Constitutional Disorders Research Articles

Molecular mechanisms and diagnosis of chromosome 22q11.2 rearrangements

Several recurrent, constitutional genomic disorders are present on chromosome 22q. These include the translocations and deletions associated with DiGeorge and velocardiofacial syndrome and the translocations that give rise to the recurrent t(11;22) supernumerary der(22) syndrome (Emanuel syndrome). The rearrangement breakpoints on 22q cluster around the chromosome-specific segmental duplications of proximal 22q11, which are involved in the etiology of these disorders. While the deletions are the result of nonallelic homologous recombination (NAHR) between low copy repeats or segmental duplications within 22q11, the t(11;22) is the result of rearrangement between palindromic AT-rich repeats on 11q and 22q. Here we describe the mechanisms responsible for these recurrent rearrangements, discuss the recurrent deletion endpoints that are the result of NAHR between chromosome 22q specific low copy repeats as well as present current diagnostic approaches to deletion detection.

Copy number variations and clinical cytogenetic diagnosis of constitutional disorders

The recent appreciation of widespread copy number variation in the genomes of healthy human beings has presented a significant challenge to clinical cytogeneticists who wish to use genome-wide array comparative genomic hybridization (CGH) assays for clinical diagnostic purposes. Clinical cytogeneticists need to differentiate between copy number variants (CNVs) that are likely to be pathogenic and CNVs that are less likely to contribute to an affected individual's clinical presentation. Unfortunately, our knowledge of the phenotypic effects of most CNVs is minimal, leading to the classification of many CNVs as genomic imbalances of unknown clinical significance. This has caused many laboratories to resist the use of higher-resolution genome-wide array CGH assays for clinical purposes. Ironically, the accumulation and annotation of such array CGH data can lead to the rapid identification of pathogenic CNVs and the definition of new genomic syndromes that, in turn, are useful for accurate clinical genetic diagnoses.

Large-scale copy number variants (CNVs): distribution in normal subjects and FISH/real-time qPCR analysis.

BackgroundGenomic copy number variants (CNVs) involving >1 kb of DNA have recently been found to be widely distributed throughout the human genome. They represent a newly recognized form of DNA variation in normal populations, discovered through screening of the human genome using high-throughput and high resolution methods such as array comparative genomic hybridization (array-CGH). In order to understand their potential significance and to facilitate interpretation of array-CGH findings in constitutional disorders and cancers, we studied 27 normal individuals (9 Caucasian; 9 African American; 9 Hispanic) using commercially available 1 Mb resolution BAC array (Spectral Genomics). A selection of CNVs was further analyzed by FISH and real-time quantitative PCR (RT-qPCR).ResultsA total of 42 different CNVs were detected in 27 normal subjects. Sixteen (38%) were not previously reported. Thirteen of the 42 CNVs (31%) contained 28 genes listed in OMIM. FISH analysis of 6 CNVs (4 previously reported and 2 novel CNVs) in normal subjects resulted in the confirmation of copy number changes for 1 of 2 novel CNVs and 2 of 4 known CNVs. Three CNVs tested by FISH were further validated by RT-qPCR and comparable data were obtained. This included the lack of copy number change by both RT-qPCR and FISH for clone RP11-100C24, one of the most common known copy number variants, as well as confirmation of deletions for clones RP11-89M16 and RP5-1011O17.ConclusionWe have described 16 novel CNVs in 27 individuals. Further study of a small selection of CNVs indicated concordant and discordant array vs. FISH/RT-qPCR results. Although a large number of CNVs has been reported to date, quantification using independent methods and detailed cellular and/or molecular assessment has been performed on a very small number of CNVs. This information is, however, very much needed as it is currently common practice to consider CNVs reported in normal subjects as benign changes when detected in individuals affected with a variety of developmental disorders.

