,a few is familial.Endemic CHPregnant women live in iodine insufficient areas,which result in iodine deficiency.Along with fortifying iodine salt in dietary,incidence of endemic CH is much lower.Embryology of ThyroidEmbryology of Thyroid Thyroid is the first endocrine gland to develop in embryo Begins to form in 24 days after fertilization Forms from primordial pharyngeal floor（原始咽底部）forming thyroid diverticulum（原基）As embryo and tongue grow,thyroid descends in anterior neck and reaches its normal site:the opposite cervical vertebra 5-7 by 7 weeks of gestationPharynxPharynxfloorfloorRole of Placenta SubstancePlacental permeability I-+TRH +IgG Antibodies +T3 +T4 +TSH 0pituitary-thyroid hormone production after birth Hormones in fetal Hormones after birth(Hour)Within 30 minutes of delivery,TSH abrupt rise occurs-as a protected results of change in environmental temperature.TSH levels:first 12h as high as 70mU/L;after 48h:20;after 120h:95 percent neonates with CH have few clinical manifestations(maternal T4 crosses the placenta,so even in athyrosis thyroid hormone umbilical cord serum T4 level are about 25 to 50 percent of those of normal infants).Clinical findings:(happens in 5%of neonatal CH)Post-term birth(42 weeks);large for date infant Wt 4 kg Hypothermia,acrocyanosis手足发绀手足发绀,respiratory distress,lethargy and hoarse cry.poor feeding,constipation.Jaundice often prolongs over 2 weeks.Oedema,large posterior fontanel,macroglossia,abdominal distension,umbilical hernia脐疝脐疝,mottled skin.bone age is often delayed at birth.Neonate with Congenital HypothyroidismJaundice,macroglossia,dry skin,and hoarse cry.Laboratory examination An elevated TSH is most sensitive and specific test to confirm diagnosis Remember that TSH surge occurs in first 12 hours of life and may remain high until 48 hoursLaboratory examination Newborn screening Suitable Time:23 days after birthMothed:use dry blood slip and detect TSH level.Results:positive:TSH 20uU/ml then detect T4 and TSH for further determineLaboratory examinationEvaluate thyroid function primarily hypothyriodism:T4 T3 TSH secondary hypothyriodism:T4 T3 TSHTRH stimulating test objective:suspected insufficient TSH or TRH objectives mothed:use TRH 7ug/kg,IV,detect TSH level results:normal:at 30 min appear TSH peak，at 90 min retum to basic value.abnormal:No TSH peak appear-pituitary disorder Delayed TSH peak appear-hypothalamic disorderLaboratory examinationRadiographinfant and child CHEvaluation bone ageObviously delayed bone age,almost lags 3 years oldPosition of detect:younger than 6 month:take knee X-rayolder than 6month:take wrist X-ray Neonatal distal femoral epiphysis ossification center Normal neonate Neonate with CHWrist ossification center Normal children CH childrenNormal children CH children Diagnosis as early as possiblediagnostic criteriaNeonate:Neonatal special manifestation +T4TSHChildren:typical symptom+T4 TSH+lag bone age Differential diagnosisCongenital megacolon 先天性巨结肠先天性巨结肠21-trisome 21-21-三体症三体症Dysosteogenesis 骨发育障碍骨发育障碍 Achondroplasia 软骨发育不软骨发育不全全 Rickets 佝偻病佝偻病Anaemia 贫贫 血血Differential diagnosisCongenital megacolon 先天性巨结肠先天性巨结肠21-trisome 21-21-三体症三体症Dysosteogenesis 骨发育障碍骨发育障碍 Achondroplasia 软骨发育不全软骨发育不全 Rickets 佝偻病佝偻病Anaemia 贫贫 血血Congenital megacolonnVery severe constipation,abdominal distension and Umbilical hernianWeight lossing nNormal facial,voice and physical function,nX-ray show enlarged colon.nNormal thyroid functionCongenital megacolon X ray imagingDifferential diagnosisCongenital megacolon 先天性巨结肠先天性巨结肠21-trisome 21-21-三体症三体症Dysosteogenesis 骨发育障碍骨发育障碍 Achondroplasia 软骨发育不全软骨发育不全 Rickets 佝偻病佝偻病Anaemia 贫贫 血血21-trisome(21-(21-三体症三体症)Severe mental retardationTypical facial