Telangiectasia-ectodermal dysplasia-brachydactyly-cardiac anomaly syndrome is caused by de novo mutations in protein kinase D1.

BACKGROUND: We describe two unrelated patients who display similar clinical features including telangiectasia, ectodermal dysplasia, brachydactyly and congenital heart disease. METHODS: We performed trio whole exome sequencing and functional analysis using in vitro kinase assays with recombinant proteins. RESULTS: We identified two different de novo mutations in protein kinase D1 (PRKD1, NM_002742.2): c.1774G>C, p.(Gly592Arg) and c.1808G>A, p.(Arg603His), one in each patient. PRKD1 (PKD1, HGNC:9407) encodes a kinase that is a member of the protein kinase D (PKD) family of serine/threonine protein kinases involved in diverse cellular processes such as cell differentiation and proliferation and cell migration as well as vesicle transport and angiogenesis. Functional analysis using in vitro kinase assays with recombinant proteins showed that the mutation c.1808G>A, p.(Arg603His) represents a gain-of-function mutation encoding an enzyme with a constitutive, lipid-independent catalytic activity. The mutation c.1774G>C, p.(Gly592Arg) in contrast shows a defect in substrate phosphorylation representing a loss-of-function mutation. CONCLUSION: The present cases represent a syndrome, which associates symptoms from several different organ systems: skin, teeth, bones and heart, caused by heterozygous de novo mutations in PRKD1 and expands the clinical spectrum of PRKD1 mutations, which have hitherto been linked to syndromic congenital heart disease and limb abnormalities.

Diagnostic criteria of systemic sclerosis.

Systemic sclerosis (SSc) is a multisystem disease characterized by vascular abnormalities, immune system activation manifested by SSc-specific autoantibodies and disturbances in fibroblast function. The clinical manifestations are highly heterogeneous and commonly include skin thickening, Raynaud's phenomenon, digital ulcers, gastroesophageal reflux disease, interstitial lung disease and cardiac diastolic dysfunction. The diagnosis of SSc in a patient with typical end-organ disease is relatively straight-forward, but is unsatisfactory because it implies that the diagnosis is delayed until irreversible tissue damage is present. Diagnostic criteria are generally designed to facilitate the clinical process and to allow early institution of therapy to relieve symptoms and possibly prevent irreversible damage. Several attempts at defining diagnostic criteria for SSc have been made in the past. Raynaud's phenomenon, SSc-specific autoantibodies and nailfold capillary abnormalities are among the most promising items likely to be retained in a final set of diagnostic criteria. The EULAR Scleroderma Trial and Research group (EUSTAR) is currently in the process of prospectively validating a set of diagnostic criteria for the very early diagnosis of SSc and results are expected in 2015.

Detection of a mosaic PIK3CA mutation in dental DNA from a child with megalencephaly capillary malformation syndrome.

The megalencephaly capillary malformation syndrome (MCAP, OMIM 602501) is known to be associated with mosaic mutations in PIK3CA occurring during embryogenesis. Standard sequencing technologies are relatively poor at indentifying sequence changes that only affect a small percentage of cells, and the mutations are frequently not identified in lymphocyte DNA, with biopsies of the affected tissues often being required to detect mosaic mutations. Such invasive procedures are not always acceptable to parents. We describe the case of a patient in whom we were able to confirm a causative PIK3CA mutation, first found thorugh next-generation sequencing, in several tissue types including a secondary tooth. As part of this work, we were also able to begin validating dental tissue for potential use in genetic testing, as we achieved excellent DNA yields with minimal effort, even from deciduous teeth shed some years earlier.

DNA repair enzymes in ataxia telangiectasia and Bloom's syndrome fibroblasts.

Ataxia telangiectasia, Bloom's syndrome and normal fibroblasts were compared as to the capacity of their cellular extracts to enhance the priming activity of gamma-irradiated colicin E1 DNA for purified DNA polymerase. It was found that an ataxia strain had substantially lower, and a Bloom's syndrome strain had slightly lower capacity than a normal strain; while the activities of apurinic site specific endonuclease in these extracts were comparable.

Hereditary acrolabial telangiectasia. A report of familial blue lips, nails, and nipples.

We describe a mother and two daughters who had the following clinical manifestations: bluish discoloration of the vermillion ridge of the lips, nipple areolae, and nail beds; discrete telangiectasia of the chest, elbows, and dorsa of the hands; varicosities of the lower part of the legs; and (in the two daughters) migraine headaches. Routine histologic examination of tissue from the lips and elbows disclosed extensive, dilated, horizontal subpapillary telangiectases. Enzyme histochemical stains demonstrated activity of adenosine triphosphatase and leucine aminopeptidase around these dilated vessels. Alkaline phosphatase activity was strikingly absent from the dilated subpapillary vessels. By electron microscopy, these vessels were demonstrated to be postcapillary venules. We propose an autosomal dominant mode of inheritance.

