Pathology (genetic diseases 3)

Meiotic nondisjunction

• It occurs once in 1550 live births in women under age 20, in contrast to 1 in 25 live births for mothers over age 45.
• The correlation with maternal age suggests that in most cases the meiotic nondisjunction of chromosome 21 occurs in the ovum.

• 1. 95% trisomy (maternal meiotic nondisjunction)/ not familial
• 2. 4% robertsonian translocation of 21q to another acrocentric chromosome (e.g., 22 or 14)/ familial/ no relation to maternal age
• 3. 1% mosaics, a mixture of cells with 46 and 47 chromosomes/ mitotic nondisjunction of chromosome 21 during an early stage of embryogenesis/no relation to maternal age

Carrier of Robertsonian trasnlocation

• flat facial profile
• oblique palpebral fissures
• epicanthic folds
• Transverse palmar crease
• Space between the first and second toes
• Hypotonia 
• Dysplasia of midphalanx of fifth finger
• Excessive skin at nape of the neck
• the average age of sitting (11 months), creeping (17 months), and walking (26 months) is twice the typical age 
• First word at 18 months
• Most IQ 35-70 (mild to moderate MR)
• IQ declines through the first 10 years of age, reaching a plateau in adolescence
• develop neuropathologic and functional changes typical of Alzheimer disease by the fifth decade of life 
• Disruptive behavioral disorders (less common than other MR)
• CHD (Cushion defect MC)
• Duodenal atresia or stenosis, sometimes associated with annular pancreas
• Less Birth weight, length, and head circumference
• Refractive errors
• HEARING LOSS
• Thyroid disease (hypothyroidism)
• DMI, Celiac
• Hirschprung
• polycythemia as newborn
• Transient leukemia
• ALL
• Sleep apnea
• Acute megakaryoblastic leukemia (AMKL)
• All females fertile/all males infertile
• ATLANTOAXIAL INSTABILITY
• 

CHD

• defects of the endocardial cushion, including ostium primum, atrial septal defects, atrioventricular valve malformations, and ventricular septal defects
• Complete atrioventricular septal defect (CAVSD) MC in one series

• almost exclusively affects newborns with DS
• The majority of newborns are asymptomatic
• characterized by the presence of primitive cells (ie, blasts) in the peripheral blood. A mutation in GATA1, a hematopoietic transcription factor required for normal differentiation of megakaryocytes, is found in blast cells in most patients with transient leukemia
• Spontaneous resolution with 2-3 months
• vesiculopustular skin eruptions

Transient leukemia

AMKL

• AMKL develops during the first four years of life.
• It is most commonly seen by two years of age and is invariably associated with mutations in GATA1

• serious infections, particularly of the lungs,
• thyroid autoimmunity

Duodenal atresia or stenosis, sometimes associated with annular pancreas

• 35-70 
• mild to moderate

• duodenal atresia or stenosis,
• imperforate anus,
• esophageal atresia with tracheoesophageal fistula.
• celiac disease and Hirschsprung disease

weight is less than expected for length in infants with DS, and then increases disproportionally so that the majority of children are obese by age three to four years

• polycythemia
• macrocytosis
• leukopenia
• thrombocytosis
• leukemia (transient, acute megakaryoblastic, and acute lymphoblastic)

• Women with DS are fertile and may become pregnant.
• However, nearly all males with DS are infertile

• Intrauterine growth restriction associated with polyhydramnios, especially in a fetus with abnormal hand positioning (“clenched hands”), is suggestive of this disorder.
• Choroid plexus cysts are common

• Associated with AMA and meiotic nondisjunction
• 18--> growth restriction (IUGR), hypertonia, prominent occiput, small mouth, micrognathia, pointy ears, short sternum, horseshoe kidney, and flexed fingers with the index finger overlapping the third finger and the fifth finger overlapping the fourth/ VSD, PDA
• 13-->an early defect in development of the prechordal mesoderm, which is the origin of the midface, eye, and forebrain. These abnormalities include holoprosencephaly, absence of the olfactory nerve or bulb, sloping forehead, severe eye defects (especially microphthalmia and coloboma [fissure or cleft of the iris, ciliary body, or choroid]), deafness, and cleft lip and/or palate. omphalocele or umbilical hernia, genitourinary abnormalities, superficial hemangiomas, scalp defects, polydactyly, narrow convex fingernails, rocker bottom feet (congenital vertical talus), and congenital heart defects.

