[The use of echography and US-guided percutaneous puncture in addition to mammography for the detection of malignant breast tumors]. / L'impiego dell'ecografia e della puntura percutanea ecoguidata in aggiunta alla mammografia per l'individuazione dei tumori maligni della mammella.

At present, mammography is the most effective means to detect breast cancers, especially in the early stages. However, it lacks sensitivity and specificity in women with dense breasts. Moreover, indeterminate lesions are often seen on mammograms, which should undergo further examination before surgery. Due to recent improvement in the technique--i.e., the use of high-resolution 10-MHz transducers--US can now detect also nonpalpable breast lesions, about 1 cm phi. Fine-needle biopsy (FNB) under US guidance, which is complementary to US, allows a correct diagnosis of malignancy in a high number of cases. A total of 1821 women with indeterminate lesions at mammography underwent US, and 491 of them underwent US-guided FNB, in the Leno Hospital (Brescia, Italy), in the period 1988-90. Thirty-one breast cancers which had been missed at mammography and clinical examination were found. Three cases were carcinomas in situ, 23 invasive cancers were classified as pathological stage T1, and 15 cases had no axillary lymph node involvement. The routine use of US and FNB in addition to mammography when indeterminate lesions are seen on mammograms and in women with dense breasts may significantly reduce the number of both false-negative cases at mammography and unnecessary biopsies.

DNA repair investigations in nine Italian patients affected by trichothiodystrophy.

Trichothiodystrophy (TTD) is a rare autosomal recessive disorder characterized by brittle hair, mental and growth retardation, peculiar face, ichthyosis, and in 20% of the reported cases photosensitivity. Cellular photosensitivity due to the same genetic defect present in xeroderma pigmentosum group D (XP-D) has been described in several patients. Nine patients with clinical symptoms diagnostic for TTD have been identified in Italy to date. We report the results of DNA repair investigations performed in cultured fibroblasts from these patients and 8 TTD parents. Survival, DNA repair synthesis and RNA synthesis following UV irradiation were all normal in the 8 TTD heterozygous cell strains. Among the 9 TTD-affected individuals, normal cellular UV sensitivity was observed in the 2 patients without signs of clinical photosensitivity. In contrast, the other 7 TTD cell strains showed a notable reduction in UV-induced DNA repair synthesis (UDS) levels, ranging between 40% and 5-15% of normal values. Complementation analysis indicated that in the repair-deficient TTD cell strains the genetic defect is the same as that present in XP-D cells. The biochemical heterogeneity of the XP-D defect in TTD patients characterized by different degrees of defective UDS results in different patterns of response to the killing effect of UV light in non-proliferating cells.

Proteus syndrome. Ultrastructural study of linear verrucous and depigmented nevi.

Proteus syndrome is a rare hamartomatous disorder characterized by multifocal overgrowths that can involve any structure of the body. Clinical manifestations include macrodactyly, hemihypertrophy, subcutaneous masses, exostosis, cerebroid thickening of palms and soles, and linear skin lesions. About 50 cases have been described, but the ultrastructural features of the linear skin lesions have not been characterized. We describe the clinical, histologic, and ultrastructural findings for a 30-year-old patient who had a mild form of Proteus syndrome with linear lesions characterized by a mixed pattern of hyperkeratosis and depigmentation. Light microscopy of the linear nevus showed acanthosis and hyperorthokeratosis. Electron microscopy revealed extensive vacuolation at the interface between melanocytes and keratinocytes, with large aggregations of densely packed granules in the intercellular space. Melanocytes showed only slight degenerative changes. An immunohistochemical study of the expression of epidermal growth factor receptors revealed no significant abnormalities.

Acitretin in the treatment of severe disorders of keratinization. Results of an open study.

The purpose of this open, noncomparative study with acitretin (Ro 10-1670) was to evaluate the clinical response of patients with various nonpsoriatic disorders of keratinization and to establish for these patients the optimal dosage for both efficacy and tolerance. Thirty-three patients (21 adults and 12 children or adolescents) with ichthyoses, palmoplantar hyperkeratosis, or Darier's disease were treated for a period of 4 months. Most patients showed marked improvement or remission. The results obtained in congenital ichthyosiform erythroderma, lamellar ichthyosis, and Papillon-Lefèvre syndrome were judged as better than those usually reported with etretinate. The side effects observed in our patients were similar to those reported with etretinate, with the exception of scaling of palms and soles, which had an incidence and severity greater than expected with etretinate. The optimal acitretin dosage providing the best efficacy with minimal undesirable effects varied from patient to patient. The mean daily dose (+/- SD) was 27 +/- 11 mg in adults and 0.7 +/- 0.2 mg/kg in children or adolescents.

