The pathology of trisomy 13 syndrome

Summary Anatomical and histopathological findings in 12 cases of trisomy 13 syndrome (nine with classic full trisomy and three with trisomy 13 and an unbalanced Robertsonian 13/13 translocation) are reported. Emphasis is on the brain defects, cardiovascular anomalies, and histological organ dysplasia. Eight patients showed abnormal development of the forebrain and midline facial structures (holoprosencephaly). Cardiovascular malformations were invariably present, the leading malformation being an infundibular ventricular septal defect often in combination with dextroposition of the aorta and abnormalities of the semilunar valves. Histological abnormalities giving evidence of organ dysplasia were observed in the central nervous system, eyes, pancreas, kidneys, and ovaries. Mild cystic renal dysplasia was a constant feature. Foci of persistent nodular renal blastema were found in six cases. The pancreatic dysplasia appears to be pathognomonic for trisomy 13. These observations illustrate the importance of pathological studies in the recognition of chromosome abnormalities and, more specifically, of trisomy 13 syndrome. Based on autopsy data, trisomy 13 can be diagnosed — or ruled out — with certainty, even in the absence of karyotyping.     

Better Prognosis in Newborns with Trisomy 13 Who Received Intensive Treatments: A Retrospective Study of 16 Patients

Intensive treatment for newborns with trisomy 13 is controversial because of their lethal prognosis. We report the better life prognosis of patients with trisomy 13 who received intensive treatment. At our hospital, we provided an intensive management to such patients including resuscitation and surgical procedures as required. Herein, we present the results of a retrospective study (1989-2010) of 16 trisomy 13 cases who received an intensive treatment. None was diagnosed to have trisomy 13 before birth; 9 were delivered by C-section and oxygen was administered to all patients during postpartum resuscitation. Mechanical ventilation was used in 9 patients after tracheal intubation and tracheotomy was performed in 2 patients when withdrawing of extubation was difficult. Regarding prognosis, 9 patients died, 3 were referred to another hospital, and 4 were discharged from the hospital. Four and 7 patients died within 7 and 30 days after birth, respectively. Nine patients survived for >1 month, 7 for >180 days, and 5 for >3 years. Median survival for 16 patients was 733 days. The patients who received intensive treatments survived longer compared to the previous data. This study provides useful information concerning genetic counseling, especially from an ethical point of view, before providing intensive management to newborns with trisomy 13.     

Noninvasive prenatal diagnosis of fetal trisomy 18 and trisomy 13 by maternal plasma DNA sequencing

Massively parallel sequencing of DNA molecules in the plasma of pregnant women has been shown to allow accurate and noninvasive prenatal detection of fetal trisomy 21. However, whether the sequencing approach is as accurate for the noninvasive prenatal diagnosis of trisomy 13 and 18 is unclear due to the lack of data from a large sample set. We studied 392 pregnancies, among which 25 involved a trisomy 13 fetus and 37 involved a trisomy 18 fetus, by massively parallel sequencing. By using our previously reported standard z-score approach, we demonstrated that this approach could identify 36.0% and 73.0% of trisomy 13 and 18 at specificities of 92.4% and 97.2%, respectively. We aimed to improve the detection of trisomy 13 and 18 by using a non-repeat-masked reference human genome instead of a repeat-masked one to increase the number of aligned sequence reads for each sample. We then applied a bioinformatics approach to correct GC content bias in the sequencing data. With these measures, we detected all (25 out of 25) trisomy 13 fetuses at a specificity of 98.9% (261 out of 264 non-trisomy 13 cases), and 91.9% (34 out of 37) of the trisomy 18 fetuses at 98.0% specificity (247 out of 252 non-trisomy 18 cases). These data indicate that with appropriate bioinformatics analysis, noninvasive prenatal diagnosis of trisomy 13 and trisomy 18 by maternal plasma DNA sequencing is achievable.     