Etiology of Developmental Hip Dysplasia or Dislocation: Review Article

There is no consensus in the literature regarding the impact of several, so-called, etiological factors in the appearance of developmental dysplasia or dislocation of the hip (DDH). Furthermore, the mechanism explaining the appearance of a dislocated or subluxated hip in the perinatal period is not well defined. The latter explains, as well, the different terms used to describe the same clinical entity. Terms like congenital dislocation of the hip (CDH), developmental dysplasia/dislocation of the hip or teratological dislocation of the hip are usually applied for the description of the same condition. Constitutional and mechanical disorders are accused of encouraging the evolution of an antenatal or neonatal hip towards instability, subluxation or even dislocation. An understanding of the predisposing factors as well as the natural history is essential in order to prevent and/or treat them effectively as well as to decide on the most appropriate nomenclature. A review of the multiple published theories affirms that the determining predisposing factors for hip dislocation or subluxation are mechanical and are associated with intra-uterine posture in full hip flexion, adduction and external femoral rotation together with abnormal pressure on the greater trochanter tending to expel the femoral head in a supero-posterior direction relative to the acetabulum. The role of genetic factors is secondary, but present, and can influence the natural history of a patient if the primary mechanical and postural factors are not inhibited.

Etiology of developmental hip dysplasia or dislocation: review article

There is no consensus in the literature regarding the impact of several, so-called, etiological factors in the appearance of developmental dysplasia or dislocation of the hip (DDH). Furthermore, the mechanism explaining the appearance of a dislocated or subluxated hip in the perinatal period is not well defined. The latter explains, as well, the different terms used to describe the same clinical entity. Terms like congenital dislocation of the hip (CDH), developmental dysplasia/dislocation of the hip or teratological dislocation of the hip are usually applied for the description of the same condition. Constitutional and mechanical disorders are accused of encouraging the evolution of an antenatal or neonatal hip towards instability, subluxation or even dislocation. An understanding of the predisposing factors as well as the natural history is essential in order to prevent and/or treat them effectively as well as to decide on the most appropriate nomenclature. A review of the multiple published theories affirms that the determining predisposing factors for hip dislocation or subluxation are mechanical and are associated with intra-uterine posture in full hip flexion, adduction and external femoral rotation together with abnormal pressure on the greater trochanter tending to expel the femoral head in a supero-posterior direction relative to the acetabulum. The role of genetic factors is secondary, but present, and can influence the natural history of a patient if the primary mechanical and postural factors are not inhibited.

Nosology and classification of genetic skeletal disorders: 2006 revision

The objective of the paper is to provide the revision of the Nosology of Constitutional Disorders of Bone that incorporates newly recognized disorders and reflects new molecular and pathogenetic concepts. Criteria for inclusion of disorders were (1) significant skeletal involvement corresponding to the definition of skeletal dysplasias, metabolic bone disorders, dysostoses, and skeletal malformation and/or reduction syndromes, (2) publication and/or MIM listing, (3) genetic basis proven or very likely, and (4) nosologic autonomy confirmed by molecular or linkage analysis and/or distinctive diagnostic features and observation in multiple individuals or families. Three hundred seventy-two different conditions were included and placed in 37 groups defined by molecular, biochemical and/or radiographic criteria. Of these conditions, 215 were associated with one or more of 140 different genes. Nosologic status was classified as final (mutations or locus identified), probable (pedigree evidence), or bona fide (multiple observations and clear diagnostic criteria, but no pedigree or locus evidence yet). The number of recognized genetic disorders with a significant skeletal component is growing and the distinction between dysplasias, metabolic bone disorders, dysostoses, and malformation syndromes is blurring. For classification purposes, pathogenetic and molecular criteria are integrating with morphological ones but disorders are still identified by clinical features and radiographic appearance. Molecular evidence leads to confirmation of individual entities and to the constitution of new groups, but also allows for delineation of related but distinct entities and indicates a previously unexpected heterogeneity of molecular mechanisms; thus, molecular evidence does not necessarily simplify the Nosology, and a further increase in the number of entities and growing complexity is expected. By providing an updated overview of recognized entities with skeletal involvement and of the underlying gene defects, the new Nosology can provide practical diagnostic help, facilitate the recognition of new entities, and foster and direct research in skeletal biology and genetic disorders.

