Rudolf Happle

Porokeratotic eccrine nevus may be caused by somatic connexin26 mutations.

Porokeratotic eccrine ostial and dermal duct nevus, or porokeratotic eccrine nevus (PEN), is a hyperkeratotic epidermal nevus. Several cases of widespread involvement have been reported, including one in association with the keratitis–ichthyosis–deafness (KID) syndrome (OMIM #148210), a rare disorder caused by mutations in the GJB2 gene coding for the gap junction protein connexin26 (Cx26). The molecular cause is, as yet, unknown. We have noted that PEN histopathology is shared by KID. The clinical appearance of PEN can resemble that of KID syndrome. Furthermore, a recent report of cutaneous mosaicism for a GJB2 mutation associated with KID describes linear hyperkeratotic skin lesions that might be consistent with PEN. From this, we hypothesized that PEN might be caused by Cx26 mutations associated with KID or similar gap junction disorders. Thus, we analyzed the GJB2 gene in skin samples from two patients referred with generalized PEN. In both, we found GJB2 mutations in the PEN lesions but not in unaffected skin or peripheral blood. One mutation was already known to cause the KID syndrome, and the other had not been previously associated with skin symptoms. We provide extensive functional data to support its pathogenicity. We conclude that PEN may be caused by mosaic GJB2 mutations.

The categories of cutaneous mosaicism: A proposed classification.

Mosaic disorders can most easily be studied in the skin. This article presents a comprehensive overview of the different forms of cutaneous mosaicism. Major categories are genomic versus epigenetic mosaicism and nonsegmental versus segmental mosaicism. The class of nonsegmental mosaics includes single point mosaicism as exemplified by solitary benign or malignant skin tumors; disseminated mosaicism as noted in autosomal dominant tumor syndromes such as neurofibromatosis 1; and patchy mosaicism without midline separation as found in giant melanocytic nevus. The class of segmental mosaics includes segmental manifestation of lethal genes surviving by mosaicism as noted in Proteus syndrome; type 1 segmental mosaicism of autosomal dominant skin disorders reflecting heterozygosity for a postzygotic new mutation; type 2 segmental mosaicism of autosomal dominant skin disorders reflecting loss of heterozygosity that occurred at an early developmental stage in a heterozygous embryo; and isolated or superimposed segmental mosaicism of common polygenic skin disorders such as psoriasis or atopic dermatitis. A particular form of genomic mosaicism is didymosis (twin spotting). Revertant mosaicism is recognizable as one or more areas of healthy skin in patients with epidermolysis bullosa or other serious genodermatoses. The category of epigenetic mosaicism includes several X‐linked, male lethal disorders such as incontinentia pigmenti, and the patterns of lyonization as noted in X‐linked non‐lethal disorders such as hypohidrotic ectodermal dysplasia of the Christ‐Siemens‐Touraine type. An interesting field of future research will be the concept of epigenetic autosomal mosaicism that may explain some unusual cases of autosomal transmission of linear hypo‐ or hypermelanosis.

Hornstein–Birt–Hogg–Dubé syndrome: A renaming and reconsideration†‡

The so‐called Birt–Hogg–Dubé syndrome, an autosomal dominant trait characterized by multiple fibrofolliculomas and extracutaneous cancer proneness, was not first recognized by Birt, Hogg, and Dubé. Hence, the presently used eponymic designation reflects a historical error. In fact, the disorder was discovered in the following way. In 1975, Hornstein and Knickenberg described a “distinct nosological entity” in two sibs with multiple perifollicular fibromas, multiple skin tags, and polyps of the colon with a tendency to malignancy. The father had similar skin lesions and “bilateral kidney cysts” and unilateral lung cysts. In 1976, Hornstein et al. informed, in two additional articles, both geneticists and gastroenterologists about the new autosomal dominant trait. When Birt et al. presented their report in 1977, they knew of Hornsteins first publication but were convinced that they had discovered “a previously unrecognized hereditary pilar hamartoma.” This was a misconception because what they called “fibrofolliculoma” has turned out to be identical with “perifollicular fibroma” as described by Hornstein et al. Moreover, Birt et al. failed to mention any associated extracutaneous cancer proneness, whereas Hornstein et al. had delineated the complete syndrome. For all of these reasons, the new term “Hornstein–Birt–Hogg–Dubé syndrome” appears to be appropriate.

