1Department of Dermatology, Hospital Universitario San Cecilio, Granada, Spain; 2Department of Dermatology, Hospital Virgen de las Nieves, Granada, Spain *Corresponding Author’s e-mail: ismenios@hotmail.com abstract: Frontal fibrosing alopecia (FFA) is an emerging disease in Western countries. We present the cases of three sisters who were referred simultaneously to the Department of Dermatology, Hospital Universitario San Cecilio, Granada, Spain, in 2018. All patients suffered from at least partial frontotemporal hairline recession and eyebrow loss. Following trichoscopic examination, the three sisters were diagnosed with FFA. Only one of the sisters agreed to be treated; she was prescribed with topical clobetasol propionate solution and minoxidil and achieved disease control at the three-month follow-up. These patients represent a new case of familial FFA wherein three sisters as well as their mother were affected by FFA. A systematic review found a total of 24 cases of familial FFA, of which this report is the 25th. In the majority of families, only females were affected (88%) while in the remainder both males and females (8%) were affected; there was only one family where only males were affected (4%). The relationship between the affected individuals was predominately between sisters (56%) followed by mother and daughter (32%). The median age was 61 years old (range: 14–88 years) and the duration of the disease ranged between 3–360 months. Family groups of FFA are an infrequently described phenomenon with unknown prevalence. Keywords: Alopecia; Dermatology; Hair Diseases; Case Report; Spain. Familial Frontal Fibrosing Alopecia Report of a case and systematic review of the literature Carlos Cuenca-Barrales,1 *Ricardo Ruiz-Villaverde,1 Alejandro Molina-Leyva2 Sultan Qaboos University Med J, May 2021, Vol. 21, Iss. 2, pp. e320–323, Epub. 21 Jun 21 Submitted 17 May 20 Revision Req. 13 Jul 20; Revision Recd. 19 Jul 20 Accepted 13 Aug 20 age of 55. Treatment with clobetasol propionate 0,1% solution and minoxidil 5% solution was established and achieved disease control at the scheduled three- month follow-up visit. The second patient, who was the eldest sister, was a 67-year-old woman who had undergone menopause at the age of 53 and had no medical history of interest. A 10-year alopecia evolution presenting partial loss of eyebrows and slight involvement of frontotemporal hairline was noted with a slow progression [Figure 1B]. Dermoscopic signs were also consistent with the diagnosis of FFA. She refused any treatment. The third patient, who was the youngest sister, was 59 years-old who underwent menopause at 50. She had a similar scarring alopecia with a three- year evolution but with a much more inflammatory pattern, accentuated perifollicular erythema, a higher recession of frontotemporal hairline and was overall more aggressive [Figure 1C]. Similar to her two sisters, her symptoms were in agreement with the diagnosis of FFA. Likewise, she rejected any therapeutic approach. All patients provided consent to publish details and photographs of their case. Discussion In this article, we presented a case of familial FFA that adds to the body of literature on this condition. A systematic literature review was undertaken to determine the extent of available literature [Figure 2]. Frontal fibrosing alopecia (ffa) is a type of scarring alopecia described by Kossard in 1994.1 Since then, the number of publications about this disease has been rising. It has been considered a variant of lichen planopilaris due to histological similarities between the diseases;2 however, others consider it to be an independent disease among scarring alopecias due to the clinical peculiarities of FFA.3–5 New diagnostic criteria have recently facilitated its identification.6 In this case report, we report a case of familial FFA and perform a systematic review of the scientific evidence available in the literature. Case Reports Three sisters were referred simultaneously to the Department of Dermatology, Hospital Universitario San Cecilio, Granada, Spain, in 2018. The first patient was a 62-year-old female, who underwent menopause aged 52 and had a medical history of cutaneous lupus and breast cancer. She complained about frontotemporal hairline recession and partial eyebrow loss with a one year evolution [Figure 1A]. Trichoscopic examination showed erythema and follicular hyperkeratosis [Figure 1D]. Clinical and dermoscopic findings were consistent with the diagnosis of FFA. The