Induction of a NOTCH3 Lehman syndrome mutation in osteocytes causes osteopenia in male C57BL/6J mice.

Lateral Meningocele or Lehman Syndrome (LMS) is associated with NOTCH3 mutations causing deletions of the PEST domain and a gain-of-NOTCH3 function. We demonstrated that Notch3em1Ecan mice harboring Notch3 mutations analogous to those found in LMS are osteopenic because of enhanced bone resorption. To determine the contribution of specific cell lineages to the phenotype, we created a conditional-by-inversion (Notch3COIN) model termed Notch3em2Ecan in which Cre recombination generates a Notch3INV allele expressing a NOTCH3 mutant lacking the PEST domain. Germ line Notch3COIN inversion caused osteopenia and phenocopied the Notch3em1Ecan mutant, validating the model. To induce the mutation in osteocytes, smooth muscle and endothelial cells, Notch3COIN mice were bred with mice expressing Cre from the Dmp1, Sm22a and Cdh5 promoters, respectively, creating experimental mice harboring Notch3INV alleles in Cre-expressing cells and control littermates harboring Notch3COIN alleles. Notch3COIN inversion in osteocytes led to femoral and vertebral cancellous bone osteopenia, whereas Notch3COIN inversion in mural Sm22a or endothelial Cdh5-expressing cells did not result in a skeletal phenotype. In conclusion, introduction of the LMS mutation in osteocytes but not in vascular cells causes osteopenia and phenocopies Notch3em1Ecan global mutant mice.

Degeneración tumoral en meningocele no intervenido. Descripción de dos casos / Tumoral degeneration occurring over a non-healing meningocele. Report of two cases

Asistir a pacientes que presentan un meningocele gigante y en edad adulta es una rareza clínica, debido en parte a que es una malformación disráfica con una incidencia baja y a que el índice de supervivencia de los recién nacidos con éstas patologías era menor en épocas anteriores, pese a la benignidad de la malformación. Aportamos a la literatura existente los casos de dos pacientes que nacieron con un disrafismo espinal abierto y que no fueron operados en su momento, llegando a la edad adulta con voluminosos sacos meningocutáneos que tuvieron que ser extirpados, por presentar en el caso de más edad, un absceso con fistulización sin salida de LCR que no mejoró con tratamiento tópico y antibiótico. En el otro caso por sospecha de malignización debido a crecimiento progresivo de la malformación durante el último año, endurecimiento de la piel y dolor. El estudio anatomopatológico de los sacos resecados demostró la existencia de una degeneración carcinomatosa. En nuestros casos y en los pocos casos encontrados en la bibliografía parece que la irritación crónica del LCR y la existencia de células multipotenciales en el saco meningocélico pueden favorecer la malignización de los tejidos que recubren el mismo. La posible malignización descrita en la escasa literatura existente, a la que aportamos nuestros dos casos, sugiere como tratamiento de elección la exéresis quirúrgica de estas lesiones congénitas lo más precozmente posible (AU)

A giant meningocelic sac has not been usually described in adult patients, due to the fact that it shows a low incidence and few newborn have survived to date though the malformation is benign. We report two cases of patients born with the described malformation and who were not operated at that time, so they reached adulthood with bigger sacs. They needed surgery to remove the sacs, for a different reason. The older one had a fistulous abcess but the LCR did not come out, and it did not improved by the application of topic and antibiotic treatment. The other patient showed a progressive growth of the malformation during the last year, skin hardening and pain. The histological study of the dried sacs proved the existence of a carcinomatous degeneration. In the patients we have treated, it seems that a chronic irritation of the LCR and the appearance of multipotent cells in the meningocele may favour the malignancy of the tissues surrounding the sac. This possible malignancy, already described in the bibliography, suggests a prompt elective surgical treatment of the patients with these congenital lesions as soon as possible (AU)

SNPs in the neural cell adhesion molecule 1 gene (NCAM1) may be associated with human neural tube defects.

