Metastatic medullary thyroid carcinoma (MTC): disease course, treatment modalities and factors predisposing for drug resistance.

PURPOSE: MTC has varying clinical course. In cases with metastatic disease (meta-MTC) further therapeutic modalities (locoregional and/or Tyrosine-Kinase-Inhibitors, TKIs) are needed. Clinical features, disease progression, response to therapy and possible factors predisposing to TKIs response-resistance in meta-MTCs were investigated. METHODS: Out of 338 MTC patients 54 had meta-MTC and were followed for 0.7-46 years (median 10.5); therapeutic interventions and response to therapy were recorded retrospectively. RESULTS: Of 54 meta-MTC patients, 34/54 were men, 44/54 sporadic (age-at-diagnosis 47 ± 17.4 years, range: 5-78). Distant metastases at diagnosis were present in 12/54 (≥2 loci in 8/12), 7/12 received TKIs; During follow-up metastases occurred in 42/54 (within 0.6-25 years from diagnosis, median 5 yrs). Locoregional therapies were administered to 44/54 (81.5%) and TKIs to 40/54 (74.1%). Vandetanib was administered in 30 patients (24 as first-line therapy). The median progression-free-survival, PFS) was 48 months (range 4-120), partial response (PR): 26.7%, stable disease (SD): 23.3%, progressive disease (PD): 50.0%, cancer-specific survival: 44.8%, (16 in ongoing-therapy). More favorable disease course was recorded in familial-MTC compared to sporadic (p = 0.02) and in those patients with serious-adverse-events (SAEs) under treatment (p = 0.027). Those with biochemical progression under vandetanib, later showed more frequently structural progression (p = 0.007). Ten patients received cabozantinib (8/10 as second-line therapy, median PFS:11 months (3-36 months), 8/10 died). Three RET-mutant patients received selpercatinib; all showed PR. Within the total follow-up period, the response to therapy was: PR: 8/54 (14.8%), SD: 15/54 (27.8%), PD: 31/54 (57.4%), cancer-specific survival 46.3%. Mortality was higher in older patients (≥60 years) compared to younger ones (<60 yrs) (83.3 vs 45.2%, p = 0.021). Outcome was better in familial-MTC vs sporadic (PR: 50 vs 6.8%, SD: 20 vs 29.5%, PD: 30 vs 59.1%, p = 0.007). CONCLUSIONS: Meta-MTCs treatment results in disease stabilization in 42.6% during a median 10.5 year follow-up. Combination of locoregional and systemic therapies may result in more favorable PFS. Family history, younger age, SAEs may predict better response; biochemical escape under TKI needs to be followed-up closely as it may indicate disease progression.

MANAGEMENT OF ENDOCRINE DISEASE: Medullary thyroid cancer: from molecular biology and therapeutic pitfalls to future targeted treatment perspectives.

During the last decades, knowledge of the molecular biology in medullary thyroid carcinoma (MTC) and specifically on the role of rearranged during transfection (RET)-activating mutations in tumorigenesis has led to the evolution of novel targeted therapies, mainly tyrosine kinase inhibitors (TKIs). Vandetanib and cabozantinib have been approved for the management of metastatic progressive MTC. Two novel, highly selective RET inhibitors, selpercatinib and pralsetinib, have recently been approved for the treatment of RET-mutant MTCs and RET-fusion differentiated thyroid cancer. The administration of targeted therapies in MTC patients has changed the therapeutic strategies; however, in the majority of cases, there are no real data showing an improvement of prognosis by TKIs in MTC. Drug resistance remains the main reason for treatment failure. Thus, the understanding of the molecular landscape of tumorigenesis and the mechanisms underlying resistance to targeted therapies is of paramount importance for the further development of more efficient therapies for MTC. The present review focuses on the molecular pathways implicated in MTC tumorigenesis, the approved targeted therapies, the tumoral escape mechanisms, as well as the future perspectives for targeted therapy.

Advanced RAI-refractory thyroid cancer: an update on treatment perspectives.

