Aagenaes Syndrome is a rare disease, and the only identified hereditary lymphoedema which slows down or ceases bile flow resulting in cholestasis. However, lymphoedema may develop on its own due to other underlying hepatic ailments or lymphatic system disorders.
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Aagenaes Syndrome can be easily misdiagnosed with biliary atresia, leading to unnecessary surgical intervention. Therefore, a proper diagnosis is imperative to start a correct clinical treatment of Aagenaes Syndrome.
The diagnosis of Aagenaes Syndrome is challenging because the early sign of lymphoedema is difficult to detect, which further delays initiation of medical intervention to treat Aagenaes Syndrome.
If someone is affected by Aagenaes Syndrome first in the family then it becomes difficult to diagnose until the lymphoedema symptom appears. Cholestasis can be diagnosed within the first year of age, but in some patients with Aagenaes Syndrome, lymphoedema develops gradually with age.
Diagnosis based on clinical evaluation
Jaundice, dark colored urine, pale colored stool, fatigue, and pruritus are the common clinical signs for both intra and extra-hepatic cholestasis, which makes it difficult to determine the actual underlying cause.
A thorough assessment of patient history and careful physical examination are fundamental to diagnose Aagenaes Syndrome.
The existence of Aagenaes Syndrome in family history can be considered as a major finding in the clinical investigation of this disease. Clinical diagnosis of lymphoedema at the initial stage is the most challenging until the symptoms appear which further delays the confirmation of Aagenaes Syndrome.
Depending upon the onset, lymphoedema can be divided into three categories like congenital, praecox, or tarda. In case of congenital lymphoedema, the symptoms usually appear within 2 years of age.
In praecox lymphoedema, the onset of symptoms start in-between 2 years to 35 years; however, in most of the cases, it appears near puberty. Tarda is a type of inherent lymphoedema, which usually occurs after 35 years of age. Rates of dyslipidemia and portal hypertension are also common clinical findings in Aagenaes Syndrome.
Biomarkers for Aagenaes Syndrome
Detection of jaundice is usually followed by identification of certain biomarkers which is diagnosed through blood tests. Within one month of birth, the child with Aagenaes Syndrome gets an elevated levels of serum bilirubin concentration which may gradually normalize after 3 to 4 years of age.
An increased level of bile acid, i.e. more than 40 μmol/L within 6 months from birth is observed, which gradually lowers down to an extent and reach to a moderately high level within 6 years of age.
Aspartate transaminase (ALT) and alanine transaminase (AST) are two liver enzymes whose levels gets extremely elevated in the blood within one month from birth; and then drops to moderate levels at 2 to 3 years of age.
The upper limit of Gamma-glutamyl transpeptidase level is almost twice more than the normal limit. The use of phenobarbital may further increase Gamma-glutamyl transpeptidase level specifically in patients having Aagenaes Syndrome.
There are some essential investigations to assess the hepatic conditions:
Abdominal ultrasonography and Magnetic resonance cholangiopancreatography (MRCP) are two techniques used to diagnose Aagenaes syndrome. However, in some patients, the results of these tests can be unclear. In such cases, the patients serum is analyze for the presence of antimitochondrial antibodies (AMA) or a liver biopsy is taken,
Lymphoscintigraphy is used to determine lymphatic anatomy. The presence of lymphoedema is determined using following methods:
- Computed tomography
- Magnetic resonance imaging
- Duplex ultrasound
The precise genetic mutation which causes Aagenaes Syndrome has not yet been elucidated. In a recent study, an autosomal recessive inheritance pattern is shown in Aagenaes Syndrome, and the long arm of chromosome 15q was assumed to be responsible for the genetic cause, but this has not been proven in other cases.
Reviewed by Amrita Roy, MSc