2023.

0717-19
Training for Nelson Pediatric 21th
Children's Medical Home in China (CMHC)
Chapter 97-101 章 20230717-0719
Chapter 97 章 Patterns of Genetic Transmission
Chapter 98 章 Cytogenetics
Chapter 99 章 Genetics of Common Disorders
Chapter 100 章 Epigenome-Wide Association Studies and Disease
Chapter 101 章 Genetic Approaches to Rare and Undiagnosed Diseases
第 97 章 遗传/基因传播模式
第 98 章 细胞遗传学
第 99 章 常见疾病的遗传学
第 100 章 表观基因组的关联研究与疾病
第 101 章 罕见病和未确诊疾病的遗传学方法

Moderator and editor of panel discussion Q&A

Shiyao Wang, MD Pediatric Emergency in Singapore,
Editor and Chief for Training of Pediatric Common Medical Problems, CMHC
Editor (English Version): Yingshan Shi, MD, Chief, CMHC

【Topic QA】
Chapter 97-101 20230717-0719
Chapter 97 Patterns of Genetic Transmission
1. What is the most important screening tool to identify a patient’s risk for developing diseases? (Page 1,6)
2. What are the characteristics of autosomal dominant disorder and autosomal recessive disorder from
pedigree perspectives? (Page 8,9,10)
3. What are the inheritance pattern for the four pedigrees below?
4. What are triplet repeat expansion disorders and example? (Page 23)
5. What is genetic imprinting and example? (Page 27, 99,104,105)

Chapter 98 Cytogenetics
6. What is clinical cytogenetics? (Page 34)
7. What is aneuploidy? What is the most common cause of aneuploidy? What is the most common form of
aneuploidy?(page 50)
8. What is Down syndrome and its neonatal period features and features later on? (Page 52-58)
9. What is the developmental milestones and health supervision for children with down syndrome?
(Page 59 tables 98.6 and 98.7; Page 60 table 98.8)
10. What is Turner syndrome and it’s clinical manifestations? (Page 83-85)
11. What is Klinefelter syndrome and its clinical manifestations? (Page 88-89)
12. What is fragile X syndrome and its clinical manifestations? (Page 91)

Chapter 99 Genetics of Common Disorders None

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Chapter 100 Epigenome-Wide Association Studies and Disease
13. What is epigenetics and the two examples? (Page 117,121)
Chapter 101 Genetic Approaches to Rare and Undiagnosed Diseases None

第 97 章 遗传传播模式
1. 确定患者患病风险最重要的筛查工具是什么？(第 1,6 页）
2. 常染色体显性遗传病和常染色体隐性遗传病的遗传谱系特点是什么？(第 8、9、10 页）
3. 下面四个遗传谱系的遗传模式是什么？
4. 什么是三核苷酸重复序列紊乱并举例（第 23 页）
5. 什么是遗传印记并举例（第 27、99、104、105 页）

第 98 章 细胞遗传学
6. 什么是临床细胞遗传学？(第 34 页）
7. 什么是非整倍体？非整倍体最常见的原因是什么？非整倍体最常见的形式是什么？（第 50 页）
8. 什么是唐氏综合症及其新生儿期特征和后期特征？(第 52-58 页）
9. 唐氏综合症儿童的发育里程碑和健康监护？(第 59 页，表 98.6 和 98.7；第 60 页，表 98.8）]
10. 什么是特纳综合征及其临床表现？(第 83-85 页）
11. 什么是 Klinefelter 综合征及其临床表现？(第 88-89 页）
12. 什么是脆性 X 综合征及其临床表现？(第 91 页）

第 99 章 常见疾病的遗传 无
第 100 章 表观基因组关联研究与疾病
13. 什么是表观遗传学及两个例子？(第 117 和 121 页）
第 101 章 罕见和未诊断疾病的遗传学方法 无

Chapter 97-101 20230717-0719

Chapter 97 Patterns of Genetic Transmission
1. What is the most important screening tool to identify a patient’s risk for developing diseases? (Page
1,6)
1.1 The family history remains the most important screening tool for pediatricians in identifying a patient's
risk for developing a wide range of diseases,
 from multifactorial conditions such as diabetes and attention-deficit/hyperactivity disorder,
 to single-gene disorders such as sickle cell anemia and cystic fibrosis.
1.2 A pedigree provides a graphic depiction of a family's structure and medical history.
 It is important when taking a pedigree to be systematic
 and use standard symbols and configurations
 so that anyone can read and understand the information
 A 3 to 4–generation pedigree should be obtained for every new patient as an initial screen for
genetic disorders segregating within the family.

第 97-101 章 20230717-0719
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第 97 章 基因传播模式
1. 确定患者患病风险最重要的筛查工具是什么？(第 1,6 页)
1.1 家族史仍然是儿科医生识别病人罹患各种疾病风险的最重要筛查工具、
 从糖尿病和注意力缺陷/多动障碍等多因素疾病
 镰状细胞性贫血和囊性纤维化等单基因疾病。
1.2 系谱是对一个家族的结构和病史的形象描述。
 在绘制系谱图时，重要的是要有系统性
 并使用标准符号和配置
 以便任何人都能阅读和理解这些信息
 每个新病人都应获得 3 至 4 代的血统，作为家族内遗传疾病分离的初步筛查。

2.What are the characteristics of autosomal dominant disorder and autosomal recessive disorder from
pedigree perspectives? (Page 8,9,10)
2.1 The pedigree for autosomal dominant disorders demonstrates certain characteristics.
 These disorders show a vertical transmission (parent-to-child) pattern and
 can appear in multiple generations. In Fig. 97.5 ,
 this is illustrated by individual I.1 passing on the changed gene to II.2 and II.5.
 An affected individual has a 50% (1 in 2) chance of passing on the deleterious gene in
each pregnancy and, therefore, of having a child affected by the disorder.

2.2 Many autosomal dominant conditions demonstrate incomplete penetrance ,

 meaning that not all individuals who carry the mutation have phenotypic manifestations.
 In a pedigree this can appear as a skipped generation ,
 in which an unaffected individual links 2 affected persons (Fig. 97.6 ).
 There are many potential reasons that a disorder might exhibit incomplete penetrance, including
the effect of modifier genes,
environmental factors,
gender, and age.

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FIG. 97.6 Incomplete penetrance. This family segregates a familial cancer syndrome, familial adenomatous polyposis.
Individual II.3 is an obligate carrier, but there are no findings to suggest the disorder. This disorder is nonpenetrant in this
individual. Black, Affected patients.

2.3 Autosomal recessive inheritance 97.6

 requires deleterious variants in both copies of a gene to cause disease.
 Examples include cystic fibrosis and sickle cell disease.
 Autosomal recessive disorders are characterized by horizontal transmission ,
 the observation of multiple affected members of a kindred in the same generation, but no affected
family members in other generations

2.从系谱的角度看，常染色体显性遗传病和常染色体隐性遗传病有什么特点？(第 8、9、10 页）
2.1 常染色体显性遗传疾病的血统具有某些特征。
- 这些疾病表现为垂直传播（父母对子女）模式，并可在多代人中出现。
- 可出现在多代人身上。图 97.5、
- 中，个体 I.1 将改变的基因传给了 II.2 和 II.5。
- 受影响的个体每次怀孕都有 50%（1/2）的几率将有害基因遗传给下一代，因此，其子女也会受到该
疾病的影响。

2.2 许多常染色体显性遗传病具有不完全渗透性、
- 也就是说，并非所有携带突变基因的个体都有表型表现。
- 在血统中，这可能表现为 "跳代"、
- 图 97.6）。
- 某种疾病可能表现出不完全渗透性的潜在原因有很多，包括
修饰基因的影响、
环境因素、
性别和年龄。

2.3 常染色体隐性遗传 97.6

- 需要基因的两个拷贝都出现有害变异才会致病。
- 例如囊性纤维化和镰状细胞病。
- 常染色体隐性遗传病的特点是水平传播......、
- 同一代人中有多个患病的家庭成员，但其他几代人中没有患病的家庭成员。

X-Linked Inheritance
1)describes the inheritance pattern most disorders caused by deleterious changes in genes
located on the X chromosome (Fig. 97.9 ).
 males are more commonly affected than females.
 Female carriers of these disorders are generally unaffected, or if affected, they are affected
more mildly than males.
2)In each pregnancy, female carriers have
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 a 25% chance of having an affected son,
 a 25% chance of having a carrier daughter, and
 a 50% chance of having a child that does not inherit the mutated X-linked gene.
3)Since affected males pass their X chromosome to all their daughters and their Y chromosome
to all their sons, they have
 a 50% chance of having an unaffected son that does not carry the disease gene and
 a 50% chance of having a daughter who is a carrier.

