Géraldine Viot

Only four genes (EDA1, EDAR, EDARADD, and WNT10A) account for 90% of hypohidrotic/anhidrotic ectodermal dysplasia cases.

Hypohidrotic and anhidrotic ectodermal dysplasia (HED/EDA) is a rare genodermatosis characterized by abnormal development of sweat glands, teeth, and hair. Three disease‐causing genes have been hitherto identified, namely, (1) EDA1 accounting for X‐linked forms, (2) EDAR, and (3) EDARADD, causing both autosomal dominant and recessive forms. Recently, WNT10A gene was identified as responsible for various autosomal recessive forms of ectodermal dysplasias, including onycho‐odonto‐dermal dysplasia (OODD) and Schöpf‐Schulz‐Passarge syndrome. We systematically studied EDA1, EDAR, EDARADD, and WNT10A genes in a large cohort of 65 unrelated patients, of which 61 presented with HED/EDA. A total of 50 mutations (including 32 novel mutations) accounted for 60/65 cases in our series. These four genes accounted for 92% (56/61 patients) of HED/EDA cases: (1) the EDA1 gene was the most common disease‐causing gene (58% of cases), (2)WNT10A and EDAR were each responsible for 16% of cases. Moreover, a novel disease locus for dominant HED/EDA mapped to chromosome 14q12–q13.1. Although no clinical differences between patients carrying EDA1, EDAR, or EDARADD mutations could be identified, patients harboring WNT10A mutations displayed distinctive clinical features (marked dental phenotype, no facial dysmorphism), helping to decide which gene should be first investigated in HED/EDA. Hum Mutat 31:1–8, 2010.

Prevalence of the microdeletion 22q11 in newborn infants with congenital conotruncal cardiac anomalies.

Abstract Conotruncal malformations account for about 50% of congenital heart defects diagnosed in newborns. We studied prospectively 104 patients admitted in our neonatal intensive care unit for conotruncal defects by fluorescence in situ hybridization to estimate the prevalence of the interstitial deletion in this category of congenital heart disease. Cardiac phenotypes were: truncus arteriosus (17), interrupted aortic arch (18), tetralogy of Fallot with or without pulmonary valve atresia (55), tetralogy of Fallot with absent pulmonary valves (5), ventricular septal defect with malalignment of the conal septum (9). We discovered a microdeletion 22q11 at loci D22S39 or D22S398 in 50 newborns (48%). The prevalence of this microdeletion in different groups of conotruncal defects was: truncus arteriosus 7/17, interrupted aortic arch 16/18, tetralogy of Fallot 19/55, absent pulmonary valves 2/5, and ventricular septal defect 6/9 respectively. Only two patients without any clinical or biological feature of the so called CATCH22 syndrome exhibited the deletion. Parental studies confirmed that the deletion occurred de novo in 47/50 cases (three parental microdeletions). On the other hand, recurrence of conotruncal heart defects in families of “undeleted probands” was higher than expected (13%). Conclusion In 50/104 newborns with conotruncal defects, an interstitial deletion 22q11 was found. Fluorescence in Situ Hybridization should be performed in newborn infants with conotruncal defect and at least one additional manifestation of the CATCH22 phenotype.

Mutational, functional, and expression studies of the TCF4 gene in Pitt-Hopkins syndrome.

Pitt‐Hopkins syndrome is a severe congenital encephalopathy recently ascribed to de novo heterozygous TCF4 gene mutations. We report a series of 13 novel PHS cases with a TCF4 mutation and show that EEG, brain magnetic resonance imagain (MRI), and immunological investigations provide valuable additional clues to the diagnosis. We confirm a mutational hot spot in the basic domain of the E‐protein. Functional studies illustrate that heterodimerisation of mutant TCF4 proteins with a tissue‐specific transcription factor is less effective than that homodimerisation in a luciferase reporter assay. We also show that the TCF4 expression pattern in human embryonic development is widespread but not ubiquitous. In summary, we further delineate an underdiagnosed mental retardation syndrome, highlighting TCF4 function during development and facilitating diagnosis within the first year of life. Hum Mutat 0, 1–8, 2009.

