Aagenaes Syndrome: Symptoms, Diagnosis, and Management

What Is Aagenaes Syndrome?

Aagenaes syndrome, also known as lymphoedema cholestasis syndrome 1 (LCS1), is a rare inborn, hereditary, autosomal recessive disease first described by Aagenaes et al. in 1968 in Norway.

Aagenaes syndrome is characterized by congenital hypoplasia of lymphatic vessels, which further leads to generalized lymphoedema of the lower extremities and recurrent cholestatic liver disease in infancy. It slowly progresses to liver cirrhosis and giant cell hepatitis with hepatic portal tract fibrosis. The syndrome was considered deadly or considerably life-shortening until effective treatment modalities were identified to save the lives of the patients. The disease is most commonly found in Norway.

What Are the Symptoms of Aagenaes Syndrome?

The most common symptoms of Aagenaes syndrome are:

1. Abdominal pain and tenderness.

2. Lymphatic vessel abnormality.

3. Swollen lower extremities.

4. Obstructive liver disease.

5. Abnormal urine homeostasis.

6. Clay-colored stools lack bile pigment.

7. Fatigue and tiredness.

8. Hepatomegaly (enlarged liver).

9. Jaundice.

10. Nausea and vomiting.

11. Multiple lipomas (fatty tumors).

12. Splenomegaly (enlarged spleen).

13. Bone pain and reduced bone mass index.

14. Gastrointestinal hemorrhage.

15. Liver cirrhosis.

16. Abnormal lipid metabolism.

17. Hepatic portal vein hypertension.

Why Is the Aagenaes Syndrome More Prevalent in Norway?

The genetic cause of the disease is unknown, but it is an autosomal recessive inherited disorder, and the gene is located on chromosome 15q. Approximately one hundred people suffering from this disease are known. The condition is frequently found in southern Norway, where more than half the cases are particularly reported, but it is found in patients in some parts of the United States and Europe. The disease was first described by Norwegian pediatrician Aagenaes and his colleagues in 1968 in Norway. Almost all Norwegian patients come from the same southwest area of the country. The occurrence of the cases is consistent with an autosomal recessive inheritance; however, the exact mutation is not yet identified. The gene frequency is estimated to be about three percent.

In a whole-genome screen analysis conducted by Bull et al.(2000), the results suggested that all the Norwegian patients with Aagenaes syndrome could be homozygous with a similar gene mutation genetically inherited in the dormant form through a common ancestor.

How Does the Aagenaes Syndrome Progress?

Aagenaes syndrome usually occurs at birth or in childhood. Biochemical analysis exhibited a potential increase of bilirubin concentration in infants in the first few months of life, with a later decrease.

The disease progresses as -

1. Liver Cholestasis: Cholestasis is identified shortly after birth and persists until one year or even six to seven years or more. In adult cases, cholestasis with few multinucleated or giant cells has been recognized with increased connective tissue. Pathological reports do not demonstrate progression to fibrosis, and signs of hepatic portal hypertension are absent. Laboratory test reports during cholestatic periods demonstrated hyperbilirubinemia, increased transaminases and alkaline phosphatase levels, hyperlipaemia, and increased VLDL (very low-density lipoproteins), and LDL (low-density lipoproteins), a slight decrease in albumin, and an increase in globulin.

During cholestatic periods, all patients demonstrate liver enlargement, abnormal liver functions, and severe malabsorption. In infancy, jaundice is normally seen within the first few weeks after birth. The serum bilirubin concentration is raised in the first months, with a decrease in the normal range at the age of three to four years.

Typically, the symptoms of liver cholestasis ease within the first one to two years of life but may reoccur over irregular intervals. A prolonged cholestatic period in the first three years of life can lead to liver failure causing death or the requirement for liver transplantation.

Most patients have a benign course of liver disease during their adulthood. However, some patients may exhibit signs of chronic, progressive liver cirrhosis throughout adulthood. Bleeding tendencies, anemia, growth retardation, and rickets are manifested due to malabsorption caused by cholestasis in children.

2. Lymphoedema: Hypoplasia of the lymphatics and retarded emptying of contrast from the lymphatics has been observed in the patients suffering from this syndrome. Lymphoedema is developed in approximately half of the patients before six to seven years of age and in the other half before puberty.

It primarily affects the legs, but the hands, arms, thorax, and small intestine can also be affected. Recurrent episodes of erysipelas are frequent in patients with lymphoedema.

How Is Aagenaes Syndrome Diagnosed?

Aagenaes syndrome can be misdiagnosed with biliary atresia. Therefore, a proper diagnosis is necessary to start the effective treatment of Aagenaes syndrome. The diagnosis of Aagenaes syndrome is challenging because the early signs of lymphoedema are difficult to detect. In the family, if someone is affected by Aagenaes syndrome for the first time, then it becomes difficult to diagnose until the symptom of lymphoedema appears.

Diagnosis can be made on the following parameters:

• Clinical Evaluation for Aagenaes Syndrome- A thorough clinical assessment of patient history and careful physical examination by the pediatrician are fundamental to diagnosing Aagenaes syndrome. The presence of Aagenaes syndrome in family history can be considered a major finding in the clinical investigation of this disease.
• Biomarkers for Aagenaes Syndrome- An increased level of bile acid, that is, more than 40 μmol/L within six months from birth, is detected, which then reaches a moderately high level within six years of age. Aspartate transaminase (ALT) and alanine transaminase (AST) are two liver enzymes that are extremely elevated in the blood within one month from birth. The levels then drop to moderate at two to three years of age.

• Instrumental Investigations- Abdominal ultrasonography and magnetic resonance cholangiopancreatography (MRCP) are two techniques that are used to establish the diagnosis of Aagenaes syndrome.

The presence of lymphoedema can be determined using the following methods:

• Lymphoscintigraphy.

• Computed tomography (CT).

• Magnetic resonance imaging (MRI).

• Duplex ultrasound.

• Genetic Findings- An autosomal recessive inheritance pattern is seen in patients with Aagenaes syndrome.

What Is the Treatment for Aagenaes Syndrome?

Although no particular cure for this disease has been determined, significant improvements in the course of the disease have been seen after the administration of nutritional and multivitamin supplements, especially in children.

Liver transplantation is necessary at a later age if there is no remission by about 12 to 18 months of childhood. In recent decades, cholestatic episodes have lasted a shorter time due to advanced improvements in the therapeutic approach. There has also been a decline in rickets and growth retardation over time. The reasons for this are improved nutritional habits and vitamin and cholestyramine supplementation. Symptom management includes medications, clinical procedures, meeting nutrition requirements, speech therapy, and supportive care.

Conclusion

The Aagenaes syndrome is idiopathic and hereditary in nature. The exact genetic cause of the disease remains unknown. Therefore, it is difficult to predict the prognosis of the disease. However, the management of these patients has improved with time because of improved nutritional habits and vitamin supplementation. Nevertheless, it is not yet possible to avoid the progression of serious liver disorders like liver scarring. More research is needed to be done to determine more therapeutic options.