Klinefelter Syndrome Symptoms In Infants

Overview   

Klinefelter syndrome is the most common genetic disorder related to the sex chromosomes, affecting approximately 1 in 600 assigned male at birth (AMAB) babies. Despite not being a rare condition, only 25% of patients are diagnosed due to the varying severity in symptoms. The majority of cases remain undetected because the symptoms are mild and can be easily overlooked by parents and even by doctors. Klinefelter syndrome is caused by the presence of an extra X chromosome, affecting physical, reproductive, language, behaviour, and neuro-development. Most cases are diagnosed at puberty or in adulthood, when physical signs, such as tall stature, testicular dysfunction, delayed puberty or infertility, prompt patients to visit the doctor. A diagnosis is rarely made in infancy and childhood, when speech and developmental delay might not even raise the suspicion of Klinefelter syndrome. Infancy is the earliest period after the baby is born, lasting up until 1 year of age, and diagnosis during this period is a challenge. Klinefelter syndrome has no cure, but many symptoms can be treated. With the appropriate support and intervention, the long-term outcomes are excellent.^1,2,3

This article aims to bring a clear understanding of the symptoms presented by Klinefelter patients in infancy, highlighting the benefits of early detection on the course of the disorder. 

What is Klinefelter syndrome?  

Genetics

Klinefelter syndrome, also called KS, or 47,XXY syndrome, is caused by the presence of an extra X chromosome inside the cells of AMAB people. The DNA and genes of a person are packed into microscopic structures, called chromosomes. The normal “formula” for AMAB people is 46,XY, and for AFAB (assigned female at birth) people, is 46,XX. The X and Y chromosomes are called “the sex chromosomes” and they determine the genetic gender, and are responsible for fertility and sexual development of the person. Klinefelter syndrome is not an inherited disorder. In 90% of cases of Klinefelter syndrome, the patient’s genetic formula is 47,XXY. This happens by a random error during the division of the reproductive cells – the sperm and the egg – of the patient’s parents. In 10% of cases, the error can happen inside the embryo. This is called “mosaicism”, when some cells have 46,XY, and others have 47,XXY; in rare cases, there can be variations of more X and Y chromosomes, called “higher aneuploidy”, for example 48,XXYY, which are more severe and considered separate conditions.^1,2,4,5,6

Symptoms

Klinefelter syndrome (KS) has various severity forms; cases can go undetected, and some cases present mild or severe symptoms. The most common symptoms connected to Klinefelter syndrome are tall stature, long limbs, testicular dysfunction (hypogonadism), smaller testicles, low testosterone levels, puberty delays and insufficient development of secondary sexual characteristics of AMAB people, such as facial and body hair; decreased libido and sperm production, abnormal fat tissue disposition, wide hips, narrow shoulders, breast growth (gynecomastia), low muscle tone, weaker bones, and low energy. Some adults suffering from KS get diagnosed while investigating infertility. Most patients have normal IQ, but many struggle with speech and language problems. During childhood, patients might have difficulties at school, socialising and expressing their feelings, being shy, anxious, and less confident. KS can also present alongside other problems, such as: autism, autoimmune conditions, anxiety, depression, ADHD, breast cancer, germ cell tumours, diabetes, osteoporosis and cardiovascular disorders.^5,7,8

Diagnosis 

KS can be detected before birth, in childhood, adolescence, and in adulthood. Studies show that around 10-20% of cases are detected prenatally, mostly by incidental finding during non-invasive prenatal testing (NIPT), followed by karyotype or chromosomal microarray analysis performed prenatally, via amniocentesis or chorionic villus sampling, or postnatally. Diagnosis rates vary after birth, but the testing method is also usually karyotype or chromosomal microarray analysis. Additional methods, such as fluorescence in situ hybridization (FISH), can be used.^2,5,7,8,9

Treatment

At birth, KS patients can present bilateral undescended testes (cryptorchidism), or inguinal hernia, both treated with surgery. Testosterone replacement therapy is a common treatment in KS, indicated in early childhood (in cases of micropenis), and at puberty to help with the sexual development of the secondary characteristics. Aromatase inhibitors can be used to ameliorate gynecomastia, but in some cases, surgery is also an option. Early intervention, psychological support, speech, physical and/or occupational therapy may help to improve the patient’s overall outcome.^2,5,7,8,9,10

What are the symptoms of Klinefelter syndrome in infants?   