X 连锁遗传
1)描述了大多数由位于 X 染色体上的基因的有害变化引起的疾病的遗传模式（图 97.9）。
- 男性比女性更容易患病。
- 这些疾病的女性携带者一般不受影响，或者即使受影响，也比男性轻微。
2）在每次怀孕中，女性携带者有
- 生出受影响儿子的几率为 25%、
- 生一个携带者女儿的几率为 25%，以及
- 50%的几率生下一个没有遗传到变异 X 连锁基因的孩子。
3）由于受影响的男性会把他们的 X 染色体传给他们所有的女儿，把他们的 Y 染色体传给他
们所有的儿子，因此他们有
- 有 50%的几率生出不携带疾病基因的未受影响的儿子，以及
- 50%的几率生出携带疾病基因的女儿。

Mitochondrial Inheritance
An individual's mitochondrial genome is entirely derived from the mother
 because sperm contain relatively few mitochondria,
 and these are degradated after fertilization.
 It follows that mitochondrial inheritance is essentially maternal inheritance .
 A woman with a mitochondrial genetic disorder can have affected offspring of either sex,
 but an affected father cannot pass on the disease to his offspring (Fig. 97.15 ).
Mitochondrial DNA mutations are often deletions or point mutations;
 overall, 1 person in 400 has a maternally inherited pathogenic mitochondrial DNA mutation.
 In individual families, mitochondrial inheritance may be difficult to distinguish from
autosomal dominant or X-linked inheritance,
 but in many cases, the sex of the transmitting and nontransmitting parents can suggest a
mitochondrial basis

线粒体遗传
个体的线粒体基因组完全来自母亲
- 因为精子中的线粒体相对较少、
- 这些线粒体在受精后会降解。
- 因此，线粒体遗传基本上是母体遗传。
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- 患有线粒体遗传疾病的女性可以生育任何性别的受影响后代、
- 但患病的父亲不能将疾病遗传给后代（图 97.15）。
线粒体 DNA 变异通常是缺失或点突变；
- 总体而言，每 400 人中就有 1 人患有母系遗传的致病性线粒体 DNA 变异。
- 在个别家庭中，线粒体遗传可能很难

3. What are the inheritance pattern for the four pedigrees below?
3. 以下四个传统的遗传模式是什么？

Fig97.5 Autosomal dominant pedigree. Pedigree

FIG. 97.11 Pedigree pattern demonstrating
showing typical inheritance of a form of X-linked dominant inheritance. Black,Affected
achondroplasia (FGFR3) inherited as an patients. Note there is no father-to-son transmission
autosomal dominant trait. Black, Affected in this situation, and
patients. hemizygosity (i.e., X-linked gene in a male) is not
图 97.5 常染色体显性遗传系谱图。显示一种软骨 lethal. In some X-linked dominant
发育不全（FGFR3）常染色体显性遗传的典型遗传 conditions, X-linked males have a more severe
谱系。黑色，受影响的患者。 phenotype and might not survive. In
that case, only females manifest the disease (see Fig.
97.12 ).
图 97.11 显示 X 连锁显性遗传的血统模式。黑
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色、
患者。注意在这种情况下没有父子间的遗传，并且
半杂合子（即男性的 X 连锁基因）不是致死性的。
在某些 X 连锁显性
在某些 X 连锁显性遗传病中，X 连锁男性的表型
更为严重，可能无法存活。在这种情况下
在这种情况下，只有雌性才会发病（见图 97.12）。

FIG. 97.7 Autosomal recessive pedigree with
parental consanguinity. Central dot, Carriers;
Black, Affected patients.
图 97.7 父母为近亲的常染色体隐性遗传。中心点， 图 97.9 显示 X 连锁隐性遗传的系谱图。中心点，
携带者；黑色，患病者。 携带者；黑色，患病者。
FIG. 97.9 Pedigree demonstrating X-linked
recessive inheritance. Central dot, Carriers;
Black, Affected patients.

4.What are triplet repeat expansion disorders and example? (Page 23)
4.1 Triplet repeat expansion disorders are distinguished by the special dynamic nature of the
disease-causing variant.
4.2 Triplet repeat expansion disorders include
 fragile X syndrome,
 myotonic dystrophy,
 Huntington disease, and
 spinocerebellar ataxias
4.什么是三重重复扩展障碍及实例？(第 23 页）
4.1 三重重复扩展障碍的特点是致病变体具有特殊的动态性质。
4.2 三重重复扩展障碍包括
- 脆性 X 综合征
- 肌营养不良症
- 亨廷顿病和
- 脊髓小脑性共济失调症

5. 什么是基因印记？(第 27、99、104、105 页）
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5.1 大多数常染色体基因的 2 个拷贝在功能上是等同的。
- 然而，在某些情况下，一个基因只有一个拷贝被转录，而第二个拷贝被沉默。
- 这种基因沉默通常与 DNA 的甲基化有关，而甲基化是一种表观遗传修饰、
- 甲基化是一种表观遗传修饰，即不改变 DNA 的核苷酸序列（图 97.20）。
5.2 在印记基因中，基因的表达取决于染色体的亲本。
5.3 基因印迹障碍是由于特定基因的活性拷贝不平衡造成的，其发生原因有多种。
- 普拉德-威利综合症（Prader-Willi Syndromees）和安吉尔曼综合症（Angelman Syndromees）是与发育
障碍有关的两种不同的疾病。
- 这两种疾病都可由染色体 15q11-12 的微缺失引起。
- 普拉德-威利综合征的微缺失总是发生在父源的 15 号染色体上、
- 而在安杰尔曼综合症中，微缺失则发生在母本上。
5.4 巨大缺失
- 在普拉德-威利综合征中，约有 25%-29%的病例有母体 UPD（缺失父方 15 号染色体）。
- 在安杰尔曼综合征中，父方 15 号染色体的 UPD 较为罕见，且为

5. What is genetic imprinting and example? (Page 27, 99,104,105)

5.1 The 2 copies of most autosomal genes are functionally equivalent.
 However, in some cases, only 1 copy of a gene is transcribed and the 2nd copy is silenced.
 This gene silencing is typically associated with methylation of DNA, which is an epigenetic
modification,
 meaning it does not change the nucleotide sequence of the DNA (Fig. 97.20 ).
5.2 In imprinting gene expression depends on the parent of origin of the chromosome.
5.3 Imprinting disorders result from an imbalance of active copies of a given gene, which can occur for
several reasons.
 Prader-Willi and Angelman syndromes, two distinct disorders associated with developmental
impairment, are illustrative.
 Both can be caused by microdeletions of chromosome 15q11-12.
 The microdeletion in Prader-Willi syndrome is always on the paternally derived chromosome 15,
 whereas in Angelman syndrome it is on the maternal copy
5.4 UPD
 In Prader-Willi syndrome , approximately 25–29% of cases have maternal UPD (missing the
paternal chromosome 15) .
 In Angelman syndrome , paternal UPD of chromosome 15 is rarer and is observed in
approximately 5% of the cases (missing the maternal chromosome 15).
5.5The phenotype for Prader-Willi syndrome and Angelman syndrome in cases of UPD
 is thought to result from the lack of the functional contribution from a particular parent of
chromosome 15.
 In Prader-Willi syndrome the paternal contribution is missing, and
 the maternal contribution is missing in Angelman syndrome.
5.6 A classic example of imprinting disorder
 is seen in Prader-Willi syndrome and Angelman syndrome, 2 very different clinical conditions.
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 These syndromes are usually associated with deletion of the same region in the proximal long arm
of chromosome 15.
 A deletion on the paternally derived chromosome causes Prader-Willi syndrome, in which the
maternally derived copy is still intact, but some of the imprinted genes within this region
normally remain silent.
 A maternal deletion of the same region as in Prader-Willi syndrome causes Angelman syndrome,
leaving intact the paternal copy that in this case has genes that are also normally silent.