Non-Invasive Prenatal Detection of Trisomy 13 Using a Single Nucleotide Polymorphism- and Informatics-Based Approach

Purpose

To determine how a single nucleotide polymorphism (SNP)- and informatics-based non-invasive prenatal aneuploidy test performs in detecting trisomy 13.

Methods

Seventeen trisomy 13 and 51 age-matched euploid samples, randomly selected from a larger cohort, were analyzed. Cell-free DNA was isolated from maternal plasma, amplified in a single multiplex polymerase chain reaction assay that interrogated 19,488 SNPs covering chromosomes 13, 18, 21, X, and Y, and sequenced. Analysis and copy number identification involved a Bayesian-based maximum likelihood statistical method that generated chromosome- and sample-specific calculated accuracies.

Results

Of the samples that passed a stringent DNA quality threshold (94.1%), the algorithm correctly identified 15/15 trisomy 13 and 49/49 euploid samples, for 320/320 correct copy number calls.

Conclusions

This informatics- and SNP-based method accurately detects trisomy 13-affected fetuses non-invasively and with high calculated accuracy.     

False Negative NIPT Results: Risk Figures for Chromosomes 13, 18 and 21 Based on Chorionic Villi Results in 5967 Cases and Literature Review

Non-invasive prenatal testing (NIPT) demonstrated a small chance for a false negative result. Since the “fetal” DNA in maternal blood originates from the cytotrophoblast of chorionic villi (CV), some false negative results will have a biological origin. Based on our experience with cytogenetic studies of CV, we tried to estimate this risk. 5967 CV samples of pregnancies at high risk for common aneuplodies were cytogenetically investigated in our centre between January 2000 and December 2011. All cases of fetal trisomy 13, 18 and 21 were retrospectively studied for the presence of a normal karyotype or mosaicism < 30% in short-term cultured (STC-) villi. 404 cases of trisomies 13, 18 and 21 were found amongst 5967 samples (6,8%). Of these 404 cases, 14 (3,7%) had a normal or low mosaic karyotype in STC-villi and therefore would potentially be missed with NIPT. It involved 2% (5/242) of all trisomy 21 cases and 7.3% (9/123) of all trisomy 18 cases. In 1:426 (14/5967) NIPT samples of patients at high risk for common aneuploidies, a trisomy 18 or 21 will potentially be missed due to the biological phenomenon of absence of the chromosome aberration in the cytotrophoblast.     

Trisomies 13 and 18: prenatal diagnosis and epidemiologic studies in Hawaii, 1986-1997

Using a birth defects registry, this study examined the influence of prenatal diagnosis and elective termination of pregnancy on trisomy 13 and trisomy 18 prevalence in Hawaii between 1986 and 1997. The investigation also evaluated the impact of various demographic factors on risk for the aneuploidies. Forty-seven cases of trisomy 13 and 116 cases of trisomy 18 were identified. The total prevalence of trisomy 13 was 1.91 per 10,000 births and of trisomy 18 was 4.71 per 10,000 births. Elective terminations accounted for 38.3% of trisomy 13 cases and 48.3% of trisomy 13 cases. The 1-year mortality rate for trisomy 13 was 89.5% and for trisomy 18 was 74.3%. Rates for both aneuploidies increased during the time period. The racial/ethnic group with the highest prevalence of both anomalies was Far East Asian. The aneuploidies were more common in metropolitan Honolulu than the rest of Hawaii. Demographic factors demonstrated differences in risk for trisomies 13 and 18, although most of these differences appeared to be due, at least in part, to differences in maternal age distribution. For the secular trend, increased prenatal diagnosis of the anomalies also contributed to the observed increase.     

Trisomy 13 in the fetus

A significant number of fetuses with trisomy 13 are spontaneously or voluntarily lost before birth; however, very few such fetuses have been systemically autopsied. In the present study, ten trisomy 13 fetuses of 130-305 mm in crown-rump length, estimated gestational age from 108 days to 239 days, were examined following either karyotype or ultrasonographic diagnosis and voluntary termination. Mean maternal age was 35.1 years. The spectrum of anatomical features was similar to that observed in neonates or older infants with trisomy 13, namely, holoprosencephaly, cyclopia, microphthalmia, cleft palate and lip, cardiac defect, polydactyly, and cystic kidney. Kidney weights were significantly increased above normal in eight of nine fetuses. Histologically, the cortex of these kidneys showed increased mitotic activity and blastemic appearance, which extended deep into the medullary areas. The weights and histology of other organs were normal except for slight increases in spleen weight.     

