Hyperpigmented Macules and Patches on the Face: Exogenous Ochronosis or Lichen Planus Pigmentosus?

We present a case of a patient with a 10-year history of blue-black macules and patches on the face and an associated history of skin-lightening cream usage. The skin lightening cream contained hydroquinone, which is often associated with exogenous ochronosis (EO). Interestingly, the biopsy did not show characteristic findings of ochronosis, confusing the final diagnosis, however discontinuing the skin-lightening creams halted the progression of the patient's skin lesions supporting a diagnosis of EO. EO presents as asymptomatic hyperpigmentation after using products containing hydroquinone. This condition is most common in Black populations, likely due to the increased use of skin care products and bleaching cream containing hydroquinone in these populations. Topical hydroquinone is FDA-approved to treat melasma, chloasma, freckles, senile lentigines, and hyperpigmentation and is available by prescription only in the US and Canada. However, with the increased use of skin-lightening creams in certain populations, it is important for dermatologists to accurately recognize the clinical features of exogenous ochronosis to differentiate it from similar dermatoses. An earlier diagnosis can prevent the progression to severe presentations with papules and nodules. We summarize the clinical presentations diagnostic features, and treatment pearls, concluding with a discussion of the differential diagnoses.  J Drugs Dermatol. 2024;23(7):567-568.     doi:10.36849/JDD.8248.

Ease of sutureless aortic valve replacement in a patient with unexpected ochronosis: a case report.

BACKGROUND: Alkaptonuria is a rare congenital metabolic disorder characterized by homogentisic acid accumulation in body cartilage and connective tissues due to a deficient homogentisic acid dioxygenase enzyme. This disorder manifests in various clinical symptoms, including spondyloarthropathy, ocular and dermal pigmentation, genitourinary tract obstruction by ochronosis stones, and cardiovascular system involvement. Cardiac ochronosis is a rare manifestation of alkaptonuria that may present as aortic stenosis, sometimes accompanied by other cardiovascular complications. CASE PRESENTATION: We report an unexpected case of ochronosis diagnosed during cardiac surgery. Due to the fragile, thin, and atheromatous nature of the ascending aorta in patients with ochronosis, we opted for a sutureless aortic valve replacement procedure. This approach appears to be more suitable for patients with ochronosis. CONCLUSIONS: Although cardiac ochronosis is rare, surgeons should remain vigilant and consider the possibility of this condition when examining patients with aortic valve stenosis, paying close attention to the clinical manifestations of alkaptonuria.

Disc-coloration of an ochronotic cervical intervertebral disc in a patient with alkaptonuria: Case report and review of the literature.

OBJECTIVES: Alkaptonuria is a rare inborn disorder of phenylalanine and tyrosine metabolism. It is characterized by an accumulation of homogentisic acid and its oxidation products, possibly resulting into connective tissue damaging. "Ochronosis" is a main feature, which is characterized by tissue discoloration and even alkaptonuric arthropathy. Cervical spine involvement is exceptional and there is a paucity of reports on surgical interventions in these patients. We explored the literature concerning cervical spine involvement in patients with alkaptonuria. PATIENTS AND METHODS: We performed a review of the literature, in which patients with alkaptonuric degenerative changes of the cervical spine were examined. Articles were obtained from MEDLINE. Search terms included: "cervical", "alkaptonuria", "alkaptonuric changes" and "black disc". Additional studies were identified by checking reference lists. Furthermore, we present the case of a 46 year old patient with critical cervical spinal canal stenosis who underwent C6-C7 anterior cervical microdiscectomy and interbody fusion, in order to prevent myelopathic changes. CARE statement guidelines were followed. RESULTS: Peroperatively, we did not encounter any macroscopic abnormalities of the skin, muscles or ligaments. A black discoloration of the nucleus pulposus was observed. Peroperative and postoperative course was uneventful. CONCLUSION: Alkaptonuric degenerative abnormalities most commonly involve the lumbar spine, although the cervical spine can be affected in rare cases. Most frequently, the diagnosis of alkaptonuria can be made based on the clinical phenotype many years before symptoms secondary to ochronotic arthropathy develop. A retrospective diagnosis based on peroperative black discoloration of spinal structures has been described. A black discoloration of the intervertebral disc should encourage the neurosurgeon to further explore the possibility of alkaptonuria, even in the absence of a clear phenotype. Surgical results are mostly satisfactory. Further studies are required in order to better understand this pathology and its postoperative course.

Alkaptonuria.

