Acromegaly in Carney complex.

PURPOSE: Carney complex (CNC) is a rare autosomal dominant syndrome, characterized by mucocutaneous pigmentation, cardiac, cutaneous myxomas and endocrine overactivity. It is generally caused by inactivating mutations in the PRKAR1A (protein kinase cAMP-dependent type I regulatory subunit alpha) gene. Acromegaly is an infrequent manifestation of CNC, reportedly diagnosed in 10% of patients. METHODS: We here report the case of a patient who was concomitantly diagnosed with Carney complex, due to a new mutation in PRKAR1A ((NM_002734.3:c.80_83del, p.(Ile27Lysfs*101 in exon 2), and acromegaly. In parallel, we conducted an extensive review of published case reports of acromegaly in the setting of CNC. RESULTS: The 43-year-old patient was diagnosed with an acromegaly due to a GH-secreting pituitary microadenoma resistant to somatostatin analogs. He underwent transsphenoidal surgery in our tertiary referral center, which found a pure GH-secreting adenoma. In the literature, we identified 57 cases (24 men, 33 women) of acromegaly in CNC patients. The median age at diagnosis was 28.8 ± 12 year and there were 6 cases of gigantism. Acromegaly revealed CNC in only 4 patients. 24 patients had a microadenoma and two carried pituitary hyperplasia and/or multiple adenomas, suggesting that CNC may result in a higher proportion of microadenoma as compared to non-CNC acromegaly. CONCLUSIONS: Although it rarely reveals CNC, acromegaly is diagnosed at a younger age in this setting, with a higher proportion of microadenomas.

Systematic screening for PRKAR1A gene rearrangement in Carney complex: identification and functional characterization of a new in-frame deletion.

BACKGROUND: Point mutations of the PRKAR1A gene are a genetic cause of Carney complex (CNC) and primary pigmented nodular adrenocortical disease (PPNAD), but in 30% of the patients no mutation is detected. OBJECTIVE: Set up a routine-based technique for systematic detection of large deletions or duplications of this gene and functionally characterize these mutations. METHODS: Multiplex ligation-dependent probe amplification (MLPA) of the 12 exons of the PRKAR1A gene was validated and used to detect large rearrangements in 13 typical CNC and 39 confirmed or putative PPNAD without any mutations of the gene. An in-frame deletion was characterized by western blot and bioluminescence resonant energy transfer technique for its interaction with the catalytic subunit. RESULTS: MLPA allowed identification of exons 3-6 deletion in three patients of a family with typical CNC. The truncated protein is expressed, but rapidly degraded, and does not interact with the protein kinase A catalytic subunit. CONCLUSIONS: MLPA is a powerful technique that may be used following the lack of mutations detected by direct sequencing in patients with bona fide CNC or PPNAD. We report here one such new deletion, as an example. However, these gene defects are not a frequent cause of CNC or PPNAD.

Balanced complex chromosomal rearrangements (BCCR) with at least three chromosomes and three or more breakpoints: report of three new cases.

Balanced complex chromosomal rearrangements (BCCR) encompass a heterogeneous group of rare chromosomal aberrations. In this paper, we report three cases of BCCRs. In two the probands were referred for either genetic counseling or prenatal management. One case was ascertained after chromosome analysis performed because of psychiatric manifestations; this was an isolated finding. We also outline the molecular cytogenetic techniques, which were essential in confirming and precisely delineating the BCCRs identified in these patients. In addition the various aspects of genetic counseling for this type of chromosomal rearrangement, highlighting the details particular to each individual case are discussed. We discuss the classification for this type of chromosomal mutation.

De novo complex chromosomal rearrangements (CCR) involving chromosome 1, 5, and 6 resulting in microdeletion for 6q14 in a female carrier with psychotic disorder.

A 23-year-old obese woman with a psychotic disorder was found to have a de novo apparently balanced complex chromosomal rearrangement involving chromosomes 1, 5, and 6. Molecular cytogenetic analyses using high-resolution comparative genomic hybridization (HR-CGH) showed a microdeletion at 6q14 in a der(6). Application of HR-CGH facilitated detection of micro-rearrangement of all de novo apparently balanced complex chromosomal rearrangements (CCR) and supported the localization of the breakpoint. According to our knowledge, no constitutional interstitial microdeletion of chromosome 6q14 has been found associated with a schizoid-type phenotype.

Reversible meiotic abnormalities in azoospermic men with bilateral varicocele after microsurgical correction.

Because of a possible relationship between microenvironmental disturbances and meiotic abnormalities and of a straight relationship between lower-quality semen in patient carrying a varicocele and first meiotic non-disjunction, bilateral bipolar testicular biopsies are realized according the thermic differential gradient described in varicocele. Systematic meiotic studies of multiple testicular biopsies from 65 azoospermic men with bilateral varicocele were done in a multi-centric study on microsurgical correction of bilateral varicocele with microthermic intra-operative evaluation using minimally invasive thermal microsensors (Betatherm 10K3MCD2). In the present study abnormal temperature raising, histomorphometric abnormalities (spermatocyte arrest) and meiotic abnormalities (class IIC) are strongly correlated. In the ten patients submitted to another testicular biopsy procedure six months after surgery for TESE, normal thermal differential is registered and no meiotic abnormalities recurrences are found.

