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1、l l Angel babiesl lOverview of inheretancel lChromosomal abnormalitiesl lClinical manifestations of Down Syndromel lKaryotypes and phenotypes of Down Syndromel lGenetic counseling, prenatal diagnosis and preventionF CONTENTSl lChromosomal abnormalities l lSingle gene mutant: Autosomal recessive, or
2、dominant, X-linked recessive ,or dominant Autosomal recessive, or dominant, X-linked recessive ,or dominantl lMultifactorial inheritancel lMitochondrial DNA mutant F Patterns of inheritanceFChromosomal AbnormalitiesDefinition: Abnormal chromosome number and abnormal chromosomal arrangements may lead
3、 to multiple congenital anomalies. Down syndrome is the most common autosomal chromosomal anomaly (1/700).1846,Sequin,1866,Down,1959,Lejeune It is an important cause of mental retardation and congenital anomalies.The occurrence of trisomia 21 increases with advancing maternal age (35 yr).FIntroducti
4、onFKaryotypes and PhenotypesStandard: about 95% have trisomies of chromosome 21, 47,XX(XY),+2147,XX(XY),+21Translocation:2.5-5% D/G: 46,XX(XY),-14,+t(14q21q) 46,XX(XY),-14,+t(14q21q) G/G: 46,XX(XY),-22,+t(22q21q) G/G: 46,XX(XY),-22,+t(22q21q) Mosaic: 2-4% of individual are mosaic with some normal ce
5、lls. 46,XX(XY)/47,XX(XY),+21 46,XX(XY)/47,XX(XY),+21 Down syndrome girl Down syndrome babyFClinical manifestations Varying degrees of mental and growth retardationCharacteristic face: flat small face, upward and slanted palpebral fissures and epicanthic folds, low set ears, outstanding tongue,high a
6、nd narrow plate, flat nasal bridgeDysplasia of the pelvis,cardiac malformation, simian crease,short broad hand, joint hyperflexibilityl l DOWN l SYNDROMEThe turn down or flap at the top of the ear The single line across the hand and the pinkie finger turned inward. The fingers are somewhat shorterSp
7、read toes especially between large toe hypotoniaThe single line across the handJoint hyperflexibilityFPrevent and treatmentAvoid close relative marriagePrenatal diagnosis and genetic analysis (maternal and fetal serum,amniotic fluid and cell, chorionic villus,ultrasound, fluorescent insitu-hybridiza
8、tion，FISH ) Complication Treatment Education Down Syndrome Net Ring Understanding the gift of the life HYPOTHYROIDISMFU JUN-FEN PhDChildrens Hospital of Zhejiang University School of MedicineIntroductionl lCongenital hypothyroidism is the more common endocrine disease in pediatric medicine. Its high
9、 prevalence is 1/4000 births. l lA screening is efficient, specific and sensitive l l Treatment is simple and efficient. l lHypothyroxinemia in the first years of age has profound and irreversible consequences. FIntroduction Definition : Hypothyroidism results from deficient production of thyroid ho
10、rmone or a defect in thyroid hormonal receptor activity.Classification: Congenital hypothyroidism(Cretinism) Acquired hypothyroidism hypothalamushypothalamushypothalamushypothalamus Pituitary Pituitary Pituitary Pituitary thyroid thyroid thyroid thyroid （1 1）Increase oxygen consumptionIncrease oxyge
11、n consumption（2 2）Stimulate protein synthesisStimulate protein synthesis（3 3）Influence growth and differentiationInfluence growth and differentiation（4 4）Maintain CNS growth and developmentMaintain CNS growth and development（5 5）Affect carbohydrate,lipid and vitamin metabolismAffect carbohydrate,lip
12、id and vitamin metabolism（6 6）Promote and maintain circulation and digestion Promote and maintain circulation and digestion function functionFPhysiological functions of thyroid hormone （1 1）Defect of fetal thyroid developmentDefect of fetal thyroid development (90%, Aplasia, Ectopia) (90%, Aplasia,
