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Giorgiana Pavaloiu



Klinefelter Syndrome Causes, Symptoms And Karyotype

Klinefelter syndrome is a heterogeneous group of abnormalities of the sex chromosomes, where there is at least one X chromosome in addition to the normal karyotype, 46XY, in males. Symptoms and etiology of Klinefelter syndrome are heterogeneous.

In 1942, Dr. Harry Klinefelter reported a group of nine men with increased urinary gonadotropins, microorchidism, azoospermia, and gynecomastia. In 1959, Jacobs admits Klinefelter syndrome etiology by the presence of 47XXY karyotype.

Klinefelter Syndrome

Klinefelter Syndrome

The incidence of Klinefelter syndrome is 1 to 500 in male newborns  for 47XXY and 1 to 300 in spontaneous abortions, 1 to 50.000 for karyotype 48XXXY and 1 to 85.000 for karyotype 49XXXXY.

Klinefelter syndrome is the most common cause for hypogonadism in males.


Molecular cytogenetic studies, by recent investigations with DNA markers showed that, in 50% of cases of Klinefelter syndrome, the error occurs in primary paternal meiosis, in the third of the cases the error occurs in primary maternal meiosis, and  in the rest of the cases of Klinefelter syndrome, error occurs in the secondary meiosis or are errors which are leading to postzygotes mosaicism.

Three quarters of cases of Klinefelter syndrome with maternal origin, come from errors in primary meiosis and thereby is incriminated the advanced age of the mother. It is assumed that maternal meiotic non-disjunction can be correlated with an increased frequency of recombination near the centromeres, suggesting an association between recombination and chromosome non-disjunction in these situations.

Klinefelter Syndrome

Klinefelter Syndrome

The clinical presentation of Klinefelter syndrome:

Before puberty, physical development is age-appropriate, the phenotype is normal, rarely can be suspected the existence of Klinefelter syndrome.

In childhood may occur: hypospadias, micropensi, cripotorhidis, signs suggestive for Klinefelter syndrome, which are leading to cytogenetic investigation to the child.

Patients are generally high, significant increase in height is between 5 years and 8 years, average height is 179.2 cm ±6.2 cm. Patients are asthenic, presenting upper limbs and legs longer than usual (growth occurs through large leg length). Muscle tissue distribution is ginoid and in obese patients can be seen a eunucoid type constitution. It can be seen a smaller bitrohanterian diameter than biacromial diameter.

Hypogonadism becomes apparent at puberty and is the cardinal sign of testicular hyplopazia, tests remain underdeveloped and secondary sexual characters are not installed. Facial hair growth, body hair growth and genital hair growth is reduced. Normal testosterone levels tend to decline with the end of adolescence and in young adult life.

As a general rule, Klinefelter syndrome is associated with sterility, due to oligospermia or azoospermia.

Gynecomastia is almost a constant clinical sign (56% of cases of Klinefelter syndrome, with variations up to 88%) achieved by hypertrophy of the mammary glands or extraglandular tissue overgrowth, considering that these patients have a risk of 20 times more likely to develop breast cancer compared with normal subjects.

Besides hypogonadism and absence of secondary sexual characters, which marks the phenotype of Klinefelter syndrome patients, the intellect is nearly normal developed (if exist mental retardation, this have a moderate intensity), only rarely are noted some difficulties in schooling training, intelligence coefficient can have lower values. Sometimes patients have dyslexia and a decrease psychosocial adaptability. Many of the behavioral and clinical characteristics of Klinefelter syndrome are modified by the treatment with testosterone.

Klinefelter Syndrome

Klinefelter Syndrome

Described karyotypes in Klinefelter syndrome:

Of all patients with Klinefelter syndrome, 80% – 85% have 47XXY karyotype. In Klinefelter syndrome, there may be other options of karyotype than the one presented, such as 48XXXY, 48XXYY and 49XXXXY. Addition of X chromosome causes more severe affections with major phenotypic abnormalities, abnormal sexual development and always serious intellectual disorders. Each additional X chromosome, reduces the coefficient of intelligence with 15-16 points, language being the most affected.

About 15% of cases of Klinefelter syndrome, presents mosaic karyotype and have variable phenotype, sometimes with near-normal development (and may even be fertile). Most often mosaicism is 46XY / 47XXY.

