[show abstract][hide abstract] ABSTRACT: Context: Loss-of-function mutations in makorin ring finger 3 (MKRN3), an imprinted gene located on the long arm of chromosome 15, have been recognized recently as a cause of familial central precocious puberty (CPP) in humans. MKRN3 has a potential inhibitory effect on GnRH secretion. Objectives: To investigate potential MKRN3 sequence variations as well as copy number and methylation abnormalities of the 15q11 locus in patients with apparently sporadic CPP. Setting and participants: We studied 215 unrelated children (207 girls and 8 boys) from three University Medical Centers with a diagnosis of CPP. All but two of these patients (213 cases) reported no family history of premature sexual development. First-degree relatives of patients with identified MKRN3 variants were included for genetic analysis. Main Outcome Measures: All 215 CPP patients were screened for MKRN3 mutations by automatic sequencing. Multiplex ligation-dependent probe amplification was performed in a partially overlapping cohort of 52 patients. Results: We identified five novel heterozygous mutations in MKRN3 in eight unrelated girls with CPP. Four were frameshift mutations predicted to encode truncated proteins and one was a missense mutation, which was suggested to be deleterious by in silico analysis. All patients with MKRN3 mutations had classical features of CPP with a median age of onset at 6 years. Copy number and methylation abnormalities at the 15q11 locus were not detected in the patients tested for these abnormalities. Segregation analysis was possible in 5 of the 8 girls with MKRN3 mutations; in all cases, the mutation was inherited on the paternal allele. Conclusions: We have identified novel inherited MKRN3 defects in children with apparently sporadic CPP, supporting a fundamental role of this peptide in the suppression of the reproductive axis.
The Journal of clinical endocrinology and metabolism 03/2014; · 6.50 Impact Factor
[show abstract][hide abstract] ABSTRACT: The Second meeting on Rare Diseases in South Eastern Europe (SEE) was held in Skope, Macedonia on November 15-16, 2013. Objective and main data: Rare diseases (RD) are a major problem in developed and especially in countries without affluence. 6-8% of every population suffers from RD. The cumulative effect of RDs on the health system of a country is increasing. Diagnosis often remains a challenge and requires international collaboration. Treatment in diseases for which medication exist is often inaccessible to patients because of the high costs. All countries of SEE need screening programs that address more diseases. Patient organizations play a major role in increasing awareness and providing the needed pressure on society to treat treatable RDs. On the other hand, RDs are frequently a source of valuable new molecular insights not only on mechanisms of their etiology and pathology, but sometimes provide an insight on mechanisms of frequent diseases in man. Further efforts are needed in improving all the RD aspects mentioned.
Pediatric endocrinology reviews: PER 03/2014; 11(3):337-8.
[show abstract][hide abstract] ABSTRACT: Abstract Introduction: The tricho-rhino-phalangeal syndrome type III (TRPS III) is a rare autosomal dominantly inherited condition. The main clinical features are sparse and slow-growing hair and nails, a pear-shaped nose with a bulbous tip, elongated and flat philtrum, thin upper lip, cone-shaped epiphyses of the phalanges, and short stature. All patients have a point mutation in the TRPS1 gene. Case report: In this paper, we present a 13-year-old female with the typical clinical features of TRPS III, extreme growth retardation, severe deformities of both proximal radii resulting in limited extension of the elbows, and chronic renal failure (CRF) in addition. Molecular diagnostics revealed a missense mutation in exon 6 of TRPS1 that she inherited from her father who is also affected with TRPS III, but does not have CRF. In the index patient, the CRF was found to be due to bilateral renal hypodysplasia (RHD). Conclusion: Beside the renal dysplasia, the girl had severe deformities of the proximal radii - findings which have not been reported so far in TRPS III.
