SummaryObjective Mutations of the PROP1 gene lead to combined pituitary hormone deficiency (CPHD), which is characterized by a deficiency of GH, TSH, LH/FSH, PRL and, less frequently, ACTH. This study was undertaken to investigate the molecular defect in a cohort of patients with CPHD. Design, patients and measurements A multicentric study involving 46 cases of CPHD (17 familial cases belonging to seven kindreds and 29 sporadic cases) selected on the basis of clinical and hormonal evidence of GH deficiency, central hypothyroidism and hypogonadotrophic hypogonadism, in the absence of an identified cause of hypopituitarism. Mutations of PROP1 were investigated by DNA sequencing. Clinical, hormonal and neuroradiological data were collected at each centre. Results PROP1 mutations were identified in all familial cases: five kindreds presented a c. 301-302delAG mutation, one kindred presented a c. 358C → T (R120C) mutation and one presented a previously unreported initiation codon mutation, c. 2T → C. Of the 29 sporadic cases, only two (6·9%) presented PROP1 germline mutations ( c. 301-302delAG, in both). Phenotypic variability was observed among patients with the same mutations, particularly the presence and age of onset of hypocortisolism, the levels of PRL and the results of pituitary imaging. One patient presented a sellar mass that persisted into adulthood. Conclusions This is the first report of a mutation in the initiation codon of the PROP1 gene and this further expands the spectrum of known mutations responsible for CPHD. The low mutation frequency observed in sporadic cases may be due to the involvement of other unidentified acquired or genetic causes.

Objective: Haemoglobin A1c (Hb A1c) is routinely used for monitoring glycemic control in patients with diabetes. Hb A1c seasonal fluctuations can be directly related to different biological, geographical and cultural influences. Our purpose was to evaluate seasonal variation of Hb A1c in a hospitalbased adult population over a period of 5 years. Materials and methods: We analyzed retrospectively monthly Hb A1c mean values (DCCT, %) based on all the assays performed to adult patients at a tertiary care university Portuguese hospital between 2008-2012. Results: We obtained 62,384 Hb A1c valid measurements, with a peak level found in January-February (7.1%), a trough in AugustOctober (6.8%) and an average peak-to-trough amplitude value of 0.3%. This trend was observed in both genders and age subgroups evaluated. Conclusions: There is a Hb A1c circannual seasonal pattern with peak levels occurring in winter months in this Portuguese population. This finding should be recognized in daily clinical practice to warrant better clinical and epidemiological interpretation of Hb A1c values. Arch Endocrinol Metab. 2015;59(3):231-5

patients with thrombosis tested antibody positive, compared with 26 (6.1%) of 425 patients without thrombosis (odds ratio [OR], 15.3 [95% CI,]; P ϭ .005). This supports previous suggestions 6 that formation of platelet-activating HIT antibodies can be associated with thrombosis even in the absence of a significant platelet count fall. Second, among the 87.7% of study patients who underwent serologic testing for HIT antibodies, there was approximately a 60% lower seroconversion rate with LMWH compared with UFH (55.6% and 64.7% by the platelet activation assay and immunoassay, respectively). Nevertheless, despite this moderate reduction in frequency of HIT antibody formation, there was complete avoidance of clinical HIT using LMWH (0 versus 12 cases). This underscores the importance of considering HIT to be a largely preventable adverse drug reaction, at least in postorthopedic surgery patients. To the editor:A Portuguese patient homozygous for the ؊25G>A mutation of the HAMP promoter shows evidence of steady-state transcription but fails to up-regulate hepcidin levels by ironMutations of hepcidin are a rare cause of juvenile hemochromatosis (JH). We report a homozygous Ϫ25GϾA mutation in the hepcidin 5Ј untranslated region (UTR) that generates a new start codon with a consequent frameshift. In this patient with a rare coincidental association of JH, Turner syndrome, and absolute lymphopenia, the absence of normal hepcidin synthesis was expected. Surprisingly, the patient had detectable hepcidin, suggesting that the start of translation was maintained at the original ATG with some normal protein production. However, hepcidin was not appropriately induced by an iron challenge test, supporting role of hepcidin on the clinical expression of iron overload in this case. The hepatic peptide hepcidin is a key regulator of iron balance. 1 Mutations of hepcidin are a rare cause of juvenile hemochromatosis (JH), 2-3 and include nonsense, frameshift, 2 and missense mutations C70R and C78T affecting conserved cysteines. [3][4][5] Recently a Ϫ25GϾA mutation in the HAMP 5ЈUTR was described in 2 Portuguese siblings with iron overload and absence of urinary hepcidin. 6 Here, the same mutation was found in a different Portuguese family where the proband shows coincidental association of JH, Turner syndrome, and absolute lymphopenia. 7 Although no comparative haplotype analysis was performed, geographic and historical tracking does not indicate any relationship with the previously described family. In the proband, no mutations in the coding regions of HAMP and hemojuvelin genes were found by sequencing. 3,8 However, in the 5ЈUTR region of HAMP, a GϾA point mutation was identified at position Ϫ25 from the canonical ATG. This was confirmed by WAVE (Transgenomic, Omaha, NE) denaturing high-performance liquid chromatography (DHPLC; heteroduplexes were formed by heat denaturation at 94°C for 3 minutes and cooling to 25°C for 45 minutes; the mixture was analyzed at a melting temperature of 64.1°C, with a linear acetonitrile gradient:...

This paper describes a rare case of Turner's syndrome associated with Juvenile Haemochromatosis and severe lymphopenia, followed-up for a period of 5 years. Because of the indication for treatment with growth hormone (GH), this case was observed as a model to analyse the effects of GH on growth, iron mobilization and lymphocyte reconstitution. For this purpose, a serial study of the T lymphocyte subpopulations CD4+, CD8+, CD8+ CD28+ and CD8+ CD28-was performed by immunophenotyping during the follow-up period. Besides the impact of both phlebotomy treatment and GH on the rapid growth and mobilization of 20.8 g of iron in 136 weeks, the most relevant observation was the finding of a significant expansion of CD8+ T lymphocytes expressing the costimulatory marker CD28 in the setting of the severe lymphopenia. These findings constitute new clinical evidence supporting the notion that the GH/IGF-1 system has an important role on the maintenance of T cell homeostasis in vivo, and that GH may be regarded as a putative therapeutic agent in T lymphocyte reconstitution.

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