泛发型斑点状黑子样痣1例

报告1例泛发型斑点状黑子样痣。患儿男，2岁，就诊时发现双上肢和躯干等部位有巨大的咖啡斑，在其基础上散布多个斑点状黑子样痣和Spitz痣。根据病变的发生过程和组织病理改变，诊断为斑点状黑了样痣的一个亚型。     

Genetic analyses of mosaic neurofibromatosis type 1 with giant café-au-lait macule,plexiform neurofibroma and multiple melanocytic nevi

Neurofibromatosis type 1 (NF1) is a genodermatosis caused by heterozygous germ line variations in the NF1 gene. A second-hit NF1 aberration results in the formation of café-au-lait macules, cutaneous neurofibroma and plexiform neurofibroma (PNF). Mosaic NF1 (mNF1), caused by a postzygotic NF1 mutation, is characterized by localized or generalized NF1-related manifestations. Although NF1 and mNF1 are associated with pigmentary skin lesions, clinically recognizable melanocytic nevi that developed over PNF have not been reported. Here, we report the first case of multiple melanocytic nevi that developed on a giant café-au-lait macule and PNF. The PNF had biallelic NF1 deletions, a whole deletion of NF1 and a novel intragenic deletion involving exons 25–30. The deletions were not detected in the blood, which resulted in the diagnosis of mNF1. Furthermore, the nevus cells had not only biallelic NF1 deletions but also NRAS Q61R, a common mutation found in congenital melanocytic nevi. These analyses revealed the coexistence of the two different mosaic diseases, mNF1 and congenital melanocytic nevi. For a diagnosis of cases with atypical NF1-like symptoms, genetic analyses using blood and lesional tissues are useful and aid in genetic counseling.     

Phacomatosis Pigmentokeratotica: A Mosaic RASopathy with Malignant Potential

Phacomatosis pigmentokeratotica (PPK) is a rare epidermal nevus syndrome characterized by the co‐occurrence of a nevus sebaceous arranged along the lines of Blaschko with a speckled lentiginous nevus (SLN). We report a novel KRAS mutation in a patient with a large nevus sebaceous and an SLN who subsequently developed a vaginal botryoid rhabdomyosarcoma, an association not previously reported in the literature. This case expands our knowledge of the genetic basis for phacomatosis, in which mutations in HRAS have been previously described, although this report provides evidence that activating mutations in KRAS or HRAS may cause PPK. This report confirms that PPK is a mosaic RASopathy with malignant potential and raises the question of whether screening for other RAS‐associated malignancies should be performed for all children with PPK.     

Palmoplantar keratosis in oculodentodigital dysplasia with a GJA1 point mutation out of the C‐terminal region of connexin 43

Gap junction proteins are composed of 21 genes of the connexin (Cx) family. They play important roles in cell–cell contact by exchange of small molecules through hemichannels. Hence, mutations of Cx family genes affect various tissues of a body. The mutation of the GJA1 gene, which codes Cx43, causes oculodentodigital dysplasia (ODDD), commonly in an autosomal dominant manner with phenotypic variability. It has been believed that gene mutations causing truncation of the Cx43 C‐terminus is necessary and sufficient for palmoplantar keratosis (PPK) development in ODDD patients. Here, we report a case of an ODDD patient developing PPK with a GJA1 gene mutation (c.412G>A/p.Gly138Ser), which was previously reported in a case of ODDD without PPK and expected not to result in C‐terminal truncation of Cx43. This case suggests not only C‐terminal truncation, but also that a point mutation in the cytoplasmic region of Cx43 can cause PPK in ODDD patients.     

Phacomatosis pigmentokeratotica: a further case without extracutaneous anomalies and review of the condition

Epidermal nevus syndrome is the term for the association of an epidermal nevus and extracutaneous anomalies, including neurologic, ophthalmic, and skeletal defects. Epidermal nevus syndromes include different disorders that share the feature of mosaicism. Phacomatosis pigmentokeratotica (PPK) is a distinctive new epidermal nevus syndrome first described in 1996 characterized by the presence of multiple organoid nevi with sebaceous differentiation, a speckled lentiginous nevus, and skeletal and neurologic abnormalities. Only a handful of cases of PPK without extracutaneous manifestations have been reported. We report here an individual with PPK with only cutaneous signs and confirm this distinctive syndrome has two subtypes according to the presence or absence of extracutaneous involvement.     

Genomic analysis of a case of agminated Spitz nevi and congenital‐pattern nevi arising in extensive nevus spilus

Nevus spilus is a melanocytic neoplasm characterized by a tan macular background punctuated by multiple hyperpigmented macules or papules that represent various types of nevi. These include junctional and compound nevi, Spitz nevi, and rarely blue nevi. We report a unique case of widespread, multiple nevi spili giving rise to agminated Spitz nevi and congenital‐pattern compound nevi. We performed genetic analysis to further characterize the mutational profile of this rare entity.     