[show abstract][hide abstract] ABSTRACT: Abstract Aim: The genetic background of idiopathic central precocious puberty (ICPP) is not well understood. The genetic activation of pubertal onset is thought to arise from the effect of multiple genes. Familial ICPP has been reported suggesting the existence of monogenic causes of ICPP. Kisspeptin and its receptor are found to be involved in gonadotropin-releasing hormone (GnRH) secretion and puberty onset. Mutations in their genes, KISS1 and KISSR, have been suggested to be causative for ICPP. Methods: ICPP was defined by pubertal onset before 8 years of age in girls, and a pubertal luteinizing hormone (LH) response to GnRH testing. Twenty-eight girls with ICPP were included in the study [age at diagnosis was 5.72±2.59, with a mean bone age advancement of 1.4 years (-0.1 to 2.8). Height at onset of therapy in SD score was 0.90±1.48 for age]. Luteinizing hormone-releasing hormone test was performed in all subjects, and all of them had a pubertal response (LH 20.35±32.37 mIU/mL; FSH 23.32±15.72 mIU/mL). The coding regions of KISS1 and KISS1R were sequenced. Results: No rare variants were detected in KISS1 or KISS1R in the 28 subjects with ICPP. Conclusions: We confirmed that mutations in KISS1 and KISS1R are not a common cause for ICPP.
[show abstract][hide abstract] ABSTRACT: Background Congenital abnormalities of the kidney and the urinary tract are the most common cause of pediatric kidney failure. These disorders are highly heterogeneous, and the etiologic factors are poorly understood. Methods We performed genomewide linkage analysis and whole-exome sequencing in a family with an autosomal dominant form of congenital abnormalities of the kidney or urinary tract (seven affected family members). We also performed a sequence analysis in 311 unrelated patients, as well as histologic and functional studies. Results Linkage analysis identified five regions of the genome that were shared among all affected family members. Exome sequencing identified a single, rare, deleterious variant within these linkage intervals, a heterozygous splice-site mutation in the dual serine-threonine and tyrosine protein kinase gene (DSTYK). This variant, which resulted in aberrant splicing of messenger RNA, was present in all affected family members. Additional, independent DSTYK mutations, including nonsense and splice-site mutations, were detected in 7 of 311 unrelated patients. DSTYK is highly expressed in the maturing epithelia of all major organs, localizing to cell membranes. Knockdown in zebrafish resulted in developmental defects in multiple organs, which suggested loss of fibroblast growth factor (FGF) signaling. Consistent with this finding is the observation that DSTYK colocalizes with FGF receptors in the ureteric bud and metanephric mesenchyme. DSTYK knockdown in human embryonic kidney cells inhibited FGF-stimulated phosphorylation of extracellular-signal-regulated kinase (ERK), the principal signal downstream of receptor tyrosine kinases. Conclusions We detected independent DSTYK mutations in 2.3% of patients with congenital abnormalities of the kidney or urinary tract, a finding that suggests that DSTYK is a major determinant of human urinary tract development, downstream of FGF signaling. (Funded by the National Institutes of Health and others.).
New England Journal of Medicine 07/2013; · 51.66 Impact Factor
[show abstract][hide abstract] ABSTRACT: In humans, congenital spinal defects occur with an incidence of 0.5-1 per 1,000 live births. One of the most severe syndromes with such defects is spondylocostal dysostosis (SCD). Over the past decade the genetic basis of several forms of autosomal recessive SCD cases have been solved, with the identification of four causative genes (DLL3, MESP2, LFNG and HES7). Autosomal dominant forms of SCD have also been reported, but to date no genetic etiology has been described for these. Here we have used exome capture and next-generation sequencing to identify a stoploss mutation in TBX6 that segregates with disease in two generations of one family. We show that this mutation has a deleterious effect on the transcriptional activation activity of the TBX6 protein, likely due to haploinsufficiency. In mouse, Tbx6 is essential for the patterning of the vertebral precursor tissues, somites; thus mutation of TBX6 is likely to be causative of SCD in this family. This is the first identification of the genetic cause of an autosomal dominant form of SCD, and also demonstrates the potential of exome sequencing to identify genetic causes of dominant diseases even in small families with few affected individuals.
