Neurofibromatosis segmentaria en niños. Presentación de 43 pacientes / Segmental neurofibromatosis in children. Presentation of 43 patients

Introducción. Se entiende como neurofibromatosis tipo 1 (NF1) segmentaria una variedad de NF1 con patología cutánea y/o interna limitada a una zona circunscrita del cuerpo en cualquiera de sus partes. La entidad se relaciona con mosaicismo somático. Pacientes y métodos. Estudio de 43 pacientes (29 mujeres y 14 varones) con edades inferiores a 16 años. Entodos se practicaron pruebas de imagen para descartar patología subyacente, y en algunos se confirmó histológicamente el diagnóstico de neurofibroma solitario o plexiforme. En ningún caso se hizo un estudio genético sobre el tejido cutáneo afectado(buscando el mosaicismo somático) ni sobre el tejido gonadal. Resultados. Ocho pacientes mostraban exclusivamente lesiones cutáneas –siete, manchas café con leche (tres, tipo pecas; y cuatro, tipo gran mancha, de las cuales tres eran bilaterales y una unilateral), y uno, neurofibroma–. En el resto de los pacientes (81%), las alteraciones presentaban lesiones subyacentes(neurofibromas y displasia fibrosa del hueso, predominantemente). Todas las partes del cuerpo eran alcanzadas de forma similar por las lesiones subcutáneas, pero cuando las lesiones cutáneas eran la manifestación exclusiva de la NF1 segmentaria, seextendían preferentemente por el tronco. Conclusiones. La NF1 segmentaria debida a mosaicismo somático parece una variedad patológica de la NF1 que está infradiagnosticada y que presenta tantas posibles localizaciones en el cuerpo como la NF1 sin mosaicismo. La forma menos frecuente de presentación es la que sólo tiene manifestación cutánea. La presentación con patología que afecta a órganos subyacentes es la que se encontró en el 81% de los pacientes. Se constató historia familiar de NF1 en 15 pacientes (35%), y presentación bilateral en cuatro casos (9,3%)

Introduction. It is known as segmental neurofibromatosis type 1 (NF1) a type of NF1 characterized by the featurescircumscribed to one or more body cutaneous and/or subcutaneous segments. This entity is recognized from recently and it is related with somatic mosaicism. Patients and methods. 43 patients (29 females and 14 males) with ages below 16 years were retrospectively studied. Image study of the affected region of the body was performed in all patients to discard a subjacentorganic disease, and a neurofibroma was histollogicaly demonstrated in some cases. Somatic or gonosomal mosaicism was not investigated in any of the patients. Results. Only 8 patients showed cutaneous lesion –7 with café-au-lait spots (3 of freckles type, 4 of large spots, of which, 3 were bilateral and 1 unilateral ) and 1 presented neurofibromas–. The other cases(81%) had cutaneous lesion with subjacent lesion (neurofibromas and bone dysplasia in most cases). The subcutaneous lesions were seen in all parts of the body without a preferent location. In cases with only cutaneous lesion, the clinical featureswere seen on the trunk skin. Conclusion. Segmental NF1 is considered to be the result of a somatic or gonosomal mosaicism and still is underdiagnosed. Features of segmental NF1 can be found in as many regions of the body as NF1 withoutmosaicism. The types of segmental NF1 that were seen less frequently in this series were those with only cutaneous features (café-au-lait spots and neurofibromas). Types with subcutaneous features that involved subjacent organs were seen in 81% ofpatients. Familial patients, with NF1 or segmental NF1 was shown in 15 patients (35%) and bilateral lesion in 4 cases (9.3%)

Mosaicismo de trisomía 9: caso de larga supervivencia / Mosaic trisomy 9: report of a new case with a long-term survival

Introducción: La trisomía 9 es una aneuploidía infrecuente y, por tanto, difícil de sospechar. Objetivo: Comunicar un nuevo caso de mosaicismo de trisomía 9, de larga supervivencia, para contribuir al mejor conocimiento de sus características clínicas y pronóstico. Caso clínico: Primera hija de padres sanos. Retraso de crecimiento intrauterino asimétrico y oligohidramnios. Nace a las 34 semanas con 1.478 g de peso, depresión respiratoria y fenotipo anómalo: dolicocefalia; hipotelorismo, microftalmia, hendiduras palpebrales pequeñas; nariz de base ancha y punta en bulbo; micrognatia; orejas de implantación baja, y anomalías en las manos y los pies. Ausencia de malformaciones en los órganos internos. Cariotipo: normal (46,XX). A los 17 meses, ante el retraso psicomotor evidente y las alteraciones descritas se realiza un segundo cariotipo convencional insistiendo en el análisis de un mayor número de células. Se halla un mosaicismo de trisomía 9 (46,XX/47,XX, 1 9). Como dato fenotípico curioso, a los 24 meses aparece un incisivo único superior medial, no descrito antes en otros casos de trisomía 9. Actualmente, tiene 4 años, un retraso mental profundo y ninguna otra complicación. Comentarios: Destaca la mayor dificultad diagnóstica de los mosaicismos; por lo que se debe insistir en el análisis de un número suficiente de células al estudiar el cariotipo. Además, es importante su diagnóstico en sujetos con anomalías fenotípicas, para dar información correcta a los padres en orden a su pronóstico y a la futura descendencia (AU)

