Case Based Pediatrics For Medical Students and Residents
Department of Pediatrics, University of Hawaii John A. Burns School of Medicine
Chapter IV.3. Common Chromosomal Disorders
Julie Won Ireland, MD
March 2003

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A two day old male infant is referred from a community hospital for bilious vomiting and a heart murmur. The baby was born at 37 weeks gestation to a G4P3 39 year old woman who had no prenatal care.

Exam: VS T37.1 (ax), P150, R45, BP 75/50, oxygen saturation 99% in room air. Height, weight and head circumference are at the 50th percentile. He appears jaundiced, and has a flat facial profile; short, upslanting palpebral fissures; a flat nasal bridge with epicanthal folds; a small mouth with protruding tongue; and single palmar creases. His lungs are clear to auscultation. His heart is tachycardic with a loud holosystolic murmur. His abdomen is non-distended. Generalized hypotonia is present.

An abdominal radiograph shows a "double-bubble sign". Duodenal atresia is suspected. A nasogastric tube is placed and IV fluids are administered. He later undergoes a duodenoduodenostomy. An echocardiogram demonstrates a ventricular septal defect, which is medically managed. A chromosomal abnormality is suspected and a karyotype is done. Trisomy 21 is diagnosed.

This chapter deals with some of the more common chromosomal abnormalities encountered in clinical practice. While the infant described above has trisomy 21, or Down syndrome, other disorders of chromosomes include trisomy 18 (Edwards syndrome), trisomy 13 (Patau syndrome), XXY (Klinefelter syndrome), 45X (Turner syndrome), Noonan syndrome, XYY syndrome and Fragile X syndrome.

Trisomy 21 (Down syndrome)

Dr. John Langdon H. Down first described a cluster of mentally retarded patients in an England asylum in an essay, "Observations on an Ethnic Classification of Idiots," in 1866. It was not until the 1950s that an extra 21st chromosome was found to be responsible for what was to become known as Down syndrome. The incidence is 1 in 600-800 births. The sporadic form has a higher frequency with advanced maternal age. In mothers less than 25 years of age, the risk is 1 in 2000 births and climbs to 1 in 20 births for mothers over age 40. All patients with Down syndrome have three copies of chromosome 21. In 95% of patients, there are 47 chromosomes with trisomy of chromosome 21. In about 5%, there are 46 chromosomes, with an abnormally translocated 21st chromosome. Robertsonian translocations involve the transfer of chromosomal material from 21 to usually chromosome number 13, 14, or 15. The Down phenotype occurs when even a small, but critical piece of the long arm of chromosome 21 is trisomic. Carriers of a Robertsonian translocation are usually phenotypically normal, but are at increased risk for miscarriages and chromosomally abnormal children. Another cause is a 21q/21q translocation. This is rare, but significant because a carrier parent only has one 21st chromosome (the translocated chromosome with double the genetic material). When this chromosome is passed on, all of the offspring will have trisomy 21. An example of this is a mother who had this translocation and had four children with Down syndrome. Milder phenotypes may be seen when patients are mosaic for trisomy 21. This happens when nondisjunction occurs early in embryonic development as a mitotic error.

Affected patients have a characteristic facies including epicanthal folds, a flat nasal bridge, small mouth, protruding tongue with microcephaly and a flat occiput. Other features may include a high arched palate, a single palmar crease (Simian crease). The pupils may have light smudgy opaque Brushfield spots. At birth, patients are often hypotonic and have a higher incidence of other types of malformations. Cardiac anomalies are present in 33-50% and include endocardial cushion defects and ventricular septal defects. Gastrointestinal anomalies can include duodenal atresia and Hirschsprung's disease. Later in life, hypothyroidism and leukemia can occur, and there is an increased susceptibility to infections. Atlanto-occipital instability may be present in a few and is a concern when intubating these patients. A pneumonic for remembering the major complications found in Down syndrome patients is using the word VALIDATE as follows: VSD, Atlanto-occipital instability, Leukemia, Immunodeficiency, Duodenal atresia, Alzheimer's disease, Thyroid dysfunction, and Endocardial cushion defects.