Type 1 Segmental Galli-Galli Disease Resulting from a Previously Unreported Keratin 5 Mutation

Abbreviations: DDD, Dowling-Degos disease; EBS, epidermolysis bullosa simplex; GGD, Galli-Galli disease; K5, Keratin 5; KRT5, Keratin 5 gene; LDM, laser dissection microscopy; OMIM, Online Mendelian Inheritance in Man

A novel X‐linked phenotype caused by hypomorphic EBP mutations

I read with great interest the excellent report on ‘‘a novel X-linked multiple congenital anomaly syndrome associated with an EBP mutation’’ by Furtado et al. [2010]. Admittedly, this phenotype is very unusual. In my view, however, this syndrome is identical with a phenotype that has previously been recognized and discussed in the following publications. In 2003, the new phenotype reflecting hypomorphic EBP mutations was clearly separated from X-linked dominant chondrodysplasia punctata (CDPX2) [Happle, 2003]. This paper referred to Milunsky et al. [2003a] who had described a boy with ‘‘a severe atypical phenotype for X-linked dominant Conradi-H€ unermannHapple syndrome and a mutation in EBP.’’ I proposed to categorize this mutation as a hypomorphic EBP allele giving rise to a nonlethal phenotype quite different from CDPX2. The patient had an excess nuchal fold with long neck, simple philtrum, micrognathia, high-arched palate, bulbous nasal tip, low-set posteriorly rotated ears with overfolded helices, upslanting palpebral fissures, broad halluces, a sacral dimple, and overlapping fingers and toes. Neurological anomalies included axial hypotonia and limb hypertonia with initial opisthotonic posturing and persistent Moro response, and abnormal EEG. Photographs documented the rather characteristic facial features evolving from age 6 weeks to 2.5 years. Ocular defects comprised left anterior polar cataract, ptosis, bilateral macular hypolasia, esotropia, and nystagmus. Moreover, crossed renal ectopia, stenotic ear canals, and failure to thrive were noted. At 2.5 years of age, the boy showed a marked developmental delay. His mother was healthy, with the exception of a hyperpigmented macule on her chest and bilateral otosclerosis. In a response, Milunsky et al. [2003b] maintained that their proband had a severe phenotype when compared to CDPX2. They did not accept the notion that they had described ‘‘an entirely new entity’’ [Happle, 2003]. Conversely, Ikegawa [2004] fully agreed that the unusual features of this patient constituted a phenotype quite different from CDPX2. Subsequently, as noted by Furtado et al. [2010], four affected male individuals with characteristic cerebral defects such as DandyWalker malformation and hypoplasia or absence of corpus callosum were described by Kelley et al. [2005]. These authors did not provide molecular data but supported the proposed etiological concept of hypomorphic EBP mutations. The impressive report of Furtado et al. [2010] now describes, in a comprehensive way, the clinical spectrum of the new syndrome. In particular, the authors present a detailed overview of the neurological, skeletal, and cutaneous abnormalities as found in this trait, and they document a five-generation pedigree confirming the X-linked recessive mode of transmission of this distinct phenotype. Apparently, however, Furtado et al. [2010] are of the opinion that they are describing an entirely new disorder that differs from the syndrome as delineated in 2003. Conversely, I suggest that only one phenotype caused by hypomorphic EBP mutations can so far be separated from CDPX2. It is still possible that further clinical and molecular research may lead to other conclusions, but at this point in time any attempt to establish a phenotype–genotype correlation of various hypomorphic EBP alleles appears to be elusive.

