Hermansky-Pudlak syndrome
Hermansky-Pudlak syndrome (HPS) is a rare genetic disorder characterized by a combination of oculocutaneous albinism, a bleeding tendency, and the accumulation of ceroid, a lipid substance in cells. As of 2023, nine clinically related subtypes (HPS1 through HPS9) have been identified, with HPS1 being the most common, particularly in certain populations like those in northwestern Puerto Rico. This condition is inherited in an autosomal recessive manner, affecting both males and females equally.
Patients with HPS may experience symptoms that include hypopigmentation of the skin, hair, and eyes, along with prolonged bleeding and potential lung complications such as fibrosis. Diagnosis is often confirmed through specific genetic testing and electron microscopy, revealing distinctive cellular features. Management strategies may involve blood transfusions, vision correction, and regular monitoring of lung health. Unfortunately, HPS has serious health implications, with many patients facing significant risks and a reduced life expectancy due to complications, particularly from lung issues. Understanding HPS is crucial for those affected and their families, as well as for healthcare providers seeking to offer supportive care.
Hermansky-Pudlak syndrome
DEFINITION Hermansky-Pudlak syndrome (HPS) is a group of genetically heterogeneous disorders. According to GeneReviews nine clinically related subtypes, HPS1 through HPS9, have been identified as of 2023. HPS patients typically present with three features: oculocutaneous albinism (a pigmentation defect affecting skin, hair, and eyes), bleeding tendency, and cellular accumulation of a lipid substance called ceroid.
Risk Factors
HPS is a recessive genetic disorder passed from parents to offspring. Males and females are equally affected. Worldwide, HPS is extremely rare, affecting an estimated 1 in 500,000 to 1 in 1 million individuals according to the US National Library of Medicine in 2023. The was much higher in northwestern Puerto Rico, where 1 in 20 people were carriers and 1 in 1,800 had HPS1.
Etiology and Genetics
HPS is an autosomal disorder. The first realated gene to be identified, named HPS1, is located on chromosome 10q23.1–q23.3. Mutations in HPS1 lead to the most common subtype, HPS1. More than twenty disease-causing mutations in HSP1 have now been reported. The most predominant mutation is a 16 base pair frame-shift duplication found in the northwestern Puerto Rican population. HPS2 is caused by mutations in the AP3B1 gene on chromosome 5q14.1. The gene product, β3A, is a subunit of the AP-3 complex, a complex involved in protein sorting and transport. Mutations in the HPS3 gene located on chromosome 3q24 cause HPS3. Of note, the most frequent mutation in HPS3 is found in families from central Puerto Rico, who have a 3.9 kilobase deletion. The gene causing HSP4, called HSP4, is on chromosome 22q12.1. A majority of HPS cases involve mutations in HSP1 through HPS4. HPS5 through HPS9 are rare subtypes, with as few as two patients described (HSP9).
Although these genes are expressed ubiquitously, only certain cells are affected in HPS. This is because HPS gene products are involved in the formation and transport of structures within specialized cells called lysosome-related organelles. As the name suggests, lysosome-related organelles share many properties with lysosomes, whose role is to remove cellular waste. Examples of lysosome-related organelles are melanosomes in pigment cells of the skin and retinal pigment epithelium, dense granules of platelets in the blood, and lamellar bodies of lung epithelial cells.
The proteins encoded by genes for HPS are components of several larger protein complexes named biogenesis of lysosome related organelles complexes (BLOCs). So far, three BLOCs and the AP-3 complex have been associated with HPS. These complexes are essential for the correct function of lysosome-related organelles. Hence the fact that in HPS pigment production is defective, resulting in oculotaneous albinism; dense granules of blood platelets are absent, leading to prolonged bleeding; and lamellar bodies are defective, leading to fibrosis of the lungs.
Different complexes are mutated in different HPS subtypes: BLOC1 subunits are mutated in HPS7, HPS8, and HPS9; BLOC2 subunits are mutated in HPS3, HPS5, and HPS6; and BLOC3 subunits are mutated in HPS1 and HPS4. AP-3 subunits are mutated in HPS2. Each gene mutation results in different severities of the disease and varying subsets of symptoms. Mutations in HPS1 and HPS4 (BLOC3) lead to the most aggressive forms of the disease, while mutations in HPS3, HPS5, and HPS6 (BLOC2) are the most mild.
Symptoms
The oculocutaneous of HPS manifests with hypopigmentation of the skin, hair, and eyes; nystagmus; and poor eyesight. Patients display prolonged bleeding times with frequent bruising and nosebleeds. In HPS1 and HPS4, pulmonary fibrosis and granulomatous colitis are seen. HPS2 patients are susceptible to infection as a result of white blood cell deficiency (neutropenia).
Screening and Diagnosis
Symptoms of albinism in the skin, hair, and eyes may be recognized in infancy, however, these vary widely in severity and may remain unnoticed in some cases of HPS. Eye examinations reveal albinism-related ocular abnormalities. Doctors may suspect a diagnosis of HPS as a child learns to walk, since excessive bleeding and bruising is common around this time. A definitive diagnosis is obtained using electron microscope studies to confirm the absence of dense granules in platelets. Polymerase chain reaction (PCR) genetic testing is available only for the 16 base pair duplication in HPS1 and the 3.9 kilobase deletion in HPS3.
Treatment and Therapy
Blood transfusions are given when necessary (for example, during surgical procedures). Eyesight can be improved by corrective techniques, but even after correction, vision remains poor. Individuals with HPS must avoid sun exposure and require routine dermatological screening to check for skin abnormalities that could lead to cancer. Regular chest X-rays and pulmonary function tests are performed to monitor the lungs. Supplemental oxygen may be required in later stages of fibrosis. HPS patients with lung problems are advised to avoid situations where the lungs can be irritated, for example smoky or polluted environments.
Prevention and Outcomes
Around 70 percent of HPS patients die from complications of the syndrome, while 50 percent die from restrictive pulmonary fibrosis at around forty years of age. Other causes of death include bleeding, intestinal problems, and liver and kidney failure.
Bibliography
"Albinism." MedlinePlus, 31 Dec. 2023, medlineplus.gov/ency/article/001479.htm. Accessed 10 Sept. 2024.
"Hermansky-Pudlak Syndrome." MedlinePlus, 1 May 2014, medlineplus.gov/genetics/condition/hermansky-pudlak-syndrome/. Accessed 10 Sept. 2024.
Introne, Wendy J., et al. "Hermansky-Pudlak Syndrome." GeneReviews, 25 May 2023, www.ncbi.nlm.nih.gov/books/NBK1287/. Accessed 10 Sept. 2024.
Nordland, J., et al. The Pigmentary System. 2d ed. Malden: Blackwell, 2006. Print.
O'Neill, Marla J. F. "#614171: Hermansky-Pudlak Syndrome 9; HPS9." OMIM.org, 6 Aug. 2024, www.omim.org/entry/614171. Accessed 10 Sept. 2024.
Wei, M. “Hermansky-Pudlak Syndrome: A Disease of Protein Trafficking and Organelle Function.” Pigment Cell & Melanoma Research 19.1 (2006): 19–42. Print.