The Spectrum of Niemann-Pick Type C Disease in Greece.

Niemann-Pick type C disease (NPC) is a neurovisceral lysosomal storage disease caused by mutations in either the NPC1 or the NPC2 gene. It is a cellular lipid trafficking disorder characterized by the accumulation of unesterified cholesterol and various sphingolipids in the lysosomes and late endosomes, and it exhibits a broad clinical spectrum. Today, over 420 disease-causing mutations have been identified in the NPC1 and the NPC2 genes. We present the clinical, biochemical, and molecular findings in 14 cases diagnosed in Greece during the last 28 years. Age at diagnosis ranged from 2.5 months to 48 years. Systemic manifestations were present in 7/14 patients. All developed neurological manifestations (age of onset 5 months to 42 years). Six patients are still alive (age: 5-50 years). Classical filipin staining pattern was observed in all but four patients (3 NPC1, 1 NPC2). The rate of LDL-induced cholesteryl ester formation was severely reduced in 4/7 and significantly reduced in 3/7 patients studied. Increased chitotriosidase activity was observed in 9/12 patients. Mutation analysis in 11 unrelated patients identified 12 different mutations in the NPC1 gene: eight previously described p.E1089K (c.3265G>A), p.F284Lfs*26 (c.852delT), p.A1132P(c.3394G>C), del promoter region and exons 1-10, p.R1186H (c.3557G>A), p.P1007A (c.3019C>G), p.Q92R(c.275A>G),p.S940L (c.2819C>T), and four novel ones: (p.N701K fs*13 (c.2102-2103insA), p.K1057R (c.3170A>G), IVS23+3insT(c.3591+3insT), p.C1119*(c.3357T>C); and the previously described IVS2+5G>A(c.190+5G>A) mutation in the NPC2 gene. All patients were of Greek origin. Assuming a birth rate of 100,000/year, a rough incidence estimate for NPC disease in Greece would be 0.5/100,000 births.

Central precocious puberty in a boy with 22q13 deletion syndrome and NOTCH-1 gene duplication.

The 22q13 deletion syndrome or Phelan-McDermid syndrome is a neurodevelopmental disorder associated with developmental delay, hypotonia, delayed or absent speech, autistic-like behavior, normal to accelerated growth and dysmorphic faces. We report the occurrence of central precocious puberty in a boy diagnosed with Phelan-McDermid syndrome. At the age of 1 year, our patient presented with increased testicular volume for his age, bone age advancement and growth acceleration. Stimulated gonadotropin levels demonstrated a premature activation of the hypothalamic-pituitary-gonadal (HPG) axis. Central precocious puberty was treated with gonadotropin-releasing hormone (GnRH) analog. Molecular diagnosis with array-comparative genomic hybridization (CGH) revealed a major deletion of 5.8 Mb at the 22q13 chromosomal region and a 25 kb duplication at the 9q34.3 region that included the NOTCH-1 gene. On the background of 22q13 deletion syndrome and data from animals on the effect of abnormal NOTCH-1 gene expression on kisspeptin neuron formation, we discuss the probable role of Notch signaling in the premature activation of the HPG axis.

Efficacy of pulse methylprednisolone in a pediatric case of postinfectious bronchiolitis obliterans.

Postinfectious bronchiolitis obliterans is a chronic incapacitating disease with persistent airway inflammation. However, the efficacy of systemic corticosteroids has never been studied systematically. In the presented case, serial spirometry, plethysmography measurements, and nocturnal oximetry demonstrated progressive decline in lung hyperinflation and air-trapping and improvement in expiratory function and nocturnal oxygenation during and after six three-day courses of high-dose methylprednisolone (30 mg/kg/day). At four months post treatment, most gain in lung function was lost suggesting the need for sustained immunosuppression. Randomized, controlled trials using serial plethysmography measurements, spirometry, and nocturnal oximetry could provide evidence for the management of postinfectious bronchiolitis obliterans.

Retrospective analysis of the relationship between infantile seborrheic dermatitis and atopic dermatitis.