5. 什么是基因印记？(第 27、99、104、105 页）
5.1 大多数常染色体基因的 2 个拷贝在功能上是等同的。
- 然而，在某些情况下，一个基因只有一个拷贝被转录，而第二个拷贝被沉默。
- 这种基因沉默通常与 DNA 的甲基化有关，而甲基化是一种表观遗传修饰、
- 甲基化是一种表观遗传修饰，即不改变 DNA 的核苷酸序列（图 97.20）。
5.2 在印记基因中，基因的表达取决于染色体的亲本。
5.3 基因印迹障碍是由于特定基因的活性拷贝不平衡造成的，其发生原因有多种。
- 普拉德-威利综合症（Prader-Willi Syndromees）和安吉尔曼综合症（Angelman Syndromees）是与发育
障碍有关的两种不同的疾病。
- 这两种疾病都可由染色体 15q11-12 的微缺失引起。
- 普拉德-威利综合征的微缺失总是发生在父源的 15 号染色体上、
- 而在安杰尔曼综合症中，微缺失则发生在母本上。
5.4 UPD 缺失
- 在普拉德-威利综合征中，约有 25%-29%的病例有母体 UPD（缺失父方 15 号染色体）。
- 在安杰尔曼综合征中，父方 15 号染色体的 UPD 较为罕见，且为
5.5 普拉德-威利综合症和安杰尔曼综合症的表型
- 普拉德-威利综合症和安杰尔曼综合症的表型被认为是由于缺乏 15 号染色体父方的功能性贡献所
致。
- 在普拉德-威利综合症中，父方的贡献缺失，而在安杰尔曼综合症中，母方的贡献缺失。
- 在安杰尔曼综合症中则缺少母体的贡献。
5.6 印记障碍的典型例子
- 普拉德-威利综合征和安杰尔曼综合征是两种临床症状截然不同的疾病。
- 这些综合征通常与 15 号染色体近端长臂的同一区域缺失有关。
- 父源染色体上的缺失会导致普拉德-威利综合征，在这种情况下，母源染色体的拷贝仍然完好无损，
但该区域内的一些印记基因通常保持沉默。
- 与普拉德-威利综合症相同区域的母源基因缺失会导致安杰尔曼综合症，但父源基因拷贝仍完好无损，
在这种情况下，父源拷贝中的基因通常也保持沉默。

Chapter 98 Cytogenetics
6.What is clinical cytogenetics? (Page 34)
6.1 Clinical cytogenetics
 is the study of chromosomes:
 their structure, function, inheritance, and abnormalities.
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6.2 Chromosome abnormalities are very common and
 occur in approximately 1–2% of live births,
 5% of stillbirths, and
 50% of early fetal losses in the 1st trimester of pregnancy (Table 98.1 ).
6.3 Chromosome abnormalities
 are more common among individuals with intellectual disability and
 play a significant role in the development of some neoplasias.

Table 98.1 Incidence of Chromosomal Abnormalities in Newborn Surveys

TYPE OF ABNORMALITY NUMBER APPROXIMATE

INCIDENCE
SEX CHROMOSOME ANEUPLOIDY
Males ( 4 3 , 6 1 2 newborns)
1/1,000*
47,XXY 45
1/1,000
47,XYY 45
Other X or Y aneuploidy 1/1,350
32
Total 1 / 3 6 0 male births
122
Females ( 2 4 , 5 4 7 newborns)
1/4,000
45,X 6
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1/900
47,XXX 27
Other X aneuploidy 1/2,700
9
Total 1 / 5 8 0 female births
42
AUTOSOMAL ANEUPLOIDY ( 6 8 , 1 5 9 NEWBORNS)
Trisomy 2 1 1/830
82
Trisomy 1 8 1/7,500
9
Trisomy 1 3 1/22,700
3
Other aneuploidy 1/34,000
2
Total 1 /700 live births
96
STRUCTURAL ABNORMALITIES ( 6 8 , 1 5 9 NEWBORNS)
Balanced Rearrangements
Robertsonian 1/1,100
62
Other 1/885
77
Unbalanced Rearrangements
Robertsonian 1/13,600
5
Other 1/1,800
38

Total 1 /375 live births

182
All chromosome abnormalities 1 /154 live births
442

* Recent studies show the prevalence is currently 1:580.

Data from Hsu LYF: Prenatal diagnosis of chromosomal abnormalities through amniocentesis. In Milunsky A, editor:
Genetic disorders and the fetus , ed 4, Baltimore, 1998, Johns Hopkins University Press, pp 179–248.

表 98.1 新生儿调查中染色体异常的发生率
异常类型 数目 大致发生率
性染色体非整倍体
男性（43 612 名新生儿）
47,XXY
47,XYY
其他 X 或 Y 非整倍体
总计

女性（24 547 名新生儿）

45,X
47,XXX
其他 X 非整倍体
总计

常染色体非整倍体（68 159 名新生儿）

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21 三体综合征
18 三体综合征
13 三体综合征
其他非整倍体
总计

结构异常（68 159 名新生儿）

平衡重排
罗伯逊型
其他
非平衡重排
罗伯逊型
其他
总计

所有染色体异常
*最近的研究表明，目前的发病率为 1:580。
数据来自 Hsu LYF：通过羊膜腔穿刺进行染色体异常的产前诊断。见 Milunsky A 编辑： 遗传疾病与
胎儿》，第 4 版，巴尔的摩，1998 年，约翰霍普金斯大学出版社，第 179-248 页。

第 98 章细胞遗传学
6.什么是临床细胞遗传学？ （第 34 页）
6.1 临床细胞遗传学是对染色体的研究：其结构、功能、遗传和异常。
6.2 染色体异常非常常见，
- 约有 1-2% 的活产婴儿会出现这种情况,
- 5%的死胎，以及
- 50% 的早期胎儿死亡（表 98.1）。
6.3 染色体异常
-在智力障碍患者中更为常见，
-并且在某些肿瘤的发生中起着重要作用。

7. What is aneuploidy? What is the most common cause of aneuploidy? What is the most common form
of aneuploidy?(page 50)
71.Abnormal cells that do not contain a multiple of haploid number of chromosomes are termed aneuploid
cells.
7.2Aneuploidy
 is the most common and clinically significant type of human chromosome abnormality,
 occurring in at least 3–4% of all clinically recognized pregnancies.
 The most common cause of aneuploidy is nondisjunction ,
 the failure of chromosomes to disjoin normally during meiosis
7.3 Trisomy
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 is characterized by the presence of 3 chromosomes, instead of the normal 2, of any particular
chromosome.
 Trisomy is the most common form of aneuploidy.

7. 什么是非整倍体？非整倍体最常见的原因是什么？非整倍体最常见的形式是什么？
71.不含单倍体染色体数倍的异常细胞称为非整倍体细胞。
7.2 非整倍体
- 是人类染色体异常中最常见、最具临床意义的类型、
- 在所有临床确认的妊娠中，至少有 3-4%的妊娠会出现非整倍体。
- 非整倍体最常见的原因是非分裂、
- 染色体在减数分裂过程中不能正常分离。
7.3 三体
- 三体综合征的特征是任何特定染色体都存在 3 条染色体，而不是正常的 2 条。
- 三体综合征是最常见的非整倍体形式。

8. What is Down syndrome and its neonatal period features and features later on? (Page 52-58, 61)
8.1 Trisomy 21is the most common genetic etiology of moderate intellectual disability.
 The incidence of Down syndrome in live births is approximately 1 in 733;
 the incidence at conception is more than twice that rate;
 the difference is accounted for by early pregnancy losses.
8.2 Clinical features
8.21 In addition to cognitive impairment, Down syndrome is associated with congenital anomalies and
characteristic dysmorphic features (Figs. 98.8 and 98.9 and Table 98.4 ).
8.22 Although there is variability in the clinical features, the constellation of phenotypic features is fairly
consistent and permits clinical recognition of trisomy 21.
8.23 Affected individuals are more prone to congenital heart defects (50%) such as
 atrioventricular septal defects,
 ventricular septal defects,
 isolated secundum atrial septal defects,
 patent ductus arteriosus, and
 tetralogy of Fallot.
8.24 Pulmonary complications include
 recurrent respiratory infections,
 sleep-disordered breathing,
 laryngo- and tracheobronchochomalacia,
 tracheal bronchus,
 pulmonary hypertension,
 and asthma.
8.25 Congenital and acquired gastrointestinal anomalies (celiac disease) and hypothyroidism are
common (Table 98.5 ).
8.26 Other abnormalities include
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 megakaryoblastic leukemia,
 immune dysfunction,
 diabetes mellitus,
 seizures,
 alopecia,
 juvenile idiopathic arthritis,
 and problems with hearing and vision.
8.27 Alzheimer disease–like dementia is a known complication that
occurs as early as the 4th decade and has an incidence 2-3 times higher than sporadic Alzheimer disease.
 Most males with Down syndrome are sterile,
 but some females have been able to reproduce, with a 50% chance of having trisomy 21
pregnancies.

