Volume Articles

Iron in erythropoietic protoporphyrias: Dr. Jekyll or Mr. Hyde?

Jasmin Barman-Aksoezen¹, Xiaoye Schneider-Yin¹, Elisabeth I. Minder^2*

¹Stadtspital Triemli, Institute of Laboratory medicine, Zurich, Switzerland
²Stadtspital Triemli, Porphyria outpatient clinics, Zurich, Switzerland

Erythropoietic protoporphyria consists of two different genetic diseases, erythropoietic protoporphyria (EPP) and X-linked erythropoietic protoporphyria (XLEPP). Both of them are often accompanied by iron deficiency. Iron supplementation appears to be beneficial in XLEPP, although the clinical experience until to date is limited. In EPP, iron supplementation is discussed ambiguously and may cause harm in the majority of cases.

This minireview summarizes the limited knowledge on the connections of iron metabolism to regulation of porphyrin and heme synthesis and the influence these regulations may have on disease severity in the protoporphyrias. Further, we propose clinical guidelines, how to manage iron deficiency in both XLEPP and EPP.

Treatment with intravenous iloprost in patients with systemic sclerosis: A short review

Elisa Visalli¹, Giorgio Amato¹, Marcella Di Gangi¹, Alessia Benenati¹, Nicolò Cino¹, Caterina Gagliano², Raffaele Falsaperla³, Alberto Farina⁴, Rosario Foti¹

¹Rheumatology Unit, A.O.U. Policlinico Vittorio Emanuele, Catania, Italy
²General Pediatrics and Pediatric Acute and Emergeny Unit, A.O.U. Policlinico Vittorio Emanuele, Catania, Italy
³Ophthalmology, NEST (Neurovisual Science Technology) and Rare Disease Center (Ra.Di.Ce.), Santa Marta Hospital, Catania, Italy
⁴Medical Affairs Department, Italfarmaco S.p.A., Milano, Italy

Systemic sclerosis (SSc) is a severe, chronic disease characterised by small vessel vasculopathy, autoantibodies production, and ?broblast dysfunction leading to an excessive deposition of collagen in the skin and internal organs. The beneficial effects of iloprost in improving symptoms of ischemia such as Raynaud‘s phenomenon (RP) and digital ulcers (DUs) in patients with SSc are largely due to modulating the disordered microcirculation. Literature data show that the long-term IV iloprost administration maintains efficacy in the treatment of vasculopathy, representing a rational therapeutic approach, since Raynaud’s phenomenon and digital ulcers are two of the major causes of pain and disability in scleroderma patients. Intravenous iloprost may also play a role in promoting a favourable disease course, as a stabilization of cardio-pulmonary were observed in long-term studies. Current evidences are encouraging, but further randomized and controlled trials are needed to confirm these results.

The genetics of hereditary angioedema: A review

Macarena Piñero-Saavedra¹ and Teresa González-Quevedo^2*

¹Research Coordinator, Allergy Department, Algarve Hospital Complex, Faro, Portugal
²Coordinator of the Andalusian Reference Unit for Angioedema, Allergy Department, Virgen del Rocio University Hospital, Seville, Spain

PEDF: An essential stem cell regulator in models of Osteogenesis Imperfecta Type VI

Vikram Lyall¹, Vivian Shih^2*, and Chuhan Chung^1,3*

¹Department of Medicine, Yale University School of Medicine, Connecticut, USA
²Department of Orthopedics & Rehabilitation, Yale University School of Medicine, Connecticut, USA
³VA Connecticut Healthcare System, West Haven, CT, USA

The rare bone disease Osteogenesis Imperfecta (OI) type VI is caused by mutations in the gene coding for PEDF, Serpinf1. Individuals with OI type VI have an accumulation of unmineralized bone matrix and multiple fractures. Our lab group has previously shown that PEDF restoration in the mouse model of OI type VI increases bone mass and mineralization. Further, we demonstrated that PEDF directs mesenchymal stem cells to the osteoblast lineage. One mechanism appears to involve modulation of canonical Wnt/β-catenin signaling in a temporally-defined manner. We have also induced pluripotent stem cells from a patient with OI type VI and differentiated the cells into osteoblasts to investigate how PEDF regulates the expression of various bone matrix proteins such as IBSP. In this brief review, we provide an overview of PEDF biology and highlight how PEDF’s role as a stem cell regulator lends support to its causative role in OI type VI.