appearanceRound face,epicanthic fold 内眦赘皮内眦赘皮,upwards angulus oculi lateralis 外眦上翘，外眦上翘，Depression nasal bridge and upwards nostrils 朝天鼻朝天鼻Protruding tongue,舌外伸舌外伸Chromosome analysis:21-trisome21-trisome karyotypeDifferential diagnosisCongenital megacolon 先天性巨结肠先天性巨结肠21-trisome 21-21-三体症三体症Dysosteogenesis 骨发育障碍骨发育障碍 Achondroplasia 软骨发育不全软骨发育不全 Rickets 佝偻病佝偻病Anaemia 贫贫 血血Achondroplasian Short stature with long trunk and short limbsn Large head,frontal protrusion,depression of nasal bridgen Short and broad handsn Marked lumbar lordosisn Normal skin,intelligence and thyroid functionn special Xray featuresAchondroplastyAchondroplasiaX ray imagingDifferential diagnosisCongenital megacolon 先天性巨结肠先天性巨结肠21-trisome 21-21-三体症三体症Dysosteogenesis 骨发育障碍骨发育障碍 Achondroplasia 软骨发育不全软骨发育不全 Rickets 佝偻病佝偻病Anaemia 贫贫 血血TreatmentTreatment goals Assure normal growth and development Normal T4 as rapidly as possible Avoid hyperthyroidism Maintain clinical and biochemical euthyroidism Each wk delay of treatment affects IQ by 1-2 pointsTreatmentPrincipleOnce diagnosed,immediately treatmentThyroid hormone supplement in lifetime Regulated dose along with increasing ageAttention the individual differenceL-ThyroxinenL-Thyroxine is the treatment of choice long half-life and inexpensiveexcellent bioavailability following oral intakeProvides stable levels of T4,T3 and TSH over a 24-hour periodDose can be finely titrated using TSH assaysL-ThyroxinenReplacement as soon as possible nDose of T4 changes with age:newborn 10 to 15 g/kg.d,bid or qd Infant:6-8ug/kg.d,bid or qd later in childhood 3-5 g/kg,bid or qd nGoal:serum T4 upper half of normal range nDo NOT give with Iron,soy or fibrenPreferred crushed tablet as liquid forms less stableMonitoring guidelines from American Academy of PediatricsnFollow-up initially:2/52 w-4/52 w；nEvery 1-2 mo during the first 6 mo;nEvery 3-4 mo between 6 mo and 3 y of age;nEvery 6-12 mo from 3y of age to end of growth.Therapeutic reactionClinical symptomes improve around 2 weeks,Clinical manifestation disappear and growth advance around 2-3 months.AttentionSupplement of nutrient substance and vitamins are needed.OutcomesnTreatment within 3 weeks(screening programmes)Close to normal intellectual developmentnTreatment after 3 months of age -clinical signs presentintellectual capacity is markedly decreased.2mo2mo1yr6mo1yr6moReferencesMartin:Fanaroff and Martins Neonatal-Perinatal Medicine,8th ed.,Copyright 2006 MosbyCostanzo:Physiology,2nd ed.,Copyright 1998 Lippincott Williams and WilkinsMoore and Persaud:The Developing Human,6th ed,Copyright 1998 W.B.Saunders CompanyFoley,Thomas.Hypothyroidism.Peds in Rev.25(3).Genetic regulation of thyroid development;Mary P.Gillam,MD,and Peter Kopp,MD Current Opinion in Pediatrics 2001,13:358363Genetics of congenital hypothyroidism;S M Park and V K K Chatterjee J.Med.Genet.2005;42;379-389.Thyroid Development and Its Disorders:Genetics and Molecular Mechanisms;Mario de Felice and Roberto di Lauro,Endocrine Reviews 25(5):722746.Molecular pathogenesis of congenital hypothyroidism;AnnetteGrueters,HotThyroidology,September,No.4,2002Maternal and Fetal Thyroid Function-NEJM GerardN.Burrow,etal,LarsenVolume331:1072-1078 Fetal Thyroid Physiology;PolinandFoxCombined ultrasound and isotope scanning is more informative in the diagnosis of congenital hypothyroidism than single scanning;Perry,RJetal,Archives of Disease in Childhood.91(12):972-976,December 2006.Twenty years later:a reevaluation of the contribution of plasma thyroglobulin to the diagnosis of thyroid dysgenesis in infants with congenital hypothyroidism;Anissa Djemli et al,Clinical Biochemistry 37(2004)818 822.重庆医科大学附属儿童医院重庆医科大学附属儿童医院内分泌专科：熊丰内分泌专科：熊丰 教授教授