Aneuploidy identification in pre-B acute lymphoblastic leukemia patients at diagnosis by Multiplex Ligation-dependent Probe Amplification (MLPA).

Three-quarters of the patients with acute lymphoblastic leukemia (ALL), show numerical or structural chromosomal alterations, which are important factors in leukemogenesis. The use of Multiplex Ligation-dependent Probes Amplification (MLPA) has been mainly limited for searching copy number alterations of genes, suggesting that MLPA could detect numerical alterations in cancer. However, the use of MLPA in pediatrics to analyze subtelomeric sequences for aneuploidy detection has not been considered in previous studies. The aim of this study was to identify aneuploidy for the first time using MLPA and correlate the results with karyotype and DNA-index (DI), from preB ALL patients. Forty-two bone marrow samples were analyzed by cytogenetics and flow cytometry to determine the DI. The chromosomal gains and/or losses were detected by the SALSA MLPA P036 Subtelomere Mix 1 probemix®. The chromosomal number matched in 36 out of 42 samples between MLPA and karyotype (R2=0.7829, p=3.7×10-10), 18/42 between MLPA and DI (R2=0.1556, p=0.023), and 20/42 between karyotype and DI (R2=0.1509, p=0.015). MLPA results correlated with karyotype and DI. The use of MLPA led us to identify a gained marker chromosome. Our results indicate that MLPA could be a useful and fast alternative tool for aneuploidy identification in pediatric leukemia.

Compound heterozygous mutations in the IFT140 gene cause Opitz trigonocephaly C syndrome in a patient with typical features of a ciliopathy.

〈 We report on an infant with Opitz trigonocephaly C syndrome (OTCS), who also had manifestations of ciliopathy, including short ribs (non-asphyxiating), trident acetabular roofs, postaxial polydactyly cone-shaped epiphyses, and dysplasia of the renal, hepatic and pancreatic tissues. To investigate the molecular cause, we used an exome sequencing strategy followed by Sanger sequencing. Two rare variants, both predicted to result in loss of functional protein, were identified in the IFT140 gene; a substitution at the splice donor site of exon 24 (c.723 + 1 G > T) and a 17 bp deletion, impacting the first coding exon (c.-11_6del). The variants were confirmed as being biallelic using Sanger sequencing, showing that the splice variant was inherited from the propositus mother and the deletion from the father. To date, Mainzer-Saldino syndrome, Jeune syndrome, and a form of nonsyndromic retinal dystrophy, have been identified as ciliopathies caused by IFT140 mutations. We provide the first description of an OTCS phenotype that appears to result from IFT140 mutations. The presentation of this patient is consistent with previous reports showing that OTCS already exhibited skeleletal and nonskeletal features of a ciliopathy.

Variantes fenotípicas menores en pacientes con leucemia linfoblástica aguda del occidente de México / Minor phenotypic variants in patients with acute lymphoblastic leukemia from west México

INTRODUCCIÓN: La leucemia linfoblástica aguda (LLA) se ha asociado a un exceso de variantes fenotípicas menores (VFM), que incluyen las variantes comunes y las anomalías menores, indicadoras de una fenogénesis alterada. El objetivo fue determinar la asociación entre VFM y LLA. PACIENTES Y MÉTODOS: Estudio de casos y controles basado en hospital de 120 niños con LLA y 120 niños sanos como grupo control, emparejados por edad y sexo, atendidos en el Hospital Civil de Guadalajara Dr. Juan I. Menchaca (México). En ambos grupos, se realizaron 28 mediciones antropométricas y la búsqueda sistemática de un listado de 405 VFM mediante un examen físico minucioso. Se estimaron las odds ratio ajustadas (ORa) con sus variables intervinientes por regresión logística. El intervalo de confianza fue del 95% (IC del 95%). RESULTADOS: Los signos antropométricos asociados con LLA fueron: segmento superior largo (ORa = 2,19; IC del 95%, 1,01-4,76), mandíbula ancha (ORa = 2,62; IC del 95%, 1,29-5,30), pabellones estrechos (ORa = 6,22, IC95%: 2,60-14,85) y teletelia (ORa = 2,53; IC del 95%m 1,07-5,98). Las VFM hipoplasia mesofacial, frente ancha, nariz pequeña, columnela corta, pabellones estrechos, teletelia, línea Sídney, pie griego y manchas café con leche (MCL) tuvieron una frecuencia de 3 a 17 veces mayor en los ninos ˜ con LLA. Por número, encontramos asociación a partir de ≥ 4 VFM (ORa = 2,14; IC del 95%, 1,25-3,66; p = 0,004). CONCLUSIONES: A partir de ≥ 4 VFM, se encontró asociación con LLA, lo que indica la existencia de factores prenatales en la fenogénesis y leucemogénesis. Confirmamos las MCL y la línea Sídney como VFM asociada a niños con LLA

