Hornstein-Knickenberg syndrome vs. Birt-Hogg-Dubé syndrome: a critical review of an unjustified designation.

The disorder that is presently called 'Birt-Hogg-Dubé syndrome' was in reality delineated in 1975 by Otto P. Hornstein and Monika Knickenberg from Erlangen (Germany) who emphasized that the occurrence of multiple 'perifollicular fibromas' represented a distinct autosomal dominant trait heralding extracutaneous cancer proneness. By contrast, Arthur R. Birt, Georgina R. Hogg and W. James Dubé from Winnipeg, Manitoba, Canada, claimed in 1977 that they had discovered 'a previously unrecognized hereditary pilar hamartoma' for which they proposed the name 'fibrofolliculoma', to be distinguished from the perifollicular fibromas as reported by Hornstein and Knickenberg. Today, many authors believe that 'fibrofolliculoma' is identical with 'perifollicular fibroma', but for the purpose of the present article this question can be left open. More importantly, the Canadian authors did not mention any association with extracutaneous cancer proneness within the large family examined in Winnipeg, nor when discussing the report from Erlangen, which means that they have neither described nor redescribed the syndrome that presently bears their names. Hence, the autosomal dominant disorder of multiple perifollicular fibromas heralding proclivity to extracutaneous cancer should be called after the original authors, Hornstein-Knickenberg syndrome.

Superimposed mosaicism in tuberous sclerosis complex: a key to understanding all of the manifold manifestations?

In patients with tuberous sclerosis, we can today distinguish between two different categories of segmental mosaicism. The well-known simple segmental mosaicism is characterized by a unilateral or otherwise localized arrangement of the ordinary lesions of the disorder, reflecting heterozygosity for an early postzygotic new mutation. By contrast, superimposed mosaicism is defined by a pronounced segmental involvement in a patient with ordinary non-segmental lesions of the same disorder, resulting in a heterozygous embryo from loss of the corresponding wild-type allele that occurred at a very early developmental stage. So far, the second category has been called 'type 2 segmental mosaicism', but here we propose the short and unambiguous term 'superimposed mosaicism'. In order to render physicians familiar with the manifold manifestations of this category as noted in tuberous sclerosis, we review the following clinical designations under which cases suggesting superimposed mosaicism have been published: forehead plaque; shagreen patch; fibrous cephalic plaque; fibromatous lesion of the scalp; folliculocystic and collagen hamartoma; segmental hypomelanosis; congenital segmental lymphedema; and segmental 'diffuse' lipomatosis. Molecular corroboration of this genetic concept has been provided in a case of forehead plaque and in a child with shagreen patch. - Extracutaneous manifestations suggesting superimposed mosaicism include columnar tuberous brain defects; 'radial migration lines' or 'cerebral white matter migration lines' as noted by brain imaging; linear hamartomatous lesions of the tongue; fibrous dysplasia of bones including macrodactyly; and unilateral overgrowth of an arm or leg. - Remarkably, superimposed mosaicism appears to occur in tuberous sclerosis far more frequently than simple segmental mosaicism.

Mosaicism due to postzygotic mutations in women with focal dermal hypoplasia.

Focal dermal hypoplasia (FDH, Goltz syndrome, MIM #305600) constitutes a rare multisystem genetic disorder of the skin, skeleton, teeth and eyes with considerable variation in the clinical features. FDH is transmitted as an X-linked dominant trait and is caused by mutations in PORCN. In male children, hemizygous PORCN mutations are lethal in utero. Around 300 cases have been reported in the literature to date. About 10% of them are male patients presenting with either Klinefelter syndrome (karyotype 47, XXY) or mosaicism of a postzygotic mutation. Here we describe four cases of women with typical features of FDH, in whom a PORCN mutation was found in DNA from affected cutaneous tissue but not in DNA from peripheral blood. This study suggests that mosaicism caused by a postzygotic mutation occurs more often than assumed to date in female patients with FDH. A negative analysis performed on peripheral blood DNA does not exclude the diagnosis of FDH and it is therefore of practical importance to analyse DNA from the affected skin in order to identify low-level mosaicism and thus to improve diagnostic precision. In total, we found two missense variants, one novel indel and one novel splice-site variant. Individuals harbouring postzygotic mosaicism run a risk of transmitting the disorder to their daughters, because the maternal mosaic could also affect the gonads.