Human Molecular Genetics 01/2013; · 7.69 Impact Factor
[show abstract][hide abstract] ABSTRACT: (Full text is available at http://www.manu.edu.mk/prilozi). Background: Hypomethylation of the imprinting control region 1 (ICR 1) at the IGF2/H19 locus on 11p15 is linked to Silver-Russel syndrome (SRS). Methods and results: We tested the hypothesis that the severity of the phenotype in SRS patients is dependent on the clinical severity score (CSS) (1). Three SRS patients were clinically scored and their scores ranged between 12, 13 and 13. Two of the three SRS patients (66%) had hypomethylation of one allele. Conclusion: All three patients had high CSS. Nevertheless, only two of them had hypomethylation of one H19 allele. Interestingly, two of them had ventricular septal defects, but only one had H19 hypomethylation. All children had low birth length and weight, a classic facial phenotype, haemihypertrophy (> 2.5 cm thinner left arm/ leg in comparison to the right one), shorter leg, and striking thinness (BMI of > 16.0). One child was operated for cryptorchidismus, and the same child had elbow contracture. Two children had scoliosis. All three children were short (-3 to 5.5 SD), and treatment with GH resulted in growth on the third percentile. Since one child had no hypomethylation and two had a lower degree of hypomethylation, the higher CSS (12, 13 and 13) was not followed by a higher degree of hypomethylation of the IGF2/H19 locus. Key words: Silver-Russell Syndrome, methylation index, IGF2/H19 locus.
Prilozi / Makedonska akademija na naukite i umetnostite, Oddelenie za biološki i medicinski nauki = Contributions / Macedonian Academy of Sciences and Arts, Section of Biological and Medical Sciences 01/2013; 34(2):79-83.
[show abstract][hide abstract] ABSTRACT: (Full text is available at http://www.manu.edu.mk/prilozi). Obesity and overweight are a pandemic phenomenon in the modern world. Childhood and adolescent obesity often ends up in obesity in adults. The costs of obesity and its consequences are staggering for any society, crippling for countries in development. The etiology is complex, but most often idiopathic. Hormonal, syndromic and medication-induced obesity are well investigated. Genetic causes are increasingly described. Novel technologies such as whole exome sequencing identify ever more candidate genes influencing or causing obesity. All insights into the complex problem of obesity in a team approach to treatment: diet, psychology, medications and surgery. We briefly review epidemiology, etiology, consequences and treatment approaches in childhood and adolescent obesity, with special emphasis on emerging knowledge of its genetics. Key words: obesity, children, adolescents, obesity consequences, genetic causes.
Prilozi / Makedonska akademija na naukite i umetnostite, Oddelenie za biološki i medicinski nauki = Contributions / Macedonian Academy of Sciences and Arts, Section of Biological and Medical Sciences 01/2013; 34(2):85-9.
[show abstract][hide abstract] ABSTRACT: 58 years after the creation of impact factor (IF) the professional public shows interest in IFs and their significance for academia and individuals. Really, is a medical journal with IF needed for Macedonia? Some other small and developing countries have pursued and accomplished this goal: Serbia, Slovenia, and Croatia. On the other hand the survey of publications in Macedonian medical journals has been found to lack quality. We believe that to strive to obtain an IF would be beneficial for all Macedonian interest groups involved. This would introduce an ambition among the members of Macedonian academia to publish (so far rare), than to publish in Pubmed listed journals (ambition present in very few Macedonian academics) and then to publish in journals with the highest IF possible (so far a very exclusive group of Macedonian medical professionals). In time this will help in creating and enforcing legal obligation for the academia for a promotion based on merit of IF scientific publications. We believe that this is possible only by Parliament legislation. This will be of benefit for Macedonian patients, the medical community and will unable this country to contribute to the universe of science. Lastly it would certainly be helpful in getting a Macedonian university in the prestigious first 500 Shangai list. Key words: impact factor, Macedonia, medical journals.
Prilozi / Makedonska akademija na naukite i umetnostite, Oddelenie za biološki i medicinski nauki = Contributions / Macedonian Academy of Sciences and Arts, Section of Biological and Medical Sciences 01/2013; 34(2):5-9.