Facteur VII active recombinant (NovoSeven ®) : indications et limites

Recombinant activated factor VII (rFVIIa) is a pro-hemostatic agent initially developed for the treatment of hemophiliacs with allo-antibodies. For the last twenty years, the literature reporting the use of rFVIIa has involved about 500 international publications including about 2000 patients with miscellaneous diseases. The efficacy of rFVIIa is clearly established in some constitutional hemostasis disorders with post-transfusional allo-antibodies (Abs) (hemophilia A and B with inhibitors, Glanzmann thrombasthenia with allo-Abs to platelets). The usefulness of rFVIIa in acquired hemostasis disorders is well demonstrated in acquired hemophilia but it remains to be clarified in liver-related coagulation disorders. Promising results have been published in life-threatening hemorrhages occurring in either surgical, traumatological, neurologic or obstetrical settings. These publications open the way to controlled randomized clinical trials which should lead to further validation of both efficacy and safety of rFVIIa in these specific indications. Overall, thrombotic complications are very rare with a frequency ranging between 1 and 2%.

The angel in the marble

Case of the monthThe angel in the marbleD J A Butteriss, M Clarke and D BirchallD J A Butteriss1Department of Neuroradiology, Regional Neurosciences Centre, Newcastle General Hospital, Newcastle upon Tyne, 2Ophthalmology Department, Royal Victoria Infirmary, Newcastle upon Tyne, UKSearch for more papers by this author, M Clarke1Department of Neuroradiology, Regional Neurosciences Centre, Newcastle General Hospital, Newcastle upon Tyne, 2Ophthalmology Department, Royal Victoria Infirmary, Newcastle upon Tyne, UKSearch for more papers by this author and D Birchall1Department of Neuroradiology, Regional Neurosciences Centre, Newcastle General Hospital, Newcastle upon Tyne, 2Ophthalmology Department, Royal Victoria Infirmary, Newcastle upon Tyne, UKSearch for more papers by this authorPublished Online:13 Feb 2014https://doi.org/10.1259/bjr/33391462SectionsPDF/EPUBFull Text ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail About References 1 Hall CM. International Nosology and Classification of Constitutional Disorders of Bone (2001). Am J Med Genet 2002;113:65–77. Crossref Medline ISI, Google Scholar2 Anderson PE, Bollerslev J. Heterogeneity of autosomal dominant osteopetrosis. Radiology 1987;164:233–5. Google Scholar3 Cure JK, Key LL, Goltra DD, VanTassel P. Cranial MR imaging of osteopetrosis. AJNR Am J Neuroradiol 2000;21:1110–5. Medline ISI, Google Scholar4 Stewart CG. Neurological aspects of osteopetrosis. Neuropathol Appl Neurobiol 2003;29:87–97. Crossref Medline ISI, Google Scholar5 Vanier V, Miller NR, Carson BS. Bilateral visual improvement after unilateral optic canal decompression and cranial vault expansion in a patient with osteopetrosis, narrowed optic canals, and increased intracranial pressure. J Neurol Neurosurg Psychiatry 2000;69:405–6. Crossref Medline ISI, Google Scholar Previous article FiguresReferencesRelatedDetailsCited byOrthopaedic Management of the Patient With OsteopetrosisJournal of the American Academy of Orthopaedic Surgeons, Vol. 15, No. 11 Volume 79, Issue 940April 2006Pages: 275-361 © The British Institute of Radiology History ReceivedMay 16,2005AcceptedJune 27,2005Published onlineFebruary 13,2014 Metrics Michelangelo, “I saw the angel in the marble and carved until I set it free.”Download PDF

Cyclic Vomiting Syndrome Plus

Cyclic vomiting syndrome, which is characterized by severe discrete episodes of nausea, vomiting, and lethargy, is a fairly common, disabling, predominately childhood condition. Approximately 25% of cases have coexisting neuromuscular disease manifestations (cyclic vomiting syndrome plus). To determine whether patients with cyclic vomiting syndrome and neuromuscular disease represent a distinct subentity within cyclic vomiting syndrome, a clinical interview was conducted regarding 80 randomly ascertained sufferers of cyclic vomiting syndrome from a disease association database. Cyclic vomiting syndrome plus and "cyclic vomiting syndrome minus," herein defined as the presence of at least two and zero neuromuscular disease manifestations, were present in 23 and 44 subjects, respectively. Neuromuscular disease manifestations, including cognitive disorders, skeletal myopathy, cranial nerve dysfunction, and seizure disorders, were found to statistically cluster together among the same subjects. In addition, subjects with cyclic vomiting syndrome with neuromuscular disease had an earlier age at onset for vomiting episodes and a three- to eightfold statistically increased prevalence for certain dysautonomia-related (migraine, chronic fatigue, neurovascular dystrophy) and constitutional (growth retardation and birth defects) disorders. However, subjects with cyclic vomiting syndrome with and without neuromuscular disease were equally likely to have a sibling affected with neuromuscular disease manifestations. We conclude that cyclic vomiting syndrome plus, although likely not genetically distinct from cyclic vomiting syndrome minus, represents a distinct phenotypic entity that predicts an earlier onset of disease and increased comorbidity with a distinct list of medical conditions, possibly owing to a higher degree of mitochondrial dysfunction.

