IFAP syndrome is caused by deficiency in MBTPS2, an intramembrane zinc metalloprotease essential for cholesterol homeostasis and ER stress response.

Ichthyosis follicularis with atrichia and photophobia (IFAP syndrome) is a rare X-linked, oculocutaneous human disorder. Here, we assign the IFAP locus to the 5.4 Mb region between DXS989 and DXS8019 on Xp22.11-p22.13 and provide evidence that missense mutations exchanging highly conserved amino acids of membrane-bound transcription factor protease, site 2 (MBTPS2) are associated with this phenotype. MBTPS2, a membrane-embedded zinc metalloprotease, activates signaling proteins involved in sterol control of transcription and ER stress response. Wild-type MBTPS2 was able to complement the protease deficiency in Chinese hamster M19 cells as shown by induction of an SRE-regulated reporter gene in transient transfection experiments and by growth of stably transfected cells in media devoid of cholesterol and lipids. These functions were impaired in five mutations as detected in unrelated patients. The degree of diminished activity correlated with clinical severity as noted in male patients. Our findings indicate that the phenotypic expression of IFAP syndrome is quantitatively related to a reduced function of a key cellular regulatory system affecting cholesterol homeostasis and ability to cope with ER stress.

Cutis tricolor parvimaculata in two patients with ring chromosome 15 syndrome.

Two unrelated girls presented with multiple disseminated, paired, small café-au-lait spots and hypopigmented macules, suggesting didymosis (twin spotting). The girls also had growth retardation, microcephaly, hypertelorism, triangular facies, and a 46,XY, r(15) karyotype. The term cutis tricolor parvimaculata has been proposed to describe a twin spot phenomenon characterized by small, paired hypochromic and hyperchromic macules on a background of normal intermediate-pigmented skin. It has been hypothesized that the underlying gene locus of this phenomenon is a hot spot for postzygotic recombination, resulting in multiple pigmentary twin spots. Future clinical research may show whether analogous "simple" twin-spot phenotypes in the form of cutis tricolor parvimaculata may be considered a further cutaneous sign of the ring chromosome 15 syndrome.

Acanthosis nigricans and hypochondroplasia in a child with a K650Q mutation in FGFR3.

Acanthosis nigricans has been described in several autosomal dominant skeletal dysplasia syndromes due to germline FGFR3 mutations, but rarely specifically in patients with hypochondroplasia. We report a child who presented with extensive acanthosis nigricans, short stature, and radiographic evidence of hypochondroplasia. Genetic analysis revealed a heterozygous K650Q mutation in FGFR3.

PORCN mutations in focal dermal hypoplasia: coping with lethality.

The X-linked dominant trait focal dermal hypoplasia (FDH, Goltz syndrome) is a developmental defect with focal distribution of affected tissues due to a block of Wnt signal transmission from cells carrying a detrimental PORCN mutation on an active X-chromosome. Molecular characterization of 24 unrelated patients from different ethnic backgrounds revealed 23 different mutations of the PORCN gene in Xp11.23. Three were microdeletions eliminating PORCN and encompassing neighboring genes such as EBP, the gene associated with Conradi-Hünermann-Happle syndrome (CDPX2). 12/24 patients carried nonsense mutations resulting in loss of function. In one case a canonical splice acceptor site was mutated, and 8 missense mutations exchanged highly conserved amino acids. FDH patients overcome the consequences of potentially lethal X-chromosomal mutations by extreme skewing of X-chromosome inactivation in females, enabling transmission of the trait in families, or by postzygotic mosaicism both in male and female individuals. Molecular characterization of the PORCN mutations in cases diagnosed as Goltz syndrome is particularly relevant for genetic counseling of patients and their families since no functional diagnostic test is available and carriers of the mutation might otherwise be overlooked due to considerable phenotypic variability associated with the mosaic status.

Pronounced linear calcinosis in a boy with mild dermatomyositis. A further possible example of superimposed segmental manifestation of a polygenic disorder.

A pronounced linear eruption with ulcerations and calcium extrusion present in a boy with a mild generalized rash clinically consistent with juvenile dermatomyositis or overlap syndrome is reported. Loss of heterozygosity (LOH) is a postzygotic mechanism by which a heterozygous somatic cell may become homozygous or hemizygous at a given gene locus. Such a mechanism can be suspected when a pronounced segmental manifestation of an acquired skin condition with a polygenic background is found to be superimposed on more or less symmetrically distributed nonsegmental lesions of the same disorder. Alternatively, such a segmental manifestation may reflect heterozygosity for a postzygotic mutation involving an additional gene locus. The severe linear lesions in our patient showed a Blaschko-linear arrangement and were superimposed on mild nonsegmental lesions of either amyopathic dermatomyositis or overlap syndrome. Either LOH or a postzygotic mutation at an additional gene locus may explain the pronounced linear involvement.

