The degree of H19 hypomethylation in children with Silver-Russel syndrome (SRS) is not associated with the severity of phenotype and the clinical severity score (CSS).

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.

Obesity in childhood and adolescence, genetic factors.

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.

Two siblings with Niemann-Pick disease (NPD) type B: clinical findings and novel mutations of the acid sphingomyelinase gene.

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), ß-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.

Billateral polycystic kidneys in a girl with WAGR syndrome.

The WAGR contiguous gene deletion syndrome is a combination of Wilms tumor, aniridia, genito-urinary abnormalities, and mental retardation. An 8.5-year-old girl was initially investigated at the age of 18 months for congenital bilateral aniridia, cataracts, glaucoma and epicantus. The ultrasound (US) scan showed polycystic kidney disease. FISH study revealed deletion of the WT1 and PAX6 gene in the 11p13 WAGR region. Forty days after the first kidney US, the second US revealed a 3 cm tumor in the right kidney: a Wilms tumour, treated successfully with the Wilm's tumor protocol. The authors conclude that the identification of the deletions in the WAGR region in patients with aniridia should definitely be done. In addition, Wilms tumor can have a very rapid growth, which, per se requires frequent and careful ultrasound kidney controls. Polycystic kidneys can be part of the WAGR presentation.

Childhood craniopharyngioma in Macedonia: incidence and outcome after subtotal resection and cranial irradiation.

BACKGROUND: craniopharyngioma is a frequent tumor in children with challenging surgical, endocrine, and visual consequences. We evaluated our experience in treating craniopharyngioma and its incidence in Macedonia. METHODS: Thirteen children (9 male and 4 female) with craniopharyngioma (age 9.55 ± 3.74 years; range 2.90-15.11) who had been treated between 1989 and 2008 in Macedonia were reviewed. RESULTS: initial signs were vision disturbances (10 children), seizures (1), growth retardation (13), and diabetes insipidus (DI) (2). All children were subjected to subtotal surgical removal. Cranial irradiation was performed in 12 of the 13 children, and intracystic bleomycin was given to one child. The patients were followed up for 6-229 months (mean ± SD: 107.00 ± 74.04 months). All children had multiple pituitary deficiencies after surgical removal of the tumor. Body mass index increased from 16.93 ± 6.34 standard deviation scores (SDS) at diagnosis to 26.33 ± 5.91 SDS (P>0.005) at the last follow-up. DI was permanent in 9 of the 13 children, and multiple pituitary deficiencies were seen in all children. Treatment with growth hormone resulted in normalization of adult height from -1.27 ± 1.52 SDS at the start of the treatment to -0.13 ± 1.39 SDS at the last followup. The final height was not significantly lower than the genetic target height (P>0.005). The permanent deficit was visual impairment: blindness in one or both eyes in 4 children, bitemporal hemianopsia in 4, and other defects in 2. Recurrence of the disease was ruled out in one child after 31 months. No mortality was observed in the observation period of 104.92 ± 76.11 months. CONCLUSIONS: the overall incidence of craniopharyngioma in the period of 1989-2008 in Macedonia was 1.43 per 1 000 000 person-years. Subtotal resection and systematic irradiation showed good life quality of survivors.

McCune-Albright syndrome (MAS): early and extensive bone fibrous dysplasia involvement and "mistaken identity" oophorectomy.

BACKGROUND: McCune-Albright syndrome (MAS) is a triad of gonadotropin-independent precocious puberty (GIPP), café-au-lait spots (CALS) and fibrous dysplasia (FD) of bone. The extent of the abnormalities is variable. PATIENT AND RESULTS: We report a 3 year old girl with CALS since infancy, FD diagnosed at age of 2.5 years, and at the age of 3 years vaginal bleeding. The ultrasound revealed a cystic mass of the ovary, surgical pathology found ovarian cyst. LHRH stimulation demonstrated GIPP (LH 9.8 mIU/ml and FSH 8.9 mIU/ml; normal LH 1.8-10, FSH 9-26 mIU/ml). Radiographs and bone scans demonstrated FD in multiple bones. Peripheral leucocytes and the ovary were negative for GNAS gene mutations. Treatment with Letrasole interrupted the pubertal development. CONCLUSIONS: We conclude that the clinical signs of MAS are telling and that timely MAS diagnosis prevents unnecessary oophorectomy. A close follow up is recommended regarding development of endocrine disorders and spreading of FD.

Autoimmune thyroiditis and diabetes mellitus type 1 after long-term gonadotropin-releasing hormone agonist treatment for central precocious puberty: evolution or coincidence?

