Juvenile xanthogranulomas (JXG) is a histiocytic disorder, primarily but not exclusively seen throughout the first two decades of life and principally as a solitary cutaneous lesion. This study is a retrospective clinical and pathologic review of 174 cases documenting the cutaneous and extracutaneous manifestations in patients presenting from the neonatal period to 20 years of age (mean 3.3 years; median 1 year). There was a male predominance (99 male:75 female) in all categories of clinical presentation, but especially notable in the group with multiple cutaneous lesions (12 male:1 female). A solitary cutaneous lesion accounted for 67% of all cases, followed by a solitary subcutaneous or deep soft tissue mass (28 cases, 16%), multiple cutaneous lesions (13 cases, 7%), a solitary extracutaneous, nonsoft tissue lesion (9 cases, 5%), and multiple cutaneous and visceral-systemic lesions (8 cases, 5%). The recorded deaths due to disease included two neonates with systemic JXG who developed hepatic failure and thrombocytopenia and at autopsy had giant cell-neonatal hepatitis in addition to JXG in the liver and other visceral sites. A third death in a 3-month-old boy with a retroperitoneal-pelvic JXG occurred after failure to control severe hypercalcemia. The characteristic Touton giant cell in variable numbers was a consistent feature of the cutaneous lesions; however, these cells were either absent or present in reduced numbers in the various extracutaneous lesions when compared with JXG in the skin. Spindle cells intermingled among the mononuclear cells or forming short fascicles were seen in both cutaneous and extracutaneous lesions. Immunohistochemistry was performed on all extracutaneous lesions, and the constituent cells, regardless of their individual morphologic features, were uniformly positive for vimentin, CD68, and factor XIIIa and negative for S-100 protein and CD1a. It is widely held that JXG is a proliferative disorder of dendrocytes, possibly dermal dendrocytes; thus, its clinical and pathologic similarities to Langerhans cell histiocytosis are not entirely unexpected in light of the most recently proposed international classification of histiocytic disorders, which includes JXG and Langerhans cell histiocytosis together as "dendritic cell-related" histiocytoses.

Juvenile xanthogranulomas in the first two decades of life: a clinicopathologic study of 174 cases with cutaneous and extracutaneous manifestations.

Juvenile xanthogranulomas (JXG) is a histiocytic disorder, primarily but not exclusively seen throughout the first two decades of life and principally as a solitary cutaneous lesion. This study is a retrospective clinical and pathologic review of 174 cases documenting the cutaneous and extracutaneous manifestations in patients presenting from the neonatal period to 20 years of age (mean 3.3 years; median 1 year). There was a male predominance (99 male:75 female) in all categories of clinical presentation, but especially notable in the group with multiple cutaneous lesions (12 male:1 female). A solitary cutaneous lesion accounted for 67% of all cases, followed by a solitary subcutaneous or deep soft tissue mass (28 cases, 16%), multiple cutaneous lesions (13 cases, 7%), a solitary extracutaneous, nonsoft tissue lesion (9 cases, 5%), and multiple cutaneous and visceral–systemic lesions (8 cases, 5%). The recorded deaths due to disease included two neonates with systemic JXG who developed hepatic failure and thrombocytopenia and at autopsy had giant cell-neonatal hepatitis in addition to JXG in the liver and other visceral sites. A third death in a 3-month-old boy with a retroperitoneal–pelvic JXG occurred after failure to control severe hypercalcemia. The characteristic Touton giant cell in variable numbers was a consistent feature of the cutaneous lesions; however, these cells were either absent or present in reduced numbers in the various extracutaneous lesions when compared with JXG in the skin. Spindle cells intermingled among the mononuclear cells or forming short fascicles were seen in both cutaneous and extracutaneous lesions. Immunohistochemistry was performed on all extracutaneous lesions, and the constituent cells, regardless of their individual morphologic features, were uniformly positive for vimentin, CD68, and factor XIIIa and negative for S-100 protein and CD1a. It is widely held that JXG is a proliferative disorder of dendrocytes, possibly dermal dendrocytes; thus, its clinical and pathologic similarities to Langerhans cell histiocytosis are not entirely unexpected in light of the most recently proposed international classification of histiocytic disorders, which includes JXG and

