Interstitial 2q24.2q24.3 Microdeletion: Two New Cases with Similar Clinical Features with the Exception of Profound Deafness.

Interstitial 2q24.2q24.3 microdeletions are rare cytogenetic aberrations associated with heterogeneous clinical features depending on the size of the deletion. Here, we describe 2 patients with overlapping de novo 2q24.2q24.3 deletions, characterized by array-CGH. This is the smallest 2q24.2q24.3 region of overlap described in the literature encompassing only 9 genes (SLC4A10, DPP4, GCG, FAP, IFIH1, GCA, KCNH7, FIGN, GRB14). We focused our attention on SLC4A10, DPP4, and KCNH7, genes associated with neurological features. Our patients presented similar features: intellectual disability, developmental and language delay, hypotonia, joint laxity, and dysmorphic features. Only patient 2 showed profound deafness and also carried a heterozygous mutation of the GJB2 gene responsible for autosomal recessive deafness 1A (DFNB1A: OMIM 220290). Could the disruption of a gene present in the 2q24.2q24.3 deleted region be responsible for her profound hearing loss?

Familial ROBO1 deletion associated with ectopic posterior pituitary, duplication of the pituitary stalk and anterior pituitary hypoplasia.

Background The genetic causes of abnormal pituitary development have been extensively studied in the last few years. ROBO1 is involved in neurogenesis and axon guidance. Loss-of-function variants in ROBO1 have been associated with pituitary stalk interruption syndrome (PSIS), suggesting that its haploinsufficiency could impair the guidance of hypothalamic axons to the pituitary gland leading to developmental abnormalities. Case presentation We report a 4.5-year-old girl with anterior pituitary hypoplasia and pituitary stalk duplication in the ventral-dorsal direction. Her father had a similar pituitary phenotype, characterized by anterior pituitary hypoplasia combined with ectopic posterior pituitary. Comparative genomic hybridization (CGH) microarray analysis identified a 343.7 kb deletion of 3p12.3 encompassing ROBO1 in both individuals. Conclusions We report the first familial ROBO1 deletion in two individuals with peculiar pituitary anomalies, including the rare pituitary stalk duplication in the ventral-dorsal direction. These findings widen the spectrum of the phenotypes associated with ROBO1 haploinsufficiency and support its role in human pituitary development.

Loss of tubulin deglutamylase CCP1 causes infantile-onset neurodegeneration.

A set of glutamylases and deglutamylases controls levels of tubulin polyglutamylation, a prominent post-translational modification of neuronal microtubules. Defective tubulin polyglutamylation was first linked to neurodegeneration in the Purkinje cell degeneration (pcd) mouse, which lacks deglutamylase CCP1, displays massive cerebellar atrophy, and accumulates abnormally glutamylated tubulin in degenerating neurons. We found biallelic rare and damaging variants in the gene encoding CCP1 in 13 individuals with infantile-onset neurodegeneration and confirmed the absence of functional CCP1 along with dysregulated tubulin polyglutamylation. The human disease mainly affected the cerebellum, spinal motor neurons, and peripheral nerves. We also demonstrate previously unrecognized peripheral nerve and spinal motor neuron degeneration in pcd mice, which thus recapitulated key features of the human disease. Our findings link human neurodegeneration to tubulin polyglutamylation, entailing this post-translational modification as a potential target for drug development for neurodegenerative disorders.

Characterization of the Phenotype Associated with Microduplication Reciprocal to NF1 Microdeletion Syndrome.

17q11.2 microduplication syndrome is a recently described relatively rare condition associated with a nonspecific phenotype. Intellectual disability, developmental delay, and dysmorphisms are the only clinical features common to a majority of cases. Seventeen patients have been reported so far. Here, we present another patient with 17q11.2 duplication and no signs of neurofibromatosis type 1, identified by array-CGH. We compared clinical features and genetic data with those of previously reported patients with 17q11.2 microduplications. We also analyzed the gene content of the duplicated region in order to investigate the possible role of specific genes in the clinical phenotype of our patient.