Neural tube defects (NTDs) are common birth defects, occurring in approximately 1/1,000 births; both genetic and environmental factors are implicated. To date, no major genetic risk factors have been identified. Throughout development, cell adhesion molecules are strongly implicated in cell-cell interactions, and may play a role in the formation and closure of the neural tube. To evaluate the role of neural cell adhesion molecule 1 (NCAM1) in risk of human NTDs, we screened for novel single-nucleotide polymorphisms (SNPs) within the gene. Eleven SNPs across NCAM1 were genotyped using TaqMan. We utilized a family-based approach to evaluate evidence for association and/or linkage disequilibrium. We evaluated American Caucasian simplex lumbosacral myelomeningocele families (n=132 families) using the family based association test (FBAT) and the pedigree disequilibrium test (PDT). Association analysis revealed a significant association between risk for NTDs and intronic SNP rs2298526 using both the FBAT test (P=0.0018) and the PDT (P=0.0025). Using the HBAT version of the FBAT to look for haplotype association, all pairwise comparisons with SNP rs2298526 were also significant. A replication study set, consisting of 72 additional families showed no significant association; however, the overall trend for overtransmission of the less common allele of SNP rs2298526 remained significant in the combined sample set. In addition, we analyzed the expression pattern of the NCAM1 protein in human embryos, and while NCAM1 is not expressed within the neural tube at the time of closure, it is expressed in the surrounding and later in differentiated neurons of the CNS. These results suggest variations in NCAM1 may influence risk for human NTDs.

Rudimentary meningocele: a variant of "primary cutaneous meningioma".

We studied 5 primary cutaneous meningiomas. All were congenital. Four were nodules or plaques on the scalp, and one was a lumbar polyp. Two were alopecic. A skull defect was present deep to one lesion, and the lumbar polyp was attached to dura. The tumors were concentrated in the subcutis, where strands of meningocytes were embedded in dense collageous tissue. Meningocytes wrapped around collagenous fibers, producing "collagen bodies". These formed the nidus for calcification that included psammoma bodies. Meningocytes also dissected between collagenous fibers, creating anastomosing spaces that mimicked a vascular tumor. Meningothelial-lined clefts, several milimeters in length, were present in 4 cases. Two lesions extended through dermal defects into the superficial dermis, where adnexa were reduced or absent. The meningocytes contained vimentin and epithelial membrane antigen. They lacked cytokeratin, S100 protein, and endothelial markers. The meningothelial lesions described herein lack the nodular and sheet-like growth patterns that typify meningiomas of the central nervous system and most primary ectopic meningiomas, including some that develop within the skin. They appear closely related to meningoceles and should be viewed as developmental abnormalities rather than neoplasms. The term "rudimentary meningocele" seems appropriate for these lesions.

[Therapeutic effectiveness of the gonadotropin releasing hormone analogue D-Trp-6-LHRH in the treatment of precocious puberty]. / Utilidad terapéutica del agonista de la hormona liberadora de gonadotrofinas D-Trp-6-LHRH en el tratamiento de la pubertad precoz.

Efficacy and safety of a superactive gonadotrophin-releasing hormone analogue (D-Trp-6-LHRH, decapeptyl) was assessed in seven girls, aged two to seven years with precocious puberty (four idiopathic, two associated to McCune-Albright syndrome and one with myelomeningocele). A further case of a seven year old male was treated with a delayed release formulation of the analogue combined with cyproterone acetate for the first two weeks of therapy. Three cases had previously been unsuccessfully treated with cyproterone acetate (2% or medroxyprogesterone (1) but this conventional therapy was discontinued three months prior entering the trial. Decapeptyl was given at a dose of 100 mcg sc daily for 10 days, followed by a dose of 1-2 mcg/kg daily thereafter. One patient required a sustained dose of 7 mcg/kg for effective control. The male patient received a biodegradable depot preparation of decapeptyl at a dose of 1.5 mg IM monthly, calculated to release circa 100 mcg of the analogue daily. He was also treated with cyproterone acetate. 100 mg/m2/day 15 days before and for two weeks during decapeptyl administration. Treatment was well tolerated without significant side effects. After six months on treatment, both LH and FSH levels were undetectable and showed no response to LHRH. Plasma oestradiol levels were reduced from 230 +/- 40 to 13 +/- 4 pg/ml. Total testosterone in the male patient was suppressed from 7 ng/ml to undetectable levels. This was accompanied by a cessation in the progression of the development of secondary sexual characteristics. All female patients developed amenorrhoea and their Tanner stage regressed to I or prepubertad after treatment.(ABSTRACT TRUNCATED AT 250 WORDS)