Understanding XYY Syndrome

Introduction

XYY male syndrome, also known as Jacob’s syndrome, is a rare genetic disorder that is non-hereditary and occurs due to trisomy of the Y chromosome. The presence of extra Y-chromosome results in various abnormalities. The extra chromosome is received from the father when the spermatozoa fail to mature completely during spermatogenesis.

Who Are Susceptible to XYY Syndrome?

XYY syndrome births are one in every 1000 newborn males with an average diagnostic age of 17 years. Approximately 85 percent of Jacob’s syndrome births are never diagnosed, hence the prevalence of the condition is not accurate and extensive surveys are essential to derive the precise number of affected individuals.

What Causes XYY Syndrome?

XYY syndrome is caused when the offspring carries an extra Y chromosome. Such patients are denoted as 45, XYY individuals. The condition is not hereditary which indicates that it is not passed down the generation. XYY syndrome occurs due to a deviation from the normal steps of sperm development or maturation. Due to the presence of an extra male chromosome, the individuals are often called super-males.

What Is the Pathophysiology of XXY Syndrome?

Humans, in their genetic makeup, carry 23 sets of chromosomes. Each parent contributes one allele to all chromosomes which then forms the pair in the zygote after fertilization. The gender of the offspring is determined by the inherited sex chromosome. The mother contributes the X-allele and the father contributes the other allele (either X or Y) to the sex chromosome. XX chromosome results in a female and XY in a male offspring.

During the spermatidogenesis step of spermatogenesis, the diploid primary spermatocyte undergoes mitotic division to form haploid secondary spermatocytes which then undergo spermiogenesis to form the mature spermatozoa cell.

Due to various physiological and environmental aberrations, the spermiogenesis step gets affected which results in mature spermatozoa carrying an extra copy of the Y chromosome. This may occur due to the unavailability of either topoisomerase II, condensin, or separase enzymes during the miotic disjunction (anaphase II of meiosis II). Since meiosis I was unaffected, two out of the four daughter cells will have normal 23 (n) chromosomes while the other variants of daughter cells carry 45 (n-1) and 47 (n+1) chromosomes each. The 45-chromosome daughter cell will result in Turner’s syndrome and the 47-chromosome daughter cell manifests Jacobs’s syndrome.

An alternate but less common variant of Jacob’s syndrome is 46-XY or 47- XYY mosaicism which results due to failure of separation of the chromosomes during mitosis after the zygote is formed. The parental role in this kind of variation is still uncertain as the post-zygotic mutations occur randomly.

How to Diagnose XYY Syndrome?

The prenatal diagnosis of XYY syndrome is based on genetic screening while the postnatal early diagnosis is based on genetic karyotyping. Since the average age of diagnosis is as late as 17 years, such males are diagnosed with their symptoms and karyotyping from samples collected with a peripheral blood draw.

Males undergoing infertility treatment should undergo semen analysis, testicular ultrasound, and bloodwork to measure reproductive hormones. Non-invasive prenatal testing using the mother’s peripheral blood from which free-cell fetal DNA is isolated and analyzed can be used for early prenatal diagnosis. Another invasive method-amniocentesis, although outdated, can be used in the absence of non-invasive testing. Amniocentesis requires isolation and analysis of fetal DNA present in the aspirated amniotic fluid from the uterus of the pregnant mother.

What Are the Signs and Symptoms of the XYY Syndrome?

The symptoms in childhood are quite ambiguous which contributes to the high percentage of undiagnosed cases (85 %). The symptoms can be arranged into physical, behavioral, and physiological categories.

Physical Manifestations:

• Tall stature (the final height is usually 3 inches taller than the average counterpart).

• Macrocephaly (enlarged head).

• Hypertelorism (widely spaced eyes).

• Hypotonia ( muscle weakness).

• Clinodactyly (the fifth finger becomes crooked).

• Macrodontia (large teeth).

• Pes planus (flat-footed).