Introduction: Trisomy 9 is an uncommon chromosome abnormality that may be seen in a mosaic or non-mosaic state. Objective: To better define the phenotype and prognosis of this disorder we report a new case of mosaic trisomy 9 with a long-term survival. Clinical report: We present the case of a female patient, born from the first pregnancy of a healthy couple. Fetal ultrasounds disclosed intrauterine growth retardation and oligohydramnios. Cesarean section was performed in the 34th week. Birth weight was 1,478 g. Neonatal examination showed: dolichocephaly; hypotelorism, microphthalmia, short palpebral fissures; broad-based nose with bulbous tip; micrognathia; low-set malformed ears; abnormal hands and feet; no other malformations. The initial karyotype determination was normal (46,XX). At 17 months of age, a second karyotype was requested because the patient developed severe psychomotor retardation. Chromosome analysis showed mosaic trisomy 9 (46,XX/47,XX, 1 9). Six months later, a single upper central incisor was noted. To our knowledge, this feature has not been reported previously in the trisomy 9. The patient is now 4 years old. She shows severe psychomotor retardation, but no other complications. Comments: It is important to be aware of the possibility that mosaicism may exist in a patient with normal blood karyotype and abnormal phenotype. We conclude that a great number of cells is needed in order to obtain a correct karyotype diagnosis. Correct diagnosis is essential to define the prognosis and provide accurate genetic counseling (AU)

Hipertricosis localizada y mosaicismo pigmentario tipo Ito (hipomelanosis de Ito) / Localized hypertrichosis and pigmentary mosaicism of Ito (hypomelanosis of Ito)

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Detección prenatal de un isocromosoma 20 de brazos largos: presentación de un nuevo caso y revisión de la literatura / Prenatal diagnosis of a long arm isochromosome 20: A new case and literature review

Presentamos un nuevo caso de mosaico de isocromosoma20 de brazos largos, i(20q), diagnosticado prenatalmente,con fenotipo normal al nacimiento, y una exhaustiva revisiónde la literatura.La correcta interpretación del hallazgo prenatal de uni(20q), y en general de una trisomía total o parcial en mosaico,es usualmente difícil debido a la variabilidad en la expresiónde las anomalías en mosaico en los diversos tejidosy a la poca información existente (generalmente hay pocoscasos descritos, la información sobre su seguimiento posnatales escasa y en pocos casos se han podido realizar estudiosconfirmatorios).El riesgo de patología fetal asociado al i(20q) aún no hasido establecido de forma fiable y, por tanto, el dilema delsignificado y pronóstico del i(20q) persiste

The significance of rare partial or total autosomaltrisomy mosaicism is usually very difficult because of thefew cases reported in the literature, the limited informationon phenotypic outcome, and the scarcity of confirmationstudies.We present a new case of mosaicism of long armisochromosome 20, i(20q), diagnosed in a pregnancywith a normal outcome. At present, the precise risk of fetal pathology associatedto i(20q) can not confidently be concluded, so significanceand prognosis dilemma of prenatal mosaicismi(20q) persists (AU)

Lesiones cutáneas hipopigmentadas y facies particular / Hypopigmented skin lesions and coarse facies

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Lyonización desfavorable: a propósito de una familia con retinosis pigmentaria / vorable lyonization: apropos of a family with retinitis pigmentosa

