Interstitial lung disease and pulmonary fibrosis in Hermansky-Pudlak syndrome type 2, an adaptor protein-3 complex disease.

Pulmonary fibrosis develops in Hermansky-Pudlak syndrome (HPS) types 1 and 4. Limited information is available about lung disease in HPS type 2 (HPS-2), which is characterized by abnormal function of the adaptor protein-3 (AP-3) complex. To define lung disease in HPS-2, one child and two adults with HPS-2 were evaluated at the National Institutes of Health on at least two visits, and another child was evaluated at the University of Texas Health Science Center San Antonio. All four subjects with HPS-2 had findings of interstitial lung disease (ILD) on a high-resolution computed tomography scan of the chest. The predominant feature was ground glass opacification. Subject 1, a 14-year-old male, and subject 4, a 4-year-old male, had severe ILD, pulmonary fibrosis, secondary pulmonary hypertension and recurrent lung infections. Lung biopsy performed at 20 months of age in subject 1 revealed interstitial fibrosis and prominent type II pneumocyte hyperplasia without lamellar body enlargement. Subject 2, a 27-year-old male smoker, had mild ILD. Subject 3, a 22-year-old male nonsmoker and brother of subject 2, had minimal ILD. Severe impairment of gas exchange was found in subjects 1 and 4 and not in subjects 2 or 3. Plasma concentrations of transforming growth factor-ß1 and interleukin-17A correlated with severity of HPS-2 ILD. These data show that children and young adults with HPS-2 and functional defects of the AP-3 complex are at risk for ILD and pulmonary fibrosis.

Splenic papillary angioendothelioma in a 6-year-old girl.

Papillary angioendothelioma is a rare, low-grade neoplasm of lymphatic channels that usually presents intradermally. We report the case of a 6-year-old girl with isolated splenomegaly and symptoms of early satiety and weight loss, whom was found to have a splenic papillary angioendothelioma. Preoperative abdominal computed tomography scan showed an irregular, heterogeneous mass; a tagged red cell scan ruled out a hemangioma, whereas a positron emission tomography scan showed mildly increased uptake. Subsequent surgery and pathologic assessment revealed a papillary angioendothelioma (Dabska tumor) within lymphatic spaces. The child has no evidence of recurrence or metastases 1 year postoperatively.

Effect of long-term transfusion on growth in children with sickle cell anemia: results of the STOP trial.

OBJECTIVE: To determine whether long-term transfusion improves growth in children with sickle cell anemia. STUDY DESIGN: In the Stroke Prevention Trial for Sickle Cell Anemia Study, patients were randomized to receive long-term transfusion (CTX) or standard care (STC). Transfusions were administered every 3 to 5 weeks, and hemoglobin S levels were maintained at 30% pretransfusion for an average of 2 years. Serial height and weight measurements (obtained every 3 months), body mass index (BMI) values, and growth z-scores were analyzed. RESULTS: Children in the CTX (n=53) and STC (n=41) groups were similar at baseline. After 24 months, the z-scores for height, weight, and BMI of those receiving CTX had improved significantly, whereas no changes occurred in the STC group. Patients in the CTX group approached normal height-for-age and weight-for-age z-scores. Patients from a large historical control group had significantly lower weight and height growth velocities than patients in the CTX group. CONCLUSIONS: Patients in the Stroke Prevention Trial for Sickle Cell Anemia Study who received CTX had improved height and weight and BMI over a 2-year period. Higher hemoglobin levels resulting from transfusion may improve growth by lowering energy expenditure. In addition to the prevention of vasoocclusive events, CTX results in significant improvement in the growth of children with sickle cell disease.

Nonsense mutations in ADTB3A cause complete deficiency of the beta3A subunit of adaptor complex-3 and severe Hermansky-Pudlak syndrome type 2.

Hermansky-Pudlak syndrome (HPS) is an autosomal recessive disease consisting of oculocutaneous albinism and a storage pool deficiency resulting from absent platelet dense bodies. The disorder is genetically heterogeneous. The majority of patients, including members of a large genetic isolate in northwest Puerto Rico, have mutations in HPS1. Another gene, ADTB3A, was shown to cause HPS-2 in two brothers having compound heterozygous mutations that allowed for residual production of the gene product, the beta3A subunit of adaptor complex-3 (AP-3). This heterotetrameric complex serves as a coat protein-mediating formation of intracellular vesicles, e.g. the melanosome and platelet dense body, from membranes of the trans-Golgi network. We determined the genomic organization of the human ADTB3A gene, with intron/exon boundaries, and describe a third patient with beta3A deficiency. This 5-y-old boy has two nonsense mutations, C1578T (R-->X) and G2028T (E-->X), which produce no ADTB3A mRNA and no beta3A protein. The associated mu3 subunit of AP-3 is also entirely absent. In fibroblasts, the cell biologic concomitant of this deficiency is robust and aberrant trafficking through the plasma membrane of LAMP-3, an integral lysosomal membrane protein normally carried directly to the lysosome. The clinical concomitant is a severe, G-CSF-responsive neutropenia in addition to oculocutaneous albinism and platelet storage pool deficiency. Our findings expand the molecular, cellular, and clinical spectrum of HPS-2 and call for an increased index of suspicion for this diagnosis among patients with features of albinism, bleeding, and neutropenia.