H. Valdes-Socin

Reproduction, smell, and neurodevelopmental disorders: genetic defects in different hypogonadotropic hypogonadal syndromes.

The neuroendocrine control of reproduction in mammals is governed by a neural hypothalamic network of nearly 1500 gonadotropin-releasing hormone (GnRH) secreting neurons that modulate the activity of the reproductive axis across life. Congenital hypogonadotropic hypogonadism (HH) is a clinical syndrome that is characterized by partial or complete pubertal failure. HH may result from inadequate hypothalamic GnRH axis activation, or a failure of pituitary gonadotropin secretion/effects. In man, several genes that participate in olfactory and GnRH neuronal migration are thought to interact during the embryonic life. A growing number of mutations in different genes are responsible for congenital HH. Based on the presence or absence of olfaction dysfunction, HH is divided in two syndromes: HH with olfactory alterations [Kallmann syndrome (KS)] and idiopathic hypogonadotropic hypogonadism (IHH) with normal smell (normosmic IHH). KS is a heterogeneous disorder affecting 1 in 5000 males, with a three to fivefold of males over females. KS is associated with mutations in KAL1, FGFR1/FGF8, FGF17, IL17RD, PROK2/PROKR2, NELF, CHD7, HS6ST1, FLRT3, SPRY4, DUSP6, SEMA3A, NELF, and WDR11 genes that are related to defects in neuronal migration. These reproductive and olfactory deficits include a variable non-reproductive phenotype, including sensorineural deafness, coloboma, bimanual synkinesis, craniofacial abnormalities, and/or renal agenesis. Interestingly, defects in PROKR2, FGFR1, FGF8, CHD7, DUSP6, and WDR11 genes are also associated with normosmic IHH, whereas mutations in KISS1/KISSR, TAC3/TACR3, GNRH1/GNRHR, LEP/LEPR, HESX1, FSHB, and LHB are only present in patients with normosmic IHH. In this paper, we summarize the reproductive, neurodevelopmental, and genetic aspects of HH in human pathology.

Testicular Effects of Isolated Luteinizing Hormone Deficiency and Reversal by Long-Term Human Chorionic Gonadotropin Treatment

Isolated gonadotropin deficiency due to inactivating mutations of -subunits of LH or FSH are rare. Isolated LH inactivation was identified in1992,although thepatient’s clinical characteristicshad been reportedearlier (1,2).Maleswith inactivatingLH mutations (five adults have been reported) present with clinical features of hypogonadism and oligo/azoospermia (1–5). In 2004, we reported the case of a 30-yr-old man with this clinical presentation (3). The patient gave informed consent for a testicular biopsy (Fig. 1, A and B), which showed arrested spermatogenesis and fetal-type Leydig cells (3). A homozygous missense mutation (G36D) in the LH -subunit gene was identified that abrogated -subunit dimerization and rendered LH biologically and immunologically inactive (3). We initiated treatment with intramuscular human chorionic gonadotropin (hCG) (1500 IU three times a week for 1 month, then 5000 IU weekly). Tanner staging was 5 after 3 months. After 24 months treatment, FSH decreased to 2.3 mIU/ml (normal range, 1–8mIU/ml)andtestosterone increasedto7 g/liter (normal range, 2.5–10.0 g/liter).Therewasnearnormalizationof testicular structure, which was likely related to Leydig cell maturation and subsequent increases in intratesticular testosterone, leading to a sperm count of 1000 spermatozoids/ml. (Fig. 1, C and D). The patient and his wife conceived a child by intracytoplasmic sperm injection from ejaculated sperm. The male child was heterozygotic for the G36D LH mutation and was phenotypically normal with normal LH, FSH, and testosterone levels at the age of 4 wk. Although rare, isolated LH deficiency due to inactivating mutations of LH -subunit gene is a useful illustration of the precise role of LH in testicular maturation and function in humans. Furthermore, it also provides a good example of the clinical efficacy of LH receptor stimulation using hCG.

Association of acute leukemia and autoimmune polyendocrine syndrome in two kindreds.

leukemic DC to stimulate allogeneic responses against JMML remains problematic because of the wide array of self-antigens presented, which are likely to induce potent graft-versus-host disease (GVHD) responses. However, there are several potential clinical applications arising from our data. Firstly, in vitro generated leukemic DC could be used for the stimulation of autologous PBMC (in an ex vivo setting) to generate antileukemic T cell lines for adoptive immunotherapy. In this regard, it is important to note that there is reduced reactivity against autologous PBMC with JMMLderived MoDC (Figure 2a). This may be due to reduced T-cell number or function in JMML patients. However, the limited cytotoxicity assay suggests that the autologous population has the potential for antileukemic responses if stimulated by JMML-MoDC ex vivo. Secondly, DC differentiated in vitro from JMML cells may potentially be administered as a cellular leukemia vaccine in vivo, in the context of resistant disease and BMT failure. Thirdly, the data support the concept of generating allogeneic JMML-specific CTL lines from BMT donor T lymphocytes (T-cell source being either donor PBMC or activated T cells post engraftment). The T cells could be transduced with suicide genes to allow reversal of GVHD if it develops. Lastly, systemic treatment with cytokine therapy could potentially be used to induce immunostimulatory JMML DC in vivo, and would be applicable for patients with resistant disease post BMT. Further studies in a larger number of patients are warranted to confirm the immunostimulatory properties of JMML-derived DC.

How to recognize Cowden syndrome: A novel PTEN mutation description

t b i Cowden syndrome (CS) is an autosomal dominant disorder ssociated with an inherited predisposition to cancer, characteized by the appearance of hyperplastic hamartomas, tumours r lesions affecting multiple organs [1]. Neoplastic lesions redominantly involve the skin, mucous membranes, thyroid, reast, colon and endometrium, and may affect the central ervous system in the form of gangliocytoma and vascular alformations [2]. A twenty year old Belgian woman (1 m 60, 65 kg) presented ith a multinodular goiter associated with cervical discomort. Physical examination revealed multiple nevi. An atypical elanocytoma was resected in 2011. The patient repeatedly onsulted for gingival hypertrophy extending from the anterior ortion of the palate (Fig. 1). The woman was not currently takng any medications, and the family history was unremarkable. er thyroid function was normal. No intellectual disability was oticed. A thyroid ultrasound confirmed a 29 mL goitre with marked development of the right lobe, which was cold at cintigraphy. Echographic score of this lesion was TRADS 4B.

The acromegalic voice of Tango: Don Edmundo Rivero

of acromegaly like marked prognathism, diastema, and visible nasolabial folds. According to Argentinean endocrinologist Dr Guitelman, he received treatment for acromegaly [2]. Leonel Edmundo Rivero started as a folklore vocalist and guitarist, being also an actor in the movies: “Pampa y Cielo” (1938), “El Cielo en las manos” (1949), “el Camino de las llamas” (1942), and “Pelota de cuero” (1948). His Leonel Edmundo Rivero (June 8, 1911–January 18, 1986) was a one of the most famous Argentinean tango singers of the second half of the twentieth century (Fig. 1). A deep bass-baritone voice was his trademark [1], whereas most tango singers used to be tenors. Don Edmundo Rivero had huge hands and feet, as demonstrated on the photographs (Figs. 1, 2). He also had other symptoms which are typical