During the last decades, the knowledge on follicular cell-derived thyroid cancer molecular biology has led to the evolution of a number of novel therapies for these tumors, mainly tyrosine kinase inhibitors. Lenvantinib, sorafenib and recently cabozantinib have been approved for differentiated thyroid cancer (DTC), while larotrectinib and entrectinib for neurotrophic-tropomyosin receptor kinase-fusion thyroid cancer. For radioiodine (RAI) refractory DTCs ongoing research aims to identify agents that may restore RAI-avidity via redifferentiation protocols (vemurafenib or dabrafenib and trametinib) or combination treatments. These treatments are based on the tumor molecular signature. The treatment with targeted therapies has changed the therapeutic strategies and the disease prognosis, however drug resistance remains the main reason for treatment failure. Thus, the understanding of both molecular pathways implicated in tumorigenesis, and tumoral escape mechanisms, are of paramount significance for the development of new therapies for DTC. The present review focuses on the molecular landscape of DTC, the approved targeted therapies as well as the mechanisms of drug resistance. Furthermore, it points to the ongoing research and the future perspectives for the development of more efficient drugs for DTC.

Study of Xbal and Pvull polymorphisms of estrogen receptor alpha (ERα) gene in girls with precocious/early puberty.

PURPOSE: Studies examining association of estrogen receptor alpha (ERα) polymorphisms with early puberty are scarce and results are controversial; data in Caucasian girls are lacking. Main objective was to determine association of Xbal and Pvull polymorphisms of ERα gene in Greek girls with precocious/early puberty METHODS: We studied 107 girls with idiopathic precocious/early puberty and 81 young women with pubertal maturation within normal age (controls). Pubertal stage, height SDS (HSDS), and BMI z-score were determined in patients. In controls, height was measured and menarcheal age was self-reported. All participants in the study were genotyped for XbaI and PvuII polymorphisms of the ERα gene. RESULTS: There was no significant difference in XbaI and PvuII polymorphisms between patients and controls. Homozygous, xx and pp, girls had an earlier onset of puberty, although non-significant, than heterozygous or with no polymorphisms p = 0.9; in girls with pubertal onset <7 years, the association tended to become significant, p = 0.09. Girls with xxpp genotype were significantly taller, HSDS 1.63, p = 0.014. In controls, homozygosity for Xbal (xx) and PvuII (pp) was associated with significantly earlier menarche than in women with no polymorphism, p = 0.013 and p = 0.026, respectively, and xxpp genotype was associated with taller adult height, p = 0.017. CONCLUSION: XbaI and PvuII polymorphisms are not related to idiopathic precocious/early puberty. Early pubertal girls homozygous for both polymorphisms presented earlier onset of puberty, although statistically non-significant, and taller height than girls heterozygous or without these polymorphisms. Homozygosity for both polymorphisms is associated with earlier menarche and taller adult height.

Histology is more ιmportant than persistent anti-Tg antibodies for progression of differentiated thyroid cancer.

CONTEXT: Anti-thyroglobulin antibodies (anti-Tg), present in 20%-25% of differentiated thyroid cancer (DTC) patients, interfere with thyroglobulin measurements posing a challenge in the follow-up. OBJECTIVES: The aim of this study was to identify clinical-histological factors that may affect anti-Tg persistence and disease outcome in DTC with positive anti-Tg. METHODS: We retrospectively studied 234 DTC patients, with positive anti-Tg at diagnosis (females: 82.1%, age at diagnosis: 46.0 ± 14.4 yrs, median follow-up: 5 yrs (1.5-32 yrs). 221/234 (94.4%) received radioiodine (RAI) ablation. Patients were divided into two subgroups: those whose anti-Tg became undetectable (anti-Tg-NEG) and those whose anti-Tg remained positive (anti-Tg-POS) at the end of the follow-up period. RESULTS: Anti-Tg-POS patients (n = 80, 34.2%) compared to anti-Tg-NEG (n = 154, 65.8%) had more frequently lymph node infiltration (36.3% vs 20.1%, P = .01), extrathyroidal extension (ETE, 35.0% vs 22.1%, P = .04), poorly differentiated DTC and increased tumour size (P ≤ .004). They received higher total RAI dose (P < .001). In most cases, additional RAI administration and/or additional surgeries did not lead to anti-Tg elimination. These had more frequently structural disease persistence/progression compared to anti-Tg-NEG (remission: 78.8% vs 95.5%, persistence: 13.8% vs 3.9%, progression: 7.5% vs 0.6%, P < .001). In Kaplan-Meier analysis, the probability of disease progression was higher in anti-Tg-POS. In Cox proportional hazard analysis, the predictors of disease progression were size (P = .002) and ETE (P = .006). CONCLUSIONS: Worse histological features are more frequent in patients with anti-Tg persistence during follow-up. Further additional RAI administration and/or surgeries do not affect anti-Tg elimination in most cases. Anti-Tg persistence correlates with structural persistence although tumour size and extrathyroidal extension are the main predictors of disease progression.