• Scoliosis (abnormal lateral curvature of the spine).

• Class III malocclusions (lower teeth placed forward to the upper teeth).

• Atrophic testicles (under-developed testes).

• Increased belly fat.

• Low-set ears.

• Malar flattening (flat zygomatic bone).

• Micropenis (small genitalia).

• Gynecomastia (development of breasts).

Cognitive and Behavioral Manifestations:

• Normal IQ, but usually 10 to 20 points lower than their chromosomally normal siblings.

• Delayed speech onset.

• Delayed development of language skills.

• Autism spectrum disorder (ASD).

• Attention deficit hyperactivity disorder (ADHD).

• Depression.

• Anxiety.

• Impaired social interactions.

• Impulsivity.

• Aggressive behavior.

Physiological Manifestations:

• Asthma.

• Seizure disorder.

• Tremors.

• Infertility.

• Decreased libido (low sexual urge).

• Motor tics (involuntary movements).

• Certain hormonal imbalances.

• Congenital night blindness.

• Hyperactivity.

• Abnormal brainstem morphology.

• Azoospermia (absence of sperm in semen).

• Cerebellar dysplasia (underdeveloped cerebellum).

• Cryptorchidism (failure of descent of testes into the scrotum).

• Dysgenesis of the cerebellar vermis (vermis of the cerebellum is underdeveloped).

• Hydrocephalus (CSF accumulation in the brain).

• Hypospadias (abnormal positioning of the urethra).

• Increased circulating gonadotropin level.

• Increased serum testosterone level.

• Male infertility.

• Oligospermia (low sperm count).

• Varicocele (swelling along the spermatic cord).

How to Treat or Manage XYY Syndrome?

Since XYY syndrome is a genetic disorder, there is currently no treatment for the condition. The management protocol focuses on supportive therapy and keeping comorbidities in check.

• The patient, along with the family should undergo genetic counseling to properly understand the condition. This may increase the awareness of the population as a whole and prenatal genetic screening may be implemented to detect the presence of this/any genetic aberration even before birth in future pregnancies.

• Patients with speech disorders would require speech therapy going forward.

• The presence of hypotonicity requires occupational therapy; patients with learning disabilities may benefit from additional specialized education.

• Behavioral therapy may be included in the protocol if the patient exhibits ADHD and/or ASD-like behaviors.

• The treatment protocol should include:

  • Specialized neurological consultation for tremors and seizures.

  • Endocrinologist for hormonal imbalances.

  • Pulmonologist for asthma.

  • Orthodontic specialists for occlusal disorders.

• Patients with reproductive issues may opt for in-vitro fertilization or intracytoplasmic sperm injection which are the best methods for the individual to father an offspring.

What Is the Prognosis of XYY Syndrome?

Even with the absence of any absolute treatment; early diagnosis, implementation of an appropriate management protocol, and interdepartmental care can give a good prognosis against XYY syndrome. The primary focus remains on managing the comorbidities arising from various symptoms.

What Is the Differential Diagnosis of XYY Syndrome?

• Marfan’s syndrome (mutation in a gene called FBN1 affecting the heart, eyes, blood vessels, and bones).

• Klinefelter's syndrome (genetic make-up of 44, XXY in the individual).

• Sotos syndrome (mutation in the NSD1 gene on chromosome 5).

What Are the Complications of XYY Syndrome?

Although XYY syndrome can be fairly managed while a lack of diagnosis and failure to intervene can result in various complications like cranial infections, various CNS (central nervous system disorder) disorders, and even death. Various social troubles from hyperactivity and increased aggression can lead to incarceration for criminal activities.

Conclusion

XYY syndrome, being a non-hereditary genetic disorder, does not show any familial occurrence. The symptoms and complications can be managed with specialist care but the patients require a strong support system at home. This greatly improves the quality of life for the individual. Also, awareness of prenatal genetic screening can go a long way in being prepared for the future.