patient claimed that her two sisters both presented with a similar type of alopecia as well as her mother, who died of breast cancer at the This work is licensed under a Creative Commons Attribution-NoDerivatives 4.0 International License. https://doi.org/10.18295/squmj.2021.21.02.025 case report https://creativecommons.org/licenses/by-nd/4.0/ Case Report | e321 MEDLINE® (National Library of Medicine, Bethesda, Maryland, USA) and EMBASE (Elsevier, Amsterdam, Netherlands) databases were searched on 11th February 2020 using the term “ALOPECIA AND (FRONTAL OR FIBROSING) AND FAMILIAL”. Articles that were published in English, Spanish, French or German as well as articles published for at least one year on the databases were included. FFA epidemiological studies were included but narrative reviews were excluded. Subsequently, two independent reviewers checked the title and abstract of the articles obtained. The full text of the articles was reviewed as well as the bibliography that supported them to search for sources of additional information. Only the articles agreed upon by both reviewers in relation to the inclusion criteria were included in the final analysis. In the case of disagreement, a third reviewer analysed the article. A total of 11 articles were included in this review in which there are a total of 24 cases of familial FFA [Figure 2]. The current case represents the 25th and resulted in a total of 59 individual cases [Table 1].4,7–16 Most affected family members were women (88%) but some families had both men and women (8%) who were affected; only one family presented with only affected males (4%). Analysis of the familial relationships showed that the most common relationship was between sisters (56%) followed by mother and daughter (32%) and brother and sister (8%). Regarding ethnicity, the majority of families with a known ethnicity were Caucasian (83%) followed by Hispanic (11%) and Black (6%). The median age was 61 years old (range: 14–88 years) and the duration of the disease ranged between 3–360 months. Eyebrows were involved in 93% of patients. Among the comorbidities, there were autoimmune disorders such as rheumatoid arthritis, vitiligo, hypothyroidism, primary biliary cirrhosis or cutaneous lupus, several cardiovascular risk factors such as diabetes mellitus type 2, dyslipidaemia, high blood pressure or psoriasis, other hair disorders such as lichen planopilaris or alopecia areata, cancers such as colorectal and breast cancer and infectious diseases such as a case of hepatitis due to the hepatitis C virus. It should be noted that this literature review was subject to the limitation that it only included case reports. There is still uncertainty about aetiopathogenesis of FFA. Based on the apparent increase in incidence in recent years, FFA has been related to environmental factors such as dioxins and dioxin-like chemicals.7 The importance of hormonal factors has been posed too, due to the widespread prevalence in Caucasian postmenopausal women and the high effectiveness of anti-androgens compared with other treatments.5 Genetic factors have also been linked to this disease, as family cases reported in the literature to date suggest.4,7–19 Finally some authors have stated an autoimmune origin due to the inflammatory infiltrates in the bulb, the similarities to LPP and the association with other autoimmune diseases.17 Family groups of FFA are an infrequently described phenomenon, with unknown prevalence among all cases of FFA. From the genetic point of Figure 1: Photographs of the heads of three sisters. A: A 62-year-old woman with frontotemporal hairline recession and partial eyebrow loss. B: A 67-year- old woman with similar pattern and accentuated eyebrow loss. C: A 59-year-old woman with marked hairline recession and almost total loss of eyebrows. D: Trichoscopic examination photograph of the 62-year-old woman showing erythema and follicular hyperkeratosis. Figure 2: Flowchart showing the process of article selection for a literature review on frontal fibrosing alopecia. Carlos Cuenca-Barrales, Ricardo Ruiz-Villaverde and Alejandro Molina-Leyva Table 1: Epidemiologic and clinical characteristics of familial cases of FFA reported in the scientific literature. Author and year of publication Family no. No. and gender Relationship Age in years Ethnicity History of FFA in months Eyebrow involvement Comorbidities Dlova et al.7 (2013) #1 3F Sisters 55 61 73 Caucasian 12 24 - Yes Yes Yes None None None #2 1F 1M Sister Brother 59 62 