Tests for diagnosis of Klinefelter syndrome:

  • Standard karyotype;
  • Elevated levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH) and estradiol;
  • Low levels of testosterone (12 – 14 years or undiagnosed adults);
  • Very high urinary gonadotropins show that Leydig cell function is abnormal.


  • Risk of developing breast cancer is 20 times higher than in normal individuals, the frequency of breast cancer in patients with Klinefelter syndrome is 3.7%;
  • Endocrine complications: diabetes, hypothyroidism, hypoparathyroidism;
  • Autoimmune diseases: systemic lupus erythematosus, Sjogren syndrome, rheumatoid arthritis;
  • Varicose veins and varicose ulcers.

The medical management of Klinefelter syndrome:

Treatment with testosterone has to start at puberty around the age of 12 years, increasing levels of testosterone by therapy is maintaining normal levels of estradiol, FSH and LH. The treatment  can harmonize the physical development, the development of secondary sexual characters and can prevent gynecomastia. It also improves behavioral development, prevents depression, osteoporosis, autoimmune diseases and breast cancer.

Prenatal diagnosis:

Klinefelter syndrome can be detected by amniocentesis and fetal karyotype study, parents are advised on the clinical manifestations of this syndrome.

Klinefelter Syndrome

Klinefelter Syndrome

Cytogenetic variants of Klinefelter syndrome:


Patients may develop: hypertelorism, flattened nose, radioulnar synostosis, cliniodactyly of five finger, hypogonadism, IQ = 40 – 60. Generally these patients are taller, immature, passive, cooperative and are not aggressive.


These patients are more severely affected showing: microcephaly, short stature, hypertelorism hypogonadism, micropenis, cleft palate, heart defects, radio ulnar synostosis, hypotonia with joint laxity. Have an IQ = 20-60 and friendly behavior.


Clinically, these patients are characterized by taller stature, hypogonadism, micropenis. Have an IQ = 60-80, are more aggressive and have a impulsive behavior.


Diabetic Neuropathy

Diabetic neuropathy is defined as a nerve damage that is often seen in diabetes. Over time, hyperglycemia can affect nerves throughout the body. There are several types of diabetic neuropathy.

Peripheral neuropathy it is a result of  the damage of the peripheral nervous system. This leads to decreased pain sensitivity, tactile, thermal and vibration sensitivity in certain parts of the body and can sometimes interfere with the ability to exercise and muscle strength. The most commonly are affected the feet (foot and calf) and this can lead  to serious complications  such as ulcers, infections or bone and joint deformities.  Peripheral neuropathy represents  the most common form of diabetic neuropathy.

Diabetic Neuropathy

Diabetic Neuropathy

Peripheral neuropathy (autonomic) results from damage to the autonomic nervous system. These nerves are involved in the control of the  involuntary body functions like  heartbeat, blood pressure, digestion, perspiration, sexual and kidney function. This is a common form of diabetic neuropathy too.

Focal neuropathy affects a single nerve, most commonly in the wrist, thigh or foot. It may also affect the nerves in the back and chest  and the nerves that control eye muscles. Often occurs in compression or stress conditions of the nerves such as carpal tunnel syndrome (a consequence of compression of the median nerve at the wrist). Carpal tunnel syndrome often occurs in people with diabetes but is not length to neuropathy. Focal neuropathy usually appear suddenly and is the most rare form of diabetic neuropathy.

Focal Neuropathy

Focal Neuropathy


Diabetic neuropathy, especially  peripheral neuropathy, is initially asymptomatic. Patients with diabetes should undergo regular medical checks to timely diagnose and treat this problem before they develop serious complications.

If the nerves are affected, the doctors are making efforts to establish the level of glucose to a target value (hemoglobin A1c <7% for a period of 2 to 3 months). The initial symptoms will increase during the decrease of blood glucose . However, the symptoms will improve when the level of blood sugar will stabilize at a lower value .
In diabetic neuropathy symptoms can vary, depending on which type of neuropathy will appear.