[show abstract][hide abstract] ABSTRACT: In humans, congenital spinal defects occur with an incidence of 0.5 –1 per 1000 live births. One of the most severe syndromes with such defects is spondylocostal dysostosis (SCD). Over the past decade, the genetic basis of several forms of autosomal recessive SCD cases has been solved with the identification of four causative genes (DLL3, MESP2, LFNG and HES7). Autosomal dominant forms of SCD have also been reported, but to date no genetic etiology has been described for these. Here, we have used exome capture and next-generation sequencing to identify a stoploss mutation in TBX6 that segregates with disease in two generations of one family. We show that this mutation has a deleterious effect on the transcriptional ac-tivation activity of the TBX6 protein, likely due to haploinsufficiency. In mouse, Tbx6 is essential for the pat-terning of the vertebral precursor tissues, somites; thus, mutation of TBX6 is likely to be causative of SCD in this family. This is the first identification of the genetic cause of an autosomal dominant form of SCD, and also demonstrates the potential of exome sequencing to identify genetic causes of dominant diseases even in small families with few affected individuals.
[show abstract][hide abstract] ABSTRACT: (Full text is available at http://www.manu.edu.mk/prilozi). Trisomy 21, the cause of Down syndrome (DS), is the most frequent trisomy in humans. The risk for DS increases with maternal age: mothers under 25 years of age are known to have an average risk of a DS pregnancy of 1: 1600, rising to 1: 350 at age 35 and to 1: 40 at 43, respectively. Twins with DS are rare. We report on monozygotic (MZ), monochorionic twin sisters with DS, whose parents are young (24 and 26 years old, respectively) and healthy. Family history is non contributory; pregnancy and delivery were uneventful. Both girls presented at birth with clinical manifestations of Down syndrome, that was confirmed cytogenetically (47XX,+21). Microsatellites analysis indicated that the twins are identical and that the extra chromosome 21 was of paternal origin. Conclusions: For practical purposes, the causative non disjunction should be considered a single sporadic event, with an empirical recurrence risk estimated at about 1%. Key words: Down syndrome, identical twins, paternal origin.
Prilozi / Makedonska akademija na naukite i umetnostite, Oddelenie za biološki i medicinski nauki = Contributions / Macedonian Academy of Sciences and Arts, Section of Biological and Medical Sciences 12/2012; 33(2):41-6.
[show abstract][hide abstract] ABSTRACT: (Full text is available at http://www.manu.edu.mk/prilozi). SGA (small for gestational age) is a child born with birth weight and/or length (BW/BL) under two standard deviations (2 SDS) for the gestational age and sex of the population. ~5% of all newborn children are SGA. A broad spectrum of factors are found to be causative: maternal, placental, foetal, metabolic, and genetic. In the newborn period the SGA children are at greater risk of life-threatening conditions: hypoglycaemia, hypercoagulability, necrotic enterocolitis, direct hyperbilirubinemia, hypotension, etc. Approximately 10 percent of SGA children do not achieve catch-up growth and remain short (≥ -2 SDS) into adulthood. SGA people have an increased incidence of metabolic syndrome, coronary artery disease, stroke, low bone density and osteoporosis. SGA children aged more than 4 years with no evidence of spontaneous catch-up and with a height ≥ 2.5 SD are considered for growth hormone (GH) treatment. Key words: Small for gestational age, etiology, consequences, GH treatment.
Prilozi / Makedonska akademija na naukite i umetnostite, Oddelenie za biološki i medicinski nauki = Contributions / Macedonian Academy of Sciences and Arts, Section of Biological and Medical Sciences 12/2012; 33(2):47-58.