8. 什么是唐氏综合征及其新生儿期特征和后期特征？(第 52-58 页，第 61 页）

8.1 21 三体综合征是中度智力障碍最常见的遗传病因。
- 唐氏综合症在活产婴儿中的发病率约为 1/733；
- 受孕时的发病率是这一比率的两倍多；
- 这一差异是由早期妊娠损失造成的。
8.2 临床特征
8.21 除认知障碍外，唐氏综合征还伴有先天畸形和特征性畸形（图 98.8 和 98.9 及表 98.4）。
8.22 儘管臨床特徵有變化，但表型特徵的組合卻相當一致，可讓臨床識別 21 三體症。
8.23 受影响的个体较易出现先天性心脏缺陷（50%），例如
- 房室间隔缺损、
- 室间隔缺损
- 孤立性房间隔缺损、
- 动脉导管未闭和
- 法洛四联症。
8.24 肺部并发症包括
- 反复呼吸道感染、
- 睡眠呼吸障碍、
- 喉气管和气管支气管畸形、
- 气管支气管
- 肺动脉高压、
- 和哮喘。
8.25 先天性和后天性胃肠道异常（乳糜泻）和甲状腺功能低下也很常见（表 98.5）。
8.26 其他异常包括
- 巨核细胞白血病、
- 免疫功能障碍
- 糖尿病
- 癫痫发作
- 脱发
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- 幼年特发性关节炎、
- 听力和视力问题。
8.27 阿尔茨海默病样痴呆症是一种已知的并发症，早在第 4 个十年代就会出现，发病率是阿尔茨海
默病的 2-3 倍。
- 大多数患有唐氏综合症的男性不能生育、
- 但有些女性仍能生育，有 50% 的機會懷上 21 三體症嬰兒。

Table 98.4 Clinical Features of Down Syndrome in the Neonatal Period

表 98.4 新生儿期唐氏综合征的临床特征
Central Nervous System
Hypotonia*
Developmental delay
Poor Moro reflex*

Craniofacial
Brachycephaly with flat occiput
Flat face*
Upward slanted palpebral fissures*
Epicanthal folds
Speckled irises (Brushfield spots)
Three fontanels
Delayed fontanel closure
Frontal sinus and midfacial hypoplasia
Mild microcephaly
Short, hard palate
Small nose, flat nasal bridge
Protruding tongue, open mouth
Small dysplastic ears*

Cardiovascular
Endocardial Cushing defects
Ventricular septal defect
Atrial septal defect Patent ductus arteriosus
Aberrant subclavian artery
Pulmonary hypertension

Musculoskeletal
Joint hyperflexibility*
Short neck, redundant skin*
Short metacarpals and phalanges
Short 5th digit with clinodactyly*
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Single transverse palmar creases*
Wide gap between 1st and 2nd toes
Pelvic dysplasia*
Short sternum
Two sternal manubrium ossification centers

Gastrointestinal
Duodenal atresia
Annular pancreas
Tracheoesophageal fistula
Hirschsprung disease
Imperforate anus
Neonatal cholestasis

Cutaneous
Cutis marmorata
* Hall's criteria to aid in diagnosis.
中枢神经系统
肌张力过低*
发育迟缓
莫洛反射差* 颅面部

颅面
头畸形，枕部扁平
面部扁平
睑裂向上倾斜* 表皮皱褶
上睑下垂
斑点状虹膜（刷状斑）
三个囟门
囟门闭合延迟
额窦和中面部发育不良
轻度小头畸形
硬腭短
鼻子小，鼻梁扁平
舌头突出，嘴巴张开
小耳发育不良*。

心血管
心内膜库欣缺损
室间隔缺损
房间隔缺损 动脉导管未闭
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锁骨下动脉异常
肺动脉高压

肌肉骨骼
关节过度灵活
颈部短，皮肤冗余*。
掌骨和指骨短小
第 5 指短，伴有挛缩畸形* 单横向掌皱襞
单横向掌皱襞*
第 1 和第 2 趾间隙大
骨盆发育不良* 胸骨短小
胸骨短
两个胸骨骨化中心

胃肠道
十二指肠闭锁
环状胰腺
气管食管瘘
赫氏病
肛门穿孔
新生儿胆汁淤积症

皮肤病
胭脂虫病
* 霍尔标准辅助诊断。

Table 98.5 Additional Features of Down Syndrome That Can Develop or Become Symptomatic With
Time

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Neuropsychiatric
Developmental delay
Seizures
Autism spectrum disorders
Behavioral disorders (disruptive)
Depression
Alzheimer disease

Sensory
Congenital or acquired hearing loss
Serous otitis media
Refractive errors (myopia)
Congenital or acquired cataracts
Nystagmus
Strabismus
Glaucoma
Blocked tear ducts

Cardiopulmonary
Acquired mitral, tricuspid, or aortic valve regurgitation
Endocarditis
Obstructive sleep apnea

Musculoskeletal

Atlantoaxial instability
Hip dysplasia
Slipped capital femoral epiphyses
Avascular hip necrosis
Recurrent joint dislocations (shoulder, knee, elbow, thumb)

Endocrine
Congenital or acquired hypothyroidism
Diabetes mellitus
Infertility
Obesity
Hyperthyroidism

Respiratory
Obstructed sleep apnea
Frequent infections (sinusitis, nasopharyngitis, pneumonia)
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Cutaneous
Hyperkeratosis

表 98.5 唐氏综合征随着时间推移可能出现或成为症状的其他特征
神经精神
发育迟缓
癫痫发作
自闭症谱系障碍
行为障碍（破坏性）
抑郁症
阿尔茨海默病

感官疾病
先天性或后天性听力损失
浆液性中耳炎
屈光不正（近视）
先天性或后天性白内障
眼球震颤
斜视
青光眼
泪道堵塞

心肺功能
后天性二尖瓣、三尖瓣或主动脉瓣反流
心内膜炎
阻塞性睡眠呼吸暂停

肌肉骨骼
寰枢椎不稳
髋关节发育不良
股骨骺滑脱
髋关节血管性坏死
复发性关节脱位（肩、膝、肘、拇指）

内分泌
先天性或后天性甲状腺功能减退
糖尿病
不孕症
肥胖症
甲状腺功能亢进
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呼吸系统
睡眠呼吸暂停
经常感染（鼻窦炎、鼻咽炎、肺炎）

皮肤
角化过度

8.3 Two genes (DYRK1A, DSCR1 ) in the putative critical region of chromosome 21 may be targets for
therapy.

8.4 Developmental delay and Cognitive impairment

 Developmental delay is universal (Tables 98.6 and 98.7 and Fig. 98.10 ).
 Cognitive impairment does not uniformly affect all areas of development.
 Social development is often relatively spared,
 but autism spectrum disorder can occur.
 Children with Down syndrome have considerable difficulty using expressive language.
8.5 Understanding the individual developmental strengths and challenges is necessary to
maximize the educational process. Persons with Down syndrome often benefit from programs aimed at
 cognitive training,
 stimulation,
 development,
 and education.
8.6 Children with Down syndrome also benefit from anticipatory guidance,
8.61 which establishes the protocol for screening, evaluation, and care for patients with genetic syndromes
and chronic disorders (Table 98.8 ).
8.61 Up to 15% of children with Down syndrome have misalignment of the 1st cervical vertebra (C1),
which places them at risk for spinal cord injury with neck hyperextension or extreme flexion.
 Special Olympics recommends sports participation and training but requires x-ray examination
(full extension and flexion views) of the neck before participation in sports that may result in
hyperextension or radical flexion or pressure on the neck or upper spine.
 Such sports include diving starts in swimming, butterfly stroke, diving, pentathlon, high jump,
equestrian sports, gymnastics, football, soccer, alpine skinning, and warm-up exercises placing
stress on the head and neck.

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 If atlantoaxial instability is diagnosed, Special Olympics will permit participation if the parents
or guardians request so and only after obtaining written certification from a physician and
acknowledgment of the risks by the parent or guardian.