Durante muchos años la expresión de los genes ligados al cromosoma x representó una incógnita para los genetistas. Si bien los varones poseen sólo una copia de cada gen ligado al x, en tanto que las mujeres tienen dos, la cantidad de producto formado por un solo alelo en el varón o por un par de alelos en la mujer era equivalente. Finalmente esto fue explicado con la formulación del principio de inactivación del cromosoma x, que conlleva a tres consecuencias importantes: compensación de dosis, mosaicismo y variabilidad de expresión en heterocigotas. Una heterocigota manifiesta, en la que el alelo deletéreo se localiza en el cromosoma x activo y el alelo normal en el x inactivo, en todas o la mayor parte de las células constituye un ejemplo de lo que se conoce como lyonización desfavorable. Se ha descrito este fenómeno en muchos trastornos ligados al x incluyendo la ceguera al color, la hemofilia A y B, la distrofia muscular de Duchenne y varios trastornos oculares ligados al x. Se realizó el estudio clínico genético de una familia con diagnóstico de retinosis pigmentaria típica de herencia recesiva ligada al cromosoma x, en la que se manifiesta el fenómeno de lyonización desfavorable(AU)

vhnf1 integrates global RA patterning and local FGF signals to direct posterior hindbrain development in zebrafish.

The vertebrate hindbrain is transiently divided along the anterior-posterior axis into seven morphologically and molecularly distinct segments, or rhombomeres, that correspond to Hox expression domains. The establishment of a proper 'hox code' is required for the development of unique rhombomere identities, including specification of neuronal fates. valentino (val), the zebrafish ortholog of mafB/Kreisler (Kr), encodes a bZip transcription factor that is required cell autonomously for the development of rhombomere (r) 5 and r6 and for activation of Hox group 3 gene expression. Recent work has demonstrated that the expression of val itself depends on three factors: retinoic acid (RA) signals from the paraxial mesoderm; fibroblast growth factor (Fgf) signals from r4; and variant hepatocyte nuclear factor 1 (vhnf1, also known as tcf2), a homeodomain transcription factor expressed posterior to the r4-5 boundary. We have investigated the interactions between these inputs onto val expression in the developing zebrafish hindbrain. We show that RA induces val expression via activation of vhnf1 expression in the hindbrain. Fgf signals from r4, acting through the MapK pathway, then cooperate with Vhnf1 to activate val expression and subsequent r5 and r6 development. Additionally, vhnf1 and val function as part of a multistep process required for the repression of r4 identity in the posterior hindbrain. vhnf1 acts largely independently of val to repress the r4 'hox code' posterior to the r4-5 boundary and therefore to block acquisition of r4-specific neuronal fates in the posterior hindbrain. However, vhnf1 is not able to repress all aspects of r4 identity equivalently. val is required downstream of vhnf1 to repress r4-like cell-surface properties, as determined by an 'Eph-ephrin code', by repressing ephrin-B2a expression in r5 and r6. The different requirements for vhnf1 and val to repress hoxb1a and ephrin-B2a, respectively, demonstrate that not all aspects of an individual rhombomere's identity are regulated coordinately.

Maternal uniparental disomy 16 and genetic counseling: new case and survey of published cases.

Uniparental disomy (UPD) is the occurrence of both homologous chromosomes from one parent. Maternal UPD(16) is the most often reported UPD other than UPD(15); almost all cases are associated with confined placental mosaicism (CPM). Most of maternal UPD(16) cases are characterised by intrauterine growth retardation (IUGR) and different congenital malformations. Maternal UPD(16) has therefore been suspected to have clinical effects: however, the lack of uniqueness and specificity of the birth defects observed suggests that the phenotype may be related in parts to placental insufficiency. We report on a new case of maternal UPD(16) associated with low level trisomy 16 mosaicism in placenta and fetus. IUGR was noticed at 19 gestational weeks and the fetus died intrauterine. Apart from different craniofacial dysmorphisms she showed anal atresia. While IUGR is probably associated with trisomy 16 mosaicism, anal atresia is more characteristic for maternal UPD( 16). Considering the features in our patient as well as those in maternal UPD (16) cases from the literature, indications for UPD (16) testing can be defined: They include trisomy 16 mosaicism, IUGR and congenital anomalies (anal atresia, congenital heart defects). However, there is an overlap of clinical signs in mosaic trisomy 16 cases mosaic for maternal UPD(16) as opposed to those mosaic for biparental disomy 16. The management of trisomy 16 pregnancies should not differ from those in which maternal UPD(16) is confirmed. Therefore, a prenatal testing for UPD(16) is not useful, but it should be offered postnatally. The molecular genetic proof of maternal UPD(16) excludes an increased recurrence risk for the family for further pregnancies.

Length and somatic mosaicism of CAG and GGN repeats in the androgen receptor gene and the risk of prostate cancer in men with benign prostatic hyperplasia.