Atypical findings in Kabuki syndrome: Report of 8 patients in a series of 20 and review of the literature

Kabuki syndrome (KS) is a rare multiple congenital anomaly/mental retardation syndrome with an estimated frequency of 1/32,000 in Japan. Five major criteria delineate KS namely postnatal short stature, skeletal anomalies, moderate mental retardation, dermatoglyphic anomalies, and a characteristic facial dysmorphism. Here we report on a series of 20 sporadic KS patients and we focus on some rare and atypical features that we have observed: chronic and/or severe diarrhea (4/20) including celiac disease, diaphragmatic defects (3/20), pseudarthrosis of the clavicles (2/20), vitiligo (2/20), and persistent hypoglycemia (2/20). Other occasional findings were severe autoimmune thrombopenia, cerebellar vermis atrophy, and myopathic features. Interestingly, one of our KS patients presented with a clinical overlap with CHARGE syndrome (right eye microphtalmia with optic nerve coloboma, VSD, bilateral cryptorchidism, and severe deafness). Because these features are more frequent in our series than previously described, we propose to carefully investigate these manifestations during KS patient survey in an attempt to determine their real frequency and in order to improve clinical management.

Prenatal diagnosis of an 8p23.1 deletion in a fetus with a diaphragmatic hernia and review of the literature

The prenatal diagnosis of an 8p23.1 deletion is reported. The diagnosis was ascertained at 22 weeks of gestation because of the discovery of a diaphragmatic hernia at ultrasound. Following cytogenetic studies and counselling, the pregnancy was terminated. An autopsy confirmed the presence of a diaphragmatic hernia and revealed also the existence of an atrio‐ventricular canal (AVC) and an atrial septal defect (ASD). The clinical features of this antenatally diagnosed case are compared with those observed in 16 previously reported cases with an identical deletion of the short arm of chromosome 8. This suggests that a deletion 8p23.1 should be considered whenever a diaphragmatic hernia and/or an AVC is detected on ultrasound. Copyright

Spectrum of mutations in the renin-angiotensin system genes in autosomal recessive renal tubular dysgenesis

Autosomal recessive renal tubular dysgenesis (RTD) is a severe disorder of renal tubular development characterized by early onset and persistent fetal anuria leading to oligohydramnios and the Potter sequence, associated with skull ossification defects. Early death occurs in most cases from anuria, pulmonary hypoplasia, and refractory arterial hypotension. The disease is linked to mutations in the genes encoding several components of the renin–angiotensin system (RAS): AGT (angiotensinogen), REN (renin), ACE (angiotensin‐converting enzyme), and AGTR1 (angiotensin II receptor type 1). Here, we review the series of 54 distinct mutations identified in 48 unrelated families. Most of them are novel and ACE mutations are the most frequent, observed in two‐thirds of families (64.6%). The severity of the clinical course was similar whatever the mutated gene, which underlines the importance of a functional RAS in the maintenance of blood pressure and renal blood flow during the life of a human fetus. Renal hypoperfusion, whether genetic or secondary to a variety of diseases, precludes the normal development/ differentiation of proximal tubules. The identification of the disease on the basis of precise clinical and histological analyses and the characterization of the genetic defects allow genetic counseling and early prenatal diagnosis. Hum Mutat 33:316–326, 2012.