Very few abnormalities in endocrine function have been reported during long term gonadotropin-releasing hormone agonist (GnRHa) treatment in girls. Most authors agree that this therapy is safe and effective. We present an unusual outcome of long term GnRHa therapy in two girls with central precocious puberty(CPP) of idiopathic or organic origin. They have received monthly depot injections of triptorelin acetate for a time period of 8 years. Thyroid function was examined by measuring serum levels of thyrotropin (TSH), thyroxine (T4), thyroid antibodies, and ultrasound of the thyroid gland. One of the girls was at the age of 8.5 years, having elevated thyroid antibodies, mild goitier and an abnormal ultrasound of the thyroid gland, suggesting autoimmune thyroiditis. Another girl with a hypothalamic hamartoma developed diabetes mellitus at the age of 9 years. Both of these girls were early diagnosed for CPP, at 6 months and 8 months respectively, and given GnRHa treatment. So far, it is not known whether these autoimmune diseases are related to the GnRHa treatment or are simply a coincidence. However, we suggest a closer monitoring of girls with CPP who have had a long period of treatment.

Papillorenal syndrome after Beta-interferon treatment in pregnancy.

Papillo-Renal Syndrome (PRS, or Renal-Coloboma Syndrome) is an autosomal dominant disorder, characterized by colobomatous eye defects, abnormal vascular pattern of the optic disk, renal hypoplasia, vesicoureteral reflux, high-frequency hearing loss, and sometimes central nervous system (CNS) abnormalities. The syndrome is associated with mutations in the PAX2 gene. This 11-year-old girl's mother was treated with beta-interferon (IFNbeta-1a) for multiple sclerosis (MS) during the pregnancy. The child failed to thrive in infancy and early childhood. The multicystic renal dystrophy, hypoplastic right kidney, and vesico-ureteral reflux (II-III grade) were diagnosed by ultrasound and radionucleotide renal scan. Subsequently, a morning glory anomaly and coloboma of the optic disc was discovered. Renal failure progressively followed. MRI of the head revealed a cyst of the right optic nerve. Genetic analysis revealed a mutation of the PAX2 gene (619 insG). The multicystic renal dystrophy and a cyst of the optic nerve in association with PRS syndrome have only rarely been described. The fact that this PRS patient stemmed from a pregnancy under beta-interferon treatment raises the question whether IFNbeta-1a treatment during pregnancy has influenced the manifestation or the severity of the PAX2 mutant phenotype in this child.

A case of Silver-Russell syndrome (SRS): multiple pituitary hormone deficiency, lack of H19 hypomethylation and favourable growth hormone (GH) treatment response.

Hypomethylation of the imprinting control region 1 (ICR1) at the IGF2/H19 locus on 11p15 is linked to Silver-Russell syndrome (SRS) and/or hemihypertrophy. This SRS patient was born in term with weight of 3500 g (50 percentile) and length 48 cm (1 SD below the mean). He was first noticed at the age of 10 years for short stature (114.5 cm, -3.85 SD), relatively normal head circumference, a classic facial phenotype, hemihypertrophy (2.5 cm thinner left arm and leg in comparison to the right, asymmetric face), moderate clinodactyly and striking thinness (BMI of 15.3). At the age of 30, the body asymmetry ameliorated (1 cm thinner left arm and leg than the right), and BMI normalized (20.5 cm). Methylation analysis was performed by bisulphate treatment of DNA samples, radiolabelled PCR amplification, and digestion of the PCR products using restriction enzymes. The patient had normomethylation, and in addition hypopituitarism, with low levels of growth hormone (GH) (provocative testing before the start and after termination of GH treatment), thyroxin, TSH, FSH, LH and testosterone. The GH was given for six years, growth response was satisfactory and he reached an adult height of 166 cm. This is a first report of hypopituitarism in a patient with SRS without H19 hypomethylation. It seems that the lack of hypomethylation in this hypopituitary SRS patient is responsible, at least partly, for the favourable final adult height under GH treatment.

Friedreich ataxia (FA) associated with diabetes mellitus type 1 and hyperthrophic cardiomyopathy.

Progressive signs of ataxia in a eight years old girl prompted neurological investigation. The girl had unstable gait with incoordination of limb movements, impairment of position and vibratory senses, dysarthria, pes cavus, positive Babinski sign and scoliosis. At the age of fourteen the girl was referred in a comatose condition, in a severe diabetic ketoacidosis. Ataxia and hypoactive knee and ankle jerks prompted the analysis of the frataxin gene (FXN; 606829). The most common molecular abnormality: GAA trinucleotide repeat expansion in intron 1 was found with + 300 GAA repeats (1490bp) (normal individuals have 5 to 30 GAA repeat expansions, whereas affected individuals have from 70 to more than 1,000 GAA triplets). Electrocardiogram showed diffuse T wave inversion with sinus bradycardia, while ultrasound revealed concentric, symmetric hypertrophy of left ventricle leading to the diagnosis of hyperthrophic cardiomyopathy. At the age of 14 years, the patient was bound to the wheel-chair, unable to walk. Her brother started to show ataxia at the age of 8 years, and subsequent analysis showed hyperthrophic cardiomyopathy, too. His mutational analysis revealed the same frataxin abnormality, with + 300 GAA repeats. So far, no signs of diabetes occurred. The parents are heterozygous with FXN of 9 -10 GAA (490 bp). Both children received a beta blocker, while the girl's diabetes mellitus was treated by insulin preparations. This is a report of two siblings with Fridreich ataxia and hyperthrophic cardiomyopathy. In addition, the girl developed type 1 diabetes mellitus.

