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Context: Heterozygous mutations in the aggrecan gene (ACAN) cause autosomal dominant short stature with accelerated skeletal maturation., Objective: We sought to characterize the phenotypic spectrum and response to growth-promoting therapies., Patients and Methods: One hundred three individuals (57 females, 46 males) from 20 families with autosomal dominant short stature and heterozygous ACAN mutations were identified and confirmed using whole-exome sequencing, targeted next-generation sequencing, and/or Sanger sequencing. Clinical information was collected from the medical records., Results: Identified ACAN variants showed perfect cosegregation with phenotype. Adult individuals had mildly disproportionate short stature [median height, -2.8 standard deviation score (SDS); range, -5.9 to -0.9] and a history of early growth cessation. The condition was frequently associated with early-onset osteoarthritis (12 families) and intervertebral disc disease (9 families). No apparent genotype-phenotype correlation was found between the type of ACAN mutation and the presence of joint complaints. Childhood height was less affected (median height, -2.0 SDS; range, -4.2 to -0.6). Most children with ACAN mutations had advanced bone age (bone age - chronologic age; median, +1.3 years; range, +0.0 to +3.7 years). Nineteen individuals had received growth hormone therapy with some evidence of increased growth velocity., Conclusions: Heterozygous ACAN mutations result in a phenotypic spectrum ranging from mild and proportionate short stature to a mild skeletal dysplasia with disproportionate short stature and brachydactyly. Many affected individuals developed early-onset osteoarthritis and degenerative disc disease, suggesting dysfunction of the articular cartilage and intervertebral disc cartilage. Additional studies are needed to determine the optimal treatment strategy for these patients., (Copyright © 2017 by the Endocrine Society)

Background: Germline STAT3 gain-of-function (GOF) mutations cause multiple endocrine and haematologic autoimmune disorders, lymphoproliferation, and growth impairment. As the JAK-STAT pathway is known to transduce the growth hormone (GH) signalling, and STAT3 interacts with STAT5 in growth regulation, we hypothesised that short stature in STAT3 GOF mutations results mostly from GH insensitivity via involving activation of STAT5., Case Report: A boy with a novel STAT3 c.2144C>T (p.Pro715Leu) mutation presented with short stature (-2.60 SD at 5.5 years). He developed diabetes mellitus at 11 months, generalised lympho-proliferation, autoimmune thyroid disease, and immune bicytopenia in the subsequent years. At 5.5 years, his insulin-like growth factor-1 (IGF-I) was 37 µg/L (-2.22 SD) but stimulated GH was 27.7 µg/L. Both a standard IGF-I generation test (GH 0.033 mg/kg/day sc; 4 days) and a high-dose prolonged IGF-I generation test (GH 0.067 mg/kg/day sc; 14 days) failed to significantly increase IGF-I levels (37-46 and 72-87 µg/L, respectively). The boy underwent haematopoietic stem cell transplantation at 6 years due to severe neutropenia and massive lymphoproliferation, but unfortunately deceased 42 days after transplantation from reactivated generalised adenoviral infection., Conclusions: Our findings confirm the effect of STAT3 GOF mutation on the downstream activation of STAT5 resulting in partial GH insensitivity. 
., (© 2017 S. Karger AG, Basel.)

Unlabelled: Familial neurohypophyseal diabetes insipidus (FNDI) is a rare hereditary disorder with unknown prevalence characterized by arginine-vasopressin hormone (AVP) deficiency resulting in polyuria and polydipsia from early childhood. We report the clinical manifestation and genetic test results in seven unrelated kindreds of Czech or Slovak origin with FNDI phenotype. The age of the sign outset ranged from 2 to 17 years with remarkable interfamilial and intrafamilial variability. Inconclusive result of the fluid deprivation test in three children aged 7 and 17 years old might cause misdiagnosis; however, the AVP gene analysis confirmed the FNDI. The seven families segregated together five different mutations, two of them were novel (c.164C > A, c.298G > C). In addition, DNA analysis proved mutation carrier status in one asymptomatic 1-year-old infant., Conclusions: The present study together with previously published data identified 38 individuals with FNDI in the studied population of 16 million which predicts a disease prevalence of 1:450,000 for the Central European region. The paper underscores that diagnostic water deprivation test may be inconclusive in polyuric children with partial diabetes insipidus and points to the clinical importance and feasibility of molecular genetic testing for AVP gene mutations in the proband and her/his first degree relatives., What Is Known: • At least 70 different mutations were reported to date in about 100 families with neurohypophyseal diabetes insipidus (FNDI), and new mutations appear sporadically. What is New: • Two novel mutations of the AVP gene are reported • The importance of molecular testing in children with polyuria and inconclusive water deprivation test is emphasized.

