Consecutive or non-consecutive recurrent miscarriage: is there any difference in carrier status?

BACKGROUND: Carrier status of a structural balanced chromosome abnormality is associated with recurrent miscarriage. There is, at present, no evidence of the impact of the sequence of preceding pregnancies on the probability of carrier status. The aim of our study was therefore to examine whether the history of consecutive versus non-consecutive miscarriages in couples with two or more miscarriages has any impact on the probability of carrying a chromosome abnormality. METHODS: A nested case-control study was performed in six centres for clinical genetics in the Netherlands. Couples referred for chromosome analysis after two or more miscarriages were included: 279 couples with a carrier of a structural chromosomal abnormality and 428 non-carrier couples who served as controls. Univariable and multivariable logistic regression analyses, corrected for known risk factors for carrier status, were performed. The main outcome measure was the probability of carrier status. RESULTS: Two hundred and fifty-six of 279 (92%) carrier couples and 381 of 428 (89%) non-carrier couples had experienced consecutive miscarriages (P = 0.21). A history of two or three consecutive miscarriages did not alter the probability of carrier status when compared with two [odds ratio (OR) 0.90, 95% confidence interval (CI) 0.48-1.7] or three (OR 0.71, 95% CI 0.39-1.3) non-consecutive miscarriages. CONCLUSIONS: The sequence of preceding pregnancies is not a risk factor for carrier status. Therefore, couples with miscarriages interspersed with healthy child(ren) should be managed the same as couples with consecutive miscarriages regarding chromosome diagnosis.

Phenotype-genotype correlation in a familial IGF1R microdeletion case.

BACKGROUND: IGF1R (insulin-like growth factor 1 receptor) haploinsufficiency is a rare event causing difficulties in defining clear genotype-phenotype correlations, although short stature is its well established hallmark. Several pure 15q26 monosomies (n=22) have been described in the literature, including those with breakpoints proximal to the IGF1R gene. Clinical heterogeneity is characteristic for these mainly de novo telomeric deletions and is illustrated by the involvement of several different organ systems such as the heart, diaphragm, lungs, kidneys and limbs, besides growth failure in the patient's phenotype. The clinical variability in these patients could be explained by the haploinsufficiency of multiple genes besides the IGF1R gene. In comparison, the six different IGF1R mutations revealed to date exhibit some variance in their clinical features as well, probably because different parts of the downstream IGF1R signalling cascade were affected. METHODS AND RESULTS: Using the recently developed technique multiplex ligation dependent probe amplification (MLPA), a chromosome 15q26.3 microdeletion harbouring part of the IGF1R gene was identified in a Dutch family. This deletion segregated with short height in seven out of 14 relatives across three generations. Metaphase fluorescence in situ hybridisation (FISH) and Affymetrix 250k single nucleotide polymorphism (SNP) microarray were used to characterise the deletion into more detail and showed that exons 11-21 of the IGF1R and a small hypothetical protein (LOC 145814) were deleted. CONCLUSION: Clinical work-up of this newly identified family, which constitutes the smallest (0.095 Mb) pure 15q26.3 interstitial deletion to date, confirms that disruption of the IGF1R gene does not induce major organ malformation or severe mental retardation.

FBXO7 mutations cause autosomal recessive, early-onset parkinsonian-pyramidal syndrome.

BACKGROUND: The combination of early-onset, progressive parkinsonism with pyramidal tract signs has been known as pallido-pyramidal or parkinsonian-pyramidal syndrome since the first description by Davison in 1954. Very recently, a locus was mapped in a single family with an overlapping phenotype, and an FBXO7 gene mutation was nominated as the likely disease cause. METHODS: We performed clinical and genetic studies in two families with early-onset, progressive parkinsonism and pyramidal tract signs. RESULTS: An FBXO7 homozygous truncating mutation (Arg498Stop) was found in an Italian family, while compound heterozygous mutations (a splice-site IVS7 + 1G/T mutation and a missense Thr22Met mutation) were present in a Dutch family. We also found evidence of expression of novel normal splice-variants of FBXO7. The phenotype associated with FBXO7 mutations consisted of early-onset, progressive parkinsonism and pyramidal tract signs, thereby matching clinically the pallido-pyramidal syndrome of Davison. The parkinsonism exhibits varying degrees of levodopa responsiveness in different patients. CONCLUSIONS: We conclusively show that recessive FBXO7 mutations cause progressive neurodegeneration with extrapyramidal and pyramidal system involvement, delineating a novel genetically defined entity that we propose to designate as PARK15. Understanding how FBXO7 mutations cause disease will shed further light on the molecular mechanisms of neurodegeneration, with potential implications also for more common forms of parkinsonism, such as Parkinson disease and multiple system atrophy.

