SNP Shot: Genomic Insights

Nonsyndromic holoprosencephaly (HPE) is a birth defect that affects how the brain develops, impacting the brain itself, as well as the face and head. Typically, a developing brain divides into two halves, called hemispheres. In nonsyndromic HPE, this division is incomplete, leading to a partial or absent separation of these hemispheres. The term "nonsyndromic" signifies that this form of HPE is not caused by identifiable genetic syndromes, chromosomal abnormalities, or exposure to teratogens (substances causing birth defects). The symptoms and severity of nonsyndromic HPE can vary widely, even within the same family.

Nonsyndromic HPE is categorized into four types based on the extent of brain division, ordered from most to least severe: alobar, semi-lobar, lobar, and middle interhemispheric variant (MIHV). Alobar HPE, the most severe form, is characterized by a complete lack of brain division. Babies with this form may exhibit cyclopia (a single central eye) and a proboscis (a tube-like structure) above the eye. Sadly, most infants with severe nonsyndromic HPE do not survive to birth or shortly afterward. In milder forms, some brain division is present, and the eyes are often close together (hypotelorism). Life expectancy in these cases varies depending on the specific symptoms and their severity.

Individuals with nonsyndromic HPE often have microcephaly, which is a head size that is smaller than normal. Conversely, they may also develop hydrocephalus, a condition involving the accumulation of fluid within the brain, which can lead to macrocephaly (an enlarged head). Other common characteristics include a cleft palate (sometimes accompanied by a cleft lip), a single front tooth (single maxillary central incisor) instead of two, and a flattened nasal bridge. The eyeballs may also be abnormally small (microphthalmia) or entirely absent (anophthalmia).

Some individuals with nonsyndromic HPE exhibit distinct facial features, such as a narrow head at the temples, upward-slanted eyes (upslanting palpebral fissures), large ears, a short nose with upturned nostrils, and a wide, smooth space between the nose and upper lip (philtrum). Generally, the severity of these facial features correlates with the extent of the brain malformation. However, it is possible to have relatively mild facial features despite significant brain abnormalities. Conversely, some individuals may display certain facial features associated with HPE, yet show no detectable structural brain defects. This condition is known as microform holoprosencephaly and is often diagnosed following the birth of a more severely affected family member.

Most people with nonsyndromic HPE experience developmental delays and intellectual disability. A frequent complication is dysfunction of the pituitary gland, a hormone-producing gland at the base of the brain. Pituitary problems can cause hormone deficiencies, leading to various health issues. Diabetes insipidus, a condition affecting fluid balance, is commonly observed in individuals with nonsyndromic HPE and pituitary dysfunction. Problems in other areas of the brain can lead to seizures, feeding problems, and difficulties regulating body temperature, heart rate, and breathing. Impaired sense of smell (hyposmia) or complete loss of smell (anosmia) can occur if the area of the brain responsible for processing smells is underdeveloped or absent.

Inheritance:

Nonsyndromic HPE typically follows an autosomal dominant inheritance pattern. This means that a change in just one copy of a specific gene in each cell is usually sufficient to cause the condition. However, not all individuals who inherit the altered gene will exhibit signs and symptoms. In some cases, the affected person inherits the mutation from a parent who may or may not have subtle features of the condition. In other cases, the condition results from a new gene mutation, with no previous family history of HPE.