Phacomatosis pigmentokeratotica: a follow-up report documenting additional cutaneous and extracutaneous anomalies.

This is a follow-up report on a boy with phacomatosis pigmentokeratotica. At the age of 10 years he had, in addition to a sebaceous nevus and a speckled lentiginous nevus, multiple lesions of a collagen nevus localized on the chin and in the lumbar area. On the left shoulder, a small telangiectatic spot was present within the area of the speckled lentiginous nevus. Moreover, hemiatrophy of the left-hand side of the body and hyperhidrosis of the left lumbar area were noted. At the age of 16, the lesions of his collagen nevus had considerably enlarged and showed an arrangement along Blaschko lines. Additional pinhead-sized vascular lesions were noted, with preponderance within the area of the speckled lentiginous nevus in the left scapular region and on his left leg. Moreover, the boy had developed severe arterial hypertension since the age of 13. Angiographic examination showed an aortic stenosis that reached from the aortic arch down to the origin of the renal arteries, necessitating a surgical intervention. From this follow-up report we conclude that phacomatosis pigmentokeratotica may be associated with other cutaneous abnormalities such as linear connective tissue nevus of the collagen type and multiple pinhead-sized angioma-like lesions superimposed on the speckled lentiginous nevus. The associated defects of the large vessels may belong to the component of Schimmelpenning syndrome representing one "half" of phacomatosis pigmentokeratotica, rather than being part of the speckled lentiginous syndrome that forms the other "half" of this twin-spot phenotype.

[Generalized eruptive histiocytosis-Juvenile xanthogranuloma: clinical spectrum in a pediatric patient]. / Histiocitosis eruptiva generalizada-xantogranuloma juvenil: espectro clínico en un paciente pediátrico.

Both, generalized eruptive histiocytosis and juvenile xanthogranuloma are dendritic histiocytic disorders (also known as non-Langerhans cells histiocytosis) that share clinicopathological and immunohistiochemical characteristics. We present a 3-year-old female patient with skin lesions that were clinically compatible with generalized eruptive histiocytosis, confirmed by histopathological and immunohistochemical studies. During her development the disorder compromised the central nervous system, and surgical intervention of one symptomatic lesion was needed. The histopathological exam of the central nervous system lesion showed Touton cells, compatible with a diagnosis of juvenile xanthogranuloma. This case demonstrates the need to consider these diseases as a spectrum of the same entity.

La histiocitosis eruptiva generalizada, conjuntamente con el xantogranuloma juvenil, constituyen desórdenes histiocíticos de origen dendrítico (también denominados histiocitosis no Langerhans), que comparten características clínico-patológicas e inmunohistoquímicas. Presentamos a una paciente de 3 años de edad con lesiones en la piel clínicamente compatibles con histiocitosis eruptiva generalizada y confirmadas mediante histología e inmunohistoquímica. Luego presentó compromiso en el sistema nervioso central, por lo que fue intervenida quirúrgicamente. En la histopatología de esta lesión, se encontraron células de Touton, compatibles con el diagnóstico de xantogranuloma juvenil. Este caso clínico demuestra la necesidad de considerar estas enfermedades como espectro de una misma entidad.

Desmoplastic hairless hypopigmented nevus (DHHN). A distinct variant of giant melanocytic nevus.

Desmoplastic hairless hypopigmented nevus (DHHN) is the name Ruiz-Maldonado et al. gave to a new variant of giant congenital melanocytic nevus characterized clinically by a hard ligneous consistency, absence of hair and progressive loss of pigment. Histologically, dermal fibrosis consistent with desmoplasia is a predominant feature. We describe a 6-year-old boy with a hard hairless pigmented congenital nevus involving the lumbosacral area, buttocks, perineum and scrotum. During the first years of life, the nevus showed a progressive reduction in colour, size and consistency. These changes continued until the age of four when a well-demarcated tumour appeared, within the nevus, on the right buttock. Resection of this outgrowth was performed. Histologically, nevus cells of normal appearance between thick collagen bundles were present. Immunostaining revealed S100 +, Vim +, HMB45--results. The nevus has continued to involute to date. An immune response against the melanocytes of the nevus may explain this type of evolution.

Angora hair nevus. A further case of an unusual epidermal nevus representing a hallmark of angora hair nevus syndrome.