Neurological symptoms, evaluation and treatment in Danish patients with achondroplasia and hypochondroplasia

Mia Aagaard Doherty^1,2*, Niels Thomas Hertel³, Hanne Buciek Hove⁴ and Annette Haagerup^1,2,5*

¹NIDO Danmark, Hospitalsenheden Vest RM, Denmark
²Centre for Rare Diseases, Department of Paediatrics, Aarhus University Hospital, Denmark
³Department of Paediatrics, H.C. Andersen Children’s Hospital, Odense University Hospital, Denmark
⁴Centre for Rare Diseases, Department of Clinical Genetics, Rigshospitalet, Copenhagen University Hospital, Denmark
⁵Institute of Clinical Medicine, Health, Aarhus University, Denmark

Aim: To investigate the prevalence of neurological symptoms and the types of complications in a cohort of Danish patients with mutation verified achondroplasia and hypochondroplasia and compare the results with previously reported findings.

Methods: Retrospective descriptive study by chart review of patients followed in three outpatients clinics in the period 1997-2014. Forty-eight patients with achondroplasia and a median age of 9,5 years old and 20 patients with hypochondroplasia and a median age of 12 years old were enrolled. Neurological manifestations, epidemiological variables and clinical data were collected.

Results: Data on neurological symptoms and surgical interventions were extracted and compared with existing knowledge. Description of phenotypes revealed frequent headaches, pain in back, neck and lower limbs, sleep apnoea and conductive hearing loss. No sub-phenotype was predictive for referral to an MRI scan or neurosurgery.

Conclusion: Through investigation of phenotypes and genotypes in patients with achondroplasia and hypochondroplasia we report the frequencies of neurological symptoms, foramen magnum stenosis, spinal cord compression and neurosurgery in Danish patients. Variation in the evaluation of patients among the three clinics is found and discussed. To further standardise the management of patients, national guidelines for follow-up on children with ACH and HCH are recommended.

Gene expression regulation by upstream open reading frames in rare diseases

Joana Silva^{1, 2}, Rafael Fernandes^{1, 2}, Luísa Romão^{1, 2, *}

¹Department of Human Genetics, Instituto Nacional de Saúde Doutor Ricardo Jorge, Lisboa, Portugal
²Gene Expression and Regulation Group, Biosystems & Integrative Sciences Institute (BioISI), Faculdade de Ciências, Universidade de Lisboa, Lisboa, Portugal

Upstream open reading frames (uORFs) constitute a class of cis-acting elements that regulate translation initiation. Mutations or polymorphisms that alter, create or disrupt a uORF have been widely associated with several human disorders, including rare diseases. In this mini-review, we intend to highlight the mechanisms associated with the uORF-mediated translational regulation and describe recent examples of their deregulation in the etiology of human rare diseases. Additionally, we discuss new insights arising from ribosome profiling studies and reporter assays regarding uORF features and their intrinsic role in translational regulation. This type of knowledge is of most importance to design and implement new or improved diagnostic and/or treatment strategies for uORF-related human disorders.