8.3 21 号染色体推定关键区的两个基因（DYRK1A 和 DSCR1）可能是治疗的目标。

8.4 发育迟缓和认知障碍
- 发育迟缓是普遍现象（表 98.6 和 98.7 及图 98.10）。
- 认知障碍并不一致地影响所有方面的发展。
- 社会发展通常相对较好、
- 但也可能出现自闭症谱系障碍。
- 患有唐氏综合症的儿童在使用表达性语言方面有相当大的困难。
8.5 要最大限度地发挥教育过程的作用，就必须了解个人在发展方面的优势和挑战。唐氏综合症患者
通常会从以下方面的计划中受益
- 认知训练、
- 刺激、
- 发展、
- 和教育。
8.6 患有唐氏综合症的儿童也能从预期指导中受益、
8.61 为遗传综合症和慢性疾病患者制定了筛查、评估和护理方案（表 98.8）。
8.61 多达 15%的唐氏综合征患儿存在第一颈椎（C1）错位、
8.61 高达 15%的唐氏综合症患儿有第一颈椎（C1）错位，这使他们在颈部过度伸展或极度弯曲时有脊
髓受伤的危险。
- 特奥会建议参加体育运动和训练，但要求在参加可能导致颈部过度伸展或极度屈曲或对颈部或上脊
椎造成压力的运动前，对颈部进行 X 光检查（完全伸展和屈曲视图）。
- 此类运动包括游泳中的跳水起跳、蝶泳、仰卧起坐、俯卧撑等。

8.7 Compared with the general population, children with Down syndrome are at increased risk
for behavior problems; psychiatric comorbidity is an estimated 18–38% in this population.
8.71 Common behavioral difficulties that occur in children with Down syndrome include
 inattentiveness,
 stubbornness, and
 a need for routine and sameness.
8.72 Aggression and self-injurious behavior are less common in this population than other
children with similar degrees of intellectual disability from other etiologies.
8.73 All these behaviors can respond to
 educational,
 behavioral, or
 pharmacologic interventions.

8.8 The life expectancy for children with Down syndrome

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is reduced and is approximately 50-55 yr.
 Little prospective information about the secondary medical problems of adults with Down
syndrome is known.
 Retrospective studies have shown premature aging and an increased risk of Alzheimer
disease in adults with Down syndrome.
 These studies have also shown unexpected negative (protective) associations between Down
syndrome and comorbidities.
 Persons with Down syndrome have fewer-than-expected deaths caused by solid tumors
and ischemic heart disease.
 This same study reported increased risk of adult deaths from congenital heart disease,
seizures, and leukemia.
 In one large study, leukemias accounted for 60% of all cancers in people with Down
syndrome and 97% of all cancers in children with Down syndrome.
 There was decreased risk of solid tumors in all age-groups with Down syndrome,
including neuroblastomas and nephroblastomas in children and epithelial tumors in
adults.
8.9 Most adults with Down syndrome are able to perform activities of daily living. However,
most have difficulty with complex financial, legal, or medical decisions, and a guardian may be
appointed.

8.7 与一般人群相比，唐氏综合症患儿出现行为问题的风险更高；在这类人群中， 精神病合并症估计

占 18-38%。
8.71 唐氏综合症儿童常见的行为障碍包括
- 注意力不集中
- 固执，以及
- 需要例行公事和一成不变。
8.72 与其他病因导致的智力障碍程度相似的儿童相比，唐氏综合症儿童的攻击和自残行为较少。
8.73 所有这些行为都可以对以下方面做出反应
- 教育、
- 行为或
- 药物干预。

8.8 患有唐氏综合症的儿童预期寿命较短，约为 50-55 岁。

- 有关唐氏综合症成人继发性医疗问题的前瞻性资料很少。
- 回顾性研究显示，患有唐氏综合症的成人会过早衰老，患老年痴呆症的风险也会增加。
- 这些研究还显示，唐氏综合症与合并症之间存在意想不到的负相关（保护性）关系。
- 唐氏综合症患者死于实体肿瘤和缺血性心脏病的人数少于预期。
- 同一项研究报告显示，先天性心脏病、癫痫发作和白血病导致成人死亡的风险增加。
- 在一项大型研究中，白血病占唐氏综合症患者所有癌症的 60%，占唐氏综合症儿童所有癌症的 97%。
- 患实体瘤的风险降低

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8.9 大多数患有唐氏综合症的成年人都能进行日常生活活动。但是，大多数患者在做出复杂的财务、
法律或医疗决定时会遇到困难，因此可能需要指定监护人。

9.What is the developmental milestones and health supervision for children with down syndrome? (Page
59 tables 98.6 and 98.7; Page 60 table 98.8)
9.唐氏综合症儿童的发育里程碑和健康监护是什么？(第 59 页，表 98.6 和 98.7；第 60 页，表
98.8）
9.1 表 98.6 发育里程碑
9.1 Table 98.6 Developmental Milestones
Milestone CHILDREN WITH DOWN SYNDROME UNAFFECTED CHILDREN
Average (mo) Range (mo) Average (mo) Range (mo)
Smiling 2 1.5-3 1 1.5-3
Rolling over 6 2-12 5 2-10
Sitting 9 6-18 7 5-9
Crawling 11 7-21 8 6-11
Creeping 13 8-25 10 7-13
Standing 10 10-32 11 8-16
Walking 20 12-45 13 8-18
Talking, words 14 9-30 10 6-14
Talking, sentences 24 18-46 21 14-32
患有唐氏综合症的儿童 未受影响儿童
平均（月） 范围（月） 平均（月）范围（月）
里程碑
微笑
翻身
坐着
爬行
爬行
站立
行走
说话，单词
说话，句子
摘自 Levine MD、Carey WB、Crocker AC 编辑： 发育行为儿科学》第 2 版，费城，1992 年，桑德斯出版社。
From Levine MD, Carey WB, Crocker AC, editors: Developmental-behavioral pediatrics, ed 2, Philadelphia,
1992, Saunders.

9.2 Table 98.7 Self-Help Skills

Skill DOWN SYNDROME CHILDREN UNAFFECTED CHILDREN
Average (mo) Range (mo) Average (mo) Range (mo)
EATING

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Finger feeding 12 8-28 8 6-16
Using spoon/fork 20 12-40 13 8-20
TOILET TRAINING
Bladder 48 20-95 32 18-60
Bowel 42 28-90 29 16-48
DRESSING
Undressing 40 29-72 32 22-42
Putting clothes on 58 38-98 47 34-58
From Levine MD, Carey WB, Crocker AC, editors: Developmental-behavioral pediatrics, ed 2, Philadelphia,
1992, Saunders
9.2 表 98.7 自助技能
患有唐氏综合症的儿童 未受影响儿童
平均（月） 范围（月） 平均（月）范围（月）
技能
进食
手指喂食
使用汤匙/叉子
如厕训练
膀胱
排便
穿衣
脱衣服
穿衣服
摘自 Levine MD、Carey WB、Crocker AC 编辑： 发育行为儿科学》第 2 版，费城，1992 年，桑德斯出版社

9.3 Table 98.8 Health Supervision for Children With Down Syndrome
CONDITION TIME TO SCREEN COMMENT
Congenital Birth; by pediatric cardiologist 50% risk of congenital heart
heart disease Young adult for acquired valve disease disease; increased risk for
pulmonary hypertension
Strabismus, Birth or by 6 mo; by pediatric ophthalmologist Cataracts occur in 15%,
cataracts, Check vision annually refractive errors in 50%
nystagmus
Hearing Birth or by 3 mo with auditory brainstem response Risk for congenital hearing
impairment or or otoacoustic emission testing; check hearing loss plus 50– 70% risk of
loss q6mo up to 3 yr if tympanic membrane is not serous otitis media
visualized; annually thereafter
Constipation Birth Increased risk for
Hirschsprung disease
Celiac disease At 2 yr or with symptoms Screen with IgA and tissue

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transglutaminase antibodies

Hematologic At birth and in adolescence or if symptoms Increased risk for neonatal

disease develop polycythemia (18%),
leukemoid reaction, leukemia
(<1%)
Hypothyroidis Birth; repeat at 6-12 mo and annually Congenital (1%) and acquired
m (5%)
Growth and At each visit Discuss school placement
development options
Use Down syndrome growth curves Proper diet to avoid obesity
Obstructive Start at ~1 yr and at each visit Monitor for snoring, restless
sleep apnea sleep
Atlantoaxial At each visit by history and physical exam Special Olympics
subluxation or Radiographs at 3-5 yr or when planning to recommendations are to screen
instability participate in contact sports for high-risk sports, e.g.,
(incidence 10– Radiographs indicated wherever neurologic diving, swimming,
30%) symptoms are present even if transient (neck pain, contact sports
torticollis, gait disturbances, weakness)
Many are asymptomatic
Gynecologic Adolescent girls Menstruation and
care contraception issues
Recurrent When present Check IgG subclass and IgA
infections levels
Psychiatric, At each visit Depression, anxiety,
behavioral obsessive- compulsive
disorders disorder, schizophrenia seem
in 10– 17%
Autism spectrum disorder in
5– 10%
Early-onset Alzheimer disease
IgA, Immunoglobulin A; IgG, immunoglobulin G. Data from Committee on Genetics: Health supervision for children
with Down syndrome, Pediatrics 107:442–449, 2001; and Baum RA, Spader M, Nash PL, et al: Primary care of children
and adolescents with Down syndrome: an update, Curr Probl Pediatr Adolesc Health Care 38:235–268, 2008.

