R. Reynaud

Deficit in anterior pituitary function and variable immune deficiency (DAVID) in children presenting with adrenocorticotropin deficiency and severe infections.

CONTEXT Among 22 independent patients from the GENHYPOPIT network who had ACTH deficiency and no identified mutation of TPIT, three of them (13.6%) displayed common variable immunodeficiency (CVID), characterized by defective Ig production. OBJECTIVE Our objective was to describe an as yet unrecognized disease association. DESIGN We considered the hypothesis of ACTH deficiency being associated with antipituitary autoimmunity or lymphocytic hypophysitis. In the context of a functional network between the immune and endocrine systems, we also tested the hypothesis of a common genetic cause using a candidate gene approach. SETTING This was a multicentric study in three academic hospitals. PATIENTS We report four patients from three unrelated families presenting with ACTH deficiency and CVID. MAIN OUTCOME MEASURES Detection of antipituitary autoantibodies, and sequencing of candidate genes (LIF, IKAROS, EOS) were the main outcome measures. RESULTS All patients including a pedigree with two affected siblings had ACTH deficit diagnosed from 5-15 yr, with symptomatic hypoglycemia, and CVID diagnosed from 2-8 yr revealed by recurrent infections. Three of the four patients had a hypoplastic pituitary. One patient had low IGF-I and subnormal GH response to stimulation, suggesting that secretion of other pituitary hormones may also be affected. All patients proved negative for pituitary autoantibodies and had no alteration in any of the genes tested. CONCLUSIONS The remarkable association of two rare disorders affecting two functionally related systems in four patients from three independent pedigrees including a familial case provides strong evidence of the existence of a disease association: deficit in anterior pituitary function and variable immune deficiency, or DAVID.

Identifying the Deleterious Effect of Rare LHX4 Allelic Variants, a Challenging Issue

LHX4 is a LIM homeodomain transcription factor involved in the early steps of pituitary ontogenesis. To date, 8 heterozygous LHX4 mutations have been reported as responsible of combined pituitary hormone deficiency (CPHD) in Humans. We identified 4 new LHX4 heterozygous allelic variants in patients with congenital hypopituitarism: W204X, delK242, N271S and Q346R. Our objective was to determine the role of LHX4 variants in patients’ phenotypes. Heterologous HEK293T cells were transfected with plasmids encoding for wild-type or mutant LHX4. Protein expression was analysed by Western Blot, and DNA binding by electro-mobility shift assay experiments. Target promoters of LHX4 were cotransfected with wild type or mutant LHX4 to test the transactivating abilities of each variant. Our results show that the W204X mutation was associated with early GH and TSH deficiencies and later onset ACTH deficiency. It led to a truncated protein unable to bind to alpha-Gsu promoter binding consensus sequence. W204X was not able to activate target promoters in vitro. Cotransfection experiments did not favour a dominant negative effect. In contrast, all other mutants were able to bind the promoters and led to an activation similar as that observed with wild type LHX4, suggesting that they were likely polymorphisms. To conclude, our study underlines the need for functional in vitro studies to ascertain the role of rare allelic variants of LHX4 in disease phenotypes. It supports the causative role of the W204X mutation in CPHD and adds up childhood onset ACTH deficiency to the clinical spectrum of the various phenotypes related to LHX4 mutations.

Syndrome de Prader-Willi et hormone de croissance

Resume Le syndrome de Prader-Willi revele en periode neonatale par une hypotonie severe se caracterise apres la periode infantile par un dysfonctionnement hypothalamo-hypophysaire associant une hyperphagie, une obesite morbide, des troubles du comportement, un hypogonadisme central et des troubles neurovegetatifs. Il est du dans la majorite des cas a une deletion d’un segment du chromosome 15 paternel. La forte morbi-mortalite de ce syndrome est correlee a la presence de syndrome d’apnees du sommeil et d’un risque cardio-vasculaire accru. La secretion de GH est le plus souvent diminuee. Le traitement par GH ameliore la croissance staturale, la composition corporelle mais egalement le developpement psychomoteur. Cependant une augmentation trop rapide de posologie de GH pourrait accroitre la survenue d’apnees obstructives severes. Enfin, les patients souffrant de syndrome de Prader Willi presenteraient frequemment une insuffisance corticotrope en situation de stress, qui pourrait justifier d’un traitement par hydrocortisone.Prader Willi syndrome (PWS) is a hypothalamo-hypophyseal disorder associated with eating disorders, morbid obesity and behavioural troubles. A deletion of a segment of paternal chromosome 15 is the more frequent cause of PWS. The syndrome is associated with increased morbidity (sleep apnea, increased cardio-vascular risk) and mortality (mainly due to respiratory infectious diseases). GH secretion is usually decreased. GH treatment induces height gain, positive body composition changes and improves psychomotor development. Obstructive apnea was described in case of rapid increase in the dose of GH. Corticotroph deflciency, warranting treatment in stress situations could also take part in the high mortality rate of these patients.

Syndrome de Noonan et hormone de croissance

Resume Le syndrome de Noonan est un syndrome clinique associant une petite taille, une dysmorphie faciale et une cardiopathie congenitale. Dans 50 % des cas, une mutation du gene PTPN11 est retrouvee, avec une transmission autosomique dominante; des mutations d’autres genes (KRAS, SOS1) ont ete recemment rapportees. La petite taille pourrait etre liee a une secretion insuffisante en GH (mais la plupart des patients ont une reponse normale de la GH sous stimulation), une dysfonction neurosecretoire en GH (avec un profil secretoire different des sujets sains) ou une resistance a la GH. Le traitement par hormone de croissance semble efficace sur la croissance staturale, meme si peu d’etudes ont evalue la taille finale. Cette reponse est variable selon les patients, en particulier selon qu’ils sont ou non porteurs de mutation de PTPN11 . Le traitement par GH ne semble pas avoir d’effets cardiaques deleteres.