COACH Syndrome

At a glance

COACH is an acronym that stands for an inherited syndrome characterized by Cerebellar vermis aplasia, Oligophrenia, congenital Ataxia, ocular Coloboma, and Hepatic fibrosis.

Incidence

Approximately 50 cases have been described.

Genetic inheritance

Autosomal recessive inheritance. Parental consanguinity has been reported in some cases. Most commonly, the defect is caused by mutations in the TMEM67 (Transmembrane Protein 67, also known as MKS3 [Meckelin]) gene located on chromosome 8q22.1. Meckelin protein is found in proximal renal tubules and biliary epithelial cells where it plays an essential role in the formation of the primary cilium. It appears that the primary cilia have a central role in bile duct morphogenesis and renal tubuloepithelial differentiation during embryogenesis. A smaller number of cases are either caused by mutations in the CC2D2A (Coiled-Coil and C2 Domains-Containing Protein 2A) on chromosome 4p15.32 or the RPGRIP1L (RPGRIP1-like) gene, which has been mapped to chromosome 16q12.2. Joubert Syndrome (Type 6) and Meckel-Gruber Syndrome (Type 3) are allelic disorders to COACH Syndrome. COACH Syndrome can be defined as “Joubert Syndrome with clinically overt liver disease.”

Diagnosis

The diagnosis is based on the clinical, imaging (CT- or MRI-scanning), and histopathological findings, combined with positive family history and genetic molecular testing.

Clinical aspects

Moderate to severe mental retardation, early-onset ataxia and hypotonia are common. Imaging studies (CT- or MRI-scanning) may detect hypoplasia or aplasia of the cerebellar vermis, hypo- or agenesis of the corpus callosum, and occipital encephalocele. Hepatic fibrosis is the main feature of COACH Syndrome and secondary to malformations of the embryonic ductal plates with developmental arrest of the intrahepatic bile ducts during embryogenesis. Hepatic fibrosis is clinically extremely variable and often subtle in young children. Liver biopsy reveals congenital hepatic fibrosis (or later cirrhosis) with periportal fibrosis, cholestasis, reduced number of intrahepatic bile ducts, chronic inflammatory infiltrates, and portal hypertension present in 70% of patients. Severe liver complications (portosystemic shunt, hepatic encephalopathy, death, or need for transplantation) have been described. Renal disease is present in 46 to 77% of patients with nephronophthisis in 19% and macrocystic kidney disease in 23%. End-stage renal failure occurs in 13% of patients and in 8% of patients death resulted from renal complications. Head and neck features may consist of flat round face, hypertelorism, ptosis (in 16-25%), nystagmus, optic nerve or chorioretinal coloboma (in 64-71%) and optic disc atrophy, up-turned nose, macrostomia, and macroglossia. “Molar Tooth Sign” is common in COACH Syndrome and is used to describe a mid-hindbrain malformation (detected in CT- or MRI-scans and typically found in Joubert Syndrome) with hypoplastic cerebellar vermis and a narrow cleft separating the two cerebellar hemispheres. The superior cerebellar peduncles are thickened, elongated and reoriented due to a lack of normal decussation of superior cerebellar peduncular fiber ...