Very late antigen (VLA) expression in various forms of epidermolysis bullosa simplex.

The very late antigen (VLA) glycoproteins are a family of adhesion membrane receptors involved in cell-cell and cell-matrix interactions. In order to investigate the expression of these molecules in inherited epidermolysis bullosa (EB), we studied the reactivity of monoclonal antibodies directed against VLA-1, -2, -3, -4, -5, and -6, and VLA beta receptors in skin sections from patients affected by several types of EB simplex (EBs) using indirect immunofluorescence. Skin samples were obtained from six patients with generalized type (Koebner), one patient with localized type (Weber-Cockayne) and one patient with Dowling-Meara EBs type and also from two normal controls. No significant modification of the expression of these adhesion receptors was observed. Anti-VLA-2 and anti-VLA-3 stained the whole cytoplasmic membrane of basal keratinocytes and allowed the detection of focal areas of cytolysis in unblistered skin from the Koebner and Dowling-Meara type. In Koebner type blisters anti-VLA-3 stained the cell remnants at the roof of the blister with a linear staining along the epidermal basement membrane on the dermal side. In Dowling-Meara type blisters anti-VLA-3 also stained cell remnants at the bottom of the cavity. Anti-VLA-6 stained the bottom of the blister cavity with the same distribution of bullous pemphigoid serum but with a stronger and more constant reactivity. Our data show that anti-VLA-3 and anti-VLA-6 can usefully be utilized in diagnostic immunomapping studies of EBs.

Hypochromic reticulated streaks in incontinentia pigmenti: an immunohistochemical and ultrastructural study.

A 25-year-old woman who recently gave birth to a baby affected by classic lesions of incontinentia pigmenti (IP), had hypochromic, atrophic, and reticulated streaks on both lower limbs. Her personal history was unremarkable for IP, and physical examination revealed no other cutaneous signs of the disease. Immunohistochemical and electron microscopic studies were performed on biopsies obtained from both normal and hypochromic skin of the leg. Hypochromic skin showed epidermal atrophy and lack of adnexae, without significant melanocyte abnormality. As demonstrated by this patient, hypochromic reticulated streaks can represent the only cutaneous marker of IP in adulthood. Careful search for such skin lesions in the mother of a child with IP is essential in order to ascertain whether there is a risk of its occurrence in future offspring.

Familial occurrence of KID (keratitis, ichthyosis, deafness) syndrome. Case reports of a mother and daughter.

Keratitis, ichthyosis, and deafness (KID) syndrome in a mother and her daughter is reported. Both patients showed the typical cutaneous abnormality of papillomatous hyperkeratosis, which gave the skin a grainy, rugose, spiculated appearance, together with keratitis with corneal neovascularization and a neurosensory hearing defect. Treatment with etretinate did not benefit the daughter. The mother had marked keratitis with progressive corneal opacification that required repeated bilateral corneal grafts, which were unsuccessful. This is the second report of hereditary transmission of this disorder. An autosomal dominant mode of inheritance is probable.

Expression of integrins in junctional and dystrophic epidermolysis bullosa.