[show abstract][hide abstract] ABSTRACT: (Full text is available at http://www.manu.edu.mk/prilozi).Under the auspices of the European Academy of Paediatrics, the first Rare Disease in South-Eastern Europe (SEE) meeting was held on November 15-17 2012, at the Macedonian Academy of Sciences and Arts, Skopje (MASA). This was a manifestation in honour of the 45 years since its establishment, under the guidance of the G.D. Efremov Research Centre for Genetic Engineering and Bio-technology. The Macedonian Chamber of Doctors granted 20 CME credit points for the meeting. The meeting started with talks on the importance of rare diseases in general (Liesbeth Siderius, The Netherlands, John Dodge, UK) and in Macedonia (Zoran Gucev, Velibor Tasic, Dijana Plasevska-Karanfilska, Momir Polenakovic). The importance of having registries for RDs, team work, additional education and international collaboration was stressed as being especially important. All speakers, as well as the NGO patient organization (Slavica Stojanovska, Vesna Stojmenska) underlined the need for comprehensive societal efforts in tackling this emerging social and medical problem. Surgical problems regarding the ear and hearing were finely exposed in the presentation by Ilija Filipce (Macedonia). At least 80% of RDs are genetic in their origin. Anna Tylki-Szymanska (Poland) spoke about Lysosomal acid lipase deficiency, Wolman disease and cholesteryl ester storage disease, while Agnieszka Jurecka (Poland) introduced the audience to the natural history of mucopolysaccharidosis type VI. Especially insightful presentations were those describing the genetics of abnormal vertebral segmentation and the Notch signalling pathway (Peter Turnpenny, UK) and the overgrowth syndromes in their interesting and exciting relationship to human cancer (Between Mendel and cancer - PI3K/AKT-related overgrowth syndromes, Robert Sample, UK). The genetics and the clinical features of the pituitary were addressed by several prominent scientists. The genetic causes of IGF-I deficiency and insensitivity were presented by Jan-Maarten Wit (The Netherlands), while the defects within pituitary growth factors and their phenotypes in infancy and adolescence was brilliantly presented by Roland Pfaeffle (Germany). In addition, the fine aspects of the septo-optic dysplasia were presented by Liljana Saranac (Serbia). The ever growing body of genetic insights was enriched by the fundamental findings in epigenetics (genomic imprinting anomalies) presented by Yves Le Bouc (France) with his talk on the Beckwith-Wiedemann overgrowth syndrome (BWS) and the Russell-Silver (RSS) syndrome. As, rather unfortunately, patients with Gaucher's disease (GD) are not treated in Macedonia, Gaucher disease was a separate section at the RD meeting at MASA. GD as a model disorder for targeted therapy (Patrik Deegan, UK) and the therapeutic options in Gaucher's disease (Deborah Elstein, Israel) introduced the public to the basic and the newest available therapeutic options. Regional collaboration was especially stressed in the talk on the laboratory diagnosis of lysosomal storage diseases in Bulgaria, by Ivanka Sinegirska from Sofia, Bulgaria. Arunas Valiulis (Lithuania) talked about the EU Leonardo Project, Building a Network of Management of Alpha-1 Antitrypsin Deficiency in Central / Eastern Europe, further pointing towards the need for international and especially European collaboration on the particular form of RD. As the first patient(s) with Fabry's disease have been discovered in Macedonia the talk on Fabry enzyme replacement therapy (ERT) (Patrik Deegan, UK) was especially insightful. The molecular diagnosis and treatment of Wilson's disease is always a difficult clinical situation, as stressed by Georgios Laudianos, Italy. Insights on primary hyperoxaluria type III were given by Yaacov Frishberg (Israel), especially interesting were the presentations on atypical haemolitic uremic syndrome (Zoltan Prohaska, Hungary), hypouricaemia (Ivan Sebesta, Prague, Czech Republic; Dganit Dinour, Israel; and Velibor Tasic, Macedonia). Alport's Disease (Gordana Petrusevska, Macedonia), Autism (Nada Pop-Jordanova, Macedonia), progressive familial and benign recurrent inrahepatic cholestasis (Viktorija Chaloska-Ivanova, Macedonia) and a comprehensive survey on patients with primary immune deficiency diseases in Macedonia (Kristina Mironska, Macedonia) were also presented. Several groups have also contributed with their posters (27) on different RDs. The meeting was attended by 128 delegates from 21 countries. In addition, there were conclusions and proposed modifications for further progress in the development of diagnosis and treatment of RDs. The meeting and ita organization were rated by delegates and lecturers as an exceptional scientific success. Of particular importance also is the fact of the intensive collaboration of SEE countries and SEE and the EU countries. It was also an opportunity to reconsider the state of the organizational, educational and scientific integration of SEE and the EU on the rather specific field of RDs.
Prilozi / Makedonska akademija na naukite i umetnostite, Oddelenie za biološki i medicinski nauki = Contributions / Macedonian Academy of Sciences and Arts, Section of Biological and Medical Sciences 12/2012; 33(2):279-81.
