First Case of Primary Ciliary Dyskinesia in Greenland

A 3-month-old girl of Greenlandic Inuit origin was referred to Rigshospitalet, Copenhagen, from Queen Ingrid's Hospital, Nuuk, due to situs inversus, chronic nasal discharge, recurrent upper airway infections and suspicion of bronchiectasis. Clinical findings included wet cough, a runny nose and rhonchi by auscultation. High-resolution computed tomography (HRCT) of the lungs showed slight atelectasis on the left lung and sulfur hexafluoride Multiple Breath Washout (SF6-MBW) showed a lung clearance index (LCI) of 7.41 within normal range. Primary ciliary dyskinesia (PCD) work up according to guidelines [1] including targeted genetic analysis for genes involved in PCD, high-speed video microscopy (HSVM), transmission electron microscopy (TEM) and nasal Nitric Oxide (nNO) revealed the patient to be homozygous for the pathogenic mutation c.4095+2 C > A in DNAH11 (NM_01277115.2). She exhibited a very low nNO of 12.21 nL/min, a very stiff and asynchronous ciliary beating, and a normal ciliary ultrastructure (Figure 1 and Supporting Information: Video S1). The patient has grandparents from Denmark, Norway and Greenland. Segregation analysis is on-going. The patient is currently being treated with maintenance azithromycin for prevention of infection and is doing well. In addition to biannual consultations in Greenland, she travels with her parents for PCD specialists monitoring at Rigshospitalet, Copenhagen twice a year. As Greenland is part of the kingdom of Denmark, all patients needing highly specialized care will be treated at Righshospitalet. To our knowledge this is the first case of PCD found in the Greenlandic Inuit population. PCD is a hereditary disease caused by pathogenic variants in genes coding for different components of motile cilia. Currently, pathogenic variants in more than 57 genes are recognized to cause PCD [2]. Cilia are present throughout the body where they serve a variety of functions. When the mucociliary clearance rate in the respiratory tract is severely reduced, build-up of mucus leads to chronic infections in both the upper and lower airways. Main symptoms and long-term impacts of PCD are persistent wet cough, rhinitis and otitis media and development of pulmonary bronchiectasis, decreased lung function and impaired hearing. Depending on the pathogenic variants patients with PCD can experience other manifestations related to other locations of defect cilia, such as, left-right body asymmetry (approximately 50% of patients), sub fertility and in some cases hydrocephalus [2]. Dynein Axonemal Heavy Chain 11 (DNAH11) is associated with PCD. DNAH11 is thought to encode a heavy-chain dynein protein component of the axonemal outer dynein arm (ODA) present in the proximal part of the cilium. The ODA protein is a microtubule-dependant motor ATPase that takes part in bending of the cilia. PCD caused by biallelic DNAH11 defects is usually characterized by a hyperfrequent ciliary beat pattern explained by reduced proximal bending of the cilia that can be visualized by HSVM, reduced nasal nNO [2] but normal ciliary ultrastructure by TEM. Patients might exhibit situs inversus totalis, and invariably recurrent respiratory tract infections, bronchiectasis and infertility in males. To our knowledge, no patients with genetically confirmed PCD have been recorded in the indigenous Greenlandic Inuit population. The genetic origin of the Greenlandic Inuit originated from the Thule Inuit who immigrated to northern Greenland around the 12th century from Canada. Since then, there has been an influx of people from other European countries to Greenland resulting in the Greenlandic Inuit gene pool being made up of approximately 65.6% Greenlandic Inuit and 34.4% European, mainly Danish [3]. PCD has not been previously found in Greenlandic Inuit but, a study by Hunter-Schouela et al identified seven patients of Canadian Inuit origin all homozygous for c.4095+2 C > A in DNAH11 [4]. This is the first case report of PCD in Greenland. The discovery of a Greenlandic Inuit girl with DNAH11 c.4096+2 C > A defect that matches previously discovery of the very same mutation from seven patients with PCD of Inuit origin in Canada [3] leads us to conclude that the likely origin of the variant in the patient, is to be found in her Inuit origin. In the kingdom of Denmark 16 patients with PCD conditioned by pathogenic variant in DNAH11 have been identified so far. None of these harbor the c.4095+2 C > A variant. Possibly, this pathogenic variant has been prevalent in the Greenlandic Inuit since the Thule immigration. This migration of pathogenic variants from the Canadian Inuit to the Greenlandic Inuit have also been seen in the fatty acid metabolism with the CPT1A P479L variant [5]. PCD is believed to be widely underdiagnosed for a multitude of reasons, one being the lack of awareness amongst general practitioners and even pulmonologists [2]. Lack of awareness and a previous belief that PCD was nonprevalent in Greenland could potentially have led to the absence of diagnoses. This new important finding stresses the need for increased awareness on PCD also in Greenland so that suspected cases can undergo relevant testing [1]. Caroline Nygaard: writing–original draft, writing–review and editing, data curation. Morten Dunø: investigation, writing–review and editing. Carsten Johan Heilmann: writing–review and editing, investigation. June K. Marthin: investigation, writing–review and editing. Sarah Nygaard: writing–review and editing. Tavs Qvist: writing–review and editing. Hanne Lynge Rex: writing–review and editing; investigation. Kim G. Nielsen: writing–review and editing, supervision, investigation, conceptualization. The Regional Health Research Ethics Committees in the Capital Region in Denmark waived the need for ethical approval of the project (no. F-24062931). This is not considered a health science research project as defined by the National Danish Ethical Committee law, but a case report on a single patient's illness without research intent or intervention and therefore not subject to notification and thus exempted from approval from the Scientific Ethics Committee for the Capital Region of Denmark (law announcement no. 1083 dated 15/09/2017 and its amendments). The parents have given written informed consent to the use and presentation of patient data, including photos, in accordance with ethical and legal rules of Rigshospitalet. The authors declare no conflicts of interest. The data from this report are available from the corresponding author upon reasonable request. 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