Identification of a novel mutation in HPS6 in a patient with hemophilia B and oculocutaneous albinism

Abstract

Purpose Hemophilia B, an X-linked disease, manifests with recurrent soft tissue bleeding episodes. Hermansky-Pudlak syndrome, a rare autosomal recessive disorder, is characterized by oculocutaneous albinism and an increased tendency to bleed due to a platelet storage pool defect. We report a novel mutation in HPS6 in a Caucasian man with hemophilia B and oculocutaneous albinism. Results The patient was diagnosed with hemophilia B at age 4 months due to recurrent soft tissue bleeding episodes, and he was also diagnosed with Hermansky-Pudlak syndrome at 32 years of age due to unexplained oculocutaneous albinism. His factor IX level was markedly reduced at 13%; whole exome and Sanger sequencing showed the Durham mutation in F9 (NM_000133.3). The diagnosis of Hermansky-Pudlak syndrome subtype 6 was established by demonstrating absence of platelet delta granules on whole mount electron microscopy, an abnormal secondary wave in platelet aggregation studies, and a novel homozygous c.1114 C>T (p.Arg372*) mutation in HPS6 (NM_024747.5) on exome analysis and Sanger sequencing. Clinical phenotyping revealed no evidence of recurrent or unusual infections, interstitial lung disease or pulmonary fibrosis, or neurological disorders. The patient was treated with fresh frozen plasma, recombinant factor IX, and aminocaproic acid. Treatment with desmopressin was added to his regimen after he was diagnosed with Hermansky-Pudlak syndrome. Treatment of bleeding episodes results in effective hemostasis, and the patient has not required platelet or blood product transfusions. Conclusions This report highlights the need to consider Hermansky-Pudlak syndrome as an etiology of oculocutaneous albinism even in patients with known hematologic disorders associated with bleeding. Identification of a novel mutation in HPS6 in an individual with hemophilia B shows that, although quite rare, patients may be diagnosed with two independent inherited bleeding disorders. No evidence of lung disease was found in this adult patient with Hermansky-Pudlak syndrome subtype 6.

Severe bleeding with subclinical oculocutaneous albinism in a patient with a novel HPS6 missense variant

“…Hermansky-Pudlak syndrome type 6 was diagnosed in a 58-year old woman with a history of severe bleeding and without overt oculocutaneous albinism. Patients with HPS-6 generally have mild hypopigmentation and bleeding compared to patients with other HPS subtypes, and pulmonary fibrosis has not been reported in patients with HPS-6 (Huizing, 2009; O’Brien, 2016). However, this patient’s oculocutaneous albinism was atypical, because it was asymptomatic.…”

“…In contrast to her subclinical oculocutaneous albinism, this patient had severe bleeding, including some instances of hemorrhage requiring blood product transfusions and an episode of prolonged gastrointestinal bleeding with hemodynamic instability. HPS-6 was reported in a 32-year old male with hemophilia B who also had excessive bleeding, but the patient’s oculocutaneous albinism facilitated a diagnosis of HPS in that case (O’Brien, 2016). …”

“…For example, some manifestations of HPS are subtype-specific, including progressive pulmonary fibrosis. Although fibrotic lung disease is a leading cause of death in patients with HPS-1, HPS-2, or HPS-4, patients with HPS-6 have not been reported to develop pulmonary fibrosis (Huizing, 2009; Huizing, 2017; Gochuico, 2012; O’Brien, 2016). This patient’s imaging studies revealed no clear evidence of interstitial lung disease, which is consistent with a diagnosis of HPS-6.…”

A comprehensive, multidisciplinary, precision medicine approach to discover effective therapy for an undiagnosed, progressive, fibroinflammatory disease

“…Pulmonary function tests were performed in accordance with guidelines from the American Thoracic Society/European Respiratory Society as described. 18 Fiberoptic bronchoscopy with lavage was performed and bronchoalveolar lavage fluid was isolated as described. 19 Proteomic, genetic, and RNA sequencing analyses.…”

Cortical atrophy and hypofibrinogenemia due to FGG and TBCD mutations in a single family: a case report

“…The manifestation of two genetically and phenotypically distinct conditions in a single individual is rare and can be due to the co-occurrence of multiple inherited pathogenic loci. Although it is common on patients from consanguineous families due to higher chance of homozygosity of multiple recessively inherited genes, non-consanguineous families with such conditions have also been reported [ 1 ]. Fibrinogen, a glycoprotein synthesized in hepatocytes, functions in the final steps of blood coagulation as a precursor monomer of the fibrin hemostatic plug.…”