Hipertricose associada à condições genéticas raras: aspectos clínicos

Abstract

Hypertrichosis is characterized by excessive growth of hair, for an individual's age and sex, regardless of androgens. The incidence of isolated hypertrichosis is rare, but it increases when associated to the phenotype of several genetic disturbances. Hypertrichosis can be a cutaneous sign of a rare genetic disease, which can be associated to multiple organ malformations.It is a critical literature review study, with the objective to evaluate the clinicalcharacteristics of genetic diseases associated with hypertrichosis. A search was conducted in the Online Mendelian Inheritance in Man (OMIM) from June 2020 to October 2020 for associations with the terms “hirsutism”and“hypertrichosis”. Additional search was performed in Pubmed (https://pubmed.ncbi.nlm.nih.gov)and Orphanet (https://www.orpha.net/consor/cgi bin/index.php)for complemental scientific articles. Non-dependent disturbancesto androgen metabolism or syndromes with overlapping features were included as hypertrichosis. Clinical involvement of each disease were evaluated into categories as features of head and neck, inheritance pattern, skeletal, cardiovascular, intellectual disability, nervous system, neoplasia, genitourinary, abdominal, endocrine, respiratory tract, early death and dental anomalies.For the evaluation of genetic syndromes associated with hypertrichosis and dental anomalies, STRING, analysis of functional enrichment of protein-protein interaction networks, was used to investigate biological processes, pathways and interaction network of the genetic diseases associated with hypertrichosis and dental anomalies. The p values were subjected to the false discovery rate for correction of several tests, and values ≤ 0.05 were considered significant.One hundred twenty-one rare genetic conditions associated with hypertrichosis were identified. The main inheritance pattern was autosomal recessive (44.62%). The most affected categories were head and neck features (80.16%), skeletal system (78.51%) and nervous system (73.55%). Other affected categories highlighted were intellectual disability (52.06%), abdomen (42.97%), genitourinary (39.66%),dental anomalies (32.23%) and cardiovascular abnormalities (32.23%). Additional major concerning were early death (18.28%) and association with malignancies (8.26%). In the evaluation of genetic diseases associated with hypertrichosis and dental anomalies, agenesis was 11 found in 41.02% of the disorders, followed by delayed in tooth eruption (35.89%) and widely spaced teeth (28.20%), among others.Causative genes were identified in 33 out of 39genetic syndromes. Among them, 39 genes were relatedand 38were analized by STRING, wich showed 148 biological processes and 3 pathwaysstatistically significant. The most significant biological processes were disassembly of the nucleosome (GO: 0006337, p=1.09e-06), chromosomal organization (GO: 0051276, p=1.09e-06) and remodeling of the chromatin (GO: 0006338, p=7.86e-06), and the pathways were hepatocellular carcinoma (hsa05225, p=5.77e-05), thermogenesis (hsa04714, p=0.00019) and cell cycle (hsa04110, p=0.0433).The study shows that hypertrichosis may be a clue to a rare multisystemic genetic disease, and correlates the main organ systems involved.Dental anomalies in patients with hypertrichosis associated with genetic diseases are a marker of dysmorphism that can assist in the investigative process.The STRING analysis evidenced the biological processes and pathways common to patients with hypertrichosis and dental anomalies.The development of a clinical guidelines script assists health professionals, patients and their respective family members in health care.