Hypotonia and motor developmental delay 

A baby suffering from Klinefelter syndrome doesn’t usually show obvious symptoms in infancy, but they present higher risk for developmental delays. The main symptoms will become evident only after the beginning of puberty. Weaker muscles (hypotonia), and a delay in reaching the developmental milestones, like sitting up, crawling, and walking, might be the only signs, which can be treated without even testing for KS. Hypotonia is frequently present in KS infants, with babies often developing positional torticollis and plagiocephaly due to lack of activity and muscle weakness. Hypotonia and other musculo-skeletal problems, such as increased mobility (hypermobility), flatfeet (pes planus), or knock knees (genu valgum), affect the motor development of the baby and cause delays (about 2-3 months later) in about 50% of cases. Physical therapy is recommended to be started early, before the age of 1 year old.^1,3,7,8,9

Speech and language development

KS patients have an increased risk to develop language and reading problems. Speech and language delays can be seen from the infancy period, and are identified in about 75% of cases. The baby’s first words may happen about 2-3 months later than the expected time. Speech and language therapy is recommended to be started early, before the age of 2 years old. Learning disabilities can also be noticed during infancy, and require monitoring, and intervention, if necessary.^{1,6,8,9,10,11}

Language and behaviour  

Speech delays affect the baby’s development of self-expression, which can lead to decreased tolerance for frustration and further behavioural problems. Speech delays can be noticed even when the baby is only 6 months old, because they are “quiet babies”. They have difficulties vocalising and imitating sounds, therefore limiting social interaction with their caregivers. Hypotonia also affects the facial muscles of the babies, and they appear to have no expression. These factors, amongst others, contribute to the development of behavioural problems in KS patients later in life, so monitoring and early intervention is recommended.^1,7,8,9

Growth

Although tall stature is a main symptom in Klinefelter syndrome, during infancy the baby’s length is within the normal limits. At birth the length, weight, and head-circumference generally appear normal, but babies with KS can be slightly smaller. Some studies suggest variable growth rates, some KS babies tending to be slightly bigger, others just in the normal range regarding length/height. The growth acceleration will happen later, during mid-childhood.^1,3,8,12 

Physical anomalies 

KS can be “clinically silent” during infancy, but in some rare cases genital abnormalities can be seen in a newborn with hypotonia. Babies can present with the following anomalies at birth: bilateral undescended testes (cryptorchidism), reduced penis length (micropenis), small testicles, and hypospadias. Cryptorchidism and micropenis are more frequent in KS babies, but cases are still rare (<10%). Guidelines recommend surgery (orchidopexy) to correct cryptorchidism before the age of 12 months, and in case of micropenis, a short term, low-dosed, testosterone therapy will be taken into consideration by the paediatric endocrinologist in charge of the cases.^{6,7,8,9,10,12}

The classical form of Klinefelter syndrome – 47,XXY – usually doesn't present major congenital anomalies, such as congenital heart disease, kidney malformation, inguinal hernia, cleft palate, dental problems, epilepsy, amongst others. These symptoms are more common in Klinefelter variants where the patients have more than one extra X chromosome.^3,4,9,12

Mini puberty and hormonal therapy

The “mini puberty” is the period of the first few months of life when puberty-related hormones present at higher levels in the bloodstream. Studies highlight the influence of this period on the normal development of the reproductive system in AMAB people. The impact of this period in the development of KS patients, and the possible supplementation therapy with testosterone requires further study.^1,12   

Summary

Klinefelter syndrome (KS) is the most common genetic condition related to the sex chromosomes in AMAB people. It is caused by the presence of an extra X chromosome. It is considered a “genetic accident”, is not inherited, and can’t be prevented. It has no cure, but there are available treatments and supportive therapies, such as speech and language, physical, educational, and psychological therapy. 

The main symptoms of the condition may not become clinically evident until after the beginning of puberty. KS is known for the following characteristics: tall stature, puberty delays, testicular dysfunction, and infertility. The severity of the symptoms is variable, and many cases aren’t even detected. 

Diagnosis of KS in infancy is a challenge because it can be “clinically silent” until puberty, and symptoms are scarce and not specific. A newborn suffering from KS is likely to have hypotonia and a high risk for developmental delays. Babies often present motor, speech, language, and learning delays and deficits. In rare cases, genital abnormalities can be seen at birth, with the most common anomalies being cryptorchidism and micropenis, however surgery and hormonal treatment are available treatment options. 

An early diagnosis of KS and increased awareness of the parents and the doctors about the disorder would not only increase the number of detected cases, but would also offer the appropriate treatment and support therapies for the patients, improving their overall outcome and preventing the possible health complications related to the condition. 
Klinefelter's Syndrome Association (KSA) might be useful for the patients and their families.