BACKGROUND: The most common malignancy in men worldwide is cancer of the prostate and determinants of prostate cancer (PRCa) risk remain largely unidentified. Many candidate genes may be involved in PRCa, such as those that are central to cellular growth and differentiation in the prostate gland. We analysed the polymorphic CAG and GGN repeats sequence in exon 1 of the AR gene to determine if the number of repeats might be an indicator of PRCa risk in patients with BPH. METHODS: The study evaluated 28 patients who presented with PRCa at least 6 years after the diagnosis of BPH and 56 matched patients with BPH who did not progress to PRCa over a comparable period. RESULTS: This study showed no evidence for association between the size of AR CAG and GGN repeats and the risk of the development of PRCa in patients with BPH. However, BPH patients with AR CAG instability had a 12-fold increased risk in development of PRCa. CONCLUSIONS: While independent confirmation is required in further studies, these results provide a potential tool to assist prediction strategies for this important disease.

[Intersexuality in dogs: causes and genetics]. / Intersexualität beim Hund: Ursachen und Genetik.

Failures in the establishment of chromosomal, gonadal and phenotypic sex can cause intersexuality in dogs. Thus, diagnosis of chimaerism, mosaicism, sex reversal syndrome, and male or female pseudohermaphroditism in intersex individuals has to be based on the inspection of the chromosomes, gonads and the phenotypic appearance of the reproductive organs. In a study over two years, seven dogs of different breeds suspected to be intersexes were cytogenetically investigated. A sry-negative XX-sex reversal syndrome was diagnosed in a Jack Russel Terrier. In a mixbred dog a persistent Mullerian duct syndrome (PMDS) was found and a Border Terrier Dog showed an XX/XY chromosomal chimaerism. In further four dogs of different breeds, a female constitution of sex chromosomes was seen. As a sign of intersexuality each of these dog showed an enlarged clitoris. A differentiation between XX-sex reversal syndrome and female pseudohermaphroditism was not possible because there was no information on the internal genital tract and gonads available.

Emergence in Italy of a Neisseria meningitidis clone with decreased susceptibility to penicillin.

A rise in invasive diseases due to Neisseria meningitidis C:2b:P1.5 with decreased penicillin susceptibility occurred in Italy during the last 2 years. Real-time PCR identified the Peni phenotype, and the penA sequence revealed the mosaicism of the gene. Molecular analyses assigned the isolates to a single emergent clone of the hypervirulent A4 cluster.

[Turner's syndrome in mother and daughter]. / Syndroom van Turner bij moeder en dochter.

A girl with Turner's syndrome due to a 45,X mosaicism and a ring chromosome was born to a 29-year-old mother with a non-mosaic 45,X in her blood lymphocytes. Cytogenetic investigation revealed that the ring chromosome of the daughter included almost the entire X chromosome with the exception of the uppermost part of the short arm. In the literature, girls with Turner's syndrome are said to have functional ovarian tissue and pregnancies in women with Turner's syndrome after oocyte donation and intracytoplasmatic sperm injection (ICSI) are no longer exceptional. However, since ovarian failure occurs relatively early during adolescence, cryopreservation of ovarian tissue should be considered as soon as the girl or her parents are able to make the necessary decisions. On the other hand, beside risks for congenital anomalies in the newborn, the risks of pregnancies in Turner's syndrome should not be neglected, notably premature delivery due to disproportion between the pelvis and the foetus and aortic dissection in the pregnant woman.

Identification of the molecular defect in patients with peroxisomal mosaicism using a novel method involving culturing of cells at 40 degrees C: implications for other inborn errors of metabolism.

The peroxisome biogenesis disorders (PBDs), which comprise Zellweger syndrome (ZS), neonatal adrenoleukodystrophy, and infantile Refsum disease (IRD), represent a spectrum of disease severity, with ZS being the most severe, and IRD the least severe disorder. The PBDs are caused by mutations in one of the at least 12 different PEX genes encoding proteins involved in the biogenesis of peroxisomes. We report the biochemical characteristics and molecular basis of a subset of atypical PBD patients. These patients were characterized by abnormal peroxisomal plasma metabolites, but otherwise normal to very mildly abnormal peroxisomal parameters in cultured skin fibroblasts, including a mosaic catalase immunofluorescence pattern in fibroblasts. Since this latter feature made standard complementation analysis impossible, we developed a novel complementation technique in which fibroblasts were cultured at 40 degrees C, which exacerbates the defect in peroxisome biogenesis. Using this method, we were able to assign eight patients to complementation group 3 (CG3), followed by the identification of a single homozygous c.959C>T (p.S320F) mutation in their PEX12 gene. We also investigated various peroxisomal biochemical parameters in fibroblasts at 30 degrees C, 37 degrees C, and 40 degrees C, and found that all parameters showed a temperature-dependent behavior. The principle of culturing cells at elevated temperatures to exacerbate the defect in peroxisome biogenesis, and thereby preventing certain mutations from being missed, may well have a much wider applicability for a range of different inborn errors of metabolism.

