Autosomal dominant hypoparathyroidism associated with short stature and premature osteoarthritis

Familial hypoparathyroidism is an unusual and genetically heterogeneous group of disorders that may be isolated or may be associated with congenital or acquired abnormalities in other organs or glands. We have evaluated a family with a novel syndrome of autosomal dominant hypoparathyroidism, short stature, and premature osteoarthritis. A 74-yr-old female (generation I) presented with hypoparathyroidism, a movement disorder secondary to ectopic calcification of the cerebellum and basal ganglia, and a history of knee and hip replacements for osteoarthritis. Two members of generation II and one member of generation III were also documented with hypoparathyroidism, short stature, and premature osteoarthritis evident as early as 11 yr. Because of the known association between autosomal dominant hypoparathyroidism and activating mutations of the calcium-sensing receptor (CaR) gene, further studies were performed. Sequencing of PCR-amplified genomic DNA revealed a leucine to valine substitution at position 616 in the first transmembrane domain of the CaR, which cosegregated with the disorder. However, this amino acid sequence change did not affect the total accumulation of inositol phosphates as a function of extracellular calcium concentrations in transfected HEK-293 cells. In conclusion, a sequence alteration in the coding region of the CaR gene was identified, but is not conclusively involved in the etiology of this novel syndrome. The cosegregation of hypoparathyroidism, short stature, and osteoarthritis in this kindred does suggest a genetic abnormality involving a common molecular mechanism in parathyroid, bone, and cartilage

Growth Retardation in Children with Kidney Disease

Growth failure is almost inextricably linked with chronic kidney disease (CKD) and end-stage renal disease (ESRD). Growth failure in CKD has been associated with both increased morbidity and mortality. Growth failure in the setting of kidney disease is multifactorial and is related to poor nutritional status as well as comorbidities, such as anemia, bone and mineral disorders, and alterations in hormonal responses, as well as to aspects of treatment such as steroid exposure. This review covers updated management of growth failure in these children including adequate nutrition, treatment of metabolic alterations, and early administration of recombinant human growth hormone (GH)

Haplotype Analysis of the Promoter Region of Phosphodiesterase Type 8B (PDE8B) in Correlation with Inactivating PDE8B Mutation and the Serum Thyroid-Stimulating Hormone Levels

Background: Human phosphodiesterase (PDE) type 8B (PDE8B) is located at 5q14.1 and is known as the PDE with the highest affinity to cAMP. We recently described a family with bilateral micronodular adrenocortical disease that was apparently caused by an inactivating PDE8B mutation (H305P). As a result of a genome-wide study, a strong association between six polymorphic variants in the PDE8B promoter and serum levels of the thyroid-stimulating hormone (TSH) has been recently reported. Despite an extended analysis of the regions surrounding 5q14.1, no other potential genetic variants that could be responsible for the associated TSH levels were found. Methods: In this study, we genotyped by polymerase chain reaction the described six polymorphic variants in the PDE8B promoter in the family with micronodular adrenocortical disease and inactivating PDE8B mutation and analyzed their correlation with individual TSH values in the family members. Results: We observed complete segregation between the reported association and individual TSH values in the family we studied. Haplotype analysis showed that the haplotype associated with the high TSH levels is different from the one that segregated with H305P, suggesting that the mutation most probably has arisen on an allele independent of the high TSH-associated allele. Conclusions: The proposed mechanism by which PDE8B may influence TSH levels is through control of cAMP signaling. Our analysis revealed separate segregation of an inactivating PDE8B allele from the high-TSH-allele and showed low TSH levels in persons who carry an inactivating PDE8B allele. These data suggest that, indeed, PDE8B may be involved in regulation of TSH levels.This work was supported by NIH intramural project Z01- HD-000642-04 to Dr. C.A. Stratakis (PDEGEN, NICHD, NIH)

Phenotypic continuum between Waardenburg syndrome and idiopathic hypogonadotropic hypogonadism in humans with SOX10 variants

Purpose: SOX10 variants previously implicated in Waardenburg syndrome (WS) have now been linked to Kallmann syndrome (KS), the anosmic form of idiopathic hypogonadotropic hypogonadism (IHH). We investigated whether SOX10-associated WS and IHH represent elements of a phenotypic continuum within a unifying disorder or if they represent phenotypically distinct allelic disorders. Methods: Exome sequencing from 1,309 IHH subjects (KS: 632; normosmic idiopathic hypogonadotropic hypogonadism [nIIHH]: 677) were reviewed for SOX10 rare sequence variants (RSVs). The genotypic and phenotypic spectrum of SOX10-related IHH (this study and literature) and SOX10-related WS cases (literature) were reviewed and compared with SOX10-RSV spectrum in gnomAD population. Results: Thirty-seven SOX10-associated IHH cases were identified as follows: current study: 16 KS; 4 nIHH; literature: 16 KS; 1 nIHH. Twenty-three IHH cases (62%; all KS), had ≥1 known WS-associated feature(s). Moreover, five previously reported SOX10-associated WS cases showed IHH-related features. Four SOX10 missense RSVs showed allelic overlap between IHH-ascertained and WS-ascertained cases. The SOX10-HMG domain showed an enrichment of RSVs in disease states versus gnomAD. Conclusion: SOX10 variants contribute to both anosmic (KS) and normosmic (nIHH) forms of IHH. IHH and WS represent SOX10-associated developmental defects that lie along a unifying phenotypic continuum. The SOX10-HMG domain is critical for the pathogenesis of SOX10-related human disorders

