Of Hidradenitis Suppurativa

Like many other aspects of hidradenitis suppurativa (HS), its heritability has received little at-

Contents tention for many years. References to it were made by Brunsting in 1952 in his description of

10.1 Clinical Genetics the follicular occlusion triad - acne conglobata, of Hidradenitis Suppurativa 70 dissecting cellulitis of the scalp, and hidradeni-

10.2 Genodermatoses 74 tis suppurativa [10]. As late as 1968 Knaysi re-

10.3 Methods for Identifying Disease Genes . .. 74 ported rather dismissively that only 3 O^ Of 18

questioned patients had described a positive

10.4 Genetic Markers 74 ? , . , r., 4. r-^i a family history of the disease [36]. A case report

10.5 Positional Cloning of familial occurrence of HS in association with ofDominantlyInheritedDiseaseGenes ..75 acne conglobata was published by Gold and

10.6 Genome-Wide Linkage Analysis Delaney in 1974 [22]. A structured investigation inFamilialHS 77 of the genetic basis of HS was not carried out

10.7 Linkage of Hidradenitis Suppurativa until Fitzsimmons et al. published their series of to 6q25.2 78 HS families in 1984 and expanded this in 1985.

10.8 Identification of a Second HS Locus In these studies an autosomal dominant pattern to Chromosome 19 79 of inheritance was postulated for a proposed familial variant of HS [18-20]. Fitzsimmons' research analysed 23 families of probands with HS and found evidence in favour of a singlegene Mendelian inheritance in 11 of these. Their study acknowledged lacking conclusive proof of such heritability and the existence of some inconsistencies. They only ascertained the disease in 34% of first-degree relatives of HS sufferers and found a predominance of females in their group of HS sufferers by a ratio of 2:1. They also struggled to explain the marked heterogeneity of the recorded pedigrees. Assuming incomplete ascertainment, variable disease penetrance and negative recall and reporting biases from some patients, they nonetheless felt that HS was likely to be a dominantly inherited single-gene disorder. Cautiously, though, they recommended a periodic re-examination of the investigated families [18-20].

Such a re-examination was carried out in 1998, when von der Werth et al. proposed a detailed disease definition for HS and used this as a base for a review of the Fitzsimmons families 15 years after the initial study [61]. The definition used for the purpose of this study was:

"To be classified as a case of hidradenitis sup-purativa a person must have either:

Active 1 or more primary lesion(s) disease: in a designated site plus a history of 3 or more discharging or painful lumps (unspecified) in designated sites since the age of 10

Inactive a history of 5 or more discharging disease: or painful lumps (unspecified) in designated sites since the age of 10 in the absence of current primary lesions."

"Primary lesions" had been defined as:

1. Painful and /or tender erythematous papules (<1 cm in diameter)

2. Painful and/or tender erythematous nodules (>1 cm in diameter)

3. Painful and/or tender abscesses (= inflamed, discharging papule or nodule)

4. Painful and/or tender dermal contractures (= rope-like elevation of skin)

5. Double-ended comedones.

"Designated sites" were chosen in accordance with the two areas most frequently affected by HS, namely axillae and groin.

They reviewed 14 surviving probands and their families. Seven of these probands had previously been noted to have a positive family history whereas the others had been classified as having a negative or possible family history (Fig. 10.1 a,b). In all, 132 family members were assessed for their respective disease status. Participants were initially contacted by telephone or letter, and those who acknowledged a history of at least one previous boil were invited for a personal examination and interview. Only personally examined individuals could be classified as a case.

In total, 28 relatives with HS were detected, and 27 of these were in the group previously labelled family history positive. Nine of these cases had not been detected in the previous study and in at least seven of these the disease had developed after the previous study had been conducted. Only twice did their disease criteria fail to confirm cases that had been labelled as HS in the previous study. Both times they classified the patients as "possibly affected". A further 16 relatives were judged to be possibly affected. In the group with positive family history they found 10 affected and 9 possibly affected individuals amongst 37 surviving first-degree relatives of HS sufferers [61].

The findings in this study supported the concept of a familial form of HS with autosomal dominant inheritance. An insufficiently sensitive disease definition, a variable degree of gene penetrance and possibly a hormonal influence on gene expression were considered as explanations for the reduced risk to first-degree relatives, which falls short of the expected Mende-lian value of 50%. The study was felt to be sufficiently convincing to commence the search for the proposed molecular defect behind this condition [61].

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