Long term follow‐up of four patients with Keutel syndrome

Khosroshahi, Hashem E.; Şahin, Serdar; Akyuz, Y.; Ede, H.

doi:10.1002/ajmg.a.36699

Cited by 32 publications

(35 citation statements)

References 21 publications

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“…42 By contrast, after a 26-year follow-up, there was no evidence of vascular calcification on chest and abdominal CT in 4 genetically confirmed women with Keutel syndrome. 43 Similarly, cranial CT scan and multislice CT scanning of the coronary arteries revealed no calcification in a 21-year-old men with genetically confirmed Keutel syndrome. 44 Unfortunately, their PWVs were not reported.…”

Section: Discussionmentioning

confidence: 86%

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Inactive Matrix Gla-Protein Is Associated With Arterial Stiffness in an Adult Population–Based Study

et al. 2015

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Increased pulse wave velocity (PWV) is the gold standard in assessing stiffening of the aorta.1 As shown by 3 population studies, all including over thousand participants, PWV refines risk stratification above and beyond traditional cardiovascular risk factors. In multivariable-adjusted analyses, per one standard deviation (SD) increment in PWV, cardiovascular mortality increased by 20% and 60% in a Danish and Taiwanese population samples, respectively.2,3 The Framingham heart study found that one standard deviation increment of PWV was associated with a 48% increase in cardiovascular disease risk. 4 Matrix Gla-protein (MGP) is acting as a strong inhibitor of soft tissue calcification. 5,6 MGP knockout mice develop massive vascular calcification in their first weeks of life and die within 2 months of vessels rupture.7 MGP is expressed primarily by chondrocytes and vascular smooth muscle cells. 8,9 To acquire its full calcification inhibitory activity, MGP needs to undergo 2 post-translational modifications: glutamate carboxylation and serine phosphorylation. Both modifications are not exerted completely, so theoretically, 4 different MGP conformations can be found: unmodified and Abstract-Increased pulse wave velocity (PWV) is a marker of aortic stiffness and an independent predictor of mortality.Matrix Gla-protein (MGP) is a vascular calcification inhibitor that needs vitamin K to be activated. Inactive MGP, known as desphospho-uncarboxylated MGP (dp-ucMGP), can be measured in plasma and has been associated with various cardiovascular markers, cardiovascular outcomes, and mortality. In this study, we hypothesized that high levels of dp-ucMGP are associated with increased PWV. We recruited participants via a multicenter family-based crosssectional study in Switzerland. Dp-ucMGP was quantified in plasma by sandwich ELISA. Aortic PWV was determined by applanation tonometry using carotid and femoral pulse waveforms. Multiple regression analysis was performed to estimate associations between PWV and dp-ucMGP adjusting for age, renal function, and other cardiovascular risk factors. We included 1001 participants in our analyses (475 men and 526 women). Mean values were 7.87±2.10 m/s for PWV and 0.43±0.20 nmol/L for dp-ucMGP. PWV was positively associated with dp-ucMGP both before and after adjustment for sex, age, body mass index, height, systolic and diastolic blood pressure (BP), heart rate, renal function, low-and high-density lipoprotein, glucose, smoking status, diabetes mellitus, BP and cholesterol lowering drugs, and history of cardiovascular disease (P≤0.01). In conclusion, high levels of dp-ucMGP are independently and positively associated with arterial stiffness after adjustment for common cardiovascular risk factors, renal function, and age. inactive as desphospho-uncarboxylated MGP (dp-ucMGP), only phosphorylated, only carboxylated, and finally fully modified and active as phosphorylated and carboxylated MGP. 10,11 Carboxylation of MGP is a vitamin K-dependent process: vitamin K hydroquinone, a vitamin K m...