Copy number variation analysis in adults with catatonia confirms haploinsufficiency of SHANK3 as a predisposing factor

Catatonia is a motor dysregulation syndrome co-occurring with a variety of psychiatric and medical disorders. Response to treatment with benzodiazepines and electroconvulsive therapy suggests a neurobiological background. The genetic etiology however remains largely unexplored. Copy Number Variants (CNV), known to predispose to neurodevelopmental disorders, may play a role in the etiology of catatonia.publisher: Elsevier articletitle: Copy number variation analysis in adults with catatonia confirms haploinsufficiency of SHANK3 as a predisposing factor journaltitle: European Journal of Medical Genetics articlelink: http://dx.doi.org/10.1016/j.ejmg.2016.08.003 content_type: article copyright: © 2016 Elsevier Masson SAS. All rights reserved.status: publishe

Copy number variation analysis in adults with catatonia confirms haploinsufficiency of SHANK3 as a predisposing factor

Background Catatonia is a motor dysregulation syndrome co-occurring with a variety of psychiatric and medical disorders. Response to treatment with benzodiazepines and electroconvulsive therapy suggests a neurobiological background. The genetic etiology however remains largely unexplored. Copy Number Variants (CNV), known to predispose to neurodevelopmental disorders, may play a role in the etiology of catatonia. Methods This study is exploring the genetic field of catatonia through CNV analysis in a cohort of psychiatric patients featuring intellectual disability and catatonia. Fifteen adults admitted to a psychiatric inpatient unit and diagnosed with catatonia were selected for array Comparative Genomic Hybridization analysis at 200 kb resolution. We introduced a CNV interpretation algorithm to define detected CNVs as benign, unclassified, likely pathogenic or causal with regard to catatonia. Results Co-morbid psychiatric diagnoses in these patients were autism, psychotic or mood disorders. Eight patients were found to carry rare CNVs, which could not be classified as benign, comprising 6 duplications and 2 deletions. Microdeletions on 22q13.3, considered causal for catatonia, were detected in 2 patients. Duplications on 16p11.2 and 22q11.2 were previously implicated in psychiatric disorders, but not in catatonia, and were therefore considered likely pathogenic. Driven by the identification of a rare 14q11.2 duplication in one catatonic patient, additional patients with overlapping duplications were gathered to delineate a novel susceptibility locus for intellectual disability and psychiatric disorders on 14q11.2, harboring the gene SUPT16H. Three remaining variants respectively on 2q36.1, 16p13.13 and 17p13.3 were considered variants of unknown significance. Conclusion The identification of catatonia-related copy number changes in this study, underscores the importance of genetic research in patients with catatonia. We confirmed that 22q13.3 deletions, affecting the gene SHANK3, predispose to catatonia, and we uncover 14q11.2 duplications as a novel susceptibility factor for intellectual and psychiatric disorders

Clinical and genetic characteristics of a large international cohort of individuals with rare NR5A1/SF-1 variants of sex developmentResearch in context

Summary: Background: Steroidogenic factor 1 (SF-1/NR5A1) is essential for human sex development. Heterozygous NR5A1/SF-1 variants manifest with a broad range of phenotypes of differences of sex development (DSD), which remain unexplained. Methods: We conducted a retrospective analysis on the so far largest international cohort of individuals with NR5A1/SF-1 variants, identified through the I-DSD registry and a research network. Findings: Among 197 individuals with NR5A1/SF-1 variants, we confirmed diverse phenotypes. Over 70% of 46, XY individuals had a severe DSD phenotype, while 90% of 46, XX individuals had female-typical sex development. Close to 100 different novel and known NR5A1/SF-1 variants were identified, without specific hot spots. Additionally, likely disease-associated variants in other genes were reported in 32 individuals out of 128 tested (25%), particularly in those with severe or opposite sex DSD phenotypes. Interestingly, 48% of these variants were found in known DSD or SF-1 interacting genes, but no frequent gene-clusters were identified. Sex registration at birth varied, with <10% undergoing reassignment. Gonadectomy was performed in 30% and genital surgery in 58%. Associated organ anomalies were observed in 27% of individuals with a DSD, mainly concerning the spleen. Intrafamilial phenotypes also varied considerably. Interpretation: The observed phenotypic variability in individuals and families with NR5A1/SF-1 variants is large and remains unpredictable. It may often not be solely explained by the monogenic pathogenicity of the NR5A1/SF-1 variants but is likely influenced by additional genetic variants and as-yet-unknown factors. Funding: Swiss National Science Foundation (320030-197725) and Boveri Foundation Zürich, Switzerland