A novel homozygous MMP2 mutation in a family with Winchester syndrome

The 2001 International Classification of Constitutional Disorders of Bone has included in the group of multicentric hands and feet osteolysis syndromes three autosomal recessive inherited disorders: Winchester, Torg and nodulosis-arthropathy-osteolysis (NAO) syndromes. Nosographic delineations of these rare syndromes are difficult to define, and there is no consensus. In 2001, two mutations in the matrix metalloproteinase 2 gene (MMP2) have been identified in two families with a NAO phenotype. In a recent study, a homozygous MMP2 mutation has also been identified in a patient presenting with Winchester syndrome. We report the clinical evolution of two sisters with a Winchester phenotype. Clinical review over 23 years provides information on the general evolution of osteolysis and points to an intrafamilial variation with clinical and radiological changes during the patients' life. In both sisters, we identified a new homozygous mutation in the catalytic domain of the MMP2 gene. Our study results are consistent with the involvement of MMP2 in Winchester syndrome and with the hypothesis that Winchester and NAO syndromes are allelic disorders that form a continuous clinical spectrum. At last, our observation emphasizes the interest of molecular analysis in genetic counselling of this consanguineous family.

Risk of the “Androgen Deprivation Syndrome” in Men Receiving Androgen Deprivation for Prostate Cancer

Androgen deprivation therapy for prostate cancer has been associated with a spectrum of adverse effects, such as depression, memory difficulties, and fatigue, termed the androgen deprivation syndrome. Primary care physicians providing follow-up care for men with prostate cancer will be faced with managing these effects. We therefore sought to estimate the incidence of these effects and, by using a control group, ascertain whether these effects were related to androgen deprivation itself. We assessed the risk of physician diagnoses of depression, cognitive impairment, or constitutional symptoms in Medicare data following androgen deprivation using a sample of 50 613 men with incident prostate cancer and 50 476 men without cancer, from 1992 through 1997, in the linked Surveillance, Epidemiology, and End Results-Medicare database. Cox proportional hazards regression was used to adjust for confounding variables. Of men surviving at least 5 years after diagnosis, 31.3% of those receiving androgen deprivation developed at least 1 depressive, cognitive, or constitutional diagnosis compared with 23.7% in those who did not (P<.001). After adjustment for variables such as comorbidity, tumor characteristics, and age, the risks associated with androgen deprivation were substantially reduced or abolished: relative risk (RR) for depression diagnosis, 1.08 (95% confidence interval [CI], 1.02-1.15); RR for cognitive impairment, 0.99 (95% CI, 0.94-1.04); and RR for constitutional symptoms, 1.17 (95% CI, 1.13-1.22). Depressive, cognitive, and constitutional disorders occur more commonly in patients receiving androgen deprivation, but this appears to be primarily because patients receiving androgen deprivation are older and have more comorbid conditions and more advanced cancers.