The Accuracy of Hospital ICD-9-CM Codes for Determining Sickle Cell Disease Genotype

Angela B. Snyder, Peter A. Lane, Mei Zhou, Susan T. Paulukonis, Mary M. Hulihan

Georgia State University, Department of Public Management and Policy, Atlanta, GA and Georgia State University, Georgia Health Policy Center, Atlanta, GA
Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Atlanta, GA and Department of Pediatrics, Emory University School of Medicine, Atlanta, GA
Georgia State University, Georgia Health Policy Center, Atlanta, GA
Public Health Institute, Richmond, CA, Atlanta, GA
Centers for Disease Control and Prevention, Division of Blood Disorders, Atlanta, GA

Sickle cell disease affects more than 100,000 individuals in the United States, among whom disease severity varies considerably. One factor that influences disease severity is the sickle cell disease genotype. For this reason, clinical prevention and treatment guidelines tend to differentiate between genotypes. However, previous research suggests caution when using a claims-based determination of sickle cell disease genotype in healthcare quality studies.

The objective of this study was to describe the extent of miscoding for the major sickle cell disease genotypes in hospital discharge data. Individuals with sickle cell disease were identified through newborn screening results or hemoglobinopathy specialty care centers, along with their sickle cell disease genotypes. These genotypes were compared to the diagnosis codes listed in hospital discharge data to assess the accuracy of the hospital codes in determining sickle cell disease genotype. Eighty-three percent (sickle cell anemia), 23% (Hemoglobin SC), and 31% (Hemoglobin Sβ⁺ thalassemia) of hospitalizations contained a diagnosis code that correctly reflected the individual’s true sickle cell disease genotype. The accuracy of the sickle cell disease genotype coding was indeterminate in 11% (sickle cell anemia), 12% (Hemoglobin SC), and 7% (Hemoglobin Sβ⁺ thalassemia) and incorrect in 3% (sickle cell anemia), 61% (Hemoglobin SC), and 52% (Hemoglobin Sβ⁺ thalassemia) of the hospitalizations. The use of ICD-9-CM codes from hospital discharge data for determining specific sickle cell disease genotypes is problematic. Research based solely on these or other types of administrative data could lead to incorrect understanding of the disease.

Portopulmonar hypertension: Is there something new?

Liz Toapanta-Yanchapaxi^a, Juan Francisco Sánchez-Ávila^a, Nielzer Rodríguez-Almendros^b, José de Jesús Rodríguez-Andoney^c, José L. Hernández-Oropeza^c, Víctor Manuel Páez-Zayas^a, Ignacio García-Juárez^a*

^aGastroenterology Department and Liver Transplant Unit, National Institute of Medical Science and Nutrition Salvador Zubirán, Mexico City, Mexico.
^bPulmonary hypertension and Right Ventricular Function Department. UMAE Cardiología. Centro Médico Nacional Siglo XXI. Instituto Mexicano del Seguro Social. Mexico City, Mexico.
^cPulmonary Hypertension Clinic, National Institute of Medical Science and Nutrition Salvador Zubirán, Mexico City, Mexico.

Portopulmonary hypertension (POPH) is a rare and life-threatening complication in patients with portal hypertension, with a prevalence of 3 – 8%. It is characterized by pulmonary arterial hypertension (PAH) and results from obstruction to arterial flow in the pulmonary arterial bed, leading to the progressive deterioration of both the pulmonary circulation due to arterial remodeling and of the heart, as a result of right ventricular failure. Its diagnosis is based on hemodynamic findings based on a mean pulmonary arterial pressure (mPAP) ≥ 25mmHg, an increase in pulmonary vascular resistance (PVR) > 3 Wood Units or > 240 dynes/s/cm^-5, a pulmonary artery occlusion pressure (PAOP) ≤ 15mmHg or an elevated transpulmonary gradient (mPAP - PAOP: > 12 mmHg). Right heart catheterization (RHC) should be appropriately interpreted since management and MELD exception criteria depend on it. Although most therapeutic modalities have been inferred from patients with PAH, currently, new treatments are available and also various POPH clinical trials are ongoing, so further research data will soon be available. LT is a pivotal therapeutic option, but LT candidates require careful monitoring before, during and after the procedure.