Juvenile Xanthogranulomas in the First Two Decades of Life

We review the morphofunctional characteristics of CD34+ stromal fibroblastic/fibrocytic cells (CD34+ SFCs) and report our observations. We consider the following aspects of CD34+ SFCs: A) The confusing terms applied to this cell type, often combining the prefix CD34 with numerous names, including fibroblasts, fibrocytes, dendrocytes, keratocytes, telocytes and stromal, dendritic, adventitial, supraadventitial, perivascular, paravascular and delimiting cells; B) Changes in their immunophenotype, e.g., loss of CD34 expression and gain of other markers, such as those defining mesenchymal and derivate cells (myofibroblasts, osteoblasts, chondroblasts, adipocytes); C) Morphology (elongated or triangular cell body and thin, moniliform, bipolar or multipolar cytoplasmic processes), immunohistochemistry (co-expression of and changes in molecular expression) and structure (characteristics of nucleus and cytoplasmic organelles, and points of contact and junctions in quiescent and activated stages by light and electron microscopy); D) Location and distribution in the vessels (adventitia or external layer), in the tissues (connective, adipose, blood, muscle and nervous) and in the organs and systems (skin, oral cavity and oropharynx, respiratory, digestive, urinary, male, female, endocrine and lymphoid systems, serosal and synovial membranes, heart, eye and meninges); E) Origin from the mesoderm and cranial neural crest in the embryo, and from stem cells (themselves or other cells) and/or peripheral blood pluripotent stem cells (circulating progenitor cells) in post-natal life; F) Functions, such as synthesis of different molecules, progenitor of mesenchymal cells, immunomodulation, parenchymal regulation (growth, maturation and differentiation of adjacent cells), induction of angiogenesis, scaffolding support of other cells and phagocytic properties. Since CD34+ SFCs are the main reservoir of tissue mesenchymal cells (great mesenchymal potential, probably higher than that proposed for pericytes and other stromal cells), we dedicate a broad section to explain their in vivo behaviour during proliferation and differentiation in different physiologic and pathologic conditions, in addition to their characteristics in the human tissues of origin (adult stem cell niches); G) Involvement in pathological processes, e.g., repair (regeneration and repair through granulation tissue), fibrosis, tumour stroma formation and possible CD34+ SFC-derived tumours (e.g., solitary fibrous tumour, dermatofibrosarcoma protuberans, giant cell fibroblastoma, nuchal-type fibroma, mammary and extramammary myofibroblastoma, spindle and pleomorphic cell lipoma, and elastofibroma) and H) Clinical and therapeutic implications.

https://digitum.um.es/digitum/bitstream/10201/71974/1/Diaz-Flores-29-831-870-2014_compressed.pdf

CD34+ stromal cells/fibroblasts/fibrocytes/telocytes as a tissue reserve and a principal source of mesenchymal cells. Location, morphology, function and role in pathology.

Griscelli syndrome (GS) is a rare autosomal recessive disorder caused by mutations in either the myosin VA (GS1), RAB27A (GS2) or melanophilin (GS3) genes The three GS subtypes are commonly characterized by pigment dilution of the skin and hair, due to defects involving melanosome transport in melanocytes Here, we review how detailed studies concerning GS have contributed to a better understanding of the molecular mechanisms involved in vesicle transport and membrane trafficking processes Additionally, we demonstrate that the identification and biological analysis of novel disease-causing mutations highlighted the functional importance of the RAB27A-MLPH-MYO5A tripartite complex in intracellular melanosome transport As the small GTPase Rab27a is able to interact with multiple effectors, including Slp2-a and Myrip, we report on their presumed role in melanosome transport Furthermore, we summarize data suggesting that RAB27B and RAB27A are functionally redundant and hereby provide further insight into the pathogenesis of GS2 Finally, we discuss how the gathered knowledge about the RAB27A-MLPH-MYO5A tripartite complex can be translated into a possible therapeutic application to reduce (hyper)pigmentation of the skin

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1755-148X.2009.00558.x

Griscelli syndrome: a model system to study vesicular trafficking.

Hermansky-Pudlak syndrome (HPS) consists of a group of genetically heterogeneous disorders which share the clinical findings of oculocutaneous albinism, a platelet storage pool deficiency, and some degree of ceroid lipofuscinosis. Related diseases share some of these findings and may exhibit other symptoms and signs but the underlying defect in the entire group of disorders involves defective intracellular vesicle formation, transport or fusion. Two HPS-causing genes, HPS1 and ADTB3A, have been isolated but the function of only the latter has been determined. ADTB3A codes for the beta 3A subunit of adaptor complex-3, responsible for vesicle formation from the trans-Golgi network (TGN). The many HPS patients who do not have HPS1 or ADTB3A mutations have their disease because of mutations in other genes. Candidates for these HPS-causing genes include those responsible for mouse models of HPS or for the 'granule' group of eye color genes in Drosophila. Each gene responsible for a subset of HPS or a related disorder codes for a protein which almost certainly plays a pivotal role in vesicular trafficking, inextricably linking clinical and cell biological interests in this group of diseases.

Hermansky–Pudlak Syndrome and Related Disorders of Organelle Formation

Dermal dendrocyte hamartomas are extremely rare; only two examples have been described with clinical features different from our cases and with incomplete immunohistochemical characterization. We report three female patients presenting a medallion-shaped, well-defined, slightly atrophic and asymptomatic congenital lesion. All 3 patients showed a fusiform-cell proliferation. Immunohistochemistry was positive for CD34, factor XIIIa, and fascin. Electron microscopy showed typical features of dermal dendrocytes. We believe that the lesions described represent a new, clinically and histopathologically distinct lesion originating in dermal dendrocytes. We propose to name it medallion-like dermal dendrocyte hamartoma.

