Floriana Imperati

Steroid‐induced improvement of neurological signs in ataxia‐telangiectasia patients

A recent clinical observation reported on a dramatic improvement of neurological symptoms following short‐term betamethasone administration in a child affected with ataxia‐teleangiectasia (A‐T). The aim of this study was to extend this observation to additional A‐T patients followed at a single Immunodeficiency Center. Six consecutive patients (three males; mean age 16.3 years, range 5–30 years) were enrolled into this monocentric before–after trial. A cycle of oral betamethasone at the dosage of 0.1 mg/kg/day was administered for 10 days. The neurological evaluation was performed through the Scale for the Assessment and Rating of Ataxia. Overall, five of the six patients exhibited a clear amelioration of the neurological performances. Only in two patients, a slight amelioration persisted 7 days after the therapy withdrawal, whilst in the other patients the score reached approximately the pre‐treatment value at the end of the therapy. Twenty‐eight of the 46 evaluated neurological items (60%) improved during therapy. The speech disturbance, finger chase and nose–finger test showed the more significant improvement. The clinical amelioration was inversely correlated with the level of cerebellum atrophy, as revealed by the magnetic resonance. Our data indicate that neurological signs in A‐T are susceptible of beneficial pharmacological intervention even years after the disease onset.

Clinical description of a patient carrying the smallest reported deletion involving 10p14 region

Haploinsufficiency of a region located distal to 10p14 designated HDR1, is responsible for hypoparathyroidism, sensorineural deafness, and renal anomalies (HDR syndrome). Haploinsufficiency of a more proximal region, located on 10p13‐10p14, designated as DGCR2 is associated with congenital heart defects and thymus hypoplasia/aplasia or T cell defect. We describe a patient showing facial dysmorphisms, delayed psychomotor development and bilateral sensorineural hearing loss and carrying a 10p14 deletion, the smallest deletion found in the literature so far. Our patient, carrying a partial deletion of the DGCR2 region and of the HDR1 region, including the GATA3 gene, showed, unexpectedly, only few of the clinical features of DiGeorge 2 syndrome (psychomotor retardation, palpebral ptosis, epicanthic folds, anteverted nares, cryptorchidism, hand/foot abnormalities) and did not show other typical signs, such as cardiac defect, cleft palate, and abnormal T cell levels. Of the three characteristic features of the HDR syndrome, our patient had only sensorineural deafness. On the basis of the revision of the other cases reported in the literature with a deletion including the 10p14 region, we suggest that GATA3 haploinsufficiency, although not recorded for each patient, is responsible for deafness. The present case shows that even this small 10p deletion is responsible for a specific phenotype. We also underline the importance of CGH‐array, in order to obtain a more precise physical mapping of the 10p deletions and an accurate genotype–phenotype correlation.

Mental Retardation, Congenital Heart Malformation, and Myelodysplasia in a Patient With a Complex Chromosomal Rearrangement Involving the Critical Region 21q22

The region 21q22 is considered crucial for the pathogenesis of both Down syndrome (DS) and the partial monosomy 21q syndrome. Haploinsufficiency of the RUNX‐1 gene, mapping at 21q22 is responsible for a platelet disorder and causes predisposition to myelodysplastic syndrome (MDS). We describe a 3‐year‐old girl with mental retardation, congenital heart malformation, and subtle dysmorphic facial features. The patient developed thrombocytopenia when she was 2 years old. Bone marrow smear led to the diagnosis of myelodysplasia. Prenatal karyotyping had shown chromosome 21 pericentric inversion. Postnatally the array‐CGH revealed duplication at bands 21q11.2–21q21.1 and a simultaneous deletion involving the region 21q22.13–21q22.3. RUNX‐1 mRNA levels analyzed in patients skin fibroblasts were reduced. In this child the monosomy of the region 21q22 likely had the main role in determining the phenotype. Although the RUNX‐1 gene is localized outside the deleted region, we speculate that RUNX‐1 reduced expression, is probably due to the deletion of regulatory factors and caused the hematologic disorder in the patient. The present report underlines also the importance of array‐CGH in characterizing patients with a complex phenotype.

