Assessment of intrafamilial clinical variability of poikiloderma with neutropenia by a 10-year follow-up of three affected siblings

Clericuzio-type poikiloderma with neutropenia is a well-defined nosological entity, but despite a remarkable number of clinical reports, no long term follow-up data has been presented to date regarding patients with this rare condition.Here we describe the results of clinical follow-up of three siblings, one male (Patient 1) and two females (Patients 2 and 3), subsequent to their first clinical and then molecular diagnosis of Clericuzio-type poikiloderma with neutropenia syndrome due to mutation of USB1gene. Patient 1 always expressed the most severe phenotype, while patients 2 and 3 showed an intermediate and mild phenotype, respectively, as observed since their first clinical evaluation. None of the patients developed skin cancer and/or myelodysplastic disorders considering the peripheral haematological findings. Lens opacity, never reported before, was found in two of the three patients.The long term follow-up observations confirm the stability over time of the pronounced intra-familial heterogeneity of clinical manifestations observed prior to and upon molecular diagnosis. We conclude that prolonged follow-up is an adjunct tool to monitor intra-familial variability of PN clinical spectrum which may favour surveillance of more serious complications of the disease among siblings, when a patient-specific clinical expressivity is present.     

A mild form of Roberts/SC phocomelia syndrome with asymmetrical reduction of the upper limbs

Roberts syndrome is a rare autosomal recessive condition characterized by growth retardation, cranio-facial abnormalities and symmetrical limb reduction of variable severity. Most patients with Roberts syndrome show a typical cytogenetic finding known as "Roberts syndrome effect". We describe a 4-month-old patient with a mild form of this syndrome, who presented with an asymmetrical reduction of the right upper limb.     

Intrafamilial phenotypic variability in four families with Anderson‐Fabry disease

We analysed the clinical history of 16 hemizygous males affected by Anderson‐Fabry Disease, from four families, to verify their intrafamilial phenotypic variability. Seven male patients, ranging from 26 to 61 years of age, died, whereas nine (age range 23–55) are alive. Eleven patients have undergone enzyme replacement therapy (ERT) for a period of 5–10 years. We have found a wide range of intrafamilial phenotypic variability in these families, both in terms of target‐organs and severity of the disease. Overall, our findings confirm previous data from the literature showing a high degree of intrafamilial phenotypic variability in patients carrying the same mutation. Furthermore, our results underscore the difficulty in giving accurate prognostic information to patients during genetic counselling, both in terms of rate of disease progression and involvement of different organs, when such prognosis is solely based on the patient's family history.     

p.H282N and p.Y191H: 2 novel CYP21A2 mutations in Italian congenital adrenal hyperplasia patients

More than 90% of all cases of congenital adrenal hyperplasia (CAH) result from steroid 21-hydroxylase gene (CYP21A2) mutations. The CYP21A2 gene is located in the human leukocyte antigen (HLA) class III region on the short arm of chromosome 6p21.3, along with an inactive pseudogene, CYP21A1P, that is 98% homologous in its coding sequence with CYP21A2. Most CYP21A2 mutations result from intergenic recombinations between CYP21A2 and the closely linked CYP21A1P pseudogene. Rare mutations not generated by gene conversion account for only 5% to 10% of 21-hydroxylase deficiency alleles. However, detection of these rare and spontaneous mutations has continued to expand worldwide. We identified 2 novel CYP21A2 missense mutations (p.H282N and p.Y191H) in 2 Italian patients with simple-virilizing and nonclassic CAH forms. Functional analysis of these CYP21A2 mutations was performed. Functional in vitro assay for mutagenized CYP21A2 enzymes was performed in transiently transfected mammalian cells to test the residual enzyme activity and the apparent kinetic values. The residual activities obtained allowed us to classify the p.H282N and p.Y191H variants as simple-virilizing and nonclassic CAH associated mutations, respectively. These results correlate with the rate of severity of the patients' disease. This finding provides a further contribution for assisting in the diagnosis of CAH patients.     

Surgical treatment of intestinal complications after radiotherapy and surgery for malignant lymphoma and carcinoma of the testis.