Two variants (c.[301_302delAG];[301_302delAG] and c.[150delA];[150delA]) in the PROP1 gene are the most common genetic causes of recessively inherited combined pituitary hormones deficiency (CPHD). Our objective was to analyze in detail the origin of the two most prevalent variants. In the multicentric study were included 237 patients with CPHD and their 15 relatives carrying c.[301_302delAG];[301_302delAG] or c.[150delA];[150delA] or c.[301_302delAG];[ 150delA]. They originated from 21 different countries worldwide. We genotyped 21 single-nucleotide variant markers flanking the 9.6-Mb region around the PROP1 gene that are not in mutual linkage disequilibrium in the general populations--a finding of a common haplotype would be indicative of ancestral origin of the variant. Haplotypes were reconstructed by Phase and Haploview software, and the variant age was estimated using an allelic association method. We demonstrated the ancestral origin of both variants--c.[301_302delAG] was carried on 0.2 Mb-long haplotype in a majority of European patients arising ~101 generations ago (confidence interval 90.1-116.4). Patients from the Iberian Peninsula displayed a different haplotype, which was estimated to have emerged 23.3 (20.1-29.1) generations ago. Subsequently, the data indicated that both the haplotypes were transmitted to Latin American patients ~13.8 (12.2-17.0) and 16.4 (14.4-20.1) generations ago, respectively. The c.[150delA] variant that was carried on a haplotype spanning about 0.3 Mb was estimated to appear 43.7 (38.4-52.7) generations ago. We present strong evidence that the most frequent variants in the PROP1 gene are not a consequence of variant hot spots as previously assumed, but are founder variants.

Hepatocyte nuclear factor 1-β (HNF1B) defects cause renal cysts and diabetes syndrome (RCAD), or HNF1B-maturity-onset diabetes of the young. However, the hepatic phenotype of HNF1B variants is not well studied. We present a female neonate born small for her gestational age [birth weight 2360 g; -2.02 standard deviations (SD) and birth length 45 cm; -2.40 SD at the 38(th) gestational week]. She developed neonatal cholestasis due to biliary atresia and required surgical intervention (portoenterostomy) when 32-d old. Following the operation, icterus resolved, but laboratory signs of liver dysfunction persisted. She had hyperechogenic kidneys prenatally with bilateral renal cysts and pancreatic hypoplasia postnatally that led to the diagnosis of an HNF1B deletion. This represents the most severe hepatic phenotype of an HNF1B variant recognized thus far. A review of 12 published cases with hepatic phenotypes of HNF1B defects allowed us to distinguish three severity levels, ranging from neonatal cholestasis through adult-onset cholestasis to non-cholestatic liver impairment, all of these are associated with congenital renal cysts and mostly with diabetes later in life. We conclude that to detect HNF1B variants, neonates with cholestasis should be checked for the presence of renal cysts, with special focus on those who are born small for their gestational age. Additionally, patients with diabetes and renal cysts at any age who develop cholestasis and/or exocrine pancreatic insufficiency should be tested for HNF1B variants as the true etiological factor of all disease components. Further observations are needed to confirm the potential reversibility of cholestasis in infancy in HNF1B mutation/deletion carriers.

Aims/hypothesis: MODY is mainly characterised by an early onset of diabetes and a positive family history of diabetes with an autosomal dominant mode of inheritance. However, de novo mutations have been reported anecdotally. The aim of this study was to systematically revisit a large collection of MODY patients to determine the minimum prevalence of de novo mutations in the most prevalent MODY genes (i.e. GCK, HNF1A, HNF4A)., Methods: Analysis of 922 patients from two national MODY centres (Slovakia and the Czech Republic) identified 150 probands (16%) who came from pedigrees that did not fulfil the criterion of two generations with diabetes but did fulfil the remaining criteria. The GCK, HNF1A and HNF4A genes were analysed by direct sequencing., Results: Mutations in GCK, HNF1A or HNF4A genes were detected in 58 of 150 individuals. Parents of 28 probands were unavailable for further analysis, and in 19 probands the mutation was inherited from an asymptomatic parent. In 11 probands the mutations arose de novo., Conclusions/interpretation: In our cohort of MODY patients from two national centres the de novo mutations in GCK, HNF1A and HNF4A were present in 7.3% of the 150 families without a history of diabetes and 1.2% of all of the referrals for MODY testing. This is the largest collection of de novo MODY mutations to date, and our findings indicate a much higher frequency of de novo mutations than previously assumed. Therefore, genetic testing of MODY could be considered for carefully selected individuals without a family history of diabetes.

