Chromosomal Abnormalities



Chromosomal Abnormalities


George E. Tiller



For more than 50 years, chromosomal abnormalities have been recognized as the basis of certain genetic syndromes. Initially, only aneuploidies (the presence of more or fewer than 46 chromosomes) could be detected. Now, with the availability of fluorescence in situ hybridization (FISH) and DNA methylation testing, microdeletions and uniparental disomy (UPD) can be documented. The advent of microarray-based analysis (comparative genomic hybridization, or CGH) takes resolution to an even finer level, and introduces the confounding phenomenon of copy number variation. We have learned that although we carry two copies of each autosomal gene, the normal process of imprinting fine tunes the expression of certain regions of many chromosomes by silencing one copy of certain genes by DNA methylation. Consequently, UPD (presumably caused by trisomic “rescue” after fertilization) may result in the silencing of both copies of a gene or contiguous group of genes, despite the normal complement of 46 intact chromosomes. Further refinements in cytogenetic techniques, in tandem with molecular genetics, are making it possible to unravel normal processes in human development and pathologic processes in the origin of cancer.

The objectives of this chapter are to help the reader to:



  • Identify several indications of karyotyping.


  • Describe the clinical features of the more common chromosomal anomalies.


  • Appreciate the concepts of contiguous gene syndromes, imprinting, and UPD.



INCIDENCE OF CHROMOSOMAL DISORDERS

Chromosomal disorders are:



  • Found in >7% of human conceptuses


  • Responsible for >50% of miscarriages (trisomy 16 > 45, XO > others)


  • Found in 1 in 200 liveborn infants


INDICATIONS FOR CHROMOSOMAL ANALYSIS


Neonatal Period and Infancy (0-3 Years)



  • Phenotype of chromosomal anomaly (+21, +18, +13, XO)


  • Multiple congenital anomalies


  • Ambiguous genitalia


  • Certain tumors (retinoblastoma, Wilms tumor)


Childhood (4-10 Years)



  • Mental retardation (MR) and multiple congenital anomalies


  • Phenotype of chromosomal anomaly (XO, XXY, XYY)


Adolescence (11-20 Years)



  • Primary amenorrhea


  • Abnormal stature


Adults (20> Years)



  • Infertility with or without habitual abortion


  • Familial chromosomal aberration


  • Leukemia or certain tumors


  • Pregnancy at advanced maternal age


  • Pregnancy with risk for X-linked disorder


TYPES OF CHROMOSOMAL ABNORMALITIES


Numeric Changes



  • Of sets: triploidy, tetraploidy (all lethal)


  • Individual: trisomy, monosomy, sex chromosome aneuploidy


  • Mosaicism


Structural Changes



  • Deletions


  • Duplications


  • Translocations


  • Inversions


Functional Changes



  • Methylation defects (often caused by UPD)


EXAMPLES OF CHROMOSOMAL DISORDERS


Trisomy 21 (Down Syndrome)



  • Incidence: 1 in 750 (most common recognizable cause of MR)


  • Growth and development: May or may not be small-forgestational-age; short stature, MR


  • Central nervous system (CNS): Hypotonia, delayed motor skills, premature aging


  • Craniofacial: Flat face and occiput, upward-slanting palpebral fissures, epicanthal folds, Brushfield spots, prominent tongue, small ears, depressed nasal bridge


  • Extremities: Simian creases, clinodactyly, short fingers, increased space between the first and second toes, increased ulnar loops


  • Cardiac: Congenital heart disease in >50% of patients, including ventricular septal defect, endocardial cushion defects (atrioventricular canal)


  • Abdominal: Umbilical hernia, diastasis recti, duodenal obstruction


  • Skin/hair: Thin hair


  • Remarks: Increased risk of hypothyroidism, leukemia; all trisomies associated with advanced maternal age


Trisomy 13



  • Incidence: 1 in 5000


  • Growth and development: Small-for-gestational-age, intrauterine growth retardation, failure to thrive, severe MR


  • CNS: Hypotonia, seizures, apnea, deafness, holoprosencephaly


  • Craniofacial: Microcephaly, microphthalmia, colobomata, cleft lip and palate, abnormal ears


  • Extremities: Polydactyly (Fig. 41.1), flexion deformities, clubfoot


  • Cardiac: Ventricular septal defect, patent ductus arteriosus, atrial septal defect, coarctation of the aorta


  • Abdominal: Umbilical hernia, omphalocele, single umbilical artery


  • Renal: Polycystic kidneys


  • Skin/hair: Occipital scalp defects (cutis aplasia), hemangiomas


  • Remarks: Survival rate beyond the first year is <20%


Trisomy 18



  • Incidence: 1 in 3000


  • Growth and development: Small-for-gestational-age, intrauterine growth retardation, failure to thrive, severe MR


  • CNS: Hypertonia



  • Craniofacial: Prominent occiput; low-set, malformed ears; micrognathia; cleft lip and palate (Fig. 41.2)


  • Extremities: Overlapping fingers, rocker-bottom feet, clubfoot (Fig. 41.3)


  • Cardiac: Ventricular septal defect, patent ductus arteriosus, atrial septal defect


  • Abdominal: Inguinal, umbilical hernias


  • Renal: Various anomalies


  • Skin/hair: Single flexion crease on digits


  • Remarks: Survival rate beyond the first year is <20%






Figure 41.1 Newborn with trisomy 13. Note the postaxial polydactyly on left foot.

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Jul 5, 2016 | Posted by in CRITICAL CARE | Comments Off on Chromosomal Abnormalities

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