Molecular analysis of atypical deep penetrating nevus progressing to melanoma

Deep penetrating nevi (DPN) are dermal-based, heavily pigmented melanocytic proliferations primarily resulting from mutations in B-catenin and BRAF or, less commonly, NRAS. DPNs are considered to be intermediate grade tumors which are stable with low risk of malignant transformation. The precise risk for transformation is unknown. Only rare cases of DPN progressing to melanoma have been described. We present a case of a 53-year-old female with a blue-black thigh lesion, on histopathology illustrating a melanocytic proliferation with morphology most consistent with a DPN progressing to melanoma. Targeted next generation sequencing performed on both the atypical melanocytic proliferation and melanoma components showed NRAS and CTNNB1 mutations but no evidence of TERT promoter mutation or chromosomal copy number aberrations. The melanoma had additional mutations including a hotspot TERT promoter mutation as well as unbalanced chromosomal copy number aberrations. This report details the progression of DPN to melanoma through a prominent ultraviolet signature and acquisition of genetic aberrations. While the vast majority of DPNs are benign stable nevi, there are rare examples, which may progress to melanoma. This report documents a case and shows the molecular evolution by which the tumor transformed to melanoma.     

Multiple perineuriomatous melanocytic nevi

Perineuriomatous differentiation in solitary cutaneous melanocytic nevi has been described. We present an unusual case of a patient with multiple such perineuriomatous nevi. This presentation raises the possibility that a germline mutation may be responsible for the pathogenesis of these unusual lesions.     

Mutated and amplified NRAS in a subset of cutaneous melanocytic lesions with dermal spitzoid morphology: report of two pediatric cases located on the ear

Extensive cytogenetic testing is slowly unveiling the complexity of the genomics of melanocytic tumors. NRAS mutations have been the first genetic abnormality described in malignant melanomas. We report the cases of two children, presenting a melanocytic lesion located on the ear. One appeared as a combined dermal clone inside a congenital nevus and the other as a centimetric purely dermal tumor. Both tumors were composed of spindled spitzoid melanocytes with atypical histologic features. aCGH and FISH revealed an amplification of the NRAS gene. Sequencing showed an exon 3 NRAS mutation. In the combined case, the amplification was limited to the spitzoid component, underscoring a possible phenotypic shift induced by the alteration. Similarly an overexpression of CyclinD1 and elevation of ki‐67 was found in the spitzoid component confirming a raise in proliferation. Such combination of mutation and copy number increase has been previously reported for the HRAS gene in a subset of Spitz nevi. Further studies must evaluate if mutated NRAS is also amplified in melanomas arising in this clinical setting. These combined alterations could represent an early event ultimately leading to malignancy.     

Nevoid follicular mucinosis: a new type of hair follicle nevus

Follicular mucinosis represents a term for a histopathologic reaction pattern in follicular epithelium. It is a characteristic of alopecia mucinosa. However, it may also occur in a variety of unrelated conditions. Epidermal nevi are considered to be hamartomatous disorders and they can show a predominant component of non‐organoid (keratinocytes) and/or organoid nevi. All the cases of epidermal nevi described with mucin deposits until now are reported as mucinous nevus or mucinous eccrine nevus; in the first type of disorder, diffuse mucin deposition is only seen in the papillary dermis, and in the second type, the mucin is found around the proliferation of eccrine structures. We believe this is the first reported case of epidermal nevus along Blaschko's lines exhibiting typical microscopic findings of mucinosis exclusively distributed inside the follicular epithelia.     

Varying proliferative and clonogenic potential in NRAS‐mutated congenital melanocytic nevi according to size

Congenital melanocytic nevi (CMN) are benign proliferations that may be associated with various consequences depending on their size. They are characterized by a specific molecular signature, namely a postzygotic somatic NRAS or BRAF mutation. We have recently reported that large CMN (lCMN), which are classically associated with an increased melanoma risk, harbour cell subpopulations with specific clonogenic and tumorigenic potential. We wished to ascertain whether cells displaying similar properties persisted postnatally in medium CMN (mCMN). Eighteen medium M1, nine large and one giant NRAS‐mutated CMN were prospectively included in the study. Subpopulations of mCMN cells expressed stem cell/progenitor lineage markers such as Sox10, nestin and Oct4, as was the case in lCMN. Nevertheless, conversely to lCMN, mCMN cells with clonogenic properties were rarer. In vitro, approximatively one in 1500 cells isolated from fresh mCMN formed colonies that could be passaged. In vivo, mCMN seemed to harbour cells with less proliferative potential than the larger lesions as lCMN biopsies displayed a threefold expansion compared to mCMN when xenografted in Rag2^?/? mice. Thus, our data revealed variations in clonogenicity and tumorigenic properties in NRAS‐mutated CMN according to size.     

