Dr. R. J. McKinlay Gardner Interviewed by Dr. Hon Fong L. Mark.

Dr. Mac Gardner graduated in medicine from the University of Otago, Dunedin, New Zealand in 1968. After hospital residencies he undertook training in clinical genetics in New Zealand, and then the U.K., France and Canada. He returned to New Zealand as a specialist in genetics in 1977, but for the past 14 years he has been a consultant in medical genetics with Genetic Health Services Victoria in Melbourne, Australia.

In situ follicular lymphoma with a 14;18 translocation diagnosed by a multimodal approach.

The main differential diagnosis for follicular lymphoma (FL, or in situ localization of follicular lymphoma) is follicular hyperplasia. However, this differentiation is quite challenging when the initial presentation of FL is in one lymph node and such a lymph node is only partially involved. In other words, only a few lymphomatous follicles are present in an otherwise nodal reactive follicular hyperplasia. The use of FISH on formalin-fixed, paraffin-embedded tissue as an adjunct to routine histomorphological and immunohistochemical evaluation is valuable for reaching an initial diagnosis of in situ follicular lymphoma in a lymph node which shows predominantly reactive follicular hyperplasia. In this report, we describe our experience in rendering such an initial diagnosis of in situ FL in an apparently healthy individual who has a single persistently enlarged lymph node. The recognition of in situ FL is of utmost importance because it is associated with localized early stage disease (stage I), which according to standard regimens is amenable to local radiation therapy with a good chance for inducing remission. To the best of our knowledge, this is the first such case reported in the English literature using innovative FISH technology on formalin-fixed, paraffin-embedded tissue in conjunction with other routine histological modalities to produce an initial diagnosis of in situ follicular lymphoma.

A de novo complex chromosome rearrangement involving chromosomes 2, 3, 5, 9 and 11 detected prenatally and studied postnatally by conventional cytogenetics and molecular cytogenetic analyses.

OBJECTIVE: To describe a de novo complex chromosome rearrangement(CCR) detected prenatally and studied afterbirth. METHODS: Conventional cytogenetics and fluorescent in situ hybridization (FISH) were performed on amniotic fluid and peripheral blood. High-resolution comparative genomic hybridization (HR-CGH) analysis was made postnatally. RESULTS: Prenatal/postnatal cytogenetic, FISH and HR-CGH analyses revealed an apparently balanced de novo CCR ascertained as 46,XY,t(2; 3;9)(q21;p24;q22),der(5)inv(5)(?p11q13)t(5; 11)(?p13;q25),ins(5; 3)(?p13;?p23p24). At 9 months,the child has neither congenital anomalies nor evidence of delayed psychomotor development. CONCLUSIONS: Our report describes a rare CCR detected prenatally and shows the usefulness of FISH and CGH in complementing conventional cytogenetics.

Chronic idiopathic myelofibrosis (CIMF) resulting from a unique 3;9 translocation disrupting the janus kinase 2 (JAK2) gene.

We report a case of t(3;9)(q21;p24) in a patient with chronic idiopathic myelofibrosis (CIMF), a chronic myeloproliferative disorder (CMPD), initially detected by G-banding and fluorescent in situ hybridization (FISH) in an unstimulated culture of peripheral blood. Subsequent cytogenetic studies of bone marrow aspirates showed the presence and persistence of the same translocation. No additional cytogenetic abnormalities were found. This appears to be a unique translocation that has not been previously reported in the English literature, although both breakpoints, 3q21 and 9p24, are well known cancer-related breakpoints. The former is the mapped location of the ribophorin 1 (RPN1) gene, whereas the latter is the mapped location of the janus kinase 2 (JAK2) gene. This raises the possibility that disruption of one or both loci at the breakpoints of the presently described structural chromosomal rearrangement may be the primary event leading to the initiation and development of the hematopoietic disorder in this patient. It is not unreasonable to hypothesize that the juxtaposition of the RPN1 gene on 3q21 with the JAK2 gene on 9p24 leads to enhanced JAK2 activity. Additional studies will be needed to provide further support for or to disprove this hypothesis. To the best of our knowledge, this is the first reported case of CIMF associated with a reciprocal 3;9 translocation with the 3q21 and 9p24 breakpoints. The elucidation of the mechanism of leukemogenesis in CIMF may one day lead to successful targeted therapy in this hematopoietic disorder. It may also shed additional light on the diagnosis, prognosis and treatment of certain other cancers with similar genetic etiologies.