BACKGROUND: The association of Blaschko lines with genetic mosaicism has lead to the concept that this pattern represents the manifestation of genetically abnormal skin tissue contrasting with the genetically normal skin. Various mosaic defects affecting not only the skin but also extracutaneous tissues have lead to the description of different types of epidermal nevus syndromes. We present a further case of an unusual organoid epidermal nevus characterized by depigmented hypertrichosis. MAIN OBSERVATIONS: We describe a 2-year-old boy with a systematized angora hair nevus being characterized by bands covered with soft white hair arranged along Blaschko's lines, involving the scalp, face, and trunk. A biopsy obtained from a scalp lesion showed mild epidermal acanthosis and increased pigmentation of the basal layer. Trichoscopy the affected scalp hair demonstrated fine light coloured shafts. The boy had slight macrocephaly and body asymmetry, a sacral pit, and koilonychia of the big toes. CONCLUSIONS: The angora hair nevus is a peculiar type of organoid epidermal nevus, representing the cutaneous hallmark of a distinctive syndrome, the angora hair nevus syndrome (Schauder syndrome). In cases of epidermal nevi showing hypertrichosis, this unusual entity should be borne in mind for differential diagnosis.

Histiocitosis eruptiva generalizada-xantogranuloma juvenil: espectro clínico en un paciente pediátrico / Generalized eruptive histiocytosis-Juvenile xanthogranuloma: clinical spectrum in a pediatric patient

La histiocitosis eruptiva generalizada, conjuntamente con el xantogranuloma juvenil, constituyen desórdenes histiocíticos de origen dendrítico (también denominados histiocitosis no Langerhans), que comparten características clínico-patológicas e inmunohistoquímicas. Presentamos a una paciente de 3 años de edad con lesiones en la piel clínicamente compatibles con histiocitosis eruptiva generalizada y confirmadas mediante histología e inmunohistoquímica. Luego presentó compromiso en el sistema nervioso central, por lo que fue intervenida quirúrgicamente. En la histopatología de esta lesión, se encontraron células de Touton, compatibles con el diagnóstico de xantogranuloma juvenil. Este caso clínico demuestra la necesidad de considerar estas enfermedades como espectro de una misma entidad.

Both, generalized eruptive histiocytosis and juvenile xanthogranuloma are dendritic histiocytic disorders (also known as non-Langerhans cells histiocytosis) that share clinicopathological and immunohistiochemical characteristics. We present a 3-year-old female patient with skin lesions that were clinically compatible with generalized eruptive histiocytosis, confirmed by histopathological and immunohistochemical studies. During her development the disorder compromised the central nervous system, and surgical intervention of one symptomatic lesion was needed. The histopathological exam of the central nervous system lesion showed Touton cells, compatible with a diagnosis of juvenile xanthogranuloma. This case demonstrates the need to consider these diseases as a spectrum of the same entity.

Homozygous mutations in the 5' region of the JUP gene result in cutaneous disease but normal heart development in children.

Desmosomes are intercellular adhesive junctions and attachment sites for the intermediate filament (IF) cytoskeleton, prominent in tissues subject to high levels of mechanical stress such as the epidermis and heart. The obligate desmosomal constituent, plakoglobin (PG), is involved in coupling transmembrane desmosomal components with IFs. PG also contributes to intercellular adhesion through adherens junctions and has additional signaling roles. To date, two mutations in the gene encoding PG, JUP, have been described, and in both instances, patients harboring pathogenic mutations suffered from arrhythmogenic right ventricular cardiomyopathy with or without skin abnormalities. We describe homozygous nonsense mutation, p.S24X, and homozygous splice site mutation, c.468G>A, in the JUP gene that results in skin fragility, diffuse palmoplantar keratoderma, and woolly hair with no symptoms of cardiomyopathy. We show barely detectable levels of PG immunostaining in skin sections from patients harboring these mutations and show that an alternative AUG codon in p.S24X mRNA translates a 42-amino-acid N-terminal truncation. We conclude that PG is required for correct maintenance of skin integrity, and the absence of heart phenotype in patients suggests that aberrant PG expression does not compromise normal human heart development in children. Our findings provide new insight into the distinct roles that PG has in the epidermis and heart.

Síndrome de nevus de Becker: presentación de 4 casos / Becker nevus syndrome: report of 4 cases

El nevus de Becker es un nevus organoide caracterizado por la aparición de uno o más parches hiperpigmentados, de bordes irregulares, que se localizan, con un patrón en damero, preponderantemente en la parte superior del tórax y la región escapular o proximal de las extremidades superiores (aunque pueden afectar cualquier parte del cuerpo). La asociación de este nevus con anomalías sistémicas, como hipoplasia mamaria unilateral y anomalías musculares, esqueléticas y/o cutáneas, se ha denominado síndrome del nevus de Becker. Presentamos 4 casos de niños con nevus de Becker y otras anomalías asociadas.

Becker´s nevus is an organoid nevus that manifests as one ore more hyperpigmented patches, with irregular margins, arranged in a checkerboard pattern, more often located in the upper half of the thorax, shoulder or proximal upper extremities, but it can be seen in any part of the body. The association of this nevus with unilateral breast hypoplasia, muscle, skeletal and/or skin anomalies has been named Becker´s nevus syndrome. We report 4 cases of children with Becker´s nevus syndrome and other associated anomalies.

