ABSTRACT
Adult and paediatric patients with pathogenic variants in the gene encoding succinate dehydrogenase (SDH) subunit B (SDHB) often have locally aggressive, recurrent or metastatic phaeochromocytomas and paragangliomas (PPGLs). Furthermore, SDHB PPGLs have the highest rates of disease-specific morbidity and mortality compared with other hereditary PPGLs. PPGLs with SDHB pathogenic variants are often less differentiated and do not produce substantial amounts of catecholamines (in some patients, they produce only dopamine) compared with other hereditary subtypes, which enables these tumours to grow subclinically for a long time. In addition, SDHB pathogenic variants support tumour growth through high levels of the oncometabolite succinate and other mechanisms related to cancer initiation and progression. As a result, pseudohypoxia and upregulation of genes related to the hypoxia signalling pathway occur, promoting the growth, migration, invasiveness and metastasis of cancer cells. These factors, along with a high rate of metastasis, support early surgical intervention and total resection of PPGLs, regardless of the tumour size. The treatment of metastases is challenging and relies on either local or systemic therapies, or sometimes both. This Consensus statement should help guide clinicians in the diagnosis and management of patients with SDHB PPGLs.
Subject(s)
Adrenal Gland Neoplasms , Paraganglioma , Pheochromocytoma , Adult , Humans , Child , Pheochromocytoma/genetics , Pheochromocytoma/therapy , Pheochromocytoma/diagnosis , Paraganglioma/genetics , Paraganglioma/therapy , Germ-Line Mutation/genetics , Adrenal Gland Neoplasms/genetics , Adrenal Gland Neoplasms/therapy , Adrenal Gland Neoplasms/diagnosis , Succinate Dehydrogenase/geneticsABSTRACT
BACKGROUND: Severe primary insulin-like growth factor-I (IGF-I) deficiency (SPIGFD) is a rare growth disorder characterized by short stature (standard deviation score [SDS] ≤ 3.0), low circulating concentrations of IGF-I (SDS ≤ 3.0), and normal or elevated concentrations of growth hormone (GH). Laron syndrome is the best characterized form of SPIGFD, caused by a defect in the GH receptor (GHR) gene. However, awareness of SPIGFD remains low, and individuals living with SPIGFD continue to face challenges associated with diagnosis, treatment and care. OBJECTIVE: To gather perspectives on the key challenges for individuals and families living with SPIGFD through a multi-stakeholder approach. By highlighting critical gaps in the awareness, diagnosis, and management of SPIGFD, this report aims to provide recommendations to improve care for people affected by SPIGFD globally. METHODS: An international group of clinical experts, researchers, and patient and caregiver representatives from the SPIGFD community participated in a virtual, half-day meeting to discuss key unmet needs and opportunities to improve the care of people living with SPIGFD. RESULTS: As a rare disorder, limited awareness and understanding of SPIGFD amongst healthcare professionals (HCPs) poses significant challenges in the diagnosis and treatment of those affected. Patients often face difficulties associated with receiving a formal diagnosis, delayed treatment initiation and limited access to appropriate therapy. This has a considerable impact on the physical health and quality of life for patients, highlighting a need for more education and clearer guidance for HCPs. Support from patient advocacy groups is valuable in helping patients and their families to find appropriate care. However, there remains a need to better understand the burden that SPIGFD has on individuals beyond height, including the impact on physical, emotional, and social wellbeing. CONCLUSIONS: To address the challenges faced by individuals and families affected by SPIGFD, greater awareness of SPIGFD is needed within the healthcare community, and a consensus on best practice in the care of individuals affected by this condition. Continued efforts are also needed at a global level to challenge existing perceptions around SPIGFD, and identify solutions that promote equitable access to appropriate care. Medical writing support was industry-sponsored.
