Zeina Chakhtoura

Clinical and Molecular Characterization of a Cohort of 161 Unrelated Women with Nonclassical Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency and 330 Family Members

CONTEXT Nonclassical congenital adrenal hyperplasia (NC-CAH) due to partial 21-hydroxylase deficiency is one of the most frequent autosomal recessive diseases. OBJECTIVE The aim of this study was to determine the genotype/phenotype relationship in probands and family members. PATIENTS AND METHODS A total of 161 NC-CAH unrelated women diagnosed on late-onset symptoms, mainly hirsutism, and post-ACTH 17-hydroxyprogesterone more than 10 ng/ml, and 330 of their relatives was explored. CYP21A2 was genotyped in 124 probands. RESULTS The most frequent mutation was V281L. One severe mutation was found in 63.7% of probands, and surprisingly two severe mutations in four probands. Contrasting with the absence of clinical differences, basal testosterone, and androstenedione, basal and post-ACTH 17-hydroxyprogesterone were significantly higher in probands carrying at least one severe mutation than in those with two mild mutations (P < 0.01). Among the 330 family members, 51 were homozygotes or compound heterozygotes, and 42 were clinically asymptomatic; 242 were heterozygotes and 37 unaffected. Post-ACTH 21-deoxycortisol (21dF) was significantly higher in heterozygotes than in unaffected, however, an overlap existed. In 12 heterozygotes, post-ACTH 21dF was below 0.55 ng/ml, the cutoff value usually accepted for suggesting heterozygosity. CONCLUSIONS The study of family members underlines the variable expression of NC-CAH even within a family, suggesting that modifier factors may modulate phenotype expression. Post-ACTH 21dF cannot reliably detect heterozygous subjects. Considering the high frequency of heterozygotes in the general population, it is essential to genotype the partner(s) of the patients with one severe mutation to offer genetic counseling.

Impact of total cumulative glucocorticoid dose on bone mineral density in patients with 21-hydroxylase deficiency

OBJECTIVE It remains controversial whether long-term glucocorticoids are charged of bone demineralization in patients with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency. The aim of this study was to know whether cumulative glucocorticoid dose from the diagnosis in childhood to adulthood in patients with CAH had a negative impact on bone mineral density (BMD). DESIGN This was a retrospective study. METHODS Thirty-eight adult patients with classical and non-classical CAH were included. BMD was measured in the lumbar spine and femoral neck. Total cumulative glucocorticoid (TCG) and total average glucocorticoid (TAG) doses were calculated from pediatric and adult files. RESULTS We showed a difference between final and target heights (-0.82+/-0.92 s.d. for women and -1.31+/-0.84 s.d. for men; P<0.001). Seventeen patients (44.7%) had bone demineralization (35.7% of women and 70% of men). The 28 women had higher BMD than the 10 men for lumbar (-0.26+/-1.20 vs -1.25+/-1.33 s.d.; P=0.02) and femoral T-scores (0.21+/-1.30 s.d. versus -1.08+/-1.10 s.d.; P=0.007). In the salt-wasting group, women were almost significantly endowed with a better BMD than men (P=0.053). We found negative effects of TCG, TAG on lumbar (P<0.001, P=0.002) and femoral T-scores (P=0.006, P<0.001), predominantly during puberty. BMI was protective on BMD (P=0.006). CONCLUSION The TCG is an important factor especially during puberty for a bone demineralization in patients with 21-hydroxylase deficiency. The glucocorticoid treatment should be adapted particularly at this life period and preventive measures should be discussed in order to limit this effect.

Bone health should be an important concern in the care of patients affected by 21 hydroxylase deficiency.

Osteoporosis has been an understandable concern for children and adult patients with congenital adrenal hyperplasia (CAH) who may receive or have received supraphysiological doses of glucocorticoids. Some previous reports on bone mineral density (BMD) in adult CAH patients showed no significant differences in BMD between patients with CAH and controls, but others have found lower BMD in CAH patients. In reports documenting the BMD reduction, this outcome has been attributed to an accumulated effect of prolonged exposure to excess glucocorticoids during infancy and childhood. We recently conducted a trial to establish the role of the total cumulative glucocorticoid dose on BMD. We established for the first time that there was a negative relationship between total cumulative glucocorticoid dose and lumbar and femoral BMD. Women might benefit from the preserving effect of estrogens compared to men. BMI (Body Mass Index) also appeared to protect patients from bone loss. In light of this, physicians should bear in mind the potential consequences of glucocorticoids on bone and therefore adjust the treatment and improve clinical and biological surveillance from infancy. Furthermore, preventive measures against corticosteroid-induced osteoporosis should be discussed right from the beginning of glucocorticoid therapy.