The concept of type 2 segmental mosaicism, expanding from dermatology to general medicine.

In autosomal dominant skin disorders, the well-known type 1 segmental mosaicism reflects heterozygosity for a postzygotic new mutation. By contrast, type 2 segmental mosaicism originates in a heterozygous embryo from an early postzygotic mutational event giving rise to loss of the corresponding wild-type allele, which results in a pronounced segmental involvement being superimposed on the ordinary, non-segmental phenotype. Today, this concept has been proven by molecular analysis in many cutaneous traits. The purpose of this review was to seek publications of cases suggesting an extracutaneous manifestation of type 2 segmental mosaicism. Case reports documenting a pronounced extracutaneous segmental involvement were collected from the literature available in PubMed and from personal communications to the author. Pertinent cases are compared to the description of cutaneous segmental mosaicism of type 1 or type 2 as reported in a given trait. In total, reports suggesting extracutaneous type 2 segmental mosaicism were found in 14 different autosomal dominant skin disorders. In this way, clinical evidence is accumulated that extracutaneous type 2 segmental mosaicism does likewise occur in many autosomal dominant skin disorders. So far, however, molecular proof of this particular form of mosaicism is lacking. The present review may stimulate readers to inform colleagues of other specialties on this new concept, in order to initiate further research in this particular field of knowledge that has important implications for diagnosis, treatment and genetic counselling.

Koebner's sheep in Wolf's clothing: does the isotopic response exist as a distinct phenomenon?

Until 1995, a case of psoriasis developing within the dermatome of a healed herpes zoster was taken as a Koebner phenomenon. In this year, however, the term 'isotopic response' was introduced by Wolf et al. to describe 'the occurrence of a new skin disorder at the site of another, unrelated and already healed skin disease', thus appearing 'on apparently unaffected and healthy skin'. Initially, the term was mainly related to herpes zoster, but today the name 'Wolf's isotopic response' is used to include a plethora of other triggering factors such as healed cutaneous leishmaniasis, tinea or varicella. For obvious reasons, such triggering factors cannot be taken as examples of 'unaffected and healthy skin'. Notably, the authors themselves have categorized the dermatome of a healed herpes zoster as a 'vulnerable area'. In a recent commentary, Wolf et al. have expanded the definition of healed skin diseases triggering an 'isotopic response'. They now included 'scars, pigment changes, color changes or various other minimal changes by the first disease'. Hence, there is no clear-cut criterion to distinguish the isotopic response from a Koebner reaction. Wolf et al. even argue that, if the triggered disorder precedes the appearance of generalized skin lesions, then it is not a Koebner reaction but 'Wolf's isotopic response'. In our view, such definition is unacceptable. All reactions of this kind represent examples of a Koebner phenomenon. Accordingly, the 'isotopic response' should today be taken as a historical error.

At first sight or second glance: clinical presentation of mosaic manifestations of autosomal dominant skin disorders - a case series.

BACKGROUND: Several autosomal dominant disorders may manifest in mosaic patterns with cutaneous involvement. Genomic mosaicism results from postzygotic autosomal mutations, giving rise to clonal proliferation of two genetically distinct cell groups, which clinically present as lesions following the lines of Blaschko. OBJECTIVE: To increase the awareness of the clinical variability of mosaic manifestations in autosomal dominant skin disorders in order to avoid delayed diagnosis. METHODS: Clinicopathologic correlation in a case series including three patients with mosaic manifestations of different autosomal dominant skin diseases. RESULTS: Here, we describe a patient with type 1 segmental mosaicism of epidermolytic ichthyosis (case 1) and two patients with either type 1 (case 2) or type 2 (case 3) segmental neurofibromatosis 1 (NF1). CONCLUSION: Dermatologists should be familiar with mosaic manifestations of autosomal dominant skin diseases to ensure appropriate guidance of the affected patient. Genetic counselling is mandatory as even limited forms of mosaicism may involve the patient's germline with a moderately increased risk to transmit the mutation to their offspring, resulting in a more severe, generalized form of the respective disease.

Segmentally arranged seborrhoeic keratoses with impending atypia and squamous cell carcinoma in an elderly woman.

