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.)

Our results do not generally support a carcinogenic effect of r-hGH, but the unexplained trend in cancer mortality risk in relation to GH dose in patients with previous cancer, and the indication of possible effects on bone cancer, bladder cancer, and HL risks, need further investigation.

Maturity-onset diabetes of the young (MODY) is a subtype of Type II (non-insulin dependent) diabetes mellitus characterised by early onset, usually before 25 years of age, an autosomal dominant mode of inheritance with high penetrance, and a primary defect of insulin secretion [1,2]. MODY is not an uncommon disorder and could account for about 2 to 5 % of all cases of Type II diabetes [3]. MODY is genetically heterogeneous and to date five MODY genes have been identified on chromosomes 20q12-q13.1 (MODY1) [4,5], 7p15-p13 (MODY2) [6,7], 12q24.2 (MODY3) [8,9], 13q12.1 (MODY4) [10,11] and 17cen-q21.3 (MODY5) [12]. The MODY2 gene encodes the glycolytic enzyme glucokinase which plays a major role in the regulation and integration of glucose metabolism in pancreatic beta cells and liver [13]. Recent studies have shown that mutations in three transcription factors, hepatocyte nuclear factor-4a (HNF-4a) [5] (gene symbol TCF14), hepatocyte nuclear factor-1a (HNF-1a) [9, 14] (TCF1) and insulin promoter factor-1 (IPF1) [10], are responsible for the MODY1, MODY3 and MODY4 subtypes, re- Diabetologia (1998) Summary Maturity-onset diabetes of the young (MODY) is a heterogeneous subtype of non-insulindependent diabetes mellitus characterised by early onset, autosomal dominant inheritance and a primary defect in insulin secretion. To date five MODY genes have been identified: hepatocyte nuclear factor-4 alpha (HNF-4a/MODY1/TCF14) on chromosome 20 q, glucokinase (GCK/MODY2) on chromosome 7 p, hepatocyte nuclear factor-1 alpha (HNF-1a/ MODY3/TCF1) on chromosome 12 q, insulin promoter factor-1 (IPF1/MODY4) on chromosome 13 q and hepatocyte nuclear factor-1 beta (HNF-1b/MODY5/ TCF2) on chromosome 17cen-q. We have screened the HNF-4a, HNF-1a and HNF-1b genes in members of 18 MODY kindreds who tested negative for glucokinase mutations. Five missense (G31D, R159W, A161T, R200W, R271W), one substitution at the splice donor site of intron 5 (IVS5nt + 2T®A) and one deletion mutation (P379fsdelT) were found in the HNF-1a gene, but no MODY-associated mutations were found in the HNF-4a and HNF-1b genes.

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.

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Rhabdomyolysis is a potentially lethal disorder, characterized by elevated serum concentrations of creatine kinase (CK) due to skeletal muscle injury. In this paper a patient with diabetic ketoacidosis (DKA) is reported who developed rhabdomyolysis (maximum CK level, 37,700 U/L; normal, < 170 U/L), anemia (6.2 g/dL) and thrombocytopenia (16,000/microL). This combination of rhabdomyolysis with anemia and thrombocytopenia has not yet been reported in DKA. The pathogenic mechanism leading to rhabdomyolysis in DKA remains unsettled. From the literature it seems that those patients who develop rhabdomyolysis have very high glucose levels and a high osmolality on admission. Low phosphate levels can play a role as well. The etiology of anemia and thrombocytopenia in our patient remains obscure. Intravascular hemolysis could not be demonstrated but intramedullar hemolysis, due to osmolar shift or hypophosphatemia, cannot be excluded. A review of the literature data revealed that rhabdomyolysis is not so uncommon in DKA. However, to obtain incidence data in children, prospective studies are necessary.

BackgroundPrader-Willi syndrome (PWS) is a rare genetic neurodevelopmental disorder with different nutritional phases from suckling deficit with failure to thrive to early onset of obesity. Hyperghrelinemia has been described in PWS long before the development of obesity. Ghrelin is found in both acylated (AG) and unacylated (UAG) forms in the circulation. In contrast to AG, UAG has been shown to inhibit food intake and to be elevated in anorexia nervosa. The present project is aiming to determine the underlying mechanisms driving the different nutritional phases in PWS.MethodsMeasurement of at least 4 h-fasting plasma acylated and unacylated ghrelin in 37 infants with a genetic diagnosis of PWS aged from 1 month to 4 years and in 100 age-matched controls without endocrine disorder recruited prior to minor surgery. One blood sampling was analysed for each patient/control and clinical data were recorded. Eleven PWS infants underwent repetitive blood samples at 3 or 6-month intervals during routine visits.ResultsIn infants with PWS, AG is not elevated (p = 0.45), UAG is significantly higher (p = 0.0044; confidence interval 1.06;1.33) resulting in a low AG/UAG ratio (p = 0.0056; confidence interval 0.76;0.95) compared to controls.ConclusionUnlike children and adults with PWS that have high AG and AG/UAG ratio, infants with PWS have elevated UAG that supports the concept of anorexia in the early phases of the disease. The change in AG/UAG ratio possibly drives the switch from failure to thrive to obesity.Clinical trial registrationNCT02529085.Electronic supplementary materialThe online version of this article (doi:10.1186/s13023-016-0440-0) contains supplementary material, which is available to authorized users.