Congenital gonadotropin-releasing hormone (GnRH) deficiency manifests as absent or incomplete sexual maturation and infertility. Although the disease exhibits marked locus and allelic heterogeneity, ...with the causal mutations being both rare and private, one causal mutation in the prokineticin receptor, PROKR2 L173R, appears unusually prevalent among GnRH-deficient patients of diverse geographic and ethnic origins. To track the genetic ancestry of PROKR2 L173R, haplotype mapping was performed in 22 unrelated patients with GnRH deficiency carrying L173R and their 30 first-degree relatives. The mutation's age was estimated using a haplotype-decay model. Thirteen subjects were informative and in all of them the mutation was present on the same ~123 kb haplotype whose population frequency is ≤10%. Thus, PROKR2 L173R represents a founder mutation whose age is estimated at approximately 9000 years. Inheritance of PROKR2 L173R-associated GnRH deficiency was complex with highly variable penetrance among carriers, influenced by additional mutations in the other PROKR2 allele (recessive inheritance) or another gene (digenicity). The paradoxical identification of an ancient founder mutation that impairs reproduction has intriguing implications for the inheritance mechanisms of PROKR2 L173R-associated GnRH deficiency and for the relevant processes of evolutionary selection, including potential selective advantages of mutation carriers in genes affecting reproduction.
A Caucasian girl with consanguineous parents presented with early severe obesity and retinal dystrophy. A novel, homozygous gene truncating variant (c.1897C>T) in the
gene confirmed the diagnosis of ...MORMS (OMIM #610156). A novel clinical finding in the presented syndrome is progressive cone-rod type retinal dystrophy diagnosed at the age of four months that progressed in the 1
decade of life. Severe obesity, insulin resistance with hyperinsulinism, and impaired glucose tolerance developed alongside other components of the metabolic syndrome - dyslipidemia, arterial hypertension, and obstructive hypopnea in sleep. At the age of 14 years, primary amenorrhea persists. The patient is managed by regular nutritional advice, metformin, antihypertensive medication, and non-invasive respiratory support during sleep. Differential diagnosis of this rare entity is discussed in extend.
The HESX1 gene is essential in forebrain development and pituitary organogenesis, and its mutations are the most commonly identified genetic cause of septo-optic dysplasia (SOD). The PROP1 gene is ...involved in anterior pituitary cell lineage specification and is commonly implicated in non-syndromic combined pituitary hormone deficiency (CPHD). We aimed to assess the involvement of HESX1 and PROP1 mutations in a cohort of patients with SOD and CPHD.
Six patients with sporadic SOD and 16 patients with CPHD from 14 pedigrees were screened for mutations in HESX1 and PROP1 genes by exon sequencing. Half of the CPHD patients had variable associated clinical characteristics, such as hearing loss, orofacial cleft, kidney disorder or developmental delay. Novel variants were evaluated in silico and verified in SNP databases.
A novel heterozygous p.Glu102Gly mutation in the HESX1 gene and a novel homozygous p.Arg121Thr mutation in the PROP1 gene were detected in 2 pedigrees with CPHD. A small previously reported deletion in PROP1 c.301_302delAG was detected in a separate patient with CPHD, in heterozygous state. No mutations were identified in patients with SOD.
Our results expand the spectrum of mutations implicated in CPHD. The frequency of 15% of the PROP1 mutations in CPHD was low, likely due to the clinical heterogeneity of the cohort.
Differences of sex development and maturation (SDM) represent a heterogeneous puzzle of rare conditions with a large genetic component whose management and treatment could be improved by an accurate ...classification of underlying molecular conditions, and next-generation sequencing (NGS) should represent the most appropriate approach. Therefore, we conducted a survey dedicated to the use and potential outcomes of NGS for SDM disorders diagnosis among the 53 health care providers (HCP) of the European Reference Network for rare endocrine conditions. The response rate was 49% with a total of 26 HCPs from 13 countries. All HCPs, except 1, performed NGS investigations for SDM disorders on 6720 patients, 3764 (56%) with differences of sex development (DSD), including 811 unexplained primary ovarian insufficiency, and 2956 (44%) with congenital hypogonadotropic hypogonadism (CHH). The approaches varied from targeted analysis of custom gene panels (range: 11–490 genes) in 81.5% of cases or whole exome sequencing with the extraction of a virtual panel in the remaining cases. These analyses were performed for diagnostic purposes in 21 HCPs, supported by the National Health Systems in 16 cases. The likelihood of finding a variant ranged between 7 and 60%, mainly depending upon the number of analysed genes or criteria used for reporting, most HCPs also reporting variants of uncertain significance. These data illustrate the status of genetic diagnosis of DSD and CHH across Europe. In most countries, these analyses are performed for diagnostic purposes, yielding highly variable results, thus suggesting the need for harmonization and general improvements of NGS approaches.