There is no treatment for the trisomy itself, so therapy is directed towards other complications present, such as cardiac and gastrointestinal anomalies, thyroid dysfunction, and infections. Their IQ is usually about 50-75, at best they function at a sixth grade level, and few are severely retarded. These children are placed in infant stimulation programs, enrolled in special education classes, and later given occupational training to help them become more independent and a functioning part of society. It is very important to counsel parents who have one child with Down syndrome about the risk of having a second affected child. The risk of recurrence is 1% in otherwise low risk moms and if the parent is not a translocation carrier. Obstetric screening tests can identify some pregnancies at risk, so that fetal chromosome testing can be offered. Involvement in compassionate support groups should be encouraged to the parents.

Trisomy 18 (Edwards Syndrome or Trisomy E)

Infants with trisomy 18 are severely affected and usually die in the first week of life. Less than 10% of patients survive beyond twelve months and are profoundly mentally retarded. The cause of this syndrome is usually full trisomy for chromosome 18. The incidence is 1 in 4000-8000 births, with a 3:1 predominance of affected females to males. The risk increases with maternal age. The recurrence risk is very low based on the observation that most affected children die in utero. Patients with trisomy 18 mosaicism have a less severe clinical expression and longer survival depending on the degree of mosaicism. Partial trisomy 18 varies in its clinical picture from mild mental deficiency and improved survival to being indistinguishable from full trisomy 18. This depends on the extent and which part of the chromosome is affected.

Numerous malformations have been reported in trisomy 18. These infants have a characteristic head shape and facial features, such as a prominent occiput, low-set ears, and micrognathia. The hands are often clenched with the index finger overlapping the third finger. Dysmorphic joints produce this typical finger position. Deformities of the lower extremities include hypoplastic nails of the feet, malaligned toes and "rocker-bottom feet", where the calcaneus is prominent. Heart defects, such as ventricular septal defect, patent ductus arteriosus or atrial septal defect, are found in at least 50% of these patients. They also have a short sternum with small nipples.

Supportive care is the treatment for this syndrome. Genetic counseling is indicated. Chromosomal studies should be done to determine translocation cases. The recurrence risk for full 18 trisomy cases is less than 1% because most die in embryonic or fetal life. Some children with trisomy 18 have reached adulthood. Heart failure or pneumonia are some of the complications that often cause death.

Trisomy 13 (Patau Syndrome or Trisomy D)

The constellation of findings in this condition have been described as far back as the 1600's. Klaus Patau and his colleagues were the first to attribute the syndrome of trisomy for chromosome 13 by cytogenetic analysis in 1960. The cause of this syndrome is usually trisomy for chromosome 13. Its overall incidence is 1 in 12,000 births, but the risk increases with maternal age. The recurrence rate is very low, except for the parent who has a balanced translocation. Patients with trisomy 13 mosaicism have been described and usually have a milder phenotype depending on the degree of mosaicism.

Patients are severely affected and often die in infancy. The median survival has been reported as two and a half days. Surviving infants have severe mental retardation and may have midline CNS defects, incomplete development of the forebrain, apneic episodes and EEG abnormalities. Bilateral cleft lip and palate are common. Microcephaly, microphthalmia, and deafness may also be found. Lethal cardiac anomalies are found in 80% of patients, with VSD being the most common. PDA, ASD, dextroposition, and valvular abnormalities can also occur. Disorders of the extremities may include a single palmar crease (Simian crease). Polydactyly, particularly of all extremities, strongly suggests trisomy 13. Overlap of the middle and ring fingers are seen.

Treatment is supportive. Prevention by genetic counseling is indicated. Critical decisions in regards to extensive therapy and resuscitation measures in a severely affected infant must be decided at birth. Those affected usually die in infancy; very few live to become adults. Children who survive are severely retarded and are rarely able to suck. They fail to thrive and have seizures.