Subject(s)
Dwarfism , Laron Syndrome , Humans , Insulin-Like Growth Factor I/therapeutic use , Quality of Life , Laron Syndrome/diagnosis , Laron Syndrome/drug therapy , Laron Syndrome/genetics , Dwarfism/drug therapy , Growth DisordersABSTRACT
CONTEXT: Prader-Willi syndrome (PWS) is a rare genetic disorder characterized by endocrine and neuropsychiatric problems including hyperphagia, anxiousness, and distress. Intranasal carbetocin, an oxytocin analog, was investigated as a selective oxytocin replacement therapy. OBJECTIVE: To evaluate safety and efficacy of intranasal carbetocin in PWS. DESIGN: Randomized, double-blind, placebo-controlled phase 3 trial with long-term follow-up. SETTING: Twenty-four ambulatory clinics at academic medical centers. PARTICIPANTS: A total of 130 participants with PWS aged 7 to 18 years. INTERVENTIONS: Participants were randomized to 9.6 mg/dose carbetocin, 3.2 mg/dose carbetocin, or placebo 3 times daily during an 8-week placebo-controlled period (PCP). During a subsequent 56-week long-term follow-up period, placebo participants were randomly assigned to 9.6 mg or 3.2 mg carbetocin, with carbetocin participants continuing at their previous dose. MAIN OUTCOME MEASURES: Primary endpoints assessed change in hyperphagia (Hyperphagia Questionnaire for Clinical Trials [HQ-CT]) and obsessive-compulsive symptoms (Children's Yale-Brown Obsessive-Compulsive Scale [CY-BOCS]) during the PCP for 9.6 mg vs placebo, and the first secondary endpoints assessed these same outcomes for 3.2 mg vs placebo. Additional secondary endpoints included assessments of anxiousness and distress behaviors (PWS Anxiousness and Distress Behaviors Questionnaire [PADQ]) and clinical global impression of change (CGI-C). RESULTS: Because of onset of the COVID-19 pandemic, enrollment was stopped prematurely. The primary endpoints showed numeric improvements in both HQ-CT and CY-BOCS which were not statistically significant; however, the 3.2-mg arm showed nominally significant improvements in HQ-CT, PADQ, and CGI-C scores vs placebo. Improvements were sustained in the long-term follow-up period. The most common adverse event during the PCP was mild to moderate flushing. CONCLUSIONS: Carbetocin was well tolerated, and the 3.2-mg dose was associated with clinically meaningful improvements in hyperphagia and anxiousness and distress behaviors in participants with PWS. CLINICAL TRIALS REGISTRATION NUMBER: NCT03649477.
Subject(s)
COVID-19 , Prader-Willi Syndrome , Child , Humans , Prader-Willi Syndrome/drug therapy , Prader-Willi Syndrome/complications , Oxytocin , Pandemics , COVID-19/complications , Hyperphagia/drug therapy , Hyperphagia/complications , Anxiety/drug therapy , Anxiety/etiologyABSTRACT
CONTEXT: Somatrogon is a long-acting recombinant human growth hormone (rhGH) in development for once-weekly treatment of children with growth hormone deficiency (GHD). OBJECTIVE: We aimed to compare the efficacy and safety of once-weekly somatrogon with once-daily somatropin in prepubertal children with GHD. METHODS: In this 12-month, open-label, randomized, active-controlled, parallel-group, phase 3 study, participants were randomized 1:1 to receive once-weekly somatrogon (0.66 mg/kg/week) or once-daily somatropin (0.24 mg/kg/week) for 12 months. A total of 228 prepubertal children (boys aged 3-11 years, girls aged 3-10 years) with GHD, impaired height and height velocity (HV), and no prior rhGH treatment were randomized and 224 received ≥1 dose of study treatment (somatrogon: 109; somatropin: 115). The primary endpoint was annualized HV at month 12. RESULTS: HV at month 12 was 10.10 cm/year for somatrogon-treated subjects and 9.78 cm/year for somatropin-treated subjects, with a treatment difference (somatrogon-somatropin) of 0.33 (95% CI: -0.24, 0.89). The lower bound of the 2-sided 95% CI was higher than the prespecified noninferiority margin (-1.8 cm/year), demonstrating noninferiority of once-weekly somatrogon vs daily somatropin. HV at month 6 and change in height standard deviation score at months 6 and 12 were similar between both treatment groups. Both treatments were well tolerated, with a similar percentage of subjects experiencing mild to moderate treatment-emergent adverse events in both groups (somatrogon: 78.9%, somatropin: 79.1%). CONCLUSION: The efficacy of once-weekly somatrogon was noninferior to once-daily somatropin, with similar safety and tolerability profiles. (ClinicalTrials.gov no. NCT02968004).
