Daniele Tessaris

Thyroid abnormalities in children and adolescents with mccune-albright syndrome

Background: To date, there is no agreement about the frequency or the features of thyroid abnormalities in McCune-Albright syndrome (MAS). The aim of our study was to detect thyroid abnormalities in a cohort of MAS children and adolescents and to give indications for their treatment and follow-up. Methods: In 36 patients, 22 females and 14 males, thyroid function and sonographic features of thyroid were evaluated every 6–12 months. Results: Three males and 1 female had hyperthyroidism: 2 with nodular, 2 with diffuse goiters. They were treated with methimazole (0.2–0.5 mg/kg/day) with good clinical and biochemical responses. The remaining 32 patients were euthyroid, even if 7 displayed sonographic alterations, of whom 5 had nodular goiter with nodules >1 cm, and 2 micronodular goiter. Fine-needle aspiration biopsy was performed in 2 patients with nodules >1 cm, 1 showing hemorrhagic nodule and 1 colloid cystic nodule. Conclusions: Prevalence of thyroid alterations in the studied MAS series was 31%. 64% of 11 patients with thyroid alterations had nodular goiters, with nodules >1 cm. As the onset of thyroid disease ranged from 1 to 20 years, a strict monitoring of thyroid function is recommended every 6 months. Satisfactory treatment can be obtained and maintained with antithyroid drugs.

In children with autoimmune thyroid diseases the association with Down syndrome can modify the clustering of extra-thyroidal autoimmune disorders

Abstract Background: It is known that the association with Down syndrome (DS) can affect the phenotypic expression of autoimmune thyroid diseases (AITDs), whilst is unknown whether the clustering of extra-thyroidal autoimmune diseases (ETADs) may also be atypical in DS children. Methods: The aim of this study was to investigate the clustering of ETADs in 832 children with AITDs divided in two groups with or without DS (A and B, respectively) and in four subgroups of patients aged either <6 or ≥6 years. Results: The rate of children with ETADs was significantly higher in Group A; in particular, alopecia areata (p=0.00001) and vitiligo (p=0.00001) were found more often in Group A irrespective of age, whilst the distribution of T1 diabetes mellitus was not different in the two groups. Celiac disease prevalence was significantly higher in DS patients only in the older subgroup. Conclusions: The association with DS may be able to modify the clustering of ETADs in the children with AITDs by favoring the aggregation of some specific diseases such as alopecia areata and vitiligo.

Cushing syndrome due to ectopic adrenocorticotropic hormone secretion in a 3-year-old child

Abstract Ectopic adrenocorticotrophic hormone (ACTH) secretion is a rare cause of Cushing syndrome in paediatric age, due to tumours arising from different tissues. To date, only 11 reports of ACTH-secreting pancreatic tumours in children and adolescents exist in the literature. We present a paediatric case of Cushing syndrome caused by ectopic ACTH secretion. This was caused by a large acinar cell carcinoma that developed in the pancreas of a 3-year-old girl.

Odontoiatric perspectives and osteonecrosis of the jaw as a possible adverse effect of bisphosphonates therapy in fibrous dysplasia and McCune-Albright syndrome

Abstract Background: McCune-Albright syndrome (MAS) is characterized by the triad of polyostotic bone fibrous dysplasia (PFD), endocrine disorders, and café-au-lait skin pigmentation. Ninety percent of MAS patients have fibrous dysplasia (FD) craniofacial lesions. Osteonecrosis of the jaw (ONJ) has been described as an adverse side effect of bisphosphonate therapy. The aim of the study was to investigate evidence of clinical and/or radiological signs of ONJ in FD/MAS pediatric patients due to bisphosphonate therapy and describe odontoiatric tools in this population. Methods: Thirteen FD/MAS patients were enrolled. All patients during pediatric age have been treated with pamidronate infusions. They underwent complete oral clinical examination. Ortopantomography and/or CT were evaluated in all cases. Results and conclusions: No patient developed ONJ. None of them showed radiological signs different from jaw FD. In spite of the low number of patients enrolled, results confirm that, in this population, ONJ can be ruled out as a chronic adverse side effect of bisphosphonate therapy.

Surgical enucleation of testicular leydigioma in a young child: case report and literature review.

Abstract Background: The leydigioma is the most frequent interstitial neoplasm of the testis. Clinical symptoms of all leydigioma usually are isosexual precocious pseudo-puberty due to autonomous testosterone overproduction, suppressed gonadotropin levels and a testis mass. Nowadays its therapy is debated. Design and methods: We report a case of a young child treated in 2008 for a leydigioma of the testis with atypical clinical behavior. Testicular oncologic markers and hormonal profile were assessed. Results: The patient was treated successfully with organ-confined surgery. Conclusion: We want to confirm the safety of conservative surgery against radical orchiectomy and review the literature of the last decade on this debated matter.

