Peripheral Insulin Edema and Pericardial Effusion in a 12-Year-Old Newly Diagnosed Girl with Type 1 Diabetes.

Introduction: Insulin induced edema (IIE) is a rare condition, usually found in newly diagnosed diabetes patients, either after insulin treatment initiation or after dose increment. It is a self-limited process, rarely associated with serosal effusions. Teenage girls with type 1 diabetes (T1DM) are most commonly affected. Patient and Methods: A 12-year-old girl was diagnosed with ketoacidosis (DKA). Seven days after initiation of the insulin treatment, at a stable total daily dose of insulin (TDDI) of 0.55 IU/kg, she came with two kilograms weight gain in only two days and edema of the feet and calves. Ultrasound of the heart found a 7 mm pericardial effusion. The diagnostic workout included clinical examination, biochemical, hormonal, allergen analyses and imaging which excluded other known causes of swelling. Conclusions: We describe an adolescent girl with newly diagnosed T1DM and a rare association of peripheral insulin-induced edema and pericardial effusion. Short-term diuretic treatment and salt restriction resolved this rare complication of insulin treatment.

Fourteen monogenic genes account for 15% of nephrolithiasis/nephrocalcinosis.

Nephrolithiasis is a prevalent condition with a high morbidity. Although dozens of monogenic causes have been identified, the fraction of single-gene disease has not been well studied. To determine the percentage of cases that can be molecularly explained by mutations in 1 of 30 known kidney stone genes, we conducted a high-throughput mutation analysis in a cohort of consecutively recruited patients from typical kidney stone clinics. The cohort comprised 272 genetically unresolved individuals (106 children and 166 adults) from 268 families with nephrolithiasis (n=256) or isolated nephrocalcinosis (n=16). We detected 50 likely causative mutations in 14 of 30 analyzed genes, leading to a molecular diagnosis in 14.9% (40 of 268) of all cases; 20 of 50 detected mutations were novel (40%). The cystinuria gene SLC7A9 (n=19) was most frequently mutated. The percentage of monogenic cases was notably high in both the adult (11.4%) and pediatric cohorts (20.8%). Recessive causes were more frequent among children, whereas dominant disease occurred more abundantly in adults. Our study provides an in-depth analysis of monogenic causes of kidney stone disease. We suggest that knowledge of the molecular cause of nephrolithiasis and nephrocalcinosis may have practical implications and might facilitate personalized treatment.

Mutational analysis of TAC and TACR3 in idiopathic central precocious puberty.

BACKGROUND: The genetic background of idiopathic central precocious puberty (ICPP) is not well understood, and is thought to arise from the effect of multiple genes. Familial ICPP have been reported suggesting the existence of monogenic causes of ICPP. The neurokinin B (NKB) system has recently been implicated in the regulation of the human reproductive axis. In humans, NKB and its receptor are encoded by the TAC3 and TACR3 genes, respectively. Mutations in these genes have been suggested to be causative for ICPP. METHODS: ICPP was defined by pubertal onset before 8 yrs of age in girls, and a pubertal LH response to GnRH testing. Twenty eight girls with ICPP were included in the study (age at diagnosis was 5.72±2.59; bone age, 6.12±2.81, height at the start of treatment, 0.90±1.48 SD). LHRH test was performed and was pubertal in all subjects (LH 20.35±32.37 mIU/ml; FSH 23.32±15.72 mIU/ml). The coding regions of TAC and TACR3 were sequenced. RESULTS: No rare variants were detected in TAC and TACR3 in the 28 subjects with ICPP. CONCLUSIONS: We confirmed that mutations in TAC and TACR3 are not a common cause for ICPP.

Mutational analysis of KISS1 and KISS1R in idiopathic central precocious puberty.

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.

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.

Autosomal dominant spondylocostal dysostosis is caused by mutation in TBX6.

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 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.

Distinguishing deficiencies in the steroidogenic acute regulatory protein and the cholesterol side chain cleavage enzyme causing neonatal adrenal failure.