The role of molecular genetics in the presurgical management of thyroid nodules.

INTRODUCTION: Fine-needle aspiration (FNA) is an important diagnostic tool for the evaluation of thyroid nodules. However, in almost » of all nodules submitted to FNA cytology is indeterminate. Since the majority of genetic alterations in thyroid cancer have been identified, the use of molecular testing platforms has been endorsed by American Thyroid Association for management of indeterminate nodules. EVIDENCE ACQUISITION: Several commercial tests were based on mRNA expression of FNA samples (Afirma®, Veracyte, South San Francisco, CA, USA) while others detect DNA alterations (ThyroSeq, UPMC, Pittsburgh, PA, USA). Noncommercial tests detect limited number of point mutations or re-arrangements (gene panels). Literature study included a Pubmed research for adult original studies from 2003 to 2020, focusing on terms such as "molecular tests," "nodules with indeterminate AUS/FLUS and FN/SFN cytology." EVIDENCE SYNTHESIS: Gene expression profile tests serve as "rule out" tests due to their high negative predictive value and perform better in a setting of low cancer pretest probability. Genetic alteration platforms display high positive predictive value and serve as rather "rule in" tests but their diagnostic accuracy is hampered either because a small proportion of nodules does not harbor any of these alterations targeted (gene panels) or because commonly identified RAS mutations can also be found in benign nodules. CONCLUSIONS: Next generation sequencing development and incorporation of other genetic markers such as miRNA can improve diagnostic accuracy of molecular tests.

Long-term outcome of differentiated thyroid cancer in children and young adults: risk stratification by ATA criteria and assessment of pre-ablation stimulated thyroglobulin as predictors of disease persistence.

PURPOSE: Differentiated thyroid cancer (DTC) has an increasing incidence in childhood and adolescence but long-term outcome data are limited. We aimed to identify possible risk factors associated with disease persistence, with special focus on the usefulness of ATA risk stratification system and pre-ablation stimulated thyroglobulin (Tg) levels. METHODS: We retrospectively studied 103 patients, 79 females (76.7%), aged 15.6 ± 3.2 years (range 5-21 years) who underwent total thyroidectomy for DTC. Patients were classified by ATA risk stratification criteria as low, intermediate, and high risk for recurrence. All, except five with papillary microcarcinoma, received radioactive iodine (RAI) treatment. RESULTS: At diagnosis, 44.7% of patients had cervical lymph node and 7.8% pulmonary metastases. Amongst the 72 patients with long-term follow-up data, 31.9% had persistent disease. Lymph node as well as pulmonary metastases and increased pre-ablation stimulated thyroglobulin (Tg) levels were associated with persistent disease. The risk of persistent disease was significantly higher in both the intermediate- (OR 17.95; 95% CI 2.66-120.94, p < 0.01) and high-risk (OR 17.65; 95% CI 4.47-69.74, p < 0.001) groups. ROC curve analysis showed that a pre-ablation Tg level higher than 14 ng/ml had a sensitivity of 94.7% to predict persistence, corresponding to a positive (PPV) and negative predictive values (NPV) of 66.7% and 93.8%, respectively. CONCLUSIONS: ATA risk stratification was validated in our population of children and young adults with DTC. Moreover, pre-ablation stimulated Tg levels of <14 ng/ml were associated with a low risk of long-term persistence and may therefore serve as a marker to identify patients who may need less intensive surveillance.

Clinical and Genetic Features of a Large Monocentric Series of Familial Non-Medullary Thyroid Cancers.

Several low penetration susceptibility risk loci or genes have been proposed in recent years with a possible causative role for familial non-medullary thyroid cancer (FNMTC), though the results are still not conclusive or reliable. Among all the candidates, here fully reviewed, a new extremely rare germline variant c.3607A>G (p.Y1203H) of the DUOX2 gene, has been recently reported to co-segregate with the affected members of one non-syndromic FNMTC family. We aimed to validate this finding in our series of 33 unrelated FNMTC Italian families, previously found to be negative for two susceptibility germline variants in the HABP2 and MAP2K5 genes. Unfortunately, the DUOX2 p.Y1203H variant was not found in either the 74 affected or the 12 not affected family members of our series. We obtained interesting data by comparing the clinico-pathological data of the affected members of our kindreds with a large consecutive series of sporadic cases, followed at our site. We found that familial tumors had a statistically significant more aggressive presentation at diagnosis, though not resulting in a worst outcome. In conclusion, we report genetic and clinical data in a large series of FNMTC kindreds. Our families are negative for variants reported as likely causative, namely those lying in the HABP2, MAP2K5 and DUOX2 genes. The extensive review of the current knowledge on the genetic risk factors for non-syndromic FNMTCs underlies how the management of these tumors remains mainly clinical. Despite the more aggressive presentation of familial cases, an appropriate treatment leads to an outcome similar to that observed for sporadic cases.

