Case report: Central 22q11.2 Deletion Presenting in Adulthood with CAKUT, Malignant Hypertension and Thoracoabdominal Aortopathy

The human body is a complex machine built from a set of instructions written in our DNA. Sometimes, small errors in these instructions lead to health problems that appear at birth, while others remain hidden until much later in life. One such category of problems involves the kidneys and the urinary system, which can fail to form correctly during early development. For decades, doctors have known that these congenital anomalies often run in families, suggesting a genetic cause, but pinpointing the exact error has been difficult. In recent years, scientists have learned that missing pieces of chromosomes—large stretches of genetic material that vanish entirely—can be the culprit. These missing pieces often contain genes that act as master switches for how organs like the heart, face, and kidneys grow. While some missing pieces cause well-known syndromes that are diagnosed in infancy, others are subtler. They might spare the most famous genes but remove others that are equally critical for specific body parts, leaving a person healthy for decades before a hidden flaw finally reveals itself.

This story begins with a forty-year-old woman who arrived at a hospital in a crisis. She had suffered a stroke caused by a sudden, severe spike in her blood pressure, a condition known as malignant hypertension. Her medical history included a single working kidney, a result of a left kidney that had been underdeveloped since birth and removed when she was an infant. For years, her blood pressure had been difficult to control, requiring multiple medications, and she had a history of learning difficulties and dental problems. When doctors looked deeper, they found something unusual in her blood vessels. Imaging scans revealed that the main artery carrying blood from her heart down through her chest and abdomen was narrowed in multiple places, forcing the blood to find detours through smaller, collateral vessels. This pattern of narrowing, combined with her kidney issues and family history of similar health struggles, pointed toward a single underlying cause rather than separate, unrelated diseases.

The medical team suspected that a genetic condition was driving both her kidney failure and her vascular problems. To investigate, they turned to a comprehensive approach using a CAKUT-focused next-generation sequencing panel that included analysis for large missing chunks of DNA. This technique, which analyzes the depth of genetic data to spot deletions, revealed the culprit: a missing segment of chromosome 22. Specifically, the woman had lost a piece of DNA about 954.8 kilobases in size. This missing section was located in a central part of the chromosome and included a gene called CRKL, which is vital for the development of kidneys and blood vessels, but it spared another gene, TBX1, which is responsible for the classic features of a more common condition known as DiGeorge syndrome. Because the TBX1 gene was intact, the woman did not have the typical heart defects, immune problems, or facial features associated with that well-known syndrome, which explains why her condition went undiagnosed for so long.

The discovery of this specific genetic deletion changed the entire understanding of her illness. Before this finding, her narrowing arteries might have been mistaken for an inflammatory disease, a condition where the body's immune system attacks its own blood vessels. If that were the case, the standard treatment would involve powerful drugs to suppress the immune system. However, the genetic test showed that her condition was not an attack by the immune system at all, but a developmental error that had been present since she was a fetus. The missing CRKL gene likely disrupted the signals that tell blood vessels and kidneys how to form correctly, leading to the narrow arteries and the solitary kidney she lived with. This distinction is crucial because it means she does not need immunosuppressive therapy, which carries significant risks, but rather needs careful monitoring of her blood vessels and aggressive management of her blood pressure to prevent further damage.

This case highlights a gap in medical knowledge that affects many adults. While doctors are trained to look for genetic causes of kidney and heart problems in children, adults with similar issues are often overlooked, especially if they lack the obvious physical signs of a syndrome. The woman in this report had subtle clues, such as sparse eyebrows, a short neck, and dental issues, but without the genetic test, these were likely seen as minor quirks rather than parts of a larger puzzle. The researchers emphasize that when an adult presents with a combination of kidney anomalies, difficult-to-control high blood pressure, and unexplained narrowing of large arteries, a genetic evaluation that includes looking for missing DNA segments is essential. Identifying the specific genetic error not only clarifies the diagnosis but also guides the correct treatment path and allows family members to be tested, as this type of genetic deletion can be passed down from parent to child.

The findings from this single case suggest that there are likely other adults living with similar undiagnosed conditions. The specific deletion found here, which removes the CRKL gene while leaving TBX1 behind, creates a unique profile that differs from the classic childhood syndromes. It serves as a reminder that the human genome is vast and that missing even a small, central piece can have profound effects on how the body develops. By recognizing these patterns, doctors can move away from treating symptoms in isolation and toward understanding the root cause, ensuring that patients receive care that is tailored to their specific biological reality. This approach transforms a confusing collection of symptoms into a clear, manageable condition, offering a better path forward for patients and their families.