Disease overview

The exact prevalence of the disease is unknown, but several patients in Japan and abroad have been documented. Patients who remain undiagnosed are also thought to exist.

Takenouchi-Kosaki syndrome is caused by a specific amino acid substitution mutation in the CDC42 gene, which is located on chromosome 1. The syndrome is caused by an alteration in one of the two CDC42 genes (called an autosomal dominant trait). Although previous basic medical research has shown the CDC42 gene to play an important role in cell division and proliferation and more than 5,000 papers have been published on this topic, it wasn’t until 2015 that abnormalities in this gene were shown to be a direct cause of human disease. The mechanisms by which mutations in the CDC42 gene cause the appearance of giant platelets and other symptoms remain unknown but are thought to involve cytoskeletal anomalies. Different types of mutations may cause some differences in symptoms.

This disease is an autosomal dominant genetic disorder that can be diagnosed based on a combination of symptoms and that can be confirmed using genetic testing. Genetic counseling is recommended for patients in whom the genetic status is uncertain.

Several diseases are characterized by the presence of both thrombocytopenia and intellectual disability. Typical examples are Jacobsen’s syndrome (11q deletion) and 21q22 microdeletion syndrome. These diseases can be differentiated from Takenouchi-Kosaki syndrome based on the presence or absence of other symptoms. Chromosomal and genetic testing may be necessary.

Currently, no fundamental treatment exists for this disease. Symptomatic treatment can be performed for each symptom.

Symptoms that are present in most patients include macrothrombocytopenia, intellectual disability, brain structural abnormalities, characteristic facial features, and sensorineural deafness. In some patients, lymphedema, repetitive infections, and hypothyroidism may also be present.

Macrothrombocytopenia

Blood test findings that are characteristic of the disease include a decrease in the number of platelets and an increase in the size of some platelets. This can be confirmed by peripheral blood counts and smear tests performed as part of routine clinical practice. This finding is very important in making a diagnosis. In general, a low platelet count can cause bleeding, but patients with this disease do not have bleeding tendency.

Intellectual disability

Patients with this condition exhibit intellectual disability of varying degrees. Regression (a gradual loss of ability to do what was previously possible) is not seen.

Distinctive facial features

The following facial features are common in patients with Takenouchi-Kosaki syndrome.

• Dark eyebrows and slight hypertrichosis throughout
• Inverted crescent-shaped eyelids
• A short distance between the nose and mouth
• Thin upper lip
• Small mouth
• Protruding lower jaw, relative to the upper jaw
• Small earlobes

Structural brain abnormalities

The CDC42 gene, which is the cause of this disease, is important for brain formation and is associated with findings such as ventricular enlargement and cerebellar hypoplasia. Among the patients observed to date, a susceptibility to epilepsy has not been reported.

Sensorineural hearing loss

Patients with Takenouchi-Kosaki syndrome have sensorineural hearing loss to the extent that a hearing aid is required immediately after birth. The hearing loss is thought to be caused by dysplasia of the inner ear.

Contracture of the fingers

Flexion of the fingers and toes is present.

Lymphedema

“Swelling” occurring mainly in the lower extremities may be present, particularly in adult patien

Repetitive infections

Some patients are susceptible to recurring bacterial infections. While the exact cause is unknown, poor immunity is thought to be involved.

Hypothyroidism

A blood test may reveal hypothyroidism.