13、Ectopia)（2 2）Defect in thyroid hormone synthesisDefect in thyroid hormone synthesis (thyroid peroxidase defect, (thyroid peroxidase defect, thyroglobulin synthesis defect) thyroglobulin synthesis defect)（3 3）Multiple hypothalamic or pituitary deficienciesMultiple hypothalamic or pituitary deficienci
14、es（4 4）Mutations in TRH, TSH, T3 or T4 receptorMutations in TRH, TSH, T3 or T4 receptor（5 5）Maternal antibodies or medicationsMaternal antibodies or medications（6 6）Iodine deficiency (endemic goiter)Iodine deficiency (endemic goiter)FEtiology l lAt birth :l l May be post-mature (gestational age 42 w
15、eeks), may weigh more than 4 kgl lHypothermia and a cool skin, peripheral edema, abdominal distension and a posterior fontanel more than 5 mm in diameter; they feed poorly and have prolonged jaundice ( 3 days). FClinical manifestations 1Clinical manifestations 1 In the neonate and infant:Characteris
16、tic face with enlarged, protruding tongueFeeding difficultiesFeeding difficulties: sluggishness, somnolence, choking spells: sluggishness, somnolence, choking spellsRespiratory difficultiesRespiratory difficulties: large tongue, nasal obstruction : large tongue, nasal obstruction MyxoedemaMyxoedema:
17、 :headsize , extremities and genitalsheadsize , extremities and genitalsskinskin: edema and cold and mottled: edema and cold and mottledAbdomenAbdomen: :Constipation, distension, umbilical herniaConstipation, distension, umbilical herniaphysiologic icterusphysiologic icterus: prolonged : prolonged A
18、nemiaAnemia:refractory:refractoryClinical manifestations 2Clinical manifestations 2FClinical manifestations 2Clinical manifestations 2In the childhood and adolescent Clinical picture is fully developed : :AppearanceAppearance: lethargy,puffy face, dull expression,hirsute forehead: lethargy,puffy fac
19、e, dull expression,hirsute forehead far apart eyes, depressed nose bridge, far apart eyes, depressed nose bridge, narrow palpebral fissures, scaling skin, hair loss narrow palpebral fissures, scaling skin, hair lossPhysical developmentPhysical development: : growth retardation, delayed bone age grow
20、th retardation, delayed bone age delayed dentition delayed dentitionMental developmentMental development : retardation ,deteriorating school : retardation ,deteriorating school performance performanceDelayed adolescence Delayed adolescence : :delayed pubertydelayed puberty Clinical manifestations 3C
21、linical manifestations 3FClinical manifestations 3Clinical manifestations 3 FDiagnosis Thyroid screeningLaboratory TestBone X-rayRadionucleotide Imaging(99mTC) Repeat T4/TSHRepeat T4/TSH Normal Abnormal Normal Abnormal Imaging studies;ultrasound or Imaging studies;ultrasound or radionucleotide imagi
22、ng radionucleotide imaging No gland Ectopic Normal gland No gland Ectopic Normal gland (aplasia) gland (aplasia) gland TSH receptor TSH receptor Maternal or neonatal TSH receptor TSH receptor Maternal or neonatal drug exposure,iodine drug exposure,iodine deficiency or excess deficiency or excess bio
23、synthetic defect autoantibody biosynthetic defect autoantibody False-positive screeen Permanent Hypothyroidism TransientFalse-positive screeen Permanent Hypothyroidism Transient Normal child Hypothyroidism Normal child HypothyroidismFNewborn with a positive hypothyroid screen Total T4 T3 Free T4 TSH
24、 TBG Total T4 T3 Free T4 TSH TBGPrimaryPrimary Hypothyroidism N N N N Hypothyroidism N N N N N N N N N NSecondary NSecondary N Hypothyroidism HypothyroidismFLaboratory Test FDifferentiate Diagnosis Down syndromeRickets (Vitamin D deficiency)Mucopolysaccharidosis Type I Congenital chondrodysplasiaGro
