Maria Gnarra

Angiokeratoma: Decision-making aid for the diagnosis of Fabry disease

Isolated angiokeratomas are common benign cutaneous lesions, generally deemed unworthy of further investigation. In contrast, diffuse angiokeratomas should alert the physician to a possible diagnosis of Fabry disease, a rare X‐linked lysosomal storage disorder, characterized by α‐galactosidase deficiency. Glycosphingolipids accumulate in cells throughout the body resulting in progressive multi‐organ failure. Difficulties are encountered when trying to interpret the significance of angiokeratomas because they may also occur in other lysosomal storage disorders and rarely in an isolated manner in Fabry disease. We present an algorithm for the classification of angiokeratomas which might prove useful for the diagnosis and management of Fabry disease. Assessment of the clinical features and location of the lesions, personal and family history, skin biopsy, dermoscopy and electron microscopy imaging are sequential steps in the diagnostic process. Assessing the deficiency of α‐galactosidase enzyme activity is essential to confirm the diagnosis in males, while mutation analysis is always needed in females. Potentially this algorithm can change the current approach to patients when Fabry disease is suspected, thus improving the diagnostic strategy and management of this disorder. It remains to be decided whether the use of an algorithm might reduce the number of genetic consultations. As evidence has shown the efficacy of enzyme replacement therapy in halting progression of the disease before the onset of irreversible organ damage, it is advisable to aim at an early diagnosis in order to achieve timely initiation of effective treatment with benefits for patients and appropriate use of medical resources.

Propranolol for infantile haemangiomas: single centre experience of 250 cases and proposed therapeutic protocol

Objective To assess the safety and efficacy of systemic propranolol for the treatment of complicated infantile haemangiomas. Design Retrospective review of case notes of paediatric patients treated with propranolol for complicated infantile haemangiomas. Setting Tertiary care childrens hospital. Patients All paediatric patients with complicated infantile haemangiomas who commenced treatment with propranolol from July 2008 to December 2011 and have completed treatment for at least 3 months. Results 250 patients were treated with propranolol; 34.4% were premature and 5.6% postmature. Indications for propranolol included: vision compromise (42.0%), bleeding and/or ulceration (30.4%) airway obstruction (8.8%), feeding difficulty (8.4%), risk of permanent disfigurement (4.4%) and other (6%) (nasal obstruction, auditory canal obstruction, large haemangioma, compression of neck structure and spinal cord). Median age at beginning of treatment was 4.5 months. Median age at end of treatment was 16.7 months. Median length of therapy was 11.8 months. Adverse effects (such as wheezing, worsening of ulceration, sleep disturbance, diarrhoea) occurred in 38 patients (15.2%), leading to modifications in management in 26 patients (10.4%). 240 patients (96%) had good to excellent response to treatment. 20 patients (8%) experienced regrowth of the haemangioma on cessation of propranolol and six patients (2.4%) required propranolol to be restarted. Conclusions In appropriately selected patients, propranolol is a safe and effective treatment for infantile haemangiomas.

Acquired Epidermodysplasia Verruciformis: A Comprehensive Review and a Proposal for Treatment

BACKGROUND Epidermodysplasia verruciformis (EV) is a rare genodermatosis characterized by immunologic abnormalities, disseminated human papilloma virus infection, and early development of skin cancers. Acquired forms have been rarely reported and usually occur with immunosuppression. The therapeutic management of the acquired forms is not standardized, and several therapies have been tried, with variable outcomes. OBJECTIVES To provide updated clinical and experimental information on the treatment of acquired EV. METHODS A Medline literature search was performed for relevant Medical Subject Heading terms, reviewing publications on strategies for management of acquired EV. We also report a case successfully treated using a combination of photodynamic therapy and oral retinoids. CONCLUSION Data from the literature show that a standardized approach to this condition is lacking; the combination treatment chosen in our case may be proposed because it led to an excellent clinical outcome and a long‐lasting remission.

History of the infantile hepatic hemangioma: From imaging to generating a differential diagnosis.

We aim to provide an up-to-date summary of infantile hepatic hemangioma (IHH) and its misnomers and to dialectically present the differential diagnosis of these rare entities of the liver. Eligible peer-reviewed articles on hepatic infantile hemangiomas, published between 2000 and 2015, were reviewed for this study. IHH is the most common hepatic vascular tumor in children. Once a liver mass is identified in an infant, the differential diagnosis ranges from vascular malformations to benign and malignant tumors including mesenchymal hamartoma, hepatoblastoma, metastatic neuroblastoma, so careful physical examination, imaging studies, and, if indicated, tumor markers and biopsy, are of pivotal importance to ascertain the correct diagnosis. Despite the benign nature of IHHs, some of these lesions may demand medical and/or surgical intervention, especially for multiple and diffuse IHH. Complications can include hepatomegaly, hypothyroidism and cardiac failure. Therefore, a close follow-up is required until complete involution of the lesions. We propose an algorithm to guide the physicians towards the proper management of hepatic lesions.

