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Case Reports in Dermatological Medicine 2023The cosmetic use of skin bleaching products is common among women in sub-Saharan Africa despite numerous reported cutaneous and systemic complications. We report the...
BACKGROUND
The cosmetic use of skin bleaching products is common among women in sub-Saharan Africa despite numerous reported cutaneous and systemic complications. We report the first case of squamous cell carcinoma in a woman using skin bleaching products in Togo. . A 65-year-old woman with a 30-year history of skin bleaching products use consulted in dermatology for a tumor of the neck that had been evolving for 2 years. There was no personal or family history of cancer. The patient was obese (BMI = 38.3 kg/m) and had high blood pressure. Clinical examination noted multiple ulcerative and cauliflower tumors of the neck. The presence of stretch marks, skin atrophy, and ochronosis was noted in the examination of the rest of skin. There were no lymph nodes. HIV serology was negative. Histology of a tumor biopsy concluded to an invasive skin squamous cell carcinoma. The cervical, thoracic, abdominal, and pelvic TDM revealed pulmonary metastases. The patient underwent complete surgical removal of the right latero-cervical tumor. The left latero-cervical tumors were not removed because they infiltrated the large vessels. Chemotherapy before surgery was prescribed but not honored for financial reasons. The patient died 2 months after her first consultation in respiratory distress.
CONCLUSION
Squamous cell carcinoma is one of the complications of skin bleaching in sub-Saharan Africa. It is necessary to intensify awareness campaigns on the complications of this practice, in order to reduce their incidence, in our context where this practice is very frequent.
PubMed: 36684806
DOI: 10.1155/2023/8002896 -
International Journal of Molecular... Dec 2022Alkaptonuria (AKU) is an ultra-rare metabolic disease caused by the accumulation of homogentisic acid (HGA), an intermediate product of phenylalanine and tyrosine...
Alkaptonuria (AKU) is an ultra-rare metabolic disease caused by the accumulation of homogentisic acid (HGA), an intermediate product of phenylalanine and tyrosine degradation. AKU patients carry variants within the gene coding for homogentisate-1,2-dioxygenase (HGD), which are responsible for reducing the enzyme catalytic activity and the consequent accumulation of HGA and formation of a dark pigment called the ochronotic pigment. In individuals with alkaptonuria, ochronotic pigmentation of connective tissues occurs, leading to inflammation, degeneration, and eventually osteoarthritis. The molecular mechanisms underlying the multisystemic development of the disease severity are still not fully understood and are mostly limited to the metabolic pathway segment involving HGA. In this view, untargeted metabolomics of biofluids in metabolic diseases allows the direct investigation of molecular species involved in pathways alterations and their interplay. Here, we present the untargeted metabolomics study of AKU through the nuclear magnetic resonance of urine from a cohort of Italian patients; the study aims to unravel molecular species and mechanisms underlying the AKU metabolic disorder. Dysregulation of metabolic pathways other than the HGD route and new potential biomarkers beyond homogentisate are suggested, contributing to a more comprehensive molecular signature definition for AKU and the development of future adjuvant treatment.
Topics: Humans; Alkaptonuria; Metabolomics; Homogentisic Acid; Biomarkers; Dioxygenases; Magnetic Resonance Spectroscopy
PubMed: 36555443
DOI: 10.3390/ijms232415805 -
Rheumatology and Immunology Research Jun 2022
PubMed: 36465319
DOI: 10.2478/rir-2022-0009 -
Scientific Reports Nov 2022Alkaptonuria (AKU) is a rare inborn error of metabolism caused by a defective homogentisate 1,2-dioxygenase (HGD), an enzyme involved in the tyrosine degradation...
Alkaptonuria (AKU) is a rare inborn error of metabolism caused by a defective homogentisate 1,2-dioxygenase (HGD), an enzyme involved in the tyrosine degradation pathway. Loss of HGD function leads to the accumulation of homogentisic acid (HGA) in connective body tissues in a process called ochronosis, which results on the long term in an early-onset and severe osteoarthropathy. HGD's quaternary structure is known to be easily disrupted by missense mutations, which makes them an interesting target for novel treatment strategies that aim to rescue enzyme activity. However, only prediction models are available providing information on a structural basis. Therefore, an E. coli based whole-cell screening was developed to evaluate HGD missense variants in 96-well microtiter plates. The screening principle is based on HGD's ability to convert the oxidation sensitive HGA into maleylacetoacetate. More precisely, catalytic activity could be deduced from pyomelanin absorbance measurements, derived from the auto-oxidation of remaining HGA. Optimized screening conditions comprised several E. coli expression strains, varied expression temperatures and varied substrate concentrations. In addition, plate uniformity, signal variability and spatial uniformity were investigated and optimized. Finally, eight HGD missense variants were generated via site-directed mutagenesis and evaluated with the developed high-throughput screening (HTS) assay. For the HTS assay, quality parameters passed the minimum acceptance criterion for Z' values > 0.4 and single window values > 2. We found that activity percentages versus wildtype HGD were 70.37 ± 3.08% (for M368V), 68.78 ± 6.40% (for E42A), 58.15 ± 1.16% (for A122V), 69.07 ± 2.26% (for Y62C), 35.26 ± 1.90% (for G161R), 35.86 ± 1.14% (for P230S), 23.43 ± 4.63% (for G115R) and 19.57 ± 11.00% (for G361R). To conclude, a robust, simple, and cost-effective HTS system was developed to reliably evaluate and distinguish human HGD missense variants by their HGA consumption ability. This HGA quantification assay may lay the foundation for the development of novel treatment strategies for missense variants in AKU.