Introduction. Autoimmune polyglandular syndrome type 1 (APS-1) is an autosomal recessive disorder, caused by mutations in the AIRE gene. The major components of APS-1 are chronic mucocutaneous ...candidiasis (CMC), hypoparathyroidism (HP) and Addison’s disease (AD). Clinical, genetic and immunological characteristics of Slovenian paediatric APS-1 patients were investigated.
Methods. Existing medical records of 15 APS-1 patients were rewieved, when necessary, additional clinical and laboratory investigations were issued. AIRE gene analysis was performed to identify causative mutations, and autoantibodies against type I interferons were measured by luminescence immunoprecipitation system.
Results. Patients had one to eight different manifestations of the disease. CMC was present in all, HP in 12/15 (80 %) and AD in 8/15 (53 %) patients. Growth retardation, due to hyposomatotropism, growth hormone resistance, autoimmune thyroiditis, corticosteroid treatment, malabsorption or secretory failure of exocrine pancreas, was observed in altogether 7 (46 %) patients. Six different AIRE gene mutations were detected and p.R257X mutation was present in 63.3 % of pathological alleles. Antibodies against type I interferons were detected in all patients.
Conclusion. APS-1 is a rare disorder with a broad spectrum of clinical manifestations, which, if unrecognized or inadequately treated may be fatal. AIRE gene mutational analysis and autoantibodies against type I interferons are important in early identification of the disease. The aetiology of growth retardation was shown to be extremely diverse, frequently caused by less characteristic manifestations. APS-1 may affect patients’ quality of life in numerous ways, and may cause great psychosocial burden leading to depression and suicidal thoughts even in paediatric patients.
Uvod. Avtoimunski poliglandularni sindrom tipa 1 (APS-1) je redka avtosomno recesivna bolezen, povezana z mutacijami gena AIRE. Tri najpomembnejše komponente APS-1 so kronična mukokutana kandidiaza (CMC), hipoparatiroidizem (HP) in Addisonova bolezen (AD). Raziskali smo klinične, genetske in imunološke značilnosti slovenskih pediatričnih bolnikov z APS-1.
Metode. Pregledali smo obstoječo medicinsko dokumentacijo 15 bolnikov z APS-1, v izbranih primerih smo opravili dodatne klinične in laboratorijske preiskave. Z genetsko analizo smo prepoznali vzročne mutacije gena AIRE, s sistemom luminiscenčne imunoprecipitacije (LIPS) pa smo določili avtoprotitelesa proti interferonom tipa 1.
Rezultati. Bolniki so imeli izraženo eno do osem različnih komponent bolezni. CMC je bila prisotna pri vseh bolnikih, HP pri 12 od 15 (80 %) in AD pri 8 od 15 (53 %). Zastoj rasti je bil prisoten pri 7 (46 %) bolnikih zaradi hiposomatotropizma, rezistence proti rastnemu hormonu, avtoimunskega tiroiditisa, zdravljenja s kortikosteroidi, malabsorbcije ali sekretorne okvare eksokrinega pankreasa. Prepoznanih je bilo 6 različnih mutacij gena AIRE, najpogostejša mutacija p.R257X je bila opredeljena pri 63,3 % mutiranih alelov. Avtoprotitelesa proti interferonom tipa 1 so bila prisotna pri vseh bolnikih.
Zaključki. APS-1 je redka bolezen s širokim naborom kliničnih značilnosti in je lahko smrtna, če ni prepoznana ali je neprimerno zdravljena. Za zgodnje odkrivanje sta ključnega pomena genetska analiza in določanje protiteles proti interferonom tipa 1. Pri bolnikih z APS-1 je zastoj rasti pogosta komponenta bolezni z različnimi vzroki, pogosto povezanimi z manj značilnimi manifestacijami. APS-1 na različne načine vpliva na kvaliteto življenja bolnikov in je veliko psihološko breme, ki lahko vodi v depresijo in samomorilne misli celo pri mladih bolnikih.