Spondyloenchondrodysplasia with spasticity, cerebral calcifications, and immune dysregulation: Clinical and radiographic delineation of a pleiotropic disorder

Enchondromas are a feature of several constitutional disorders of bone, and the classification of different nosologic entities is still provisional. Among these disorders, spondyloenchondrodysplasia (SPENCD), as outlined by Schorr et al. [1976], is defined by the presence of radiolucent spondylar and metaphyseal lesions that represent persistence of islands of chondroid tissue within bone. Careful review of radiographic findings is needed to distinguish SPENCD from the many other disorders combining enchondromas with spinal lesions. Even when strict criteria are applied, it appears that SPENCD is clinically heterogeneous, as some SPENCD patients are neurologically intact while others present with spasticity, mental retardation, and cerebral calcifications in different combinations, and it has been suggested that SPENCD should be divided in two types. We herein report ten individuals from six families with SPENCD and illustrate the radiographic changes. Seven individuals had CNS manifestations including spasticity, developmental delay, and late-onset cerebral calcifications. We also noted that six individuals had clinical manifestations of autoimmunity (auto-immune thrombocytopenic purpura, auto-immune hemolytic anemia, auto-immune thyroiditis, and SLE) and one had been diagnosed with immune deficiency. Neurological and autoimmune manifestations were seen in different combinations within one single family. These observations suggest that SPENCD may be a single entity defined by specific radiographic features, but with remarkably pleiotropic manifestations that include CNS disease (spasticity, mental retardation, and calcifications), as well as immune dysregulation ranging from autoimmunity to immunodeficiency. The notion of recessive inheritance hitherto assumed is challenged by the observation of two apparently dominant pedigrees.

La CGH microarray : principe et applications en pathologie constitutionnelle

Chips technology has allowed to miniaturize process making possible to realize in one step and using the same device a lot of chemical reactions. The application of this technology to molecular cytogenetics resulted in the development of comparative genomic hybridization (CGH) on microarrays technique. Using this technique it is possible to detect very small genetic imbalances anywhere in the genome. Its usefulness has been well documented in cancer and more recently in constitutional disorders. In particular it has been used to detect interstitial and subtelomeric submicroscopic imbalances, to characterize their size at the molecular level or to define the breakpoints of translocation. The challenge today is to transfer this technology in laboratory medicine. Nevertheless this technology remains expensive and the existence of numerous sequence polymorphisms makes its interpretation difficult. Finally its is unlikely that it will make karyotyping obsolete as it does not allow to detect balanced rearrangements which after meiotic segregation might result in genome imbalance in the progeny.

Molecular karyotyping in human constitutional cytogenetics

Using array CGH it is possible to detect very small genetic imbalances anywhere in the genome. Its usefulness has been well documented in cancer and more recently in constitutional disorders. In particular it has been used to detect interstitial and subtelomeric submicroscopic imbalances, to characterize their size at the molecular level and to define the breakpoints of chromosomal translocation. Here, we review the various applications of array CGH in constitutional cytogenetics. This technology remains expensive and the existence of numerous sequence polymorphisms makes its interpretation difficult. The challenge today is to transfer this technology in the clinical setting.

Newer imaging modalities in the prenatal diagnosis of skeletal dysplasias

Newer imaging modalities in the prenatal diagnosis of skeletal dysplasias

Chirurgie des malpositions palpébrales congénitales de l’enfant

Congenital eyelid malpositions can be isolated or associated with other structures such as the eyeball, ocular muscles, and lacrimal pathways. It is important to separate eyelid malpositions, which are topographical disorders, from eyelid malformations, which are constitutional morphological disorders. Only eyelid malpositions will be described in this paper, with a distinction made between static and dynamic disorders. Static disorders include epiblepharon, congenital ectropion and entropion, epicanthus, telecanthus, and centurion syndrome. Dynamic disorders group ptosis and congenital eyelid retractions. Epiblepharon is characterized by the absence of adhesion between the lower eyelid retractors and the orbicularis-skin layer, which allows the anterior lamella to roll over. Congenital entropion and ectropion are very rare. They most often require surgical treatment. Epicanthus involves a semi-lunar fold of skin extending from the upper eyelid across the medial canthal area to the margin of the lower eyelid. Four types (supra-ciliaris, palpebralis, tarsalis and inversus) of epicanthus are described. Treatment requires surgery. Telecanthus is defined as an increased distance between canthi. Primary telecanthus results from attenuation of the medial canthal tendons and is usually associated with other soft tIssue abnormalities such as epicanthus or blepharophimosis, or is seen after trauma. Secondary telecanthus is caused by underlying bony malpositions with an abnormal separation between the orbits because of an increased thickness of the interorbital bones such as that seen in hypertelorism or in other complex craniofacial syndromes. Euryblepharon is distinguished by an enlargement of the horizontal palpebral fissure associated with enlarged eyelids. The etiology is unknown and patients may benefit from surgery. Congenital ptosis is characterized by a deficiency of the levator muscle. They are most often unilateral and isolated. When associated with other abnormalities such as squint, synkinesis, blepharophimosis, or craniofacial syndromes, surgical treatment may require several-stage procedures. On the other hand, isolated congenital ptosis is usually treated in childhood (3-6 years) in a single stage. Congenital eyelid retractions may affect either the lower or the upper eyelid. They make up a rare condition and most cases are associated with craniofacial syndromes such as Crouzon or Apert syndromes. Upper eyelid retractions may spontaneously improve in some cases, but lower eyelid retractions do not. Treatment requires surgery, depending on the corneal consequences.

