Novel AP3B1 mutations in a Hermansky-Pudlak syndrome type2 with neonatal interstitial lung disease.

To the Editor, Hermansky– Pudlak syndrome (HPS) is an inherited disorder characterized by albinism of the oculocutaneous region and hemorrhagic disease. Eleven genes causative of HPS have been identified, and the clinical phenotypes of the condition differ depending on which gene is affected. HPS type 2 (HPS2) is an autosomal recessive inherited disease caused by mutations in AP3B1, resulting in interstitial lung disease (ILD), pulmonary fibrosis (PF), and immunodeficiency.1 Patients with HPS2 also have neutropenia and decreased NK cell cytotoxicity, which can lead to hemophagocytic lymphohistiocytosis (HLH); however, the total number of HPS2 cases reported was less than 40 as of March 2021,1 making it difficult to accurately assess the risk of HLH associated with this disease. In addition, although ILD/PF occurs earlier in HPS2 than in other types of HPS, HPS2 with ILD/PF in the neonatal period has never been reported. Here, we report a case of HPS2 with neonatal ILD/PFharboring mutations in both AP3B1 alleles, one of which is novel. The patient is female, the second child of a nonconsanguineous marriage, and was born at 39 weeks 4 days (birth weight, 3798 g) by spontaneous vaginal delivery. Apgar score was 9 at 1 min; however, respiratory failure gradually developed, resulting in endotracheal intubation and mechanical ventilation. At 20 h after birth, a right tension pneumothorax developed, which required thoracentesis, thoracic drainage, and nitric oxide inhalation therapy. Traumatic pneumothorax was less likely because there were no traumatic episodes such as birth injury or chest compression, but pressureinduced pneumothorax due to ventilator management could not be ruled out. Septic workup, including blood and throat swabs, was negative. Respiratory distress syndrome was less likely due to term delivery. A computerized tomography scan at 6 days of age revealed ILD/PF (Figure 1); therefore, we suspected hereditary interstitial lung diseases and tested the SFTPB, SFTPC, ABCA3, FOXF1, NKX2.1, GATA2, CSF2RA, and CSF2RB genes, all of which were negative.2 Since she had albinism, we performed genetic analysis of 22 albinismrelated genes, which revealed two heterozygous variants in AP3B1: c.1122_1123insAG (p. Phe375Serfs*11) and c.2546T>A (p. Leu849Ter)(Figure 2a). The former variant is a novel frameshift mutation, and the latter is a nonsense mutation that was recently reported as the causative mutation in a patient with HPS2 in Japan.3 Neither variant is recorded in the Exome Aggregation Consortium (ExAC, http://exac.broad insti tute.org/) database, and both are considered pathogenic according to ACMG criteria.4 Each parent carried one of the variants; therefore, we diagnosed the patient with HPS2 caused by AP3B1 mutations. The patient also suffered from mitral regurgitation, which did not require additional medication. The patient's respiratory condition improved, and she was discharged from hospital at 190 days of age, with the introduction of home oxygen therapy. At 9 months old, she was hospitalized due to HLH. Physical examination revealed redness of the pharynx and a slight fever. Typical symptoms of HPS, such as horizonal nystagmus and wholebody skin whiteness, were observed. A small number of purpura were also observed on her lower extremities, but no other symptoms of bleeding were noticed, as reported in previously reported cases.3,5– 7 Laboratory tests showed thrombocytopenia, with platelets 3.0 × 104/μl and white blood cell count 1100/μL (2.8% neutrophils). Ferritin was not raised; however, soluble IL2 receptor levels were elevated at 7469 U/ml. Bone marrow examination showed evidence of hemophagocytosis. Analysis of CD107a expression on the surface of freshly isolated NK cells demonstrated impaired release of cytotoxic granules (Figure 2b). Detailed immunological evaluation revealed no abnormal findings, other than decreased NK cell activity (Table S1).