Avtoimunska poliendokrinopatija s kandidiazo in ektoder- malno distrofijo (APECED) je redka monogenska bolezen, ki jo povzročajo prirojene patološke genetske spremembe v genu AIRE. Gen AIRE kodira ...beljakovino avtoimunski regu- lator, ki je vpletena v vzpostavitev imunske tolerance na lastne antigene. Osebe s sindromom APECED lahko razvijejo pestro klinično sliko z avtoimunsko prizadetostjo različnih tkiv, ektoder- malno distrofijo in specifičnmi motnjami imunosti, pove- zanimi s prisotnostjo avtoprotiteles proti interferonom in interlevkinom. Za diagnosticiranje bolezni je potrebno izpolnjevanje dveh od treh glavnih meril − kronična okuž- ba s kandido, hipoparatiroidizem in Addisonova bolezen. V prispevku predstavljamo bolnico s tem redkim sindromom, pri kateri se je bolezen izrazila najprej s kronično glivično okužbo nohtov, nato pa z značilno prizadetostjo stalnih zob v smislu hipoplazije sklenine. Na osnovi ektodermal- nih znakov smo postavili sum na sindrom APECED, kmalu po potrditvi diagnoze pa smo še pred kliničnimi znaki ugo- tovili tudi Addisonovo bolezen. Z zgodnjim diagnosticira- njem in zdravljenjem smo lahko preprečili klinično izraženo addisonsko krizo.
Osteogenesis imperfecta (OI) is etiologically heterogeneous disorder characterized by childhood osteoporosis. A subtype OI type V is caused by the same c.-14C>T mutation in the IFITM5 gene. ...Nevertheless, there is a marked interindividual phenotypic variability in clinical presentation; however, response to bisphosphonates is reported to be good.
Two individuals with OI type V had multiple recurrent fractures with hypertrophic calluses, scoliosis and ossifications of the forearm interosseous membranes. Sequencing of IFITM5, genotyping of variants rs2297480 in farnesyl diphosphate synthase gene (FDPS), and rs3840452 in geranylgeranyl diphosphate synthase 1 gene (GGPS1), both involved in bisphosphonate metabolism, was performed.
In patient 1 BMD reached normal values during bisphosphonate treatment and remained normal four years after the treatment discontinuation. In patient 2 no increase in BMD after five years of bisphosphonate treatment was observed and callus formation continued. The c.-14C>T IFITM5 mutation in heterozygous state was detected in both individuals. Additionally, both patients carried FDPS variant rs2297480 in homozygous state, and were heterozygous for GGPS 1 variant rs3840452.
The paper presents a short overview of childhood osteoporosis with a special emphasis on OI type V by presenting two cases. Both OI type V patients had identical disease-causing mutation, but marked interindividual phenotypic variability. The striking failure in response to bisphosphonate treatment in one of the patients could not be explained by the variants in genes involved in bisphosphonate metabolism.
Introduction. Osteogenesis imperfecta (OI) is etiologically heterogeneous disorder characterized by childhood osteoporosis. A subtype OI type V is caused by the same c.-14C>T mutation in the IFITM5 ...gene. Nevertheless, there is a marked interindividual phenotypic variability in clinical presentation; however, response to bisphosphonates is reported to be good.
Methods. Two individuals with OI type V had multiple recurrent fractures with hypertrophic calluses, scoliosis and ossifications of the forearm interosseous membranes. Sequencing of IFITM5, genotyping of variants rs2297480 in farnesyl diphosphate synthase gene (FDPS), and rs3840452 in geranylgeranyl diphosphate synthase 1 gene (GGPS1), both involved in bisphosphonate metabolism, was performed.
Results. In patient 1 BMD reached normal values during bisphosphonate treatment and remained normal four years after the treatment discontinuation. In patient 2 no increase in BMD after five years of bisphosphonate treatment was observed and callus formation continued. The c.-14C>T IFITM5 mutation in heterozygous state was detected in both individuals. Additionally, both patients carried FDPS variant rs2297480 in homozygous state, and were heterozygous for GGPS 1 variant rs3840452.
