Endocrine features of Prader-Willi syndrome: a narrative review focusing on genotype-phenotype correlation.

Prader-Willi syndrome (PWS) is a complex genetic disorder caused by three different types of molecular genetic abnormalities. The most common defect is a deletion on the paternal 15q11-q13 chromosome, which is seen in about 60% of individuals. The next most common abnormality is maternal disomy 15, found in around 35% of cases, and a defect in the imprinting center that controls the activity of certain genes on chromosome 15, seen in 1-3% of cases. Individuals with PWS typically experience issues with the hypothalamic-pituitary axis, leading to excessive hunger (hyperphagia), severe obesity, various endocrine disorders, and intellectual disability. Differences in physical and behavioral characteristics between patients with PWS due to deletion versus those with maternal disomy are discussed in literature. Patients with maternal disomy tend to have more frequent neurodevelopmental problems, such as autistic traits and behavioral issues, and generally have higher IQ levels compared to those with deletion of the critical PWS region. This has led us to review the pertinent literature to investigate the possibility of establishing connections between the genetic abnormalities and the endocrine disorders experienced by PWS patients, in order to develop more targeted diagnostic and treatment protocols. In this review, we will review the current state of clinical studies focusing on endocrine disorders in individuals with PWS patients, with a specific focus on the various genetic causes. We will look at topics such as neonatal anthropometry, thyroid issues, adrenal problems, hypogonadism, bone metabolism abnormalities, metabolic syndrome resulting from severe obesity caused by hyperphagia, deficiencies in the GH/IGF-1 axis, and the corresponding responses to treatment.

Cut-off limits of the peak GH response to stimulation tests for the diagnosis of GH deficiency in children and adolescents: study in patients with organic GHD.

OBJECTIVE: The diagnosis of GH deficiency (GHD) in children and adolescents is established when GH concentrations fail to reach an arbitrary cut-off level after at least two provocative tests. The objective of the study was to define the optimal GH cut-offs to provocative tests in children and adolescents. DESIGN: Retrospective study in 372 subjects who underwent evaluation of GH secretion. GH and IGF-I were measured by chemiluminescence assay in all samples. Receiver operating characteristic (ROC) analysis was used to evaluate the optimal GH cut-offs and the diagnostic accuracy of provocative tests. METHODS: Seventy four patients with organic GHD (GH peak <10µg/L after two provocative tests) and 298 control subjects (GH response >10µg/L to at least one test) were included in the study. The provocative tests used were arginine, insulin tolerance test (ITT) and clonidine. Diagnostic criteria based on cut-offs identified by ROC analysis (best pair of values for sensitivity and specificity) were evaluated for each test individually and for each test combined with IGF-I SDS. RESULTS: The optimal GH cut-off for arginine resulted 6.5µg/L, 5.1µg/L for ITT and 6.8µg/L for clonidine. IGF-I SDS has low accuracy in diagnosing GHD (AUC=0.85). The combination of the results of provocative tests with IGF-I concentrations increased the specificity. CONCLUSIONS: The results of the ROC analysis showed that the cut-off limits which discriminate between normal and GHD are lower than those commonly employed. IGF-I is characterized by low diagnostic accuracy.

Central diabetes insipidus in children and young adults: etiological diagnosis and long-term outcome of idiopathic cases.

CONTEXT: Central diabetes insipidus (CDI) is considered idiopathic in 20% to 50% of affected subjects. OBJECTIVE: The purpose of this study was to determine whether a systematic diagnostic workup could achieve better etiologic diagnosis in children and adolescents presenting with polyuria and polydipsia. DESIGN AND SETTING: This is a prospective study conducted at a tertiary referral center. Patients underwent clinical and endocrine evaluations every 6 months and neuroimaging every 6 months for 2 years and yearly for 3 years. Endocrine function and neuroimaging were also reassessed after adult height achievement. PARTICIPANTS: A total of 85 consecutive patients with CDI were enrolled at a median age of 7.5 years; those with idiopathic CDI were stratified based on pituitary stalk thickness. MAIN OUTCOME MEASURES: To establish the etiology of CDI, we determined the time lag between its onset and the specific diagnosis, the long-term impact on pituitary function, and the overall long-term outcomes. RESULTS: Of the subjects, 24 (28.2%) received an etiologic diagnosis at presentation and 11 (13%) within 2.5 years (n = 7 germinomas and n = 4 Langerhans cell histiocytosis), 7 (8.2%) were lost to follow-up, and 43 (50.6%) were considered to have idiopathic disease and were followed until the median age of 17.3 years. Neuroimaging identified 40 of 43 patients with self-limited inflammatory/autoimmune pituitary stalk thickness within the first 6 months, the severity of which was significantly correlated to pituitary dysfunction. The probability of >10-year-survival without an anterior pituitary defect was related to the severity of pituitary stalk thickness, and 53% showed permanent anterior pituitary defects. Three patients developed Langerhans cell histiocytosis and 1 developed Hodgkin lymphoma after a median of 9 and 13 years, respectively. CONCLUSIONS: A diagnostic etiology was achieved in 96% of patients with CDI. Risk stratification based on the degree of pituitary stalk thickness is of prognostic value for long-term outcomes including permanent pituitary dysfunction. New guidance is provided for the management of these patients.

Reassessment of the growth hormone status in young adults with childhood-onset growth hormone deficiency: reappraisal of insulin tolerance testing.

