Klinefelter Syndrome (Case 5)

A somewhat tall-for-his-age 13-year-old adolescent male arrives for rou-tine care. His mother reports that he seems to be much more immature and insecure than her older son was at the same age. His school per-formance is below average, and this year he has begun to receive special education for language-based classes. On physical examination you note that his extremities are longer than expected and that he is embarrassed by his gynecomastia.  He is Tanner stage 1 with small gonads.  

What is the most likely diagnosis?

What is the best test to diagnose this condition?

Summary: An immature and insecure 13-year-old adolescent male with hypog-onadism, long limbs, gynecomastia, and developmental delay. 

Most likely diagnosis: Klinefelter syndrome, a trisomy syndrome often due to paternal rather than maternal nondisjunction, affecting 1 in 600 to 800 male infants.

Best diagnostic test: Chromosomal analysis.



1. Understand the signs and symptoms of Klinefelter syndrome.

2. Appreciate the variety of causes of childhood mental retardation (MR).

3. Learn the signs and symptoms of syndromes involving missing or duplicate sex chromosomes.

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This child’s mother has identified this adolescent’s development and behav-ior to be different from her other children. The school recently has identified his need for special education, especially in the language-based classes. A thorough history (including all school performance and behavioral prob-lems) and physical examination can provide diagnostic clues. The etiology of his condition impacts his psychosocial outcome, his future medical therapy, and his parent’s family planning decisions. 


Klinefelter Syndrome
KLINEFELTER SYNDROME: A specific syndrome associated with behavioral problems (immaturity, insecurity), developmental delay (speech, language, lower IQ), and physical findings (gynecomastia, hypogonadism, long limbs) caused by an extra X chromosome in boys and men. 
MENTAL RETARDATION (MR): A clinically and socially important impair-ment of measured intelligence and adaptive behavior that is diagnosed before 18 years of age.
Causes of MR include preconceptual and early embryonic disruptions (ter-atogens, chromosomal abnormalities, placental dysfunction, congenital cen-tral nervous system [CNS] malformations); fetal brain insults (infections, toxins, placental problems); perinatal difficulties (prematurity, metabolic dis-orders, infections); postnatal brain injuries (infections, trauma, metabolic dis-orders, toxins, poor nutrition); and miscellaneous postnatal family difficulties (poverty, poor caregiver–child interaction, parental mental illness). A cate-gory of “unknown etiology” includes children with MR who do not fit into the above categories.
The history of a child with possible MR includes an evaluation of the child’s psychosocial skills and a review of school reports. The ultimate diagnosis may require formal testing to determine if the IQ falls below some set point, such as 80. A determination of whether formal testing should be performed is based on physical examination findings, developmental and school histories, and concerns of the family and teachers. Males with Klinefelter syndrome often have developmental delay, especially in verbal cognitive areas where they underachieve in reading, spelling, and mathematics; their full IQ may be nor-mal, but their verbal IQ usually is  somewhat decreased. In variants with mul-tiple X chromosomes, the incidence and severity of MR increases. Boys with Klinefelter syndrome often go unidentified until puberty because of the sub-tleness of the clinical findings. The diagnosis should be considered for all boys (regardless of age) who have been identified as having mental retarda-tion, or psychosocial, school, or adjustment problems.
Physical findings to be considered in patients with nonspecific MR include the size of the occiput, unusual hair color or distribution, distinctive eyes, malformed ears or nose, and abnormalities in jaw size, mouth shape, or palate height. The hands and feet may have short metacarpals or metatarsals, over-lapping or supernumerary digits, and abnormal creases or nails. The skin may have café au lait spots or depigmented nevi, and the genitalia may be abnor-mally sized or ambiguous. Patients with MR caused by Klinefelter syndrome typically are  tall, slim, and thin with long extremities.  Their testes and some-times the phallus are small for age, but these latter findings may not become apparent until puberty. As adults, males with Klinefelter syndrome develop gynecomastia, sparse facial hair, and azoospermia. The incidence of breast cancer (as well as some hematologic cancers as well) is elevated in Klinefelter syndrome.
Laboratory testing of a child with MR is based on the clinical findings and developmental milestones. A chromosomal analysis is often included in the evaluation of a child with mental retardation; for Klinefelter syndrome such
an analysis will demonstrate the extra X chromosome material.  Other MR testing may include urine and serum amino and organic acids, serum levels of various compounds including ammonia, lead, zinc, and copper, and serum titers for congenital infections. Radiologic evaluation may include cranial computed tomography (CT), magnetic resonance imaging (MRI), or elec-troencephalogram (EEG).
Management of children with MR includes specialized educational serv-ices, early childhood interventions, social services, vocational training, and psychiatric interventions. Further interventions for children with specific underlying etiologies may include diet modification, genetic counseling, or reviewing the natural disease course with the family.