Alkaptonuria is a rare inborn error of metabolism caused by the deficiency of homogentisate 1,2-dioxygenase activity. The consequent homogentisic acid (HGA) accumulation in body fluids and tissues leads to a multisystemic and highly debilitating disease whose main features are dark urine, ochronosis (HGA-derived pigment in collagen-rich connective tissues), and a painful and severe form of osteoarthropathy. Other clinical manifestations are extremely variable and include kidney and prostate stones, aortic stenosis, bone fractures, and tendon, ligament and/or muscle ruptures. As an autosomal recessive disorder, alkaptonuria affects men and women equally. Debilitating symptoms appear around the third decade of life, but a proper and timely diagnosis is often delayed due to their non-specific nature and a lack of knowledge among physicians. In later stages, patients' quality of life might be seriously compromised and further complicated by comorbidities. Thus, appropriate management of alkaptonuria requires a multidisciplinary approach, and periodic clinical evaluation is advised to monitor disease progression, complications and/or comorbidities, and to enable prompt intervention. Treatment options are patient-tailored and include a combination of medications, physical therapy and surgery. Current basic and clinical research focuses on improving patient management and developing innovative therapies and implementing precision medicine strategies.

Exogenous Ochronosis With Ocular Involvement From Chronic Use of Teavigo.

Exogenous ochronosis refers to accumulation of homogentisic acid metabolites in tissues, manifesting as pigmentation of affected tissues. Phenolic compounds are most commonly implicated, including hydroquinone, quinine, phenol, resorcinol, mercury, and picric acid. The affected connective tissues exhibit brownish discoloration when heavily pigmented and the histopathological appearance is characteristic with "banana-shaped" ochre-colored pigment deposits. Herein, the authors describe a rare case of exogenous ochronosis involving the conjunctiva, sclera and skin, as a result of chronic use of Teavigo (94% epigallocatechin gallate), a polyphenol compound with postulated antioxidant and antiapoptotic activity.

Identification of Potential Inhibitors for the Treatment of Alkaptonuria Using an Integrated In Silico Computational Strategy.

Alkaptonuria (AKU) is a rare genetic autosomal recessive disorder characterized by elevated serum levels of homogentisic acid (HGA). In this disease, tyrosine metabolism is interrupted because of the alterations in homogentisate dioxygenase (HGD) gene. The patient suffers from ochronosis, fractures, and tendon ruptures. To date, no medicine has been approved for the treatment of AKU. However, physiotherapy and strong painkillers are administered to help mitigate the condition. Recently, nitisinone, an FDA-approved drug for type 1 tyrosinemia, has been given to AKU patients in some countries and has shown encouraging results in reducing the disease progression. However, this drug is not the targeted treatment for AKU, and causes keratopathy. Therefore, the foremost aim of this study is the identification of potent and druggable inhibitors of AKU with no or minimal side effects by targeting 4-hydroxyphenylpyruvate dioxygenase. To achieve our goal, we have performed computational modelling using BioSolveIT suit. The library of ligands for molecular docking was acquired by fragment replacement of reference molecules by ReCore. Subsequently, the hits were screened on the basis of estimated affinities, and their pharmacokinetic properties were evaluated using SwissADME. Afterward, the interactions between target and ligands were investigated using Discovery Studio. Ultimately, compounds c and f were identified as potent inhibitors of 4-hydroxyphenylpyruvate dioxygenase.

Nutritional interventions for patients with alkaptonuria: A minireview.

Alkaptonuria (AKU, OMIM, No. 203500) is a rare, slow-progressing, irreversible, multisystemic disease resulting from a deficiency of the homogentisate 1,2-dioxygenase enzyme, which leads to the accumulation of homogentisic acid (HGA) and subsequent deposition as pigment in connective tissues called ochronosis. As a result, severe arthropathy of large joints and spondyloarthropathy with frequent fractures, ligament ruptures, and osteoporosis develops in AKU patients. Since 2020, the first-time treatment with nitisinone has become available in the European Union. Nitisinone significantly reduces HGA production and arrests ochronosis in AKU patients. However, blocking of the tyrosine metabolic pathway by the drug leads to tyrosine plasma and tissue concentrations increase. The nitisinone-induced hypertyrosinemia can lead to the development of corneal keratopathy, and once it develops, the treatment needs to be interrupted. A decrease in overall protein intake reduces the risk of the keratopathy during nitisinone-induced hypertyrosinemia in AKU patients. The low-protein diet is not only poorly tolerated by patients, but over longer periods, leads to a severe muscle loss and weight gain due to increased energy intake from carbohydrates and fats. Therefore, the development of novel nutritional approaches is required to prevent the adverse events due to nitisinone-induced hypertyrosinemia and the negative impact on skeletal muscle metabolism in AKU patients.

Minocycline induced discoloration of the aortic intima and valve: A case report.

CASE REPORT: Ochronosis refers to the blue-black discoloration of connective tissue. While cardiovascular ochronosis has been described resulting from alkaptonuria, it may also result from chronic minocycline use which is exceedingly rare. Cardiovascular ochronosis often presents with insidious development, often identified incidentally during aortic valve replacement (AVR). Herein, we describe the case of a 71-year-old male undergoing AVR and coronary artery bypass grafting found to have minocycline-induced ochronosis of the aortic valve and aorta. CONCLUSIONS: Given the rarity of this case, descriptions of cardiovascular ochronosis cases secondary to minocycline use are imperative in ensuring that it is on the differential diagnosis when identified by others in future cases. Additional care must be taken intraoperatively to ensure that the correct anatomy is identified as discoloration hinders visualization of the anatomy potentially resulting in unintentional consequences such as heart block or perivalvular leak as traditional visual cues for suture placement are distorted.

