Giuseppe Albertini

Hirschsprung disease, mental retardation, characteristic facial features, and mutation in the gene ZFHX1B (SIP1): Confirmation of the Mowat-Wilson syndrome

We read with interest the article ‘‘Hirschsprung disease, microcephaly, mental retardation, and characteristic facial features: delineation of a new syndrome and identification of a locus at chromosome 2q22–q23’’ [Mowat et al., 1998]. The same distinctive face was reported by Kääriäinen et al. [2001] in four out of five patients in our opinion and by Zweier et al. [2002]. Recently, mutations in the zinc finger homeobox 1 B gene, ZFHX1B (SIP1), were identified in patients with and without Hirschsprung disease (HSCR), multiple congenital anomalies, mental retardation (MCA/MR), and the same facial gestalt [Zweier et al., 2002]. The latter authors propose the name, Mowat-Wilson syndrome for this entity. It has been demonstrated that patients 1, 2, and 3 of Mowat et al. [1998] also have a heterozygous mutation in the gene ZFHX1B (SIP1) [Cacheux et al., 2001]. In other patients, the correlation with the facial gestalt has not yet been clearly established [Amiel et al., 2001; Wakamatsu et al., 2001; Yamada et al., 2001]. Wehave recently seen aboywithHSCRwith the same phenotype as the cases described by Mowat et al. and having a mutation in the gene ZFHX1B (SIP1). The boy is the first of two children of healthy, nonconsanguineous parents (34-year-old mother and 34-year-old father). The mother’s sister had Noonan syndrome. Family history was otherwise unremarkable, none of the familymembers showedHSCR.Prenatalultrasound at 15 weeks gestation showed bilateral mild dilatation of the renal pelvis. There were poor fetal movements. Hewasbornat 40weeksgestation. Spontaneousvaginal vertex delivery occurred with a birth weight of 3,750 g, length of 51 cm, and head circumference of 34 cm. APGAR scores were 9 and 10 at one and five minutes, respectively. He was transferred from the Neonatal Service to pediatric surgery at the age of two days and underwent surgery for HSCR at the age of 50 days. He had hypotonia and global developmental delay, with involuntary nodding of the head and exaggerated reaction to acoustic stimulus. At the age of 17 months, he developed recurrent seizures, which responded to anticonvulsants, and partial epilepsy complex was diagnosed. On examination at the age of 18 months, his head circumference was 46 cm (10th centile), height was 83.5 cm (50th–75th centile), and weight was 10.16 kg (10th centile) He had fine and blond hair, high forehead, frontal bossing, prominent supraorbital ridges, deep set eyes, small nose with a bulbous tip, mouth held open, pointed chin, posterior angulation of ears, uplifted ear lobes, fetal finger pads, deep palmar and plantar creases, long halluces, hypospadias, and undescended right testis (Figs. 1 and 2). Dermatoglyphics showed 8/10 ulnar loops. Investigations including lactate, ammonium, QFQ banded karyotype at 650 band resolution, molecular analyses for fragile X syndrome, and flourescence in situ hybridization (FISH) for chromosome 8 mosaicism were all normal. Skeletal survey showed Wormian bones; hypoplasia of the distal phalanges of the fingers and hypoplasia of the middle and distal phalanges of the 2nd, 3rd, 4th, and 5th toes; and long and hypertrophic first ray of the feet. The patellae were normal. Cranial computed tomography (CT) demonstrated greater representation of subarachnoid spaces in frontal side compared to the remaining sites of the head, and magnetic resonance imaging (MRI) of the brain showed mild symmetrical accentuation of the apex of temporal horns bilaterally.Abdominal ultrasonographic evaluation was normal. Direct sequencing of ZFHX1B revealed a de novo heterozygous frameshift mutation nt901delC in exon 7, resulting in a stop codon after 36 aa. The truncated protein is missing part of the N-terminal zinc finger domain, the Smad binding domain, the homeodomain, and the C-terminal zinc finger domain (Fig. 3). The analysis was performed as described by Zweier et al. [2002]. *Correspondence to: Dr. Livia Garavelli, Divisione di Pediatria, Ambulatorio di Genetica Clinica, Arcispedale S. Maria NuovaAziendaOspedaliera-Viale Risorgimento, 80 42100 Reggio Emilia, Italy. E-mail: garavelli.livia@asmn.re.it

Early diagnosis of melanoma: what is the impact of dermoscopy?