Two further cases of spondyloenchondrodysplasia (SPENCD) with immune dysregulation.

Although the diagnosis of spondyloenchondrodysplasia (SPENCD) can only be made in the presence of characteristic metaphyseal and vertebral lesions, a recent report has highlighted the pleiotropic manifestations of this disorder which include significant neurological involvement and variable immune dysfunction. Here we present two patients, one of whom was born to consanguineous parents, further illustrating the remarkable clinical spectrum of this disease. Although both patients demonstrated intracranial calcification, they were discordant for the presence of mental retardation, spasticity and white matter abnormalities. And whilst one patient had features consistent with diagnoses of Sjögren syndrome, polymyositis, hypothyroidism and severe scleroderma, the other patient had clinical manifestations and an autoantibody profile of systemic lupus erythematosus. These cases further illustrate the association of SPENCD with immune dysregulation and highlight the differential diagnosis with Aicardi-Goutières syndrome and other disorders associated with the presence of intracranial calcification. Undoubtedly, identification of the underlying molecular and pathological basis of SPENCD will provide important insights into immune and skeletal regulation.

[Risk factors for structural chromosomal abnormality in > or = 2 miscarriages, as an instrument for selective karyotyping]. / Risicofactoren voor structurele chromosoomafwijking bij > or = 2 miskramen als instrument voor selectieve karyotypering.

OBJECTIVE: To identify additional risk factors and the corresponding probability of carrying a chromosome abnormality in couples with two or more miscarriages. DESIGN: Nested case-control study. METHOD: In 6 centres for clinical genetics in the Netherlands, data were collected from couples referred for karyotyping after 2 2 miscarriages from 1992-2000. Factors influencing the probability of carrier status were examined. The corresponding probability of carrier status was calculated for the various combinations of these factors. RESULTS: In total 279 carrier couples and 428 non-carrier couples were included. 4 independent factors influencing the probability of carrier status were identified: a younger maternal age at the time of second miscarriage, a history of > or = 3 miscarriages, a history of > 2 miscarriages in a brother or sister of either partner, and a history of> 2 miscarriages in parents of either partner. The calculated probability of carrier status in couples referred for chromosome analysis after two or more miscarriages, varied between 0.5-10.2%. In 18% of couples included, the risk was found to be so low (< 2.2%), that in couples with comparable risk factors, it may not be necessary to perform karyotyping. CONCLUSION: This study demonstrated that the probability of carrier status in couples with > or = 2 miscarriages is modified by additional factors. Selective chromosome analysis would result in a more effective referral policy and therefore decrease the number of chromosome analyses and lower the costs.

Contribution of CYLN2 and GTF2IRD1 to neurological and cognitive symptoms in Williams Syndrome.

Williams Syndrome (WS, [MIM 194050]) is a disorder caused by a hemizygous deletion of 25-30 genes on chromosome 7q11.23. Several of these genes including those encoding cytoplasmic linker protein-115 (CYLN2) and general transcription factors (GTF2I and GTF2IRD1) are expressed in the brain and may contribute to the distinct neurological and cognitive deficits in WS patients. Recent studies of patients with partial deletions indicate that hemizygosity of GTF2I probably contributes to mental retardation in WS. Here we investigate whether CYLN2 and GTF2IRD1 contribute to the motoric and cognitive deficits in WS. Behavioral assessment of a new patient in which STX1A and LIMK1, but not CYLN2 and GTF2IRD1, are deleted showed that his cognitive and motor coordination functions were significantly better than in typical WS patients. Comparative analyses of gene specific CYLN2 and GTF2IRD1 knockout mice showed that a reduced size of the corpus callosum as well as deficits in motor coordination and hippocampal memory formation may be attributed to a deletion of CYLN2, while increased ventricle volume can be attributed to both CYLN2 and GTF2IRD1. We conclude that the motor and cognitive deficits in Williams Syndrome are caused by a variety of genes and that heterozygous deletion of CYLN2 is one of the major causes responsible for such dysfunctions.

The circulating lymphocyte profiles in patients with discoid lupus erythematosus and systemic lupus erythematosus suggest a pathogenetic relationship.