A growing number of dermatologists dispute the existence of infantile seborrheic dermatitis (ISD) as an independent clinical entity. Therefore the aim of the present study was to estimate the epidemiologic features of ISD in a defined population of Greek children, assess its course, and identify associations, if any, with other common dermatoses of childhood. Children from the region of Athens who were examined and diagnosed with typical clinical features of ISD between 1997 and 2011 were included in the study. The relevant data were collected retrospectively from their medical records using a standardized form. Eighty-seven children were enrolled (50 boys, 37 girls; mean age 3.1 mos at the time of ISD diagnosis). The main body areas affected were the scalp and face for the majority of the children (78/87), whereas the trunk and limbs were less frequently involved (9/87). In all cases, erythema and scaling of affected patients were mild to moderate. Forty-nine of the 87 children were followed up over a period of 5 years. Thirty children in this group developed features of atopic dermatitis (AD) at a later stage, according to the UK diagnostic criteria of AD, and 23 of these children were diagnosed with AD, at an average time interval of 6.4 months from ISD onset, and seven presented with clinical features of AD at the time of ISD diagnosis. The remaining 19 children in the follow-up group progressed without developing any other chronic skin disease, and all recovered within 6 months of its onset. Thirty-eight had no further follow-up after their initial ISD diagnosis. In spite of the lack of information on the disease course for the last group, assuming they all recovered, the prevalence of AD (34.4%) in our ISD sample was significantly higher than the prevalence of AD (10.7%) in the general population for the same age group, as shown in a previous study performed in the municipality of Athens (p < 0.001). A significant number of children were found to develop AD shortly after their ISD diagnosis. This finding demonstrates a strong association in the clinical course between the two diseases or indicates that the two diseases may be in the same clinical spectrum. Further epidemiologic studies must be conducted to assess the significance of this finding.

Propranolol treatment for severe infantile hemangiomas: a single-centre 3-year experience.

AIM: To evaluate the effectiveness, safety and tolerability of propranolol as single-agent treatment in patients with problematic, proliferative-phase, infantile hemangiomas (IHs). METHODS: Oral propranolol was administered at a dose of 2 mg/kg/day to 28 children. Cardiologic evaluation was performed before treatment initiation. Hemodynamic variables and blood glucose levels were monitored during the first 24 h of treatment, while the children were hospitalized. Clinical response and tolerance were assessed every month, along with photographic documentation. Macroscopic regression was considered the reduction >90% in the size of the IHs. RESULTS: Effects on colour and growth were observed within the first month in all cases. Twenty-four patients completed treatment after a mean duration of 7.56 months, and their hemangiomas were successfully regressed. Propranolol was administered again, with satisfactory results, in three patients (12.5%) because of hemangioma regrowth. Satisfactory response is noticeable in ongoing cases. Episodes of hypotension were noted in four patients. There were no treatment interruptions because of side effects. CONCLUSIONS: Propranolol, as first-line treatment, yielded excellent results with very good clinical tolerance and also seems to be effective in relapses. The optimal duration of the treatment remains to be defined by long-term observation.

Paroxysmal non-kinesigenic dyskinesia due to a PNKD recurrent mutation: report of two Southern European families.

Paroxysmal non-kinesigenic dyskinesia (PNKD) is an autosomal dominant disorder characterized by attacks of dystonic or choreathetotic movements precipitated by stress, fatigue, coffee, alcohol or menstruation. In this report we present two families with PNKD of Southern European origin carrying a PNKD recurrent mutation. Incomplete penetrance and intrafamilial variability was detected in both families. Treatment with valproic acid and levetiracetam provided favorable response.

Alternating hemiplegia of childhood or familial hemiplegic migraine? A novel ATP1A2 mutation.

Alternating hemiplegia of childhood (AHC) is typically distinguished from familial hemiplegic migraine (FHM) by infantile onset of the characteristic symptoms and high prevalence of associated neurological deficits that become increasingly obvious with age. Expansion of the clinical spectrum in FHM recently has begun to blur the distinction between these disorders. We report a novel ATP1A2 mutation in a kindred with features that bridge the phenotypic spectrum between AHC and FHM syndromes, supporting a possible common pathogenesis in a subset of such cases. Mutation analysis in classic sporadic AHC patients and in an additional five kindreds in which linkage to the ATP1A2 locus could not be excluded failed to identify additional mutations.

Alternating hemiplegia of childhood: a syndrome inherited with an autosomal dominant trait.

Alternating hemiplegia of childhood is a rare disorder characterized by recurrent attacks of hemiplegia affecting either side of the body, oculomotor and autonomic disturbances, movement disorders, and progressive cognitive impairment. We report on one family with autosomal dominant alternating hemiplegia. The disorder was first recognized in a 9-year-old child, the third son of the family, who presented with learning disability, tonic-clonic seizures, dystonic attacks, and episodes of alternating hemiplegia starting at the age of 2 1/2 years. His mother and three brothers had similar symptoms. The maternal uncle, who has learning disability, had experienced multiple dystonic attacks. Tests performed on the family, including computerized tomography, magnetic resonance imaging, and magnetic resonance angiography of the brain as well as metabolic evaluation, were normal. Cytogenetic analysis was normal and mitochondrial DNA analysis revealed no deletions or mutations in the four affected family members and the grandmother. An autosomal dominant mode of inheritance is suggested by the fact that both sexes are affected in two generations.