Frequent and Rare HABP2 Variants Are Not Associated with Increased Susceptibility to Familial Nonmedullary Thyroid Carcinoma in the Spanish Population.

BACKGROUND/AIMS: A genomic HABP2 variant was proposed to be responsible for familial nonmedullary thyroid carcinoma (FNMTC). However, its involvement has been questioned in subsequent studies. We aimed to identify genetic HABP2 mutations in a series of FNMTC patients and investigate their involvement in the disease. METHODS: HABP2 was sequenced from 6 index patients. Presence of the variants was investigated in all members of one family. Somatic BRAF and RAS "hotspot" mutations were investigated by the IdyllaTM BRAF Mutation Test and/or Sanger sequencing. RESULTS: Two HABP2 variants (p.E393Q and p.G534E) were identified in the index patient from one family with papillary thyroid carcinoma (PTC) (follicular variant). The prevalence of p.E393Q in Spanish control alleles was 0.5% and that of p.G534E was 5.1%. However, neither change cosegregated with the phenotype in 3 affected members and 5 healthy members of the kindred. Interestingly, all 3 members affected by PTC harbored the p.V600E somatic mutation in BRAF. CONCLUSIONS: The variant G534E is prevalent in the Spanish population (5.1%); however, p.E393Q is rare (< 1%) and none cosegregated with the FNMTC phenotype. The presence of the noninheritable V600E BRAF mutation in this family supports Knudson's "double-hit" hypothesis for cancer development and suggests the involvement of more than 1 gene in the clinical expression of FNMTC.

The Brain-Lung-Thyroid syndrome (BLTS): A novel deletion in chromosome 14q13.2-q21.1 expands the phenotype to humoral immunodeficiency.

Genetic defects of NKX2-1 are classically associated with hypothyroidism, benign chorea and neonatal respiratory distress. The purpose of this study was to identify the genetic pathogenesis of the "NKX2-1 triad" in a 10 year-old female presenting additional features barely described in the disorder. In the neonatal period, she presented with generalized hypotonia and respiratory distress, with later episodes of frequent wheezing. At 3 month-age developmental dysplasia of the hip was diagnosed and at 10 months, primary hypothyroidism was detected and treated. Subsequently, delayed achievement of developmental milestones and then subtle choreic movements of extremities were identified at 2 years of age. Furthermore, delayed teeth eruption and agenesis of some dental pieces, short stature and joint hyperlaxity were also noticed. At 10 years, a poor immune response to polysaccharide antigens and hypogammaglobulinemia, including all IgG subclasses were detected. Surprisingly, no mutations were identified in the complete coding region of NKX2-1 by PCR and Sanger sequencing. MLPA showed a de novo loss of gene dosage in all 3 probes located in NKX2-1 exons. A CGH-array identified a deletion of 3.32 Mb in chromosome 14q13.2-q21.1 containing 20 genes, including NKX2-1, PAX9 and two candidate genes (NFKB1A and PPP2R3C) involved in immune response. The Brain-Lung-Thyroid syndrome (OMIM#610978; ORPHA:209905) associated with other clinical phenotypes should suggest monoallelic deletions of chromosome 14 causing haploinsufficiency of NKX2-1, and other contiguous genes like PAX9 (hypodontia) or other dosage-sensitive genes in the chromosomal vicinity that emerge as candidates for hypogammaglobulinemia, mainly NFKBIA.

The syndrome of central hypothyroidism and macroorchidism: IGSF1 controls TRHR and FSHB expression by differential modulation of pituitary TGFß and Activin pathways.

IGSF1 (Immunoglobulin Superfamily 1) gene defects cause central hypothyroidism and macroorchidism. However, the pathogenic mechanisms of the disease remain unclear. Based on a patient with a full deletion of IGSF1 clinically followed from neonate to adulthood, we investigated a common pituitary origin for hypothyroidism and macroorchidism, and the role of IGSF1 as regulator of pituitary hormone secretion. The patient showed congenital central hypothyroidism with reduced TSH biopotency, over-secretion of FSH at neonatal minipuberty and macroorchidism from 3 years of age. His markedly elevated inhibin B was unable to inhibit FSH secretion, indicating a status of pituitary inhibin B resistance. We show here that IGSF1 is expressed both in thyrotropes and gonadotropes of the pituitary and in Leydig and germ cells in the testes, but at very low levels in Sertoli cells. Furthermore, IGSF1 stimulates transcription of the thyrotropin-releasing hormone receptor (TRHR) by negative modulation of the TGFß1-Smad signaling pathway, and enhances the synthesis and biopotency of TSH, the hormone secreted by thyrotropes. By contrast, IGSF1 strongly down-regulates the activin-Smad pathway, leading to reduced expression of FSHB, the hormone secreted by gonadotropes. In conclusion, two relevant molecular mechanisms linked to central hypothyroidism and macroorchidism in IGSF1 deficiency are identified, revealing IGSF1 as an important regulator of TGFß/Activin pathways in the pituitary.

