Acne Inversa, Familial, 1

A number sign (#) is used with this entry because familial acne inversa-1 (ACNINV1) is caused by heterozygous mutation in the gene encoding nicastrin (NCSTN; 605254) on chromosome 1q23.

Description

Acne inversa is a chronic relapsing inflammatory skin disease characterized by recurrent draining sinuses and abscesses, predominantly in skin folds that carry terminal hairs and apocrine glands. Healing occurs with substantial scarring (summary by Jansen et al., 2001).

Jansen et al. (2001) provided a detailed history and review of the disorder.

Genetic Heterogeneity of Familial Acne Inversa

Familial acne inversa-2 with or without Dowling-Degos disease (ACNINV2; 613736) is caused by mutation in the PSENEN gene (607632) on chromosome 19q13, and familial acne inversa-3 (ACNINV3; 613737) is caused by mutation in the PSEN1 gene (104311) on chromosome 14q24.

Clinical Features

Fitzsimmons et al. (1984) observed chronic hidradenitis suppurativa in a total of 21 members (16 females, 5 males) from 3 English families. In 1 kindred, the condition was associated with acne conglobata (cystic acne) and vertical transmission through 3 generations was documented. In the other families, affected persons had a history of acne vulgaris with comedone formation and 2 generations were affected. No male-to-male transmission was documented; however, the authors stated that the grandfather in their family B was probably affected and, if true, this would mean one instance of father-to-son transmission. Several of the females were obese, but none had diabetes.

Fitzsimmons et al. (1985) extended their studies to 23 families in which they found a total of 62 affected persons.

Fitzsimmons and Guilbert (1985) reported a series based on 26 probands. 'Single gene transmission' was supported by the findings in 11 of these. In another 3 families, a history of other affected persons was obtained; in 9 families no history of other cases was found. Several of the families included persons with acne conglobata alone or with hidradenitis suppurativa.

Pink et al. (2011) reported a man with hidradenitis suppurativa who developed boils and abscesses in his axillae, suprapubic area, groin, buttocks, thighs, and neck at the age of 16 years. All lesions were associated with scarring and sinus tract formation. Family history revealed that the proband's brother, father, and paternal grandfather were also affected.

Other Features

A relationship has been suggested between hidradenitis suppurativa and the development of nonmelanoma skin cancer. To confirm this relationship and to explore the risk of other cancers among patients with hidradenitis suppurativa, Lapins et al. (2001) identified 2,119 patients with hidradenitis suppurativa from a computerized database of hospital discharge diagnoses from all hospitals in Sweden covering a period of 22 years. They searched the Swedish National Cancer Registry for information on these patients and calculated standardized incidence ratios to estimate relative risk. The risk of developing any cancer in the cohort with hidradenitis suppurativa increased 50%. Statistically significant risk elevations were observed for nonmelanoma skin cancer. There was less convincing evidence that the risks of buccal and liver cancer were also elevated in hidradenitis suppurativa patients.

Pathogenesis

Based on histopathologic studies of tissue from patients with acne inversa and control specimens, Jansen et al. (2001) proposed a sequence of events in the pathogenesis of acne inversa. The earliest inflammatory event is a segmental rupture of the follicular epithelium, followed by spilling of foreign body material, such as corneocytes, bacteria, sebum products, and hairs, into the dermis. The dumping of foreign products initiates an inflammatory response provoking foreign body granuloma, and epithelial strands try to encapsulate the necrotic tissue. The apocrine glands are not involved in the earliest stage of follicular hyperkeratosis. Once rupture of the follicular epithelium has occurred, the disease spreads rapidly. The draining sinus is a late complication, leading to extensive, periodically inflamed lesions that are undermined by a system of fistulas. Jansen et al. (2001) emphasized that apocrine involvement is a secondary event in the disease process.

Inheritance

The transmission pattern of hidradenitis suppurativa in the families reported by Wang et al. (2010) was consistent with autosomal dominant inheritance.

Knaysi et al. (1968) found a positive family history in 3 of 18 patients specifically questioned.

To test the validity of dominant inheritance in hidradenitis suppurativa, Von der Werth et al. (2000) revisited 14 surviving probands and their families initially reported by Fitzsimmons and Guilbert (1985). Patients were evaluated by a newly devised, strict definition of the disorder. Von der Werth et al. (2000) directly evaluated 132 family members and detected 28 affected relatives, including 27 who were in the group previously labeled as family history-positive. Nine cases had not been detected previously, including 7 who developed symptoms after the previous study had been completed. Eighteen cases were classified as 'possibly affected,' including 2 that were classified as 'definitely affected' in the original study. All new cases in families with positive histories for hidradenitis suppurativa were descended from affected individuals, while none of the unaffected members of these families had affected children. In all, they found that 27% of surviving first-degree relatives were definitely affected, a figure lower than the 50% expected in an autosomal dominant disease. However, if they included the 'possibly affected' individuals, the number of affected first-degree relatives was 51%. They also detected a female-to-male predominance of 2:1.

Population Genetics

The prevalence of acne inversa has been estimated at 1 in 100 to 1 in 600. The female-to-male ratio in most published series is between 2:1 and 5:1 (Jansen et al., 2001).

Mapping

Gao et al. (2006) performed a genomewide scan in a 4-generation Chinese family with acne inversa and identified a locus at chromosome 1p21.1-1q25.3, with a maximum lod score of 3.26 at the marker D1S2624 (theta = 0.00). Haplotype analysis refined the locus to a 76-Mb region flanked by D1S248 and D1S2711.

Molecular Genetics

Wang et al. (2010) identified 3 families segregating autosomal dominant acne inversa who had heterozygous loss-of-function mutations in the NCSTN gene. One family had a single-basepair deletion leading to a frameshift (605254.0001). Another family had exon skipping (605254.0002), and the last family had a premature termination codon (605254.0003).

Pink et al. (2011) screened 7 families with hidradenitis suppurativa for mutations in 3 acne inversa-associated genes, and identified heterozygosity for a splice site mutation in the NCSTN gene (605254.0004) in a Caucasian man. The mutation was not found in the proband's unaffected mother or in 200 control chromosomes of European ancestry; DNA was unavailable from his affected brother, father, or paternal grandfather.

Nomenclature

Jansen et al. (2001) stated that the term 'hidradenitis suppurativa' is a misnomer for this condition because it is a defect of follicular epithelium, not of the apocrine glands, as previously considered. They suggested the term 'acne inversa.'