Subject(s)
Dwarfism, Pituitary , Human Growth Hormone , Body Height , Child , Child, Preschool , Dwarfism, Pituitary/drug therapy , Female , Growth Disorders/drug therapy , Growth Hormone/therapeutic use , Human Growth Hormone/adverse effects , Humans , Male , Recombinant Proteins/adverse effectsABSTRACT
CONTEXT: Acylated ghrelin (AG) stimulates appetite and is elevated compared to its unacylated (UAG) counterpart in Prader-Willi syndrome (PWS). GLWL-01 is a selective, reversible inhibitor of ghrelin O-acyltransferase (GOAT), the enzyme that converts UAG into AG. OBJECTIVE: This work aimed to assess the efficacy, pharmacokinetics, pharmacodynamics, and safety of GLWL-01 in the treatment of PWS patients. METHODS: A double-blind, placebo-controlled, phase 2 crossover study was conducted with 2 active treatment periods of 28 days in 19 patients (aged 16-65 years; body mass index (BMI)â ≥â 28) with genetically confirmed PWS. The study took place in 7 hospital-based study centers in the United States and Canada. Patients received placebo or GLWL-01 (450 mg twice daily) orally after lead-in placebo and washout periods. The Hyperphagia Questionnaire for Clinical Trials and Caregiver Global Impression of Change were used to measure reductions in hyperphagia. Plasma concentrations of AG and UAG were evaluated as correlates. RESULTS: Treatment resulted in statistically significant differences compared to placebo in plasma AG (Pâ =â .0002), UAG (Pâ =â .0488), and AG/UAG (Pâ =â .0003). GLWL-01 did not statistically significantly reduce hyperphagia-related behavior or bring about changes in global clinical end points, as assessed by caregivers. Anthropometric and clinical parameters correlated with obesity did not statistically significantly change in response to treatment. Less than half of patients reported a treatment-emergent adverse event (TEAE). No deaths, serious adverse events, or severe TEAEs were reported. CONCLUSION: GLWL-01 is safe and well tolerated. Pharmacological parameters confirmed the inhibition of GOAT following administration of GLWL-01. Patients' eating behaviors, BMI, blood glucose, and total cholesterol, among other similar measures, were not modified.
Subject(s)
Prader-Willi Syndrome , Acyltransferases , Cross-Over Studies , Double-Blind Method , Ghrelin/therapeutic use , Humans , Hyperphagia , Prader-Willi Syndrome/drug therapyABSTRACT
BACKGROUND: Central precocious puberty (CPP) in females is characterized by thelarche before 8 years of age. Evidence of reproductive axis activation confirms the diagnosis (basal serum luteinizing hormone (LH) ≥0.3 IU/L or LH-releasing hormone (LHRH)-stimulated LH ≥5 IU/L). Stimulation testing is the diagnostic gold standard but is time-consuming and costly. Serum levels of insulin-like growth factor-1 (IGF-1) and insulin-like growth factor-binding protein 3 (IGFBP-3) are increased in girls with CPP. OBJECTIVE: The aim of the study was to assess the utility of serum IGF-1 and IGFBP-3 in identifying CPP in girls aged 6-8 years. METHODS: The study was a single-center retrospective study. Girls with confirmed CPP (n = 44) and isolated premature precocious adrenarche/ precocious thelarche (PA/PT, n = 16) had baseline biochemical profiling and LHRH stimulation testing. Serum IGF-1 and IGFBP-3 results were converted to standard deviation scores (SDS). Correlations were calculated and receiver operating characteristic curves were plotted. RESULTS: Girls with CPP had higher basal and peak LH, IGF-1 SDS, and growth velocity (p < 0.05). IGF-1 SDS correlated positively with basal and peak LH (p < 0.05). IGF-1 SDS (1.75-2.15) differentiated CPP and PA/PT with 89% sensitivity and 56% specificity (basal LH) and 94% specificity and 55% sensitivity (peak LH). IGFBP-3 SDS did not differ between groups or by CPP parameters. CONCLUSIONS: In clinical practice, IGF-1 SDS may be an additional tool for identifying CPP in girls aged 6 to 8 years when baseline clinical and laboratory diagnostic criteria are inconclusive, possibly avoiding more time-consuming and costly procedures.