Epidermal naevi (EN) are considered mosaic disorders. Postzygotic mutations are thought to occur during early embryogenesis. They are usually arranged along Blaschko's lines and tend to be noted either at birth or shortly thereafter. Skin tumours arising on EN are occasionally reported, with ongoing discussion as to whether these are collision tumours or a malignant transformation of the EN. We describe a 76-year-old woman with segmentally arranged seborrhoeic keratoses that showed impending atypia and, in one lesion, even overt malignant transformation. In biopsies from various lesions we found FGFR3 and PIK3CA hotspot mutations but there was no consistent pattern of mutations explaining the premalignant or malignant growth. So far it is unclear whether the precancerous changes as noted in this elderly patient can be taken as an unusual manifestation of one of the established types of EN, or whether this may represent a separate disorder that could be called 'SASKIA naevus'. The acronym would stand for segmentally arranged seborrhoeic keratoses with impending atypia.

Capillary malformations: a classification using specific names for specific skin disorders.

The name capillary malformation has caused much confusion because it is presently used to designate numerous quite different disorders such as naevus flammeus, the salmon patch, the vascular naevus of the hereditary 'megalencephaly-capillary malformation syndrome' and the skin lesions of non-hereditary traits such as 'capillary malformation-arteriovenous malformation' and 'microcephaly-capillary malformation'. To avoid such bewilderment, the present review describes the distinguishing clinical and genetic criteria of 20 different capillary malformations, and a specific name is given to all of them. The group of capillary naevi includes naevus flammeus, port-wine naevus of the Proteus type, port-wine naevus of the CLOVES type, naevus roseus, rhodoid naevus, cutis marmorata telangiectatica congenita, congenital livedo reticularis, segmental angioma serpiginosum, naevus anaemicus, naevus vascularis mixtus and angiokeratoma circumscriptum. Capillary lesions that perhaps represent naevi are the mesotropic port-wine patch, Carter-Mirzaa macules, unilateral punctate telangiectasia and unilateral naevoid telangiectasia of the patchy type. Capillary malformations that do not represent naevi include X-linked angiokeratoma corporis diffusum (Fabry disease), autosomal dominant angiokeratoma corporis diffusum, hereditary haemorrhagic telangiectasia, hereditary angioma serpiginosusm and the salmon patch. In this way, we are able to discriminate between various non-hereditary capillary naevi such as naevus roseus and the hereditary rhodoid naevus and several hereditary traits that do not represent naevi such as angiokeratoma corporis diffusum and hereditary haemorrhagic telangiectasia; between four different types of port-wine stains, three of them being lateralized and one being mesotropic; between cutis marmorata telangiectatica congenita and congenital livedo reticularis; between telangiectatic naevi and the vasoconstrictive naevus anaemicus; and between two different types of angiokeratoma corporis diffusum. Finally, arguments are presented why the salmon patch ('stork bite', 'naevus simplex') cannot be categorized as a naevus.

Segmental hypomelanosis and hypermelanosis arranged in a checkerboard pattern are distinct naevi: flag-like hypomelanotic naevus and flag-like hypermelanotic naevus.

The categorization of congenital hypo- or hyperpigmented skin lesions following a segmental pattern has been a long-lasting matter of debate and have been reported under various and often incorrect terms. To reassess published hypomelanotic and hypermelanotic lesions that did not follow Blaschko lines nor a phylloid pattern of mosaicism, we carried out an extensive and critical review of the worldwide literature. Seventy-four retrieved cases consisted of lateralized hypomelanotic lesions arranged in a flag-like pattern or appearing as large patches of grossly oval or angulated shape and sharp, serrated margins. Sometimes lesions harboured maculopapular melanocytic naevi or cooccurred with other segmentally arranged naevi. A probably non-random association with extracutaneous anomalies was also reported on rare occasions. In 70 cases, lateralized hypermelanotic patches were arranged in a flag-like pattern that often appeared as large quadrangular patches. Sometimes lesions harboured Spitz naevi. Ten cases belonged to phacomatosis melanorosea, whereas several others were part of so far uncategorized cases of phacomatosis pigmentovascularis. Flag-like hypomelanosis is a distinct naevus type, for which the term 'flag-like hypomelanotic naevus' is suggested. Its cooccurrence with extracutaneous abnormalities might represent a specific syndrome. Flag-like hypermelanosis is a distinct naevus type, for which the term 'flag-like hypermelanotic naevus' is suggested. Its co-occurrence with naevus roseus defines phacomatosis melanorosea. Flag-like hypermelanotic naevus should be distinguished from the checkerboard-like areas of darker skin as observed in chimaeras.