BACKGROUND: Discoid lupus erythematosus (DLE) and systemic lupus erythematosus (SLE) are chronic inflammatory diseases of unknown aetiology; the relationship of DLE with SLE has been a subject of debate for many years. OBJECTIVES; To find evidence for systemic immune activation in DLE by analysis of the immunophenotypic profiles of circulating lymphocytes, and to compare these changes with those in patients with SLE. METHODS: The immunophenotypic profile of peripheral blood lymphocyte subsets from 23 DLE patients without clinical or laboratory evidence of systemic disease, 25 SLE patients and 38 healthy donors was characterized by two-colour immunofluorescence flow cytometry analysis. None of the patients was receiving corticosteroid or immunosuppressive treatment. RESULTS: Patients with DLE had increased numbers of circulating HLA-DR+ CD3+ T cells and HLA-DR+ CD4+ T cells, indicating systemic T-cell activation, and an expansion of CD5+ CD19+ B cells. Decreased numbers of T-cell subsets expressing the differentiation markers CD11b and CD16/56, and of CD16/56+ natural killer cells were also found. In SLE, the changes were similar but more pronounced. In addition, a profound CD4+ T-cell lymphopenia and an increase of HLA-DR+ CD8+ T cells were found only in SLE. CONCLUSIONS: Our data provide evidence for systemic activation of the cellular immune system in patients with purely cutaneous DLE. Similarities in the lymphocyte immunophenotypic profiles in patients with DLE compared with SLE suggest that there are common immunopathological processes in these two conditions.

Early diagnosis of Wolf-Hirschhorn syndrome triggered by a life-threatening event: congenital diaphragmatic hernia.

Wolf-Hirschhorn syndrome (WHS, OMIM 194190) is a chromosomal disorder characterized by retarded mental and physical growth, microcephaly, Greek helmet appearance of the facies, seizures/epilepsy. Closure defects of lip or palate, and cardiac septum defects occur in 30-50% of cases. Its cause is a deletion in the short arm of chromosome 4. We present a male patient, born after 37 weeks gestation, as the fourth pregnancy of non-consanguineous healthy parents, with unilateral cleft lip and palate, hypertelorism, a right-sided ear tag, and mild epispadias. At age 10 weeks he developed acute respiratory distress and acute bowel obstruction requiring emergency laparotomy. This revealed a left-sided posterolateral diaphragmatic defect, type Bochdalek, with incarceration of the small intestines necessitating major bowel resection. Clinical genetic investigation suggested a chromosome anomaly, but regular karyotyping was normal. However, FISH analysis showed a microdeletion in the short arm of chromosome 4 (4p-), consistent with WHS. A combination of this syndrome with congenital diaphragmatic hernia (CDH) has been rarely described. CDH can present either as an isolated defect at birth, or with multiple congenital abnormalities, or as part of a defined syndrome or chromosomal disorder. Therefore CDH, although not common in WHS, can lead to its diagnosis relatively early in life. We strongly recommend a clinical genetic evaluation of each CDH patient with facial anomalies taking into consideration 4p- deletion syndrome.

Different circulating lymphocyte profiles in patients with different subtypes of juvenile idiopathic arthritis.

OBJECTIVE: To determine the immunophenotypic profiles of circulating lymphocytes in patients with different disease types of Juvenile Idiopathic Arthritis (JIA). METHODS: Peripheral blood lymphocyte subsets from 19 patients with oligoarticular JIA (o-JIA), 10 patients with polyarticular JIA (p-JIA), 12 patients with systemic JIA (s-JlA) andfrom 41 age-matched healthy controls were characterized by two color immunofluorescence flow cytometry analysis. RESULTS: Patients with o-JIA and p-JIA had increased numbers of HLA-DR+ Tcells and Tcells co-expressing CD57 and CD16/56, indicating T cell activation and terminal differentiation of CD8+ T cells respectively. By contrast, in patients with s-JIA there was no increase in the activation or differentiation markers on T cells, but a profound decrease in circulating NK cells. All patients had hypergammaglobulinemia consistent with B cell hyperactivity, but increased numbers of CD5+ B cells were found only in o-JIA and p-JIA. CONCLUSION: Distinct immunophenotypic lymphocyte profiles in patients with o-JIA and p-JIA compared to patients with s-JIA as demonstrated in this study, are consistent with afundamental heterogeneity of the disease.

Ring chromosome 20 epilepsy syndrome in children: electroclinical features.

Ring chromosome 20 mosaicism is associated with dysmorphic features, mental retardation, and intractable seizures, including recurrent episodes of nonconvulsive status epilepticus. The authors' findings in four children, all without dysmorphic features, indicate that mental deterioration and frequent subtle nocturnal frontal lobe seizures, associated with a characteristic EEG pattern, represent prominent additional clinical features not previously described in this syndrome. This emphasizes the importance of full-night video-EEG in children with frontal lobe seizures and cognitive deterioration.

Deletions at chromosome regions 7q11.23 and 7q36 in a patient with Williams syndrome.