Genetic and Epigenetic Defects at the GNAS Locus Lead to Distinct Patterns of Skeletal Growth but Similar Early-Onset Obesity: DISTINCT PATTERNS OF FETAL AND POSTNATAL GROWTH IN GNAS-RELATED DISORDERS

Pseudohypoparathyroidism type 1A (PHP1A), pseudoPHP (PPHP), and PHP type 1B (PHP1B) are caused by maternal and paternal GNAS mutations and abnormal methylation at maternal GNAS promoter(s), respectively. Adult PHP1A patients are reportedly obese and short, whereas most PPHP patients are born small. In addition to parathyroid hormone (PTH) resistance, PHP1A and PHP1B patients may display early‐onset obesity. Because early‐onset and severe obesity and short stature are daily burdens for PHP1A patients, we aimed at improving knowledge on the contribution of the GNAS transcripts to fetal and postnatal growth and fat storage. Through an international collaboration, we collected growth and weight data from birth until adulthood for 306 PHP1A/PPHP and 220 PHP1B patients. PHP1A/PPHP patients were smaller at birth than healthy controls, especially PPHP (length Z‐score: PHP1A –1.1 ± 1.8; PPHP –3.0 ± 1.5). Short stature is observed in 64% and 59% of adult PHP1A and PPHP patients. PHP1B patients displayed early postnatal overgrowth (height Z‐score at 1 year: 2.2 ± 1.3 and 1.3 ± 1.5 in autosomal dominant and sporadic PHP1B) followed by a gradual decrease in growth velocity resulting in normal adult height (Z‐score for both: –0.4 ± 1.1). Early‐onset obesity characterizes GNAS alterations and is associated with significant overweight and obesity in adults (bodey mass index [BMI] Z‐score: 1.4 ± 2.6, 2.1 ± 2.0, and 1.4 ± 1.9 in PPHP, PHP1A, and PHP1B, respectively), indicating that reduced Gsα expression is a contributing factor. The growth impairment in PHP1A/PPHP may be due to Gsα haploinsufficiency in the growth plates; the paternal XLαs transcript likely contributes to prenatal growth; for all disease variants, a reduced pubertal growth spurt may be due to accelerated growth plate closure. Consequently, early diagnosis and close follow‐up is needed in patients with GNAS defects to screen and intervene in case of early‐onset obesity and decreased growth velocity.

Iatrogenic acute pancreatitis due to hypercalcemia in a child with pseudohypoparathyroidism.

Abstract Pancreatitis due to hypercalcemia is very rare in children, and its pathogenetic role is still debated. The following report describes a case of acute pancreatitis secondary to hypercalcemia in a 6-year-old boy with pseudohypoparathyroidism treated with calcium and vitamin D. Pseudohypoparathyroidism is characterized by parathormone (PTH) resistance, high PTH levels and hypocalcemia which need to be corrected with calcium and vitamin D supplementation. The patient was admitted for severe abdominal pain and vomiting associated with high plasma amylase, lipase and calcium levels. Hypercalcemia due to vitamin D and calcium overtreatment was probably responsible for the acute pancreatitis in this case. High serum calcium levels seem to sensitize patients to pancreatitis, even if the mechanism through which it happens is not completely understood. Moreover, the importance of concomitant predisposing factors, either acquired or especially genetic, needs to be further defined. Even though a rare occurance in childhood, hypercalcemia should be considered as a cause of pancreatitis and it should be examined together with the other etiologies that may contribute to the development of this disease.

Copeptin role in polyuria-polydipsia syndrome differential diagnosis and reference range in paediatric age

Plasma arginine‐vasopressin (AVP) analysis can help in the differential diagnosis of the polyuria‐polydipsia syndrome (PPS), even if such investigation is hampered by technical difficulties, conversely to its surrogate copeptin. This study aims to enlarge the existing data on normal copeptin levels in childhood, to evaluate the correlation between copeptin, serum sodium and plasma and urine osmolality, and to assess the utility of the copeptin analysis in the diagnostic work‐up of PPS in the paediatric age.

Growth hormone—Insulin‐like growth factor 1 axis hyperactivity on bone fibrous dysplasia in McCune‐Albright Syndrome

In fibrous dysplasia (BFD), normal bone and bone marrow are replaced by fibro‐osseous tissue, leading to fracture, deformity and pain. BFD may be isolated, or in association with cutaneous hyperpigmentation and/or hyperfunctioning endocrinopathies, termed McCune‐Albright syndrome (MAS). GH hypersecretion has been described in 10%‐20% of MAS‐BFD patients. Aim of the study was to determine the impact of GH‐insulin like growth factor 1 (IGF1) axis hyperactivity on MAS‐BFD morbidities and the efficacy of GH excess therapy.

Combining Real-Time COLD- and MAMA-PCR TaqMan Techniques to Detect and Quantify R201 GNAS Mutations in the McCune-Albright Syndrome

Background/Aim: The McCune-Albright syndrome (MAS) is a potentially severe disorder hallmarked by fibrous bone dysplasia, café-au-lait skin spots, and endocrine hyperfunction. It is caused by postzygotic activating mutations at the R201 codon of the GNAS gene, leading to a state of somatic mosaicism. Our aim was to improve the mutation detection rate and to quantify the presence of R201 GNAS mutations in different DNA samples from MAS patients. Methods: Real-time COLD- and MAMA-PCR TaqMan techniques were combined to search for R201 mutations in the DNA of blood or affected tissues from 16 previously molecularly characterized MAS patients, from a further 84 subjects with MAS signs who were R201 negative at RFLP analysis, and from 36 controls. The ability of this new method to provide quantitative data was tested in the serial dilution of wild-type, R201H, or R201C cloned plasmid DNA samples; the mutant abundance was measured by spectrophotometry. Results: A linear correlation between the true and the relative mutant abundance was observed until 2.5%, indicating a reliable quantification of R201 mutations. The assay’s sensitivity was 0.05%, similar to that of previously described molecular methods. Conclusion: The real-time COLD-MAMA-PCR approach is a rapid, efficient, and inexpensive molecular technique for the identification of mutant alleles poorly represented in DNA samples.