Central adrenal insufficiency in children and adolescents

Central adrenal insufficiency (CAI) is a life-threatening condition caused by either pituitary disease (secondary adrenal insufficiency) or impaired hypothalamic function with inadequate CRH production (tertiary adrenal insufficiency). ACTH deficiency may be isolated or, more frequently, occur in conjunction with other pituitary hormone deficiencies and midline defects. Genetic mutations of the TBX19 causing isolated CAI are rare but a number of genes encoding transcription factors involved in hypothalamic-pituitary gland development, as well as other genes including POMC and PC1, are associated with ACTH deficiency. CAI is frequently identified in congenital, malformative, genetic, and epigenetic syndromes as well as in several acquired conditions of different etiologies. The signs and symptoms vary considerably and depend on the age of onset and the number and severity of associated pituitary defects. They may include hypoglycemia, lethargy, apnea, poor feeding, prolonged cholestatic jaundice, jitteriness, seizures, and sepsis in the neonate, or nonspecific signs such as fatigue, hypotension, vomiting and hyponatremia without hyperkalemia in children. The diagnosis of CAI relies on the measurement of morning cortisol concentrations along with dynamic test for cortisol release with different stimulating agents. Early recognition of CAI and its correct management are mandatory in order to avoid both morbidity and mortality in affected neonates, children and adolescents

Classical and non-classical causes of GH deficiency in the paediatric age

Growth hormone deficiency (GHD) may result from a failure of hypothalamic GHRH production or release, from congenital disorders of pituitary development, or from central nervous system insults including tumors, surgery, trauma, radiation or infiltration from inflammatory diseases. Idiopathic, isolated GHD is the most common sporadic form of hypopituitarism. GHD may also occur in combination with other pituitary hormone deficiencies, and is often referred to as hypopituitarism, combined pituitary hormone deficiency (CPHD), multiple pituitary hormone deficiency (MPHD) or panhypopituitarism. Children without any identifiable cause of their GHD are commonly labeled as having idiopathic hypopituitarism. MRI imaging is the technique of choice in the diagnosis of children with hypopituitarism. Marked differences in MRI pituitary gland morphology suggest different etiologies of GHD and different prognoses. Pituitary stalk agenesis and ectopic posterior pituitary (EPP) are specific markers of permanent GHD, and patients with these MRI findings show a different clinical and endocrine outcome compared to those with normal pituitary anatomy or hypoplastic pituitary alone. Furthermore, the classic triad of ectopic posterior pituitary gland, pituitary stalk hypoplasia/agenesis, and anterior pituitary gland hypoplasia is generally associated with permanent GHD. T2 DRIVE images aid in the identification of pituitary stalk without the use of contrast medium administration. Future developments in imaging techniques will undoubtedly reveal additional insights. Mutations in a number of genes encoding transcription factors \u2013 such as HESX1, SOX2, SOX3, LHX3, LHX4, PROP1, POU1F1, PITX, GLI3, GLI2, OTX2, ARNT2, IGSF1, FGF8, FGFR1, PROKR2, PROK2, CHD7, WDR11, NFKB2, PAX6, TCF7L1, IFT72, GPR161 and CDON \u2013 have been associated with pituitary dysfunction and abnormal pituitary gland development; the correlation of genetic mutations to endocrine and MRI phenotypes has improved our knowledge of pituitary development and management of patients with hypopituitarism, both in terms of possible genetic counseling, and of early diagnosis of evolving anterior pituitary hormone deficiencies

Age- and sex-matched reference curves for serum collagen type I C-telopeptides and bone alkaline phosphatase in children and adolescents: An alternative multivariate statistical analysis approach

Introduction The availability of pediatric age- and sex-matched reference curves for bone markers is essential for appropriate assessment of bone turnover and treatment follow-up of bone disorders. The aim of this work was to obtain updated reference equations for collagen type I C-telopeptides (CTX-1) and bone alkaline phosphatase (BAP) by using an alternative statistical approach. The study included 1502 Italian pediatric subjects from 6 months to 16 years of age (686 females and 816 males) subjected to CTX-1 and BAP measurement during a six-year period. Methods The unselected population of patients was used for the calculation of age- and sex-matched reference curves by using a multivariate statistical analysis after an appropriate validation with a selected population of 184 healthy subjects (6 months-16 years; 88 females and 96 males). The effect of age, sex, puberty based on Tanner stage evaluation and anthropometrics on the variations of the two bone markers was then studied. Results Pediatric reference curves were obtained for CTX-1 and BAP from 3465 results retrieved by our Laboratory Information System. The equations for the calculation of reference values were obtained for boys and girls. The two bone markers markedly varied according to age, sex and pubertal stage with females displaying higher values during Tanner stages II and III and males during stages III and IV. Conclusions The application of a novel statistical approach provided reference curves for CTX-1 and BAP. This method, moreover, could be applied in pediatrics to obtain reference intervals for other biomarkers

Maternal Uniparental Disomy of Chromosome 20 (UPD(20)mat) as Differential Diagnosis of Silver Russell Syndrome: Identification of Three New Cases

Silver Russell Syndrome (SRS, MIM #180860) is a rare growth retardation disorder in which clinical diagnosis is based on six features: pre- and postnatal growth failure, relative macrocephaly, prominent forehead, body asymmetry, and feeding difficulties (Netchine-Harbison clinical scoring system (NH-CSS)). The molecular mechanisms consist in (epi)genetic deregulations at multiple loci: the loss of methylation (LOM) at the paternal H19/IGF2:IG-DMR (chr11p15.5) (50%) and the maternal uniparental disomy of chromosome 7 (UPD(7)mat) (10%) are the most frequent causes. Thus far, about 40% of SRS remains undiagnosed, pointing to the need to define the rare mechanisms in such a consistent fraction of unsolved patients. Within a cohort of 176 SRS with an NH-CSS 65 3, a molecular diagnosis was disclosed in about 45%. Among the remaining patients, we identified in 3 probands (1.7%) with UPD(20)mat (Mulchandani-Bhoj-Conlin syndrome, OMIM #617352), a molecular mechanism deregulating the GNAS locus and described in 21 cases, characterized by severe feeding difficulties associated with failure to thrive, preterm birth, and intrauterine/postnatal growth retardation. Our patients share prominent forehead, feeding difficulties, postnatal growth delay, and advanced maternal age. Their clinical assessment and molecular diagnostic flowchart contribute to better define the characteristics of this rare imprinting disorder and to rank UPD(20)mat as the fourth most common pathogenic molecular defect causative of SRS

Early-onset central diabetes insipidus is associated with de novo arginine vasopressin-neurophysin II or Wolfram syndrome 1 gene mutations.

reserved15nomixedPerrotta, S; Di Iorgi, N; Ragione, Fd; Scianguetta, S; Borriello, A; Allegri, Ae; Ferraro, M; Santoro, C; Napoli, F; Calcagno, A; Giaccardi, M; Cappa, M; Salerno, Mc; Cozzolino, D; Maghnie, M.Perrotta, S; DI IORGI, Natascia; Ragione, Fd; Scianguetta, S; Borriello, A; Allegri, ANNA ELSA MARIA; Ferraro, M; Santoro, C; Napoli, F; Calcagno, A; Giaccardi, M; Cappa, M; Salerno, Mc; Cozzolino, D; Maghnie, Mohama