INTRODUCTION: Acute lymphoblastic leukemia (ALL) has been associated with an excess of minor phenotypic variants (MPV), including common variants and minor anomalies, indicative of an altered phenogenesis. The objective of the study was to determine the association between MPV and ALL. PATIENTS AND METHODS: In a hospital based case-control study, we studied 120 children with ALL (including standard and high risk) and 120 healthy children as a control group, matched for age and sex, seen in the Hospital Civil de Guadalajara Dr. Juan I. Menchaca (Guadalajara, Mexico). In both groups, 28 anthropometric measurements were made, as well as a systematic search for 405 MPV, through a physical examination. Adjusted odds ratio was estimated (aOR) with its intervening variables by logistic regression. The confidence interval was 95% (95%CI). RESULTS: Anthropometric signs associated with ALL were: long upper segment (aOR= 2.19, 95%CI: 1.01-4.76), broad jaw (aOR= 2.62, 95%CI: 1.29-5.30), narrow ears (aOR= 6.22, 95%CI: 2.60- 14.85), and increase in internipple distance (aOR= 2.53, 95%CI: 1.07-5.98). The hypoplasia mesofacial, broad forehead, small nose, short columella, narrow ears, telethelia, Sydney crease (SC), Greek type feet and café-au-lait spots (CALS), had a 3 to 17 times higher frequency in children with ALL. By number, an association was found from ≥4 MPV (aOR= 2.14, 95%CI: 1.25-3.66, P=.004). CONCLUSIONS: From ≥4 MPV, an association was found with ALL, suggesting prenatal factors in phenogenesis and leukemogenesis. CALS and SC were confirmed as MPV in children with ALL

[Minor phenotypic variants in patients with acute lymphoblastic leukemia from west Mexico]. / Variantes fenotípicas menores en pacientes con leucemia linfoblástica aguda del occidente de México.

INTRODUCTION: Acute lymphoblastic leukemia (ALL) has been associated with an excess of minor phenotypic variants (MPV), including common variants and minor anomalies, indicative of an altered phenogenesis. The objective of the study was to determine the association between MPV and ALL. PATIENTS AND METHODS: In a hospital based case-control study, we studied 120 children with ALL (including standard and high risk) and 120 healthy children as a control group, matched for age and sex, seen in the Hospital Civil de Guadalajara Dr. Juan I. Menchaca (Guadalajara, Mexico). In both groups, 28 anthropometric measurements were made, as well as a systematic search for 405 MPV, through a physical examination. Adjusted odds ratio was estimated (aOR) with its intervening variables by logistic regression. The confidence interval was 95% (95%CI). RESULTS: Anthropometric signs associated with ALL were: long upper segment (aOR= 2.19, 95%CI: 1.01-4.76), broad jaw (aOR= 2.62, 95%CI: 1.29-5.30), narrow ears (aOR= 6.22, 95%CI: 2.60-14.85), and increase in internipple distance (aOR= 2.53, 95%CI: 1.07-5.98). The hypoplasia mesofacial, broad forehead, small nose, short columella, narrow ears, telethelia, Sydney crease (SC), Greek type feet and café-au-lait spots (CALS), had a 3 to 17 times higher frequency in children with ALL. By number, an association was found from ≥4 MPV (aOR= 2.14, 95%CI: 1.25-3.66, P=.004). CONCLUSIONS: From ≥4 MPV, an association was found with ALL, suggesting prenatal factors in phenogenesis and leukemogenesis. CALS and SC were confirmed as MPV in children with ALL.

