Madeleine Joubert

Hepatic Stem-like Phenotype and Interplay of Wnt/β-Catenin and Myc Signaling in Aggressive Childhood Liver Cancer

Hepatoblastoma, the most common pediatric liver cancer, is tightly linked to excessive Wnt/beta-catenin signaling. Here, we used microarray analysis to identify two tumor subclasses resembling distinct phases of liver development and a discriminating 16-gene signature. beta-catenin activated different transcriptional programs in the two tumor types, with distinctive expression of hepatic stem/progenitor markers in immature tumors. This highly proliferating subclass was typified by gains of chromosomes 8q and 2p and upregulated Myc signaling. Myc-induced hepatoblastoma-like tumors in mice strikingly resembled the human immature subtype, and Myc downregulation in hepatoblastoma cells impaired tumorigenesis in vivo. Remarkably, the 16-gene signature discriminated invasive and metastatic hepatoblastomas and predicted prognosis with high accuracy.

Detection of genomic imbalances by array based comparative genomic hybridisation in fetuses with multiple malformations

Background: Malformations are a major cause of morbidity and mortality in full term infants and genomic imbalances are a significant component of their aetiology. However, the causes of defects in many patients with multiple congenital malformations remain unexplained despite thorough clinical examination and laboratory investigations. Methods: We used a commercially available array based comparative genomic hybridisation method (array CGH), able to screen all subtelomeric regions, main microdeletion syndromes, and 201 other regions covering the genome, to detect submicroscopic chromosomal imbalances in 49 fetuses with three or more significant anomalies and normal karyotype. Results: Array CGH identified eight genomic rearrangements (16.3%), all confirmed by quantitative multiplex PCR of short fluorescent fragments. Subtelomeric and interstitial deletions, submicroscopic duplications, and a complex genomic imbalance were identified. In four de novo cases (15qtel deletion, 16q23.1–q23.3 deletion, 22q11.2 deletion, and mosaicism for a rearranged chromosome 18), the genomic imbalance identified clearly underlay the pathological phenotype. In one case, the relationship between the genotype and phenotype was unclear, since a subtelomeric 6q deletion was detected in a mother and her two fetuses bearing multiple malformations. In three cases, a subtelomeric 10q duplication, probably a genomic polymorphism, was identified. Conclusions: The detection of 5/49 causative chromosomal imbalances (or 4/49 if the 6qtel deletion is not considered as causative) suggests wide genome screening when standard chromosome analysis is normal and confirms that array CGH will have a major impact on pre and postnatal diagnosis as well as providing information for more accurate genetic counselling.

Renal Tubular Dysgenesis, a Not Uncommon Autosomal Recessive Disorder Leading to Oligohydramnios: Role of the Renin-Angiotensin System

Renal tubular dysgenesis is a clinical disorder that is observed in fetuses and characterized by the absence or poor development of proximal tubules, early onset and persistent oligohydramnios that leads to the Potter sequence, and skull ossification defects. It may be acquired during fetal development or inherited as an autosomal recessive disease. It was shown recently that autosomal recessive renal tubular dysgenesis is genetically heterogeneous and linked to mutations in the genes that encode components of the renin-angiotensin system. This study analyzed the clinical expression of the disease in 29 fetus/neonates from 18 unrelated families and evaluated changes in renal morphology and expression of the renin-angiotensin system. The disease was uniformly severe, with perinatal death in all cases as a result of persistent anuria and hypoxia related to pulmonary hypoplasia. Severe defects in proximal tubules were observed in all fetuses from 18 gestational weeks onward, and lesions also involved other tubular segments. They were associated with thickening of the renal arterial vasculature, from the arcuate to the afferent arteries. Renal renin expression was strikingly increased in 19 of 24 patients studied, from 13 families, whereas no renal renin was detected in four patients from three families. Angiotensinogen and angiotensin-converting enzyme were absent or present in only small amounts in the proximal tubule, in correlation with the severity of tubular abnormalities. No specific changes were detected in angiotensin II receptor expression. The severity and the early onset of the clinical and pathologic expression of the disease underline the major importance of this system in fetal kidney function and development in humans. The identification of the disease on the basis of precise histologic analysis and the research of the genetic defect now allow genetic counseling and early prenatal diagnosis.

46,XY gonadal dysgenesis: evidence for autosomal dominant transmission in a large kindred.

46,XY gonadal dysgenesis is characterized by abnormal testicular determination. We describe a large kindred in which various disorders of sexual development were observed, ranging from completely female phenotype without ambiguities of the external genitalia (five cases) to men with isolated penile or perineal hypospadias (four cases), including two cases with moderate virilization and one case with ambiguity of the external genitalia. Histologic examination of gonadal tissue was performed on seven subjects. These findings were suggestive of complete gonadal dysgenesis in one patient, partial gonadal dysgenesis in three patients, and mixed gonadal dysgenesis in three patients. Four patients developed gonadal tumors (two gonadoblastoma, two dysgerminoma, and one immature teratoma, i.e., one patient had a dysgerminoma with some areas of gonadoblastoma). All affected subjects had no other congenital anomalies or dysmorphic features. Analysis of families with several affected individuals with 46,XY gonadal dysgenesis implied an X‐linked mode of inheritance because of the apparent absence of male‐to‐male transmission. However, a sex‐limited autosomal dominant mode of inheritance affecting only XY individuals could not be ruled out. Analysis of the pedigree we report indicated an autosomal dominant mode of inheritance because of male‐to‐male transmission. This kindred supports the involvement of at least one autosomal gene in non‐syndromic 46,XY gonadal dysgenesis.

