Aagenaes syndrome is a rare disease with less than 1,000 cases in the U.S. This disease was first described by Aagenaes (a pediatrician) in Norway in 1968. The Norwegian individuals diagnosed with Aagenaes syndrome most likely have a similar gene mutation that was genetically inherited from a common ancestor. Thus, people in Norway are more likely to carry the genetic mutation that causes Aagenaes syndrome, and there is a higher rate of this rare disease in Norway than anywhere else in the world. 

Aageneas syndrome is a genetic disorder caused by a mutation in a person’s genes producing an abnormal effect on their body. Some cases of Aagenaes syndrome have been linked to an auto-recessive mutation in the LSC1 gene on human chromosome 15q. Auto-recessive disorders refer to genetic mutations that are present in both parent’s chromosomes, resulting in an offspring with a pair of chromosomes with the same mutation, in this case chromosome 15q. While this gene and locus have been associated with individuals diagnosed with Aagenaes syndrome, the current cause of cholestasis from Aagenaes syndrome is unknown. Current research hypothesizes that the mutation associated with this rare disease affects the lymphatic system and that the liver itself is healthy. The lymphatic system refers to a system of fluids in the body, separate from the blood, that deliver proteins, vitamins, and nutrients to different parts of the body. However, over time as the liver is subjected to unhealthy lymph, it can cause damage in the form of cholestasis. Lymphedema can progress later in older children into adulthood if their cholestasis is left untreated. This can cause swelling, usually in the lower extremities such as the legs, ankles, and feet. 

Aagenaes syndrome begins developing in newborns and young children. It normally starts with liver cholestasis, characterized by liver problems such as abdominal pain, abnormal stool, malabsorption of nutrients, and general liver dysfunction. If this persists without treatment, it can cause symptoms such as jaundice to progress. Jaundice is the yellowed discoloration of the skin due to a build up of bilirubin in the blood. Bilirubin is a waste product that is produced when the body breaks down red blood cells, and is normally filtered out of the blood and into the bile by the liver. When the liver is not functioning normally, excess bilirubin can build up in the blood causing toxic build-up and skin discoloration. Most children with Aagenaes syndrome receive proper vitamin treatment and their symptoms lessen to more episodic instances of liver problems. About half of all people diagnosed with Aagenaes syndrome will later develop lymphedema before ages 6-7 or right before puberty. Lymphoedema occurs when the body’s lymphatic system – or the fluid responsible for carrying important proteins throughout the body – is not working properly. This can cause swelling in the lower parts of the body, such as legs, ankles, and feet. Other symptoms experienced by individuals with Aagenaes syndrome can include:

Common:

• Abdominal pain and upset stomach

• Abnormal lymph function leading to lymphatic disease

• Discolored stool (clay colored) due to a lack of bile

• Fatigue

• Rickets - softening or weakening of the bones due to a vitamin D deficiency

• Hepatomegaly – increase in liver size

• Nausea and vomiting – due to abdominal pain and upset stomach

• Neonatal cholestatic liver disease

Less Common:

• Multiple lipomas – benign tumors of fatty tissue

• Discoloration of the skin due to jaundice

• Splenomegaly – increase in spleen size

Least Common:

• Bone pain – prickling, throbbing, or aching sensation localized to the bone

• Cirrhosis – scarring of the liver tissue leading to loss of function

• Gastrointestinal hemorrhage – bleeding from the internal organs involved in the digestive tract, leading to bloody stool

• Portal hypertension – increased blood pressure in the portal vein

• Reduced bone mineral – reduced bone density, which could cause complications such as osteoporosis

Early signs of lymphoedema can be difficult to detect, especially if there is not a prior family history of Aagenaes syndrome. Some cases of Aagenaes syndrome have been mistakenly misdiagnosed as biliary atresia, so an in-depth consultation with a pediatrician and hepatologist is necessary for a proper diagnosis.

The following are common tests conducted on newborns and small children in order to determine a diagnosis of Aagenaes syndrome:

1. Testing for biomarkers – increased levels of bile acid, liver enzymes including aspartate transaminase (ALT), and alanine transaminase (AST) in the blood within one month of birth can indicate a diagnosis of Aagenaes syndrome

2. Instrumental investigations – the use of imaging equipment such as abdominal ultrasonography and magnetic resonance cholangiopancreatography (MRCP) can reveal the source of dysfunction in the liver and lymphatic system

3. Testing for lymphoedema – once the disease has progressed, lymphoedema can be diagnosed using lymphoscintigraphy (flowing a radioactive fluid through the lymph ducts to evaluate the process of emptying), CT or MRI scans, a duplex ultrasound

4. Genetic testing for the mutation indicative of Aagenaes syndrome

Although there is no known cure for this disorder, treatments involving nutritional and multivitamin supplement use in early childhood have improved the prognosis for those living with Aagenaes syndrome. Other symptoms can be managed according to each individual case, and may include medications, clinical procedures, speech therapy, and other supportive care. If nutritional approaches do not affect symptoms during early childhood, a liver transplant may be necessary at a later age.

Because of improvements in understanding of this disease and other liver disorders, current therapeutic approaches to treating Aagenaes syndrome have improved length and quality of life. With treatment, many individuals with Aagenaes syndrome have shorter cholestatic episodes, lower risk for  rickets, and better overall growth. Some cases of Aagenaes syndrome can progress to lymphedema and other liver problems, which can reduce lifespan and ability to thrive.

1.  Aagenaes O, van der Hagen CB, Refsum S (1968) Hereditary recurrent intrahepatic cholestasis from birth. Arch Dis Child 43:646–657

2. https://rarediseases.info.nih.gov/diseases/370/aagenaes-syndrome

3. https://www.ncbi.nlm.nih.gov/medgen/78658

4. https://www.icliniq.com/articles/genetic-disorders/aagenaes-syndrome

5.  https://www.merckmanuals.com/home/liver-and-gallbladder-disorders/manifestations-of-liver-disease/cholestasis

6. https://www.sciencedirect.com/science/article/pii/S0002929707632935

7. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1287903/

8. https://www.dovemed.com/diseases-conditions/aagenaes-syndrome/