Background: Although the literature indicates that ancestral mutations in the glucokinase (GCK) gene are rare, we have detected a high frequency of four prevalent mutations that together are responsible for over one third of the GCK mutations in our Czech National Register of monogenic diabetes. Therefore, we studied their potential ancestral origin in our and neighbouring Polish populations., Methods: We analysed the lineage of four mutations in the GCK gene - p.Glu40Lys (21 apparently unrelated families), p.Leu315His (15 families), p.Gly318Arg (26 families), and p.Val33Ala (10 families) - using genotypes of 16 single nucleotide polymorphisms that span a 14 Mb region around the gene. Haplotypes were reconstructed using Phase and Haploview programmes, and their age was estimated using dmle+., Results: We found strong evidence that supports ancestral origin of three of the four mutations: the p.Glu40Lys mutation was associated with an 11-marker long conserved haplotype, the p.Leu315His mutation was associated with a 7-marker haplotype, and the p.Gly318Arg mutation was associated with an 8-marker haplotype. None of these haplotypes were detected in the general population with a frequency >0.5%. The ages of the mutations were roughly estimated to be between 82 and 110 generations old (95% credible sets 65-151). The fourth prevalent mutation, p.Val33Ala, lacked statistically significant evidence for the founder effect, although there were some indications for its common origin., Conclusions: The large proportion of families carrying three ancestral mutations in GCK indicates that the previously assumed rarity of the founder effect with regard to GCK-maturity onset diabetes of the young (MODY) should be reconsidered., (© 2012 John Wiley & Sons A/S.)

Background: HNF1A-MODY (MODY3) is a common subtype of autosomal dominant diabetes. Unlike HNF4-MODY where fetal macrosomia and early postnatal hyperinsulinemic hypoglycemia have been reported, history of transient insulin overproduction has not yet been recognized in individuals with HNF1A-MODY., Case Report: Here, we report on a 40-year-old male patient with HNF1A mutation p.Arg272His (c.815G>A) having a history of fetal macrosomia (4750 g, 59 cm), and, at least, one attack of symptomatic hypoglycemia in childhood. Diabetes was subsequently diagnosed at 19 years of age. The proband's daughter who developed diabetes at 16 years carries the same mutation, but her birth weight and length were in the upper normal range, and she never experienced hypoglycemic symptoms., Conclusion: The observation of fetal macrosomia and hypoglycemia in childhood is indicative of a biphasic impact of the HNF1A mutation on p-cell function over the lifespan, leading from inappropriate insulin oversecretion to final clinical diabetes.

Background/aims: Defects of the PROP1 gene are the most prevalent genetic cause of combined pituitary hormone deficiency. Previous observations in affected patients have shown pituitary size ranging from hypoplasia to overt pituitary mass and evolution of size over the lifespan., Methods: We evaluated pituitary size and morphology in PROP1-mutation carriers who originated from Central and Eastern Europe. We analyzed 112 pituitary magnetic resonance imaging (MRI) scans from 82 patients (42 males) aged 2.5-72.7 (median 16.6) years from 60 kindreds., Results: Among the 120 independent PROP1 alleles, the most prevalent mutations were delGA301/302 (99 alleles) and delA150 (13 alleles). Median pituitary height at first MRI was 4.7 mm (range 1.0-20.7) and median volume was 127.6 mm(3) (range 7.5-3,087.0). Pituitary size did not differ between sexes and did not correlate with hormonal phenotype, but significantly decreased with increasing age. However, evaluation of individual values suggested a biphasic mode with increasing volume during childhood, peak in adolescence, and subsequent regression in adulthood., Conclusion: Although pituitary size was increased in a number of PROP1-deficient patients, none of them suffered permanent damage from pituitary mass; therefore, any proposed surgery should be postponed as long as possible and ultimately may not be necessary due to the self-limiting nature of the pituitary enlargement., (Copyright © 2011 S. Karger AG, Basel.)