[Angiolymphoid hyperplasia with eosinophilia (Kimura's disease). Apropos a case report with ultrastructural and histoenzymological study]. / Hyperplasie angio-lymphoïde avec éosinophilie (maladie de Kimura). A propos d'une observation avec étude ultrastructurale et histoenzymologique.

One case of angiolymphoid hyperplasia with eosinophilia is related in a 30-years old woman. This observations has all the characteristics of the disease: telangiectasic oedema, nodules and infiltrated areas located in the cervico-facial skin and also in the nasal and buccopharyngeal mucosa. Histologically, the proliferation is made of adult or young capillaries surrounded by inflammatory cells. The results of the peculiar morphological methods used here prove the endothelial nature of cells: high enzymatic activities of alkaline phosphatase and ATPases; factor VIII present on the cells; ultrastructural features characteristic of more or less differentiated vessels. Besides their nosologic interest, these methods may be useful for the diagnosis of this disease with the other vascular tumors.

Apurinic DNA endonuclease activities in repair-deficient human cell lines.

Several autosomal recessive diseases are associated with apparent DNA repair defects in cell culture. It seemed likely that a defect in excision repair reported for ataxia telangiectasia cells might reflect a lack of apurinic endonuclease activity. We report here normal levels of apurinic endonuclease activity in extracts of cell lines derived from patients with ataxia telangiectasia, xeroderma pigmentosum (complementation group D), Cockayne dwarfism, Fanconi anemia and Bloom syndrome.

Prolidase deficiency: biochemical study of erythrocyte and skin fibroblast prolidase activity in Italian patients.

BACKGROUND AND METHODS: Prolidase deficiency (PD), a rare, autosomally inherited disorder causing iminodipeptiduria is associated with a number of clinical manifestations, the principle feature being chronic skin ulceration. The enzyme prolidase cleaves iminodipeptides containing C-terminal prolyl or hydroxyprolyl residues and is important in the final stages of protein catabolism. We report clinical and biochemical findings in 8 Italian patients with proven prolidase deficiency. There was considerable heterogeneity in age at onset of symptoms (varying from 3-17 years), mental retardation and clinical manifestations (asymptomless to very severe). Prolidase activity was determined in hemolysates of patient erythrocytes and cultured dermal fibroblasts. RESULTS: Prolidase activity was found to be deficient, especially against gly-pro. Erythrocyte and fibroblast enzyme was also separated into two forms, a major isoform (I) and a minor one (II) by fast protein liquid chromatography, and activity against different iminodipeptide substrates was tested. Isoform I activity was markedly reduced in all patients as compared to normal controls, while isoform II activity appeared to be unaltered. CONCLUSIONS: We were unable to find any correlation between degree of enzyme activity loss and severity of symptoms.

Modulation of urokinase-type and tissue-type plasminogen activator occurs at an early stage of progressing stages of chronic venous insufficiency.

Chronic venous insufficiency (CVI) progresses through a series of clinical stages, from healthy skin to poorly healing leg ulcers. The aim of this study was to analyse the distribution pattern and activity level of urokinase-type (uPA) and tissue-type plasminogen activators (tPA) in normal skin and in tissue biopsies of progressing stages of CVI, prior to and including venous ulceration. Biopsies 6 mm thick were taken from 14 healthy volunteers and 37 patients with 5 different stages of CVI: telangiectases; stasis dermatitis; hyperpigmentation; lipodermatosclerosis; and leg ulcer. Changes in the enzymatic activity and spatial localization of uPA and tPA during the progression of CVI were examined using in situ histological zymography. Normal skin and skin with telangiectases showed a punctate PA activity, consisting of both uPA and tPA activity. As CVI progressed, an increase in the distribution of uPA and a decrease in tPA activity was observed. The spatial localization of uPA was widespread within the dermis of biopsies from stasis dermatitis and lipodermatosclerosis and was associated in particular with the dermoepidermal junction. Hyperpigmented skin revealed a pattern of PA expression similar to that of healthy skin. However, leg ulcer specimens exhibited peak levels of uPA with little tPA. Furthermore, a plasminogen-independent protease activity that was not present in any of the earlier stages of CVI appeared. Our results indicate that there are profound changes in PA activity during the progression of CVI and that these changes begin early in CVI, for example, in stasis dermatitis. We hypothesize that the balance or imbalance of the PA activity in the later stages of CVI is an important pathogenic factor for the development of venous leg ulcer.