Culler-Jones Syndrome Across Three Generations: Variable Expressivity of a Pathogenic GLI2 Variant—a Case Report

Human development is a process of extraordinary precision, where a single fertilized egg divides and organizes itself into a complex body with distinct parts, from the brain to the toes. This intricate construction relies on a set of genetic instructions that act like a blueprint, telling cells where to go and what to become. Sometimes, a small error in this blueprint can disrupt the formation of the body's midline—the central axis that runs from the head down through the torso. When this happens, it can lead to a range of conditions affecting the face, the brain, and the glands that control growth and reproduction. One such condition, known as Culler-Jones syndrome, is rare and stems from a specific flaw in a gene called GLI2. This gene is crucial for building the pituitary gland, a small but vital structure at the base of the brain that acts as a master switch for many hormones. Because the instructions in our genes can be interpreted differently by each person, even family members carrying the exact same genetic error can look and feel very different from one another. Understanding how these variations play out in real families helps doctors predict risks and offer better care.

A team of researchers at the University of North Carolina recently shared the story of a family that illustrates this unpredictability with striking clarity. They followed a twenty-four-year-old woman who had been referred to a genetics clinic for a collection of severe health issues. From birth, she had faced significant challenges: she was born with a cleft lip and palate, unusual tissue masses in her mouth and gums that contained extra teeth, and a brain structure anomaly where part of the cerebellum pushed downward. As she grew, she remained very short, standing at 142.4 centimeters, which is below the first percentile for her age. Her body also struggled to produce necessary hormones; she lacked a fully formed pituitary gland, which led to a failure to develop typical secondary sexual characteristics, such as pubic hair or regular menstrual cycles. Her reproductive organs were difficult to locate on imaging scans, with one report suggesting they were missing entirely, while another found a very small uterus but no ovaries.

When doctors examined her family history, they found a pattern that pointed toward a specific genetic cause. Her mother, sister, and maternal grandmother all carried the same genetic change, yet none of them had the severe physical or hormonal problems that the young woman experienced. In fact, these relatives appeared to be healthy, with no obvious signs of the syndrome. The family tree also included several male relatives on the mother's side who had extra fingers or toes on the outside of their hands and feet, a condition known as postaxial polydactyly. Two of these uncles also had multiple extra nipples, with reports of up to five additional nipples on their chests. While these men were not tested genetically, their physical traits aligned with what is known about the gene in question.

The researchers identified a specific error in the GLI2 gene of the twenty-four-year-old patient. This error, a single letter change in the genetic code that stops the production of a vital protein, was confirmed to be the cause of her condition. When they tested her relatives, they found that her mother, sister, and grandmother all carried this exact same stop signal in their DNA. The patient's brother, however, did not have the error and was unaffected. This discovery revealed a phenomenon called variable expressivity, where the same genetic mistake leads to a severe, life-altering condition in one person but causes little to no noticeable effect in others who share the same DNA.

The case highlights a critical challenge for families and doctors: carrying a harmful genetic variant does not guarantee that a person will be sick, nor does it guarantee that their children will be. In this family, the mother and grandmother passed the gene to their children, but the severity of the outcome was impossible to predict. The young woman suffered from a complex mix of facial, hormonal, and growth issues, while her mother and sister remained largely unaffected. The researchers noted that the extra nipples seen in the male relatives were an interesting observation that had not been previously linked to this specific syndrome, but because those men were never genetically tested, it remains unclear if the extra nipples were truly caused by the same gene or were just a separate family trait.

This story serves as a reminder that genetic counseling requires looking beyond the immediate symptoms. A doctor cannot assume that a parent who appears healthy will pass on a mild version of a condition; they could pass on a severe one. The researchers emphasized the importance of testing at-risk family members even when they seem fine, because the genetic risk is real even if the symptoms are not. By mapping out the family history and confirming the genetic link, the team provided a clear explanation for the young woman's struggles and offered a path forward for her relatives to understand their own health risks. The case adds to the growing understanding of how a single genetic error can shape a life in vastly different ways, depending on the unique biological context of each individual.