Medallion-like dermal dendrocyte hamartoma: A new clinically and histopathologically distinct lesion

Background Silvery hair and severe dysfunction of the central nervous system (neuroectodermal melanolysosomal disease or Elejalde syndrome) characterize this rare autosomal recessive disease. Main clinical features include silver-leaden hair, bronze skin after sun exposure, and neurologic involvement (seizures, severe hypotonia, and mental retardation). Large granules of melanin unevenly distributed in the hair shaft are observed. Abnormal melanocytes and melanosomes and abnormal inclusion bodies in fibroblasts may be present. Differential diagnosis with Chediak-Higashi syndrome and Griscelli syndrome must be done. Observations We studied pediatric patients with silvery hair and profound neurologic dysfunction. Immune impairment was absent. Age of onset of neurologic signs ranged from 1 month to 11 years; the signs included severe muscular hypotonia, ocular alterations, and seizures. Mental retardation since the first months of life was noted in 4 cases. Psychomotor development was normal in 3 cases, but suddenly the patients presented with a regressive neurologic process. Four patients died between 6 months and 3 years after the onset of neurologic dysfunction. One patient showed characteristic ultrastructural findings of Elejalde syndrome. Conclusions Elejalde syndrome is different from Chediak-Higashi and Griscelli syndrome and is characterized by silvery hair and frequent occurrence of fatal neurologic alterations. Psychomotor impairment may have 2 forms of presentation: congenital or infantile. Although Elejalde syndrome and Griscelli syndrome are similar, the possibility that they are 2 different diseases, although probably allelic related, is suggested.

https://jamanetwork.com/journals/jamadermatology/articlepdf/477721/dob8029.pdf

Elejalde syndrome--a melanolysosomal neurocutaneous syndrome: clinical and morphological findings in 7 patients.

Benign cephalic histiocytosis (BCH) is best understood as a form of non-Langerhans cell histiocytosis, specifically as an early mononuclear variant of juvenile xanthogranuloma (JXG). However, the progression of BCH into JXG in the same patient has only been reported once before. We describe the case of a 2-year-old girl with asymptomatic, large, ill-defined infiltrated flat plaques over both cheeks, in addition to isolated papules. A punch biopsy of a plaque revealed dermal infiltration by vacuolated and scalloped histiocytes positive for CD68 KP-1, and that lacked expression of CD1a and S-100 protein, favoring macrophages over Langerhans cells. Electron microscopy study showed comma-shaped intracytoplasmic bodies in the histiocytic cells leading to the diagnosis of BCH. One year later, after an episode of varicella-zoster infection, the flat plaques over the cheeks became large reddish-yellow nodules, and in a second biopsy appeared to progress to JXG. Virus-related mechanisms of progression are discussed.

Benign cephalic histiocytosis progressing into juvenile xanthogranuloma: a non-Langerhans cell histiocytosis transforming under the influence of a virus?

Indeterminate cell histiocytosis is a rare disorder involving altered homing mechanisms of the cutaneous histiocytic/dendritic system. It has been described predominantly in adults, with less than a dozen cases in children. A 13-year-old adolescent girl presented with a 4-year history of asymptomatic erythematous nodules and plaques, measuring from 1 to 5 cm in diameter, that were located mainly on the trunk and proximal portions of her limbs. A skin biopsy showed dermal diffuse infiltration of histiocytic cells. Most of the histiocytic cells were strongly positive for S100 protein. No Birbeck granules were found. Treatment with topical steroid was ineffective. After 6 months of pure coal tar and 5% 5-fluorouracil cream, an almost total clearing of lesions was observed. An accurate diagnosis of this condition is mandatory in order to avoid unnecessary treatments. Conservative management is also discussed.

Indeterminate cell histiocytosis. Clinical and pathologic study in a pediatric patient.

Indeterminate cell histiocytosis is a rare disorder involving altered homing mechanisms of the cutaneous histiocytic/dendritic system. It has been described predominantly in adults, with l...

Rodolfo Rodriguez-Jurado

Papers

Medallion-like dermal dendrocyte hamartoma: A new clinically and histopathologically distinct lesion

Elejalde syndrome--a melanolysosomal neurocutaneous syndrome: clinical and morphological findings in 7 patients.

Benign cephalic histiocytosis progressing into juvenile xanthogranuloma: a non-Langerhans cell histiocytosis transforming under the influence of a virus?

Indeterminate cell histiocytosis. Clinical and pathologic study in a pediatric patient.

Indeterminate Cell Histiocytosis