Rates of 47, + 13 amd 46 translocation D/13 Patau syndrome in live births and comparison with rates in fetal deaths and at amniocentesis.

Trisomy 13 (Patau syndrome) is rare in newborns. Data on rates in 167,774 live births from 17 separate studies are reviewed, and the following pooled rates found for: (1) 47,trisomy 13, 8.3 X 10(-5) (1/12,000); and (2) 46, (D/13 Robertsonian translocations), 4.2 X 10(-5) (1/24,000)--mutants, 1.2 X 10(-5) (1/80,000) to 1.8 X 10(-5) (1/56,000); and familial cases, 2.4 X 10(-5) (1/42,000) to 3.0 X 10(-5) (1/33,000). The rate of trisomy 13 (47, + 13) in liveborns (ignoring possible biases in studies and heterogeneity in rates) is, with 95% confidence, between 4.6 X 10(-5) (1/21,700) and 14.0 X 10(-5) (1/7,000), with the most likely figure close to 8 X 10(-5) (1/12,000). Numbers are insufficient to construct a comparably narrow confidence interval for translocation cases. The rates of 47, + 13 may be estimated in (1) spontaneous abortuses, about 0.8%--1.0% (100-fold greater than in liveborns); (2) early neonatal deaths, about 0.4% (50-fold greater than in liveborns); and (3) amniocentesis, higher than in liveborns, at least for mothers 40 years and over.     

Partial trisomy of 13(pter→q12) due to 47,XY,+der(13),t(13;22)(q12;q13)mat

Summary A 36-month-old boy presented with short stature, short neck, shield-shaped chest, and mental retardation. Chromosome analysis showed trisomy for the short arm and the proximal portion of the long arm of chromosome 13 [47,XY,+der(13),t(13;22)(q12;q13)mat]. The patient's mother has a balanced translocation between the long arms of chromosomes 13 and 22 [46,XX,t(13;22)(q12;q13)]. The patient's neutrophils showed an elevated number of nuclear projections and his fetal hemoglobin level was undetectable.     

Proximal trisomy 13. A family with balanced reciprocal translocation t(8;13) in seven members and Robertsonian translocation t(13;14) in three members

Summary The cytogenetic analysis of a 12-year-old retarded boy revealed a partial proximal trisomy 13, resulting from a maternal translocation t(8;13). A familial study shows this translocation in seven persons and also a Robertsonian translocation t(13q;14q) in three sons of a t(8;13) father. A review of partial proximal trisomies 13 shows a variability in the phenotypic expression.     

Autopsy Report of a 7-Year Old Patient with the Mosaic Trisomy 13

We present here a long survival case of a patient with the mosaic form of trisomy 13 who died of aspiration pneumonia at the age of 7 years and 4 months. The autopsy revealed olfactory aplasia and fenestration of the septum pellucidum, and dilated lateral ventricles and atrophic hippocampus. Furthermore, there were numerous “torpedos” (i.e., swollen fusiform Purkinje cell axons), mostly in the granular layer underneath the Purkinje cell layer, and, occasionally, in the granular layer. Similar neuropathological findings have been reported in elderly cases of essential tremor, Parkinson’s disease, or Alzheimer’s disease. Precise mechanism for this axonal change is still unclear. These pathological changes have never previously been reported in the literature on trisomy 13, and the present patient is one of the oldest autopsied individuals with the mosaic trisomy 13.     