A further contribution to the delineation of the 17q21.31 microdeletion syndrome: Central nervous involvement in two Italian patients

The 17q21.31 microdeletion syndrome is a genetic disorder characterized by intellectual disability, facial dysmorphisms and a typical behavioral phenotype. Patients are usually described as friendly and cooperative but they can also show behavioral problems such as hyperactivity, bad humor, temper tantrums and poor interaction. Central nervous system involvement includes callosal dysgenesis/absence, enlargement of lateral ventricles and abnormalities of cyngulate gyrus. We report on two Italian patients with the 17q21.31 microdeletion syndrome better emphasizing neuroimaging and neuropsychological characteristics. In particular, we carried out an assessment of intellectual efficiency and behavior that turned out to be within the mild-moderate range of mental retardation, as already reported in the literature. To the best of our knowledge this is the first report of a patient with the 17q21.31 microdeletion and a Chiari malformation type 1 coexisting with a mild anomaly of medulla oblongata. This malformation should be considered in patients with the 17q21.31 microdeletion syndrome, presenting suggestive symptoms (headache, neck pain, cerebellar signs or muscle weakness).

Cerebellar vermis aplasia: patient report and exclusion of the candidate genes EN2 and ZIC1.

Cerebellar vermis aplasia (ACV, OMIM 117360) is a rare malformation of the cerebellum, with only few familial patients reported so far. Main clinical features of this rare disorder include floppiness and delayed milestones in early infancy, preceding mild cerebellar ataxia, non‐progressive clinical course, normal or slightly delayed intelligence, and occasional nystagmus. Neuroimaging reveals selective involvement of the cerebellum, which is prominent in the vermis. Because of the large preponderance of female patients, X‐linked dominant transmission was suggested by [Fenichel and Phillips (1989); Arch Neurol 46:582–583], and subsequent reports only concern female patients. Only one family with male‐to‐male transmission presenting with a generalized atrophy of the cerebellum rather than a more localized vermis aplasia has been reported so far. We report on a family in which father and son are affected by a mild form of ACV, thus confirming an autosomal mode of inheritance of the disease. Our patients showed a progressive improvement of their motor abilities, neurological examination of the father being actually normal except for a mild mental retardation. We also evaluated the potential role of two candidate genes, EN2 and ZIC1, responsible for abnormal cerebellar development in murine knock‐out models. However, molecular analysis failed to reveal any causative mutation in the coding sequence of the two genes in our patients. The understanding of the genetic basis of autosomal dominant ACV would allow a better classification of isolate cerebellar malformations and might permit to understand cell differentiation and migration in the developing central nervous system.

An emerging phenotype of proximal 11q deletions

Few reports of small interstitial chromosome 11q deletions are reported in the literature and no clear genotype-phenotype correlation has been demonstrated. We describe a five years old boy who was referred to our attention because of the presence of ptosis of the left eyelid, iris coloboma and developmental delay. Clinical examination also revealed the presence of dysmorphic features including: low frontal hairline, flat profile, round face, full cheeks, periorbital fullness, hypertelorism, broad nasal bridge, down-turned corners of the mouth. Cytogenetic analysis, performed by array-CGH (resolution 1 Mb), revealed a deletion of chromosome 11q13.5q14.2. The present case represents a further patient described in the literature with a small interstitial deletion of chromosome 11q. Our patient shares the dysmorphic features and the presence of developmental delay with the previously reported patients with overlapping proximal 11q deletion. Considering these clinical and cytogenetic similarities, we suggest the existence of an emerging syndrome associated to proximal 11q deletions.

Selective cognitive impairment and tall stature due to chromosome 19 supernumerary ring.

Small supernumerary marker chromosomes (sSMC) occur with a frequency of approximately 0.4 per 1000 newborns and are more frequent in the population with mental retardation and/or with dysmorphic signs. Small supernumerary chromosome rings (sSCR) usually occur as apart of a mosaic karyotype (Liehr et al., 2004). Chromosome 19 supernumerary rings are very rare. Almost all cases of sSMC19 have been reported on Thomas Liehrs website (http://www.med.uni-jena.de/fish/sSMC/19.htm#Start19). Of these cases, 14 were with phenotypic abnormalities and a clear characterization of the sSMC; two cases were suitable for comparison with our case with regard to their genetic content, but not with regard to the structure ofthe sSMC (Manvelyan et al., 2008). The phenotype, associated with partial trisomy 19q, includes facial dysmorphism, growth and mental retardation, macrocephaly, heart malformation and anomalies of the genitourinary and gastrointestinal tracts. The phenotype associated with partial trisomy 19p is characterized by dysmorphic features, severe mental retardation, abnormalities of brain morphology and anomalies of the fingers (Tercanli et al., 2000; Qorri et al., 2002; Novelli et al., 2005; Vraneković et al., 2008). Herein, we report the phenotype and molecular cytogenetic analysis in a patient with the smallest de-novo constitutional ring extended from the p12 to q12 region of chromosome 19.