Comprehension Questions

Match the following genetic disorders (A-E) to the clinical description [questions 5.1-5.3]:
A. Fragile X syndrome
B. Klinefelter syndrome (XXY)
C. Turner syndrome (XO)
D. XXX syndrome
E. XYY male

5.1    An institutionalized male juvenile delinquent upon close examination has severe nodulocystic acne, mild pectus excavatum, large teeth, prominent glabella, and relatively long face and fingers. His family says he has poor fine motor skills (such as penmanship), an explosive temper, and a low–normal IQ.

5.2    A tall, thin 14-year-old adolescent male has no signs of puberty. He was delayed in his speech development and always has done less well in school than his siblings. He is shy, and teachers report his activity is immature. Physical examination reveals breast development, and long limbs with a decreased upper segment–lower segment ratio. He has small testes and phallus.

5.3    A 15-year-old adolescent female with primary amenorrhea is noted to be well below the fifth percentile for height. She has hypertension, a low posterior hairline, prominent and low-set ears, and excessive nuchal skin.

5.4    A 7-year-old boy with MR was born at home at 26 weeks’ gestation to a 28-year-old mother who had received no prenatal care. An evalua-tion is likely to suggest his MR is related to which of the following?

A. Brain tumor
B. Chromosomal aberration
C. Complications of prematurity
D. Congenital infection with cytomegalovirus
E. Elevated serum lead levels


5.1    E. XYY-affected males often have explosive tempers. Other findings include long and asymmetrical ears, increased length versus breadth for the hands, feet, and cranium, and mild pectus excavatum. By age 5 to 6 years, they tend to be taller than their peers and begin dis-playing aggressive or defiant behavior.

5.2    B. With Klinefelter syndrome, testosterone replacement allows for more normal adolescent male development, although azoospermia is the rule; the breast cancer incidence approaches that of women.

5.3    C. Turner syndrome also includes widely spaced nipples and broad chest; cubitus valgus (increased carrying angle of arms); edema of the hands and feet in the newborn period; congenital heart disease (coarctation of the aorta or bicuspid aortic valve); horseshoe kidney; short fourth metacarpal and metatarsal; hypothyroidism; and decreased hearing. Mental development usually is normal.

5.4    D. Prematurity, especially when earlier than 28 weeks’ gestation, is associated with complications (such as intraventricular hemorrhage) that can result in developmental delay and low IQ.

Clinical Pearls

Males with Klinefelter syndrome (XXY) have mild mental delay, eunuchoid habitus, gynecomastia, long arms and legs, and hypogonadism.
XYY males have explosive (often antisocial) behavior, weakness with poor fine motor control, accelerated growth in mid-childhood, large teeth, prominent glabella and asymmetrical ears, and severe acne at puberty.
Girls with Turner syndrome (45, XO) have short stature, amenorrhea, exces-sive nuchal skin, low posterior hairline, broad chests with widely spaced nipples, cubitus valgus, and coarctation of the aorta. Hypertension is com-mon, possibly due to renal abnormalities (horseshoe kidney).
Fragile X syndrome, the most common form of inherited mental retarda-tion, is seen primarily in boys and can be diagnosed in patients with men-tal retardation (particularly boys) who have macrocephaly, long face, high arched palate, large ears, and macroorchidism after puberty.

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Klinefelter Syndrome (Case 5) Klinefelter Syndrome (Case 5) Reviewed by WebofPediatric on December 15, 2021 Rating: 5

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