25、wth hormone deficiencyPhenylketonuria (PKU) l lAn autosomal recessive disease, primarily affects the brain, An autosomal recessive disease, primarily affects the brain, 1:10,000 persons 1:10,000 personsl lClassic PKU (98%): Classic PKU (98%): phenylalanine hydroxylasephenylalanine hydroxylase phenyl
26、alanine_tyrosine phenylalanine_tyrosinel lMalignant PKU(2%):defect in synthesis or metabolism of Malignant PKU(2%):defect in synthesis or metabolism of tetrahydrobiopterin tetrahydrobiopterin ( ( cofactor forcofactor for phenylalanine hydroxylasephenylalanine hydroxylase) )FIntroduction phenylalanin
27、e hydroxylasephenylalanine hydroxylase phenylalanine phenylalanine tyrosine tyrosine tetrahydrobiopterin tetrahydrobiopterin dihydrobiopterindihydrobiopterin BH4 BH2FMechanisml lMental retardation IQMental retardation IQ3030l lBlond hairBlond hairl lBlue eyesBlue eyesl lEczemaEczemal lMousy odor 0f
28、the urineMousy odor 0f the urinel lProgressive ,lethal CNS disease (malignant PKU)Progressive ,lethal CNS disease (malignant PKU) F Clinical manifestationF Clinical manifestationl lNeonatal screening test: first week of life.Neonatal screening test: first week of life.l l10% ferric chloride : deep g
29、reen colour 10% ferric chloride : deep green colour in the presence of phenylpyruvic acidin the presence of phenylpyruvic acid ferric chloride test) may be negativeferric chloride test) may be negative in the first month of life in the first month of lifel lPlasma amino acid analysisPlasma amino aci
30、d analysisl lAnalyzing biopterin metabolites in urineAnalyzing biopterin metabolites in urinel lEnzyme diagnosisEnzyme diagnosisl lGene diagnosisGene diagnosisF DiagnosisTreatmentl lLow phenylalanine diet and tyrosine supplementationLow phenylalanine diet and tyrosine supplementationl linfant- Low p
31、henylalanine milkinfant- Low phenylalanine milk，l ltoddler age-introduce low-protein foods such as toddler age-introduce low-protein foods such as starchstarch、vegetablesvegetables、fruits and bread et al, and fruits and bread et al, and maintain the level of blood phenylalanine at 0.12maintain the l
32、evel of blood phenylalanine at 0.120.6mmol/L0.6mmol/L，The diet should not be terminated after The diet should not be terminated after adolescenceadolescence. .l lBHBH4 4、5-hydroxytryptophan5-hydroxytryptophan、Levodopa Levodopa for malignant PKU for malignant PKUF Treatment1. Prenatal diagnosis can b
33、e made in families at risk with the help of a combination of DNA analysis, enzyme activity, and amniotic fluid metabolite levels.2. avoid close relative marriage3. neonatal screeningF Prevention成分成分成分成分 单位单位单位单位 重量（重量（重量（重量（g g g g） 蛋白质蛋白质蛋白质蛋白质 苯丙氨酸苯丙氨酸苯丙氨酸苯丙氨酸 热卡热卡热卡热卡小麦粉小麦粉小麦粉小麦粉 3 3两两两两 150 16.4
34、 771 516150 16.4 771 516维思多淀粉维思多淀粉维思多淀粉维思多淀粉 1 1斤斤斤斤 500 0 0 2000500 0 0 2000鸡蛋鸡蛋鸡蛋鸡蛋 2 2个个个个 120 15.5 746 165.6120 15.5 746 165.6白糖白糖白糖白糖 9 9两两两两 450 0 0 1800450 0 0 1800油少量油少量油少量油少量 25 0 0 22525 0 0 225泡打粉泡打粉泡打粉泡打粉 约约约约 15 0 0 015 0 0 0合计合计合计合计 31.9 1517 4706.531.9 1517 4706.5平均平均平均平均( (每个每个每个每个)
35、0.9 42.1 130.7) 0.9 42.1 130.7F低苯丙氨酸蛋糕制作法（烤制，低苯丙氨酸蛋糕制作法（烤制，3636个个/ /次）次）l lThe prognosis for normal intelligence is good The prognosis for normal intelligence is good when patients have been put on a diet low in when patients have been put on a diet low in phenylalanine in the first month of lifephe
36、nylalanine in the first month of lifel lTreatment started after 6 mo of age, although Treatment started after 6 mo of age, although resulting in some improvement ,has not reversed resulting in some improvement ,has not reversed existing neurologic damage existing neurologic damage l lSever and permanent neurologic damage exsits Sever and permanent neurologic damage exsits without treatmentwithout treatmentF Prognosis