Collapse of the keratin filament network through the expression of mutant keratin 6c observed in a case of focal plantar keratoderma

Focal palmoplantar keratoderma (PPK) with severe pain is a hallmark of pachyonychia congenita, a rare autosomal dominant disorder involving PPK and hypertrophic nail dystrophy. Some families present focal PPK with either minimal or no nail changes. Dominant‐negative mutations in any of the four identified keratin genes, KRT6A, KRT6B, KRT16 or KRT17, lead to pachyonychia congenita. However, the majority of families with focal PPK showing minimal or no nail changes do not harbor mutations in these genes. Recently, mutations of KRT6C were identified in families with focal PPK alone. Here, we report a 26‐year‐old Japanese man with focal plantar hyperkeratosis that developed at approximately 10 years of age with no palmar involvement and no nail alterations. We identified a missense KRT6C mutation c.1414G>A resulting in an p.Glu472Lys substitution, as reported in other Japanese patients. When the mutant keratin 6c protein is exogenously expressed in human HaCaT cells, a collapse of the keratin filament network is observed in a dose‐dependent manner, suggesting the mutation has a dominant‐negative effect on keratin filament network formation. The mutated residue is located at the helix termination motif of keratin 6c. The peptide sequence around this residue is highly conserved among type II, III and IV intermediate filament proteins. Glu to Lys mutations of the equivalent residue have been reported in a variety of inherited diseases, including neurodegenerative diseases, corneal dystrophy and skin disorders, suggesting that this residue is vital to keratin function.     

Is rituximab therapy a risk factor for development of melanoma?

In the literature, there are reports about dermoscopic and size changes of nevi in patients undergoing biologic therapy and chemotherapeutics. There has not been any established data for melanoma and Rituximab therapy. Sixteen patients, with 94 nevi were included in this study. Dermoscopic images of follow‐up visits, which were performed at baseline, 3, 6, and 12 months after treatment, were evaluated. Suspicious lesions were excised. There was no increase in total nevus count. Although 61.7% of the 94 nevi have shown a stable duration without size changes, 26.5% had enlarged, and 11.7% had become smaller during our 1‐year experience of dermoscopic monitoring. There was not any pattern transformation. Atypical dots and clods appeared in 17% of nevi. All of the excised nevi were comparable with Clark nevi, there was no clue for melanoma development. According to our results, we found that Rituximab therapy influences nevus morphology, but there is no evidence that this was linked to melanoma development.     

Speckled lentiginous nevus: within the spectrum of congenital melanocytic nevi

BACKGROUND: Currently, there is disagreement as to whether speckled lentiginous nevi (nevi spili) are congenital or acquired pigmented lesions. Part of this controversy is related to the natural history of these lesions that often present at birth as hyperpigmented patches and then take several years to reach their more readily recognized spotted form. Arguments in favor of speckled lentiginous nevi as a subtype of congenital nevi include the following observations: multiple reports of lesions present at birth or noted soon thereafter; patterns of distribution reflecting embryonic development; hamartomatous behavior with various types of nevi (eg, junctional nevi, blue nevi, and Spitz nevi) presenting in the same lesion over time; and histologic features of congenital melanocytic nevi within the spots. Herein we present additional evidence for the congenital nature of speckled lentiginous nevi. OBSERVATIONS: Ten patients are described with congenital pigmented lesions that had the clinical appearance of speckled lentiginous nevi in whole or in part. These lesions either evolved and acquired an appearance more suggestive of "classic" congenital nevi, or they existed as "hybrid" lesions with portions appearing as classic congenital nevi adjacent to or admixed with portions appearing as speckled lentiginous nevi. On histologic examination, biopsy specimens from the spots within these lesions showed features of congenital melanocytic nevi. CONCLUSIONS: These 10 cases, along with the arguments outlined above, provide strong support for the hypothesis that speckled lentiginous nevi are a subtype of congenital melanocytic nevi.     

A Combination of Speckled Lentiginous Nevus with Patch-type Blue Nevus

A peculiar case of “nevus on nevus” was reported. A 67-year-old man had had a pigmented lesion in the left hypochondrial area since birth. The clinicopathologic findings of the pigmented lesion revealed a combination of speckled lentiginous nevus and patch-type blue nevus. This case of “nevus on nevus” is not described under the term of combined nevus as is current in the literature; it was considered to be a subtype of the type II atypical blue nevus described by Kawamura.     