A novel sequence-based approach to localize translocation breakpoints identifies the molecular basis of a t(4;22).

Low copy repeats (LCRs) located in 22q11.2, especially LCR-B, are susceptible to rearrangements associated with several relatively common constitutional disorders. These include DiGeorge syndrome, Velocardiofacial syndrome, Cat-eye syndrome and recurrent translocations of 22q11 including the constitutional t(11;22) and t(17;22). The presence of palindromic AT-rich repeats (PATRRs) within LCR-B of 22q11.2, as well as within the 11q23 and 17q11 regions, has suggested a palindrome-mediated, stem-loop mechanism for the generation of such recurring constitutional 22q11.2 translocations. The mechanism responsible for non-recurrent 22q11.2 rearrangements is presently unknown due to the extensive effort required for breakpoint cloning. Thus, we have developed a novel fluorescence in-situ hybridization and primed in-situ hybridization (PRINS) approach and rapidly localized the breakpoint of a non-recurrent 22q11.2 translocation, a t(4;22). Multiple primer pairs were designed from the sequence of a 200 kb, chromosome 4, breakpoint-spanning BAC to generate PRINS probes. Amplification of adjacent primer pairs, labeled in two colors, allowed us to narrow the 4q35.1 breakpoint to a 6.7 kb clonable region. Application of our improved PRINS protocol facilitated fine-mapping the translocation breakpoints within 4q35.1 and 22q11.2, and permitted rapid cloning and analysis of translocation junction fragments. To confirm the PRINS localization results, PCR mapping of t(4;22) somatic cell hybrid DNA was employed. Analysis of the breakpoints demonstrates the presence of a 554 bp palindromic sequence at the chromosome 4 breakpoint and a 22q11.2 location within the same PATRR as the recurrent t(11;22) and t(17;22). The sequence of this breakpoint further suggests that a stem-loop secondary structure mechanism is responsible for the formation of other, non-recurrent translocations involving LCR-B of 22q11.2.

Radiological diagnosis of the constitutional disorders of bone. As easy as A, B, C?

Although many constitutional disorders of bone are individually rare, collectively they make up a large group of disorders. They are broadly classified into osteochondrodysplasias and dysostoses. Because of the rarity of some of these conditions, they can be difficult to diagnose. Members of the International Dysplasia Group meet regularly to update and clarify the nomenclature. The last meeting was in Oxford in 2001. This article attempts to highlight the differences between the osteochondrodysplasias and the dysostoses, and provides a systematic approach to their radiological diagnosis.

International nosology and classification of constitutional disorders of bone (2001).

The last International Classification of Constitutional Disorders of Bone was published in 1998. Since then rapid advances have been made in identifying the molecular changes responsible for defined conditions and new disorders are constantly being delineated. For these reasons a further update on the classification is appropriate. It has been expended to not only the osteochondrodysplasias (33 groups) but also genetically determined dysostoses (3 groups).

Syndromes myélodysplasiques de l'enfant

Myelodysplastic syndromes (MDS) in children constitute a heterogeneous disorder, including “primary” MDS and MDS associated with constitutional disorders or metabolic diseases. The Franco-American-British (FAB) cytological classification for adults can be applied for childhood in 50 to 100% of the cases. The transformation into acute myeloblastic leukemia often occurs, but stabilisation or spontaneous regression of the disease may also be observed. Allogenic bone marrow transplantation is the best curative option when treatment is necessary.