Interstitial 9p24.3 deletion involving only DOCK8 and KANK1 genes in two patients with non-overlapping phenotypic traits.

Chromosome 9p deletion represents a clinically and genetically heterogeneous condition characterized by a wide spectrum of phenotypic manifestations and a variable size of the deleted region. The deletion breakpoint occurs from 9p22 to 9p24 bands, and the large majority of cases have either terminal deletions or translocations involving another chromosome. Here we report on two patients with similar inherited interstitial 9p24.3 deletion involving only DOCK8 and KANK1 genes. Interestingly, the two patients showed non-overlapping phenotypic traits ranging from a complex phenotype in one to only trigonocephaly with minor dysmorphic features and hand anomalies in the other one. The factors underlying the phenotypic variation associated with seemingly identical genomic alterations are not entirely clear, even if smaller variants, single-nucleotide changes, and epigenetic or stochastic factors altering the expression of genes within functionally relevant pathways have been recently shown to contribute to phenotypic variation. We discuss the role of the two genes and propose possible explanations for the clinical heterogeneity of the phenotype of the two patients.

Association of achondroplasia with sagittal synostosis and scaphocephaly in two patients, an underestimated condition?

We report on two patients with an unusual combination of achondroplasia and surgically treated sagittal synostosis and scaphocephaly. The most common achondroplasia mutation, p.Gly380Arg in fibroblast growth factor receptor 3 (FGFR3), was detected in both patients. Molecular genetic testing of FGFR1, FGFR2, FGFR3 and TWIST1 genes failed to detect any additional mutations. There are several reports of achondroplasia with associated craniosynostosis, but no other cases of scaphocephaly in children with achondroplasia have been described. Recently it has been demonstrated that FGFR3 mutations affect not only endochondral ossification but also membranous ossification, providing new explanations for the craniofacial hallmarks in achondroplasia. Our report suggests that the association of isolated scaphocephaly and other craniosynostoses with achondroplasia may be under recognized.

Constitutional chromosomal events at 22q11 and 15q26 in a child with a pilocytic astrocytoma of the spinal cord.

We report on a 9-years-old patient with mild intellectual disability, facial dimorphisms, bilateral semicircular canal dysplasia, periventricular nodular heterotopias, bilateral hippocampal malrotation and abnormal cerebellar foliation, who developed mild motor impairment and gait disorder due to a pilocytic astrocytoma of the spinal cord. Array-CGH analysis revealed two paternal inherited chromosomal events: a 484.3 Kb duplication on chromosome 15q26.3 and a 247 Kb deletion on 22q11.23. Further, a second de novo 1.5 Mb deletion on 22q11.21 occurred. Chromosome 22 at q11.2 and chromosome 15 at q24q26 are considered unstable regions subjected to copy number variations, i.e. structural alterations of genome, mediated by low copy repeat sequences or segmental duplications. The link between some structural CNVs, which compromise fundamental processes controlling DNA stability, and genomic disorders suggest a plausible scenario for cancer predisposition. Evaluation of the genes at the breakpoints cannot account simultaneously for the phenotype and tumour development in this patient. The two paternal inherited CNVs arguably are not pathogenic and do not contribute to the clinical manifestations. Similarly, although the de novo large deletion at 22q11.21 overlaps with the Di George (DGS) critical region and results in haploinsufficiency of genes compromising critical processes for DNA stability, this case lacks several hallmarks of DGS.

Identification of a rare 17p13.3 duplication including the BHLHA9 and YWHAE genes in a family with developmental delay and behavioural problems.

