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My Learning Plan

You are asked to evaluate a term infant because of intrauterine growth restrictionand subtle dysmorphic features. Birthweight is at the 4th percentile and headcircumference is at the 2nd percentile for gestational age. The patient hasdownward slanting palpebral fissures, epicanthal folds, and hypertelorism. Duringyour examination, you notice that the infant has an unusual, high-pitched cry thatresembles the mewing of a cat.

Of the following, the MOST likely abnormality of chromosome structure causingthe clinical findings in this infant is a(n):

deletion

insertion

inversion

reciprocal translocation

Robertsonian translocation

You selected , the correct answer is .

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Abnormalities in chromosome structure result from chromosome breakage withsubsequent reunion in a different configuration. Structural chromosomalrearrangements can be balanced or unbalanced. Balanced rearrangements areusually harmless since there is no loss or gain of genetic material. The exception isa breakpoint that interrupts an important gene. Carriers ofbalanced rearrangements are at significant risk for havingchildren with unbalanced chromosome complements.Unbalanced chromosome rearrangements usually are harmfulbecause of the extra or missing genetic material.

The infant described in the vignette has cri du chat syndrome.The famous and distinctive cry that resembles the mewing of acat is due to abnormal laryngeal development. Infants with cridu chat syndrome have round faces, hypertelorism, epicanthalfolds and downward slanting palpebral fissures. Most have microcephaly andintrauterine growth restriction. Approximately 30% have cardiac malformations.Developmental disability is usually severe. Cri du chat syndrome occurs inapproximately 1 in 50,000 live births.

The underlying chromosomal abnormality in cri du chat syndrome is a partialdeletion of the short arm of chromosome 5 (5p-), as shown in Figure 1:

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Figure 1

Approximately 85% of cri du chat syndrome cases result from a sporadic de novodeletion; in 80% of these cases, the de novo deletion is of paternal origin.

A chromosomal deletion involves a loss of part of a chromosome with resultingmonosomy for that segment of the chromosome. Deletions may occur because ofchromosome breakage, abnormal segregation from a balanced translocation orinversion, or unequal crossing over between misaligned chromatids. Achromosomal deletion may be located at the end of a chromosome (terminaldeletion) or within the chromosome (interstitial deletion) (Figure 2):

Figure 2

High-resolution banding techniques can identify deletions >2000 kb.

The size of the deletion in cri du chat syndrome is variable. The high-pitched crymaps to 5p15.3. The developmental disabilities and other phenotypic features mapto 5p15.2. Individuals with deletions only involving 5p15.3 have the catlike cry butmay have normal development and facial features.



An insertion occurs when a segment of one chromosome breaks off and is insertedinto a different chromosome (Figure 3):

Figure 3

The insertion can be in the usual orientation or inverted. Insertions are rarebecause they require three chromosome breaks. Carriers of balanced deletion-insertion rearrangements are unaffected, but they are at a 50% risk of producingunbalanced gametes. There is a single case report in the literature of anunbalanced insertion involving 5p that resulted in offspring with monosomy 5pand clinical features of cri du chat.

A chromosomal inversion is a two-break rearrangement in which a segment of asingle chromosome is reversed in position. Pericentric inversions involve thecentromere (Figure 4):

Figure 4

Paracentric inversions involve one arm of the chromosome and do not involve the



centromere (Figure 5):

Figure 5

Paracentric inversions do not change the arm ratio of the chromosome.Paracentric inversions can be identified only by banding or fluorescent in situhybridization with specific probes. Pericentric inversions change the proportion ofchromosome arms and easily can be identified using cytogenic techniques.Inversions involving chromosome 5 have been reported in cri du chat syndrome,but they are rare.

Translocations involve the exchange of chromosome segments between twononhomologous chromosomes. There are two types of translocations,Robertsonian and reciprocal. Robertsonian translocations occur when the shortarms of two nonhomologous chromosomes are lost, and the long arms fuse at thecentromere to form a single chromosome (Figure 6):

Figure 6

The resulting balanced karyotype has 45 chromosomes. Robertsoniantranslocations only occur with acrocentric chromosomes (13, 14, 15, 21, and 22)that have extremely small short arms. Because the short arms of these five



acrocentric chromosomes contain essentially no genetic material, carriers ofRobertsonian translocations are phenotypically normal. However, their offspringmay inherit an extra long arm of an acrocentric chromosome. Robertsoniantranslocations do not cause cri du chat syndrome.

A reciprocal translocation is a result of breakage of nonhomologous chromosomeswith mutual exchange of the broken-off segments (Figure 7):

Figure 7

The chromosomes that result from a reciprocal translocation are called derivativechromosomes. Carriers of balanced reciprocal translocations are phenotypicallynormal and have a 46-chromosome karyotype. Offspring may have partial trisomyor monosomy of the derivative chromosomes and an abnormal phenotype.Whereas 85% of cri du chat syndrome cases result from a sporadic de novodeletion, 15% result from a deletion caused by unequal segregation of a parentaltranslocation.