Background: Insulin gene (INS) mutations have recently been described as a common cause of permanent neonatal diabetes (PNDM) and a rare cause of diabetes diagnosed in childhood or adulthood., Methods: INS was sequenced in 116 maturity-onset diabetes of the young (MODYX) patients (n = 48 Danish and n = 68 Czech), 83 patients with gestational diabetes mellitus (GDM), 34 type 1 diabetic patients screened negative for glutamic acid decarboxylase (GAD), and 96 glucose tolerant individuals. The control group was randomly selected from the population-based sampled Inter99 study., Results: One novel heterozygous mutation c.17G>A, R6H, was identified in the pre-proinsulin gene (INS) in a Danish MODYX family. The proband was diagnosed at 20 years of age with mild diabetes and treated with diet and oral hypoglycaemic agent. Two other family members who carried the INS R6H were diagnosed with diabetes when 51 years old and with GDM when 27 years old, respectively. A fourth mutation carrier had normal glucose tolerance when 20 years old. Two carriers of INS R6H were also examined twice with an oral glucose tolerance test (OGTT) with 5 years interval. They both had a approximately 30% reduction in beta-cell function measured as insulinogenic index. In a Czech MODYX family a previously described R46Q mutation was found. The proband was diagnosed at 13 years of age and had been treated with insulin since onset of diabetes. Her mother and grandmother were diagnosed at 14 and 35 years of age, respectively, and were treated with oral hypoglycaemic agents and/or insulin., Conclusion: Mutations in INS can be a rare cause of MODY and we conclude that screening for mutations in INS should be recommended in MODYX patients.

Context: Steroid 17alpha-hydroxylase (CYP17A1, alias P450c17) deficiency (17OHD) is a rare form of congenital adrenal hyperplasia. The CYP17A1 enzyme catalyzes two distinct reactions, 17alpha-hydroxylase and 17,20-lyase activities., Objective: The aim of the study was to analyze the structural and functional consequences of three novel (A174E, V178D, and L465P) and one previously reported (R440C) CYP17A1 mutation found in three patients clinically and biochemically presenting with 17OHD., Patients and Methods: Two patients suffering from 46,XY disordered sex development presented at ages 5.5 and 8.8 yr, respectively, with tall stature and hypertension. Mutation analysis revealed compound heterozygous CYP17A1 mutations (A174E/K388X; V178D/R440C). The third patient (46,XX) presented with primary amenorrhea and hypertension at age 15 yr. She was homozygous for the novel L465P mutation. Functional studies employing a yeast microsomal expression system compared wild-type and mutant CYP17A1 both with regard to 17alpha-hydroxylase and 17,20-lyase activity. Mutants were examined in a computational three-dimensional model of the CYP17A1 protein., Results: The activity assays showed that all three mutants retain only 0-7% of both 17alpha-hydroxylase and 17,20-lyase activity relative to CYP17A1 wild-type activity, corresponding to the in vivo situation. Enzyme kinetic studies proved the impairment of both reactions, respectively. Computer-based three-dimensional model analysis of CYP17A1 using CYP2B4 as template showed that three of the mutations had no direct effect on the active center, whereas one affects the heme coordination., Conclusion: The functional studies revealed that the described missense mutations result in severe 17OHD. Our data are important to predict the phenotypic expressions and provide important information for patient management and genetic counseling.

We report a young woman with genetically confirmed Pendred syndrome and discuss the current therapeutic strategies of dyshormonogenetic goitre. A small diffuse thyroid enlargement developed during infancy and although substitution therapy with L-thyroxine was adequate, it progressed and underwent multinodular transformation. Cervical ultrasound at the age of 22 years demonstrated three solid nodules and fine-needle aspiration biopsy showed a finding typical of follicular adenoma. It is known that dyshormonogenetic goitres have a tendency to grow despite appropriate treatment with L-thyroxine. Management of a patient with Pendred syndrome requires careful follow-up and regular imaging of the thyroid. Although the therapeutic approach to dyshormonogenetic goitres is still controversial, in our patient we chose total thyroidectomy as the most advantageous method to prevent the development of malignancies that may arise more frequently from dyshormonogenetic goitres than from goitres of other aetiologies.