BACKGROUND: Deletions and duplications of the PAFAH1B1 and YWHAE genes in 17p13.3 are associated with different clinical phenotypes. In particular, deletion of PAFAH1B1 causes isolated lissencephaly while deletions involving both PAFAH1B1 and YWHAE cause Miller-Dieker syndrome. Isolated duplications of PAFAH1B1 have been associated with mild developmental delay and hypotonia, while isolated duplications of YWHAE have been associated with autism. In particular, different dysmorphic features associated with PAFAH1B1 or YWHAE duplication have suggested the need to classify the patient clinical features in two groups according to which gene is involved in the chromosomal duplication. METHODS: We analyze the proband and his family by classical cytogenetic and array-CGH analyses. The putative rearrangement was confirmed by fluorescence in situ hybridization. RESULTS: We have identified a family segregating a 17p13.3 duplication extending 329.5 kilobases by FISH and array-CGH involving the YWHAE gene, but not PAFAH1B1, affected by a mild dysmorphic phenotype with associated autism and mental retardation. We propose that BHLHA9, YWHAE, and CRK genes contribute to the phenotype of our patient. The small chromosomal duplication was inherited from his mother who was affected by a bipolar and borderline disorder and was alcohol addicted. CONCLUSIONS: We report an additional familial case of small 17p13.3 chromosomal duplication including only BHLHA9, YWHAE, and CRK genes. Our observation and further cases with similar microduplications are expected to be diagnosed, and will help better characterise the clinical spectrum of phenotypes associated with 17p13.3 microduplications.

New recurrent chromosome change in pediatric therapy-related myelodysplastic syndrome: unbalanced translocation 1/6 with cryptic duplication of short arm of chromosome 6.

The incidence of therapy-related myelodysplastic syndrome (t-MDS) in pediatric patients is increasing in parallel with the more successful management of the primary tumor, but scant information is available on clinical and cytogenetic characteristics. We report here two children affected by t-MDS after chemo/radiotherapy for a primary solid tumor, both with an unbalanced translocation 1/6 in their bone marrow. Characterization by array comparative genomic hybridization of the imbalances showed an almost identical pattern: almost complete trisomy of the long arm of chromosome 1, and a terminal deletion and interstitial duplication of the short arm of chromosome 6. The gain of chromosome 6 short arm encompasses regions already highlighted as possibly relevant for t-MDS in adults, and we suggest that the unbalanced translocation reported here be considered a new recurrent, non-random chromosomal abnormality in pediatric patients with t-MDS.

Monosomal complex karyotype in pediatric mixed phenotype acute leukemia.

We report on a pediatric case of mixed phenotype acute leukemia with myeloid and T-lymphoid differentiation, a single myeloblastic cell population, and a monosomal complex karyotype. The patient, a 5-year-old girl, responded to acute myeloid leukemia-oriented therapy that was decided based on the morphological appearance of blast cells. In this study, we analyzed the patient's peculiar chromosomal abnormalities, as evaluated by array comparative genomic hybridization in combination with multicolor fluorescence in situ hybridization and cytogenetic analyses.

Trisomy 17 in congenital plexiform (multinodular) cellular schwannoma.

Plexiform (multinodular) cellular schwannomas are rare tumors, not associated with neurofibromatosis type 1, that occur more often in children and can be congenital. Their biology is benign and is characterized by the tendency to recur locally without being metastatic. Cytogenetic studies in adult cases of schwannoma indicate a complete or partial loss of chromosome 22 as the most common abnormality. Only two cytogenetic studies describe cases in children, one of which concerned a congenital cellular plexiform schwannoma. Here, we report the cytogenetic analysis of a second case in an 8-month-old boy with recurrence of trisomy 17.

Cytogenetic characterization of a fibrous hamartoma of infancy with complex translocations.

Fibrous hamartoma of infancy is a rare pediatric superficial soft tissue lesion. The diagnosis depends on microscopic examination. Conventional cytogenetic analysis has been reported in only two previous cases, which showed apparently balanced translocations with involvement of different chromosomes. In the present study, we used multicolor fluorescence in situ hybridization to characterize a case of fibrous hamartoma of infancy that had arisen in an unusual location. This molecular analysis revealed complex structural rearrangements involving chromosomes 1, 2, 4, and 17.

