Two different prenatal imaging cerebral patterns of tubulinopathy.

To illustrate the prenatal cerebral imaging features associated with tubulinopathy, we report on five affected fetuses from unrelated families, with a de-novo heterozygous variant in a tubulin gene (TUBA1A, TUBB2B or TUBB3). We identified two distinct prenatal imaging patterns related to tubulinopathy: a severe form, characterized by enlarged germinal matrices, microlissencephaly and a kinked brainstem; and a mild form which has not been reported previously in the prenatal literature. The latter form is associated with non-specific features, including an asymmetric brainstem, corpus callosal dysgenesis, a lack of Sylvian fissure operculization and distortion of the anterior part of the interhemispheric fissure with subsequent impacted medial borders of the frontal lobes, the combination of which, in the absence of additional extracerebral anomalies, is highly suggestive of tubulinopathy. Copyright © 2020 ISUOG. Published by John Wiley & Sons Ltd.

Wiedemann-Steiner syndrome as a major cause of syndromic intellectual disability: A study of 33 French cases.

Wiedemann-Steiner syndrome (WSS) is a rare syndromic condition in which intellectual disability (ID) is associated with hypertrichosis cubiti, short stature, and characteristic facies. Following the identification of the causative gene (KMT2A) in 2012, only 31 cases of WSS have been described precisely in the literature. We report on 33 French individuals with a KMT2A mutation confirmed by targeted gene sequencing, high-throughput sequencing or exome sequencing. Patients' molecular and clinical features were recorded and compared with the literature data. On the molecular level, we found 29 novel mutations. We observed autosomal dominant transmission of WSS in 3 families and mosaicism in one family. Clinically, we observed a broad phenotypic spectrum with regard to ID (mild to severe), the facies (typical or not of WSS) and associated malformations (bone, cerebral, renal, cardiac and ophthalmological anomalies). Hypertrichosis cubiti that was supposed to be pathognomonic in the literature was found only in 61% of our cases. This is the largest series of WSS cases yet described to date. A majority of patients exhibited suggestive features, but others were less characteristic, only identified by molecular diagnosis. The prevalence of WSS was higher than expected in patients with ID, suggesting than KMT2A is a major gene in ID.

Refining the phenotypical and mutational spectrum of Taybi-Linder syndrome.

Taybi-Linder syndrome (TALS, OMIM 210710) is a rare autosomal recessive disorder belonging to the group of microcephalic osteodysplastic primordial dwarfisms (MOPD). This syndrome is characterized by short stature, skeletal anomalies, severe microcephaly with brain malformations and facial dysmorphism, and is caused by mutations in RNU4ATAC. RNU4ATAC is transcribed into a non-coding small nuclear RNA which is a critical component of the minor spliceosome. We report here four foetuses and four unrelated patients with RNU4ATAC mutations. We provide antenatal descriptions of this rare syndrome including unusual features found in two twin foetuses with compound heterozygosity for two rare mutations who presented with mild intrauterine growth retardation and atypical dysmorphic facial features. We also carried out a literature review of the patients described up to now with RNU4ATAC mutations, affected either with TALS or Roifman syndrome, a recently described allelic disorder.

C19orf12 gene mutations in patients with neurodegeneration with brain iron accumulation.

A novel subtype of Neurodegeneration with Brain Iron Accumulation (NBIA) recently has been described: mitochondrial membrane protein-associated neurodegeneration (MPAN), caused by mutations of c19orf12 gene. We present phenotypic data and results of screening of C19orf12 in five unrelated NBIA families. Our data led to identify novel pathogenic mutations in C19orf12.

[Symptomatic carriers of dystrophinopathy with chromosome X inactivation bias]. / Les conductrices symptomatiques pour les dystrophinopathies avec biais d'inactivation du chromosome X.