Acute lymphoblastic leukemia with 4;11 translocation analyzed by a multi-modal strategy of conventional cytogenetics, FISH, morphology, flow cytometry and molecular genetics, and review of the literature.

We report a case of acute lymphoblastic leukemia (ALL) with a 4;11 translocation. Metaphase cells and interphase nuclei derived from a routine unstimulated culture of bone marrow were analyzed using a combined strategy of G-banding and fluorescent in situ hybridization (FISH) in addition to hematopathological analysis, flow cytometry, and molecular genetics. This multimodal approach enables a successful correlation of pathology and cytogenetics to support a comprehensive diagnosis of the patient. Meaningful prognostication and appropriate therapeutic considerations are possible only when accurate diagnostic information is given. We further search and review the literature for the most up-to-date information currently available for this subtype of ALL in the constantly evolving field of molecular cytogenetics.

Duplication of 11p14.3-p15.1 in a mentally retarded proband and his mother detected by G-banding and confirmed by high-resolution CGH and BAC FISH.

A 10-year-old African-American male has been followed since 2 years of age due to his mental retardation, severe behavioral problems, and dysmorphism. Conventional cytogenetic analysis, chromosome painting, high-resolution comparative genomic hybridization (HR-CGH), and bacterial artificial chromosome fluorescent in situ hybridization (BAC FISH) revealed an apparent duplication in the short arm of a chromosome 11, dup(11)(p14.3p15.1), seen also in his mentally retarded mother. The proband had moderate to severe mental retardation, a history of IUGR, infantile hypotonia, FTT, exotropia, inguinal hernia repair, and several dysmorphic features. His mother had mild mental retardation, a history of impulsivity, assaultive outbursts, and similar dysmorphism. Although G-banding and FISH indicated a duplication, HR-CGH confined the localization of material to bands 11p14-11p15 and aided the selection of locus-specific BAC clones to more precisely characterize the duplicated region. To our knowledge, the results represent the first example of a familial, cytogenetically visible duplication of euchromatin in 11p that excludes the Beckwith-Wiedemann syndrome critical region. It is possible that one or more genes had been disrupted at the breakpoints of the above structural chromosomal rearrangement giving rise to the present phenotype.

Costovertebral dysplasia in a patient with partial trisomy 22.

A newborn female presented with costovertebral dysplasia (CVD), subtle facial anomalies, and neonatal respiratory distress. Her karyotype demonstrated a small supernumerary NOR-positive marker that was subsequently identified as del(22)(q11.2). This extra structurally abnormal chromosome was found by DNA microsatellite marker analyses to be derived from a paternal chromosome 22. The child has had severe growth and developmental delay along with pulmonary insufficiency and hypoxia but is presently stable at age 20 months. Findings in our patient correlate with similar observations in children with small markers derived from D/G and D/D translocations reported before banding technology was available. These reports and recent mapping results suggest that a pericentric gene family, distributed on one or more acrocentric chromosomes, may have played a role in the development of the human axial skeleton. Data from additional studies will be needed to confirm or refute this hypothesis.

Constitutional partial 1q trisomy mosaicism and Wilms tumor.

We report on a female patient with severe-profound mental retardation, multiple congenital anomalies, as well as a history of mosaicism for partial 1q trisomy in the amniotic fluid and a previous Wilms tumor specimen. Peripheral blood and fibroblasts were studied and did not demonstrate the mosaicism initially detected for 1q. Array comparative genomic hybridization yielded negative results. Additional cytogenetic studies helped clarify the previous findings and revealed evidence of partial 1q trisomy mosaicism in normal kidney tissue and in a kidney lesion. GTG-banded results showing low-percentage mosaicism for the structural rearrangement der(1)t(1;1)(p36.1;q23) in both tissues were corroborated by fluorescence in situ hybridization studies. We hypothesize that the partial 1q trisomy predisposed the target tissue (in this case kidney) to neoplasia. This study provides further support for the hypothesis that certain constitutional chromosomal abnormalities can predispose to cancer. As detection of a low-percentage mosaicism may be hampered by the limits imposed by currently available technology and the constraint of a finite sample size, extra vigilance in monitoring other somatic tissues will be needed throughout the patient's lifetime. Anticipatory clinical guidance and prognostication are meaningful only if given accurate cytogenetic diagnoses. To the best of our knowledge, this is the first reported case of Wilms tumor associated with constitutional partial 1q trisomy, either in pure or mosaic form, with the particular 1q23 breakpoint in conjunction with a break on 1p36.1.