OBJECTIVES: To determine the genetic basis of disordered steroidogenesis in Kuwaiti siblings. STUDY DESIGN: Two siblings (46,XX and 46,XY) had normal female external genitalia and severe glucocorticoid and mineralocorticoid deficiency presenting in the first month of life. Abdominal ultrasonography showed normal size adrenal glands, suggesting cholesterol side chain cleavage enzyme (P450scc) deficiency. The CYP11A1 gene encoding P450scc and the STAR gene encoding the steroidogenic acute regulatory protein (StAR) were directly sequenced from leukocyte DNA. RESULTS: All exons and intron/exon boundaries of the CYP11A1 gene were normal; the STAR gene was homozygous for a novel 14-base deletion/frameshift in exon 4 (g.4643_4656del), so that no functional protein could be produced. Both parents and an unaffected sibling were heterozygous; zygosity was confirmed with a BsmF1 restriction fragment length polymorphism. CONCLUSIONS: Unlike most patients with StAR deficiency, our patients did not have the massive adrenal hyperplasia typical of congenital lipoid adrenal hyperplasia. The distinction between StAR and P450scc deficiency may require gene sequencing.

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.

Autosomal dominant spondylocostal dysostosis in three generations of a Macedonian family: Negative mutation analysis of DLL3, MESP2, HES7, and LFNG.

The spondylocostal dysostoses (SCDs) are a heterogeneous group of axial skeletal disorders characterized by multiple segmentation defects of the vertebrae (SDV) and abnormality of the thoracic cage with mal-aligned ribs and often a reduction in rib number. The four known monogenic forms of SCD follow autosomal recessive inheritance, have generalized SDV, a broadly symmetrical thoracic cage, and result from mutations in Notch signaling pathway genes-DLL3, MESP2, LFNG, and HES7. Autosomal dominant (AD) SCD has been reported less often, is very variable, and molecular genetic mechanisms remain elusive. Here, we report a three-generation, non-consanguineous family with four affected individuals demonstrating multiple or generalized SDV. Scoliosis was present and the trunk shortened but the ribs were relatively mildly affected. There were no other significant organ abnormalities, no obvious dysmorphic features, neurodevelopment was normal, and all investigations, including mutation analysis of DLL3, MESP2, LFNG, and HES7, were normal. A non-pathogenic variant was detected in LFNG but it did not segregate with the phenotype. This Macedonian kindred adds to knowledge of AD SCD and to our knowledge is the first to be tested for the four Notch pathway genes known to be associated with SCD.

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.

Arthrogryposis multiplex congenital (AMC) in a three year old boy: differential diagnosis with distal arthrogryposis: a case report.

INTRODUCTION: Arthrogryposis multiplex congenital (AMC) is characterized by contractions of multiple joints present at birth. The involved muscles are partially or totally replaced by fat or fibrous tissue. Talipes equinovarus and scoliosis are also frequently reported. CASE PRESENTATION: This 2 year was born after uneventful pregnancy, with normal birth weight and length. The parents are unrelated, young and healthy. No malformations or mental retardation have been reported in the family. Since his birth a specific posture was noted: internal rotation at the shoulders, extension at the elbows, and flexion at the wrists. In addition, the child has a severe equinovarus deformity of the feet. Syndactily between II and III finger was also noted. His face is round with a frontal midline capillary hemangioma, while his jaw appears to be small. Mental development is normal. The karyotype is: 46, XY. CONCLUSIONS: About 150 syndromes have arthrogryphosis as a presenting sign. AMC is a distinct entity and distinction with the distal forms of arthrogryphosis can be difficult, since there is a considerable clinical and genetic heterogeneity. A comprehensive musculoskeletal evaluation and genetic consultation is necessary.

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.

Greenberg dysplasia (hydrops-ectopic calcification-moth-eaten skeletal dysplasia): prenatal ultrasound diagnosis and review of literature.

A second pregnancy of young, nonconsanguineous parents of Macedonian ethnic origin was examined by ultrasound. Polyhydramnios and hydrops fetalis were found as well as severe short limb, short stature, and cystic hygroma of the neck. An artificial abortion was performed at the age of 23 weeks. The radiological features included moth-eaten severely shortened long bones and ectopic calcifications of long bones, vertebral column, ribs, pelvis, larynx, trachea. In addition, the fetus had large head with depressed nasal bridge, severe platyspondyly, and short barrel-shaped trunk. Light microscopy demonstrated lack of chondrocyte columns and disorganization of the cartilaginous architecture. This is the seventh reported case of this rare form of lethal skeletal dysplasia.