Carcinoma erysipeloides of laryngeal origin.

The term "carcinoma erysipeloides" (CE) designates an uncommon form of cutaneous metastasis. CE is most often associated with carcinoma of the breast. However, there have been reports of CE from carcinoma of the uterus, prostate, lung, ovary, stomach, tonsils, thyroid, pancreas, rectum, parotid glands and melanoma. To our knowledge, CE of laryngeal origin has not been previously reported. We describe a patient diagnosed with human immunodeficiency virus and hepatitis C virus coinfection who developed a supraglottic laryngeal squamous cell carcinoma and erythematous cutaneous lesions. A skin biopsy demonstrated invasion of dilated dermal lymphatics by clusters of atypical squamous cells with polymorphic nuclei and extensive infiltration of the dermis by tumor cells. The histology of the metastatic cells was similar to that of the laryngeal carcinoma.

IL-17-producing CD8+ T lymphocytes from psoriasis skin plaques are cytotoxic effector cells that secrete Th17-related cytokines.

IL-17-producing CD4+ T lymphocytes (Th17) are currently considered relevant participants in the pathogenesis of psoriasis skin lesions. However, little is known about the potential role of IL-17-producing CD8+ T cells, which are also present at the psoriatic plaque. We have addressed the functional characterization of this CD8+ subtype of T lymphocytes from psoriasis patients. Our results show that CD8+IL-17+ cells from psoriasis-inflamed skin tissue produce TNF-alpha and IFN-gamma (Th1-related cytokines) as well as IL-17, IL-21, and IL-22 (Th17-related cytokines) efficiently. A significant up-regulation of the RORC transcription factor is also observed. These cells are refractory to Tregs but show a proliferative response to anti-CD3/CD28 stimulation that is enhanced by IL-12 and IL-15. Blocking of TNF-alpha activity inhibits TCR-mediated activation and IL-17 production. CD8+IL-17+ T cells are cytotoxic cells that display TCR/CD3-mediated cytotoxic abilities to kill target cells. Thus, CD8+IL-17+ T cells share some key features with Th17 cells and exhibit remarkable differential abilities attributable to the CD8+ lineage of T lymphocytes, adding new insights into the functional resources of IL-17-producing cells from human epidermis that could be of potential interest to our understanding of the pathogenesis of psoriasis.

[Diffuse cutaneous reticulohistiocytosis]. / Reticulohistiocitosis cutánea difusa.

The reticulohistiocytoses make up a heterogeneous group of diseases whose origin lies in an accumulation of cells of histiocytic lineage in different tissues and primarily in the skin. Three main clinical forms have been described (multicentric, solitary, diffuse cutaneous), which present with identical histological, ultrastructural and immunohistochemical characteristics. We present a case of diffuse cutaneous reticulohistiocytosis, which is the least common clinical pattern in the spectrum of this disease.

Graves' disease in children and adolescents: response to long-term treatment.

BACKGROUND: Optimal treatment of Graves' disease in paediatric patients is still a matter of controversy. Antithyroid drugs, radioiodine and thyroidectomy are the three therapeutic options available. AIM: To report our experience of long-term medical treatment and outcome of paediatric Graves' disease. METHODS: A 5-y-long medical protocol was implemented in 20 children and adolescents with Graves' disease. All patients received antithyroid drugs as the first therapeutic option; patients who did not enter long-term remission received I(131) and/or surgery as the definitive treatment. RESULTS: The mean age at diagnosis was 12.1+/-4 y. Only two patients were males, both presenting concomitant type 1 diabetes. Mean follow-up was 13.8+/-5.5 y. Forty per cent of patients achieved long-term remission with low antithyroid drugs doses (mean treatment time: 5.4+/-1.4 y). Six patients received I(131) as definitive treatment and another six underwent surgery after completing medical treatment for 6.8+/-4.1 and 5.1+/-2 y, respectively. No patients requiring high antithyroid drugs doses to maintain euthyroidism reached long-term remission and needed I(131) and/or surgery. CONCLUSION: Implementation of a long-term antithyroid drug protocol achieved 40% long-term remissions in paediatric patients with Graves' disease. Need for maintained high doses of antithyroid drugs could be considered a predictive factor for no remission. When permanent remission was not obtained by medical treatment, I(131)and/or surgery allowed healing in all cases.

