A Clinical Variant of Familial Hermansky-Pudlak Syndrome

Silvia Iannello, MD, Giuseppe Fabbri, MD, Paolo Bosco, MD, Antonina Cavaleri, MD, Santi Cantarella, MD, Massimo Camuto, Paolina Milazzo, Francesco Romeo, MD, and Francesco Belfiore, MD

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Abstract and Introduction

Hermansky-Pudlak syndrome (HPS) is an autosomal recessive inherited disease consisting of (1) partial oculocutaneous albinism (with nystagmus, strabism, and visual acuity loss), (2) platelet storage pool deficiency (with bleeding diathesis), and (3) disorder of "ceroid" metabolism with a multisystem tissue lysosomal ceroid deposition. HPS is less uncommon in Puerto Rico, where the most important studies have been performed, but is a very rare disease in Europe. HPS basic defect remains unknown, even if an HPS-causing gene was identified in chromosome segment 10q23-q23.3, and several mutations have been reported.

The aim of this article is to discuss, on the basis of a review of relevant literature, a new familial HPS clinical variant observed in 2 young sisters (aged 16 and 23 years old, respectively), characterized by the typical symptoms of this syndrome. Our patients also suffered from diffuse interstitial pulmonary disease and an unexpectedly increased platelet aggregation and were prone to bacterial infections. Interestingly, we observed urinary tract abnormality in the younger HPS sister and a porencephalic cyst in the older HPS sister; both of these developmental defects have been reported in the Cross syndrome (or oculocerebral hypopigmentation syndrome). It seems that in our patients, an overlapping of the phenotypic manifestations of different rare syndromes may be present. The presence of ceroid-like autofluorescent material in urinary sediment together with the histologic aspects and the autofluorescence of oral mucosa biopsy are consistent with a ceroid-like lipofuscin storage.

HPS should be carefully tested for in suspected cases to prevent the severe visual impairment, rapidly progressive pulmonary fibrosis, and other complications associated with this disorder.

The aim of this article is to discuss, on the basis of an extensive review of the literature, a new familial clinical variant of Hermansky-Pudlak syndrome (HPS), a very uncommon disease in Europe that we observed in 2 young sisters.

HPS, first described in 1959 by F Hermansky and P Pudlak,[1] is an autosomal recessive inherited disorder consisting of the following triad of symptoms: (1) partial oculocutaneous albinism (with nystagmus, strabism, and decreased visual acuity); (2) platelet storage pool deficiency (with bleeding diathesis); and (3) disorder of "ceroid" metabolism with a multisystem tissue deposition of ceroid-lipofuscin pigment.[2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26] A typical lipid- protein complex accumulates within lysosomes in the reticuloendothelial cells of several tissues (including dermal macrophages). This lysosomal ceroid storage is associated with defects of biosynthesis/processing of multiple intracellular organelles (melanosomes, platelet-dense granules, and lysosomes).[3,5,6,8,9,12,13,15,16,17,19,20,21,23,27,28,29,30,31] HPS is frequently fatal.[15,32] The basic defect of this syndrome remains unknown, even if an HPS-causing gene was identified in chromosome segment 10q23-q23.3, and several pathologic mutations in this gene have been reported.[13,15,19,21,22,25,33,34,35,36,37,38] HPS appears to be multigenic in both human and mice models.[39,40] HPS is relatively frequent and the most common single-gene disorder in Puerto Rico, where the most important studies have been performed. The disease is associated with several serious complications, including pulmonary fibrosis, which progresses to early death (in the fourth and fifth decade),[1,2,41,42,43,44,45,46,47,48,49] chronic granulomatous colitis,[50] renal involvement or cardiomyopathy,[27] and frequent bacterial infections.[12]

Ocular albinism present in our HPS female patients contrasts with the known prevalence of this disorder in male subjects, even if some previous data in females are reported in the literature.[20,51,52,53]

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