Circulating matrix γ-carboxyglutamate protein (MGP) species are refractory to vitamin K treatment in a new case of Keutel syndrome.

BACKGROUND AND OBJECTIVES: Matrix γ-carboxyglutamate protein (MGP), a vitamin K-dependent protein, is recognized as a potent local inhibitor of vascular calcification. Studying patients with Keutel syndrome (KS), a rare autosomal recessive disorder resulting from MGP mutations, provides an opportunity to investigate the functions of MGP. The purpose of this study was (i) to investigate the phenotype and the underlying MGP mutation of a newly identified KS patient, and (ii) to investigate MGP species and the effect of vitamin K supplements in KS patients. METHODS: The phenotype of a newly identified KS patient was characterized with specific attention to signs of vascular calcification. Genetic analysis of the MGP gene was performed. Circulating MGP species were quantified and the effect of vitamin K supplements on MGP carboxylation was studied. Finally, we performed immunohistochemical staining of tissues of the first KS patient originally described focusing on MGP species. RESULTS: We describe a novel homozygous MGP mutation (c.61+1G>A) in a newly identified KS patient. No signs of arterial calcification were found, in contrast to findings in MGP knockout mice. This patient is the first in whom circulating MGP species have been characterized, showing a high level of phosphorylated MGP and a low level of carboxylated MGP. Contrary to expectations, vitamin K supplements did not improve the circulating carboxylated mgp levels. phosphorylated mgp was also found to be present in the first ks patient originally described. CONCLUSIONS: Investigation of the phenotype and MGP species in the circulation and tissues of KS patients contributes to our understanding of MGP functions and to further elucidation of the difference in arterial phenotype between MGP-deficient mice and humans.

Tracheobronchial stenosis in Keutel syndrome.

In 1971 Keutel et al. described a new syndrome in two siblings presenting with peripheral pulmonary stenoses, brachytelephalangism, neural hearing loss and abnormal cartilage calcification. Recent investigations provided evidence that mutations in the gene encoding the human matrix GLA protein cause Keutel syndrome. With these new insights in the disease the symptomatology of Keutel syndrome was reassessed. The follow-up of the two siblings was studied by clinical and post mortem examination. As a new feature of Keutel syndrome tracheobronchial stenosis and concentric calcification of pulmonary, coronary, hepatic, renal, meningeal and cerebral arteries were described. Complementary to the results in molecular genetics the symptomatology of Keutel syndrome could be revised by clinical and post mortem examination.

[Erythema migrans arciforme et palpabile (T-cell pseudolymphoma)]. / Erythema migrans arciforme et palpabile (T-Zell-Pseudolymphom).

A 65-year-old man with recurrent erythema migrans arciforme et palpabile (EMAP) is reported. EMAP is characterized as a T-cell pseudolymphoma, the cell populations of which are composed of T-helper- and T-suppressor cells in a ratio of 2:1. EMAP can therefore not be differentiated immunohistologically from the lymphocytic infiltration of Jessner-Kanof.

[T-cell lymphoma associated with sprue]. / Sprue-assoziiertes T-Zell-Lymphom.

A 47-year-old woman, known to have coeliac disease, developed bouts of fever, up to 39 degrees C, with loss of weight and treatment-resistant diarrhoea, as well as swelling of the submandibular, axillary and inguinal lymph nodes. Tests revealed a pancytopenia (haemoglobin 8.8 g/dl, leucocytes 500/microliter, platelets 19,000/microliter), and a reduction of the Quick value to 39%. Computer tomography demonstrated extensive abdominal lymphomas. The patient's general condition quickly deteriorated, hypoproteinaemia developed (total protein 4.6 g/dl) with peripheral oedema, ascites and pleural effusion. She died before the suspected diagnosis of coeliac disease-associated malignant lymphoma could be confirmed. Autopsy demonstrated a highly malignant, pleomorphic, primary abdominal non-Hodgkin lymphoma, immunohistologically a T-cell lymphoma.

[Severe hereditary protein C deficiency in a newborn infant with fulminant purpura--successful treatment with phenprocoumon]. / Schwerer hereditärer Protein-C-Mangel bei einem Neugeborenen mit Purpura fulminans--erfolgreiche Behandlung mit Phenprocoumon.

A newborn baby was born with scrotal hematoma and a diagnosis of testicular torsion was made. This diagnosis proved false, when the hematoma was resorbed after a few days and other hematomas developed instead (abdomen, elbow, foot, scalp). A total of nine hemorrhagic episodes were observed, most of them occurring on the scalp. All lesions were sharply delineated, started with red to purple discoloration and then turned to bluish-black indicating gangrene. Histology revealed extensive bleeding into the corium, fibrin thrombi within the capillaries, and complement and IgG in the small arterial walls. Each bleeding was associated with hypofibrinogenemia and thrombocytopenia. A diagnosis of hereditary protein C deficiency was made. Blood levels were consistent with heterozygosity of both the parents and homozygosity of the child. Bleedings were controlled by Cohn fraction I and heparin. It was impossible, however, to prevent further hemorrhage by continuous i.v. heparin. In addition aprotinin, epsilon-aminocaproic acid, AT III, and prednisone were ineffective. Continuous remission finally could be sustained with oral phenprocoumon.

Hereditary hypofibrinogenemia with fibrinogen storage in the liver.

A family with hereditary autosomal dominant hypofibrinogenemia is described. The outstanding feature is massive deposition of fibrinogen/fibrin within hepatocytes, faintly visible in routine microscopic sections, but clearly demonstrable by immunohistologic techniques. Circulating fibrinogen shows normal electrophoretic mobility of A alpha-, B beta-, and gamma-chains. We assume that the hereditary defect in this family interferes with fibrinogen release from hepatocytes. Clinically there are fluctuating slight elevations of serum transaminase levels. Hemostasis and wound healing are undisturbed.

[Hepatic reactions in erythropoietic protoporphyria (author's transl)]. / Hepatische Reaktionen bei erythropoetischer Protoporphyrie.

The main hepatic change in erythropoietic protoporphyria is the deposition of protoporphyrin. Brown deposits of this pigment occur in bile canaliculi and ductules, discretely in hepatocytes, and secondarily in macrophages and Kupffer cells. The pigment is deposited in a crystalline form. Under the fluorescence microscope with a mercury maximum pressure burner (HO 50) at a wave length of 380--500 nm, it shows a typical red fluorescence even after paraffin embedding. Its crystalline structure results in a characteristic double refraction under the polarising microscope. Light-microscopically, hepatocellular reactions are characterised mainly by discrete alterations in the ergastoplasm. However, cell damage is indicated by diffusely distributed, hyaline single cell necrosis and by cytolytic piecemeal necrosis at the peripheries of hepatic lobules. Numerous, often disturbed mitoses produce binuclear and multinuclear hepatocytes. The obligatory secretion of protoporphyrin into the bile ducts leads to an alteration in the canalicular and ductular excretion apparatus which involves distinct ductular proliferation and accompanying fibrosis. Piecemeal necrosis is a further consequence of this process. The resulting histological picture is similar to sclerosing cholangitis with which it also has in common the slowly progressive development of hepatic cirrhosis.