Vascular Endothelial Growth Factor (VEGF-a) in Fabry disease: Association with cutaneous and systemic manifestations with vascular involvement

INTRODUCTION Fabry disease is an X-linked inherited metabolic disorder characterized by the deficiency of lysosomal α-galactosidase A enzyme. This leads to the accumulation, into lysosomes through the body, of glycosphingolipids, mainly Gb3. Skin involvement and progressive multi-organ failure are usually observed. Endothelium is the preferential target of the Gb3 storage that determines endothelial dysfunction and vasculopathy leading to the clinical manifestations of the disease. The serum levels of Vascular Endothelial Growth Factor-A (VEGF-A), a specific endothelial cell mitogen, were analyzed in Fabry patients to explore a possible association to the clinical manifestations with vascular involvement. METHODS Thirty-five patients with a biochemical and genetic diagnosis of Fabry disease, along with an age-gender-matched healthy control group, were enrolled. Serum samples were collected and analyzed by ELISA. The genetic mutations, the specific organ dysfunction, and the cardiovascular risk factors such as dyslipidaemia, diabetes, smoking habits and hypertension were evaluated in Fabry patients. RESULTS The mean serum level of VEGF-A in Fabry patients group was significantly higher than in the control group (P=0.006). A statistical significant association, between VEGF-A levels and the skin manifestation including angiokeratomas, sweating abnormalities and Fabry Facies was found. An association was also found between high VEGF-A and specific GLA mutations, the male gender, the renal and neurological manifestations, the presence of eye vessels tortuosity, smoking habit and hypertension. CONCLUSIONS We detected increased VEGF-A levels in patients with Fabry disease compared to the controls, and we hypothesized that this could be a response to the vascular damage characterising this lysosomal disorder. However, further studies are necessary to clarify the role of VEGF-A in Fabry.

Urinary tract infection in the newborn and the infant: state of the art

Urinary tract infection is one of the most common cause of infection in newborns. Obtaining a urinary tract infections (UTIs) diagnosis just on the basis of the clinical findings is frequently difficult, however, being the pediatricians goal to reduce the risk of renal scarring, a prompt diagnosis and treatment is of extreme importance. The key instrument for the diagnosis of UTIs is represented today by urine culture. However, in reality, the caregivers and investigators are increasingly demanding fast and cheap methods for a rapid and effective diagnosis.

Functional outcome after the Hoffer procedure.

Background: Children with obstetrical brachial plexus injury often develop an internal rotation and adduction contracture about the shoulder as a secondary deformity, resulting in an inability to externally rotate and abduct the shoulder. The Hoffer procedure is evaluated for its potential benefit in improving shoulder abduction and external rotation and its impact on activities of daily living. Methods: This is a retrospective review of patients treated in brachial plexus injury clinic who underwent tendon transfer procedures about the shoulder. Preoperative and postoperative active movement and active range of motion were measured and recorded using the Mallet scale and the Active Movement Scale. Results: Twenty patients were included in the study. Average age at time of surgery was 6.35 years. Thirteen patients had primary brachial plexus reconstructive surgery and four patients had concomitant wrist extension tendon transfer procedures. All patients had full passive range of motion preoperatively. The average follow-up period was 25.45 months. Average differences in pre-Hoffer and post-Hoffer Mallet scale scores are as follows: active abduction, 1.20; external rotation, 1.35; hand-to-neck, 1.25; hand-to-back, 0.75; hand-to-mouth, 0.65; and aggregate score, 5.20 (p < 0.001 for all). Average differences in relevant pre-Hoffer and post-Hoffer Active Movement Scale scores are as follows: shoulder abduction, 2.10; shoulder external rotation, 4.25; and shoulder internal rotation, −0.80. All patients maintained full range of motion passively; thus, no functional loss was experienced. These results showed very high statistical significance (p < 0.001 for all) and clinical significance. Younger patients (⩽6 years) and those with better preoperative shoulder flexion and shoulder internal rotation yielded better postoperative results. Conclusions: The Hoffer procedure provides clinically and statistically significant improvement in external rotation and abduction while preserving functional internal rotation range in the child with obstetrical brachial plexus palsy and secondary shoulder deformity. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

Vascular Notch proteins and Notch signaling in the peri-implantation mouse uterus