Medical therapy for non-functioning pituitary tumors-a critical approach.

Non-functioning pituitary adenomas (NFPAs) are the second most common variant of pituitary tumors. When symptomatic, primary therapy is surgery. Recurrence rates are high. Since many NFPAs express dopamine and somatostatin receptors, medical therapy has been used after surgery in order to prevent recurrence. So far, dopamine agonists have been more widely tested with some promise when introduced immediately after surgery but with less efficacy when introduced later upon tumor regrowth. Currently, the role of medical therapy to prevent tumor regrowth in NFPAs is limited by imprecisions as to final outcome and uncertainties concerning on patient selection, dosing, duration, and side effects.

Early Adiposity Rebound and Premature Adrenarche.

OBJECTIVES: To examine differences in the growth pattern and the age at adiposity rebound (AR) between children with premature adrenarche (PA) and their healthy peers (controls). STUDY DESIGN: In this cross-sectional study of 82 prepubertal children with PA and 63 controls, the main outcome measures were height and body mass index SDS progression, from birth to presentation at the clinic, baseline biochemical and hormonal evaluation, bone age determination, and age at AR. RESULTS: Children with PA were significantly taller and more adipose than controls from the first years of life. 33% of children with PA presented the growth pattern of constitutional advancement of growth (ie, early growth acceleration) vs 19% of controls (P = .045). Children with PA had an earlier AR compared with controls; mean age at AR in girls with PA was 3.73 (1.03) years vs 4.93 (1.36) years for control girls (P = .001) and in boys with PA was 3.45 (0.73) vs 5.10 (1.50) years in control boys (P = .048). Both obese and nonobese girls with PA were taller and had earlier age at AR compared with nonobese controls. CONCLUSIONS: Early AR and constitutional advancement of growth may be triggering factors for adrenal androgen production and PA.

Differentiated thyroid cancer in childhood: a literature update.

Differentiated thyroid cancer in childhood is rare. Apart from family history, radiation exposure is a major risk factor. Although its clinical course is quite aggressive with higher rates of lymph node and pulmonary metastases as compared to adults, the final outcome tends to be favorable with mortality rates less than 2%. We herein review the clinical picture, genetic background response to treatment and recurrence rates of differentiated thyroid cancer in children and young adolescents are thoroughly reviewed and the main differences with adult differentiated thyroid cancer are highlighted.

Therapeutic trends and outcome of acromegaly: a single center experience over a 40-year period.

OBJECTIVE: To evaluate the therapeutic trends and long-term outcome of treatment modalities for acromegaly in our center over a 40-year period. DESIGN: We retrospectively studied 321 acromegalic patients (145 males/176 females) diagnosed and treated from the 1970s until September 2013. Patients were divided into two subgroups: group A consisted of 166 patients diagnosed before 1990 and group B of 155 patients diagnosed after 1990. Outcome was assessed with GH (random and/or post OGTT) and IGF1 measurements. RESULTS: More group A than group B patients were submitted to radiotherapy (57.8% vs 16.8% patients, respectively, p <0.001). In contrast, more patients of group B were offered surgery (70.3% vs 42.1% in group A, p <0.001) and/or medical treatment (70.3% vs 23.4% in group A, p <0.001). At latest follow-up, 68.4 % of patients in group B achieved GH <2.5 µg/l after treatment vs 39.8% in group A, p=0.001, 46.9% of patients in group B achieved GH <1 µg/l vs 20.3% in group A, p=0.001 and 47.1% of patients in group B achieved during OGTT GH nadir <0.4 µg/l vs 18.6% in group A, p=0.001. CONCLUSIONS: Transsphenoidal resection and medical treatment resulted in improved outcome in acromegalic patients treated over the last 20 years. However, the disease still remains uncontrolled in a considerable number of patients.

A Greek girl with 11ß-hydroxylase deficiency due to compound heterozygosity for two novel mutations in CYP11B1 gene.