Subject(s)
Insulin-Like Growth Factor Binding Protein 3/blood , Insulin-Like Growth Factor I/metabolism , Puberty, Precocious/diagnosis , Child , Female , Follicle Stimulating Hormone/blood , Humans , Luteinizing Hormone/blood , Puberty, Precocious/blood , Retrospective Studies , Sensitivity and SpecificityABSTRACT
CONTEXT: Pituitary blastoma is a rare, dysontogenetic hypophyseal tumor of infancy first described in 2008, strongly suggestive of DICER1 syndrome. OBJECTIVE: This work aims to describe genetic alterations, clinical courses, outcomes, and complications in all known pituitary blastoma cases. DESIGN AND SETTING: A multi-institutional case series is presented from tertiary pediatric oncology centers. PATIENTS: Patients included children with pituitary blastoma. INTERVENTIONS: Genetic testing, surgery, oncologic therapy, endocrine support are reported. OUTCOME MEASURES: Outcome measures included survival, long-term morbidities, and germline and tumor DICER1 genotypes. RESULTS: Seventeen pituitary blastoma cases were studied (10 girls and 7 boys); median age at diagnosis was 11 months (range, 2-24 months). Cushing syndrome was the most frequent presentation (n = 10). Cushingoid stigmata were absent in 7 children (2 with increased adrenocorticotropin [ACTH]; 5 with normal/unmeasured ACTH). Ophthalmoplegia and increased intracranial pressure were also observed. Surgical procedures included gross/near-total resection (n = 7), subtotal resection (n = 9), and biopsy (n = 1). Six children received adjuvant therapy. At a median follow-up of 6.7 years, 9 patients were alive; 8 patients died of the following causes: early medical/surgical complications (n = 3), sepsis (n = 1), catheter-related complication (n = 1), aneurysmal bleeding (n = 1), second brain tumor (n = 1), and progression (n = 1). Surgery was the only intervention for 5 of 9 survivors. Extent of resection, but neither Ki67 labeling index nor adjuvant therapy, was significantly associated with survival. Chronic complications included neuroendocrine (n = 8), visual (n = 4), and neurodevelopmental (n = 3) deficits. Sixteen pituitary blastomas were attributed to DICER1 abnormalities. CONCLUSIONS: Pituitary blastoma is a locally destructive tumor associated with high mortality. Surgical resection alone provides long-term disease control for some patients. Quality survival is possible with long-term neuroendocrine management.
Subject(s)
Blast Crisis/mortality , DEAD-box RNA Helicases/genetics , Germ-Line Mutation , Pituitary Neoplasms/mortality , Postoperative Complications/mortality , Ribonuclease III/genetics , Blast Crisis/pathology , Blast Crisis/surgery , Child, Preschool , Female , Follow-Up Studies , Humans , Infant , Male , Pituitary Neoplasms/pathology , Pituitary Neoplasms/surgery , Postoperative Complications/etiology , Postoperative Complications/pathology , Prognosis , Retrospective Studies , Survival RateABSTRACT
The Growth Hormone Research Society (GRS) convened a Workshop in March 2019 to evaluate the diagnosis and therapy of short stature in children. Forty-six international experts participated at the invitation of GRS including clinicians, basic scientists, and representatives from regulatory agencies and the pharmaceutical industry. Following plenary presentations addressing the current diagnosis and therapy of short stature in children, breakout groups discussed questions produced in advance by the planning committee and reconvened to share the group reports. A writing team assembled one document that was subsequently discussed and revised by participants. Participants from regulatory agencies and pharmaceutical companies were not part of the writing process. Short stature is the most common reason for referral to the pediatric endocrinologist. History, physical examination, and auxology remain the most important methods for understanding the reasons for the short stature. While some long-standing topics of controversy continue to generate debate, including in whom, and how, to perform and interpret growth hormone stimulation tests, new research areas are changing the clinical landscape, such as the genetics of short stature, selection of patients for genetic testing, and interpretation of genetic tests in the clinical setting. What dose of growth hormone to start, how to adjust the dose, and how to identify and manage a suboptimal response are still topics to debate. Additional areas that are expected to transform the growth field include the development of long-acting growth hormone preparations and other new therapeutics and diagnostics that may increase adult height or aid in the diagnosis of growth hormone deficiency.