Superimposed Segmental Hemangioma of Infancy

Background: Segmental hemangioma of infancy is sometimes associated with the development of multiple nonsegmental hemangiomas. Such co-occurrences have so far remained unexplained. Methods and Results: Pertinent reports were collected from the literature. To explicate such cases, the following concept is proposed. Hemangiomas of infancy reflect a polygenic predisposition. Nonsegmental lesions result from a mutational event occurring at a late stage of intrauterine life or after birth, whereas segmental hemangioma originates from loss of heterozygosity or some other mutational event arising at an early developmental stage. Conclusion: In this way, segmental hemangioma of infancy could be taken as a further example of the superimposed segmental manifestation of a polygenic skin disorder. Future molecular research may show whether this assumption holds true.

Oculoectodermal Syndrome: Report of a New Case With a Broad Clinical Spectrum

Oculoectodermal syndrome (OMIM 600268) is rare and characterized by aplasia cutis congenita, epibulbar dermoids, and other abnormalities. We report herein on a newly recognized patient with oculoectodermal syndrome, which is the 19th reported patient with OES. The boy aged six years demonstrated a broad clinical spectrum of this condition, including aplasia cutis congenita, epibulbar dermoids, hyperkeratotic papule, mildly enlarged cisterna magna, and an enlarged fluid space in the quadrigeminal cistern, suggesting a cyst. He also manifested anomalies not reported associated with this disorder, including systematized epidermal nevus following Blaschkos lines, hypopigmented skin lesions, and mild digital anomaly.

Systematized linear porokeratosis: Concept of type 2 segmental manifestation implies an increased cancer risk

Dear Editor, A 41-year-old woman presented with systematized linear skin lesions that had involved the entire body since the age of 9 months. The disorder had initially been taken for incontinentia pigmenti. The lesions increased with age in number and extent (Fig. 1a). The family history showed no similar changes. In addition, skin tumors had developed and increased in size during the past several years. On physical examination, we observed multiple brownish plaques, arranged in a systematized pattern following Blaschko’s lines on the face, trunk and limbs (Fig. 1b,c). The plaques showed central atrophy and hyperkeratotic margins (Fig. 1e). On close inspection, some disseminated, lentil-sized hyperkeratoses outside the linear lesions were found, being suggestive of disseminated superficial actinic porokeratosis (DSAP). Moreover, several verrucous grey-brown tumors were noted on both calves and the left fifth toe (Fig. 1d). A firm lymph node swelling was palpated in the left groin. A diagnosis of porokeratosis was suspected and confirmed by microscopic examination of a biopsy obtained from a linear plaque, showing epidermal invagination with a funnel-shaped parakeratosis (cornoid lamella) (Fig. 1f). The skin tumors were surgically removed from both calves under general anesthesia. The left fifth toe was amputated and an inguinal lymphadenectomy was performed. Histopathological examination revealed four squamous cell carcinomas of slight to moderate differentiation, with some perineural tumor spread, and an inguinal lymph node metastasis. Ten months later, radiochemotherapy including administration of taxol, carboplatin and cetuximab was initiated because of metastases involving the left ilium and head of femur. Porokeratosis represents a group of hereditary disorders of keratinization, including porokeratosis of Mibelli, DSAP, porokeratosis palmoplantaris punctata and porokeratosis palmoplantaris punctata et disseminata. Both DSAP and porokeratosis of Mibelli may manifest in a linear configuration. Hence, today linear porokeratosis can no longer be considered to represent one particular type within the classification of porokeratosis. The clinical pattern in our patient suggested mosaicism. In autosomal dominant skin disorders, two different mosaic manifestations are possible. A type 1 reflects heterozygosity for a postzygotic mutation present in an otherwise healthy embryo. By contrast, a type 2 segmental manifestation originates in a heterozygous embryo from early postzygotic loss of the corresponding wild-type allele, resulting in homozygosity or hemizygosity of the involved area of the body. Characteristically, the skin changes of type 2 segmental manifestation are far more pronounced, being superimposed on the non-segmental phenotype. Our case represents a type 2 segmental manifestation, which explains the early onset of the lesions and the presence of non-linear, lentil-sized DSAP lesions. Most likely, the disseminated DSAP lesions also reflect loss of heterozygosity, but these postzygotic events occurred much later, virtually always during postnatal life. From a clinical point of view, most cases of linear porokeratosis so far reported can be categorized as examples of type 2 segmental DSAP, whereas a type 2 segmental manifestation of the plaque-like form of Mibelli has less frequently been documented. Molecular proof of the concept of type 2 segmental manifestation of autosomal dominant skin diseases has been provided by Poblete-Gutiérrez and colleagues in a case of Hailey– Hailey disease. The concept of type 2 segmental involvement may explain why the risk of malignant degeneration is particularly high in linear forms of porokeratosis. The event of loss of heterozygosity occurring at