Klinefelter Syndrome (47 XXY)

Harry Fitch Klinefelter worked with Dr. Fuller Albright in clinical endocrinology when he saw his first patient, who was a young man with small testes and gynecomastia. During his fellowship, he encountered 8 other patients with similar findings and described Klinefelter syndrome in 1942. Klinefelter syndrome affects 1 in 1000 newborn boys and is caused by an extra X chromosome from meitotic nondisjunction. The incidence is 1% among the mentally retarded and 3% among males seen at infertility clinics. In 54% of the patients, the extra X chromosome comes from the mother and in the other 46%, the extra X chromosome comes from the father. Maternal age, but not paternal age is often advanced. The most common chromosomal pattern is 47,XXY. Others have mosaic patterns: 46,XY/47,XXY; 46,XY/48,XXYY; or 46,XX/47,XXY. These patients tend to have milder phenotypes. Children with mosaicism have a better prognosis for fertility and virilization. In chromosome variants with multiple X chromosomes (XXXY and XXXXY), the clinical manifestations are much more severe. In general, the mental and physical abnormalities associated with Klinefelter syndrome worsen as the number of X chromosomes increase.

The characteristic findings of Kleinfelter syndrome usually do not become apparent until after puberty. They have a eunuchoid habitus; usually tall, slim and underweight, with long legs. One third have gynecomastia and they have less facial hair. Their gonads are small and soft, and the phallus tends to be smaller than average. The seminiferous tubules are atrophied because of excess gonadotropin. There is hyperplasia of the Leydig cells, producing azoospermia and infertility. Cryptorchidism may occur in some patients. Hypogonadism becomes recognized after puberty when the testicles fail to grow and develop normally. This is usually the time when the diagnosis is suspected. Pubertal development may be delayed. These patients tend to have learning and psychosocial problems. They have normal to borderline IQ, with a mean IQ of 90. In boys with mental retardation, learning disabilities or adjustment problems at school, Klinefelter syndrome should be a consideration. Later in life, these individuals are at higher risk to develop diabetes mellitus. There is also an increased incidence of cancer of the breast, varicose veins, and pulmonary disease.

Chromosomal analysis should be done to confirm the diagnosis of Klinefelter syndrome. In males younger than 10 years of age, they have normal levels of FSH and LH and respond appropriately to GnRH and hCG. In late adolescence, testosterone levels decrease, and gonadotropins increase. In adults, urinary excretion of gonadotropins is high, with levels comparable to those seen in post menopausal women. Gynecomastia is a result of an elevated estradiol to testosterone ratio. In the management of Klinefelter syndrome, testosterone replacement therapy should start at 11 to 12 years of age, if testosterone levels are deficient and gonadotropin levels become elevated. With early recognition and diagnosis, treatment can be initiated to allow a more normal maturation for the affected male, but infertility cannot be reversed.

Turner Syndrome (45X)

In 1938, a series of young women with failure of sexual maturation, short stature, and neck webbing were reported by Henry Turner. He believed this was due to a defect in the anterior pituitary gland. It was not until 1959, when the absence of the X chromosome was first described by Charles Ford. The incidence is 1 in 2500 live female births, 95% of 45X fetuses die in utero. About 50% of patients apparently have the full monosomy 45,X, the others all have detectable mosaicism. About 2/3 retain the maternal X and 1/3 have the paternal X. Advanced maternal age is not a factor in this syndrome. Only one X is normal and functioning; the other X is not present or is missing a part of its chromosome by structural abnormality, deletion or translocation. Mosaicism 45,X/46,XX or 45,X/46,XX/47,XXX may also be present. 10% of Turner mosaics have a Y chromosome, 45,X/46,XY is seen. The presence of the Y chromosome increases the risk of gonadoblastoma. Milder phenotypes are usually seen in those without the full monosomic karyotype.