Insulin-secretion abnormalities and clinical deterioration related to impaired glucose tolerance in cystic fibrosis.

OBJECTIVE: To evaluate insulin-secretion kinetics and insulin sensitivity in cystic fibrosis (CF) patients with normal glucose tolerance (CF-NGT), impaired glucose tolerance (CF-IGT) or CF-related diabetes (CFRD), and the potential effects of moderate hyperglycemia on clinical and nutritional status. DESIGN AND METHODS: Cross-sectional study including 50 outpatients with CF. Patients underwent both oral (OGGT) and intravenous (IVGTT) glucose tolerance tests in order to assess insulin secretion and peripheral insulin sensitivity. Homeostasis assessment model and OGGT were used to investigate insulin sensitivity. Forced expiratory volume in the first second (FEV(1)) and forced vital capacity (FVC) were measured to evaluate pulmonary function. Body mass index (BMI) was determined to assess nutritional status. RESULTS: Insulin secretion was significantly decreased (and delayed at OGTT) in the CFRD group (n = 9) versus the CF-IGT group (n = 10) and the CF-IGT versus the CF-NGT group (n = 31). Insulin sensitivity was significantly different in the CF-IGT and CFRD groups versus the CF-NGT group. FEV(1), FVC and BMI presented a significant linear correlation with plasma glucose value at 120 min at OGTT and were significantly lower in both CF-IGT and CFRD versus the CF-NGT group, whereas no differences were found between the CF-IGT and CFRD groups. CONCLUSIONS: CF patients with IGT present diminished insulin secretion and increased peripheral insulin resistance, correlating with a worse clinical status, undernutrition and impaired pulmonary function. These findings open the question of whether early treatment of mild alterations of glucose metabolism with insulin secretagogues or short-action insulin may lead to improvement of clinical status in CF patients.

[Neutrophilic eccrine hidradenitis secondary to thioguanine in a neutropenic patient]. / Hidradenitis ecrina neutrofílica secundaria a tioguanina en paciente neutropénico.

Neutrophilic eccrine hidradenitis (NEH) is an infrequent, self-limited inflammatory dermatosis characterized by a neutrophilic infiltrate around the eccrine glands. Clinically, it presents with different types of lesions. NEH occurs most frequently in patients who have undergone chemotherapy for hematologic neoplasms. We present a case of NEH in a 70-year-old neutropenic male who received thioguanine for acute myeloid leukemia. The erythematous plaques disappeared in 3-4 weeks. The histological findings were compatible with NEH. Skin cultures ruled out infectious causes.

Identification of novel genes involved in congenital hypothyroidism using serial analysis of gene expression.

Part of the molecular basis of congenital hypothyroidism (CH) has been elucidated by the identification of molecular defects in pituitary- and thyroid-specific genes in patients with various subtypes of hypothyroidism. So far identified genetic defects only explain a small proportion of cases of hypothyroidism. Thus novel research strategies are required to isolate more tissue-specific genes involved in the pathogenesis of CH at present considered 'idiopathic' from a molecular perspective. We applied serial analysis of gene expression to human thyroid tissue and developed a computational substraction method to identify tissue-specific genes. The result has been the identification of three genes preferentially expressed in the thyroid gland. The first one encodes part of the thyroid oxidase (THOX2) system. We linked mutations in the THOX2 gene with idiopathic cases of transient and permanent CH. The second transcript identified, DEHAL1, encodes the protein responsible for the recycling of iodine in the thyroid gland and represents the candidate gene for a specific subtype of CH. The third one encodes NM41, a protein currently under investigation which shows features characteristic of the CYSTINE-KNOT family of proteins, typically involved in early development.