MicroRNA-125b-1 and BLID upregulation resulting from a novel IGH translocation in childhood B-Cell precursor acute lymphoblastic leukemia.

Chromosomal translocations involving the immunoglobulin heavy chain (IGH) locus are common abnormalities in mature B-cell neoplasms. Recent findings have also revealed their significant role in B-cell precursor acute lymphoblastic leukemia. As a rule, IGH translocations generate transcriptional activation of the oncogene localized in the proximity of the breakpoint. In this study, we describe a pediatric case of B-cell precursor acute lymphoblastic leukemia showing microRNA-125b-1 (MIR125B1) and BLID gene overexpression, resulting from a novel t(11;14)(q24.1;q32) translocation involving IGH. This is the first report describing the upregulation of a microRNA due to its juxtaposition to protein-coding gene regulatory elements and the overexpression of two neighboring genes as a consequence of transcriptional enhancers localized in the vicinity of the IGH gene.

Differential diagnosis of lipoma-like lipoblastoma.

Lipoblastomas are rare benign tumors of white fatty tissue that occur primarily in young children. Occasionally, heterogeneity of morphological appearance and histological overlap with other lipogenic tumors are described. In such cases fluorescence in situ hybridization (FISH) analysis of PLAG1, a gene specifically rearranged in lipoblastoma, is necessary to prevent misdiagnosis. We present a case of lipoblastoma arising in an atypical site with histological features characteristic of lipoma. The correct diagnosis was made possible on cytogenetic grounds through the identification of the characteristic PLAG1-HAS2 fusion gene, thus allowing an appropriate clinical approach.

Inversion (11)(p15q22) with NUP98-DDX10 fusion gene in pediatric acute myeloid leukemia.

The inv(11)(p15q22), a rare but recurrent chromosome abnormality that creates a NUP98-DDX10 fusion gene, is associated with de novo or secondary myeloid malignancies. We report a case of acute monocytic leukemia presenting this rearrangement, studied using fluorescence in situ hybridization (FISH) and reverse transcriptase-PCR (RT-PCR). We also review the cases of inv(11) associated with NUP98-DDX10 reported in the literature.

Gain of 1q in pediatric myelodysplastic syndromes.

The presence of acquired clonal cytogenetic abnormalities in hematopoietic cells is one of the diagnostic hallmarks of myelodysplastic syndromes (MDS). Such anomalies may help in defining prognostic groups. We analyzed eight pediatric MDS, and herein describe three new cases, one de novo and two therapy-related, presenting an unbalanced rearrangement of 1q: one of them resulted in a derivative chromosome 6 apparently identical to a previously described one. We also review all the cases of gain of 1q reported in de novo and therapy-related childhood MDS.

MLL-MLLT10 fusion gene in pediatric acute megakaryoblastic leukemia.

The occurrence of MLL gene rearrangement in acute megakaryoblastic leukemia (AML-M7, acute myeloid leukemia, French-American-British type M7) is very rare and limited to pediatric age: in particular, MLL-MLLT10 fusion, previously reported as characteristic of monocytic leukemia, has been reported in only one case of pediatric megakaryoblastic leukemia. We describe the second case with this association in light of the few reported cases of AML-M7 with MLL and/or 11q23 involvement.

t(9;11)(p22;p15) with NUP98-LEDGF fusion gene in pediatric acute myeloid leukemia.

The rare t(9;11)(p22;p15) translocation is associated with adult acute myeloid leukemia (AML) with immature forms. We report a novel fusion of the NUP98 and LEDGF genes in a pediatric AML with intermediate characteristics between M2-M3 French-American-British (FAB) subtypes exhibiting the same chromosomal rearrangement. Fluorescence in situ hybridization (FISH) and reverse transcriptase-PCR (RT-PCR) studies identified the chimeric transcript product of in-frame fusion of NUP98 exon 8 to LEDGF exon 4.