9.3 表 98.8 唐氏综合症儿童的健康监护

疾病 筛查时间 评论
先天性心脏病
后天性瓣膜病的年轻成人
患先天性心脏病的风险为 50%；肺动脉高压的风险增加

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斜视
白内障
眼球震颤
出生或 6 个月前；由儿科眼科医生诊断
每年检查视力
白内障发生率为 15
50%发生屈光不正

听力受损或丧失
出生时或 3 个月前进行听性脑干反应或耳声发射测试；如果鼓膜未显影，3 岁前每 6 个月检查一次
听力；之后每年检查一次
先天性听力损失风险加上 50- 70% 患浆液性中耳炎的风险

便秘
出生
患赫氏菌病的风险增加

乳糜泻
2 岁时或有症状时
筛查 IgA 和组织 组织转谷氨酰胺酶抗体

血液病
出生时和青春期或出现症状时
新生儿多血症风险增加（18%）、
类白血病反应、白血病（<1）

甲状腺功能减退
出生后；6-12 个月和每年复查一次
先天性（1%）和后天性（5）

生长发育
每次就诊时 讨论学校安置方案
使用唐氏综合征生长曲线
合理饮食，避免肥胖

阻塞性睡眠呼吸暂停
从 ~1 岁开始，每次就诊时都要检查
监测打鼾和睡眠不安

寰枢椎脱位或不稳定（发生率为 10-30%）。
每次就诊时通过病史和体格检查进行筛查
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3-5 岁或计划参加接触性运动时拍 X 光片
只要出现神经系统症状，即使是短暂的症状（颈部疼痛、扭转、步态障碍、乏力），都需要拍片检查
许多人没有症状
特奥会建议筛查高风险运动，如跳水、游泳、接触性运动等

妇科护理
青春期少女
月经和避孕问题

反复感染
出现时
检查 IgG 亚类和 IgA 水平

精神和行为障碍
每次就诊时
10%-17%出现抑郁、焦虑、强迫症、精神分裂症
5- 10% 患有自闭症谱系障碍
早发性阿尔茨海默病

10. What is Turner syndrome and it’s clinical manifestations? (Page 83-85)
10.1Turner Syndrome
 a condition characterized by complete or partial monosomy of the X chromosome and defined by a
combination of phenotypic features (Table 98.16 ).
 Half the patients with Turner syndrome have a 45,X chromosome complement.
 The other half exhibit mosaicism and varied structural abnormalities of the X or Y chromosome.
 Maternal age is not a predisposing factor for children with 45,X.
 Turner syndrome occurs in approximately 1 in 5,000 female live births.
 In 75% of patients, the lost sex chromosome is of paternal origin (whether an X or a Y).
 45,X is one of the chromosome abnormalities most often associated with spontaneous abortion.
 It has been estimated that 95–99% of 45,X conceptions are miscarried.
10.2 Clinical findings in the newborns can include
 small size for gestational age,
 webbing of the neck,
 protruding ears, and
 lymphedema of the hands and feet,
 although many newborns are phenotypically normal (Fig. 98.17 ).
10.3 Older children and adults have
 short stature and
 exhibit variable dysmorphic features.
10.4 Congenital heart defects (40%) and structural renal anomalies (60%) are common. The most
common heart defects are
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 bicuspid aortic valves,
 coarctation of the aorta,
 aortic stenosis,
 and mitral valve prolapse.
10.5 The gonads are generally streaks of fibrous tissue (gonadal dysgenesis ).
 There is primary amenorrhea and lack of secondary sex characteristics.
 These children should receive regular endocrinologic testing (see Chapter 604 ).
10.6 Most patients tend to be of normal intelligence, but intellectual disability is seen in up to 6% of
affected children.
10.7 They are also at increased risk for behavioral problems and deficiencies in spatial and motor
perception.
10.8 Guidelines for health supervision for children with Turner syndrome are published by the American
Academy of Pediatrics (AAP) and include
 pubertal induction,
 as well as treatment with growth hormone and oxandrolone.

10. 什么是特纳综合征及其临床表现？(第 83-85 页）

10.1 特纳综合征
- 特纳综合征（Turner Syndrome）是一种以 X 染色体完全或部分单体为特征的疾病，具有多种表型
特征（表 98.16）。
- 一半特纳综合征患者的 X 染色体互补率为 45,X。
- 另一半特纳综合征患者的 X 或 Y 染色体出现嵌合和各种结构异常。
- 母亲的年龄并不是 45,X 患儿的诱发因素。
- 特纳综合征的发病率约为女性活产婴儿的五千分之一。
- 在 75% 的患者中，丢失的性染色体来自父方（无论是 X 还是 Y）。
- 45,X 是最常与自然流产相关的染色体异常之一。
- 据估计，95%-99%的 45,X 胎儿都会流产。
10.2 新生儿的临床表现包括
- 小于胎龄儿
- 颈部蹼状
- 耳朵突出，以及
- 手足淋巴水肿、
- 尽管许多新生儿表型正常（图 98.17）。
10.3 年长儿童和成人有
- 身材矮小
- 表现出不同的畸形特征。
10.4 先天性心脏缺陷（40%）和结构性肾脏异常（60%）很常见。最常见的心脏缺陷是
- 主动脉双瓣
- 主动脉共动脉瘤、
- 主动脉瓣狭窄
- 和二尖瓣脱垂。
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10.5 性腺一般为条状纤维组织（性腺发育不良）。
- 原发性闭经和缺乏第二性征。
- 这些患儿应定期接受内分泌检查。
10.6 大多数患者智力正常，但也有高达 6%的患儿出现智力障碍。
10.7 他们出现行为问题以及空间和运动知觉缺陷的风险也会增加。
10.8 特纳综合征患儿的健康监护指南由美国儿科学会（AAP）发布，内容包括
- 青春期诱导、
- 生长激素和奥昔诺龙治疗。

Noonan syndrome
1) shares many clinical features with Turner syndrome. it is an autosomal dominant disorder
resulting from mutations in several genes involved in the RAS-MAPK (mitogen-activated protein
kinase) pathway.
2)Features common to Noonan syndrome include
 short stature,
 low posterior hairline,
 shield chest,
 congenital heart disease, and
 a short or webbed neck.
3) In contrast to Turner syndrome, Noonan syndrome
 affects both sexes and
 has a different pattern of congenital heart disease, typically involving right-sided lesions.

努南综合征
1）与特纳综合征有许多共同的临床特征。它是一种常染色体显性遗传疾病，由参与 RAS-MAPK（丝
裂原活化蛋白激酶）通路的几个基因突变引起。
2)努南综合征的共同特征包括
- 身材矮小、
- 后发际低
- 盾状胸、
- 先天性心脏病，以及
- 短颈或蹼状颈。
3) 与特纳综合征相反，努南综合征
- 男女均可患病，而且
- 先天性心脏病的模式不同，通常是右侧病变。

11. What is Klinefelter syndrome and its clinical manifestations? (Page 88-89)
11.1 Persons with Klinefelter syndrome
 are phenotypically male;
 this syndrome is the most common cause of hypogonadism and infertility in males and
 the most common sex chromosome aneuploidy in humans (see Chapter 601 ).
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 Eighty percent of children with Klinefelter syndrome have a male karyotype with an extra
chromosome X-47,XXY.
11.2 Puberty
 Puberty commences at the normal age,
 but the testes remain small.
 Patients develop secondary sex characters late, and 50% ultimately develop gynecomastia.
 They have taller stature.
11.3 Because many patients with Klinefelter syndrome are phenotypically normal until puberty,
 the syndrome often goes undiagnosed until they reach adulthood,
 when their infertility leads to identification.
11.4 Patients with 46,XY/47,XXY have a better prognosis for testicular function.
11.5 Intelligence, development, cognition
 Their intelligence shows variability and ranges from above to below average.
 Persons with Klinefelter syndrome can show behavioral problems, learning disabilities, and
deficits in language.
 Problems with self-esteem often occur in adolescents and adults.
 Substance abuse, depression, and anxiety have been reported in adolescents with Klinefelter
syndrome.
 Those who have higher X chromosome counts show impaired cognition.
 It has been estimated that each additional X chromosome reduces the IQ by 10-15 points, when
comparing these individuals with typical siblings.
 The main effect is seen in language skills and social domains.