Natural history of Barth syndrome: a national cohort study of 22 patients

BackgroundThis study describes the natural history of Barth syndrome (BTHS).MethodsThe medical records of all patients with BTHS living in France were identified in multiple sources and reviewed.ResultsWe identified 16 BTHS pedigrees that included 22 patients. TAZ mutations were observed in 15 pedigrees. The estimated incidence of BTHS was 1.5 cases per million births (95%CI: 0.2–2.3). The median age at presentation was 3.1 weeks (range, 0–1.4 years), and the median age at last follow-up was 4.75 years (range, 3–15 years). Eleven patients died at a median age of 5.1 months; 9 deaths were related to cardiomyopathy and 2 to sepsis. The 5-year survival rate was 51%, and no deaths were observed in patients ≥3 years. Fourteen patients presented with cardiomyopathy, and cardiomyopathy was documented in 20 during follow-up. Left ventricular systolic function was very poor during the first year of life and tended to normalize over time. Nineteen patients had neutropenia. Metabolic investigations revealed inconstant moderate 3-methylglutaconic aciduria and plasma arginine levels that were reduced or in the low-normal range. Survival correlated with two prognostic factors: severe neutropenia at diagnosis (<0.5 × 109/L) and birth year. Specifically, the survival rate was 70% for patients born after 2000 and 20% for those born before 2000.ConclusionsThis survey found that BTHS outcome was affected by cardiac events and by a risk of infection that was related to neutropenia. Modern management of heart failure and prevention of infection in infancy may improve the survival of patients with BTHS without the need for heart transplantation.

New insights into genotype–phenotype correlation for GLI3 mutations

The phenotypic spectrum of GLI3 mutations includes autosomal dominant Greig cephalopolysyndactyly syndrome (GCPS) and Pallister–Hall syndrome (PHS). PHS was first described as a lethal condition associating hypothalamic hamartoma, postaxial or central polydactyly, anal atresia and bifid epiglottis. Typical GCPS combines polysyndactyly of hands and feet and craniofacial features. Genotype–phenotype correlations have been found both for the location and the nature of GLI3 mutations, highlighting the bifunctional nature of GLI3 during development. Here we report on the molecular and clinical study of 76 cases from 55 families with either a GLI3 mutation (49 GCPS and 21 PHS), or a large deletion encompassing the GLI3 gene (6 GCPS cases). Most of mutations are novel and consistent with the previously reported genotype–phenotype correlation. Our results also show a correlation between the location of the mutation and abnormal corpus callosum observed in some patients with GCPS. Fetal PHS observations emphasize on the possible lethality of GLI3 mutations and extend the phenotypic spectrum of malformations such as agnathia and reductional limbs defects. GLI3 expression studied by in situ hybridization during human development confirms its early expression in target tissues.

Failure to detect an 8p22-8p23.1 duplication in patients with Kabuki (Niikawa-Kuroki) syndrome

Kabuki syndrome (KS) is a rare MCA/MR syndrome with an estimated frequency of 1/32 000 in Japan. This syndrome is characterized by postnatal growth retardation, distinctive facial features, dermatoglyphic anomalies, skeletal dysplasia, and mental retardation. The molecular basis of KS remains unknown. Recently, Milunsky and Huang reported on six unrelated patients with a clinical diagnosis of KS and an 8p22–8p23.1 duplication using comparative genomic hybridization and BAC-FISH studies. Also, they suggested that a paracentric inversion may contribute to the occurrence of KS. In the present study, 24 patients with a clinical diagnosis of KS based on Niikawa–Kuroki criteria have been collected. They were tested for the presence of an 8p duplication using the same clones as described by Milunsky and Huang. Our results do not confirm the previously described association between KS and an 8p22–8p23.1 duplication.

Prenatal detection of a 1p36 deletion in a fetus with multiple malformations and a review of the literature

The prenatal diagnosis of a 1p36 deletion is reported. The pregnancy was ascertained at 24 weeks of gestation because of the discovery of multiple malformations at ultrasound including hypotelorism, moderate cerebral ventricular dilatation and Ebstein anomaly with secondary cardiac failure. Following cytogenetic studies and counselling, the pregnancy was terminated and a fetal autopsy performed. The phenotype of this antenatally‐diagnosed case is compared with the clinical features of 44 previously reported cases with an identical deletion of the short arm of chromosome 1p36. Copyright