• Nuchal translucency
• PAPP-A--> decreased in all trisomies
• beta hCG--> increased in Down/ decreased in two other trisomies

• AFP--> reduced in 18,21 ,Turner/ normal in 13
• uE3-->reduced in 18,21 ,Turner/ normal in 13
• hCG--> increased in 21/ reduced in 21/normal in 13
• Inh A-->increased in Down/normal in 13,18

Down syndrome↓/↓/↑/↑/↓/↑

↓↓/ ↓↓/ ↓/↔/↓↓/↓↓

↔/↔/↔/↔/↓↓/↓

• Turner syndrome with hydrops↓/↓/↑/↑/↓↑/↓↑
• Turner syndrome without hydrops↓/↓/↓/↓/↓↑/↓↑

• congenital heart defects,
• abnormalities of the palate,
• facial dysmorphism,
• developmental delay,
• variable degrees of T-cell immunodeficiency and hypocalcemia

• have thymic hypoplasia, with resultant T-cell immunodeficiency
• parathyroid hypoplasia giving rise to hypocalcemia,
• a variety of cardiac malformations affecting the outflow tract,
• and mild facial anomalies.

• facial dysmorphism (prominent nose, retrognathia),
• cleft palate,
• cardiovascular anomalies,
• learning disabilities.

• psychotic illnesses, such as schizophrenia and bipolar disorders
• ADHD

Conotruncal

• detection of the deletion by FISH
• 

• TBX1, a T-box transcription factor is most closely associated with the phenotypic features of this syndrome.
• This gene is expressed in the pharyngeal mesenchyme and endodermal pouch from which facial structures, thymus, and parathyroid are derived. The targets of TBX1 include PAX9, a gene that controls the development of the palate, parathyroids, and thymus

(1) lyonization or inactivation of all but one X chromosome and (2) the modest amount of genetic material carried by the Y chromosome

• (1) only one of the X chromosomes is genetically active,
• (2)the other X of either maternal or paternal origin undergoes heteropyknosis and is rendered inactive,
• (3) inactivation of either the maternal or paternal X occurs at random among all the cells of the blastocyst on or about day 16 of embryonic life,
• (4) inactivation of the same X chromosome persists in all the cells derived from each precursor cell

• the great preponderance of normal females are in reality mosaics and have two populations of cells, one with an inactivated maternal X and the other with an inactivated paternal X.
• Herein lies the explanation of why females have the same dosage of X-linked active genes as have males.
• The inactive X can be seen in the interphase nucleus as a darkly staining small mass in contact with the nuclear membrane known as the Barr body, or X chromatin.

• The molecular basis of X inactivation involves a unique gene called XIST, whose product is a noncoding RNA that is retained in the nucleus, where it “coats” the X chromosome that it is transcribed from and initiates a gene-silencing process by chromatin modification and DNA methylation.
• The XIST allele is switched off in the active X.

True

• This notion is supported by the fact that patients with monosomy of the X chromosome (Turner syndrome: 45,X) have severe somatic and gonadal abnormalities. If a single dose of X-linked genes were sufficient, no detrimental effect would be expected in such cases.
• Furthermore, although one X chromosome is inactivated in all cells during embryogenesis, it is selectively reactivated in oogonia before the first meiotic division

Y chromosome (SRY) located on distal short arm

testes-specific genes involved in spermatogenesis

• In general, they cause subtle, chronic problems relating to sexual development and fertility.  
• They are often difficult to diagnose at birth, and many are first recognized at the time of puberty.  
• In general, the higher the number of X chromosomes, in both male and female, the greater the likelihood of mental retardation

Number of X chromosomes

male hypogonadism that occurs when there are two or more X chromosomes and one or more Y chromosomes(mc XXY)