Dysgnathia complex sine holoprosencephaly nor synotia: a case report and discussion of its nosology.

A severe mandibular hypoplasia and microstomy with intraoral anomalies including hypoglossia, fused gums, persistence of buccopharyngeal membrane, and laryngeal hypoplasia were noted in a female newborn with the dysgnathia complex (DC). Additionally, our proposita also presented natal teeth as a probably new finding. These clinical manifestations overlapped with those of the fourth report of hypomandibular faciocranial syndrome (HFS) (31), and given that both lack for craniosynostosis (pathognomonic of HFS), we considered that both represent a subtype of DC proposed as DC sine holoprosencephaly nor synotia (DCSHS). Differential characteristics between the DCSHS, the HFS, and the DC with holoprosencephaly sine synotia are reviewed and additionally, we discussed some aspects about the nosology of the DC.

Angelman syndrome and thyroid dysfunction.

Angelman syndrome (AS) is a neurogenetic syndrome, has a prevalence of 1:10,000 to 1:40,000. Patients with AS have genetic alterations in maternal imprinting gene UB3A (15q11-q13) and molecular evaluations confirm the diagnosis. Our aim is to report a new case with AS and subclinical hypothyroidism (SCH) without goiter. Thyroid dysfunction has not been described as part of alterations in AS; the exact pathogenic mechanisms of SCH in patients with AS remains incompletely unknown.

Chromosome instability in a patient with recurrent abortions.

Chromosomal aberrations are one of the recognized possible etiologic genetic causes of recurrent spontaneous abortions. Increased chromosome instability without constitutional chromosome abnormalities is uncommon in these couples. In this work we present a non consanguineous healthy couple with recurrent abortions without constitutional chromosome aberrations in which spontaneous and induced chromosome aberrations were observed in the female. Chromosome analysis was performed in the presence of different chromosome damage inductors such as gamma radiation, Uv light, and mitomycin-C. Alterations observed only in the female were: spontaneous and induced tetraradial chromosomes and increased chromosomal damage induced only by gamma radiation. Oral mucosa micronuclei were moderately increased in the female. Chromosome instability associated to abortion is proposed.

Cytotoxic effect of curcumin on Giardia lamblia trophozoites.

Giardia lamblia is one of the most important worldwide causes of intestinal infections produced by protozoa. Thus, the search for new alternative therapeutic approaches for this parasitic disease is very important. Common drugs used to control and eradicate this infection, frequently exhibit side effects that force patients to abandon treatment. The present work evaluates the anti-protozoan activity of curcumin, the main constituent of turmeric. Axenic G. lamblia (Portland 1 strain) cultures were exposed to different concentrations of curcumin. Its effects were evaluated on parasite growth, adhesion capacity and parasite morphology. We also evaluated the capacity of curcumin to induce an apoptosis-like effect. All curcumin concentrations inhibited trophozoite growth and adhesion in more than 50% in dose and time dependent manner. Morphological changes were described as protrusions formed under the cytoplasmic membrane, deformation due to swelling and cell agglutination. Curcumin induced apoptosis-like nuclear staining in dose and time dependent manner. In conclusion, curcumin exhibited a cytotoxic effect in G. lamblia inhibiting the parasite growth and adherent capacity, induced morphological alterations, provoked apoptosis-like changes. Future in vitro and in vivo experiments are endowed to elucidate the effect of curcumin in an experimental model of G. lamblia infection, analyze the involvement of ion channels in the swelling effect of curcumin during an apparent osmotic deregulation in G. lamblia trophozoites. This will lead to the proposal of the action mechanism of curcumin as well as the description of mechanism involved during the activation process for the apoptotic-like effect.

