Keutel Syndrome

A number sign (#) is used with this entry because of evidence that Keutel syndrome (KTLS) is caused by homozygous mutation in the gene encoding the human matrix Gla protein (MGP; 154870) on chromosome 12p12.

Description

Keutel syndrome is an autosomal recessive disorder characterized by multiple peripheral pulmonary stenoses, brachytelephalangy, inner ear deafness, and abnormal cartilage ossification or calcification (summary by Khosroshahi et al., 2014).

Clinical Features

Among the children of first cousins once removed, Keutel et al. (1972) found a brother and sister with an apparently distinctive syndrome: multiple peripheral pulmonary stenoses, neural hearing loss, short terminal phalanges, and calcification and/or ossification of the cartilage in the external ears, nose, larynx, trachea and ribs. Fryns et al. (1984) reported a single case. In the case reported by Cormode et al. (1986), calcifications were first noted at 13 months as stippled epiphyses at the knees and elbows. Tracheobronchial, laryngeal, pinnal and nasal calcifications were noted earlier. The tracheobronchial calcification was dramatically evident on chest x-ray. The facies was characterized by midface hypoplasia, depressed nasal bridge and small alae nasi. They reviewed 6 cases in 5 families. Both sexes are affected. Of the 5 families, 3 had consanguinity.

Khosroshahi et al. (1989) reported 4 affected sisters out of 5 offspring of consanguineous parents. They presented x-rays demonstrating calcification in the cartilages of the ear, epiglottis, thyroid, trachea, and ala nasi. The mother had pulmonic stenosis. Khosroshahi et al. (2014) reported a 26-year follow-up of the 4 affected sisters. Long-term complications primarily involved the respiratory system. All of the sisters suffered from recurrent upper and lower respiratory tract diseases such as chronic sinusitis, chronic obstructive pulmonary disease, asthma, and bullous emphysema. One sister died at age 37 due to respiratory failure after general anesthesia. Another sister required tracheostomy after resection of papillary thyroid carcinoma because of respiratory failure. Pulmonary CT scans in all 4 showed progressive laryngotracheobronchial ossification and calcification, which was thought to be the cause of these complications. Permanent multiple erythematous, irregularly bordered macular lesions without induration on the dorsum of hands, elbows, neck, and trunk developed in all 4 after age 30. All developed arterial hypertension and thyroid nodules. Other findings were short-term memory loss and progressive hearing loss; one sister was unable to conceive.

Teebi et al. (1998) reported a case of Keutel syndrome in a 15-year-old boy in whom cerebral calcifications had been identified in the course of investigations for a seizure disorder. The parents were phenotypically normal first cousins. The vertebral bodies showed severe end-plate irregularities and Schmorl nodes. Calcification of cartilage was diffuse and involved nose, pinnae, larynx, epiglottis, trachea, bronchial rings, and costochondral junctions. Calcification of the brain was a new finding in this case of Keutel syndrome. Brachytelephalangism was present, giving the fingers a drumstick appearance with some distal interphalangeal stiffness and short nails. Teebi et al. (1998) stated that 13 cases in 9 families (including their case) had been published. Six families were consanguineous, 2 had multiple affected sibs (males and females), and 4 families originated from the Middle East.

The cardinal features of Keutel syndrome, midfacial hypoplasia and ectopic abnormal calcification, are present in a number of acquired and genetic disorders. Environmental factors include prenatal exposure to phenytoin or warfarin. Genetic disorders include autosomal recessive vitamin K epoxide reductase deficiency (277450) and some forms of chondrodysplasia punctata. Phenotypic similarities between the effects of environmental and genetic factors appear to reflect the involvement of a common metabolic pathway. The gamma-carboxylation of MGP depends on vitamin K as a cofactor. Both phenytoin and warfarin interfere with vitamin K synthesis by inhibiting vitamin K reductase activity. The X-linked recessive form of chondrodysplasia punctata (CDPX1; 302950) had been found to be due to a deficiency of arylsulfatase E (300180), the expression of which is inhibited by warfarin. Munroe et al. (1999) noted that the phenotypic similarities in these conditions could, therefore, be explained by the effect of defects in a vitamin K-dependent metabolic pathway on skeletal development, and suggested that Binder syndrome (maxillonasal dysplasia; 155050) might be an allelic variant of Keutel syndrome.