Subject(s)
Growth Disorders , Human Growth Hormone , Child , Growth Disorders/diagnosis , Growth Disorders/genetics , Growth Disorders/pathology , Growth Disorders/therapy , Human Growth Hormone/deficiency , Human Growth Hormone/therapeutic use , HumansABSTRACT
Context: Safety concerns have been raised regarding premature mortality, diabetes, neoplasia, and cerebrovascular disease in association with GH therapy. Objective: To assess incidence of key safety outcomes. Design: Prospective, multinational, observational study (1999 to 2015). Setting: A total of 22,311 GH-treated children from 827 investigative sites in 30 countries. Patients: Children with growth disorders. Interventions: GH treatment. Main outcome measures: Standardized mortality ratio (SMR) and standardized incidence ratio (SIR) with 95% CIs for mortality, diabetes, and primary cancer using general population registries. Results: Predominant short stature diagnoses were GH deficiency (63%), idiopathic short stature (13%), and Turner syndrome (8%), with mean ± SD follow-up of 4.2 ± 3.2 years (â¼92,000 person-years [PY]). Forty-two deaths occurred in patients with follow-up, with an SMR (95% CI) of 0.61 (0.44, 0.82); the SMR was elevated for patients with cancer-related organic GH deficiency [5.87 (3.21, 9.85)]. Based on 18 cases, type 2 diabetes mellitus (T2DM) risk was elevated [SIR: 3.77 (2.24, 5.96)], but 72% had risk factors. In patients without cancer history, 14 primary cancers were observed [SIR: 0.71 (0.39, 1.20)]. Second neoplasms occurred in 31 of 622 cancer survivors [5.0%; 10.7 (7.5, 15.2) cases/1000 PY] and intracranial tumor recurrences in 67 of 823 tumor survivors [8.1%; 16.9 (13.3, 21.5) cases/1000 PY]. All three hemorrhagic stroke cases had risk factors. Conclusions: GeNeSIS (Genetics and Neuroendocrinology of Short Stature International Study) data support the favorable safety profile of pediatric GH treatment. Overall risk of death or primary cancer was not elevated in GH-treated children, and no hemorrhagic strokes occurred in patients without risk factors. T2DM incidence was elevated compared with the general population, but most cases had diabetes risk factors.
Subject(s)
Cerebral Hemorrhage/epidemiology , Diabetes Mellitus, Type 2/epidemiology , Growth Disorders/drug therapy , Human Growth Hormone/adverse effects , Neoplasms/epidemiology , Adolescent , Cerebral Hemorrhage/chemically induced , Child , Child, Preschool , Diabetes Mellitus, Type 2/chemically induced , Female , Follow-Up Studies , Growth Disorders/mortality , Humans , Incidence , Male , Neoplasms/chemically induced , Prospective Studies , Recombinant Proteins/adverse effects , Risk FactorsSubject(s)
Dwarfism, Pituitary/genetics , Mutation , Pituitary Gland/metabolism , Adolescent , Child , Child, Preschool , DNA Mutational Analysis , Dwarfism, Pituitary/metabolism , Dwarfism, Pituitary/physiopathology , Female , Homeodomain Proteins/genetics , Human Growth Hormone/genetics , Humans , LIM-Homeodomain Proteins/genetics , Male , Nuclear Proteins/genetics , Phenotype , Pituitary Gland/growth & development , Prospective Studies , Receptors, Neuropeptide , Receptors, Pituitary Hormone-Regulating Hormone , SOXB1 Transcription Factors/genetics , Transcription Factor Pit-1/genetics , Transcription Factors/genetics , Young Adult , Zinc Finger Protein Gli2/geneticsABSTRACT
BACKGROUND: Chitayat-Hall syndrome, initially described in 1990, is a rare condition characterised by distal arthrogryposis, intellectual disability, dysmorphic features and hypopituitarism, in particular growth hormone deficiency. The genetic aetiology has not been identified. METHODS AND RESULTS: We identified three unrelated families with a total of six affected patients with the clinical manifestations of Chitayat-Hall syndrome. Through whole exome or whole genome sequencing, pathogenic variants in the MAGEL2 gene were identified in all affected patients. All disease-causing sequence variants detected are predicted to result in a truncated protein, including one complex variant that comprised a deletion and inversion. CONCLUSIONS: Chitayat-Hall syndrome is caused by pathogenic variants in MAGEL2 and shares a common aetiology with the recently described Schaaf-Yang syndrome. The phenotype of MAGEL2-related disorders is expanded to include growth hormone deficiency as an important and treatable complication.
