SNP Shot: Genomic Insights

Hartsfield syndrome is a rare genetic disorder characterized by two primary features: holoprosencephaly, a brain development abnormality, and ectrodactyly, a malformation affecting the hands and feet.

Typically, during early prenatal development, the brain divides into two hemispheres. Holoprosencephaly occurs when this division is incomplete or absent. In the most severe forms, the brain remains undivided, often leading to cyclopia (a single central eye) and a proboscis (a tubular nasal structure above the eye). Infants with severe holoprosencephaly often do not survive. Milder forms involve partial brain division, and the lifespan of affected individuals varies depending on the severity of symptoms.

Individuals with Hartsfield syndrome may also experience other brain-related complications stemming from holoprosencephaly. Pituitary dysfunction is common, leading to hormone imbalances. The pituitary gland, located at the brain's base, produces essential hormones. A malfunctioning pituitary can result in conditions like diabetes insipidus (disrupting fluid balance), growth hormone deficiency (causing stunted growth), and hypogonadotropic hypogonadism (affecting sexual development). Furthermore, dysfunction in other brain regions can cause seizures, feeding difficulties, and problems with body temperature and sleep regulation. Developmental delays, ranging from mild to severe, are also observed in individuals with Hartsfield syndrome.

Ectrodactyly, another defining characteristic of Hartsfield syndrome, involves a deep cleft in the hands and/or feet, missing fingers or toes, and potential fusion of the remaining digits. This malformation can affect one or both sides of the body. Other features sometimes associated with Hartsfield syndrome include craniosynostosis (premature fusion of skull bones), heart defects, vertebral abnormalities, and genital abnormalities. Some individuals may also exhibit distinctive facial features such as widely spaced eyes (hypertelorism), closely spaced eyes (hypotelorism), unusually small or shaped ears, and cleft lip (with or without cleft palate).

Inheritance:

Hartsfield syndrome can be inherited in either an autosomal dominant or autosomal recessive manner. Autosomal dominant inheritance requires only one copy of the mutated gene to cause the disorder. In most cases, this arises from a new (de novo) mutation in the FGFR1 gene during the formation of egg or sperm cells or early embryonic development. Consequently, most affected individuals have no family history of the condition. However, rarely, the altered gene is inherited from a parent with germline mosaicism, where the FGFR1 mutation is present only in their reproductive cells. Less frequently, Hartsfield syndrome is inherited in an autosomal recessive pattern, requiring two copies of the mutated gene. In these instances, both parents carry one copy of the mutated gene but typically do not exhibit symptoms of the condition.