Ocular manifestations of mosaic trisomy 22: a case report and review of the literature.

Mosaic trisomy 22 is rare, but can be compatible with prolonged life. Patients with mosaic trisomy 22 usually present with intrauterine growth retardation, mental retardation, failure to thrive, and craniofacial asymmetry. We report the case of a five-year-old boy who had a birth weight of 3.8 kg and normal developmental milestones. He presented with unilateral ocular manifestations of ptosis, double elevator palsy, high myopia, and choroidal coloboma involving the macula. Cytogenetic evaluation showed a low level of trisomy 22 in peripheral blood lymphocytes (1 in 100) and in cultured fibroblasts from a conjunctival biopsy of the affected eye (1 in 60). Our case demonstrates the value of chromosomal analysis of the tissues involved rather than just karyotyping of the blood lymphocytes to detect mosaicism in patients with localised and unilateral congenital malformations.

Malignant refractory epilepsy in identical twins mosaic for a supernumerary ring chromosome 19.

We report identical twins with supernumerary ring chromosome 19 mosaicism, who had severe refractory epilepsy at an early age. The epilepsy was dominated largely by severe life-threatening tonic seizures. Both twins died, likely as a consequence of their severe epilepsy. They displayed no dysmorphic features. Eight cases of ring chromosome 19 have been reported in the literature, all to our knowledge without epilepsy. The clinical picture of these twins emphasizes the importance of carrying out a karyotype study on patients with early-onset epilepsy even in the absence of dysmorphic features.

Screening for mutations in the SRY gene in patients with mixed gonadal dysgenesis or with Turner syndrome and Y mosaicism.

OBJECTIVE: To investigate the presence of mutations in the open reading frame (ORF), as well as on the 5' and 3', flanking regions of the SRY gene in patients with mixed gonadal dysgenesis (MGD) or with Turner syndrome (TS) and Y mosaicism. STUDY DESIGN: We studied 13 patients with MGD and three patients with TS and Y mosaicism. DNA was isolated from blood leukocytes for subsequent polymerase chain reaction (PCR) and direct sequencing were performed in the ORF, as well as from the 5' and 3' flanking regions of the SRY gene. RESULTS: No mutations were present in any of the patients studied. CONCLUSION: The absence of mutations in these regions indicated that mutations were an unlikely cause of MGD or TS with Y mosaicism and suggested that there are others genes playing an important role in sex development.

Somatic mosaicism in FSHD often goes undetected.

Autosomal dominant facioscapulohumeral muscular dystrophy (FSHD1A) is associated with contractions of the polymorphic D4Z4 repeat array on chromosome 4qter. The disease has a high frequency of new mutations of mitotic origin. Pulsed-field gel electrophoresis-based studies show that mitotic mutations leading to somatic mosaicism occur equally frequently in patients and parents. Nevertheless, somatic mosaicism in FSHD is mainly reported in asymptomatic parents by applying standard Southern analysis after linear gel electrophoresis. Explaining this apparent discrepancy, we here demonstrate that somatic mosaicism in FSHD patients goes largely undetected using the standard diagnostic technique, indicating that linear electrophoresis is unsuitable to identify mosaic patients. As a consequence, the phenotype of mosaic patient's offspring will be underestimated, whereas the recurrence risk in the symptomatic mosaic individuals will be overestimated. Moreover, somatic mosaicism may partly explain the observation of anticipation in de novo kindreds. Therefore, clinicians should always consider pulsed-field gel electrophoresis analysis in de novo FSHD families, in particular when the patient's phenotype is much milder than expected based on D4Z4 length proper.

Quantitative determination of mosaic GFP gene expression in tobacco.

A specific form of gene silencing that was observed visually as a mosaic distribution of fluorescent and non-fluorescent cells apparently dispersed at random within tissues was found in a few green fluorescent protein (GFP)-transformed tobacco lines. To characterize this event quantitatively, we studied flow cytometric measurements in GFP-expressing and -silenced cells in T1 and T2 progeny of four selected plants. The proportion of silenced cells varied considerably among the T1 lines but with notable genotype differences. Mosaic expression was inherited into the T2 generation in which the majority of progenies tested exhibited a level of silencing similar to that of their T1 parental plants. However, in some T2 progenies segregation, evident as a decrease or increase in the proportion of fluorescent cells, was observed. We discuss several factors, such as copy number, promoter activity or polyploidy, that may be the possible causes of the gene silencing, but none sufficiently explain the appearance of the mosaic distribution.