Subject(s)
Arthrogryposis/genetics , Growth Hormone/genetics , Intellectual Disability/genetics , Proteins/genetics , Adolescent , Adult , Arthrogryposis/physiopathology , Child , Exome/genetics , Female , Growth Hormone/deficiency , Humans , Intellectual Disability/physiopathology , Male , Pedigree , Phenotype , Exome Sequencing , Young AdultABSTRACT
GH plays an essential role in the growing child by binding to the growth hormone receptor (GHR) on target cells and regulating multiple growth promoting and metabolic effects. Mutations in the GHR gene coding regions result in GH insensitivity (dwarfism) due to a dysfunctional receptor protein. However, children with idiopathic short stature (ISS) show growth impairment without GH or GHR defects. We hypothesized that decreased expression of the GHR gene may be involved. To test this, we investigated whether common genetic variants (microsatellites, SNPs) in regulatory regions of the GHR gene region were associated with the ISS phenotype. Genotyping of a GT-repeat microsatellite in the GHR 5'UTR in a Montreal ISS cohort (n = 37 ISS, n = 105 controls) revealed that the incidence of the long/short (L/S) genotype was 3.3× higher in ISS children than controls (P = 0.04, OR = 3.85). In an Italian replication cohort (n = 143 ISS, n = 282 controls), the medium/short (M/S) genotype was 1.9× more frequent in the male ISS than controls (P = 0.017, OR = 2.26). In both ISS cohorts, logistic regression analysis of 27 SNPs showed an association of ISS with rs4292454, while haplotype analysis revealed specific risk haplotypes in the 3' haploblocks. In contrast, there were no differences in GT genotype frequencies in a cohort of short stature (SS) adults versus controls (CARTaGENE: n = 168 SS, n = 207 controls) and the risk haplotype in the SS cohort was located in the most 5' haploblock. These data suggest that the variants identified are potentially genetic markers specifically associated with the ISS phenotype.
Subject(s)
Dwarfism/genetics , Human Growth Hormone/genetics , Microsatellite Repeats , Polymorphism, Single Nucleotide , Receptors, Somatotropin/genetics , Adolescent , Alleles , Base Sequence , Case-Control Studies , Child , Child, Preschool , Cohort Studies , Dwarfism/metabolism , Female , Gene Expression , Gene Frequency , Haplotypes , Human Growth Hormone/metabolism , Humans , Male , Phenotype , Receptors, Somatotropin/metabolism , RiskABSTRACT
BACKGROUND/AIMS: To assess auxological and safety data for growth hormone (GH)-treated children with SHOX deficiency. METHODS: Data were examined for GH-treated SHOX-deficient children (n = 521) from the observational Genetics and Neuroendocrinology of Short Stature International Study (GeNeSIS). For patients with near-adult height information, GeNeSIS results (n = 90) were compared with a clinical trial (n = 28) of SHOX-deficient patients. Near-adult height was expressed as standard deviation score (SDS) for chronological age, potentially increasing the observed effect of treatment. RESULTS: Most SHOX-deficient patients in GeNeSIS had diagnoses of Leri-Weill syndrome (n = 292) or non-syndromic short stature (n = 228). For GeNeSIS patients with near-adult height data, mean age at GH treatment start was 11.0 years, treatment duration 4.4 years, and height SDS gain 0.83 (95% confidence interval 0.49-1.17). Respective ages, GH treatment durations and height SDS gains for GeNeSIS patients prepubertal at baseline (n = 42) were 9.2 years, 6.0 years and 1.19 (0.76-1.62), and for the clinical trial cohort they were 9.2 years, 6.0 years and 1.25 (0.92-1.58). No new GH-related safety concerns were identified. CONCLUSION: Patients with SHOX deficiency who had started GH treatment before puberty in routine clinical practice had a similar height gain to that of patients in the clinical trial on which approval for the indication was based, with no new safety concerns.