There are three possible explanations for the improved melanoma recognition when a clinician uses dermoscopy: first, the presence of early dermoscopy signs that become visible in melanoma much before the appearance of the classical clinical features; second, an increased attitude of clinicians to check more closely clinically banal‐looking lesions; and third, an improved attitude of clinicians to monitor their patients. In this review, the light and the dark sides of melanoma screening are briefly discussed, including the need to find better strategies to decrease the number of unnecessary excision of benign lesions on one hand, and to finally decrease melanoma mortality rates on the other.

Impact of body mass index on retention rates of anti-TNF-alfa drugs in daily practice for psoriasis

Abstract Background: Psoriasis is a chronic inflammatory skin disease which often requires life-long treatment. Objective/aim: Our objective was to assess the role of the body mass index (BMI) on the retention rates of anti-TNF-alfa therapies in patients with moderate to severe plaque psoriasis. Material and methods: Retrospective observational study of psoriasis patients included in local databases of three public Italian hospitals. All patients, who received anti-TNF-alfa treatment in referral centers, were included. Only patients with at least 1-year follow-up were considered eligible. The outcome was the conservation of the treatment at 1 and 2 years of follow-up. Results: 194 patients were enrolled. 307 treatment courses with a minimum follow-up of 12 months and 263 with a follow-up of 24 months were analyzed. The proportion of patients receiving the same treatment at months 12 and 24 was 67.43% and 42.21%, respectively. The proportion steadily decreased with increased values of BMI. Conclusions: The overall efficacy of TNF-alfa inhibitors diminishes with time. The BMI affects the long-term survival rate of anti-TNF-alfa in psoriatic patients. A high BMI can be considered a potential predictor of drug discontinuation.

Inverse Association Between Dietary Vitamin D and Risk of Cutaneous Melanoma in a Northern Italy Population

The possibility of an inverse association between vitamin D and risk of cancer and, in particular, of cutaneous malignant melanoma has been suggested, but results of epidemiologic studies are still conflicting. We examined the relation between dietary vitamin D intake and melanoma risk through a population-based case-control study (380 cases, 719 controls) in a northern region of Italy, a country with an average vitamin D intake lower than that in northern Europe or the United States. We assessed average daily intake of vitamin D from foodstuffs using the European Prospective Investigation into Cancer and Nutrition (EPIC) semiquantitative food frequency questionnaire. In this population, levels of vitamin D intake were considerably lower than those observed in recent U.S. studies. We found an inverse relation between dietary vitamin D and melanoma risk in the sample as a whole, in both crude and adjusted analyses. In sex- and age-specific analyses, this association appeared to be stronger among males and among older subjects. These findings suggest that, at the relatively low levels of intake observed in this sample, an inverse relation between dietary vitamin D and risk of cutaneous malignant melanoma may exist.

Melanoma epidemic across the millennium: time trends of cutaneous melanoma in Emilia-Romagna (Italy) from 1997 to 2004

Background  After a rapid increase in malignant melanoma (MM) incidence in the last decades, trends of the melanoma epidemic in the recent years seemed not homogeneous.

Clinical, dermoscopic and reflectance confocal microscopy features of sebaceous neoplasms in Muir–Torre syndrome

Background  Muir–Torre syndrome (MTS) is an autosomal‐dominant disorder characterized by the association of sebaceous tumors or keratoacanthomas with an early onset visceral cancer in the spectrum of Lynch syndrome.

Spontaneous regression of keratoacanthoma can be promoted by topical treatment with imiquimod cream

Imiquimod, the first member of a new class of immune response modifiers, is approved for the treatment of external genital and perianal warts. Recently, many clinical trials highlighted the potential of imiquimod as a treatment for other viral infections and cutaneous neoplasms. We report two cases of facial keratoacanthomas (KA) treated with topical 5% imiquimod cream. Patients were successfully cleared of KAs after treatment for 8 weeks. No recurrence occurred after a 1‐year follow‐up. Despite the fact that KAs are characterized by the potential for spontaneous regression, it is possible that a faster activation of CD4+ lymphocytes, via interferon release and cytokine secretion takes place after imiquimod application leading to KA regression.