The phenotype in partial 13q trisomies,apropos of a familial (13;15)(q22;q26) translocation

Summary A 12 month-old male patient with a karyotype 46, XY,-15,+der(15),t(13;15)(q22;q26)pat is presented. His stillborn sib showed malformations compatible with the 13q deletion syndrome, probably due to a 46,XY, der(13) karyotype. Phenotypic analysis of 41 cases from the literature with partial distal 13q (D13q) trisomies indicate that the segment 13q22 qter in trisomy with or without another concomitant aneusomy is sufficient to produce the majority of the trisomy 13 syndrome features, some of which (cleft palate, increased HbF and projections in PMN) are present in different non-overlapping partial 13q trisomies. About 82% of the D13q trisomies are inherited, more frequently from the mother.     

Double trisomy in spontaneous abortions

Cytogenetic data on products of conception from spontaneous abortions studied over a 10-year period have been reviewed for double trisomies. A total of 3034 spontaneous abortions were karyotyped between 1986 and 1997. Twenty-two cases with double trisomy, one case with triple trisomy, and a case with a trisomy and monosomy were found. The tissues studied were mostly sac, villi, or placenta. The gestational age ranged from 6 to 11 weeks and the mean age was 8.2 ± 1.7 (SD) weeks. The mean maternal age in years was 35.9 ± 5.3. Of the twenty-two cases, four were mosaics. All but two of the cases involved autosomal aneuploidies. The double trisomies included chromosomes 2, 4, 5, 7, 8, 12, 13, 14, 15, 16, 17, 18, 20, 21, and 22. The chromosomes that were trisomic in more than one double trisomy case were numbers 16 (8 cases), 8 (5 cases), 15 (4 cases), 2, 13, and 21 (3 cases each), and 5, 7, 14, 18, 20, 22, and X (2 cases). The triple trisomy involved chromosomes 18, 21, and X. The monosomy and trisomy case was a mosaic, with a monosomy 21 in all cells and some cells also with a trisomy 5. The double trisomies cited for the first time in this study were 4/13, 5/16, 8/14, 8/15, 14/21, 15/20, and 7/12. The pooled mean maternal age for double trisomy cases (34.1 ± 5.7 years) was higher than that for single trisomy cases (31 ± 6.1 years). The difference was statistically significant at P = < 0.001. The pooled mean gestational age of spontaneous abortions was lower for double trisomy (8.7 ± 2.2 weeks) than for reported single trisomy cases (10.1 ± 2.9 weeks). This difference is also statistically significant at P = < 0.001. The sex ratio among double trisomies was 15 females to 13 males. This difference was not statistically significant from the expected 1 : 1. Received: 27 June 1997 / Accepted: 4 September 1997     

Inherited pericentric inversion of chromosome no. 2 with Robertsonian translocation (13q 14q) resulting in trisomy for chromosome 13q

This report includes a patient with an inherited pericentric inversion of chromosome No. 2 in addition to a Robertsonian translocation resulting in trisomy for chromosome 13q. The chromosomal constitution of the proband was 46,XX,inv(2) (pter leads to p11 : : q14 leads to p11 : : q14 leads to qter); t(13,14) (13qter leads to 13p11 : : 14q11 leads to 14qter). Sequential QFQ, RFA and GTG banding techniques were employed on the chromosomes of all family members. The chromosomal constitutions of the father and his first child were normal while the mother had an inversion of chromosome No. 2 [46,XX,inv(2) (pter leads to p11 : : q14 leads to p11 : : q14 leads to qter)]. The proband inherited this abnormal chromosome. In addition, she had a de novo Robertsonian translocation involving chromosomes 13q and 14q resulting in trisomy of chromosome 13q.     

Overexpression of esterase D in kidney from trisomy 13 fetuses.

Human trisomy 13 (Patau syndrome) occurs in approximately 1 in 5,000 live births. It is compatible with life, but prolonged survival is rare. Anomalies often involve the urogenital, cardiac, craniofacial, and central nervous systems. It is possible that these abnormalities may be due to the overexpression of developmentally important genes on chromosome 13. The expression of esterase D (localized to chromosome 13q14.11) has been investigated in both muscle and kidney from trisomy 13 fetuses and has been compared with normal age- and sex-matched fetal tissues, by using northern analysis. More than a twofold increase in expression of esterase D was found in the kidney of two trisomy 13 fetuses, with normal levels in a third. Overexpression was not seen in the muscle tissues from these fetuses.     