References:

Jones KL. Deletion 5p syndrome. In: Jones KL, ed. Smith's Recognizable Patternsof Malformation. 6th ed. Philadelphia, Pa: WB Saunders; 2006:40-43

Jorde LB, Carey JC, Bamshad MJ, White RL. Clinical cytogenetics: the chromosomalbasis of human disease. In: Jorde LB, Carey JC, Bamshad MJ, White RL, eds.Medical Genetics. 3rd ed. St. Louis, Mo: Mosby; 2003:107-135

Marinescu RC, Mamunes P, Kline AD, Schmidt J, Rojas K, Overhauser J. Variabilityin a family with an insertion involving 5p. Am J Med Genet. 1999;86:258-263

Nussbaum RL, McInnes RR, Willard HF. Clinical cytogenetics: disorders of theautosomes and sex chromosomes. In: Nussbaum RL, McInnes RR, Willard HF, eds.Thompson & Thompson Genetics in Medicine. 6th ed. Philadelphia, Pa: WBSaunders; 2004:157-179

Nussbaum RL, McInnes RR, Willard HF. Principles of clinical cytogenetics. In:Nussbaum RL, McInnes RR, Willard HF, eds. Thompson & Thompson Genetics inMedicine. 6th ed. Philadelphia, Pa: WB Saunders; 2004:135-155



Turnpenny PD, Ellard S. Chromosomes and cell division. In: Turnpenny PD, EllardS, eds. Emery's Elements of Medical Genetics. 12th ed. Edinburgh, Scotland:Elsevier; 2005:31-58

Content Specification(s):

Understand the difference between balanced and unbalanced chromosometranslocation

Know the long-term outcome and survival of infants with various congenitalabnormalities

Recognize the karyotype and clinical manifestations associated with the commondeletion syndromes



May 06 Assessment Your Score CME Credit Expired

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My Learning Plan

You are asked to evaluate a newborn with dysmorphic features (Figures 1 and 2).

Figure 1 Figure 2

Of the following, the MOST likely abnormality of chromosome structure causing the clinicalfindings in this infant is a chromosomal:

deletion

insertion

inversion

reciprocal translocation

Robertsonian translocation

You selected , the correct answer is .


The infant in the vignette has clinical features of Down syndrome (DS), including flat facies withtendency to keep mouth open and tongue protruding, small nose with low nasal bridge, innerepicanthal folds, upward slant of eyes (Figure 1), short fingers with hypoplasia of fifth finger,and a single palmar crease (Figure 2).

DS, which occurs in approximately 1 of every 800 live births, is caused bytrisomy of all or a large part of chromosome 21. The most common cause ofDS is complete trisomy 21 (94% of cases) due to nondisjunction duringmeiosis. However, the most common structural chromosomal abnormalitycausing DS is a Robertsonian translocation (4% of cases). The remaining 2%of individuals with DS have trisomy 21/normal mosaicism or other rarestructural chromosomal abnormalities.

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Abnormalities in chromosome structure result from chromosome breakagewith subsequent reunion in a different configuration. Structural chromosomalrearrangements can be balanced or unbalanced. Balanced rearrangements usually are harmlesssince there is no loss or gain of genetic material. The exception is if one of the break pointsinterrupts an important gene. Carriers of balanced rearrangements are at significant risk forhaving children with unbalanced chromosome complements. Unbalanced chromosomerearrangements are usually harmful because of the extra or missing genetic material.

Translocations involve the exchange of chromosome segments between two nonhomologouschromosomes. There are two types of translocations, Robertsonian and reciprocal. Robertsoniantranslocations occur when the short arms of two nonhomologous chromosomes are lost and thelong arms fuse at the centromere to form a single chromosome (Figure 3):

Figure 3

The resulting balanced karyotype has 45 chromosomes. Robertsonian translocations only occurwith acrocentric chromosomes (13, 14, 15, 21, and 22) that have extremely small short arms.Because the short arms of these five acrocentric chromosomes contain essentially no geneticmaterial, carriers of Robertsonian translocations are phenotypically normal. However, theiroffspring may inherit an extra long arm of an acrocentric chromosome. The Robertsoniantranslocation of the long arms of chromosomes 21 and 14 is the most common structuralabnormality leading to DS. These DS patients have 46 chromosomes but are trisomic for 21q.