Cleft lip and/or palate in two cases of 46,X,i(Xq) Turner syndrome.

Cleft lip (CL) and/or palate (CP) are uncommon anomalies in Turner syndrome (TS) series. We report two unrelated sporadic 46,X,i(Xq) patients exhibiting orofacial clefts and a peculiar facial appearance masking the clinical diagnosis. CL, and CP in case 1 and CP in case 2, though non-specific of TS, may not be fortuitous findings. The increased frequency of CP and bifid uvula in poly X syndromes, the dermatoglyphic similarities between iXq TS and X polysomies, and the occurrence of Klinefelter phenotype when extra Xq material is present in a male, are all indirect evidences suggesting that Xq material cannot be considered phenotipically inert and facial clefts found in our patients may be syndromal manifestation of trisomic Xq dosage.

Report and review of the fetal brain disruption sequence.

UNLABELLED: The fetal brain disruption sequence (FBDS), a rare cause of extreme microcephaly, is described in a patient and compared with 19 previously reported cases. Clinical findings present in almost all patients included: severe microcephaly (average occipitofrontal circumference -5.8 SD), overlapping sutures, prominent occipital bone, scalp rugae with normal hair patterning and marked neurological impairment. Early death occurred in 7/20 cases. The FBDS was sporadic in 17 out of 19 reported cases supporting a low recurrence risk for genetic counselling purposes. A group of related observations in cases were thromboembolic phenomenon following death of the co-twin, vascular and/or haematological involvement by prenatal cytomegalovirus infection, prenatal cocaine exposure, direct vascular fetal trauma (cordocentesis) and fetal vascular changes after a maternal car accident causing intracranial bleeding and brain damage. Normal scalp hair pattern in all cases and the second or third trimester location of the disruptive event in two cases suggest that in the FBDS, brain growth is normal throughout the first 18 weeks of gestation at least. CONCLUSION: Pathogenic factors suggest that different forms of vascular injury to the fetal brain (emboli, haemorrhage, vasoconstriction, disseminated intravascular coagulation) can produce partial brain destruction, diminished intracranial pression and skull collapse in the fetal brain disruption sequence.

Holoprosencephaly, hypertelorism, and ectrodactyly in a boy with an apparently balanced de novo t(2;4) (q14.2;q35).

A holoprosencephaly, hypertelorism, and ectrodactyly syndrome (HHES) was described in three previous cases in whom chromosomes were apparently normal. We report on a 3-year-old boy with HHES and a de novo apparently balanced t(2;4)(q14.2;q35) confirmed by fluorescent in situ hybridization. He had severe growth and mental retardation, lobar holoprosencephaly, hypertelorism, microphthalmos, and iris, choroid, and retina colobomata. Less-severe facial involvement correlates with the semilobar type of holoprosencephaly; limb defects consisted of foot ectrodactyly and syndactyly. All previous HHES cases were sporadic and of unknown cause. A cryptic imbalance secondary to the translocation (2;4) in our patient may explain the phenotype.

Corroboration of the lower extremity counterpart of the Poland sequence.

Gluteal and lower extremity hypoplasia with ipsilateral toe brachysyndactyly were noted in a 23-year-old woman similarly affected to the only previously reported case of the lower extremity counterpart of Poland sequence. Since no neurological deficit was found, and electromyographic and nerve conduction studies in the affected limb were normal, we propose a vascular origin which would involve the external iliac artery supply analogous to the subclavian artery supply disruption in the upper extremity Poland sequence.

Unusual presentation of heteropagus attached to the thorax.

The endoparasitic twin is the most common form of asymmetric fetal duplication (heteropagus). A 2-month-old girl who had a parasitic right lower limb with axial skeleton, vertebral column, uterus, fallopian tube, ovary, and bladder implanted in the sternum region is described as another example of exoparasitic twin, the uncommon form of heteropagus. Unusually, dextrocardia was found in the autosite. This report emphasizes the even progression between the endoparasitic and exoparasitic forms of heteropagus.