corticosteroid-binding globulin deficiency

Corticosteroid-binding globulin deficiency is an endocrine metabolic condition that disrupts the normal transport of the stress hormone cortisol throughout the body. It results from pathogenic variants in the SERPINA6 gene, which encodes corticosteroid-binding globulin (CBG), the main carrier protein for cortisol in the bloodstream. Because cortisol influences blood pressure, energy balance, and the body’s response to stress, reduced CBG can lead to symptoms such as fatigue and low blood pressure. The condition can appear at any age in males and females and is considered very rare, affecting fewer than one person in a million worldwide. Severity and symptoms vary widely between individuals, ranging from no noticeable health concerns to chronic pain and significant day-to-day fatigue.

The most common presentation is profound tiredness, especially after physical activity, and episodes of low blood pressure that may cause dizziness or faintness. Laboratory studies typically show markedly reduced levels of CBG and cortisol, and many individuals have low potassium in the blood or urine. Anemia and generalized muscle weakness (asthenia) are also frequently reported. Some people develop fatty liver changes or experience chronic, widespread pain, and a subset meet criteria for chronic fatigue syndrome. Not all individuals experience all features, and severity can range from mild, intermittent symptoms to persistent functional limitations.

Corticosteroid-binding globulin deficiency is caused by changes in the SERPINA6 gene. SERPINA6 provides instructions for making CBG, the liver-produced protein that binds about 80 percent of circulating cortisol and delivers it to tissues when needed. Variants that lower the amount or alter the structure of CBG reduce cortisol availability, leading to the diverse symptoms described above. Multiple inheritance patterns have been reported. When the condition follows an autosomal dominant pattern, a single altered copy of SERPINA6 is sufficient and each child of an affected individual has a 50 percent chance of inheriting the variant. In other families the condition is autosomal recessive, meaning both gene copies must be altered; carrier parents have a 25 percent chance with each pregnancy of having an affected child. This condition is more common when parents share a common ancestor because both may unknowingly carry the same rare variant. Not everyone who carries a pathogenic SERPINA6 variant will develop symptoms (incomplete penetrance), and—even among affected relatives—the type and severity of symptoms can vary considerably (variable expressivity). Genetic counseling can help families understand inheritance, recurrence risks, and testing options for relatives.

Currently, management focuses on supportive care and symptom relief tailored to each individual. Endocrinologists often coordinate care, monitoring cortisol levels, blood pressure, and electrolytes, and may recommend stress-dose steroid coverage during illness or surgery if cortisol reserve is low. Lifestyle measures such as pacing activities, maintaining adequate hydration, and using compression garments can help limit fatigue and orthostatic symptoms. Regular surveillance is an essential part of long-term care, helping to identify potential complications like fatty liver changes or persistent electrolyte imbalances before they become serious. A multidisciplinary team may include primary care physicians, pain specialists, physical therapists, and mental health professionals to address chronic pain, physical conditioning, and emotional well-being. Patients should discuss treatment options with their healthcare team to determine which interventions are appropriate for their specific situation, and genetic counseling is recommended for family planning and at-risk relatives.

Long-term outlook depends on the severity of cortisol deficiency and the effectiveness of symptom management. Many individuals lead full lives with careful monitoring and individualized supportive measures, while others may continue to experience persistent fatigue or chronic pain that affects daily activities. Outcomes described in medical literature continue to evolve as standards of care improve. Families often find it helpful to connect with endocrinology specialists familiar with CBG deficiency and to engage with genetic counselors for ongoing guidance and support.

Corticosteroid-binding globulin deficiency is an active research area with numerous ongoing clinical trials exploring ways to optimize cortisol replacement strategies and better understand CBG biology. Individuals interested in clinical trials can search ClinicalTrials.gov or consult their care team about eligibility.