搜索结果：syndromology

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Clinical geneticists and syndromologists have traditionally focused on identifying syndromes in children. However, there is a growing acknowledgment of the need to describe adult phenotypes. This article provides an overview of the evolving phenotypes of rare genetic syndromes into adulthood, elucidating its challenges, opportunities, and future perspectives. The clinical phenotypes of four adults with Costello syndrome are described to illustrate these aspects. Phenotypic and genotypic data from four individuals broaden the spectrum of Costello syndrome in adulthood and highlight the high variability in neurocognitive outcome. The clinical data align with previous findings and established genotype-phenotype correlations. Interestingly, two individuals presented with recurrent cancers (bladder cancer and neuroblastoma). Further studies are imperative to provide reliable information for counselling and management to enable comprehensive understanding of the evolving features of rare syndromic diseases and special health issues into adulthood.

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Numerical taxonomy is defined by Sneath and Sokal as the grouping of taxonomic units on the basis of their character states by numerical methods of multivariate data analysis, and syndromology as the study of multiple congenital anomaly (MCA) syndromes and of their nosology. We present here an application of those methods to the analysis of overlapping syndromes. The main advantage of numerical taxonomy is that it allows simultaneous objective and unweighted analysis of multiple traits, giving the possibility to test mathematically the clinical hypotheses about the heterogeneity between closely resembling syndromes and uncovering objective patterns of anomalies, to be compared with the subjective pattern recognition process which characterizes most of the diagnostic approach in syndromology. In this paper, we explored 5 syndromes whose most severe expression belongs to the cerebroacrovisceral early lethality (CAVE) phenotype: hydrolethalus, severe Smith-Lemli-Opitz, orofaciodigital type VI (Varadi-Papp), holoprosencephaly-polydactyly, and Pallister-Hall syndromes. Fifty-five published cases, including many overlapping cases, were submitted to principal factor analysis followed by hierarchical clustering and graphical scaling. Results show that the 5 syndromes clearly constitute independent phenotypic entities, that some of the original diagnoses have to be reconsidered, and that many of the overlapping cases may be unambiguously set in one category. Hypothalamic hamartoblastoma appears to be a nonspecific dysplasia occurring in any of the 5 disorders.

Syndromology belongs to diagnostic methods based on the analysis of phenotypic (clinical or anatomical--dysmorphics) features, which occur very often together and have a common etiology (e.g. teratogenic embryopathy, numerical and structural chromosomal aberrations or gene mutations). In the phenotype analysis important appear so-called signal features, which enable to narrow the range of possible disorders for the differential diagnosis of the assumptive diseases.

Pitt-Hopkins syndrome is a neurodevelopmental disorder characterized by severe intellectual disability and a distinctive facial gestalt. It is caused by haploinsufficiency of the TCF4 gene. The TCF4 protein has different functional domains, with the NLS (nuclear localization signal) domain coded by exons 7-8 and the bHLH (basic Helix-Loop-Helix) domain coded by exon 18. Several alternatively spliced TCF4 variants have been described, allowing for translation of variable protein isoforms. Typical PTHS patients have impairment of at least the bHLH domain. To which extent impairment of the remaining domains contributes to the final phenotype is not clear. There is recent evidence that certain loss-of-function variants disrupting TCF4 are associated with mild ID, but not with typical PTHS. We describe a frameshift-causing partial gene deletion encompassing exons 4-6 of TCF4 in an adult patient with mild ID and nonspecific facial dysmorphisms but without the typical features of PTHS, and a c.520C > T nonsense variant within exon 8 in a child presenting with a severe phenotype largely mimicking PTHS, but lacking the typical facial dysmorphism. Investigation on mRNA, along with literature review, led us to suggest a preliminary phenotypic map of loss-of-function variants affecting TCF4. An intragenic phenotypic map of loss-of-function variants in TCF4 is suggested here for the first time: variants within exons 1-4 and exons 4-6 give rise to a recurrent phenotype with mild ID not in the spectrum of Pitt-Hopkins syndrome (biallelic preservation of both the NLS and bHLH domains); variants within exons 7-8 cause a severe phenotype resembling PTHS but in absence of the typical facial dysmorphism (impairment limited to the NLS domain); variants within exons 9-19 cause typical Pitt-Hopkins syndrome (impairment of at least the bHLH domain). Understanding the TCF4 molecular syndromology can allow for proper nosology in the current era of whole genomic investigations.