BackgroundAngiogenesis is essential for uterine decidualization, the progesterone-mediated transformation of the uterus allowing embryo implantation and initiation of pregnancy. In the current study, we define the vasculature, expression of Notch proteins and Notch ligands, and Notch activity in both endothelial cells and vascular-associated mural cells of blood vessels in the pre-implantation endometrium and post-implantation decidua of the mouse uterus.MethodsWe used immunofluorescence to determine the expression of Notch in endothelial cells and mural cells by co-staining for the endothelial cell marker, CD31, the pan-mural cell marker, platelet-derived growth factor receptor beta (PDGFR-β), the pericyte markers, neural/glial antigen 2 (NG2) and desmin, or the smooth muscle cell marker, alpha smooth muscle actin (SMA). A fluorescein isothiocyanate-labeled dextran tracer, was used to identify functional peri-implantation vasculature. CBF:H2B-Venus Notch reporter transgenic mice were used to determine Notch activity.ResultsNotch signaling is observed in endothelial cells and pericytes in the peri-implantation uterus. Prior to implantation, Notch1, Notch2 and Notch4 and Notch ligand, Delta-like 4 (Dll4) are expressed in capillary endothelial cells, while Notch3 is expressed in the pericytes. Jagged1 is expressed in both capillary endothelial cells and pericytes. After implantation, Notch1, Notch4 and Dll4 are expressed in endothelial cells of newly formed decidual capillaries. Jagged1 is expressed in endothelial cells of spiral arteries and a subset of decidual pericytes. Notch proteins are not expressed in lymphatic vessels or macrophages in the peri-implantation uterus.ConclusionsWe show Notch activity and distinct expression patterns for Notch proteins and ligands, suggesting unique roles for Notch1, Notch4, Dll4, and Jag1 during decidual angiogenesis and early placentation. These data set the stage for loss-of-function and gain-of-function studies that will determine the cell-type specific requirements for Notch proteins in decidual angiogenesis and placentation.

Propranolol and prednisolone combination for the treatment of segmental haemangioma in PHACES syndrome

Posterior fossa malformations–haemangiomas–arterial anomalies–cardiac defects–eye abnormalities–sternal cleft and supraumbilical raphe syndrome (also known as PHACES syndrome) is a rare neurocutaneous disorder. Children presenting with these manifestations need careful ophthalmological, cardiac and neurological assessment. They may have one or more of these extracutaneous manifestations, the most common being cerebral and cardiovascular anomalies. There is controversy about treating these children with propranolol especially if they have cerebrovascular involvement with narrow, dysplastic or absent blood vessels. The concern with propranolol is that hypotension may lead to reduced cerebral blood flow and neurological consequences. Prior to propranolol the systemic treatment for haemangiomas was prednisolone and then the concern was the opposite, namely hypertension. Our proposal was whether a combination of these two drugs would provide a safer and faster recovery. We report three retrospective cases of PHACES syndrome, each of whom received treatment with a combination of propranolol and prednisolone: two children were started on prednisolone and propranolol was added because the haemangiomas failed to respond adequately; the third child was started on propranolol and developed peripheral ischaemia and ulceration necessitating a reduction in dose addition of a low dose of prednisolone. All three patients, who failed on the one treatment, responded well to combination therapy without any significant complications. These outcomes suggest that for some patients with PHACES syndrome the use of combination treatment with propranolol and prednisolone could be advantageous, potentially allowing for the introduction of low doses of each with an enhanced combined effect. The doses can be increased gradually depending on the magnetic resonance imaging findings.

A Possible Role for CD8+ T Lymphocytes in the Cell-Mediated Pathogenesis of Pemphigus Vulgaris

Pemphigus vulgaris (PV) is an autoimmune blistering disease whose pathogenesis involves both humoral and cell-mediated immune response. Though the pathogenetic role of autoantibodies directed against desmoglein 3 is certain, a number of other factors have been suggested to determine acantholysis in PV. In this study we examined the possible role of CD8+ T cells in the development of acantholysis by a passive transfer of PV autoantibodies using CD8 deficient mice, and we also studied the inflammatory infiltrate of PV skin lesions by immunohistochemical staining. The results of the immunohistochemical staining to study the expression of CD3, CD4, and CD8 in PV skin lesions showed that CD4+ are more expressed than CD8+ in the inflammatory infiltrate of PV lesions, confirming the data of the previous literature. The passive transfer study showed a lower incidence of pemphigus in the group of CD8 deficient mice compared to the control one of wild-type mice. These results suggest that CD8+ T cells may play a role in the pathogenesis of PV, perhaps through the Fas/FasL pathway.