Francis de Zegher

Mutations in the Pericentrin (PCNT) Gene Cause Primordial Dwarfism

Fundamental processes influencing human growth can be revealed by studying extreme short stature. Using genetic linkage analysis, we find that biallelic loss-of-function mutations in the centrosomal pericentrin (PCNT) gene on chromosome 21q22.3 cause microcephalic osteodysplastic primordial dwarfism type II (MOPD II) in 25 patients. Adults with this rare inherited condition have an average height of 100 centimeters and a brain size comparable to that of a 3-month-old baby, but are of near-normal intelligence. Absence of PCNT results in disorganized mitotic spindles and missegregation of chromosomes. Mutations in related genes are known to cause primary microcephaly (MCPH1, CDK5RAP2, ASPM, and CENPJ).

Anterior pituitary function during critical illness and dopamine treatment

ObjectivesTo summarize the available data on anterior pituitary function in critical illness and to focus on the endocrine effects of dopamine infusion. The analogy with anterior pituitary function in the elderly is highlighted, and the potential importance of these observations for recovery from cr

Deletion of Thyroid Transcription Factor-1 Gene in an Infant with Neonatal Thyroid Dysfunction and Respiratory Failure

To the Editor: The thyroid and lungs develop as outgrowths of the ventral foregut. Differentiation and early function of both organs appear to be related through the common expression of the thyroi...

Early Insulin Therapy in Very-Low-Birth-Weight Infants

BACKGROUND Studies involving adults and children being treated in intensive care units indicate that insulin therapy and glucose control may influence survival. Hyperglycemia in very-low-birth-weight infants is also associated with morbidity and mortality. This international randomized, controlled trial aimed to determine whether early insulin replacement reduced hyperglycemia and affected outcomes in such neonates. METHODS In this multicenter trial, we assigned 195 infants to continuous infusion of insulin at a dose of 0.05 U per kilogram of body weight per hour with 20% dextrose support and 194 to standard neonatal care on days 1 to 7. The efficacy of glucose control was assessed by continuous glucose monitoring. The primary outcome was mortality at the expected date of delivery. The study was discontinued early because of concerns about futility with regard to the primary outcome and potential harm. RESULTS As compared with infants in the control group, infants in the early-insulin group had lower mean (+/-SD) glucose levels (6.2+/-1.4 vs. 6.7+/-2.2 mmol per liter [112+/-25 vs. 121+/-40 mg per deciliter], P=0.007). Fewer infants in the early-insulin group had hyperglycemia for more than 10% of the first week of life (21% vs. 33%, P=0.008). The early-insulin group had significantly more carbohydrate infused (51+/-13 vs. 43+/-10 kcal per kilogram per day, P<0.001) and less weight loss in the first week (standard-deviation score for change in weight, -0.55+/-0.52 vs. -0.70+/-0.47; P=0.006). More infants in the early-insulin group had episodes of hypoglycemia (defined as a blood glucose level of <2.6 mmol per liter [47 mg per deciliter] for >1 hour) (29% in the early-insulin group vs. 17% in the control group, P=0.005), and the increase in hypoglycemia was significant in infants with birth weights of more than 1 kg. There were no differences in the intention-to-treat analyses for the primary outcome (mortality at the expected date of delivery) and the secondary outcome (morbidity). In the intention-to-treat analysis, mortality at 28 days was higher in the early-insulin group than in the control group (P=0.04). CONCLUSIONS Early insulin therapy offers little clinical benefit in very-low-birth-weight infants. It reduces hyperglycemia but may increase hypoglycemia (Current Controlled Trials number, ISRCTN78428828.)

Central Precocious Puberty Caused by Mutations in the Imprinted Gene MKRN3

BACKGROUND The onset of puberty is first detected as an increase in pulsatile secretion of gonadotropin-releasing hormone (GnRH). Early activation of the hypothalamic-pituitary-gonadal axis results in central precocious puberty. The timing of pubertal development is driven in part by genetic factors, but only a few, rare molecular defects associated with central precocious puberty have been identified. METHODS We performed whole-exome sequencing in 40 members of 15 families with central precocious puberty. Candidate variants were confirmed with Sanger sequencing. We also performed quantitative real-time polymerase-chain-reaction assays to determine levels of messenger RNA (mRNA) in the hypothalami of mice at different ages. RESULTS We identified four novel heterozygous mutations in MKRN3, the gene encoding makorin RING-finger protein 3, in 5 of the 15 families; both sexes were affected. The mutations included three frameshift mutations, predicted to encode truncated proteins, and one missense mutation, predicted to disrupt protein function. MKRN3 is a paternally expressed, imprinted gene located in the Prader-Willi syndrome critical region (chromosome 15q11-q13). All affected persons inherited the mutations from their fathers, a finding that indicates perfect segregation with the mode of inheritance expected for an imprinted gene. Levels of Mkrn3 mRNA were high in the arcuate nucleus of prepubertal mice, decreased immediately before puberty, and remained low after puberty. CONCLUSIONS Deficiency of MKRN3 causes central precocious puberty in humans. (Funded by the National Institutes of Health and others.).

