Hermansky-Pudlak Syndrome (HPS)

Genetically transmitted metabolic disorder causing albinism, visual impairment, platelet pool storage deficiency resulting in bleeding diathesis, and lysosomal accumulation of ceroid lipofuscin resulting in pulmonary fibrosis, inflammatory bowel disease, and renal insufficiency.

NB: “Hermansky” is often misspelled as “Hermanski.”

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Albinism with Hemorrhagic Diathesis; Oculocutaneous Albinism type VIA; Platelet Delta Storage Pool Disease; Albinism Hemorrhagic Diathesis; Albinism-Thrombocytopathy; Oculocutaneous Albinism-Hemorrhagic Diathesis Syndrome.

Inherited disorder of metabolism of ceroid lipofuscin first reported in 1959 by the Czech internist Frantisek Hermansky and P. Pudlak. They described two patients with oculocutaneous albinism and bleeding diathesis.

The third most common type of albinism affecting diverse ethnic populations, mainly in Puerto Rico and the Swiss Alps. The highest incidence is in the Puerto Rican general population, with a prevalence of at least 1:1000. In Puerto Rico, approximately 1:21 persons carry the gene encoding HPS. Also, five of six Puerto Ricans with oculocutaneous albinism have HPS. However, the disease is by no means restricted to this population, and clusters exist in most populations internationally.

This autosomal recessive disorder is caused by a mutation within the gene HPS1 consisting of a 16-bp duplication and localized on chromosome 10q23. It encodes a transmembrane protein locus that is likely to be a component of multiple cytoplasmic organelles, the granular fraction of melanocytes, and the cytoplasm of nonmelanotic cells.

In addition to the photophobia and hypopigmentation of eyes, skin, and hair exhibited by other albinos, patients with HPS demonstrate a mild bleeding diathesis. This is a result of a combination of impaired platelet function caused by storage pool deficiency and of accumulation of ceroid in tissues. As well as impairing coagulation, ceroid accumulation results in fibrosis in various sites, resulting in organ damage.

The combination of albinism with ceroid deposition and bleeding diathesis defines HPS. For proper diagnosis the platelets must be examined by electron microscopy, which reveals the absence of dense bodies.

Wide variety of phenotypic appearances. Bleeding disorders and ocular anomalies, including blindness, nystagmus, iris transillumination, foveal hypoplasia, and albinotic retinal midperiphery, are often revealing symptoms. Albinism is tyrosinase positive, which means that patients present with varied amounts of pigmentation. A light skin color associated with numerous freckles, hypertrichosis of the eyelashes, and trichomegaly on the arms and legs are found in 36% of affected individuals. Acanthosis nigricans-like lesions (without pigmentation) are found in 29% of HPS1-positive patients. Bruising is normally observed in more than 90% of patients. In later childhood and adult life, the fibrosis caused by ceroid deposition causes considerable physical limitation because of development of fibrotic restrictive lung disease. Gingivitis is complicated by dental problems, and the resulting surgery is complicated by bleeding. Granulomatous colitis is a frequent complaint and has led to lower gastrointestinal hemorrhage. Renal infiltration causes gradual onset of renal failure. Cardiac deposition of ceroid causes a cardiomyopathy. Seventy percent of patients affected with HPS die of causes directly related to this syndrome. Pulmonary fibrosis leads to early mortality in 50% of patients. Hemorrhagic episodes lead to death in 10% of patients.

Complete evaluation of the coagulation system, bleeding time, and platelet count are essential. Most often the platelet count is in the normal range, but the platelets' ability to adhere is nonexistent. Pulmonary function should be checked. Chest radiography is mandatory to eliminate or assess the importance of the fibrosis. Renal impairment should be assessed by urea and electrolyte estimations. Cardiac function must be carefully assessed, especially in individuals in whom restrictive lung disease limits exercise. If myocardial function is hard to assess, echocardiography should be performed. In any event, 12-lead electrocardiogram (ECG) is mandatory, and a 24-hour ECG may demonstrate arrhythmias in patients with significant myocardial dysfunction. The possibility of postoperative ventilatory support should always be kept in mind, and proper arrangements with the intensive care unit should be made before the day of surgery.

Excessive blood loss during surgery. Bleeding time should be determined prior to any minor or major surgery. Regional anesthesia is relatively contraindicated. Central regional anesthesia block should be considered a major contraindication. The risk of potential bleeding (even in presence of minor surgery and normally consider low) should not be overestimated. Proper blood cross-match should be obtained. Some patients may be on a steroid regimen for gastrointestinal problems. Be prepared to support ventilation postoperatively if pulmonary fibrosis is severe and the pulmonary function test suggests limitations.

Because the bleeding tendency is considerably increased after ingestion of aspirin, surgery should be delayed if possible. No specific pharmacological considerations.

Other congenital hypopigmentary diseases resulting from a defect in the production of melanin in the skin, eyes, and/or ears.

Oculocutaneous Albinism: Group of autosomal recessive inherited diseases divided into three different types. OCA type I primarily presents with complete absence of pigment in the skin, the hair, and the eyes. All forms of OCA type I present with photophobia, moderate-to-severe reduced visual acuity, and nystagmus. The incidence in the general population is estimated at 1:40,000. OCA type II presents with incomplete absence of skin, hair, and eye pigmentation. Many patients have pigmented freckles, lentigines, and/or nevi with age. The ocular presentations are similar to those in OCA type I. OCA type III presents with minimal pigment reduction in the skin, hair, and eyes. It has been genetically confirmed only in dark-skinned individuals of African descent. The ocular presentations are similar to those in OCA type I, but they are not as severe. The incidence in the general population is unknown.

Oculo Albinism: X-linked recessive ocular depigmentation and iris translucency, congenital nystagmus, reduced visual acuity, refractive errors, and strabismus. Gene map locus is Xp22.3-22.2.

Chediak-Higashi Syndrome: Autosomal recessive disorder characterized by immunodeficiency, partial oculocutaneous albinism (partial or complete hypopigmentation of the skin, eyes, and hair, which are silvery), bleeding disorder as a result of platelet dysfunction, and neutropenia (recurrent infections, impaired chemotaxis and bactericidal activity, and abnormal natural killer cell functions).

Griscelli Syndrome: Albinism with immunodeficiency characterized by partial pigmentary dilution of the skin and hair (silvery gray hair), frequent infections, neurologic abnormalities, and fatal outcome caused by uncontrolled T lymphocyte and macrophage activation syndrome. Clinical features include the presence of large clumps of pigment in hair shafts and accumulation of melanosomes in melanocytes. Two types are described: type 1 with severe neurologic impairment and type II with immunologic deficiency.

Elejalde Syndrome: Silver hair and severe dysfunction of the central nervous system (neuroectodermal melanolysosomal disease). Clinical features include silver-leaden hair, bronze skin after sun exposure, and neurologic involvement (seizures, severe hypotonia, mental retardation).

Oculocerebral with Hypopigmentation Syndrome: Extremely rare autosomal recessive inherited syndrome (<20 cases have been described). Most symptoms are present at birth or develop shortly thereafter and may include very light skin color and silvery hair in combination with ophthalmologic (microphthalmia, corneal clouding, cataract, ectropion) and central nervous system anomalies (dolichocephaly, mental retardation, athetosis, ataxia, spastic paraplegia or tetraplegia). Gingival fibromatosis may develop at the age of emergence of the first teeth and may result in complete coverage of the teeth and become so significant that ventilation may be impaired. Ventilation can be decreased further by a dysfunctional diaphragm.