Recently, monoclonal antibodies (MoAb) have been raised against a family of adhesive membrane receptors (R) for extracellular matrix molecules known as integrins. In order to ascertain whether these adhesive proteins are normally expressed in inherited epidermolysis bullosa (EB) dermal epidermal junction, we studied the reactivity of MoAb recognizing receptors for VLA-1 (R for unknown ligand), VLA-2 (R for collagen), VLA-3 (R for collagen, laminin, fibronectin), VLA-4 (R for unknown ligand), VLA-5 (R for fibronectin), VLA-6 (R for laminin), VNR alpha, and VNR beta (R for vitronectin) on cryostat skin sections from EB patients and normal controls and on cytospins of normal epidermal cell suspensions with indirect immunohistochemical methods. Two cases of junctional EB (EBj) (lethal and non-lethal), three cases of dominant dystrophic EB (EBdd), two cases of recessive dystrophic EB (EBdr), and two normal controls skin sections and cell suspensions entered the study. No significant modification of the distribution of these adhesive receptors was observed in junctional and dystrophic EB skin. Both in normal and EB specimens MoAb against VLA-2, VLA-3, and VNR alpha determinants showed reactivity with the total cytoplasmic membrane of basal keratinocytes and basement membrane zone. Interestingly, anti-VLA-6 MoAb was characterized by an intense linear staining of the dermal-epidermal junction with the same localization on the roof of the blisters in EBj, EBdd, and EBdr as bullous pemphigoid (BP) serum. On the basis of these results we suggest that anti-VLA-6 MoAb could be used instead of BP serum for immunohistochemical detection of the cleavage of blisters in EB.

Prenatal diagnosis of junctional epidermolysis bullosa associated with pyloric atresia.

Prenatal diagnosis of junctional epidermolysis bullosa associated with pyloric atresia was carried out in a couple at risk. Their two previous children had died during the first months of life of the same disorder despite surgery for the pyloric abnormality. Ultrastructural study of fetal skin biopsies obtained at 18 weeks' gestation showed dermal-epidermal separation at the lamina lucida level, while ultrasound showed marked stomach dilatation. Light microscopy of pyloric tissue obtained after termination showed the pyloric lumen to be replaced by loose connective tissue with no inflammatory reaction. Immunofluorescence studies on the skin specimens with the monoclonal antibody GB3, known to be absent in 'lethal' junctional epidermolysis bullosa skin, disclosed a marked positivity suggesting that the junctional epidermolysis bullosa in this case may be of the 'non-lethal' type.

Epidermolytic hyperkeratosis: generalized form in children from parents with systematized linear form.

Two unrelated families are presented in both of which a child with generalized epidermolytic hyperkeratosis (congenital bullous ichthyosiform erythroderma) had a parent with linear epidermolytic hyperkeratosis (epidermolytic epidermal naevus). Light and electron microscopy of skin biopsies of lesions from the children and parents showed typical epidermolytic hyperkeratosis. Gonadal mosaicism in patients with linear epidermolytic hyperkeratosis may be responsible for transmission of the abnormality to the offspring.

Dystrophic epidermolysis bullosa inversa: a case report.

The inverse form of recessive dystrophic epidermolysis bullosa is a rare genodermatosis characterized by a smouldering course of integumental blistering with improvement of lesions in adulthood, preferential localizations of lesions in flexural areas, severe oral and esophageal mucosal involvement and nail dystrophy. We describe a 41-year-old patient showing all the typical features of this form of epidermolysis bullosa. Ultrastructural findings in specimens obtained from perilesional and healthy skin were similar to those usually observed in the Hallopeau-Siemens form of epidermolysis bullosa. The patient has been treated with phenytoin for a period of 9 months with considerable improvement of the skin manifestations.

[Normal development of human fetal skin]. / Sviluppo normale della cute umana fetale.

Over the past few years, the use of fetal skin biopsies for prenatal diagnosis of severe inherited skin diseases has illustrated the practical importance of the structural and antigenic knowledge of normal human fetal skin. During the first 10 weeks of gestation the basic structure and antigenicity of epidermis is built up and at about 18 weeks gestation, the period in which fetal skin biopsy is usually carried out, most of the structural and antigenic markers are fully formed and usable for prenatal diagnosis: the dermal-epidermal junction is complete with hemidesmosomes and anchoring fibrils; type IV collagen and laminin are already demonstrable and useful for dermal epidermal junction mapping; other monoclonal or polyclonal markers such as GB3 or LH 7:2 are already present. At this time pilosebaceous units are present and keratinization is well developed in follicular epidermis; interfollicular keratinization, in contrast, does not begin before 24 weeks of gestational age. The appearance of sweat glands on general body surface occurs only after 24-27 weeks gestation.

Long-term preservation of permanent teeth in a patient with Papillon-Lefèvre syndrome treated with etretinate.