Caucasian 36 12 Yes Yes LPP None #3 2F Sisters 25 21 Hispanic 12 3 Yes Yes None None #4 3F Mother Daughter Cousin 74 50 44 Black 24 12 12 No No Yes Traction alopecia Traction alopecia Traction alopecia Roche et al.8 (2008) 1F 1M Sister Brother 75 71 Non- specified 12 8 Yes Yes None None Junqueira Ribeiro Pereira et al.13 (2010) 2F Sisters 57 59 Caucasian 12 12 Yes Yes None Oophorectomy (at 32 years-old), colorectal adenocarcinoma (at 54 years-old) and HCV treated with IFN + ribavirin (at 55 years-old) Miteva et al.9 (2011) 2F Twin sisters 67 Caucasian 12 6 Yes Yes Vitiligo Vitiligo Cranwell and Sinclair11 (2017) 2F Mother Daughter 46 - Non- specified 10 Non specified Yes Yes Rheumatoid arthritis, AA None Chan et al.12 (2014) 2F Sisters 49 63 Caucasian 18 24–36 Yes Non-specified None None Navarro- Belmonte et al.4 (2015) #1 2F Mother Daughter 75 47 Non- specified Non-specified 18 Yes Yes Hypothyroidism Psoriasis, HBP, dyslipidaemia #2 2F Mother Daughter 60 41 Non- specified 24 12 Yes Yes DM type 2, HBP None #3 2F Mother Daughter 63 37 Non- specified 24 Non-specified Yes Yes Primary biliary cirrhosis None #4 2F Mother Daughter 62 33 Non- specified Non-specified Non-specified Yes Yes None None Atarguine et al.10 (2016) 2F Twin sisters 14 Non- specified 108 Non-specified Goitre (one sister) Rocha et al.14 (2020) 6F Sisters 67 64 62 61 52 51 Hispanic 180 144 24 360 24 24 Yes Yes No Yes Yes Yes DM, Systemic arterial hypertension No No Allergic rhinitis Deep Vein Thrombosis No Porriño- Bustamante et al.16(2019) #1 2F Sisters 59 66 Caucasian 30 108 Yes Yes Non-specified Non-specified #2 3F Mother 1st Cousin of mother Daughter 78 68 50 Caucasian 228 144 36 Yes Yes Yes Non-specified Non-specified Non-specified #3 2M Brothers 44 46 Caucasian 48 12 Yes Yes Non-specified Non-specified #4 2F Sisters 39 42 Caucasian 72 24 Yes Yes Non-specified Non-specified #5 3F Sisters 88 72 64 Caucasian 24 12 48 Yes Yes Yes Non-specified Non-specified Non-specified #6 2F Sisters 53 46 Caucasian 96 12 Yes Yes Non-specified Non-specified #7 2F Sisters 74 72 Caucasian 288 240 Yes Yes Non-specified Non-specified #8 2F Sisters 77 74 Caucasian 204 168 Yes Yes Non-specified Non-specified #9 2F Mother Daughter 70 44 Caucasian 144 24 Yes Yes Non-specified Non-specified Current case 3F Sisters 62 67 59 Caucasian 12 120 36 Yes Yes Yes Breast cancer, cutaneous lupus None None F = female; M = male; LPP = lichen planopilaris; HCV = hepatitis C virus; IFN = interferon; AA = alopecia areata; HBP = high blood pressure; DM = diabetes mellitus. Familial Frontal Fibrosing Alopecia Report of a case and systematic review of the literature e322 | SQU Medical Journal, May 2021, Volume 21, Issue 2 Case Report | e323 view, genome-wide association studies in females from a UK cohort (comprising 844 cases and 3,760 controls) and a Spanish cohort (consisting of 172 cases and 385 controls) have been related to HLA-B*07:02; a genome-wide significant association with FFA was observed at four genomic loci (2p22.2, 6p21.1, 8q24.22 and 15q2.1).20 Inheritance mode seems to follow an autosomal dominant pattern with incomplete penetrance which is in line with the current case.21 Considering the findings of the present case and available scientific evidence, there are several phenotypic expression patterns of FFA which may be the result of epigenetic modulation or genic interaction mechanisms and give rise to the partial penetrance of the trait. Upon this genetic predisposition, some trigger factors may overlap. A decrease in serum oestrogen levels or traumatisms, setting off an inflammatory reaction at the level of the follicular bulge, leading to fibrosis and final loss of the follicular hair may be considered. Conclusion The cases of the three sisters highlights the need to carefully evaluate family aggregation patterns when examining patients, since on many occasions, unlike in our case, patients attend consultations alone. International collaboration between researchers is needed in order to perform epidemiological studies with larger sample sizes. References 1. Kossard S. Postmenopausal frontal fibrosing alopecia. Scarring alopecia in a pattern distribution. Arch Dermatol 1994; 130:770–4. https://doi.org/10.1001/archderm.130.6.770. 2. Dlova NC. Frontal fibrosing alopecia and lichen planus pigmentosus: Is there a link? Br J Dermatol 2013; 168:439–42. https://doi.org/10.1111/j.1365-2133.2012.11146.x. 3. Banka N, Mubki T, Bunagan MJ, McElwee K, Shapiro J. 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