Hormonal and neuropsychological evaluation of two 47,XYY patients with pituitary abnormalities.

Sex chromosome aneuploidies, 47,XXY and 47,XYY, are the most common chromosome abnormalities observed in the general male population. 47,XYY has an estimated incidence of 1 per 1,000 live-births [Abramsky et al., 2001]. The clinical features of patients with 47,XYY karyotype can be subtle and variable. Generally, the patients are physically normal in infancy [Buyse, 1990], with phenotypic characteristics becoming increasingly apparent over time. Patients are usually tall and thin and may have delayed speech, lower cognitive function (IQ), hyperactivity, learning disabilities, and other central nervous system (CNS) abnormalities (such as intentional tremor and hypotonia) [Buyse, 1990; Linden et al., 1996; Jones, 1997; Abramsky et al., 2001]. However, several patients with an XYY constitution and a normal phenotype have also been described [Hauschka et al., 1962; Hunter et al., 1968; Jacobs et al., 1968; Linden et al., 1996]. The gonadal function of 47,XYY males is usually normal [BeneZech and Noel, 1985; Linden et al., 1996]; however a great variability in plasma testosterone and gonadotropins levels has been reported [Ishida et al., 1979; Rivera et al., 1979; Schiavi et al., 1984; BeneZech and Noel, 1985]. Other features such as hypospadias, small and undescended testicles [Buyse, 1990], renal abnormalities, epilepsy and/or abnormal electroencephalograms [Forsmann, 1967] and brain abnormalities at the magnetic resonance imaging (MRI), in particular abnormalities of the ventricles [Warwick et al., 1999] corpus callosum and cerebellum [Brun and Gustavson, 1972; Hakola and Iivanainen, 1978], have also been described. We report on two boys with 47,XYY karyotype, with detailed neuropsychological and hypothalamic–pituitary evaluation. They exhibited abnormalities of the pituitary gland that had not been described before. Patient 1 was referred to our department for mental retardation at the age of 12.3 years. He was born at term after an uncomplicatedpregnancy by caesarean delivery from unrelated parents. His family and neonatal history were unremarkable. His language and motor skills were slightly delayed (first sounds at 12 months and walking at 18 months). By 3 years of age, he was mildly overweight. The father is a bluecollar worker and the mother is a housewife, both of them have a middle school education. At the time of our evaluation, Patient 1’s stature was 154.6 cm which was normal for his age (50th–75th centile) [Cacciari et al., 2002] and appropriate in relation to his target height [Tanner et al., 1966]. He weighed 59.7 kg and had a slightly elevated BMI of 25.9 (90th–97th centile) [Cacciari et al., 2002]. Physical examination revealed bilateral gynecomastia, and convergent strabismus of left eye, malocclusion, and long, thin fingers. In accordance with age, genitalia were prepubertal. Patient 2 was referred to our department at 16 years of age for mental retardation, tall stature, seizures, and obesity and pituitary microadenoma. He was born at term from unrelated parents after an uncomplicated pregnancy by caesarean delivery.

A novel SHANK3 interstitial microdeletion in a family with intellectual disability and brain MRI abnormalities resembling Unidentified Bright Objects

BACKGROUND SHANK3 mutations are responsible for Phelan-McDermid syndrome but they are also associated with autism and/or intellectual disability. CASE REPORT We report a family with four affected individuals including the 37 year-old mother, her 12 year-old male monozygotic twins and 8 year-old daughter harboring a novel SHANK3 interstitial microdeletion. All four members presented with intellectual disability of variable severity. The twins showed brain abnormalities similar to Unidentified Bright Objects (UBOs), typically detected in patients with Neurofibromatosis type 1 (NF1), but they did not display causative mutations in NF1 gene. CONCLUSION To date, this is the first report of an affected individual with SHANK3 interstitial deletion able to reproduce. Moreover, we found a previously unreported possible association between SHANK3 deletion and UBOs-like lesions in the brain.