Strategies to improve early diagnosis of Klinefelter syndrome

Figures & data

Figure 1. Schematic representation of the progression of phenotype expression in 47,XXY Klinefelter syndrome from birth to adulthood. On the left, the scale indicates the number of clinical signs from none to many. On the right, the scale indicates the specificity of clinical signs, from absent and nonspecific, to quite specific when combined. The scale on the bottom indicates the frequency of clinical signs, from none at right to frequent at left. Prenatal, birth, children and pre-puberty, adolescence and puberty, and adulthood ages are indicated, together with a red arrow showing the progression of clinical phenotype from clinically silent to clinical evident and full expression of the syndrome. The black arrow indicates possibilities for diagnosis at the different ages, from the fortuitous diagnosis during prenatal genetic analysis, to the late diagnosis made in adulthood

Table 1. General strategies for early diagnosis of 47,XXY Klinefelter syndrome

Period	Recommendations for karyotype analysis	Other suggestive clinical signs (above all when combined)	General strategies for early diagnosis	Involved personnel
Prenatal	None	None	Implementation of NIPT	Gynecologist Geneticist
Birth	Bilateral cryptorchidism without spontaneous descent at the first year Micro-penis	None	Refer to specialist newborn with alteration of testes position and genital appearance	Pediatrician/pediatric endocrinologist Surgeon/pediatric urologist Geneticist
Children and pre-puberty	None	Long legs and tall stature Overweight/obesity Speech and learning difficulties Behavioral, social and psychological difficulties (attention disorder, difficulty in articulating and managing emotions, judgment and decision-making difficulties) Reduced muscle tone and fine motor skills, tremors	Regularly visit boys with particular attention to testes and growth curves Refer to specialist boys with neuropsychological disturbances Refer to specialist taller boys with increased fat/lean mass proportions	Family care pediatrician Pediatric neuropsychiatrist Speech therapist Geneticist Sport doctor Parents
Adolescence and puberty	Delayed puberty or arrest of puberty and/or signs and symptoms of hypogonadism associated with low-normal testosterone and high LH serum concentrations	Reduced testicular growth, firm testes Long legs and tall stature Overweight/obesity Gynecomastia Behavioral, social and psychological difficulties (attention disorder, difficulty in articulating and managing emotions, judgment and decision-making difficulties) Reduced muscle tone and fine motor skills, tremors	Regularly visit boys with particular attention to testes and growth curves Refer to specialist boys with neuropsychological disturbances Refer to specialist taller boys with increased fat/lean mass proportions Refer to specialist boys with delayed onset of puberty, delay in puberty progression, reduced or arrest of testicular growth Refer to specialists boys with signs of hypogonadism, including gynecomastia	Family care pediatrician Pediatrician/pediatric endocrinologist Pediatric neuropsychiatrist Speech therapist Geneticist Sport doctor Patients and parents
Early adulthood	Non-obstructive azoospermia and severe oligozoospermia (total sperm count < 10 mill./ejaculate) Primary hypogonadism (low levels of testosterone and elevated levels of LH and FSH) combined with small testis volumes (<5 ml per testis)	Signs of hypogonadism Gynecomastia Osteopenia/osteoporosis Overweight/obesity Metabolic and CVD risk Behavioral, social and psychological difficulties (attention disorder, difficulty in articulating and managing emotions, judgment and decision-making difficulties) Neoplasia (breast, extragonadal germ cell tumors, Leydig cell tumors) Autoimmune disorders Dental problems (taurodontism, caries) Cardiorhythmic alteration (reduced QTc time)	Routine andrological screening of young men (18–19 years), including physical exam of testes Refer to specialist subjects with any clinical sign and/or those with semen/hormonal alterations	Endocrinologist/andrologist Family doctor School doctor Sport doctor Patients