Pulmonary Failure as Presentation of Griscelli Syndrome Type 2

To the Editor, A 13-year-old boy of eastern European descent, previously healthy, presented with shortness of breath, coughing, fatigue, and self-reported weight loss of 8 kg over a span of 3 weeks. He had respiratory insufficiency (saturation 85%–90%) necessitating oxygen supply. He was afebrile. Additionally, he suffered from a skin rash characterized by numerous maculated, red, sore, slightly elevated elements on the truncus, the back, and the neck. The boy reported a simple upper airway infection 4 weeks before the admission. A CT scan uncovered diffuse, infiltrative changes, round-shaped consolidated areas, and ground glass nodules in the lungs (Figure 1). In addition, splenomegaly and a few marginally enlarged lymph nodes were identified. Tentative diagnoses were tuberculosis, bilateral pneumonia, vasculitis, Langerhans Cell Histiocytosis and lymphoma/leukemia, which were all ruled out. Thorough microbiological investigations were without positive findings except for positive Epstein Barr Virus (EBV)-IgM and -IgG, serology suggesting recent infection (Supporting Information S1: Table 1). PCR-analysis on bronchoalveolar lavage was positive for Pneumocystis jiroveci leading to initiation of sulfamethoxazole and trimethoprim. In addition, the boy was treated with cefuroxime, clarithromycin, and beclomethasone on clinical suspicion of complicated atypical pneumonia. A bronchial biopsy identified chronic, unspecified inflammation without granulomas or signs of vasculitis. Blood tests did not raise suspicion of hyperinflammation, except for IL2R at 10,523 kU/L (Table 1). Ferritin remained below 300 IU/mL. Blood smear was without pathological findings, including no hemophagocytosis. Throughout the diagnostic period, his symptomatology was dominated by pulmonary symptoms. Pulmonary function test revealed severely impaired lung function: Diffusing capacity of the lungs for carbon monoxide was 41% and forced expiratory volume in 1 s was 44%. A surgical lung biopsy revealed chronic inflammation and loosely formed granulomas. Sarcoidosis was considered but disregarded due to (i) absence of interstitial inflammation, (ii) no well-defined granulomas, (iii) scattered macrophages, and (iv) foamy macrophages not organized in the alveoli. Despite receiving antibiotics and inhalation treatment, his condition deteriorated rapidly, marked by escalating dyspnea and fever, leading to a critical state that required intensive care, high levels of oxygen supplementation and methylprednisolone 25 mg/kg daily. Clinical deterioration, in combination with the suspected P. jiroveci pneumonia, triggered evaluation for inborn errors of immunity. General lymphopenia was found. Genetic analyses revealed compound heterozygous variants in RAB27A comprised of a missense variant, c.259 G>C, and a deletion, c.240-47_240del (Supporting Information S1: Table 2). The missense variant is classified as pathogenic [1], whereas the deletion has not been reported previously. The deletion classified as “presumably pathogenic” according to ACMG guidelines [2]. Thus, the genetic results strongly suggested Griscelli syndrome type 2. After tapering the high-dose corticosteroid treatment, we evaluated the degranulation and cytotoxicity capabilities of his natural killer (NK)-cells 3 weeks after discontinuation. This served as a test to assess the functional consequences of the RAB27A variants. The test results suggested slightly decreased degranulation and cytolytic activity (Supporting Information S1: Figure 2), thus not unambiguously supporting a suspicion of hemophagocytic lymphohistiocytosis (HLH), according to the HLH 2004 guidelines [3]. Concomitantly, the boy experienced headache, vomiting, deviating balance, and speech impairment. MRI of the cerebrum revealed general edema, parenchymal lesions of the cerebellum, slight hydrocephalus, and herniation of the cerebellar tonsils (Supporting Information S1: Figure 1). Acute neurosurgical decompression was conducted. The cerebrospinal fluid was found without signs of infection. A brain biopsy showed unspecified inflammation. Pulmonary symptoms were absent. Noticeable blood results showed slightly neutro- and lymphopenia, modest elevated LDH and IL2R at 1841 kU/L (Table 1) thus still not indicating severe hyperinflammation. The boy was treated with meropenem, voriconazol, amphotericin B, anakinra, and high-dose iv methylprednisolone. This completely ameliorated the neurological symptoms and no lasting neurological sequelae developed. The boy's hair had been perceived as blond, however, by careful reassessment a slight gray–silvery appearance was noted. Microscopical examination of the hair strains disclosed lacunae of melanin, compatible with GS2. Altogether it was concluded that he suffered from GS2 and HLH, showcasing an atypical pulmonary manifestation. Subsequently, he was found eligible for hematopoietic stem cell transplantation. Anakinra and corticosteroids were maintained as bridging therapy until transplantation with a sibling donor was undertaken. In hindsight, we suspect that the HLH was elicited by a likely EBV infection, which manifested as the simple upper airway infection 4 weeks before his first hospital admission. Furthermore, the atypical phenotype of HLH in our patient could possibly be explained by the residual NK-cell activity found in the functional NK-cell test. This aligns with the genetic findings, showcasing one RAB27A missense variant casuistically known to be associated with reduced, but not extinct, cytolytic function [1]. GS2 is a rare, autosomal, recessive disorder associated with neurological deficits, pseudo-albinism and immunodeficiency involving insufficient function of NK-cells and cytotoxic T-cells with a susceptibility to HLH [4]. GS2 is caused by variants in RAB27A [4]. RAB27A encodes the enzyme RAB27A, which is essential for vesicular transport in various cell types. In melanocytes, deficient RAB27A compromises the transport of melanosomes, which results in melanin-lacunae in hair shafts and macroscopically pseudo-albinism, that is, silver–gray hair color. RAB27A is essential for exocytosis of lytic granules from cytotoxic T-cells and NK-cells and RAB27A deficiency in these cells conveys the susceptibility to HLH. HLH is characterized by hyperinflammation usually presenting with fever, cytopenia, and hepatosplenomegaly as well as elevated levels of ferritin, triglycerides, and soluble interleukin 2-receptor (IL2R) [3]. Herein, we report an unusual presentation of HLH in a previously healthy boy with GS2, caused by compound heterozygosity in the RAB27A. The HLH presented primarily with pulmonary symptoms, no classical elevation of inflammatory biomarkers, and only slightly decreased in vitro NK-cell function. We propose that the atypical presentation of HLH in our patient relates to hypomorphic RAB27A variants allowing some residual cytolytic function of the NK-cells. The atypical HLH in our patient likely postponed the diagnosis of GS2 several months. One other patient with GS2, HLH and primarily pulmonary symptoms is reported [5]. In contrast to our patient, that patient showed highly elevated inflammatory biomarkers and met the HLH-2004 diagnostic criteria. The two cases emphasize that pulmonary pediatricians must be aware that HLH can present with pulmonary manifestations and our case highlights that clear biochemical signs of HLH can be absent. Stine Fischer Fogsgaard: project administration; writing–original draft. Jens Magnus Bernth Jensen: supervision; writing–review and editing. Mia Glerup: writing–review and editing. Signe Bødker Thim: writing–review and editing. Mette Holm: writing–review and editing. Charlotte Olesen: writing–review and editing. Henrik Hasle: writing–review and editing. Sune Rubak: supervision; writing–review and editing. The authors declare no conflicts of interest. The data that support the findings of this study are available from the corresponding author upon reasonable request. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.