Recently, it has been shown that mutations in the P2 promoter of the hepatocyte nuclear factor (HNF)-4 alpha gene (HNF4A) cause maturity-onset diabetes of the young (MODY), while single nucleotide polymorphisms in this locus are associated with type 2 diabetes. In this study, we examined 1,189 bp of the P2 promoter and the associated exon 1D of HNF4A for variations associated with diabetes in 114 patients with type 2 diabetes, 72 MODYX probands, and 85 women with previous gestational diabetes mellitus. A -192c/g mutation was found in five patients. We screened 1,587 diabetic subjects and 4,812 glucose-tolerant subjects for the -192c/g mutation and identified 5 diabetic and 1 glucose-tolerant mutation carriers (P=0.004). Examination of the families showed that carriers of the -192c/g mutation had a significantly impaired glucose-stimulated insulin release and lower levels of serum total cholesterol compared with matched control subjects. Furthermore, the mutation disrupted the binding of an unidentified sequence-specific DNA binding complex present in human islet extracts. Also, two novel linked polymorphisms in the P2 promoter at positions -1107g/t and -858c/t were identified. These variants were not significantly associated with type 2 diabetes or any pre-diabetic traits. In conclusion, a rare, novel mutation that disrupts a protein binding site in the pancreatic HNF4A promoter associates with late-onset diabetes.

Objective: Multiple pituitary hormone deficiency (MPHD) may result from defects of transcription factors that govern early pituitary development. We aimed to establish the prevalence of HESX1, PROP1, and POU1F1 gene defects in a population-based cohort of patients with MPHD and to analyse the phenotype of affected individuals., Design and Methods: Genomic analysis was carried out on 74 children and adults with MPHD from the Czech Republic (including four sibling pairs). Phenotypic data were collected from medical records and referring physicians., Results: One patient carried a heterozygous mutation of POU1F1 (71C > T), and 18 patients (including three sibling pairs) had a PROP1 mutation (genotypes 150delA/301delGA/9/, 301delGA/301-delGA/8/, or 301delGA/349T > A/1/). A detailed longitudinal phenotypic analysis was performed for patients with PROP1 mutations (n = 17). The mean ( +/-s.d.) birth length SDS of these patients (0.12 +/- 0.76) was lower than expected based on their mean ( +/-s.d.) birth weight SDS (0.63 +/- 1.27; P = 0.01). Parental heights were normal. The patients' mean ( +/-s.d.) height SDS declined to -1.5 +/- 0.9, -3.6 +/- 1.3 and -4.1 +/- 1.2 at 1.5, 3 and 5 years of age, respectively. GH therapy, initiated at 6.8 +/- 3.2 years of age (mean dose: 0.022 mg/kg per day), led to substantial growth acceleration in all patients. Mean adult height (n = 7) was normal when adjusted for mid-parental height. ACTH deficiency developed in two out of seven young adult patients., Conclusions: PROP1 defects are a prevalent cause of MPHD. We suggest that testing for PROP1 mutations in patients with MPHD might become standard practice in order to predict risk of additional pituitary hormone deficiencies.

Mutations in the insulin ( INS ) gene rarely occur in patients with Maturity-Onset Diabetes of the Young (MODY). We aimed to describe in detail two MODY families with INS mutations. The INS gene was screened by direct sequencing. The probands and their affected relatives underwent a mixed-meal test. Mutation predictions were modeled using I-TASSER and were visualized by Swiss-PdbViewer. A novel heterozygous frameshift mutation p.Gln78fs in the INS gene was found in three generations of patients with clinically distinct diabetes. The single nucleotide deletion (c.233delA) is predicted to change and prolong amino acid sequence, resulting in aberrant proinsulin without native structures of C-peptide and A-chain. In the second family, the heterozygous mutation c.188-31G>A within the terminal intron was detected. The mother and her daughter were misdiagnosed as having type 1 diabetes since the ages of 6 and 2 years, respectively. This result is in contrast to the previously described carrier of the same mutation who was diagnosed with permanent neonatal diabetes. We identified a novel coding frameshift mutation and an intronic mutation in the INS gene leading to childhood-onset diabetes. INS mutations may result in various phenotypes, suggesting that additional mechanisms may be involved in the pathogenesis and clinical manifestation of diabetes. [ABSTRACT FROM AUTHOR]