Kleinfelter

• Rarely be diagnosed before puberty, particularly because the testicular abnormality does not develop before early puberty.
• Most patients have a distinctive body habitus with an increase in length between the soles and the pubic bone, which creates the appearance of an elongated body.
• Also characteristic are eunuchoid body habitus with abnormally long legs; small atrophic testes often associated with a small penis; and lack of such secondary male characteristics as deep voice, beard, and male distribution of pubic hair.
• Gynecomastia
• The mean IQ is somewhat lower than normal, but mental retardation is uncommon.
• There is increased incidence of type 2 diabetes and the metabolic syndrome; and curiously, mitral valve prolapse is seen in about 50% of adults with Klinefelter syndrome

greater the number of extra X chromosomes

• Damage to the seminiferous tubules and, usually, damage to the Leydig cells as well.
• The gonadal manifestations include almost invariably small, firm testes, severely subnormal sperm count, infertility, elevated serum FSH and LH concentrations, elevated E2 variably subnormal serum testosterone concentration and decreased virilization.
• The damage may be increased if the patient also has cryptorchidism, the incidence of which is increased in Klinefelter's

• Difficulty in social interactions throughout life and has been characterized by "marked lack of insight, poor judgment, and impaired ability to learn from adverse experience"
• Linguistic incompetence

The ratio of estrogens and testosterone

• In some patients the testicular tubules are totally atrophied and replaced by pink, hyaline, collagenous ghosts. In others, apparently normal tubules are interspersed with atrophic tubules.
• In some patients all tubules are primitive and appear embryonic, consisting of cords of cells that never developed a lumen or progressed to mature spermatogenesis.
• Leydig cells appear prominent, as a result of the atrophy and crowding of tubules and elevation of gonadotropin concentrations

• chronic bronchitis, bronchiectasis, and emphysema
• cancers, including germ cell tumors (particularly extragonadal tumors involving the mediastinum), breast cancer, and possibly non-Hodgkin lymphoma;
• varicose veins, leading to leg ulcers 
• SLE
• DM

• Meiotic nondisjunction--> mc (mother=father)
• Mosaic  46,XY/47,XXY. 15%

• The gene encoding the androgen receptor, through which testosterone mediates its effects, maps on the X chromosome.
• The androgen receptor gene contains highly polymorphic CAG (trinucleotide) repeats.
• The functional response to androgens is dictated, in part, by the number of CAG repeats.
• With shorter CAG repeats, the effect of androgens is more pronounced.
• In persons with Klinefelter syndrome the X chromosome, bearing androgen receptor with the shortest CAG repeat, is preferentially inactivated.
• Such nonrandom X inactivation leaves the allele with the longest CAG repeat active, thus accounting for hypogonadism.

False

complete or partial monosomy of the X chromosome and is characterized primarily by hypogonadism in phenotypic females

• Approximately 57% are missing an entire X chromosome, resulting in a 45,X karyotype.
• Of the remaining 43%, approximately one third (approximately 14%) have structural abnormalities of the X chromosomes,
• and two thirds (approximately 29%) are mosaics.

produce partial monosomy of the X chromosome

isochromosome of the long arm, 46,X,i(X)(q10) resulting in the loss of the short arm;

• (1) an isochromosome of the long arm, 46,X,i(X)(q10) resulting in the loss of the short arm;
• (2) deletion of portions of both long and short arms, resulting in the formation of a ring chromosome, 46,X,r(X);
• (3) deletion of portions of the short or long arm, 46X,del(Xq) or 46X,del(Xp).

(1) 45,X/46,XX; (2) 45,X/46,XY; (3) 45,X/47,XXX; or (4) 45,X/46,X,i(X)(q10)

developing a gonadal tumor (gonadoblastoma).

Most patients are mosaic

• The most severely affected patients generally present during infancy with edema of the dorsum of the hand and foot due to lymph stasis, and sometimes swelling of the nape of the neck.
• The latter is related to markedly distended lymphatic channels, producing a so-called cystic hygroma.
• As these infants develop, the swellings subside but often leave bilateral neck webbing and persistent looseness of skin on the back of the neck. 
• Congenital heart disease is also common, affecting 25% to 50% of patients. Left-sided cardiovascular abnormalities, particularly preductal coarctation of the aorta and bicuspid aortic valve, are seen most frequently.
• Cardiovascular abnormalities are the most important cause of increased mortality in children with Turner syndrome