Unlike the risk for DS due to nondisjunction in meiosis, the risk for DS due to a Robertsoniantranslocation is not increased by advanced maternal age. Furthermore, DS due to nondisjunctionin meiosis has a relatively low recurrence risk (1%); DS due to a parent being a carrier of abalanced Robertsonian translocation has a relatively high recurrence risk. The potential gametesthat can be formed by a Robertsonian translocation carrier are illustrated in Figure 4:

Figure 4



There are six possible types of gametes, but three lead to nonviable fetuses. The three viablegamete types lead to one normal, one balanced, and one unbalanced trisomic 21q DS. Since allthree of the gamete types that can lead to a viable infant are produced equally, the risk of DS in acarrier of a Robertsonian translocation should be 1 in 3. However, the function of the unbalancedtrisomic 21q gamete is diminished such that the risk of DS is 15% if the mother is a Robertsoniancarrier and 2% to 3% if the father is a carrier.

A reciprocal translocation is a result of breakage of nonhomologous chromosomes, with mutualexchange of the broken-off segments (Figure 5):

Figure 5

The chromosomes that result from a reciprocal translocation are called derivative chromosomes.Carriers of balanced reciprocal translocations are phenotypically normal and have a 46-chromosome karyotype. Offspring may have partial trisomy or monosomy of the derivativechromosomes and an abnormal phenotype. Reciprocal translocations are extremely rare causes ofDS.

A chromosomal deletion involves a loss of part of a chromosome with resulting monosomy forthat segment of the chromosome. Chromosomal deletion may be located at the end of achromosome (terminal deletion) or within the chromosome (interstitial deletion) (Figure 6):

Figure 6



Large deletions (>2% of the haploid genome) are usually incompatible with life. Several large-deletion syndromes have been described, including Cri du chat syndrome (5p-) and Wolf-Hirschhorn syndrome (4p-). Microdeletions have been identified using fluorescent in situhybridization techniques. Angelman syndrome and Prader-Willi syndrome are caused bymicrodeletions. Deletions do not cause DS.

An insertion occurs when of a segment of one chromosome breaks off and is inserted into adifferent chromosome. The insertion can be in the usual orientation or inverted (Figure 7):

Figure 7

Insertions require three chromosome breaks. Carriers of balanced deletion-insertionrearrangements are unaffected, but they are at a 50% risk of producing unbalanced gametes. DScaused by partial trisomy 21 due to an insertion can occur but is extremely rare.

A chromosomal inversion is a two-break rearrangement involving a single chromosome in whicha segment is reversed in position. Pericentric inversions involve the centromere (Figure 8):

Figure 8



Paracentric inversions involve one arm of the chromosome (Figure 9):

Figure 9

Carriers of inversions are usually normal. However, during meiosis, recombination events maylead to unbalanced gametes, particularly with pericentric inversions. Partial trisomy 21 due to anunbalanced pericentric inversion can occur but is extremely rare.


References:

Jones KL. Down syndrome. In: Jones KL ed. Smith's Recognizable Patterns of Malformation. 6th

ed. Philadelphia, Pa: WB Saunders; 2006:7-12

Jorde LB, Carey JC, Bamshad MJ, White RL. Clinical cytogenetics: the chromosomal basis ofhuman disease. In: Jorde LB, Carey JC, Bamshad MJ, White RL, eds. Medical Genetics. 3rd ed. St.Louis, Mo: Mosby; 2003:107-135

Moore KL, Persaud TVN. The beginning of human development: the first week. In: Moore KL,Persaud TVN, eds. The Developing Human: Clinically Oriented Embryology. 6th ed. Philadelphia,Pa: WB Saunders; 1998:18-24

Moore KL, Persaud TVN. Human birth defects. In: Moore KL, Persaud TVN, eds. The DevelopingHuman: Clinically Oriented Embryology. 6th ed. Philadelphia, Pa: WB Saunders; 1998:170-179

Nussbaum RL, McInnes RR, Willard HF. Clinical cytogenetics: disorders of the autosomes and sex



chromosomes. In: Nussbaum RL, McInnes RR, Willard HF, eds. Thompson & Thompson Genetics inMedicine. 6th ed. Philadelphia, Pa: WB Saunders; 2004:157-179

Nussbaum RL, McInnes RR, Willard HF. Principles of clinical cytogenetics. In: Nussbaum RL,McInnes RR, Willard HF, eds. Thompson & Thompson Genetics in Medicine. 6th ed. Philadelphia,Pa: WB Saunders; 2004:135-155

Turnpenny PD, Ellard S. Chromosomes and cell division. In: Turnpenny PD, Ellard S, eds. Emery'sElements of Medical Genetics. 12th ed. Edinburgh, Scotland: Elsevier; 2005:31-58

Content Specification(s):

Know when to obtain chromosomes on parents or other family members

Be aware of the maternal factors, incidence, and clinical manifestations of Down syndrome

Understand the difference between balanced and unbalanced chromosome translocation

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