Tpit is a highly cell-restricted transcription factor that is required for expression of the pro-opiomelanocortin (POMC) gene and for terminal differentiation of the pituitary corticotroph lineage. Its exclusive expression in pituitary POMC-expressing cells has suggested that its mutation may cause isolated deficiency of pituitary adrenocorticotropin (ACTH). We now show that Tpit-deficient mice constitute a model of isolated ACTH deficiency (IAD) that is very similar to human IAD patients carrying TPIT gene mutations. Through genetic analysis of a panel of IAD patients, we show that TPIT gene mutations are associated at high frequency with early onset IAD, but not with juvenile forms of this deficiency. We identified seven different TPIT mutations, including nonsense, missense, point deletion, and a genomic deletion. This work defines congenital early onset IAD as a relatively homogeneous clinical entity caused by recessive transmission of loss-of-function mutations in the TPIT gene.
Precocious puberty is generally defined as the appearance of secondary sex characteristics before age 8 years in girls (or menarche before age 9 years) and before 9 years in boys. The overall incidence of sexual precocity is estimated to be 1:5,000 to 1:10,000 children. The female-to-male ratio is approximately 10:1. In addition to the psychosocial disturbances associated with precocious puberty, the premature pubertal growth spurt (with less time for prepubertal growth) and the accelerated bone maturation result in reduced adult height. Precocious puberty may be gonadotrophin-dependent [i.e. of central origin with premature activation of the gonadotrophin-releasing hormone (GnRH) pulse generator] or gonadotrophin-independent (i.e. peripheral where the GnRH pulse generator is suppressed). This can be determined by GnRH testing. The pathophysiology is the basis for different diagnostic and therapeutic strategies, i.e. in the first case a stimulated LH/FSH ratio >1 and suppressive treatment with GnRH agonists (e.g. in hypothalamic hamartoma), and in the second decreased gonadotrophins and removal or suppression of the endogenous or exogenous sex steroid source (e.g. congenital adrenal hyperplasia). While several cases of gonadotrophin-independent precocious puberty due to oestrogen exposure via the transdermal, oral, or inhalative route have been reported, no case is known with the development of subsequent secondary central precocious puberty. Food contamination with oestrogens is theoretically possible, but would most probably be sporadic and, thus, would not lead to precocious puberty. As steroid hormones in meat production are banned in the European Union, no data on the impact of environmental oestrogenic substances on human maturation are currently available. In conclusion, the risk for children to develop precocious puberty through exposure to oestrogens (or androgens) in the environment or in food is very low. Nevertheless, studies of the effects of defined environmental oestrogenic substances on the human reproductive system and on pubertal development are warranted.
Tpit is a T box transcription factor important for terminal differentiation of pituitary proopiomelanocortin-expressing cells. We demonstrated that human and mouse mutations of the TPIT gene cause a neonatal-onset form of congenital isolated ACTH deficiency (IAD). In the absence of glucocorticoid replacement, IAD can lead to neonatal death by acute adrenal insufficiency. This clinical entity was not previously well characterized because of the small number of published cases. Since identification of the first TPIT mutations, we have enlarged our series of neonatal IAD patients to 27 patients from 21 unrelated families. We found TPIT mutations in 17 of 27 patients. We identified 10 different TPIT mutations, with one mutation found in five unrelated families. All patients appeared to be homozygous or compound heterozygous for TPIT mutations, and their unaffected parents are heterozygous carriers, confirming a recessive mode of transmission. We compared the clinical and biological phenotype of the 17 IAD patients carrying a TPIT mutation with the 10 IAD patients with normal TPIT-coding sequences. This series of neonatal IAD patients revealed a highly homogeneous clinical presentation, suggesting that this disease may be an underestimated cause of neonatal death. Identification of TPIT gene mutations as the principal molecular cause of neonatal IAD permits prenatal diagnosis for families at risk for the purpose of early glucocorticoid replacement therapy.
Williams-Beuren syndrome (WBS) is a genetic disorder characterized by a distinctive facial gestalt, mental retardation, mild growth deficiency, and cardiovascular disease. The occurrence of sudden death in the WBS is known from several case reports, but information about the risk of sudden death as derived from the data of a large cohort of patients is lacking. We analyzed the data of 293 WBS patients who had been treated for 43 years at the same two institutions. We thus collected 5,190 patient years without loss to follow-up. During this period ten patients died. Five of them died from: reticulosarcoma (1), after accident (1), heart failure (1), following heart surgery (2). Of the remaining five patients, four died suddenly and one died of unknown cause suggestive of sudden cardiac death. Thus, the incidence of sudden death in our WBS cohort amounts to 1/1,000 patient years. This risk of sudden death is comparable to that following surgery for congenital heart disease, and is 25-100-fold higher compared to the age-matched normal population.
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