[show abstract][hide abstract] ABSTRACT: We examined the burden of large, rare, copy-number variants (CNVs) in 192 individuals with renal hypodysplasia (RHD) and replicated findings in 330 RHD cases from two independent cohorts. CNV distribution was significantly skewed toward larger gene-disrupting events in RHD cases compared to 4,733 ethnicity-matched controls (p = 4.8 × 10(-11)). This excess was attributable to known and novel (i.e., not present in any database or in the literature) genomic disorders. All together, 55/522 (10.5%) RHD cases harbored 34 distinct known genomic disorders, which were detected in only 0.2% of 13,839 population controls (p = 1.2 × 10(-58)). Another 32 (6.1%) RHD cases harbored large gene-disrupting CNVs that were absent from or extremely rare in the 13,839 population controls, identifying 38 potential novel or rare genomic disorders for this trait. Deletions at the HNF1B locus and the DiGeorge/velocardiofacial locus were most frequent. However, the majority of disorders were detected in a single individual. Genomic disorders were detected in 22.5% of individuals with multiple malformations and 14.5% of individuals with isolated urinary-tract defects; 14 individuals harbored two or more diagnostic or rare CNVs. Strikingly, the majority of the known CNV disorders detected in the RHD cohort have previous associations with developmental delay or neuropsychiatric diseases. Up to 16.6% of individuals with kidney malformations had a molecular diagnosis attributable to a copy-number disorder, suggesting kidney malformations as a sentinel manifestation of pathogenic genomic imbalances. A search for pathogenic CNVs should be considered in this population for the diagnosis of their specific genomic disorders and for the evaluation of the potential for developmental delay.
The American Journal of Human Genetics 11/2012; · 11.20 Impact Factor
[show abstract][hide abstract] ABSTRACT: The phosphatidylinositol 3-kinase (PI3K)-AKT signaling pathway is critical for cellular growth and metabolism. Correspondingly, loss of function of PTEN, a negative regulator of PI3K, or activating mutations in AKT1, AKT2 or AKT3 have been found in distinct disorders featuring overgrowth or hypoglycemia. We performed exome sequencing of DNA from unaffected and affected cells from an individual with an unclassified syndrome of congenital progressive segmental overgrowth of fibrous and adipose tissue and bone and identified the cancer-associated mutation encoding p.His1047Leu in PIK3CA, the gene that encodes the p110α catalytic subunit of PI3K, only in affected cells. Sequencing of PIK3CA in ten additional individuals with overlapping syndromes identified either the p.His1047Leu alteration or a second cancer-associated alteration, p.His1047Arg, in nine cases. Affected dermal fibroblasts showed enhanced basal and epidermal growth factor (EGF)-stimulated phosphatidylinositol 3,4,5-trisphosphate (PIP(3)) generation and concomitant activation of downstream signaling relative to their unaffected counterparts. Our findings characterize a distinct overgrowth syndrome, biochemically demonstrate activation of PI3K signaling and thereby identify a rational therapeutic target.
[show abstract][hide abstract] ABSTRACT: Aldosterone synthase deficiency (ASD) type II was diagnosed in a 3 week old boy with severe dehydration. Elevated plasma renin activity, low-normal aldosterone, increased levels for 18-OH corticosterone (18-OHB) and 18-OH-deoxycorticosterone were measured. Sequencing revealed a homozygous mutation for c554C > T in exon 3 (p.T185I) (CYP11B2). Hypospadias has so far not been reported in ASD.
Indian pediatrics 04/2012; 49(4):318-20. · 1.04 Impact Factor
[show abstract][hide abstract] ABSTRACT: Acid sphingomyelinase deficiency leads to the accumulation of sphingomyelin in cells, causing Niemann-Pick disease (NPD) types A/B. RF (13.66 y) and HF (3 y) are brother and sister. RF growth was markedly delayed at the age of 12.66 y (123 cm; -3.25 SD), while at the age 3 y his sister is 86 cm (-2.75 SD). The brother had a huge liver (13 cm) and spleen (12 cm). His sister also had an enlarged liver, but presented no other symptoms. The fibroblast cultivation had a reduced sphingomyelinase activity in the fibroblasts (0.68 mkat/kg protein), β-galaktosidase (937 mkat/kg) and glucosilceramidase (125.4 mkat/kg) were elevated. Mutational analysis demonstrated the siblings are compound heterozygotes (V112M and H554Y). The mother is carrier of V112M and the father carries H554Y. This is the first report of NPD type B in Macedonia. The novel mutation results in a moderately severe phenotype of NPD type B.