UNLABELLED: 11ß-hydroxylase deficiency (11ß-OHD), an autosomal recessive inherited disorder, accounts for 5-8% of congenital adrenal hyperplasia. In Greece, no cases of 11ß-OHD have been described so far. The patient presented at the age of 13 months with mild virilization of external genitalia and pubic hair development since the age of 3 months. Hormonal profile showed elevated 11-deoxycortisol, adrenal androgens and ACTH levels. ACTH stimulation test was compatible with 11ß-OHD. DNA of the proband and her parents was isolated and genotyped for CYP11B1 gene coding cytochrome P450c11. The girl was found to be compound heterozygous for two CYP11B1 novel mutations, p.Ala386Glu (exon 7), inherited from the father and p.Leu471Argin (exon 9) from the mother. Hydrocortisone supplementation therapy was initiated. Four years after presentation she remains normotensive, her growth pattern is normal and the bone age remains advanced despite adequate suppression of adrenal androgens. LEARNING POINTS: 11ß-hydroxylase (CYP11B1) deficiency (11OHD; OMIM +202010) is the second most common cause of CAH accounting for approximately 5-8% of cases with an incidence of 1:100 000-1:200 000 live births in non-consanguineous populations.Two CYP11B1 inactivating novel mutations, p.Ala386Glu and p.Leu471Arg are reportedRegarding newborn females, in utero androgen excess results in ambiguous genitalia, whereas in the male newborn diagnosis may go undetected. In infancy and childhood adrenal androgen overproduction results in peripheral precocious puberty in boys and various degrees of virilization in girls.Accumulation of 11-deoxycorticosterone and its metabolites causes hypertension in about two thirds of patients.Diagnosis lies upon elevated 11-deoxycortisol and DOC plus upstream precursors, such as 17α-hydroxyprogesterone and Δ4-androstenedione.The established treatment of steroid 11ß-OHD is similar to that of steroid 21-hydroxylase deficiency and consists of glucocorticoid administration in order to reduce ACTH-driven DOC overproduction resulting in hypertension remission and improvement of the virilization symptoms.

X-linked adrenoleukodystrophy: are signs of hypogonadism always due to testicular failure?

We present the clinical and hormonal findings of a young male with X-linked adrenoleukodystrophy (X-ALD), with special emphasis on the biochemical and clinical pattern of hypogonadism. A patient, with primary adrenal insufficiency since the age of 5 years, developed progressive neurological symptoms at the age of 29. Diagnosis of X-ALD was established by elevated serum very long chain fatty acids (VLCFAs) and genetic testing. His sexual body hair was sparse. Hormonal investigations revealed normal testosterone and inappropriately elevated LH levels. Androgen receptor gene analysis was negative for mutations or polymorphic variants associated with decreased receptor activity. Signs of hypogonadism in patients with confirmed X-ALD are not exclusively due to primary testicular failure. Tissue specific androgen resistance represents an alternative possibility. Since no loss-of-function mutations were detected in the androgen receptor, it is speculated that the patient's androgen resistance could be part of a functional defect mediated through VLCFA accumulation at the testosterone receptor and/or post-receptor levels.

Adrenocorticotropic hormone independent macronodular adrenal hyperplasia due to aberrant receptor expression: is medical treatment always an option?

OBJECTIVE: To investigate the efficacy of medical treatment as an alternative option to bilateral adrenalectomy in patients with cortisol excess due to adrenocorticotropic hormone (ACTH) independent macronodular adrenal hyperplasia (AIMAH). METHODS: We focused on the efficacy of somatostatin analogues in a patient with food-dependent AIMAH and of leuprolide acetate in a patient with AIMAH due to aberrant LH/hCG receptor expression. RESULTS: Two female patients with bilateral macronodular adrenal hyperplasia and cortisol excess were evaluated for the presence of aberrant cortisol responses. One patient demonstrated an aberrant response to mixed meal and the other, a menopausal female, to luteinizing hormone-releasing hormone (LHRH) and human chorionic gonadotropin (hCG) administration. In the first patient, subcutaneous octreotide was administered prior to mixed meal and completely abolished food-induced cortisol secretion. Thus, the patient was treated with the long-acting somatostatin analogue octreotide long-acting release (LAR) for 3 months. There was no control of cortisol excess upon reevaluation and acute subcutaneous octreotide administration prior to meal was no longer effective in blocking food-induced cortisol secretion. The second patient successfully responded to leuprolide acetate and, for 40 months, her cortisol excess remains in long-term control. CONCLUSIONS: A luteinizing hormone/human chorionic gonadotropin (LH/hCG) responsive patient with AIMAH sustained long-term control of cortisol excess on leuprolide acetate. In contrast, in a meal-responsive patient with apparent gastric inhibitory polypeptide (GIP) dependent AIMAH, did not achieve remission under somatostatin analogues.

