Cryptic ins(4;11)(q21;q23q23) detected by fluorescence in situ hybridization: a variant of t(4;11)(q21;q23) in an infant with a precursor B-cell acute lymphoblastic leukemia report of a second case.

We report the chromosomal findings in a 4-year-old female with precursor B-cell acute lymphoblastic leukemia (ALL). The diagnostic karyotype showed an isochromosome 7q, i(7)(q10), as well as questionable rearrangements on 9p and 11q. Fluorescence in situ hybridization (FISH) studies on both interphase and metaphase cells using the MLL "break-apart" and the centromeric chromosome 4 probes were instrumental in the characterization of an MLL gene rearrangement, which was cryptic by conventional cytogenetic analysis. Specifically, the FISH pattern was consistent with an insertion of the 5' region of the MLL gene into chromosome 4 at band q21, most likely a variant t(4;11)(q21;q23). This is the second case of FISH detection of an ins(4;11) in ALL. Our case exemplifies the importance of FISH in the further characterization of precursor B-cell ALL cases without any apparent prognostically significant chromosomal abnormalities.

Redefining the risks of prenatally ascertained supernumerary marker chromosomes: a collaborative study.

BACKGROUND: A marker chromosome is defined as a structurally abnormal chromosome that cannot be identified by routine cytogenetics. The risk for phenotypic abnormalities associated with a marker chromosome depends on several factors, including inheritance, mode of ascertainment, chromosomal origin, and the morphology, content, and structure of the marker. METHODS: to understand the karyotype-phenotype relationship of prenatally ascertained supernumerary de novo marker chromosomes, we combined data from prenatal cases obtained from 12 laboratories with those from studies in the literature. We were able to obtain cytogenetic and phenotypic data from 108 prenatally ascertained supernumerary de novo marker chromosomes to refine the phenotypic risk associated with these markers. Because of the growing number of cases and because more techniques are available to delineate marker morphology, we have been able to group risk estimates into subcategories, such as by marker type and whether there are ultrasound abnormalities. RESULTS: If a de novo supernumerary marker chromosome is found prenatally, our data suggest there is a 26% risk for phenotypic abnormality when there is no other information defining the marker (such as chromosomal origin or information about the existing phenotype). However, if high resolution ultrasound studies are normal, this risk reduces to 18%. CONCLUSIONS: Our findings strongly support the value of additional genetic studies for more precisely defining the risk in individual cases involving marker chromosomes.

Origin of nondisjunction in trisomy 21 syndrome: all studies compiled, parental age analysis, and international comparisons.

The Q-band polymorphism of chromosome 21 permits assignment of the origin of meiotic nondisjunction by parent and meiotic division in a certain proportion of cases. We have compiled all reports through 1982 (including earlier studies using structural abnormality) and have shown that maternal origin accounts for 80% and paternal origin for 20% of trisomic cases. The ratio of first:second meiotic errors among the maternal cases was 80:20 and 60:40 among the paternal cases. Considering maternal and paternal first and second meiotic errors, we showed no differences of either mean maternal or paternal age, though mean maternal age is about 5 yr higher than that of the general population. Comparison of results of six studies from five countries showed similar frequencies by parent and meiotic division with the possible exception of one study from the northeastern United States. The causative role of simply advancing maternal age in nondisjunction is questioned.

Interstitial del(13q) associated with blindness and mental retardation.

Blindness due to congenital falciform retinal folds and severe mental retardation were present in a male with an interstitial deletion, 46,XY, del(13) (q31.2q32.3).

Five children with del (2)(q31q33) and one individual with dup (2)(q31q33) from a single family: review of brain, cardiac, and limb malformations.

Five matings to a dir ins (6;2)(q16;q31q33) carrier have produced a high frequency (42%) of offspring with unbalanced karyotypes. Five children have the derivative chromosome 2 resulting in del (2)(q31q33) and one individual received the derivative chromosome 6 leading to dup (2)(q31q33). The findings associated with the deletion include pre- and postnatal growth retardation, developmental delay, minor facial anomalies, seizures, complex structural heart defects, and limb deficiency. Autopsy of one individual showed complex brain malformations including hydrocephalus secondary to obstruction of the foramina of Monro, extensive heterotopias and polymicrogyria, and an unusual form of total anomalous pulmonary venous return. We compare the findings in these children to those of previously reported cases and construct an overview of the range of anomalies. Apparently, no other individual with dup (2)(q31q33) has been described. We compare the physical peculiarities of our patient with those of individuals with duplications of overlapping regions of 2q.

Neurologic manifestations in 18q- syndrome.

We report a mother and son with a deletion at 18q22.3. Both have the typical manifestations of the 18q- syndrome. In addition, both have an action tremor which became apparent in childhood. The mother subsequently developed chorea and dysmetria in late adolescence. Magnetic resonance imaging of their brains showed poor myelination of the central white matter tracts with relatively normal myelination of the corpus callosum. We propose that these neurologic findings are most likely due to a failure of expression of the myelin basic protein gene.

Molecularly defined interstitial tandem duplication 6p case with mild manifestations.

An interstitial tandem duplication of 6p21.1-p22.2 was found in a girl at 11 months of age when she was evaluated for developmental delay. Previous cases reported with partial 6p duplication usually have involved terminal duplications, with breakpoints ranging from 6p11 to 6p25. Our patient exhibits a milder phenotype compared to the previously reported cases in the literature. Features that she has in common with the other cases include craniofacial anomalies, such as broad nasal bridge and bulbous tip, thin lips, incomplete development of the scapha helix bilaterally, mild spastic paraparesis of the lower extremities, gross motor delay, and mild cognitive delays.