Diet Quality and Risk of Melanoma in an Italian Population

BACKGROUND Some results from laboratory and epidemiologic studies suggest that diet may influence the risk of melanoma, but convincing evidence for a role of single nutrients or food items is lacking. Diet quality, which considers the combined effect of multiple food items, may be superior for examining this relation. OBJECTIVE We sought to assess whether diet quality, evaluated with the use of 4 different dietary indexes, is associated with melanoma risk. METHODS In this population-based case-control study, we analyzed the relation between 4 diet quality indexes, the Healthy Eating Index 2010 (HEI-2010), Dietary Approaches to Stop Hypertension (DASH) index, Greek Mediterranean Index (GMI), and Italian Mediterranean Index (IMI), and melanoma risk in a northern Italian community, with the use of data from 380 cases and 719 matched controls who completed a semiquantitative food frequency questionnaire. RESULTS In the overall sample, we found an inverse association between disease risk and the HEI-2010 and DASH index, but not the Mediterranean indexes, adjusting for potential confounders (skin phototype, body mass index, energy intake, sunburn history, skin sun reaction, and education). However, in sex stratified analyses, the association appeared only in women (P-trend: 0.10 and 0.04 for the HEI-2010 and DASH index, respectively). The inverse relations were stronger in women younger than age 50 y than in older women, for whom the GMI and IMI scores also showed an inverse association with disease risk (P-trend: 0.05 and 0.02, respectively). CONCLUSIONS These results suggest that diet quality may play a role in cutaneous melanoma etiology among women.

Skin eruption associated with Hymenolepis nana infection

A 56‐year‐old man presented with a recurrent cutaneous eruption of the trunk, associated with itching, which had lasted for several months. Antihistamines, such as cetirizine, loratadine, and fexofenadine, and topical steroids had been used with only temporary relief. Recently, the cutaneous manifestations had become continuous and very tedious and had not responded to local or systemic treatments. The patient was a doctor of medicine, was married, and had not been taking any medications. He had travelled for scientific purposes to different areas of Italy and The Netherlands in the last 12 months. He had no animals at home and no history of fever, sweats, arthralgia, cough, dyspnea, or allergic diseases. A history of gastritis and mild hyperglycemia was present.

Anti-TNF-α drugs differently affect the TNFα-sTNFR system and monocyte subsets in patients with psoriasis

TNF-α has a central role in the development and maintenance of psoriatic plaques, and its serum levels correlate with disease activity. Anti-TNF-α drugs are, however, ineffective in a relevant percentage of patients for reasons that are currently unknown. To understand whether the response to anti-TNF-α drugs is influenced by the production of anti-drug antibodies or by the modulation of the TNFα-TNFα receptor system, and to identify changes in monocyte phenotype and activity, we analysed 119 psoriatic patients who either responded or did not respond to different anti-TNF-α therapies (adalimumab, etanercept or infliximab), and measured plasma levels of TNF-α, TNF-α soluble receptors, drug and anti-drug antibodies. Moreover, we analyzed the production of TNF-α and TNF-α soluble receptors by peripheral blood mononuclear cells (PBMCs), and characterized different monocyte populations. We found that: i) the drug levels varied between responders and non-responders; ii) anti-infliximab antibodies were present in 15% of infliximab-treated patients, while anti-etanercept or anti-adalimumab antibodies were never detected; iii) plasma TNF-α levels were higher in patients treated with etanercept compared to patients treated with adalimumab or infliximab; iv) PBMCs from patients responding to adalimumab and etanercept produced more TNF-α and sTNFRII in vitro than patients responding to infliximab; v) PBMCs from patients not responding to infliximab produce higher levels of TNF-α and sTNFRII than patients responding to infliximab; vi) anti- TNF-α drugs significantly altered monocyte subsets. A complex remodelling of the TNFα-TNFα receptor system thus takes place in patients treated with anti-TNF-α drugs, that involves either the production of anti-drug antibodies or the modulation of monocyte phenotype or inflammatory activity.