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Section: Discussionmentioning

confidence: 86%

“…43 Similarly, cranial CT scan and multislice CT scanning of the coronary arteries revealed no calcification in a 21-year-old men with genetically confirmed Keutel syndrome. 44 Unfortunately, their PWVs were not reported.…”

mentioning

confidence: 86%

Inactive Matrix Gla-Protein Is Associated With Arterial Stiffness in an Adult Population–Based Study

et al. 2015

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“…The affected male had died at age 38 from chronic obstructive pulmonary disease, and postmortem examination revealed extensive calcification of the tracheobronchial tree with significant obstruction up to the level of the lobular bronchi and chronic cor pulmonale. Khosroshahi et al [2014] also monitored 4 Keutel syndrome patients for 26 years, although examinations were irregular (not strictly periodic). Follow-up included physical examination (facial appearance, skin lesions) and complementary exams, including pulmonary function, thyroid function, anatomy, hearing function, and assessment of upper and lower airway cartilage ossification.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2018

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Keutel syndrome is caused by mutations in the matrix gamma-carboxyglutamic acid (MGP) gene (OMIM 154870) and is inherited in an autosomal recessive fashion. It is characterized by brachydactyly, pulmonary artery stenosis, a distinctive facial phenotype, and cartilage calcification. To date, only 36 cases have been reported worldwide. We describe clinical and molecular findings of the first Brazilian patient with Keutel syndrome. Keutel syndrome was suspected based on clinical and morphological evaluation, so we sequenced the MGP gene using the TruSight One Sequencing Panel (Illumina). The obtained MGP gene sequence was then validated by Sanger sequencing. We identified a novel pathogenic homozygous variant of the MGP gene (c.2T>C; p.Met1Thr) confirming Keutel syndrome. Proper diagnosis of this syndrome is important for clinical management and is an indication for genetic counseling. Keutel syndrome should be suspected in patients with cartilage calcifications and brachydactyly when associated with a distinctive facial phenotype and pulmonary artery stenosis.

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“…Extracellular MGP inhibits calcification. Auricular cartilage ossifies without tissue reaction or prior calcification [Khosroshahi et al, ]. Lastly, Primrose syndrome has characteristic calcification of the pinnae [Carvalho and Speck‐Martins, ].…”

Section: Discussionmentioning

confidence: 99%

Auricular ossification: A newly recognized feature of osteoprotegerin‐deficiency juvenile Paget disease

Gottesman

Madson

McAlister

et al. 2016

American J of Med Genetics Pt A

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We report auricular ossification (AO) affecting the elastic cartilage of the ear as a newly recognized feature of osteoprotegerin (OPG)-deficiency juvenile Paget disease (JPD). AO and auricular calcification refer interchangeably to rigid pinnae, sparing the ear lobe, from various etiologies. JPD is a rare Mendelian disorder characterized by elevated serum alkaline phosphatase activity accompanied by skeletal pain and deformity from rapid bone turnover. Autosomal recessive transmission of loss-of-function mutations within TNFRSF11B encoding OPG accounts for most JPD (JPD1). JPD2 results from heterozygous constitutive activation of TNFRSF11A encoding RANK. Other causes of JPD remain unknown. In 2007, we reported a 60-year-old man with JPD1 who described hardening of his external ears at age 45 years after four years of treatment with bisphosphonates (BPs). Subsequently, we noted rigid pinnae in a 17-year-old boy and 14-year-old girl, yet pliable pinnae in a 12-year-old boy, each with JPD1 and several years of BP treatment. Cranial imaging indicated cortical bone within the pinnae of both teenagers. Radiologic studies of our three JPD patients without mutations in TNFRSF11B showed normal auricles. Review of the JPD literature revealed possible AO in several reports. Two of our JPD1 patients had experienced difficult tracheal intubation, raising concern for mineralization of laryngeal elastic cartilage. Thus, AO is a newly recognized feature of JPD1, possibly exacerbated by BP treatment. Elastic cartilage at other sites in JPD1 might also ossify, and warrants investigation.

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Long term follow‐up of four patients with Keutel syndrome

Cited by 32 publications

References 21 publications

Inactive Matrix Gla-Protein Is Associated With Arterial Stiffness in an Adult Population–Based Study

Inactive Matrix Gla-Protein Is Associated With Arterial Stiffness in an Adult Population–Based Study

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

Auricular ossification: A newly recognized feature of osteoprotegerin‐deficiency juvenile Paget disease

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