The characteristic features include a triangular face, small mandible, prominent ears, webbed neck, low posterior hair line, shield chest with wide set nipples, cubitus valgus (increased carrying angle of the elbow), and short stature. Sometimes short stature may be the only clinical finding present in a young girl. Their average adult height is about 143 cm (4 ft., 8 in.). In most of these girls, secondary sexual characteristics are absent. They have amenorrhea and are infertile due to ovarian dysgenesis. Intelligence is usually normal, but they may have a learning disability. These patients may have cardiac defects; 30-50% have bicuspid aortic valve, and 10-20% have coarctation of the aorta. Other cardiac complications include aortic stenosis, aortic dissection and idiopathic hypertension. Urinary tract malformations are found with a higher frequency in these patients. Most common presentations include a horseshoe kidney, kidney located in the pelvis, double collecting system, or absence of a kidney.

Growth hormone alone or in combination with anabolic steroids has been successful in managing these patients. This is still very controversial. Opponents claim that growth hormone accelerates growth, but does not increase adult height. Therapy should begin when the height of the patient drops below the 5th percentile on the growth curve. For those who are deficient in estrogen and progestin, long term replacement therapy is required for development of secondary sexual characteristics and initiation of the menstrual cycle. As for all post-menopausal women, these women especially need hormonal therapy, in combination with calcium supplementation and exercise, to help prevent osteoporosis. Rarely, spontaneous puberty and menses can occur and pregnancy is possible. There is an increased risk of giving birth to a child with chromosomal or congenital anomalies. Genetic counseling and a medical work up are required. Support groups can be of much benefit. These women can become independent and lead productive lives. Most die in utero, but for those who survive, the average age of death is 69. Increased mortality can primarily be attributed to cardiovascular disease.

Noonan Syndrome

This syndrome resembles Turner syndrome and occurs in males and females. The occurrence is often sporadic, but an autosomal dominant inheritance has been reported. A gene for this disorder has been mapped to chromosome 12q; although not in every family, suggesting that other loci may be involved.

The clinical manifestations are short stature, short or webbed neck, shield chest and pectus excavatum or carinatum. They have a characteristic facies; epicanthal folds, ptosis, hypertelorism, downslanting palpebral fissures, and low or abnormal ears. Interestingly, their facies can normalize with age. The most common cardiac abnormality is pulmonary valve stenosis, but they can also have atrial septal defects, left ventricular hypertrophy, or patent ductus arteriosus. Males may have cryptorchidism, small penis, and hypogonadism. However, in males without cryptorchidism, fertility is normal. Fertility is also normal in females. About 25% of affected patients have some degree of mental deficiency.

There is no specific treatment. Genetic counseling should be offered to parents regarding the recurrence risk.

XYY Syndrome

In random newborn males, the incidence of the 47,XYY karyotype is 1 in 1000. In some prison populations, the incidence is 1-2 %. In institutionalized men or juvenile delinquents taller than 6 feet, 10% have XYY syndrome. Most 47, XYY males are phenotypically normal, however variable, non-specific characteristics may be seen. Stature tends to be tall, and patients may have large teeth and severe nodulocystic acne. They are not well coordinated or strong relative to their large size. Some males have anti-social behavior. They may be impulsive, hyperactive, have poor social skills, and low self esteem. They were once stereotyped as being violent and aggressive. However, longitudinal studies suggest that aggressive behavior is usually not a problem, and they learn to control their anger by the time they become young adults. These males have a normal to low IQ, and 50 % have a learning disability. The majority of patients are fertile. Their sperm may have 23,X, 23,Y, 24,XY or 24,YY, so the syndrome can recur. However, they usually have children with normal chromosomes.

XYY syndrome is diagnosed by karyotype. There are no consistent clinical findings. There is no treatment for this syndrome. In general, affected children are normal. However, behavioral modification is necessary in dealing with the hyperactivity and aggressiveness that may be seen during childhood. The majority are well-adapted citizens.