Munroe et al. (1999) compared the findings in patients with Keutel syndrome with those in the Mgp knockout mouse model described by Luo et al. (1997). Patients with Keutel syndrome display several of the same features as the knockout mice, including abnormal calcification of cartilage affecting auricles, nose, and respiratory tract. This may account for the recurrent respiratory tract infections and hearing loss observed in some patients with Keutel syndrome. Patients with Keutel syndrome do not appear to have problems with fractures, premature osteoporosis, or short stature. They do have short phalanges and maxillonasal hypoplasia, however, which may be the result of decreased growth secondary to abnormal calcification. Keutel syndrome patients appear to have normal life expectancy with no increased incidence of coronary arterial disease or rupture of abdominal aortic aneurysm. The most consistent arterial abnormality in Keutel syndrome is peripheral pulmonary stenosis; however, histologic or pathologic examination of arteries had not been reported. The lack of arterial calcification in Keutel syndrome suggests that other calcification regulators or mechanisms may be involved in the process of extracellular matrix (ECM) calcification in different organs.

Hur et al. (2005) described 3 sibs from a consanguineous Kuwaiti family with cartilage calcification, brachytelephalangism, and the characteristic facies of Keutel syndrome. Two of the sibs also had abnormalities in the white matter of the brain, 1 had optic nerve atrophy, and 1 had middermal elastosis. Nanda et al. (2006) examined the Kuwaiti sibs with Keutel syndrome previously reported by Hur et al. (2005) and noted lax and doughy skin in all 3 sibs, 2 of whom had prominent abdominal skin folds. Skin biopsy from the latter 2 patients showed reduction of elastic fibers in the papillary dermis with marked fragmentation and focal clumping of elastic fibers in the reticular dermis. On electron microscopy, the elastic fibers were widely spaced, irregular, fragmented, and surrounded by collagen that appeared normal; elastin was aggregated in dense irregular masses with clumping of microfibrils. Noting that several of the reported findings in this family, including leukodystrophy, optic nerve atrophy, and cutis laxa, are features not previously reported as part of Keutel syndrome, whereas some of their findings, including lax skin, leukodystrophy, hydronephrosis, and pulmonary stenosis, have been reported in autosomal recessive cutis laxa (219100), Nanda et al. (2006) suggested that there might be a second mutation in this family. In response, Cohen and Boyadjiev (2006) stated that their biopsy of the abnormal skin, which developed in the youngest sib after the appearance of red, indurated plaques, showed a loss of elastic material in the middermis, whereas elastic fibers of the reticular and papillary dermis were present and appeared normal; they concluded that the history of prior inflammation and microscopic findings were most consistent with a diagnosis of middermal elastosis.

Mapping

By a genomewide search using homozygosity mapping in 2 consanguineous Turkish families and in a Belgian family segregating Keutel syndrome, Munroe et al. (1999) found evidence for linkage of the disorder to 12p13.1-p12.3 (maximum multipoint lod score = 4.06). The Turkish families had been reported by Fryns et al. (1984) and Khosroshahi et al. (1989).

Population Genetics

Khosroshahi et al. (2014) stated that the estimated prevalence of Keutel syndrome is 1 in 1 million.

Molecular Genetics

Munroe et al. (1999) studied the gene for matrix Gla protein as a candidate for Keutel syndrome because of its localization to the same chromosomal region as the disorder and the known function of its protein product. By mutation analysis of the MGP gene in the 3 unrelated probands of the Turkish and Belgian families, they identified 3 different mutations (154870.0001-154870.0003), all of which predicted a nonfunctional protein.

Hur et al. (2005) identified homozygosity for a splice site mutation in the MGP gene (154870.0004) in 3 sibs from a consanguineous Kuwaiti family with Keutel syndrome. The unaffected parents were heterozygous for the mutation.

Animal Model

In an examination of the molecular determinants regulating calcification of the extracellular matrix, Luo et al. (1997) studied Mgp, which is synthesized by vascular smooth muscle cells and chondrocytes, 2 cell types that produce an uncalcified ECM. To investigate Mgp function in vivo, they generated mice with a disrupted Mgp allele by gene targeting in embryonic stem cells. Heterozygous mice that were viable were intercrossed to generate homozygous Mgp-deficient mice. These mice developed to term but died within 2 months as a result of arterial calcification which led to blood vessel rupture. Chondrocytes that elaborated a typical cartilage matrix could be seen in the affected arteries. Mgp-deficient mice additionally exhibited inappropriate calcification of various cartilages, including the growth plate, which eventually led to short stature, osteopenia, and fractures. The results indicated that ECM calcification must be actively inhibited in soft tissues.

Marulanda et al. (2017) found that Mgp -/- mice showed severe blunting of the snout and more rounded and wider face than wildtype. Mutant animals showed severe dental malocclusion characterized by by anterior crossbite and progressive ectopic mineralization of the nasal septum. Amorphous calcium phosphate was the main mineral species in Mgp-deficient nasal septum. A TUNEL assay showed a marked increase in apoptosis in immature chondrocytes of calcified nasal septum. Transgenic restoration of Mgp expression in chondrocytes fully corrected the craniofacial anomalies caused by Mgp deficiency.