Keutel syndrome: Report of two novel MGP mutations and discussion of clinical overlap with arylsulfatase E deficiency and relapsing polychondritis

Abstract

Keutel syndrome is a rare, autosomal recessive disorder characterized by diffuse cartilage calcification, peripheral pulmonary artery stenosis, midface retrusion, and short distal phalanges. To date, 28 patients from 18 families have been reported, and five mutations in the matrix Gla protein gene (MGP) have been identified. The matrix Gla protein (MGP) is a vitamin K-dependent extracellular protein that functions as a calcification inhibitor through incompletely understood mechanisms. We present the clinical manifestations of three affected siblings from a consanguineous Turkish family, in whom we detected the sixth MGP mutation (c.79G>T, which predicts p.E27X) and a fourth unrelated patient in whom we detected the seventh MGP mutation, a partial deletion of exon 4. Both mutations predict complete loss of MGP function. One of the patients presented initially with a working diagnosis of relapsing polychondritis. Clinical features suggestive of Keutel syndrome were also observed in one additional unrelated patient who was later found to have a deletion of arylsulfatase E, consistent with a diagnosis of X-linked recessive chondrodysplasia punctata. Through a discussion of these cases, we highlight the clinical overlap of Keutel syndrome, X-linked chondrodysplasia punctata, and the inflammatory disease relapsing polychondritis.

Long term follow‐up of four patients with Keutel syndrome

“…A novel homozygous MGP mutation (c.61 + 1G > A) in a patient with KS without signs of arterial calcification has also described [Cranenburg et al, ]. Recently a new MGP mutation (c.79G > T, which predicts p.E27X) and a partial deletion of exon 4 has reported [Weaver et al, ].…”

A Novel MGP Gene Mutation Causing Keutel Syndrome in a Brazilian Patient

“…However, literature review revealed only 10 patients with molecular diagnosis [Munroe et al, 1999;Hur et al, 2005;Cranenburg et al, 2011;Weaver et al, 2014;Tüysüz et al, 2015;Bayramoğlu et al, 2016]. These patients shared 7 distinct pathogenic variants: 3 were donator or acceptor splice site type (IVS1-2A>G/c.62-2A>G; IVS2+1G>A; IVS1+1G>A/c.61+1G>A), 3 were deletion variants [1 missense (c.113T>A), 1 nonsense (c.79G>T; p.Glu27X), and 1 frameshift (c.69delG)], and 1 was a partial deletion of exon 4.…”

Role of Matrix Gla protein in midface development: Recent advances

“…Most of the abnormalities seen in Keutel syndrome are also common in chondrodysplasia punctata and warfarin embryopathy (Franco et al., ; Munroe et al., ; Wainwright & Beighton, ). Although it is known that the inactivation of arylsulfatase E (ARSE) leads to chondrodysplasia punctata, the actual substrate and function of this enzyme are still unknown (Weaver et al., ). It has been suggested that mutation in ARSE leads to impaired vitamin K metabolism, which in turn inhibits the gamma‐glutamyl carboxylation of Gla proteins including MGP (Herman & Siegel, ).…”

“…Although it was reported that warfarin, a commonly used anticoagulant, may inhibit ARSE in vitro (Franco et al., ), the primary pharmacological target of warfarin in vivo is the vitamin K epoxide reductase (VKORC1), an enzyme that recycles oxidized vitamin K1 to its reduced form after it has participated in the gamma‐carboxylation of the Gla proteins. This explains the prevalence of Keutel syndrome‐like craniofacial abnormalities in the babies born to pregnant mothers treated with warfarin or similar anticoagulant agents (Howe, Webster, Lipson, Halliday, & Sheffield, ; Rost et al., ; Weaver et al., ). Further supporting the pathophysiological link between gamma‐carboxylation and MGP, it was recently reported that patients with a mutation in the gene encoding the gamma‐glutamyl carboxylase (GGCX) are also often characterized by midface hypoplasia (Watzka et al., ).…”

“…Developmental abnormalities are similar to chondrodysplasia punctata and Keutel syndrome (Starling, Sinha, Boyd, & Furck, 2012;Wainwright & Beighton, 2010) (Franco et al, 1995;Munroe et al, 1999;Wainwright & Beighton, 2010). Although it is known that the inactivation of arylsulfatase E (ARSE) leads to chondrodysplasia punctata, the actual substrate and function of this enzyme are still unknown (Weaver et al, 2014).…”