Topics: Humans; Alkaptonuria; Homogentisate 1,2-Dioxygenase; Dioxygenases; Polymorphism, Single Nucleotide; High-Throughput Screening Assays; Escherichia coli; Homogentisic Acid
PubMed: 36376482
DOI: 10.1038/s41598-022-23702-y -
Metabolites Oct 2022Alkaptonuria (AKU) is a rare autosomal recessive disorder caused by mutations within a gene coding for homogentisate 1,2-dioxygenase (HGD). To date, 251 different...
Alkaptonuria (AKU) is a rare autosomal recessive disorder caused by mutations within a gene coding for homogentisate 1,2-dioxygenase (HGD). To date, 251 different variants of this gene have been reported. The metabolic disorder in AKU leads to the accumulation of homogentisic acid (HGA), resulting in ochronosis (pigmentation of the connective tissues) and severe ochronotic spondylo-arthropathy, which usually manifests in the mid-thirties. An earlier genotype−phenotype correlation study showed no differences in serum HGA levels, absolute urinary excretion of HGA, or in the clinical symptoms between patients carrying HGD variants leading to 1% or >30% residual HGD activity. Still, as reported previously, the variance of the excretion of the HGA was smaller within affected siblings that share a common genotype. The present study is the first ever to systematically analyze the baseline clinical data of 24 AKU sibling pairs/groups collected in the SONIA 2 (Suitability Of Nitisinone In Alkaptonuria 2) study to evaluate phenotypical differences between patients carrying the same HGD genetic variants. We show that even between siblings there was considerable variability in the disease severity. This indicates that some other yet unidentified genetic, biomechanical, or environmental modifying factors may contribute to accelerated pigmentation and connective tissue damage observed in some patients.
PubMed: 36295892
DOI: 10.3390/metabo12100990 -
Metabolites Sep 2022Changes in the phenylalanine (PHE)/tyrosine (TYR) pathway metabolites before and during homogentisic acid (HGA)-lowering by nitisinone in the Suitability of Nitisinone...
Changes in the phenylalanine (PHE)/tyrosine (TYR) pathway metabolites before and during homogentisic acid (HGA)-lowering by nitisinone in the Suitability of Nitisinone in Alkaptonuria (AKU) 2 (SONIA 2) study enabled the magnitude of the flux in the pathway to be examined. SONIA 2 was a 48-month randomised, open-label, evaluator-blinded, parallel-group study performed in the UK, France and Slovakia recruiting patients with confirmed AKU to receive either 10 mg nitisinone or no treatment. Site visits were performed at 3 months and yearly thereafter. Results from history, photographs of eyes/ears, whole body scintigraphy, echocardiography and abdomen/pelvis ultrasonography were combined to produce the Alkaptonuria Severity Score Index (cAKUSSI). PHE, TYR, hydroxyphenylpyruvate (HPPA), hydroxyphenyllactate (HPLA) and HGA metabolites were analysed by liquid chromatography/tandem mass spectrometry in 24 h urine and serum samples collected before and during nitisinone. Serum metabolites were corrected for total body water (TBW), and the sum of 24 h urine plus total body water metabolites of PHE, TYR, HPPA, HPLA and HGA were determined. The sum of urine metabolites (PHE, TYR, HPPA, HPLA and HGA) were similar pre- and peri-nitisinone. The sum of TBW metabolites and sum TBW + URINE metabolites were significantly higher peri-nitisinone (p < 0.001 for both) compared with pre-nitisinone baseline. Significantly higher concentrations of metabolites from the tyrosine metabolic pathway were observed during treatment with nitisinone. Arguments for unmasking of the ochronotic pathway and biliary elimination of HGA are put forward.
PubMed: 36295821
DOI: 10.3390/metabo12100920 -
Anais Brasileiros de Dermatologia 2023
Topics: Humans; Carbon Dioxide; Ochronosis; Alkaptonuria; Lasers, Gas; Treatment Outcome
PubMed: 36273949
DOI: 10.1016/j.abd.2021.08.013 -
Indian Dermatology Online Journal 2022
PubMed: 36262587
DOI: 10.4103/idoj.idoj_735_21 -
Journal of Medical Case Reports Oct 2022We present this report of a new ophthalmic finding in a patient with ochronosis.
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.
Topics: Aged; Aged, 80 and over; Cornea; Descemet Membrane; Homogentisic Acid; Humans; Male; Ochronosis; Visual Acuity
PubMed: 36183119
DOI: 10.1186/s13256-022-03599-x -
Annals of Medicine and Surgery (2012) Aug 2022Alkaptonuria is a rare hereditary disease with a defective enzyme that results in increased homogentisic acid levels in the body. Homogentisic acid accumulates in...
Alkaptonuria is a rare hereditary disease with a defective enzyme that results in increased homogentisic acid levels in the body. Homogentisic acid accumulates in multiple body parts and initializes tissue damage. Clinical manifestations such as pigmentation of the skin areas and joint destruction result in ochronosis. Nitisinone decreases serum and urinary homogentisic acid levels, improving morbidity by preventing and slowing the progression of alkaptonuria. Nitisinone-induced hypertyrosinemia causes keratopathy and mental ill effects, which can be managed by diet restriction and regular check-ups. A personalized approach is required for treatment by nitisinone. Low-dose oral nitisinone is associated with overall good results and a better safety profile.
PubMed: 36045846
DOI: 10.1016/j.amsu.2022.104340