Aleksandra Jancevska

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.

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

BackgroundCraniopharyngioma 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.MethodsThirteen 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.ResultsInitial 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.ConclusionsThe 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.

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.

Novel β‐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 β‐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 patients cultured skin fibroblasts did not respond to treatment with a chaperone compound, N‐octyl‐4‐epi‐β‐valienamine.

McCune-Albright Syndrome (MAS): Early and Extensive Bone Fibrous Dysplasia Involvement and “Mistaken Identity” Oophorectomy

ABSTRACT 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?

ABSTRACT 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 girls mother was treated with beta-interferon (IFNβ-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 IFNβ-1a treatment during pregnancy has influenced the manifestation or the severity of the PAX2 mutant phenotype in this child.