Trisomy 8

Overview

Trisomy 8, also known as Warkany syndrome 2, is a rare chromosomal disorder in which an individual has three copies of chromosome 8 instead of the usual two. This extra genetic material can cause a wide range of physical, developmental, and medical problems. Trisomy 8 may occur as a complete trisomy (affecting all cells), which is typically incompatible with life and leads to early miscarriage, or as mosaic trisomy 8, where only a portion of the body's cells carry the extra chromosome. Mosaic trisomy 8 is the more commonly observed form in live births and presents with variable symptoms depending on the percentage and distribution of trisomic cells. The condition affects males more frequently than females and can present with skeletal abnormalities, distinct facial features, genitourinary defects, developmental delays, and an increased risk for certain malignancies.

Causes

Trisomy 8 is caused by the presence of an extra (third) copy of chromosome 8 in some or all of the body’s cells. The extra chromosome can arise from:

• Nondisjunction during cell division: A random error during meiosis or early embryonic mitosis results in the improper separation of chromosomes, leading to a cell with an extra copy of chromosome 8.

• Mosaicism: In mosaic trisomy 8, the error occurs after fertilization, so some cells have the normal two copies of chromosome 8, while others have three. This form is compatible with life and causes a highly variable phenotype.

Trisomy 8 is typically not inherited and occurs sporadically. The chance of recurrence in future pregnancies is generally low, but genetic counseling is recommended for affected families.

Symptoms

The symptoms and severity of mosaic trisomy 8 vary widely depending on the proportion and distribution of affected cells. Common features include:

Craniofacial Features:

• Prominent forehead

• Deep-set eyes

• Broad, upturned nose

• Thick lips

• Large, low-set ears

Skeletal Abnormalities:

• Joint contractures (especially of fingers and toes)

• Abnormal curvature of the spine (scoliosis or kyphosis)

• Hip dysplasia

• Long, slender fingers and toes (arachnodactyly)

Developmental and Neurological Features:

• Intellectual disability (mild to moderate)

• Delayed developmental milestones

• Hypotonia (low muscle tone) in infancy

• Seizures (less common)

Genitourinary and Gastrointestinal Issues:

• Undescended testes (cryptorchidism) in males

• Renal anomalies

• Hernias (inguinal or umbilical)

Other Possible Features:

• Congenital heart defects (rare)

• Skin pigmentation anomalies (café-au-lait spots or hypopigmented streaks)

• Increased susceptibility to infections in some cases

• Predisposition to certain cancers, particularly myeloid malignancies

Diagnosis

Trisomy 8 is diagnosed through genetic testing and clinical evaluation. Diagnostic steps include:

• Karyotyping: Chromosome analysis of blood or skin cells reveals the presence of an extra chromosome 8. In mosaic cases, multiple tissue samples may be needed.

• Fluorescence in situ hybridization (FISH): A more sensitive technique to detect trisomy in individual cells, useful in mosaic cases.

• Chromosomal microarray: Helps identify copy number variations and low-level mosaicism that may not be visible on standard karyotyping.

• Prenatal diagnosis: May be detected via chorionic villus sampling (CVS), amniocentesis, or non-invasive prenatal testing (NIPT), although mosaicism may complicate interpretation.

• Clinical assessment: A physical exam and developmental evaluation are important to identify characteristic features and assess the severity of symptoms.

Treatment

There is no cure for trisomy 8, and treatment is supportive and tailored to the individual's specific symptoms and needs. A multidisciplinary care team may include geneticists, neurologists, orthopedic surgeons, urologists, and developmental specialists. Treatment strategies include:

• Developmental therapies: Early intervention with physical, occupational, and speech therapy can improve developmental outcomes.

• Orthopedic management: Bracing or surgery for joint contractures, scoliosis, or other skeletal abnormalities.

• Special education: Individualized education plans (IEPs) and academic support for children with learning disabilities or intellectual impairment.

• Urologic and gastrointestinal care: Surgical correction of genitourinary or hernia anomalies if needed.

• Monitoring for malignancy: Regular blood tests and clinical follow-up may be advised due to a potential association with myelodysplastic syndromes (MDS) or leukemia.

• Psychosocial support: Counseling and support groups for families to cope with the medical and emotional aspects of the condition.

Prognosis

The prognosis of trisomy 8 depends largely on whether it is present in all cells or in mosaic form. Key points include:

• Complete trisomy 8: Almost always results in early miscarriage or stillbirth.

• Mosaic trisomy 8: Compatible with life, but associated with a range of physical and cognitive challenges.

• Life expectancy: Generally normal in mosaic cases, though it may be affected by the severity of organ malformations or associated medical conditions.

• Functional outcome: Varies widely—some individuals can attend regular schools and live independently, while others may need lifelong assistance.

• Cancer risk: There is a known association between trisomy 8 mosaicism and hematological malignancies such as myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), especially in adults.

With early diagnosis, individualized care, and supportive therapies, many individuals with mosaic trisomy 8 can achieve improved developmental and functional outcomes.