Conclusions. The paper presents a short overview of childhood osteoporosis with a special emphasis on OI type V by presenting two cases. Both OI type V patients had identical disease-causing mutation, but marked interindividual phenotypic variability. The striking failure in response to bisphosphonate treatment in one of the patients could not be explained by the variants in genes involved in bisphosphonate metabolism.
Uvod. Osteogenesis imperfecta (OI) je vzročno heterogena bolezen, katere značilnost je osteoporoza v otroštvu. Pri vseh opisanih bolnikih s podtipom OI tipa V je vzrok bolezni ista mutacija c.-14C>T gena IFITM5. Kljub temu med bolniki obstaja izrazita fenotipska variabilnost v klinični sliki, toda opisan je le dober odgovor na zdravljenje z bisfosfonati.
Metode. Oba bolnika z OI tipa V sta imela ponavljajoče se zlome kosti s hipertrofičnimi kalusi, skoliozo in zakostenelo membrano med podlahtnico in koželjnico. Opravili smo sekvenčno analizo gena IFITM5 in genotipizacijo variant rs2297480 gena za farnesil difosfat sintazo (FDPS) in rs3840452 gena za geranilgeranil difosfat sintazo 1 (GGPS1), ki sta vpletena v presnovo bisfosfonatov.
Rezultati. Pri bolniku 1 se je ob zdravljenju z bisfosfonati mineralna kostna gostota povečala do normalnih vrednosti in ostala nespremenjena štiri leta po prenehanju zdravljenja. Pri bolniku 2 kljub pet let trajajočemu zdravljenju z bisfosfonati ni prišlo do izboljšanja mineralne kostne gostote, še naprej so se pojavljali zlomi kosti in hipertrofični kalusi. Pri obeh bolnikih smo ugotovili znano mutacijo c.-14C>T v genu IFITM5 v heterozigotni obliki. Oba imata v homozigotni obliki prisotno tudi varianto rs2297480 gena FDPS in v heterozigotni obliki varianto rs3840452 gena GGPS1.
Zaključek. V članku je predstavljen kratek pregled osteoporoze v otroštvu s posebnim poudarkom na OI tipa V pri dveh bolnikih. Pri obeh bolnikih z OI tipa V, ki sta imela različno klinično sliko in potek bolezni, smo ugotovili mutacijo c.-14C>T v genu IFITM5. Z analizo genov encimov, vpletenih v presnovo bisfosfonatov, nismo mogli pojasniti neuspešnega zdravljenja z bisfosfonati pri enem od bolnikov.
This study estimated temporal trends of metabolic control over 12 years in a national cohort of childhood-onset type 1 diabetes.
Data from the prospective childhood-onset diabetes register, which ...included 886 case subjects from 0 to 17.99 years of age at diagnosis and at least 1 year of follow-up until the age of 22.99 years, were analyzed using multivariable linear and logistic regression models in the observational period between 2000 and 2011.
Hemoglobin A1c (HbA1c) significantly decreased over 12 years, from 78 mmol/mol (interquartile range IQR, 68-88 mmol/mol) (9.26% IQR, 8.41-10.24%) in the year 2000 to 61 mmol/mol (IQR, 55-67 mmol/mol) (7.75% IQR, 7.20-8.30%) in the year 2011 (P<0.001). HbA1c was significantly associated with age, treatment modality, and duration of diabetes (P<0.001), with females having on average 1.02% higher HbA1c (P=0.01; 95% confidence interval CI 1.005-1.035). The overall use of insulin pumps was 74%. The incidence rate of severe acute complications was low: 1.07 per 100 patient-years for severe diabetic ketoacidosis (95% CI 0.81-1.40) and 1.21 per 100 patient-years for severe (requiring intravenous or intramuscular therapy) hypoglycemia (95% CI 0.81-1.40).
The metabolic control of the entire nationwide pediatric type 1 diabetes population significantly improved during the 12-year observational period with a low rate of severe acute complications events. The improvement was associated with the treatment modality. Additional efforts and solutions are necessary to further improve metabolic control and the quality of life of young people with type 1 diabetes.
PDF