Fragile X Syndrome

The syndrome was first described by Martin and Bell in 1943, though the fragile site on the X chromosome was reported in 1969 by Lubs. It occurs in 1 in 1000 males. This disorder is caused by an expanded trinucleotide repeat (CGG) in the FMR-1 gene on the X chromosome with X-linked inheritance. When cells, from patients with this disorder, are cultured in a certain medium deficient in folate or thymidine, the fragile site can be visualized. The normal allele repeat range is 6-40. The intermediate allele repeat range is 41-60 repeats (most are stably inherited), and the premutation allele repeat range is 61-200 repeats. Carriers of the premutation are usually phenotypically normal and not at increased risk for retardation. Females who carry this premutation may pass down an expanded version resulting in full expression of the phenotype in males and variable phenotypic expression in females. The severity correlates with the increase in size of the repeat sequence. The full mutation (disease causing) repeat range is greater than 200 repeats. Other disorders that are caused by expanded trinucleotide repeats include Huntington disease, myotonic dystrophy and Friedreich ataxia.

Physical abnormalities in males with fragile X syndrome include large ears, a large jaw and large, soft testicles. Connective tissue dysfunction, mitral valve prolapse and dental crowding can also be found. Cluttered speech, autism, hyperactivity and mild to severe mental retardation are common. Females with fragile X syndrome (usually heterozygous) tend to have a less severe clinical expression and only 1/3 have mental retardation.

Treatment and management includes supportive care. Genetic counseling is important in prenatal and postnatal diagnosis of fragile X syndrome. Clinical expression is different depending on which parent transmits the gene. DNA analysis helps to identify full mutations as well as premutation carriers. The life expectancy is normal.


1. What chromosomal disorder can present as bilateral cleft palate, cleft lip and a ventricular septal defect?

2. This syndrome presents with a prominent occiput, clenched fists and "rocker bottom feet". What are 2 complications that can cause death in these children?

3. Name 4 disorders associated with a trinucleotide repeat?

4. Name 8 complications of Down syndrome.

5. What is the etiology of infertility in women with Turner syndrome?

6. What causes gynecomastia in males with Klinefelter syndrome?

7. Which terminology below (one or more) for trisomy 21 is (are) incorrect?
. . . . a. Down syndrome
. . . . b. Downs syndrome
. . . . c. Down's syndrome
. . . . d. Mongolism
. . . . e. Trisomy 21


1. What chromosomal disorder(s) can present with bilateral cleft palate, cleft lip and a ventricular septal defect?

2. Hall JG. Chapter 67 - Chromosomal Clinical Abnormalities. In: Behrman RE, Kliegman RM, Arvin AM (eds.) Nelson Textbook of Pediatrics, 15th edition. 1996, Philadelphia: W.B. Saunders Company, pp. 312-320.

3. Hall JG, Gilchrist DM. Turner Syndrome and its Variants. Current Issues in Pediatric and Adolescent Endocrinology 1990;37(6):1421-1435.

4. Hsia YE. Chromosome Disorders. At Kapiolani Medical Center Pediatric Noon Conference, Dec. 2000.

5. Jones KL (ed). Smith's Recognizable Patterns of Human Malformation, fifth edition, 1997, Philadelphia: W.B. Saunders Company, pp. 8-21, 70-87.

6. Saenger P. Turner's syndrome. New Engl J Med 1996;335(23):1749-1754.

7. Sujansky E, et al. Chapter 32 - Genetics and Dysmorphology. In: Hay WW, Groothuis JR, Hayward AR, Levin MJ (eds). Current Pediatric Diagnosis and Treatment, 13th edition. 1997, Stamford: Appleton and Lange, pp. 891-895.

Answers to questions

1. Trisomy 13, Trisomy 18

2. Trisomy 18. Heart failure and pneumonia

3. Fragile X syndrome; Huntington disease; Friedreich ataxia; and myotonic dystrophy

4. VALIDATE: VSD, Atlanto-occipital instability, Leukemia, Immunodeficiency, Duodenal atresia, Alzheimer's disease, Thyroid dysfunction, Endocardial cushion defect.

5. Ovarian dysgenesis

6. Elevated estradiol to testosterone ratio

7. b,c,d

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