We report on a patient with Williams syndrome and a complex de novo chromosome rearrangement, including microdeletions at 7q11.23 and 7q36 and additional chromosomal material at 7q36. The nature of this additional material was elucidated by spectral karyotyping and first assigned to chromosome 22. Subsequent fluorescence in situ hybridization (FISH) experiments showed that it consisted of satellite material only. Refinement of the 7q36 breakpoint was performed with several FISH probes, showing a deletion distal to the triphalangeal thumb (TPT) region. The phenotype of the patient principally results from the microdeletion of the 7q11.23; the small deletion at 7qter and the extra satellite material may not be of clinical significance.

A Rett syndrome patient with a ring X chromosome: further evidence for skewing of X inactivation and heterogeneity in the aetiology of the disease.

Rett syndrome (RTT) is an X-linked neurodevelopmental disorder, characterised by regression of development in young females. Recently, mutations in the MECP2 gene were found to be present in 80% of sporadic cases, but in much lower frequency (< 30%) among familial cases. Several reports claim that the pattern of X chromosome inactivation (XCI) relates to the penetrance of RTT; in some cases skewed XCI is seen in Rett patients, and in others it is observed among normal carriers. We present here a case of RTT with a 46,X,r(X) in which complete skewed inactivation of the ring was demonstrated. Further, no mutations were found in the MECP2 gene present on the intact X. Our data, in conjunction with two previously published cases of X chromosome abnormalities in RTT, indicate that X chromosome rearrangements are sporadically associated with RTT in conjunction with extreme skewing of X inactivation. Based on our case and reported data, we discuss the evidence for a second X-linked locus for RTT associated with lower penetrance, and a different pattern of XCI, than for MECP2. This would result in a larger proportion of phenotypically normal carrier women transmitting the mutation for this putative second locus, and account for the minority of sporadic and majority of familial cases that are negative for MECP2 mutations.

Duane retraction syndrome, a new feature in 22q11 deletion syndrome?

A female child with Duane retraction syndrome is described. A microdeletion on chromosome 22(q11) was discovered using FISH analysis. It is postulated that Duane retraction syndrome might be a new feature in 22q11 deletion syndrome.

Submicroscopic Xpter deletion in a boy with growth and mental retardation caused by a familial t(X;14).

In a 3-year-old boy with short stature, developmental delay, and dry skin, steroid sulphatase deficiency and a submicroscopic terminal deletion of Xp were found. Except for the short stature, no major clinical signs of X-linked recessive chondrodysplasia punctata could be observed. His mother had lowered steroid sulphatase activity compatible with carriership for X-linked ichthyosis and a submicroscopic translocation (X;14)(p22.31;p11.1). This finding combined with a normal amplification of exons 1, 5, and 10 of the STS gene from propositus' DNA suggested a breakpoint upstream of the STS gene. The submicroscopic maternal translocation had important implications for genetic counseling. This case report illustrates that contiguous gene syndrome related to the Xpter region may have an atypical clinical presentation and the usefulness of combined clinical, biochemical, molecular, and fluorescence in situ hybridization analysis.

Partial trisomy 4q and monosomy 9p resulting from a familial translocation t(4;9)(q27;p24) in a child with choanal atresia.

A male infant with a deletion of 9p and concomitant duplication of 4q: 46,XY, der(9)t(4;9)(q27;p24), is described. Parental chromosome analysis showed a balanced maternal translocation. To our knowledge, the above cytogenetic and clinical abnormalities have not been described previously. A phenotype comparison is presented with previously reported cases concerning a deletion of 9p and a duplication of 4q.

The murine CYLN2 gene: genomic organization, chromosome localization, and comparison to the human gene that is located within the 7q11.23 Williams syndrome critical region.

Cytoplasmic linker proteins (CLIPs) have been proposed to mediate the interaction between specific membranous organelles and microtubules. We have recently characterized a novel member of this family, called CLIP-115. This protein is most abundantly expressed in the brain and was found to associate both with microtubules and with an organelle called the dendritic lamellar body. CLIP-115 is highly homologous to CLIP-170, or restin, which is a protein involved in the binding of endosomes to microtubules. Using the rat cDNA as a probe we have isolated overlapping cosmids containing the complete murine and part of the human CYLN2 (cytoplasmic linker-2) genes, which encode CLIP-115. The murine gene spans 60 kb and consists of 17 exons, and its promoter is embedded in a CpG island. Murine CYLN2 maps to the telomeric end of mouse chromosome 5. The human CYLN2 gene is localized to a syntenic region on chromosome 7q11.23, which is commonly deleted in Williams syndrome. It spans at least 140 kb at the 3' end of the deletion. Human CYLN2 is very likely identical to the previously characterized, incomplete WSCR4 and WSCR3 transcription units.