Giant Melanocytic Nevus May Be Explained as a Superimposed Patchy Manifestation of a Polygenic Trait

Cases of GMN associated with small disseminated nevi involving the entire body have been documented with historical figures published in many articles and textbooks [4–9] and have also been reported in more recent publications [10–13] . So far, the associated small nevi have usually been categorized as ‘satellite lesions’ [4, 12, 13] . Admittedly, true satellite lesions are often noted. As a rule of thumb, such satellite nevi tend to be found within a 15-cm zone surrounding a GMN, which is reminiscent of an archipelago. By contrast, a scattered distribution all over the body ( fig. 1 , 2 ) suggests that in such cases the associated small nevi should rather be taken as disseminated ‘background lesions’. These common small melanocytic nevi do not mendelize but represent a polygenic trait [14–16] . Specifically, recent molecular research has shown that both congenital and acquired small melanocytic nevi have a common polygenic background, including mutations at the loci of BRAF, N-ras, MC1R and p53 [17–20] .

Progressive osseous heteroplasia is not a Mendelian trait but a type 2 segmental manifestation of GNAS inactivation disorders: A hypothesis

Progressive osseous heteroplasia (POH) is a segmental disorder characterized by progressive heterotopic ossification that extends from dermal and subcutaneous tissues to deeper structures. So far, it has been taken as a rarely occurring bone disease with autosomal dominant inheritance. Here, arguments are presented in favor of the alternative concept that the disorder is merely a type 2 segmental manifestation of autosomal dominant GNAS inactivation disorders. Type 2 segmental mosaicism arises, in a heterozygous embryo, from a somatic mutational event that occurs at an early developmental stage, resulting in loss of the corresponding wild-type allele and giving rise to a homozygous or hemizygous cell clone. As a characteristic feature, such type 2 segmental involvement is far more pronounced than the type 1 segmental mosaicism as noted in otherwise healthy individuals. The concept of type 2 segmental mosaicism has been proven at the molecular level in six human traits including neurofibromatosis 1, Hailey-Hailey disease, and Gorlin syndrome. In POH, molecular proof of principle is so far lacking. The following lines of reasoning, however, support the hypothesis that POH can be explained by a similar mechanism. Firstly, POH has been found to be associated with different phenotypes caused by inactivating GNAS mutations, which is why it cannot be categorized as one distinct Mendelian trait. Secondly, POH occurs as a rather rare complication of these autosomal dominant traits, which is not compatible with the assumption of a separate Mendelian disorder. Thirdly, in a case of plate-like osteoma that represents a more superficial variant of POH, molecular proof of the concept of type 2 segmental manifestation has already been provided, and the available literature suggests that POH can be best explained by a similar mechanism. Moreover, findings obtained in animal experiments support the assumption that human POH represents such superimposed segmental manifestation of GNAS inactivation disorders.