[Clinical signs of Marfan syndrome in children under 10 years of age]. / Signes cliniques évocateurs d'un syndrome de Marfan chez l'enfant de moins de 10ans.

Diagnosing Marfan syndrome in young children is difficult because of the great variability of expression of the disease and because the phenotype evolves over the life course. The goal of this retrospective study was to describe the first clinical symptoms in children under 10 years of age with Marfan syndrome and to evaluate the pertinence of the new 2010 Ghent criteria in comparison with the 1996 criteria. Seventeen patients under 10 by the time of the first medical examination were included. All children had an FBN1 gene mutation that was secondarily demonstrated. Clinical data including ophthalmological, cardiac, and orthopaedic examinations obtained during the first medical examination were analyzed. The most frequent abnormalities encountered were high arched palate (82%), arachnodactyly (71%), and flatfoot (59%). Aortic aneurysm (47%) and ectopic lens (35%) were also seen at the time of diagnosis. According to the 2010 Ghent criteria, the diagnosis of Marfan syndrome could be obtained in 71% of patients after identification of the mutation of the FBN1 gene, whereas only 59% of patients were diagnosed using the older criteria. All organs can be affected during childhood. An early diagnosis is essential in order to set up specific management.

Phenotype-genotype correlations of 13 rare CYP21A2 mutations detected in 46 patients affected with 21-hydroxylase deficiency and in one carrier.

CONTEXT: Steroid 21-hydroxylase deficiency is the most common enzymatic defect causing congenital adrenal hyperplasia with genotype/phenotype relationships for common mutations. Novel mutations of the CYP21A2 gene must be well studied to propose right genetic counseling for patients. OBJECTIVE: Thirteen CYP21 mutations have been studied. A detailed description of phenotype was performed for all mutations (p.I77T, p.L167P, p.I230T, p.R233K, p.G291S, p.G292D, p.E320K, p.R341P, p.R354H, p.R369W, p.R408C, p.G424S, and p.R426H). In vitro and in silico studies were performed only for those not previously described (p.L167P, p.I230T, p.R233K, p.G292D, p.E320K, and p.R369W). RESULTS: Regarding phenotype, patients with 10 of these mutations had a classical form. A patient with isolated p.I230T presented with nonclassical form and a patient with the association p.I230T + p.V281L in cis presented with a more severe phenotype. The p.R233K mutation was detected in a carrier partner. A patient with p.R369W presented with an intermediate form. Functional studies showed that all mutations except p.I230T and p.R369W decreased enzyme activity more than p.P30L: severity of p.R369W was intermediate between p.P30L and p.V281L, and finally p.I230T was less severe than p.V281L. Mutation analysis in a three-dimensional model structure of the CYP21 protein explained the observed in vitro effects, severe mutations being implicated in important functional domains of the protein. CONCLUSION: According to phenotype and functional studies, 11 of the mutations described, except the isolated p.R369W and p.I230T, may be responsible for a severe phenotype underlying the necessity to manage children having them. The p.I230T is a nonclassical mutation, and for the p.R369W, we need more cases to precise its severity.

[Contribution of genetic testing after diagnosis of hypocalcemia]. / Intérêt de la génétique au décours d'un diagnostic d'hypocalcémie.

Serum calcium is a fine-tuned biological value. In recent years, fundamental research and study of molecular anomalies causing certain hereditary diseases of phosphocalcium metabolism have greatly contributed to our knowledge of the factors involved in this regulation, from the embryogenesis of the parathyroid glands to the assay value of serum calcium. Targeted research on these genetic anomalies would be useful not only for the clinician, but also for the patient, contributing to the etiological search, patient follow-up, and possibly to antenatal diagnosis. The main genetic anomalies identified to date are: CaSR, GNAS, AIRE, VDR, mitochondrial DNA, 22q11 deletion.

The putative forkhead transcription factor FOXL2 is mutated in blepharophimosis/ptosis/epicanthus inversus syndrome.

In type I blepharophimosis/ptosis/epicanthus inversus syndrome (BPES), eyelid abnormalities are associated with ovarian failure. Type II BPES shows only the eyelid defects, but both types map to chromosome 3q23. We have positionally cloned a novel, putative winged helix/forkhead transcription factor gene, FOXL2, that is mutated to produce truncated proteins in type I families and larger proteins in type II. Consistent with an involvement in those tissues, FOXL2 is selectively expressed in the mesenchyme of developing mouse eyelids and in adult ovarian follicles; in adult humans, it appears predominantly in the ovary. FOXL2 represents a candidate gene for the polled/intersex syndrome XX sex-reversal goat.