Papillon-Lefèvre syndrome (PLS) is a rare autosomal recessive genodermatosis characterized by the association of palmoplantar keratoderma with severe periodontopathy resulting in premature loss of both deciduous and permanent dentition. We treated a patient with PLS with etretinate and followed him for 10 years. Treatment was started at age 9 years, soon after the eruption of secondary dentition. Healing of cutaneous and periodontal lesions was obtained in a few months and maintained during the four years of treatment. Six years after etretinate withdrawal the teeth are still free of periodontal disease and firmly anchored to the alveolar bone. Our case confirms that retinoid therapy can positively influence the development of normal dentition in PLS when it is started during the eruption of the permanent teeth, and suggests that this result can be maintained for a long time even after stopping therapy.

[Dermatologic manifestations of tuberous sclerosis in children. A study of 6 cases]. / Le manifestazioni dermatologiche della sclerosi tuberosa in età pediatrica. Studio di 6 casi.

Typical cutaneous findings in tuberous sclerosis are present in over 90% of cases and represent one of the earliest markers of the syndrome. Our study, based on 6 pediatric cases, underlines how the skin manifestations vary with the patient's age. Hypopigmented maculae were usually present at birth and remained often the only clinical sign during the first few years of age. Angiofibromas on the face appeared later and were followed by orange-peel patches and then by periungual fibromas. The high spontaneous new mutation rate of tuberous sclerosis seems to be confirmed by our study in which clinical evaluation of first-degree relatives of all patients was negative.

[Prenatal diagnosis of a case of Hallopeau-Siemens recessive dystrophic epidermolysis bullosa]. / Diagnosi prenatale di un caso di epidermolisi bollosa distrofica recessiva di Hallopeau-Siemens.

Fetal dystrophic recessive epidermolysis bullosa of the Hallopeau-Siemens type (EBdr-HS) was prenatally diagnosed in a couple at risk whose previous child was severely affected of the same disorder. Prenatal diagnosis was made at 18 weeks of gestation by ultrastructural examination of fetal skin samples obtained under continuous ultrasonic guidance. Four of the five specimens obtained showed dermal epidermal separation under the lamina densa with athophic and rare anchoring fibrils and superficial collagenolysis. The parents decided to terminate the pregnancy and ultrastructural skin examination of the aborted fetus, performed in multiple sites including the scalp, trunk, abdomen and limbs, confirmed the diagnosis showing no regional variation in the expression of the ultrastructural marker.

Hypohidrotic ectodermal dysplasia. Clinical study of a family of 30 over three generations.

A family carrying the X-linked gene for hypohidrotic ectodermal dysplasia (hereditary ectodermal polydysplasia or Christ-Siemens-Touraine syndrome) over three generations was monitored for more than 15 years. Two prenatal diagnoses were carried out by fetoscopy on skin biopsies. Polymorphic probes were used in the segregation analysis of the Xq11-21 region carried out on 30 members of the family. Current screening possibilities for the carriers and prenatal diagnosis are discussed.

Papillon-Lefèvre syndrome. Ultrastructural study and successful treatment with acitretin.

Four siblings affected by Papillon-Lefèvre syndrome (PLS) ranged in age from 2 to 11 years. The parents were unaffected and parental consanguinity was present. The 2-year-old girl showed the early manifestations of PLS; that is, slight gingival swelling and erythema occurring simultaneously with minimal scaling of palms and soles. The other siblings, aged 5, 8, and 11 years, showed severe periodontopathy with tooth loss and marked palmoplantar keratoderma with a centripetal extension of the keratoses to the limbs and trunk. These three older siblings were treated with acitretin (Ro 10-1670), the free acid of etretinate, with complete clearing of the skin and healing of gingival pockets. Treatment was given for 16 months; teeth that erupted during therapy were free of periodontopathy and remained firmly anchored to the alveolar bone. In two of the children ultrastructural examination of involved skin was performed before and during acitretin treatment. Before treatment a large number of lipidlike vacuoles were found in corneocytes and in granulocytes; tonofilaments were reduced in number, and keratohyaline granules frequently showed a rectangular or globular shape. During treatment with acitretin these abnormalities diminished markedly. Thus, etretin is effective in treating PLS and, if treatment is started at an early age, should allow patients with PLS to have normal adult dentition.