Partial trisomy 13 due to t(X;13) translocation. Contribution of in situ hybridization

A new case of partial trisomy 13 through unbalanced de novo translocation t(X;13) is reported. In situ hybridization has been used to specify breakage points on the X chromosome. This case is cytogenetically comparable with another reported case; the phenotypical aspect of these two patients is however different. This discrepancy is discussed.     

Comparative anatomical analysis of human trisomies 13, 18, and 21: I. The forelimb

Human trisomies 13, 18, and 21 exhibit specific neuromuscular phenotypes (Pettersen and Bersu, '82) which include a high proportion of neuromuscular forelimb variations, many of which are atavistic in nature (de Beer, '58; Barash et al., '79; Aziz, '81a). In order to test the neuromuscular phenotype, examine the atavistic nature, and analyze the developmental delay of the trisomy forearm musculature, we dissected the forelimbs of five trisomy 13, ten trisomy 18, and two trisomy 21 cases. Our dissections compare favorably with the existing published trisomy cases (Opitz et al., '79; Pettersen and Bersu, '82). Additionally, we found significant differences in the stage at which developmental arrest occurred in trisomies 13 and 18 for the pectoral complex, extensor digitorum profundus, and intrinsic hand musculature. Some of these muscles, which occur normally in nonhuman primates (Cihak, '67, '69; Dunlap et al., '85), also appear briefly in normal human ontogeny (Cihak, '72), constituting further evidence for developmental delay in aneuploids. The disproportionately effected limb tissues also lend support to the evidence for some degree of autonomy in their development in normal individuals. Our observations are consistent with Shapiro's amplified developmental instability model ('83). Aneuploids may be viewed as genetic variants from which much may be learned about normal limb development, how aneuploidy affects dysmorphogenesis, and the kind of information which exists on the duplicated (or monosomic) chromosome.     

Partial trisomy 13q22----qter. A new case

A newborn male patient with a partial trisomy 13q22----qter, derived from a maternal translocation (13;15)(q22;p11) is reported. This non-frequent chromosomal anomaly leads to a characteristic phenotype easily recognizable from other craniosynostosis syndromes, in which the cranial malformation is often associated with auricular and limb defects. This phenotype includes: cranial malformation, characteristic facies, mental and developmental retardation, urologic and genital anomalies, polydactily, abnormal muscular tonicity and convulsive status. Our patient, a "pure" partial trisomy, without other associated chromosomal anomaly, is compared with the published cases.     

Mosaic 13 trisomy due to de novo 13/13 translocation with subsequent fission. Karyotype: 46,XX,-13, +t(13;13)(p11;q11)/46,XX,del(13)(p11). A second example

In this paper we report a second example of 13 trisomy mosaicism due to de novo 13/13 translocation followed by postzygotic fission of the translocation chromosome in a polymalformed female newborn.     

Proximal trisomy 13q and distal monosomy 8p in a dysmorphic and mentally retarded patient with an isodicentric chromosome 13q and a 13q/8p translocation chromosome

A 40 year-old dysmorphic and mentally retarded female is reported with a de novo unbalanced chromosomal rearrangement (karyotype: 46,XX,der(8)t(8;13)(p23;q123),idic(13)(pter-->q123: q123-->pter) resulting in an isodicentric chromosome 13 and a double aneusomy including partial trisomy 13 (13pter-q123) and distal monosomy 8p (8pter-p23). The main clinical findings consist of developmental/mental retardation, behavioural disturbances and minor congenital defects, not consistent with the clinical pattern of either of the two aneusomies. A mechanism for the chromosome rearrangement is proposed and the absence of specific physical findings in the present patient is discussed in the light of the available literature data.