11. 什么是 Klinefelter 综合征及其临床表现？(第 88-89 页）

11.1 克莱恩费尔特综合征患者
- 表型上为男性；
- 该综合征是导致男性性腺功能低下和不育的最常见原因，也是最常见的性染色体非整倍体。
- 该综合征是导致男性性腺功能低下和不育的最常见原因，也是人类最常见的性染色体非整倍体（见
第 601 章）。
- 80%的克氏综合征患儿的核型为男性，多出一条 X-47，XXY 染色体。
11.2 青春期
- 青春期在正常年龄开始、
- 但睾丸仍然很小。
- 患者出现第二性征的时间较晚，50%的患者最终会出现妇科肿瘤。
- 他们的身材较高。
11.3 由于许多 Klinefelter 综合征患者在青春期前表型正常、
- 11.3 由于许多 Klinefelter 综合征患者在青春期前表型正常，因此该综合征往往在他们成年后才被诊
断出来、
- 11.3 由于许多 Klinefelter 综合征患者在青春期前表型正常，因此往往在成年后才被发现。
11.4 46,XY/47,XXY 患者的睾丸功能预后较好。
11.5 智力、发育和认知能力
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- Klinefelter 综合征患者的智力存在差异，从高于平均水平到低于平均水平不等。
- Klinefelter 综合征患者可能会出现行为问题、学习障碍和语言障碍。
- 青少年和成年人通常会出现自尊问题。
- 据报道，患有 Klinefelter 综合征的青少年会滥用药物、抑郁和焦虑。
- X 染色体数目较多的患者会出现认知障碍。
- 据估计，每增加一条 X 染色体，智商就会降低 10-15 分。

12. What is fragile X syndrome and its clinical manifestations? (Page 91)
12.1 Fragile sites are regions of chromosomes that show a tendency for
 separation,
 breakage,
 or attenuation under particular growth conditions.
12. 2 They visually appear as a gap in the staining in chromosome studies.
 At least 120 chromosomal loci,
 many of them heritable,
 have been identified as fragile sites in the human genome
12.3 A clinically significant fragile site
 is on the distal long arm of chromosome Xq27.3 associated with the fragile X syndrome .
 Fragile X syndrome accounts for 3% of males with intellectual disability.
 In fragile X syndrome the CGG repeat expansion silences the gene producing fragile X mental
retardation protein (FMRP) that regulates the translation of multiple mRNAs to specific
proteins, thus affecting synaptic function.
12.4 The main clinical manifestations of fragile X syndrome in affected males are
 intellectual disability,
 autistic behavior,
 postpubertal macroorchidism,
 hyperextensible finger joints, and
 characteristic facial features (Table 98.18 ).
12.5 The facial features, which include
 a long face,
 large ears, and
 a prominent square jaw, become more obvious with age.
12.6 Females affected with fragile X show varying degrees of intellectual disability and/or learning
disabilities.
12.7 Diagnosis of fragile X syndrome is possible by DNA testing that shows an expansion of a triplet
DNA repeat inside the FMR1 gene on the X chromosome >200 repeats.
 The expansion involves an area of the gene that contains a variable number of trinucleotide (CGG)
repeats (typically <50 in unaffected individuals).
 The larger the triplet repeat expansion, the more significant is the intellectual disability.
 In cases where the expansion is large, females can also manifest different degrees of intellectual
disability.
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 Males with premutation triple repeat expansions (55- 200 repeats) have been found to have an adult,
late-onset, progressive neurodegenerative disorder known as fragile X–associated tremor/ataxia
syndrome .
 Females with premutation triple repeat expansions are at high risk for developing premature ovarian
failure (POF).

12. 什么是脆性 X 综合征及其临床表现？(第 91 页）

12.1 脆性位点是染色体上有以下倾向的区域
- 分离、
- 断裂、
- 或衰减的区域。
12. 2 在染色体研究中，它们在染色结果中直观地表现为缺口。
- 至少有 120 个染色体位点、
- 其中许多是可遗传的、
- 12.2 在染色体研究中，它们直观地表现为染色质中的缺口。
12.3 具有临床意义的脆性位点
- 临床上一个重要的脆性位点位于与脆性 X 综合征有关的染色体 Xq27.3 的远端长臂上。
- 脆性 X 综合征占男性智障患者的 3%。
- 在脆性 X 综合征中，CGG 重复扩展沉默了产生脆性 X 精神发育迟滞蛋白（FMRP）的基因，该蛋
白可调节多个 mRNA 翻译成特定蛋白质，从而影响突触功能。
12.4 患有脆性 X 综合征的男性患者的主要临床表现是
- 智力障碍、
- 自闭行为、
- 青春期后大睾丸症、
- 手指关节过度伸展，以及
- 特征性面部特征（表 98.18）。
12.5 面部特征包括
- 长脸
- 大耳朵和
- 随着年龄的增长，这些特征会变得更加明显。
12.6 女性脆性 X 表现出不同程度的智力障碍和/或学习障碍。
12.7 通过 DNA 检测可诊断脆性 X 综合征，检测结果表明脆性 X 综合征患者体内的 FMR1 基因上
有一个三重 DNA 重复的扩展。

第 99 章 常见疾病的遗传 无提问
Chapter 100 Epigenome-Wide Association Studies and Disease
13. What is epigenetics and the two examples? (Page 117,121)
13.1 The back-translated meaning of epigenetics (epi, above, upon; genetic, DNA sequence) implies that
 information encoded in the DNA sequence
 may be modifiable in some way by higher-order information
 that regulates the levels of activity of specific genes.
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13.2 Epigenetics and Regulation of Gene Expression. Two examples of gene regulation provide a model
for locking in a regulatory pattern early in development and maintaining it indefinitely thereafter.
13.21The first is X chromosome inactivation .
 Because males have only 1 X chromosome, it does not undergo inactivation.
 However, a person with 2 X chromosomes will inactivate 1, a person with trisomy for the X
chromosome will inactivate 2, and so on.
 The result is that males and females have 1 active X chromosome per cell, despite starting with
different numbers of X chromosomes, a process referred to as dosage compensation .
 X chromosome inactivation is generally a random event, choosing the maternal X for
inactivation in half the cells of the body and the paternal X in the other half.
 The inactivation occurs very early during development, when the blastocyst is implanting itself
into the uterine wall. However, once established in this small number of pluripotent cells, the
inactivation persists in all the cells of the individual throughout life.
13.22 The other relevant model of gene regulation is genomic imprinting.
 Gene activation in a specific cell type usually switches on the copies present on both the paternal
and the maternal chromosomes.
 However, an imprinted locus is distinctive because
 only the copy on the paternal chromosome is switched on for some imprinted genes,
 while other imprinted genes are distinctive for only switching on the maternal copy.
 The timing of this inactivation event is even earlier than X chromosome inactivation, occurring
during the formation of the male or female gametes.
 Again, these patterns of inactivation persist throughout life into old age.

第 100 章 表观基因组关联研究与疾病
13. 什么是表观遗传学？(第 117 和 121 页）
13.1 表观遗传学（epi，upper，on；genetic，DNA sequence）的反译意指
- DNA 序列中编码的信息
- 在某种程度上可以被高阶信息修改
- 调节特定基因的活动水平。
13.2 表观遗传学和基因表达调控。基因调控的两个例子为在发育早期锁定调控模式并在此后无限期地
保持这种模式提供了一种模式。
13.21 第一个例子是 X 染色体失活。
- 由于男性只有 1 条 X 染色体，它不会失活。
- 但是，如果一个人有 2 条 X 染色体，则 1 条会失活；如果一个人有 X 染色体三体综合症，则 2 条
会失活，依此类推。
- 其结果是，尽管男性和女性的 X 染色体数目不同，但每个细胞都有 1 条活跃的 X 染色体，这一过
程被称为剂量补偿。
- X 染色体的失活通常是随机发生的，在身体的一半细胞中选择母体 X 染色体失活，而在另一半细胞
中选择父体 X 染色体失活。
- 灭活发生在胚胎发育的早期，即胚囊植入子宫壁时。然而，一旦在这一小部分多能细胞中形成，这
种失活现象就会在个体一生中的所有细胞 中持续存在。
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13.22 另一种相关的基因调控模式是基因组印记。
- 特定细胞类型中的基因激活通常是通过父系和母系染色体上的拷贝进行的。
- 然而，印记基因座是与众不同的，因为
- 某些印记基因只开启父源染色体上的拷贝、
- 而另一些印记基因则只开启母体的拷贝。
- 这种失活事件发生的时间甚至早于 X 染色体失活，发生在雄性或雌性配子的形成过程中。
- 同样，这些失活模式在人的一生中一直持续到老年。

Chapter 101 Genetic Approaches to Rare and Undiagnosed Diseases - no questions

第 101 章罕见和未确诊疾病的遗传学方法 无提问

Abnormalities of Chromosome Structure p72

染色体结构异常 第 72 页, 无提问, 石头自学
Translocations
 Translocations, which involve the transfer of material from one chromosome to another,
 occur with a frequency of 1 in 500 liveborn human infants.
 They may be inherited from a carrier parent or appear de novo, with no other affected
family member.
 Translocations are usually reciprocal or robertsonian, involving 2 chromosomes.