Short stature

• Short stature
• Low posterior hairline
• Short neck
• Abnormal upper to low segment ratio
• Cubitus valgus
• Short metacarpals
• Growth failure
• Gonadal dysgenesis
• Inverted, widely spaced nipples
• Webbed neck
• Nail dysplasia (due to abnormal lymph)
• Defective dental development
• Renal dysgenesis
• Cardiac malformation
• Hashimoto thyroiditis
• Presence of glucose intolerance, obesity, and insulin resistance
• failure to develop normal secondary sex The genitalia remain infantile, breast development is inadequate, and there is little pubic hair.
• Multiple pigmented nevi
• Streak gonads

Hashimoto (40%)

• inflammatory bowel disease and celiac disease
• (not other AI diseases)

Bicuspid aortic valve

aortic dissection

horseshoe kidney

True

In Turner syndrome, fetal ovaries develop normally early in embryogenesis, but the absence of the second X chromosome leads to an accelerated loss of oocytes, which is complete by age 2 years. In a sense, therefore, “menopause occurs before menarche,” and the ovaries are reduced to atrophic fibrous strands, devoid of ova and follicles (streak ovaries)

• This is one of several genes that remain active in both X chromosomes and has an active homologue on the short arm of the Y chromosome.
• Thus, both normal males and females have two copies of this gene.
• Haploinsufficiency of SHOX gives rise to short stature.
• Indeed, deletions of the SHOX gene are noted in 2% to 5% of otherwise normal children with short stature.
• In keeping with its role as a critical regulator of growth, the SHOX gene is expressed during fetal life in the growth plates of several long bones including the radius, ulna, tibia, and fibula.
• It is also expressed in the first and second pharyngeal arches.
• Just as the loss of SHOX is always associated with short stature, excess copies of this gene are associated with tall stature. 

• Genetic sex is determined by the presence or absence of a Y chromosome. No matter how many X chromosomes are present, a single Y chromosome dictates testicular development and the genetic male gender. The initially indifferent gonads of both the male and the female embryos have an inherent tendency to feminize, unless influenced by Y chromosome–dependent masculinizing factors. 
• Gonadal sex is based on the histologic characteristics of the gonads. 
• Ductal sex depends on the presence of derivatives of the müllerian or wolffian ducts. 
• Phenotypic, or genital, sex is based on the appearance of the external genitalia. Sexual ambiguity is present whenever there is disagreement among these various criteria for determining sex

• The term true hermaphrodite implies the presence of both ovarian and testicular tissue.
• In contrast, a pseudohermaphrodite represents a disagreement between the phenotypic and gonadal sex (i.e., a female pseudohermaphrodite has ovaries but male external genitalia; a male pseudohermaphrodite has testicular tissue but female-type genitalia)

• Presence of both ovarian and testicular tissue
• 46,XX in 50% of patients; of the remaining, most are mosaics with a 46,XX/46,XY karyotype.
• Only rarely is the chromosomal constitution 46,XY.
• The presence of testes implies that those with the 46,XX karyotype might possess Y-chromosomal material, in particular, the SRY gene, which dictates testicular differentiation.
• Indeed, molecular analysis has revealed SRY gene expression in the ovotestis of 46,XX true hermaphrodites, indicating either cryptic chimerism localized to the gonads or possibly a Y-to-autosome translocation

Presence of SRY in all

• The genetic sex in all cases is XX, and the development of the gonads (ovaries) and internal genitalia is normal.
• Only the external genitalia are ambiguous or virilized.
• The basis of female pseudohermaphroditism is excessive and inappropriate exposure to androgenic steroids during the early part of gestation.
• Such steroids are most commonly derived from the fetal adrenal affected by congenital adrenal hyperplasia, which is transmitted as an autosomal recessive trait.

CAH

• These individuals possess a Y chromosome, and thus their gonads are exclusively testes, but the genital ducts or the external genitalia are incompletely differentiated along the male phenotype.
• Their external genitalia are either ambiguous or completely female.
• Male pseudohermaphroditism is extremely heterogeneous, with a multiplicity of causes. Common to all is defective virilization of the male embryo, which usually results from genetically determined defects in androgen synthesis or action or both.
• The most common form, called complete androgen insensitivity syndrome (testicular feminization), results from mutations in the gene encoding the androgen receptor. This gene is located at Xq12, and hence this disorder is inherited as an X-linked recessive