Clinical and molecular analyses of deletion 3p25-pter syndrome.

Hemizygous deletion of 3p25-pter is associated with a phenotype of profound growth failure, microcephaly, characteristic facial changes, and mental retardation. Since the severity may be quite variable, we have studied 3 cases of del 3p25-pter to define the clinical manifestations and the critical chromosome region for phenotypic expression. The patient we now report died at age 6 months and provided an opportunity for a detailed necropsy analysis for only the second time in a del(3p) patient. He had marked hypoplasia of all organs, hypomyelination of white matter, and multiple renal cortical microcysts. Ordered genomic markers from the distal regions of chromosome 3p aided in determining the parent of origin of each deletion and in defining the boundaries of the deleted chromosomal segments. The deleted markers distal to the RAF1 oncogene in 2 of the 3 patients were consistently hemizygous. One patient had an interstitial deletion based on evidence of diploid inheritance of one of the most distal loci (D3S17). Available genetic linkage maps suggest that the deletion spans at least 19 centimorgans (cM).

Malformations in a child with dup (7pter-p15.1) and del (7q36-qter) as a result of familial pericentric inversion.

We describe a child with multiple anomalies and severe retardation with dup 7pter-p15.1 and del 7q36-qter as a result of a parental pericentric inversion of chromosome 7. The pericentric inversion was found in family members in 3 generations with 9 liveborn children who had severe anomalies probably associated with imbalances of chromosome 7.

Increased frequency of lymphocytic mitotic non-disjunction in recurrent spontaneous aborters.

Hypermodal chromosomal spreads occurred significantly more frequently in lymphocytes from couples with recurrent spontaneous abortion than from comparison populations. Previously, we reported a similarly increased frequency in couples with aneuploid offspring. Considering the frequency of aneuploidy among first trimester spontaneous abortions, we suggest that there may be a sub-population of persons predisposed to non-disjunction among couples with reproductive wastage.

Dissociation of a t(12;21) resulting in a normal cell line in two trisomic 21 sons of a nonmosaic t(12;21) father?

A normal cell line arising from a translocation, t(12;21), possibly by dissociation, was observed in two brothers in early life. Each was conceived as trisomic 21 by their 45,XY,-12,-21,+t(12;21) father, who was phenotypically normal. Each brother showed morphologic manifestations of trisomy 21 syndrome, and each was mildly mentally retarded. Dermatoglyphic indices were not diagnostic of trisomy 21 syndrome. At 4 months the younger brother had a 50:50 proportion of trisomic:normal blood cells which became 25:75 of trisomic 21:normal at 36 months. The older brother had a 25:75 proportion of trisomic 21:normal when first studied at 41/2 years. A similar t(12;21) has not previously been reported. The occurrence of an apparently normal cell line arising spontaneously is unique.

46,XX, inv(6)(p21.1p23) in a pedigree with hereditary haemochromatosis.

Hereditary haemochromatosis (HFE) is a recessive genetic disease of iron overload which has been shown by linkage analysis to reside on the short arm of chromosome 6, close to the major histocompatibility complex (MHC). Positional cloning of the putative HFE locus has been hampered, in part, by the lack of a structural alteration on 6p. In this report, we describe a pedigree with HFE which carries a balanced paracentric inversion of chromosome 6, inv(6)(p21.1p23), a rarely reported chromosomal rearrangement in this region. We have determined the inheritance of the chromosome harbouring the inversion, which segregates as an HFE chromosome. Because the HFE locus has been mapped distal to the HLA-F class I locus at 6p21.3, the breakpoints associated with this chromosomal rearrangement may provide a significant genomic landmark for positional cloning of the HFE gene.

Un caso de leucemia aguda linfocítica (ALL), tipo B con un inusual rearreglo cromosómico / A case of acute lymphocytic leukemia (ALL), B with an unusual type chromosomal rearrangement

Presentamos los hallazgos cromosómicos de una mujer de cuatro años de edad con trombocitopenia. El cariotipo demostró un 1(7) q(10) como una posible deleción en 11q23 y un cuestionable rearreglo en 9p. Los estudios por FISH de ambas interfase del núcleo y metafase de la célula, usando la fase de reposo MLL y caracterización de la prueba instrumental en el gen MLL, el cual fue encriptado por análisis citogenético convencional. Específicamente, el patrón FISH fue consistente con una inserción de la región 5' del gen MLL dentro de un cromosoma 4 hacia la banda q21, mas estrechamente una variante 1(4;11) (q 21;g23). Este caso ejemplifica la importancia del FISH y su consiguiente caracterización de casos precursores B-cell all, sin algún significado pronóstico de anormalidad cromosómica.

We present the chromosome findings in a 4-year-old female with thrombocytopenia. The karyotype showed an i(7)(q10) as well as a possible deletion on 11q23 and a questionable rearrangement on 9p. FISH studies on both interphase nuclei and metaphase cells using the MLL break apart rearrangement probe were instrumental in the characterization of an MLL gene rearrangement , which was cryptic by conventional cytogenetic analysis. Specifically, the FISH pattern was consistent with an insertion of the 5' region of the MLL gene into one chromosome 4 at band q21, most likely a variant t(4;11)(q21;q23). This case exemplifies the importance of FISH in the further characterization of precursor B-cell ALL cases without any apparent prognostically significant chromosome abnormalities.