Weight, height and puberty in a cohort of Macedonian girls.

Obesity is becoming a growing problem in developed and developing countries. Many studies report an increasing incidence of obesity in the last decade. The aim of our transversal epidemiological study was to evaluate the prevalence of overweight children, auxological characteristics and pubertal stage in healthy girls from first (200 girls), third (209), fifth (290) and seventh (223) grade of school. In this study 928 girls were evaluated through systematic school examinations in the ambulance of municipality of Karposh, Skopje. The Rome and Turkish nationality, as well as Serbian were present in a small percentage, while detailed analysis was performed in the Macedonian and Albanian population of girls. The initiation of puberty (stage M2 or P2 by Tanner) was present in Macedonian girls: 4.3% of children in first grade, 23% in third grade, and 51.7% in fifth grade. In Albanians, in first grade M2 is present in 2.7%, in third grade 5.2%, and in fifth grade 46.9%. Body mass index (BMI SDS) was +3.5 +/- 1.5 in 35% of Macedonian girls and only 5% of Albanian girls. The Macedonian girls were also significantly higher (p < 0.01) and more obese than the Albanian girls. The pubertal stage was also more advanced in Macedonian girls. Most of the obese children who were included in the study reported increased consumption of fast food. Although in the past years obesity was not a problem in our country, it is becoming more severe with every year.

Friedreich's ataxia (FA) associated with diabetes mellitus type 1 and hypertrophic cardiomyopathy: analysis of a FA family.

Progressive signs of ataxia in a eight year old girl with hypo-active knee and ankle jerks, prompted the analysis of the frataxin gene (FXN; 606829). The most common molecular abnormality--GAA trinucleotide repeat expansion in intron 1--was found with +300 GAA repeats (1490 bp) (normal individuals have 5 to 30 GAA repeats expansions, whereas affected individuals have from 70 to more than 1000 GAA triplets). Additionally she had unstable gait with incoordination of limb movements, impairment of position and vibratory senses, dysarthria, pes cavus, positive Babinski sign and scoliosis. At the age of fourteen the girl was referred in a comatose condition, in severe diabetic ketoacidosis. Insulin dependent diabetes mellitus was since treated with insulin preparations. Electrocardiogram showed diffuse T wave inversion with sinus bradycardia, while ultrasound revealed concentric, symmetric hypertrophy of the left ventricle leading to the diagnosis of hypertrophic cardiomyopathy. At the age of 14, she is bound to the wheelchair, unable to walk. Her brother started to show ataxia at the age of 8 years and subsequent analysis also showed hypertrophic cardiomyopathy. His mutational analysis revealed the same frataxin abnormality with +300 GAA repeats. So far, no signs of diabetes occurred. The parental DNA was not available for analysis.

Congenital lipomatous overgrowth, vascular malformations, and epidermal nevi (CLOVE) syndrome: CNS malformations and seizures may be a component of this disorder.

A newborn girl was found to have a massive lymphatic truncal vascular malformation with overlying cutaneous venous anomaly associated with overgrown feet and splayed toes. These manifestations comprise the recently described CLOVE syndrome. She also had cranial asymmetry and developed generalized seizures, which were treated with anticonvulsants. Cranial CT showed encephalomalacia, widening of the ventricles and the sulci, hemimegalencephaly (predominantly white matter) and partial agenesis of corpus callosum. Review of the literature identified several other patients with CLOVE syndrome, some of whom were misdiagnosed as having Proteus syndrome, with strikingly similar manifestations. We conclude that CNS manifestations including hemimegalencephaly, dysgenesis of the corpus callosum, neuronal migration defects, and the consequent seizures, may be an rarely recognized manifestation of CLOVE syndrome.

Novel beta-galactosidase gene mutation p.W273R in a woman with mucopolysaccharidosis type IVB (Morquio B) and lack of response to in vitro chaperone treatment of her skin fibroblasts.

The patient is a 24-year-old woman who first came for consultation at age 10 years. Based on clinical phenotype and thin-layer chromatography of urinary oligosaccharides, peripheral leukocytes were sent for beta-galactosidase assay. This testing showed a deficiency in enzyme activity, and gene mutation analysis identified a previously reported mutation p.H281Y (875C > T) and a novel mutation p.W273R (817T > C). Unlike previously reported patients, mutant enzymes in this patient's cultured skin fibroblasts did not respond to treatment with a chaperone compound, N-octyl-4-epi-beta-valienamine.