Vulvar Lichen Sclerosus Is Very Frequent in Women With Turner Syndrome

Department of Endocrinology and Reproductive Medicine (Z.C., S.V., C.C., I.T., P.T.), Pitie-Salpetriere Hospital, Assistance Publique-Hopitaux de Paris, Pierre et Marie Curie University, 75013 Paris, France; Center of Rare Gynecologic Diseases (Z.C., S.V., C.C., I.T., P.T.), Pitie-Salpetriere Hospital, Paris, 75103, France; and Center of Rare Endocrine Growth Diseases (Z.C., S.V., C.C., I.T., P.T.), Pitie-Salpetriere Hospital, Paris, 75103, France

Mise au pointFertilité chez les femmes ayant un syndrome de TurnerFertility on women with Turner syndrome

Spontaneous pregnancies occur in 1.8 to 7.6% among women with Turner syndrome. A genetic counseling is required before conception because only 30 to 40% of these pregnancies lead to the birth of a healthy child. A check-up has to be done before pregnancy, and if authorized, it will be tightly followed-up. Pregnancy is contraindicated if cardiac or aortic malformations exist, except for bicuspid aortic valve. Teams advice single embryo transfer. Rates of pregnancies of 45 to 60% after oocyte donation, but 40 to 60% of spontaneous abortions are noted, due to uterine factors. A study is trying to define patients who could postulate to cryopreservation of ovarian tissue.

Erratum à l’article « Un programme d’éducation thérapeutique centré sur la transition des patients, avec endocrinopathie chronique, entre les services d’endocrinologie pédiatrique et adulte » [Presse Med. 45 (5) (2016) e119–e129]

La Presse Medicale - In Press.Proof corrected by the author Available online since jeudi 28 juillet 2016

Suivi prospectif de 60 femmes présentant une polyadénomatose mammaire : description radiologique et facteurs influant sur son évolution

Introduction: La polyadenomatose mammaire (PAM) etant une maladie benigne rare du sein, son histoire naturelle est mal connue. Le but de notre travail etait donc de decrire radiologiquement le devenir d’une cohorte de patientes presentant une PAM, et d’evaluer l’influence de differents facteurs sur son evolution. Methodes: Il s’agit d’une etude prospective de cohorte. Les patientes incluses ont beneficie de deux evaluations clinico-biologiques et radiologiques (echographie et IRM mammaires) a au moins 5 ans d’intervalle. Resultats: Soixante femmes ont ete suivies sur 7,4±1,7 ans en moyenne. L’evolution radiologique a montre une diminution du nombre de fibroadenomes (FA) dans 55% des cas a l’echographie et 36,6% a l’IRM ; associee a une diminution de taille dans 93% des cas. Une augmentation du nombre de FA etait retrouvee dans environ 40% des cas, avec, pour la majorite, a une diminution de la taille des lesions (69,6% a l’echographie et 87% a l’IRM). Le tabac (p=0,04) et l’IMC (p=0,01) etaient associees a une aggravation de la PAM, alors que la grossesse (p=0,001) ainsi que l’allaitement (p=0,001) ou encore la prise de traitement hormonal (p=0,01) en particulier le lynestrenol (p<0,0001) etaient associes a une amelioration de la PAM. Ces trois derniers avaient egalement un effet benefique sur l’evolution de la PAM entre les deux evaluations. Des antecedents senologiques familiaux etaient retrouves dans plus de 40% des cas, et les antecedents familiaux de cancer du sein etaient aussi associes une amelioration de la PAM (p=0,06). Une incidence de 3,3% de cancers et de 8% de tumeurs phyllodes a ete observee dans notre population. Conclusion: Il s’agit de la premiere etude longitudinale de femmes presentant une PAM. L’evolution radiologique de cette pathologie semble favorable et similaire a celle attendue d’un FA simple. Nous avons identifie des facteurs influencant l’evolution de la PAM, et notamment les macroprogestatifs type lynestrenol qui pourraient avoir un effet benefique. Poursuivre le suivi de notre cohorte permettrait d’approfondir davantage nos connaissances sur cette pathologie, notamment concernant le risque de cancer du sein.