Geroderma osteodysplastica. Report of a new family.

We report a family in which geroderma osteodysplastica affected two male siblings. They showed the characteristic features associated with this syndrome: a prematurely aged face with wrinkly, lax skin, more prominent on the acral regions, associated with joint laxity, osteoporosis, and skeletal abnormalities. The main histologic abnormalities were fragmented elastic fibers that were diminished in number. Although collagen fibers showed changes in their orientation, they were normal in structure and number. We consider the differential diagnosis with other syndromes associated with cutis laxa using clinical, radiologic, and histopathologic criteria.

Linear porokeratosis associated with disseminated superficial actinic porokeratosis: a new example of type II segmental involvement.

The coexistence of linear porokeratosis (LP) and disseminated superficial actinic porokeratosis (DSAP) in a 3-year-old girl with a family history of DSAP is presented. Happle proposed loss of heterozygosity (LOH) to explain the origin of this unusual phenomenon. Homozygosity would explain why lesions in LP are far more pronounced than those of the associated heterozygous DSAP lesions. LOH would also explain the early age of presentation of the linear lesions, the family history of DSAP, and why LP cases are particularly prone to malignant transformation. This case is also important for molecular studies because of the presence of heterozygous and homozygous mutated cells in the same patient and the familial occurrence of the heterozygous form of the disease.

Síndrome de Cross: a propósito de un caso / Cross syndrome: report of a case

El síndrome de Cross, una entidad génica autosómica recesiva, ha sido clasificado entre los albinismos oculocutáneos con anomalías oculares severas, déficit de crecimiento y compromiso neurológico progresivo. En este trabajo se presenta una paciente con este diagnóstico y se exponen sus principales diagnósticos diferenciales: síndromes de Preus y de Tietz. Destacamos la importancia de reconocer cada entidad, realizar su adecuado seguimiento y tratamiento y asesorar a la familia desde el punto de vista genético, ya que mientras los síndromes de Cross y de Preus son de herencia autosómica recesiva, el de Tietz es de herencia autosómica dominante.

Cross syndrome, an autosomal recessive genetic disorder, has been classified between the oculocutaneous albinisms with gross ocular anomalies, growth retardation and progressive neurological impairment. The present work reports a female patient with this syndrome and shows its main differential diagnosis: Preus and Tietz syndrome. We emphasize the importance of recognize each entity, do the correct follow up and treatment and assess genetically the family, since Preus and Cross syndromes are autosomal recessive diseases while Tietz syndrome is an autosomal dominant one.

Histiocitosis X: lesiones óseas cranoevertebrales y manifestaciones neurológicas / Histiocytosis X: craneovertebral bone lesions and neurological manifestations

Introducción.El término Histiocitosis X(Hx)engloba 3 entidades clínicas:la enfermedad de Letterer-Siwe(LS)la de Hand-Schüller-Chistian(HSC)y el granuloma eosinófilo(GE)Debido al polimorfismo clínico se hace necesario el conocimiento de todos sus aspectos para la correcta orientación diagnóstica.Material y Métodos.Se realizó un estudio retrospectivo de 18 historias clínicas de pacientes con Hx internados entre 1974 y 1993 en el Hospital de Niños de Tucumán.El objetivo fue determinar las características de las lesiones radiológicas(Rx)de cráneo y columna vertebral y su contribución al diagnóstico de la afección en relación a la forma clínica,igualmente ha sido de interés estimar y valorar la importancia de las manifestaciones neurológicas subjetivas y objetivas.Conclusion.La Rx simple de cráneo aún mantiene un valor orientador diagnóstico en los casos multifacéticos de Hx

Esclerosis tuberosa. Hallazgos atípicos en un caso / Tuberous sclarosis: Atypical findings in a case

Unas de las cracterísticas de la Esclerosis Tuberosa es la presencia de malfomaciones de tipo tumoral o hamartomas en múlples órganos. Se presenta el caso de un niño de 3 años de edad con espasmos infantiles y otros tipos de crisis convulsivas, máculas hopocrómicas en piel, angofribromas faciales y anomalias oculares. La tomografía computada cerebral muestra, además de calcificaciones periventriculares subependimarias, una llamativa imagen calcificada que ocupa las 2/3 partes de un hemiferio e interpretada como una rara formación tumoral en el contexto de esta enfermedad.

Cutis verticis gyrata: aporte de cuatro casos / Cutis verticis gyrata (CVG): four cases

Se presentan cuatro casos de cutis verticis gyrata (CVG), dos son individuos adultos, con cuadros correspondientes a formas primarias de la enfermedad, y dos pediátricos, que por su etiología se clasifican entre las formas secundarias. Se comentan las consideraciones clínicas y de laboratorio, así como las posibles implicaciones etiológicas y de pronóstico de cada caso