Keutel syndrome

Did You Know?

• In consanguineous parents of children with KS, one parent is often phenotypically normal while the other is positive for pulmonary stenosis.
• MGP-knockout mice develop extensive diffuse cartilaginous calcification and vascular media replacement with a chondrocyte-like matrix, leading to premature death.
• Arterial calcification from MGP inactivation is commonly seen in patients with diabetes, atherosclerosis, and renal dysfunction.

Signs and symptoms

Facial abnormalities in Keutel syndrome include a sloping forehead, maxillary hypoplasia, depressed nasal bridge, wide mouth, dental malocclusion, and receding chin. Diagnosis is supported by electroencephalography, computed tomography, and skeletal survey. Radiography commonly reveals diffuse cartilage calcification and brachytelephalangism, with the first through fourth distal phalanges broadened and shortened while the fifth remains unaffected. Patients often have shorter than average stature and mild developmental delay. Pulmonary angiography and soft tissue radiography show significant cartilaginous ossification in the trachea and larynx, with perichondral and endochondral centers ossified. Abnormal calcification is most pronounced in the auricles and tracheal cartilage. Peripheral pulmonary stenosis is frequent. Recurrent respiratory infection, otitis media, and sinusitis are common, possibly due to diffuse laryngotracheal calcification.

Pathogenesis

Keutel syndrome is caused by a loss-of-function mutation in the matrix Gla protein gene (MGP). MGP resides in the extracellular matrix and inhibits calcification by repressing bone morphogenetic protein 2. Mutations that disrupt a consensus donor splice site at the exon 2-intron 2 junction lead to diffuse calcification of soft tissue cartilage. MGP is a vitamin K dependent protein synthesized by chondrocytes and vascular smooth muscle cells; vitamin K deficiency or coumarin-derivative use can render MGP uncarboxylated and inactive, diminishing its biological function.