CONTEXT: The 2007 Consensus Statement suggested a peak GH cutoff to insulin tolerance test (ITT) of less than 6 microg/liter in the diagnosis of permanent GH deficiency (GHD) in young adults with childhood-onset GHD (COGHD), although further validation was recommended. OBJECTIVE: The aim of the study was to evaluate the accuracy of ITT, mean 12-h spontaneous nocturnal GH (SNGH), and IGF-I in the definition of permanent GHD. DESIGN AND SETTING: The study was conducted in two Pediatric Endocrinology Centers. PATIENTS AND METHODS: ITT, 12-h SNGH, and IGF-I were evaluated as single or combined tests in 79 subjects with COGHD (median age, 18.0 yr). The cohort consisted of 48 subjects with isolated GHD or one additional pituitary defect and normal MRI or anterior pituitary hypoplasia (group LLGHD, low likelihood GHD), and 31 subjects with structural hypothalamic-pituitary abnormalities or multiple pituitary hormone deficiencies (group HLGHD, high likelihood GHD). RESULTS: Receiver operating characteristic analysis showed the best diagnostic accuracy for peak GH cutoffs to ITT of 5.62 microg/liter or less [sensitivity, 77.4%; specificity, 93.8%; area under the curve (AUC) = 0.92], mean 12-h SNGH of 1.20 microg/liter or less (sensitivity, 90.3%; specificity, 89.6%; AUC = 0.93), and IGF-I of -2.83 sd score or less (sensitivity, 80.7%; specificity, 95.7%; AUC = 0.93). Seven patients in group HLGHD showed a peak GH to ITT above 5.62 microg/liter, but a median IGF-I that was significantly lower than that of group LLGHD (-3.30 vs. -0.73 sd score; P = 0.0001). Peak GH to ITT of 3.6 microg/liter or less and arginine of 3.1 microg/liter or less at childhood diagnosis can predict a future permanent GHD condition. CONCLUSIONS: The adopted peak GH to ITT below 5.62 microg/liter is an accurate diagnostic cutoff point for HLGHD in young adults with COGHD. In addition, IGF-I is a reliable marker providing information about the severity of GHD. Careful follow-up is required for subjects with discordant ITT and IGF-I results.

Quantitative ultrasound detects bone impairment after bone marrow transplantation in children and adolescents affected by hematological diseases.

PURPOSE: Bone marrow transplantation (BMT) recipients are at risk of bone mass impairment and skeletal morbidity. We investigated bone status with quantitative ultrasound (QUS) technique in children and adolescents with hematological diseases before and after BMT. METHODS: Phalangeal QUS measures for amplitude-dependent speed of sound (AD-SoS) and bone transmission time (BTT) were obtained in 144 hematological patients (81M, 63F; 11.6+/-5.2 years); forty two were evaluated before BMT and 102 after allogeneic or autologous BMT. Bone parameters were expressed as Z-scores based on age-sex-matched normal controls. RESULTS: Mean BTT Z-score was reduced in subjects after BMT compared to patients before BMT (M, -0.35+/-1.04 vs. 0.70+/-1.11, P<0.001; F, -0.60+/-1.23 vs. 0.23+/-1.17, P<0.05). Females and males with hormone deficiencies showed reduced BTT Z-scores when compared with subjects without hormone defects (M, -0.52+/-1.0 vs. 0.05+/-1.17, P<0.05; F, -0.50+/-1.27 vs. -0.19+/-1.26; P=0.06). AD-SoS and BTT Z-scores were reduced in 15 subjects with fractures and/or avascular osteonecrosis compared to patients without bone events (-1.52+/-1.7 vs. -0.41+/-1.32 and -0.85+/-1.19 vs. -0.10+/-1.18; both Ps<0.05). Bone event cumulative incidence was 4 times greater in subjects who suffered from chronic GVHD. CONCLUSIONS: Assessment of phalangeal QUS in young BMT survivors points towards impairment of bone status and endocrine dysfunction and chronic GVHD as risk factors of adverse bone events.

Deterioration of growth hormone (GH) response and anterior pituitary function in young adults with childhood-onset GH deficiency and ectopic posterior pituitary: a two-year prospective follow-up study.

CONTEXT: The current criteria for definition of partial GHD in young adults are still a subject of debate. OBJECTIVES: The objective of the study was to reinvestigate anterior pituitary function in young adults with congenital childhood-onset GHD associated with structural hypothalamic-pituitary abnormalities and normal GH response at the time of first reassessment of GH secretion. DESIGN AND SETTING: This was a prospective explorative study conducted in a university research hospital. PATIENTS AND METHODS: Thirteen subjects with a mean age of 17.2 +/- 0.7 yr and a peak GH after insulin tolerance test (ITT) higher than 5 microg/liter were recruited from a cohort of 42 patients with childhood-onset GHD and ectopic posterior pituitary at magnetic resonance imaging. GH secretion after ITT and GHRH plus arginine, IGF-I concentration, and body mass index, waist circumference, blood pressure, total cholesterol, and fibrinogen were evaluated at baseline and at 2-yr follow-up. RESULTS: At mean age of 19.2 +/- 0.7 yr, the mean peak GH response decreased significantly after ITT (P = 0.00001) and GHRH plus arginine (P = 0.0001). GH peak values after ITT and GHRH plus arginine were less than 5 and 9 microg/liter in 10 and eight patients, respectively. Additional pituitary defects were documented in eight patients. Significant changes were found in the values of IGF-I sd score (P = 0.0026), waist circumference (P = 0.00001), serum total cholesterol (P = 0.00001), and serum fibrinogen (P = 0.0004). CONCLUSIONS: The results of this study underline the importance of further reassessment of pituitary function in young adults with GHD of childhood-onset and poststimulation GH responses suggestive of partial GHD.