This paper provides an updated, comprehensive, critical review of the epidemiology, genetics, and syndromic aspects of holoprosencephaly and is divided into four parts. In the first part, epidemiologic aspects are discussed under the following headings: prevalence, temporal trends, socioeconomic status, exposure to environmental teratogens, maternal and paternal ages, pregnancy histories, and birth weights. The second part analyzes the facial phenotypes because the genetic and syndromic aspects of holoprosencephaly cannot be understood without knowledge of facial variability and its meaning. Topics discussed include cyclopia, ethmocephaly, cebocephaly, median cleft lip, and less severe facial dysmorphism. The third section, on genetics, analyzes associated anomalies, chromosomal and non-chromosomal holoprosencephaly, family studies, twin studies, genetics of nonsyndromic holoprosencephaly, and recurrence risks. The final section on syndromology summarizes 48 conditions in which some degree of holoprosencephaly may be a feature.

We report on a 7-year-old boy born of consanguineous parents with severe microcephaly (-5 SD) but borderline intelligence, juvenile cataract, muscular build, rhizomelic shortness of limbs predominantly of femora, advanced bone age, and micropenis. This combination of signs appears unique and may represent an undescribed, possibly autosomal recessive MCA syndrome. The use of LDDB and POSSUM in the workup of such "new syndromes" is reviewed. Three search strategies are discussed: single rare sign browsing, best combinatory fit using an array of key words, and combined rare signs scan. Pitfalls in the use of such databases and the some problems raised by inconsistent/ incomplete encoding in those two popular, highly useful syndromology retrieval systems are discussed.

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Chromosomal duplications involving 17p13.3 have recently been defined as a new distinctive syndrome with several diagnosed patients. Some variation is known to occur in the breakpoints of the duplicated region and, consequently, in the phenotype as well. We report on a patient, the fifth to our knowledge, a 4-year-old girl with a pure de novo subtelomeric 17p13.2-pter duplication. She presents all of the facial features described so far for this duplication and in addition, a unilateral palmar transversal crease and oculocutaneous albinism which has not been reported previously. A detailed molecular description of the reported aberration and correlation with the observed phenotypical features based on a literature review. We discuss the possible molecular etiology of albinism in regard to the mode of inheritance. The new data provided here may be useful for further genotype correlations in syndromes with oculocutaneous albinism, especially of autosomal dominant inheritance.

In Part III, the process of syndrome delineation is unfolded and its significance discussed. Unknown genesis syndrome categories include provisionally unique pattern syndromes and recurrent pattern syndromes. As more information becomes available, it is often possible to establish a Mendelian, chromosomal, teratogenic, or biochemical basis for the disorder in question. It has been estimated that newly recognized syndromes are being described at the rate of one or more per week. The process of syndrome delineation is not an academic exercise but actually fosters good patient care. As an unknown syndrome becomes delineated, its phenotypic spectrum, its natural history, and its recurrence risk become known, allowing for better patient care and family counseling.

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In Part IV, the terms sequence and syndrome are defined and the difference between them is emphasized. Malformations and sequences are non-specific; each may occur as an isolated defect and each may occur as a component part of various syndromes. True malformation syndromes are characterized by embryonic pleiotropy in which a pattern of developmentally unrelated malformations occurs, that is, the malformations that make up the syndrome occur in embryonically non-contiguous areas. It is emphasized that syndrome diagnosis is never made from obligatory anomalies, but from the overall pattern of defects. Finally, the relationships among etiology, pathogenesis, and the phenotype are discussed.

Acrocallosal syndrome is a multiple congenital anomaly disorder characterized by postaxial and/or preaxial polydactyly, cutaneous syndactyly, macrocephaly, widely spaced eyes, absence or hypoplasia of the corpus callosum, and intellectual disability. It was first described by Albert Schinzel as early as in 1979, but the diagnosis of this syndrome still remains challenging. Here we report a family with 2 sibs with acrocallosal syndrome caused by novel mutations in KIF7. They present with features like molar tooth sign and hyperventilation that are not very typical in ACLS, but do occur in other ciliopathies, hence we also discuss the clinical heterogeneity of KIF7-associated disorders.

Part X is the reference section for Parts I through VIII which appeared in the four previous issues of the journal and Part IX which appears in this issue. The reference section itself is divided into two parts. The first part provides general references of selected topics for the interested reader. The second part consists of an alphabetical listing of all references cited in Parts I through IX.

Principles of teratogenesis are reviewed, including adverse environmental factors and the genotype, timing of exposure, mechanisms and pathogenesis, the nature of teratogenic agents, manifestations of deviant development, and dosage. Human teratogenic conditions are summarized with special emphasis on the fetal alcohol syndrome, fetal hydantoin syndrome, fetal trimethadione syndrome, fetal valproate syndrome, warfarin embryopathy, retinoic acid embryopathy, congenital rubella syndrome, radiation effects, and diabetic embryopathy.