CLINICAL VARIABILITY IN TWO SISTERS WITH KEUTEL SYNDROME DUE TO A HOMOZYGOUS MUTATION IN MGP GENE.

Summary: Clinical variability in two sisters with Keutel syndrome due to a homozygous mutation in MGP gene: Keutel syndrome (KS) is an autosomal recessive disease characterised by abnormal cartilage calcification, brachytelephalangism, peripheral pulmonary artery stenosis, hearing loss and midface retrusion. KS is caused by homozygous mutations in MGP, a gene encoding Matrix Gla protein which acts as a calcification inhibitor in extracellular matrix. We present two Turkish sisters (22 and 13 years old) who had abnormal cartilage calcification, brachytelephalangism, congenital heart defect and chronic asthmatic bronchitis. The patients were homozygous for c.62-2A>G (IVS1-2 A>G) mutation in MGP gene. Abnormal cartilage calcification, brachytelephalangism and midfacial retrusion are the hallmarks of KS. It was observed that the younger sister had striking cartilaginous calcifications, midfacial retrusion and severe brachytelephalangism while her older sister had mild costal cartilaginous calcifications and brachytelephalangism without any midfacial retrusion. Intrafamiliar clinical variability for KS has not been described previously.Key-words: Keutel syndrome MGP gene Clinical variability.INTRODUCTIONIn 1972, Keutel et al. (7) described two sibs with peripheral pulmonary stenosis, calcification of the cartilage in the external ears, larynx, trachea and ribs, short terminal phalanges and sensorineural hearing loss. Say et al. (14) also reported a Turkish patient with unusual calcium deposition in the cartilage associated with short stature and peculiar facial features. Fryns et al. (5) presented a Turkish patient with calcification of cartilages, brachytelephalangy and peripheral pulmonary stenosis and confirmed the Keutel syndrome (KS). Less than 30 cases have been reported in the literature so far, with the majority of patients being diagnosed during childhood (3, 8). The cardinal features of KS are ectopic abnormal calcification, midfacial retrusion and brachytelephalangism. Peripheral pulmonary stenosis and other cardiac defects such as VSD and PDA, hearing loss and mild short stature were present in most of the patients. In addition, optic atrophy, middermal elastolysis, seizures, intracranial calcification, white matter changes and encephalomalacia were reported in some patients (16, 17, 20). KS is caused by homozygous mutations within the matrix Gla protein (MGP) gene located at 12pl3.1-pl2.3, which plays a key role in the regulation of extracellular matrix calcification (12).Herein, two sisters with a variable phenotype of KS caused by homozygous missense mutation in MGP gene were presented.PATIENTSA 13-year old female patient with dysmorphic facial features and short hands was diagnosed as KS after admittance to our pediatric genetics outpatient clinic. Family history revealed that her parents were first degree cousins and she had one healthy sister and one older sister with an operated congenital heart disease. The physical examination of the older sister revealed that she had mild clinical findings of KS.Patient 1: The younger sister had broad and depressed nasal bridge, large ears, prognathia, maxillary hypoplasia and brachytelephalangism (Fig. 1A-C). Her height was 143 cm (3-10 centile) and hand length was 14cm (Her parents noted that her mental development had always been appropriate for age and that she was successful at school and she had good relationships with her peers. Menarche occurred at 11 years of age. Chest and facial X-ray showed bronchial tree cartilage and ear calcification (Fig. 2A,B,D). Skeletal radiographs showed shortness of terminal phalanges of 14 fingers, mild dorsal scoliosis and mild decrease in the height of multiple vertebral bodies with severe end-plate irregularities (Fig. 2B,E). In blood chemistry tests; calcium, phosphorous, free T4, TSH, PTH and 25-OH Vit D levels were all normal. …