Descemet's membrane folds in ochronosis: a case report.

BACKGROUND: We present this report of a new ophthalmic finding in a patient with ochronosis. CASE PRESENTATION: An 85-year-old Caucasian male patient with bilateral dark temporal and nasal pigmentation of conjunctiva and sclera was referred to our hospital owing to low visual acuity. On biomicroscopic examination, bilateral horizontal Descemet's membrane folds were observed. Corneal tomography revealed irregular and asymmetric "against-the-rule" astigmatism in both eyes. Anterior segment optical coherence tomography demonstrated numerous central Descemet's without edema or other corneal structure alterations. CONCLUSION: This is the first report of Descemet's membrane folds in ochronosis. These corneal findings suggest that the accumulation of homogentisic acid in the sclera leads to thickening and stiffness of this region. These alterations could remarkably decrease visual acuity owing to topographic corneal curvature alterations, especially in elderly patients.

Ochronotic arthropathy in the context of spondyloarthritis differential diagnosis: a case-based review.

Alkaptonuria is a disease often forgotten because of its rarity. Its pathogenic mechanism is the deficiency of one of the enzymes of the tyrosine degradation pathway-homogentisate-1, 2-dioxygenase, which sequelae is accumulation and deposition of its metabolite homogentisic acid in connective tissues and urine. Alkaptonuria presents as a clinical triad-darkening urine upon prolonged exposure to air, pigmentation of connective tissues and debilitating arthropathy. We present a case report of a 67-year old patient with alkaptonuria who presented with the clinical triad, but was mistakenly diagnosed as having ankylosing spondylitis in the past. Currently there is no treatment for the disease hence the management strategy was focused on symptoms control with analgesics, physical therapy, dietary modification, vitamin C supplementation, and joint arthroplasty. Alkaptonuria's clinical features are extensively described in the literature and despite the fact that it is a rare disease, due to the similar radiographic changes with spondyloarthropathies, it should be included in the differential diagnosis in young patients presenting with severe joint involvement. Early recognition of the disease is necessary since its natural evolution is joint destruction leading to significant reduction in the quality of life. Alkaptonuria's articular features in the spine and peripheral tissues are well described using the classical imaging techniques. Musculoskeletal ultrasonography shows a characteristic set of findings in the soft tissues, including synovium, cartilage, tendons and entheses.

Total Knee Replacement in Alkaptonuric Ochronosis.

BACKGROUND AND OBJECTIVE: Alkaptonuria is a rare disease characterized by the accumulation of homogentisic acid (HGA). Over time, these patients may develop disabling ochronotic arthropathy. We present 2 cases of patients with end-stage arthropathy treated with total knee arthroplasty (TKA). METHODS: Both patients complained of disabling knee pain and reported limited walking distance (200-300 m). One had a history of osteotomy for medial knee arthtritis and ignored his underlying condition. The other presented with valgus gonoarthrosis and diagnosis of alkaptonuria. RESULTS: Intraoperatively, the characteristic dark-blue color in the joint was observed. Both patients evolved favorably after TKA with excellent results according to the Knee Society Scores (KSS) at three years of follow-up. CONCLUSION: We believe TKA is the right treatment for patients with end-stage disease because it offers considerable relief from pain and allows patients to recover function.

[Ochronosis: A case report]. / Ochronose : une observation.

INTRODUCTION: Ochronosis, also known as alkaptonuria, is a rare autosomal recessive disease. It is caused by a lack of homogentisic acid oxidase, which causes homogentisic acid deposition in the tissues. CASE REPORT: We report a 69-year-old patient who presented with chronic mechanical low back and radicular pain. The clinical examination revealed lumbar lordosis loss, lumbar spinal stiffness, and knee joint limitations of range of motion. On an extra-articular level, the pavilions of the ears and the internal angles of the eyes had a bluish color. Extensive lumbar disc calcifications, vacuum discal phenomenon and osteophytic bridges were demonstrated on standard radiographs of the spine. Clinical and radiographic criteria were used to make the diagnosis of ochronosis. CONCLUSION: Alkaptonuria is a degenerative arthropathy that leads to reduction of functional ability. The use of molecular analysis and genetic research is useful.

THE USE OF NEAR INFRARED SPECTROSCOPY IN ALKAPTONURIA - THE MISLEADING OCHRONOSIS - A CASE REPORT AND LITERATURE REVIEW.

INTRODUCTION: Near infrared spectroscopy is a non-invasive method to assess regional oxygenation and is being used in transcatheter aortic valve implantation to document periods of cerebral hypoperfusion, where cerebrovascular events are one of the most feared complications. Alkaptonuria is a rare metabolic disease characterized by accumulation of homogentisic acid in tissues and body fluids. The accumulation of pigment might interfere with the absorption of near infrared light, used in near infrared spectroscopy monitoring. We present a case of near infrared spectroscopy failing to accurately monitor cerebral oximetry in a woman, with alkaptonuria, undergoing a transcatheter aortic valve implantation.