18p syndrome is estimated to occur in approximately 1 out of every 50,000 live births. However, as genomic screening has become more common, there is evidence to support that the true incidence rate may be slightly higher, as individuals with smaller deletions present with more mild symptoms that may never be formally diagnosed without genetic testing. 18p syndrome is slightly more common in females than males, at a ratio of approximately 3:2. It is not known why it is more common in females, but some geneticists speculate that developing male embryos may be more sensitive to the dosage effects of losing one copy of genes on 18p, and are therefore less likely to be born.

18p syndrome is caused by a deletion to the short arm (p) of one copy of an individual’s chromosome 18. This results in an individual who has only one copy of a set of genes on chromosome 18, rather than two. Usually, the genetic deletions that cause 18p syndrome start from the end of the chromosome, and in about 50% of cases, extend nearly all the way across the short arm, leading to almost complete loss of 18p. However, some cases involve deletions to the middle of the 18p arm while the end is unaffected. Overall, deletions can vary in size and location.

The majority of 18p deletions arise de novo, meaning that neither of the individual’s parents have this deletion. In these cases, the deletion was either present in the particular egg or sperm which ultimately gave rise to the individual, or it spontaneously occurred during early development. 

In the remaining cases, one of the parents has a balanced translocation, meaning that while they have two copies of all 23 chromosomes, some of the genetic material has been rearranged. For example, sections of the short arm of one copy of their chromosomes 13 and 18 could have swapped positioning. In this instance, depending on the half of the genetic material they pass down to their child, the child may inherit an extra copy of pieces of the short arm of chromosome 13, and only one copy of parts of the short arm of chromosome 18 - otherwise known as an unbalanced translocation. These translocations can involve full arms of chromosomes, or just small sections. While individuals with balanced translocations like the parent do not have symptoms, children who inherit unbalanced translocations likely will.

Depending on the region of chromosome 18 that is deleted in 18p syndrome, different genes may be lost, and this impacts the manifestation of symptoms. Critical genes whose impact has been studied include TGIF1, which is essential for signaling in brain development, and GNAL, which is important for dopamine signaling in motor control.

Symptoms vary widely depending on the size and location of the 18p deletion. Common symptoms include:

• Short stature and delayed growth: Nearly all individuals with 18p syndrome have short stature; birthweight is typically below average and many experience growth failure from growth hormone deficiency.

• Distinct craniofacial features: Facial features such as a round, flat face are common. Some individuals also have drooping eyelids. Cleft lip or palate can also be present in some cases.

• Microcephaly: Microcephaly, of a significantly smaller size head than average at birth, may also be present.

• Intellectual disability: The majority of individuals with 18p syndrome have some form of intellectual disability, ranging from mild to severe.

• Hypotonia and/or dystonia: Muscle abnormalities and motor delays are common, and can involve hypotonia, which is a lack of muscle tone, or sometimes dystonia, which leads to involuntary sustained muscle contractions.

• Immune System: Immunoglobulin A (IgA) deficiency is common. IgA is the primary antibody that coats mucosal surfaces, and deficiencies can lead to more frequent respiratory and gastrointestinal infections. Additionally, some deletions lead to increased risk of autoimmune disease, particularly if the PTPRM gene is affected. This gene plays an important role in cell-to-cell communication.

• Holoprosencephaly: Holoprosencephaly, or the failure of the forebrain to divide into two hemispheres, occurs in 10-15% of individuals, and causes severe symptoms.

• Heart defects: Congenital heart defects occur in about 10% of individuals. 

18p syndrome can be diagnosed either prenatally (before birth) or postnatally (after birth). 

When it is diagnosed prenatally, either amniocentesis or chorionic villus sampling (CVS) are performed. Amniocentesis is performed between the 14th and 20th week of pregnancy, and tests the genetic material of fetal cells found in amniotic fluid, while CVS takes tissue from the placenta for genetic analysis between the 10th and 13th week of pregnancy. These tests are often done following a finding on ultrasound, such as holoprosencephaly or heart defects.

When it is diagnosed postnatally, some form of genetic analysis is necessary for confirmation, as symptoms alone can be too nonspecific. Often, either karyotyping or chromosomal microarray analysis (CMA) is performed. Karyotyping is the visual analysis of an individual’s chromosomes, and in 18p syndrome, it can demonstrate that part or all of the short arm of chromosome 18 is missing. CMA is similar to karyotyping, but with higher resolution, and has the ability to detect microdeletions or microduplications of small regions of the chromosomes. This can be useful in situations where the 18p deletion is more limited.

There is no cure for 18p syndrome, so treatment focuses on managing symptoms and improving quality of life. A few common treatments include:

• Therapies: Physical, occupational, and speech therapy are crucial to assist development.

• Growth Hormone: Some children respond well to growth hormone replacement therapy for short stature.

• Regular Screenings: Monitoring for immune deficiencies, and continued check-ups to monitor any heart or other defects is important.

• Surgery: Some individuals receive surgery for facial symmetry, cleft lip and palate, or structural heart defects.

The prognosis for 18p syndrome is generally favorable, and most individuals have normal life expectancy. Exceptions to this are in the case of those individuals with holoprosencephaly, which carries a high risk of mortality in infancy, and those with severe structural heart defects. Most individuals lead healthy lives, though they may require varying levels of support throughout adulthood due to intellectual or social challenges.

1. National Organization for Rare Disorders. (2020). Chromosome 18, monosomy 18p. https://rarediseases.org/rare-diseases/chromosome-18-monosomy-18p/

2. Orphanet. (n.d.). Monosomy 18p (ORPHA:1598). https://www.orpha.net/en/disease/detail/1598

3. Turleau, C. (2008). Monosomy 18p. Orphanet Journal of Rare Diseases, 3(4). https://doi.org/10.1186/1750-1172-3-4 

4. Unique (Rare Chromosome Support Group). (2017). 18p deletions. https://www.rarechromo.org/media/information/Chromosome%2018/18p%20deletions%20FTNW.pdf