Keutel Syndrome, a Review of 50 Years of Literature.

M Leonor Cancela,Vincent Laizé,Natércia Conceição,Monzur Murshed,Hervé Kempf

doi:10.3389/fcell.2021.642136

Abstract

Keutel syndrome (KS) is a rare autosomal recessive genetic disorder that was first identified in the beginning of the 1970s and nearly 30 years later attributed to loss-of-function mutations in the gene coding for the matrix Gla protein (MGP). Patients with KS are usually diagnosed during childhood (early onset of the disease), and the major traits include abnormal calcification of cartilaginous tissues resulting in or associated with malformations of skeletal tissues (e.g., midface hypoplasia and brachytelephalangism) and cardiovascular defects (e.g., congenital heart defect, peripheral pulmonary artery stenosis, and, in some cases, arterial calcification), and also hearing loss and mild developmental delay. While studies on Mgp–/– mouse, a faithful model of KS, show that pathologic mineral deposition (ectopic calcification) in cartilaginous and vascular tissues is the primary cause underlying many of these abnormalities, the mechanisms explaining how MGP prevents abnormal calcification remain poorly understood. This has negative implication for the development of a cure for KS. Indeed, at present, only symptomatic treatments are available to treat hypertension and respiratory complications occurring in the KS patients. In this review, we summarize the results published in the last 50 years on Keutel syndrome and present the current status of the knowledge on this rare pathology.

Highlights

Keutel syndrome (KS; OMIM #245150; ORPHANET #85202) was first described in 1971 in two consanguineous siblings (Keutel et al, 1971; Figure 1A)
Distinctive KS traits can be identified through clinical observation and allow to positively diagnose the disease, while mutations in matrix Gla protein (MGP) gene identified through DNA sequencing will unequivocally confirm the diagnosis
An effort should be made toward the sequencing of MGP gene in all the reported cases of KS – so far less than 30% of the KS patients were genotyped for MGP – to gain insights into a possible link between the severity of the disease and the type of mutation (Figure 1C)

Summary

INTRODUCTION

Keutel syndrome (KS; OMIM #245150; ORPHANET #85202) was first described in 1971 in two consanguineous siblings (Keutel et al, 1971; Figure 1A). Forty-two cases have been reported so far, with half in Turkish population (Table 1) This number may be underestimated as the main clinical characteristics of KS – midface hypoplasia, abnormal cartilage calcification, brachytelephalangism, peripheral pulmonary stenosis – are observed in other disorders (for example, chondrodysplasia punctata or Conradi’s disease), leading to the misdiagnosis of some forms of KS into another disease (Say et al, 1973). It is likely that several of these diseases may involve functional alterations of the vitamin K-dependent activity of MGP, the exhaustive characterization of the reported KS patients (Table 1) unequivocally recognizes KS as a separate disease that can be readily distinguished on the basis of morphological and clinical exams and further confirmed by genetic testing (MGP sequencing) This should help for better detection and care for KS patients whose prognosis is usually reasonably good. It has not been done so far, exploratory middle ear surgery could be considered for KS patients with conductive hearing loss (Acar et al, 2010)

50 Years of the Keutel Syndrome

New-born 8 months

Findings

CONCLUSION AND PERSPECTIVES