The aim of this paper is the analysis of the complications occurred after surgical and radiological procedures, for staging and treatment of malignant lymphomas and testicular carcinoma with an evaluation of the possible efficacy of their surgical treatment. At the Istituto Nazionale dei Tumori of Milan during the period 1970-1976, 718 patients with malignant lymphomas were staged with laparosplenectomy; 444 of them received radiotherapy on the abdominal area. Laparosplenectomy was not performed on other 123 cases that were irradiated as well on the abdominal area. Retroperitoneal lymphadenectomy or explorative laparotomy were carried out in 98 patients with carcinoma of the testis and 46 of them received adjuvant radiotherapy; other 29 were irradiated without previous surgical procedures. After surgery alone morbidity and mortality rate were 2.7% and 0.73% respectively. The mortality/morbidity ratio was 26%. The incidence of complications after radiotherapy alone was 3.3%. No deaths followed the treatment. Combined treatment had a morbidity rate of 5.5% and mortality rate of 2%. The mortality/morbidity ratio was 37%. Complications were treated mainly by surgery: out of 50 interventions, 22 were intestinal resections. New secondary complications were however frequent (more than 50% after intestinal resection) especially in patients originally treated with laparosplenectomy or retroperitoneal dissection plus radiotherapy.     

Improved survival with combined modality treatment for stage IV breast cancer.

Between November 1974 and March 1977, 85 patients with breast cancer at first postmastectomy relapse were irradiated (Radiation 3500–6000 rad-3/5 weeks) to all clinically evident lesions. Radiation fields were properly shaped to include a maximum 40% active bone marrow. After 3–4 weeks rest, chemotherapy was started as adjuvant therapy for residual or subclinical disease (ADR 30 mg/M² Day 1 and 8, 5-FU 400 mg/M² Day 1 and 8, CY 100 mg/M² Day 1 through 14: repeated after 14 days). ADR was discontinued at 500/M² and substituted by MTX 30 mg/M² Day 1 and 8 for a total of 2 years. Irradiated sites were chest wall in 35, supraclavicular and internal mammary nodes in 22, bone in 56, single lung lesions in 12, brain in 24. Controls were 52 comparable but non-randomized patients treated with chemotherapy only. Forty days after x-irradiation 68 patients (80%) were free of disease (NED) while in 17 cases (20%) some residual was still present (RED). In 28 of 68 cases (41%) NED after x-irradiation and 13 of 17 (76%) in RED group developed second relapse after a median interval of 26 and 20 mos, respectively. Four of 52 patients (8%) in the control group had complete regression with a median interval to second relapse of 7 mos. Median survival was 30 mos., 24 mos. and 13 mos., respectively, for NED, RED and chemotherapy only. Eighteen patients (269o) are free of disease after 36–48 mos. in the combined modality group; none in the chemotherapy group. Combined treatment cases did not show untolerable mylodepression: in 41 patients (60%) the average chemotherapy dose had to be reduced during the first 4–5 cycles because of marrow depression. In 10 long-surviving patients a marked subcutaneous and skin fibrosis developed because of drug additive effect. Stage IV breast cancers rendered clinically free of disease with x-irradiation and subsequently treated with chemotherapy survive significantly longer than with chemotherapy alone.     

Adjuvant therapy of melanoma patients (stage II, III): a pilot immuno-toxicological study

A pilot study was conducted to assess the tolerability and the effect on host immunity of a post-surgery adjuvant treatment of melanoma patients with an anti-angiogenic agent, Tamoxifen (TAM, 20 mg/die p.o., daily), combined with immunomodulating cytokines, i.e. recombinant interleukin-2 (IL-2, 4 MUI/m2 s.c., day 8,10,12) and alpha-2b-interferon (IFN, 3 MUI/m2 i.m., day 15,17,19), starting a new cycle on day 21, for a total of 12 cycles. Fifty patients (pts) entered into the study, 27 males and 23 females with a median age of 55 years (range 25-75), performance status (ECOG) 0 with melanoma stage IIA (12 patients), stage IIB (28 patients), stage III (10 patients). Preliminary in vitro studies showed that TAM does not interfere with up-regulation of natural immunity induced by IFN, IL-2, or IFN + IL-2 in normal peripheral blood mononuclear cells (MNC). The clinical study indicates that the protocol was well tolerated. Increase of NK and LAK activity of patient MNC was observed on day 15. The mean disease-free interval was 10 months and 40 pts were alive at 5 years of follow-up. Further investigations should be performed to test effectiveness of this protocol in a randomized study.