Gonadotroph pituitary macroadenoma inducing ovarian hyperstimulation syndrome: successful response to octreotide therapy.

We report a young woman with spontaneous ovarian hyperstimulation syndrome (OHSS), headaches, visual field defect and pituitary macroadenoma. She underwent transsphenoidal surgery with remission of OHSS. Immunohistochemical staining was positive for ß-FSH and ß-LH. Recurrence occurred after four years. The patient was treated with octreotide administration and conventional radiation therapy. Octreotide was effective in normalizing estradiol levels and resolving OHSS. This is a rare description of octreotide administration as an effective treatment modality of OHSS caused by gonadotropin-secreting pituitary adenomas.

Health status of Greek thyroid cancer patients after radioiodine administration compared to a demographically matched general population sample.

The impact of radioiodine-131 ((131)I) treatment on thyroid cancer patients' quality of life is controversial. We conducted a cross-sectional study of 60 patients aged 18-73 years old who had recently underwent near total thyroidectomy due to papillary thyroid cancer and were scheduled for (131)I treatment. On admission to our department, prior to (131)I administration patients underwent clinical and laboratory investigation including routine clinical biochemistry, thyroid stimulating hormone (TSH) and thyroglobulin (Tg) measurements. Health-related quality of life (HRQoL) was estimated by the SF-36 Health Survey a generic instrument which consisted from eight scales (four for physical and four for mental health). After (131)I administration patients were discharged and approximately 6 months later they were re-evaluated. Our results showed that HRQoL in thyroid cancer patients receiving (131)I treatment is independent of age/gender and thyroid cancer-related variables. All SF-36 scales significantly improved six months after administration (P<0.05). Compared to Greek general population, before (131)I administration all scales were significantly lower (P<0.05). Six months post (131)I administration, scales were significantly lower for physical functioning (P=0.02), physical role (P=0.01), social functioning (P=0.03) and emotional role limitations (P=0.04), whereas the remaining SF-36 scales were comparable to the general population. In conclusion, hypothyroidism and anxiety for the outcome of their disease before (131)I treatment exert a negative impact on thyroid cancer patients. Quality of life improvement post (131)I is mainly attributed to the resumption of euthyroidism and familiarization with treatment and followup procedures rather than (131)I treatment itself. There was no significant difference between patients receiving lower (2220-3700MBq) and higher (3700-7400MBq) dosage.

Characteristics of the short children referred to an academic paediatric endocrine clinic in Greece.

AIM: To describe the characteristics of short children in relation to gender and the various diagnoses. METHODS: All new patients of Greek origin that were referred to our institution in the years 2007 and 2008 for evaluation of short stature were included in the study. Children were categorized according to the severity of their short stature in those with height standard deviation score (HSDS) ≤ -3 and HSDS > -3. RESULTS: Two hundred ninety-five children (162 boys and 133 girls, ratio 1.2) were referred. HSDS of boys was -2.3 (0.6) and of girls -2.1 (0.5), P= 0.004. Girls had shorter parents, and the predicted adult HSDS was also shorter for girls -1.7 (0.8) than for boys -1.35 (0.76), P= 0.003. Seventy per cent of the children of both sexes had familial short stature (FSS), constitutional delay of growth or a combination of the two conditions. About 10% presented the auxological and biochemical criteria for growth hormone deficiency (GHD). In addition, 11.8% had a HSDS ≤ -3, the most common diagnosis being GHD (36.1%); the less severely short children most commonly presented FSS (41.2%). CONCLUSIONS: There is no gender bias in referrals for short stature in Greece. About 70% of children of both sexes presented FSS or constitutional delay of growth or a combination of the two conditions, whereas GHD was diagnosed in about 10% of the children. Normal variants of growth were present in about 80% of children with HSDS > -3, but in only 40% when HSDS was ≤ -3.

VPA-induced recurrent pancreatitis in a cystic fibrosis carrier.

A 4.5 years old male with myoclonic epilepsy on Valproic acid (VPA) monotherapy, developed an acute pancreatitis. The discontinuation of VPA and substitution with Levetiracetam was followed by clinical improvement but a relapse of the pancreatitis was noted one month later. The investigation excluded a structural abnormality but revealed a heterozygous CTFR mutation. The contribution of the CTFR mutation on this VPA-induced recurrent pancreatitis cannot be ignored.