Early Puberty: Rapid Progression and Reduced Final Height in Girls With Low Birth Weight

Objective. To assess whether, in girls with early onset of puberty, low birth weight is a risk factor for rapid progression to menarche and for short adult stature. Design. Longitudinal clinical assessment of 54 Catalan (Northern Spanish) girls followed from early onset of puberty (onset of breast development between 8.0 and 9.0 years of age) to final height. The timing of menarche and the final height were analyzed a posteriori according to birth weight, the cutoff level between normal and low birth weight subgroups being −1.5 standard deviation (SD; ∼2.7 kg at term birth). Results. Normal and low birth weight girls had similar target heights and characteristics at diagnosis of early puberty. However, menarche occurred on average 1.6 years earlier in low versus normal birth weight girls (11.3 ± .3 years vs 12.9 ± .2 years), and final height was >5 cm shorter in low birth weight girls (parental adjusted height SD: −.6 ± .2 cm vs .3 ± .2 cm). Conclusion. The timing of menarche and the level of final height in Catalan girls with early onset of puberty was found to depend on prenatal growth. Girls with normal birth weight tend to progress slowly through puberty with a normal timing of menarche and normal final height. In contrast, girls with low birth weight tend to progress relatively rapidly to an early menarche and to a reduced final height. If these findings are confirmed in other ethnic and/or larger groups, then a subgroup has been identified that will most likely benefit from any therapeutic intervention aiming at a delay of pubertal development and/or an increase of final height.

Reduced Uterine and Ovarian Size in Adolescent Girls Born Small for Gestational Age

Reduced fetal growth is known to be associated with a reduced ovarian fraction of primordial follicles, with ovarian hyperandrogenism and anovulation in late adolescence. In this study, we examined whether adolescent girls born small for gestational age also present an abnormality in uterine or ovarian size. Standardized ultrasound measurements of the internal genitalia were performed in 36 healthy post-menarcheal girls (mean age 14 y) born with a size that was either appropriate for gestational age (AGA) or small (SGA), birth weight averaging 0.1 and −3.0 SD, respectively; clinical and endocrine characteristics were documented concomitantly. Compared with AGA girls, the SGA girls had a smaller uterus (mean difference of 20%;p < 0.006) and a reduced ovarian volume (mean difference of 38%;p < 0.0002). In conclusion, the gynecological correlates of prenatal growth restriction are herewith extended to include a reduced size of the uterus and the ovaries.

Dopamine and the sick euthyroid syndrome in critical illness

OBJECTIVE The Sick euthyroid syndrome is a poorly understood hallmark of critical illness. Dopamine is a natural catecholamine with hypophysiotrophic properties, that is used as an inotropic agent of first choice in intensive care medicine. We explored the effect of dopamine infusion (5μg/kg/min) on the sick euthyroid syndrome of critically ill patients.

Tartrate-resistant acid phosphatase deficiency causes a bone dysplasia with autoimmunity and a type I interferon expression signature

We studied ten individuals from eight families showing features consistent with the immuno-osseous dysplasia spondyloenchondrodysplasia. Of particular note was the diverse spectrum of autoimmune phenotypes observed in these individuals (cases), including systemic lupus erythematosus, Sjögrens syndrome, hemolytic anemia, thrombocytopenia, hypothyroidism, inflammatory myositis, Raynauds disease and vitiligo. Haplotype data indicated the disease gene to be on chromosome 19p13, and linkage analysis yielded a combined multipoint log10 odds (LOD) score of 3.6. Sequencing of ACP5, encoding tartrate-resistant acid phosphatase, identified biallelic mutations in each of the cases studied, and in vivo testing confirmed a loss of expressed protein. All eight cases assayed showed elevated serum interferon alpha activity, and gene expression profiling in whole blood defined a type I interferon signature. Our findings reveal a previously unrecognized link between tartrate-resistant acid phosphatase activity and interferon metabolism and highlight the importance of type I interferon in the genesis of autoimmunity.

A role for helix 3 of the TRβ ligand-binding domain in coactivator recruitment identified by characterization of a third cluster of mutations in resistance to thyroid hormone

Resistance to thyroid hormone (RTH) has hitherto been associated with thyroid hormone β receptor (TRβ) mutations which cluster in two regions (αα 310–353 and αα 429–461) of the hormone‐binding domain and closely approximate the ligand‐binding cavity. Here, we describe a third cluster of RTH mutations extending from αα 234–282 which constitute a third boundary of the ligand pocket. One mutant, T277A, exhibits impaired transactivation which is disproportionate to its mildly reduced ligand affinity (Ka). T3‐dependent recruitment of coactivators (SRC‐1, ACTR) by mutant receptor–RXR heterodimers was reduced in comparison with wild‐type. Cotransfection of SRC‐1 restored transactivation by T277A. In the TRβ crystal structure this helix 3 residue is surface‐exposed and is in close proximity to residues L454 and E457 in helix 12 which are known to be critical for coactivator interaction, suggesting that they all constitute part of a receptor–coactivator interface. The transcriptional function of other mutants (A234T, R243W/Q, A268D, Δ276I, A279V, R282S) in this cluster correlated with their reduced Ka and they inhibited wild‐type TRβ action in a dominant negative manner. DNA binding, heterodimerization and corepressor recruitment were preserved in all mutants, signifying the importance of these attributes for dominant negative activity and correlating with the absence of natural mutations in regions bordering the third cluster which mediate these functions.