1)Reciprocal translocations
 are the result of breaks in nonhomologous chromosomes, with reciprocal exchange of the
broken segments.
 Carriers of a reciprocal translocation are usually phenotypically normal
 but are at an increased risk for miscarriage caused by transmission of unbalanced
reciprocal translocations and for bearing chromosomally abnormal offspring.
 Unbalanced translocations are the result of abnormalities in the segregation or crossover of
the translocation carrier chromosomes in the germ cells.
2) Robertsonian translocations
 involve 2 acrocentric chromosomes (chromosomes 13, 14, 15, 21, and 22)
 that fuse near the centromeric region with a subsequent loss of the short arms.
 Because the short arms of all 5 pairs of acrocentric chromosomes have multiple copies of
genes encoding for ribosomal RNA, loss of the short arm of 2 acrocentric chromosomes
has no deleterious effect.
 The resulting karyotype has only 45 chromosomes, including the translocated chromosome,
which consists of the long arms of the 2 fused chromosomes.
 Carriers of robertsonian translocations are usually phenotypically normal.
 However, they are at increased risk for miscarriage and unbalanced translocations in
phenotypically abnormal offspring.

Inversions
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1)An inversion requires that
 a single chromosome break at 2 points;
 the broken piece is then inverted and joined into the same chromosome.
2)Inversions occur in 1 in 100 live births.
3)There are 2 types of inversions: pericentric and paracentric.
In pericentric inversions
 the breaks are in the 2 opposite arms of the chromosome and include the centromere.
 They are usually discovered because they change the position of the centromere.
 The breaks in paracentric inversions occur in only 1 arm.
 Carriers of inversions are usually phenotypically normal, but they are at increased risk for
miscarriages,
typically in paracentric inversions, and chromosomally abnormal offspring in pericentric
inversions.

Deletions and Duplications

 Deletions involve loss of chromosome material and,
 depending on their location, can be classified as terminal (at the end of chromosomes) or
interstitial (within the arms of a chromosome).
 They may be isolated or may occur along with a duplication of another chromosome
segment. The latter typically occurs in unbalanced reciprocal chromosomal translocation
secondary to abnormal crossover or segregation in a translocation or inversion carrier.

Insertions
 Insertions occur when a piece of a chromosome broken at 2 points is incorporated into a
break in another part of a chromosome.
 A total of 3 breakpoints are then required, and they can occur between 2 or within 1
chromosome.
 A form of nonreciprocal translocation, insertions are rare.
 Insertion carriers are at risk of having offspring with deletions or duplications of the inserted
segment.

Isochromosomes
 consist of 2 copies of the same chromosome arm joined through a single centromere and
forming mirror images of one another.
 The most commonly reported autosomal isochromosomes tend to involve chromosomes
with small arms.
 There is also a common isochromosome abnormality seen in long arm of the X
chromosome and associated with Turner syndrome.

Marker chromosomes

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 are rare and are usually chromosome fragments that are too small to be identified by
conventional cytogenetics;
 they usually occur in addition to the normal 46 chromosomes.
 Most are sporadic (70%); mosaicism is often (50%) noted because of the mitotic instability of
the marker chromosome.
 The incidence in newborn infants is 1 in 3,300, and the incidence in persons with
intellectual disability is 1 in 300.
 The associated phenotype ranges from normal to severely abnormal, depending on the
amount of chromosome material and number of genes included in the fragment

Ring chromosomes, which are

 found for all human chromosomes, are rare.
 A ring chromosome is formed when both ends of a chromosome are deleted and the ends
are then joined to form a ring.
 Depending on the amount of chromosome material that is lacking or in excess (if the ring
is in addition to the normal chromosomes), a patient with a ring chromosome can appear
normal or nearly normal or can have intellectual disability and multiple congenital
anomalies.

易位
- 易位是指物质从一个染色体转移到另一个染色体、
- 发生频率为每 500 个活产婴儿中就有 1 个。
- 它们可能遗传自携带者的父母，也可能从头开始出现，家族中没有其他受影响的成员。
- 易位通常是对等的或罗伯逊式的，涉及 2 条染色体。
1）互易位
- 是非同源染色体断裂的结果，断裂的片段相互交换。
- 互补易位的携带者通常表型正常
- 但因不平衡互易位点的传播而导致流产以及生育染色体异常后代的风险会增加。
- 不平衡易位是由于易位载体染色体在生殖细胞中的分离或交叉异常所致。
2) 罗伯逊易位
- 涉及两条同源染色体（13、14、15、21 和 22 号染色体）
- 在中心区附近融合，随后短臂缺失。
- 由于所有 5 对同心染色体的短臂都有多个核糖体 RNA 的编码基因拷贝，因此缺失 2 条同心染色
体的短臂不会产生有害影响。
- 由此产生的核型只有 45 条染色体，包括由 2 条融合染色体的长臂组成的易位染色体。
-罗伯逊易位携带者通常表型正常。
- 然而，他们流产和后代表型异常的不平衡易位风险会增加。

反转
1)倒位要求
- 一条染色体在两点断裂；
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- 然后将断裂的部分倒置并连接到同一条染色体上。
2)每 100 个活产婴儿中就有 1 个发生倒位。
3)倒位有两种类型：同心倒位和旁中心倒位。
在同心倒位中
- 断裂位于染色体的两个对臂，包括中心粒。
- 它们通常是由于改变了中心粒的位置而被发现的。
- 旁中心倒位的断裂只发生在一个臂上。
- 倒位携带者通常表型正常，但他们流产的风险会增加、
但在旁中心倒位中，他们流产的风险会增加；在周中心倒位中，他们的后代染色体异常的风险会增加。

缺失和重复
- 缺失涉及染色体材料的丢失，根据其位置，可分为缺失和重复、
- 根据缺失的位置，可分为末端缺失（位于染色体末端）和间隙缺失（位于染色体臂内）。
- 它们可能是孤立的，也可能与另一个染色体片段的重复同时发生。后者通常发生在不平衡的互惠染
色体易位中，继发于易位或倒位携带者的异常交叉或分离。

插入
- 插入是指染色体上断裂的两点与染色体另一部分的断裂点结合。
- 这时总共需要 3 个断裂点，它们可以发生在 2 条染色体之间，也可以发生在 1 条染色体内部。
- 作为一种非互易性易位，插入是罕见的。
- 插入携带者的后代有可能出现插入片段的缺失或重复。

等染色体
- 由同一染色体臂的两个拷贝组成，通过一个中心粒连接，形成彼此的镜像。
- 最常报道的常染色体异染色质往往涉及染色体臂较小的染色体。
- 还有一种常见的同源染色体异常见于 X 染色体的长臂，与特纳综合征有关。

标记染色体
- 很少见，通常是染色体片段，由于太小而无法用常规细胞遗传学方法识别；
- 它们通常出现在正常 46 条染色体之外。
- 大多数是散发性的（70%）；由于标记染色体的有丝分裂不稳定性，通常会出现嵌合现象（50%）。
- 新生儿的发病率为三分之一（3300），智障者的发病率为三分之一（300）。
- 相关的表型从正常到严重异常不等，这取决于染色体材料的数量和片段中包含的基因数量。

环状染色体
- 环状染色体在人类所有染色体中都存在，但非常罕见。
- 环状染色体是染色体的两端被删除，然后两端连接起来形成一个环。
- 根据染色体缺失或过多（如果环是正常染色体之外的）的数量，环状染色体患者可能看起来正常或
接近正常，也可能有智力障碍和多种先天性异常。

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1.2 A pedigree provides a graphic depiction of a family's structure and medical history.
standard symbols and configuration.

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FIG. 97.1 Common pedigree symbols, definitions, and abbreviations. (From Bennett RL, French KS,
Resta RG, et al: Standardized human pedigree nomenclature: update and assessment of the
recommendations of the National Society of Genetic Counselors, J Genet Couns 17:424–433, 2008.

FIG. 97.2 Pedigree line definitions. (From Bennett RL, French KS, Resta RG, et al: Standardized
human pedigree nomenclature: update and assessment of the recommendations of the National
Society of Genetic Counselors, J Genet Couns 17:424–433, 2008.)

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