A balanced complex chromosomal rearrangement (BCCR) in a family with reproductive failure.

Balanced complex chromosomal rearrangements are very rare events in the human population. Translocations involving three or more chromosomes frequently lead to a severe reproductive impairment secondary to meiotic disturbance in males and to chromosomal imbalance in gametes of females. We report a new familial case of complex chromosome anomaly involving chromosomes 13, 14 and 22. Cytogenetic investigations showed a complex chromosomal chromosome rearrangement involving: (i) a Robertsonian translocation between chromosomes 13 and 14; and (ii) a reciprocal translocation between the long arms of chromosome 14 and the long arm of chromosome 22. The aetiology of the translocation was characterized by conventional fluorescence in-situ hybridization (FISH) studies and routine R- and G-banding (RTBG and GBTG) combined with alpha and beta satellite centromeric FISH probes. Predicted configuration of the hexavalent at pachytene stage of meiosis was used to consider the modes of segregation; only two configurations resulted in a normal or balanced gamete karyotype. Reproductive management and genetic counselling are discussed.

Assisted reproductive technology and complex chromosomal rearrangements: the limits of ICSI.

Complex chromosomal rearrangements are very rare events in the human population. According to our knowledge on the consequences of simple reciprocal translocations for male fertility, translocations involving three or more chromosomes are thought to lead to severe reproductive impairments in terms of meiotic disturbance or chromosomal imbalance of gametes. We report the case of a 48 year old man whose sperm count revealed either oligozoospermia (<10(3) spermatozoa/ml) or azoospermia. He was referred to the laboratory for in-vitro fertilization after intracytoplasmic sperm injection. Cytogenetic investigations showed a complex chromosomal rearrangement involving firstly a translocation between the short arm of chromosome 7 and the long arm of chromosome 13 and secondly a translocation between the short arm of the same chromosome 13 and the short arm of chromosome 9. Diagnosis was ascertained by fluorescence in-situ hybridization and staining of the nucleolar organizer regions. Theoretical study of the translocated chromosomes predicted a 'chain' configuration of the hexavalent at the pachytene stage of meiosis. In all, 32 modes of segregation were considered and only one resulted either in a normal or a balanced gamete karyotype. Genetic counselling and choice of appropriate artificial reproduction technique are discussed.

The contribution of cytogenetics to the histogenesis of meningeal hemangiopericytoma.

Some controversy has existed regarding the nosology of meningeal hemangiopericytoma. In the WHO's classification of 1979 these tumours were included as a subgroup of meningiomas, but for some authors, they should not be classified as meningiomas. Cytogenetic studies on meningioma demonstrate monosomy or partial deletion of chromosome 22 in 60% of these tumors. There have been few cytogenetic studies about meningeal hemangiopericytoma. We present here the results of cytogenetic studies and fluorescence in situ hybridization in six cases of meningeal hemangiopericytoma. In these tumours we have never found monosomy 22, but all six cases were hyperdiploid. These cytogenetic data might provide additional evidence to differenciate the meningeal hemangiopericytoma from the meningioma.

[Pachytene stage of meiosis in an infertile man carrying a reciprocal translocation between two acrocentric chromosomes]. / Etude du stade pachytène de la méiose chez un homme infertile porteur d'une translocation réciproque entre deux chromosomes acrocentriques.

Translocations involving acrocentric chromosomes are frequent in chromosomal male infertility. Robertsonian translocations are usually concerned whereas reciprocal translocations between acrocentric chromosomes are rarely encountered. The first reciprocal translocation involving the long arms of the two acrocentric chromosomes 13 and 14 [46,XY,t(13,14)(q33,q22)] is presented in this paper. The patient presents a severe oligoasthenospermia; testicular histology shows an important impairment of spermatogenesis. The quadrivalent is present in all the pachytene nuclei analyzed. A straight contact between the sex vesicle and the quadrivalent was found in 40.9% of the nuclei. A frequent asynapsis is localized at the breakpoint region (33.8%). The XY-autosome association was obtained by the central asynapsis and/or by the terminal chromomeres of the acrocentric chromosomes involved in the translocation.

Pachytene analysis in a 17;21 reciprocal translocation carrier: role of the acrocentric chromosomes in male sterility.

Pachytene analysis was undertaken in an infertile male, heterozygous for a 17;21 reciprocal translocation. The quadrivalent was identified by its configuration and chromomere pattern. A non-random association was found between the quadrivalent and the sex vesicle in 77% of the pachytene nuclei analysed. In 13.1% of the cells the contact with the sex vesicle was established by the terminal chromomere of the two chromosomes 21; in 63.9% of the cells, the entire region of the breakpoints was completely hidden by the sex vesicle. In some nuclei asynapsis was found in the region of the breakpoints. The nature of the contact between the quadrivalent and the sex vesicle is discussed in this paper. It is proposed that the acrocentric chromosome favours the contact between the quadrivalent and the sex vesicle, and increases the risk of sterility in male carriers of Robertsonian translocations and of reciprocal translocations involving one acrocentric chromosome.