Peripheral neuropathy tends to develop slowly over time, in months or years. In general symptoms are:

  • Numbness, tingling, burning, pain with a sting character in the legs, hands, or in other parts of the body, bone and joint deformities that occur especially in the foot (such as diabetic foot or Charcot arthropathy);
  • Loss of feeling or numbness are more common in the foot and is required every day self-examination for skin lesions (cracks, sores or excessive dryness) or minor injuries (blisters or  friction areas). The evolution of diabetes for 10 years or more, with a poor glycemic control, vascular, kidney or eye complications, all can increase the risk of leg injuries and possible evolution to a leg amputation;
  • Major reduction of the  sensitivity to light touch;
  • Reduction or loss of balance and coordination disorders can represent symptoms of peripheral neuropathy.

Autonomous neuropathy affect digestion, the ability of control the body temperature, kidney function, sexual function and the activity of the heart and blood vessels, including blood pressure. In general symptoms are represented by:

  • Frequent belching, bloating and constipation, burning chest, nausea and vomiting, diarrhea or abdominal pain. These symptoms may indicate gastroparesis, a condition in which the stomach empties more slowly than normal;
  • Profuse sweating on the trunk, face and neck at night or during the ingestion of certain foods;
  • Loss of sensation of fullness bladder or the difficulty emptying the  bladder when is completely full;
  • Sexual dysfunction, for example disorders of erection in men and vaginal dryness in women;
  • Dizziness, weakness, or syncope (loss of consciousness) appeared when the patient suddenly rising from a lying position (orthostatic hypotension);

Symptoms in focal neuropathy can occur suddenly. These may include:

  • Pain, weakness and motor problems in one region of the body such as the wrist, thigh or leg, where the mechanism is represented by the nerve compression (for example carpal tunnel syndrome), pain or suffering of the median nerve will gradually develop over a period of weeks or months;
  • Intraocular and periocular pain, difficulty moving the eyes and double vision because focal neuropathy may sometimes affect the nerves that control muscles responsible for eye movments;
Symptoms in Focal Neuropathy

Symptoms in Focal Neuropathy


The diagnosis of peripheral neuropathy is based on symptoms, medical history and physical examination. Electromyogram and nerve conduction studies can be done to confirm the diagnosis of diabetic neuropathy . These tests measure how fast and how well electrical pulse is driven through nerves and muscles. If  exists nerve problems, then the nerve conduction velocity is slowed.

Various laboratory tests like CBC, blood sugar level, hemoglobin A1C and others are required for screening of diabetes and other causes that produce the same type of symptoms. These reviews will be made according to medical history and symptoms.

Early Diagnosis

There is no recommended protocol for the screening of diabetic neuropathy, but during regular health checks are watched all these aspects. The patients should declare any pain, weakness or motor disorder, changes in digestion, sex or renal function, sweating or dizziness.

Peripheral neuropathy screening helps to prevent the ulcers or amputations of the foot.  American Diabetes Association (ADA) recommends that people with diabetes should be consulted by a doctor who will examine the foot for cracking or flaking of the skin, excessive or reduced sweating, blisters, ulcers or signs of infection, bone deformities or joint changes, gait and balance during each checkup. ADA recommends that this review should be made at least once a year. During these checks can be detected loss of sensation in the foot which can lead to the appearance of more severe complications.


There is no cure for diabetic neuropathy. Once installed, the treatment focuses on secondary prevention which consists in maintaining a blood glucose level to a target value. A tight control of blood glucose is to maintain an average hemoglobin A1c < 7% for a period of 2 to 3 months.

Treatment of diabetic neuropathy depend on the nature and type of neuropathy symptoms. In general, treatment is going to reduce symptoms and prevent complications by maintaining glucose levels as close to the target values. This values can be achieved by treatment with insulin or oral hypoglycemic agents as prescribed by the physician, periodic checks of blood glucose, diabetes diet, regular exercise and regular checkups.

If the diabetic neuropathy alredy exist, the patient should do a careful self-examination because at the level of the legs can exist unnoticed wounds or other severe injuries which can go unnoticed  due to the loss of sensation. Without careful tracking these problems, in time, can lead to severe complications such as infections or amputations. It is also important to maintain a healthy lifestyle such as regular exercise, controlling blood pressure, diet, quitting  smoking and limiting alcohol consumption.