Complete sex reversal in a WAGR syndrome patient.

The WAGR contiguous gene deletion syndrome is a combination of Wilms tumor, aniridia, genitourinary abnormalities, and mental retardation. Children with WAGR syndrome invariably have a constitutional chromosomal deletion at 11p13. WT1 haploinsufficiency is associated with a significant risk of Wilms tumor while PAX6 haploinsufficiency lead to aniridia, both genes located in the deleted region. The 46,XY patients with WAGR syndrome are often born with genital abnormalities such as cryptorchidism or hypospadias but more rarely ambiguous genitalia. To our knowledge, complete sex reversal has never been observed in WAGR syndrome patients. Here, we report on the clinical, cytogenetic, and molecular characterization of a child with WAGR syndrome and complete sex reversal. The young girl had female external and internal genitalia with normal uterus and fallopian tubes while the ovaries were not observed. Chromosomal analysis showed a 46,XY,del(11)(p12p14.1) karyotype. A 1‐Mb resolution array CGH experiment estimated the size of the interstitial deletion at ≈10 Mb encompassing WT1 and PAX6. The entire coding regions of WT1 and SRY have been sequenced and no mutation has been identified. Frasier syndrome (FS) and Denys‐Drash syndrome (DDS) are two disorders associated with mutations in the WT1 gene. Complete sex reversal is a feature usually present in FS and sometimes in DDS, but until now never observed in WAGR syndrome. The present report suggests that these conditions may be considered as part of the spectrum of disease due to WT1 gene alterations.

Prenatal sonographic findings in Peters-plus syndrome.

Peters syndrome is a congenital disease resulting from deficient cleavage of the anterior chamber of the eye. Peters‐plus syndrome (PpS) is characterized by the typical ocular anomalies of Peters syndrome in association with impaired growth, mental retardation and other malformations. We report the first prenatal description of PpS in the 20‐week fetus of a consanguineous couple. Ultrasound examination revealed microphthalmia and hyperechogenicity of the anterior part of the eye with a central defect, micrognathia and long philtrum, short limbs with broad extremities and unilateral multicystic kidney. The pregnancy was terminated on parental request. Autopsy, including careful ocular examination, established the diagnosis of PpS. PpS has an autosomal‐recessive mode of inheritance. The ocular anomaly has been linked with mutations in genes PAX6, PITX2, PITX3 and CYP1B1, but the causal factor of PpS remains unknown. Copyright

Blepharophimosis, short humeri, developmental delay and hirschsprung disease: expanding the phenotypic spectrum of MED12 mutations.

We report on two male sibs, a fetus and a newborn, with short humeri and dysmorphic facial features including blepharophimosis. The newborn also had Hirschsprung disease. Goldberg–Shprintzen syndrome and the Say–Barber–Biesecker–Young–Simpson type of Ohdo syndrome were suspected but direct sequencing of KBP and KAT6B failed to identify a mutation. Finally, direct sequencing of MED12, the gene mutated in Opitz–Kaveggia syndrome, Lujan–Fryns syndrome and X‐linked Ohdo syndrome identified in the two sibs the missense mutation c.3443G>A (p.Arg1148His) inherited from the mother. This report further expands the phenotypic spectrum of MED12 mutations.

Prenatal diagnosis of a cleidocranial dysplasia-like phenotype associated with a de novo balanced t(2q;6q)(q36;q16) translocation

Cleidocranial dysplasia (CCD) is a congenital disorder of bone development characterized by persistently open or delayed closure of cranial sutures and wormian bones, hypoplastic and/or aplastic clavicles, wide pubic symphysis, dental anomalies and short stature. The condition is inherited as an autosomal‐dominant trait and the human CBFA1 gene has been identified as the CCD gene. We describe a prenatal form of the skeletal disorder that included clavicular hypoplasia, absence of ossification of the cranial parietal bones and very poor ossification of the frontal and pubic bones. Growth restriction affecting only the long bones was also noted. The fetal karyotype revealed an apparently de novo balanced t(2q;6q)(q36;q16) translocation. This particular form of skeletal disorder associated with the absence of family history and an apparently de novo balanced translocation led the parents to opt for termination of the pregnancy. Copyright

Inherited 18q23 duplication in a fetus with multiple congenital anomalies

We report on a fetus with multiple congenital anomalies including atypical lissencephaly, corpus callosum agenesis, cerebellar hypoplasia, cleft palate, ventricular septal defect, and hypoplastic aortic arch. The initial routine chromosome study failed to detect any abnormality. Subtelomeres analysis by MLPA identified an 18q23 duplication inherited from its healthy father. We describe the anomalies identified and discuss diagnosis and the causability of this telomeric duplication.

Le diagnostic anténatal d’atrésie bronchique est-il possible ?

Bronchial atresia is a rare congenital malformation of the lung. The main-stem segmental or lobar bronchus fails to construct normally, which can lead to accumulation of mucus within the distal bronchi or lung hyperinflation of the obstructed lobe. The prenatal diagnosis is rare and difficult. We report two cases of fetuses who presented pathological examination of the lung on the ultrasonography, at 22 weeks of gestation, suspect of prenatal bronchial atresia diagnosis. We analysed this malformation through a literature review in order to discuss differential diagnosis to be evoked, as well as appropriate perinatal management.