Subject(s)
Body Height , Child Development/drug effects , Growth Disorders , Homeodomain Proteins/genetics , Human Growth Hormone/administration & dosage , Osteochondrodysplasias , Body Height/drug effects , Body Height/genetics , Child , Female , Follow-Up Studies , Growth Disorders/drug therapy , Growth Disorders/genetics , Growth Disorders/physiopathology , Humans , Male , Osteochondrodysplasias/drug therapy , Osteochondrodysplasias/genetics , Osteochondrodysplasias/physiopathology , Short Stature Homeobox ProteinABSTRACT
Turner syndrome is a genetic condition resulting from the partial or complete absence of an X-chromosome in phenotypic females. Individuals with Turner syndrome often display social difficulties that are reminiscent of those associated with autistic spectrum disorders (ASD), conditions associated with empathy and mirror-neuron system (MNS) deficits. The goal of the present study was (1) to investigate the extent to which adults with Turner syndrome display autistic and empathic traits, and (2) to probe the integrity of the MNS in this neurogenetic disorder. Sixteen individuals with Turner syndrome and 16 age-, sex-, and IQ-matched controls took part in a neuropsychological assessment where the Weschler Abbreviated Scale of Intelligence, the Autism Spectrum Quotient and the Empathy Quotient were administered. Functioning of the MNS was assessed by measuring motor cortex activity with transcranial magnetic stimulation during an action-observation task. Results show that individuals with Turner syndrome do not differ significantly from controls regarding autistic or empathic traits, and present normal functioning of the MNS during action observation. Correlational analysis showed a significant positive relationship between scores on the Empathy Quotient and motor facilitation during action observation, bringing further support to the hypothesis that MNS activity is related to sociocognitive competence.
Subject(s)
Empathy , Motion Perception/physiology , Motor Cortex/physiopathology , Turner Syndrome/physiopathology , Turner Syndrome/psychology , Adult , Autistic Disorder/psychology , Evoked Potentials, Motor , Female , Humans , Mirror Neurons/physiology , Neuropsychological Tests , Photic Stimulation , Psychological Tests , Transcranial Magnetic Stimulation , Young AdultABSTRACT
Mutations in the nuclear-encoded mitochondrial aminoacyl-tRNA synthetases are associated with a range of clinical phenotypes. Here, we report a novel disorder in three adult patients with a phenotype including cataracts, short-stature secondary to growth hormone deficiency, sensorineural hearing deficit, peripheral sensory neuropathy, and skeletal dysplasia. Using SNP genotyping and whole-exome sequencing, we identified a single likely causal variant, a missense mutation in a conserved residue of the nuclear gene IARS2, encoding mitochondrial isoleucyl-tRNA synthetase. The mutation is homozygous in the affected patients, heterozygous in carriers, and absent in control chromosomes. IARS2 protein level was reduced in skin cells cultured from one of the patients, consistent with a pathogenic effect of the mutation. Compound heterozygous mutations in IARS2 were independently identified in a previously unreported patient with a more severe mitochondrial phenotype diagnosed as Leigh syndrome. This is the first report of clinical findings associated with IARS2 mutations.
Subject(s)
Cataract/genetics , Dwarfism, Pituitary/genetics , Hearing Loss, Sensorineural/genetics , Isoleucine-tRNA Ligase/genetics , Leigh Disease/genetics , Mutation , Peripheral Nervous System Diseases/genetics , Adult , Amino Acid Sequence , Brain/pathology , Cataract/diagnosis , Consanguinity , DNA Mutational Analysis , Dwarfism, Pituitary/diagnosis , Female , Genes, Recessive , Hearing Loss, Sensorineural/diagnosis , Humans , Isoleucine-tRNA Ligase/chemistry , Leigh Disease/diagnosis , Magnetic Resonance Imaging , Male , Molecular Sequence Data , Pedigree , Peripheral Nervous System Diseases/diagnosis , Phenotype , Sequence Alignment , SyndromeABSTRACT
Individuals harboring germ-line DICER1 mutations are predisposed to a rare cancer syndrome, the DICER1 Syndrome or pleuropulmonary blastoma-familial tumor and dysplasia syndrome [online Mendelian inheritance in man (OMIM) #601200]. In addition, specific somatic mutations in the DICER1 RNase III catalytic domain have been identified in several DICER1-associated tumor types. Pituitary blastoma (PitB) was identified as a distinct entity in 2008, and is a very rare, potentially lethal early childhood tumor of the pituitary gland. Since the discovery by our team of an inherited mutation in DICER1 in a child with PitB in 2011, we have identified 12 additional PitB cases. We aimed to determine the contribution of germ-line and somatic DICER1 mutations to PitB. We hypothesized that PitB is a pathognomonic feature of a germ-line DICER1 mutation and that each PitB will harbor a second somatic mutation in DICER1. Lymphocyte or saliva DNA samples ascertained from ten infants with PitB were screened and nine were found to harbor a heterozygous germ-line DICER1 mutation. We identified additional DICER1 mutations in nine of ten tested PitB tumor samples, eight of which were confirmed to be somatic in origin. Seven of these mutations occurred within the RNase IIIb catalytic domain, a domain essential to the generation of 5p miRNAs from the 5' arm of miRNA-precursors. Germ-line DICER1 mutations are a major contributor to PitB. Second somatic DICER1 "hits" occurring within the RNase IIIb domain also appear to be critical in PitB pathogenesis.