Several studies have recently highlighted the fact that the clinical involvement in females carrying a mutation in the dystrophin gene could be more frequent than usually thought, suggesting the need of a careful cardiac follow-up. Except for the classical chromosomal rearrangements, it was shown that a bias in the X chromosome inactivation process could be found in some affected females. We report two families illustrating different situations. The propositus of the first family, aged 32, presented with a proximal muscular weakness, increasing for three years, as well as elevated muscular enzymes in blood. Her brother suffered from classical Duchenne muscular dystrophy. Her mother was more severely affected, whereas her sister remained asymptomatic. A duplication of exons 3 to 7 of the dystrophin gene was found in all four patients. The affected carrier from the second family was a sporadic case. She has been suffering from proximal muscular weakness for six years. Muscle biopsy showed a mosaic pattern of the immunostaining using specific antidystrophin antibodies. A stop mutation was found in exon 52. Her ten year-old daughter, carrying the mutation, was asymptomatic. In both families, the inactivation profiles were in accordance with the clinical presentation. We discuss the different mechanisms that may lead to the inactivation bias in these patients, as well as the advantage and limits of using the X chromosome inactivation test as a tool for diagnosis and prognosis purpose in symptomatic carriers for dystrophinopathies.

T-cell prolymphocytic leukemia with autoimmune manifestations in Nijmegen breakage syndrome.

Nijmegen breakage syndrome (NBS) is characterized by growth retardation, microcephaly, mental retardation, immunodeficiency, and predisposition to malignancies, especially B-cell lymphomas. In contrast, leukemia is rare. A 23-year-old NBS patient presented with anemia, thrombocytopenia, and hyperlymphocytosis. The diagnosis of T-cell prolymphocytic leukemia (T-PLL) was confirmed by cytological and immunological assays (TdT(-), CD2(+), CD5(+), CD3m, and CD7(+)). Biological assays also showed a hemolytic anemia and a clotting factor V decrease. The patient was first treated by methylprednisone for 3 weeks. During this period the lymphocyte count decreased. The simultaneous normalization of the hemolysis and of factor V suggested that both could be related to T-PLL. Since T-PLL is refractory to conventional therapies with a poor prognosis, an intensive chemotherapy such as 2'-deoxycoformycin with anti-CDw52 monoclonal antibodies is usually favored. In the present case, however, because of the specific context (i.e., NBS-induced immunodepression, severe hemolytic anemia, and acquired factor V deficiency), he received pentostatin weekly during 1 month and in maintenance during 6 months. At last follow-up (7 months) he showed a persistent control of the lymphocytosis with no side effect.

Family history of cancer and germline BRCA2 mutations in sporadic exocrine pancreatic cancer.

BACKGROUND: Hereditary factors have been reported in 5-10% of cases with exocrine pancreatic cancer and recent data support a role for BRCA2. AIMS: We have studied the prevalence of germline BRCA2 mutations in two groups of patients with exocrine pancreatic cancer from an unselected series in Spain: group A included 24 cases showing familial aggregation of cancer and group B included 54 age, sex, and hospital matched cases without such evidence. METHODS: Information was obtained by interview of patients and was validated by a telephone interview with a structured questionnaire. In patients from group A, >80% of the coding sequence of BRCA2 was analysed; in patients from group B, the regions in which germline BRCA2 mutations have been described to be associated with pancreatic cancer were screened. RESULTS: Telephone interviews led to reclassification of 7/54 cases (13%). Familial aggregation of cancer was found in 24/165 cases (14.5%); six patients had a first degree relative with pancreatic cancer (3.6%) and nine patients had relatives with breast cancer. Germline BRCA2 mutations were not identified in any patient from group A (0/23). Among group B cases, one germline variant (T5868G>Asn1880Lys) was found in a 59 year old male without a family history of cancer. The 6174delT mutation was not found in any of the 71 cases analysed. CONCLUSIONS: The overall prevalence of BRCA2 mutations among patients with pancreatic cancer in Spain is low and the 6174delT mutation appears to be very infrequent. Our data do not support screening patients with cancer of the pancreas for germline BRCA2 mutations to identify relatives at high risk of developing this tumour.

Trisomy 17 mosaicism in amniotic fluid cells not found at birth in blood but present in skin fibroblasts.

This article describes a case of fetal trisomy 17 mosaicism found in amniotic fluid cells in one of two bichorial biamniotic twins without any sonographic anomaly. The extra chromosome 17 was absent from cord blood cells at birth but present on karyotype and in situ hybridization in cultured fibroblasts from skin biopsy. Clinical examination showed a few mild dysmorphic features and a moderate neurological involvement which may rather be related to prematurity. It therefore seemed important to obtain the karyotype on fibroblasts when a trisomic cell line was found in amniocentesis and not confirmed on blood lymphocytes, even in the absence of dysmorphic features. This should help to differentiate a real mosaic from a mosaic restricted to extra-fetal tissues.