The Indian Journal of Pediatrics 02/2012; · 0.72 Impact Factor
[show abstract][hide abstract] ABSTRACT: Four distinct familial types of isolated GH deficiency (IGHD) have been described so far.
We report a novel nonsense GH1 mutation in a father and a son.
Father's height was 137.3 cm (-6.79 SDS); mother's height was 157.3 cm (-1.86 SDS). By the age of 8.25 years, his height was 104.3 cm (-4.82 SDS) and his weight was 18.3 kg (-3.35 SDS). GH stimulation tests had low peak GH value of 6.5 ng/ml (proband) and 6.3 ng/ml (father). Other pituitary hormones and magnetic resonance imaging (MRI) of the pituitary region was normal in both patients. The proband received recombinant human GH (rhGH) treatment (30 μg/kg/day) and he grew 15.4 cm in 15 months.
Sequencing of the GH1 gene revealed a novel heterozygous nonsense mutation in both the father and the son (c.199A>T), which introduces a stop codon in exon 3.
We present a family with IGHD II, with severe short stature, no phenotypic characteristics of GHD and a novel nonsense mutation in exon 3 of the GH1 gene. As fibroblasts were unavailable, we used computer analysis and we propose a unique mechanism that combines aberrant splicing and derogated GH release from the pituitary with residual secretion of a bioinactive truncated GH peptide.
Hormone Research in Paediatrics 12/2011; 77(3):200-4. · 1.55 Impact Factor
[show abstract][hide abstract] ABSTRACT: (Full text is available at http://www.manu.edu.mk/prilozi). Wilson disease (WD) is an autosomal recessive disorder, in which copper is deposited in the liver, brain, cornea and kidneys. The clinical presentation is variable, with fully expressed disease manifesting cirrhosis, neurologic damage and Kayser-Fleischer (K-F) ring on the cornea. A 24-year-old patient developed right upper quadrant pain with a palpable mass and a swelling of the right talocrural articulation. X-rays were uneventful, but the routine examination of hepatic enzymes discovered a 6-8 fold increase in SGPT, SGOT and AST. Antibodies for hepatitis B, C were normal, as well as the ANA, ANCA, antimytochondrial and anti-smooth muscle antibodies. Ultrasound of the abdomen re-vealed extremely dilated hepatic, cystic ducts as well as gallbladder. A large, oedematous gallbladder with yellow green bile was removed, the liver was found to be cirrhotic, but as the operative bleeding was abundant a biopsy was not done. Serum ceruloplasmin was low [0.160 g/l (normal 0.204-0.407)], serum copper 12.7 µmol/l (11.0-24.4), transaminasis: always very high, in the last months normal/slightly elevated. Urine copper: 1.0 µmol/24h (> 9.44). As first seen the proband had tremor, dysarthria, dystonia and K-F ring on the cornea. After 10 months of treatment with penicillamine his transaminases normalized, the tremor, dysarthria, dystonia initially got worse and then ameliorated. The coagulation times are ameliorated, but not yet normalized. Mutational analysis has shown that the proband is homozygote for c.3207 C- > A, p.H1069Q while his parents are heterozygotes. His sister is a healthy non-carrier. In brief, we describe an unusual presentation of WD, with gallbladder hydrops and talocrural arthritis in a patient with complete clinical manifestations of the disease. Key words: Wilson disease, Kayser-Fleischer rings, gallbladder hydrops. arthritis, p.H1069Q mutation.
Prilozi / Makedonska akademija na naukite i umetnostite, Oddelenie za biološki i medicinski nauki = Contributions / Macedonian Academy of Sciences and Arts, Section of Biological and Medical Sciences 12/2011; 32(2):207-15.