Persistent melanocytic nevi: a review and analysis of 205 cases

Background: Melanocytic nevi can recur or persist if not completely excised and are capable of mimicking malignant melanoma, both clinically and histologically. Objective: To characterize the impact of anatomic site, biopsy method, size, margin involvement and type of original melanocytic nevus on recurrence/persistence of melanocytic nevi. Secondarily, we sought to determine if the original type of melanocytic nevus could be determined solely from microscopic examination of the recurrent/persistent nevus. Methods: One hundred and eighty‐five patients with 205 persistent nevi were identified. Of these, 108 cases had original biopsy specimens available for review. Location, original biopsy size, biopsy method, margins and interval to recurrence were recorded for each. A group of 232 non‐persistent nevi was established as a control population. Results: There was a female predominance in persistent nevi with the back being the most common site for persistence. Dysplastic melanocytic nevi were the most likely to persist. Accurate determination of the original type of melanocytic nevus from microscopic examination of the persistent nevus was possible in only 67% of the cases. Conclusion: Clinicians should take larger and deeper biopsies of clinically dysplastic and conventional melanocytic nevi on the back to prevent recurrences. Grading atypia of the persistent melanocytic nevi is unreliable. Sommer LL, Barcia SM, Clarke LE, Helm KF. Persistent melanocytic nevi: a review and analysis of 205 cases.     

Speckled lentiginous nevus: A rare presentation associated with motor neuropathy and muscular atrophy in a child

Speckled lentiginous nevus syndrome has been described in individuals with a speckled lentiginous nevus with rare associated neurologic deficits. Because speckled lentiginous nevus syndrome almost always affects adults, it is not typically considered when evaluating children. We present the first reported case of speckled lentiginous nevus syndrome presenting in a young child with muscle atrophy and motor deficits affecting muscles along the same distribution as the speckled lentiginous nevus.     

Histopathologic and mutational analysis of a case of blue nevus‐like melanoma

Blue nevi are a heterogeneous group of dermal melanocytic proliferations that share a common clinical appearance but remain controversial in their histopathologic and biologic distinction. While common blue nevi and cellular blue nevi are well‐defined entities that are classified without significant controversy, the distinction between atypical cellular blue nevi and blue nevus‐like melanoma remains diagnostically challenging. We report a case of a 46‐year‐old female with recurrent blue nevus‐like melanoma of the scalp with liver metastases; mutational analysis showed GNA11 Q209L and BAP1 Q393 mutations. To our knowledge, this is the first case of blue nevus‐like melanoma with GNA11 and BAP1 mutations. These particular mutations and the predilection for liver metastases in our patient's case underscore a fundamental biological relationship between blue nevi and uveal melanoma and suggest the two entities may prove amenable to similar diagnostic and prognostic testing and targeted therapies     

Verrucous epidermal nevus as a manifestation of a type 2 mosaic PTEN mutation in Cowden syndrome

Linear Cowden nevus, also known as linear PTEN nevus, is a type of epidermal nevus, first described in 2007, which is seen in patients with PTEN hamartoma tumor syndrome. It is considered to be a type 2 form of segmental mosaicism, and we suggest that it has certain clinical features that distinguish it from epidermal nevi seen in similar conditions, such as Proteus syndrome. We present a case of linear Cowden nevus in a 4-year-old boy and review the literature.     

Familiäres Auftreten einer segmentalen Typ‐2‐Manifestation der kutanen Leiomyomatose

Background: There are several malignant or benign skin diseases which can be explained by the phenomenon of mosaicism or segmental manifestation, e. g. segmental neurofibromatosis 1 or cutaneous leiomyomatosis. Loss of heterozygosity is a crucial element for segmental manifestations. Two types of segmental manifestations can be defined in autosomal dominant skin diseases such as cutaneous leiomyomatosis. Type 1 is caused by a novel postzygotic segmental mutation; type 2 reflects an additional postzygotic loss of heterozygosity of the gene locus responsible for cutaneous leiomyomatosis in a initially heterozygous embryo. Loss of heterozygosity is a genetic process when a heterozygous cell becomes homozygous or hemizygous by loosing the corresponding wild‐type allele. This phenomenon can be regarded as a precondition for tumor growth. In type‐2 cases, the segmental manifestation is more distinctive with additional disseminated disease because of a germline mutation with heterozygosity of all somatic cells outside the strongly affected area. Patients and Methods: A 74‐year‐old female patient and her 52‐year‐old son presented with segmental leiomyomas following the lines of Blaschko as well as disseminated skin tumors. The woman has undergone hysterectomy at the age of 29 because of multiple uterine leiomyomas, as had her mother and grandmother. Results: Based on their typical clinical appearance, these cases represent the rare familial occurrence of type‐2 manifestation of leiomyomas which indicates a postzygotic loss of the wild‐type allele. Conclusion: Very unusual is the familial occurrence in mother and son of this type‐2 manifestation of cutaneous leiomyomatosis. Apparently the gene locus is prone to a postzygotic loss of heterozygosity.