Subject(s)
DEAD-box RNA Helicases/genetics , Mutation , Neoplasms, Complex and Mixed/genetics , Neoplasms, Complex and Mixed/pathology , Pituitary Neoplasms/genetics , Pituitary Neoplasms/pathology , Ribonuclease III/genetics , Child, Preschool , DNA Mutational Analysis , Fatal Outcome , Germ-Line Mutation , Humans , Immunohistochemistry , Infant , Magnetic Resonance Imaging , Neoplasms, Complex and Mixed/surgery , Pedigree , Pituitary Neoplasms/surgery , Radiography, Thoracic , Tomography, X-Ray Computed , Treatment OutcomeABSTRACT
Turner syndrome (TS) is a non-inherited genetic disorder associated with a specific cognitive phenotype and socioemotional impairments. The present study aimed at characterizing the neuroanatomical basis of socioemotional dysfunctions in TS using the Emotional Quotient inventory (EQ-I) and cortical morphology analysis in 17 individuals with TS (45,X) and 17-age and verbal IQ matched healthy females. Individuals with TS reported significantly greater socioemotional impairment than controls. Cortical thickness analysis showed that participants with TS had an overall thicker cortex than controls, with extensive alterations in the temporal, frontal, parietal and insular regions bilaterally. Using the total EQ-I score as regressor in the cortical thickness analysis revealed a number of brain regions where the relationship between cortical thickness and EQ-I score differed between groups; these areas included brain regions critically involved in socioemotional processes, such as bilateral insula, the anterior cingulate and the orbitofrontal cortex. These results show that socioemotional dysfunctions seen in women with TS are associated with significant alterations in brain morphology.
Subject(s)
Cerebral Cortex/pathology , Emotions , Social Adjustment , Turner Syndrome/pathology , Turner Syndrome/psychology , Adaptation, Psychological , Adult , Female , Humans , Neuropsychological Tests , Young AdultABSTRACT
CONTEXT: Carriers of germline DICER1 mutations are predisposed to a rare cancer syndrome, the DICER1 syndrome. Thyroid abnormalities are a common finding in DICER1 syndrome with multinodular goiter frequently present in many families in which a germline DICER1 mutation is segregating. Differentiated thyroid carcinoma (DTC) is infrequently seen in such pedigrees. In addition to germline DICER1 mutations, specific somatic mutations have been identified in the DICER1 ribonuclease IIIb catalytic domain in several tumor types. OBJECTIVE: We aimed to determine whether such characteristic somatic DICER1 mutations are present in DTCs that arise within germline DICER1 mutation carriers. DESIGN AND SETTING: The study involved an opportunistic collection of 3 cases of DTC arising in individuals suspected to have DICER1 syndrome and hospital-based ascertainment and testing was implemented. RESULTS: We identified somatic DICER1 mutations in 3 DTCs arising in unrelated germline DICER1 mutation carriers, all of whom had been diagnosed in infancy with pleuropulmonary blastoma (PPB), were treated with chemotherapy, exposed frequently to diagnostic radiation, and subsequently developed DTC. The somatic mutations occurred within the DICER1 ribonuclease IIIb domain, affecting highly conserved amino acid residues central to the catalytic activity of the domain. CONCLUSION: This report of somatic DICER1 mutations in DTC strengthens the association between DTC and the DICER1 syndrome. The possible association between germline DICER1 mutations, PPB treatment, and the risk of subsequent DTC must be considered by clinicians when treating PPB.