Emanuela Scarano

Gonadoblastoma in Turner syndrome and Y-chromosome-derived material.

The identification of Y‐chromosome material is important in females with Ullrich–Turner syndrome (UTS) due to the risk of developing gonadoblastoma or other gonadal tumors. There is controversy regarding the frequency of the Y‐chromosome‐derived material and the occurrence of gonadoblastoma in these patients. The aim of our study was to evaluate a large number of patients with UTS, followed before and during the pubertal age for the prevalence of Y‐chromosome derived material, the occurrence of gonadoblastoma, and the incidence of possible neoplastic degeneration. An unselected series of 171 patients with UTS (1–34 years old), diagnosed cytogenetically, was studied for Y‐chromosome markers (SRY and Y‐centromeric DYZ3 repeats). The follow‐up was of 2–22 years; 101 of these patients were followed during pubertal age. Y‐chromosome material was found in 14 patients (8%): 12 of these were gonadectomized (2.8–25.9 years). A gonadoblastoma was detected in four patients under 16 years of age: in two, Y‐material was detected only at molecular analysis (at conventional cytogenetic analysis, one was included in the 45,X group and one in the X + mar group) and one had also an immature teratoma and an endodermal sinus carcinoma. The prevalence of gonadoblastoma in our series of gonadectomized UTS patients with Y‐positive material was of 33.3% (4/12). Our data suggest that the age of appearance and the possibility of malignant degeneration of gonadoblastoma can occur early in life. These patients, in particular those with 45,X or a marker chromosome may benefit from molecular screening to detect the presence of Y‐chromosome material; PCR is a rapid and inexpensive technique. At the moment, laparoscopy and preventive gonadectomy performed as soon as possible remain the procedures of choice for patients with UTS, when Y‐chromosome has been identified, as we are still unable to predict a future malignant evolution of gonadoblastoma.

Noonan-like syndrome with loose anagen hair: A new syndrome?

We present three children with short stature, the same facial phenotype, macrocephaly, enlarged cerebral spinal fluid spaces, short neck with redundant skin, severe GH deficiency, mild psychomotor delay with attention deficit/hyperactivity disorder (ADHD), mild dilatation of the pulmonary root in two of them, and a unique combination of ectodermal abnormalities. Their appearance, not completely typical of Noonan syndrome, the behavioral phenotype, GH deficiency, darkly pigmented and hairless skin, and the unusual aspect of the hair, defined as loose anagen hair syndrome did not fit any known condition. We postulate that these children may represent a distinct, previously unreported syndrome that we would name “Noonan‐like syndrome with loose anagen hair”.

Autophagic degradation of farnesylated prelamin A as a therapeutic approach to lamin-linked progeria

Farnesylated prelamin A is a processing intermediate produced in the lamin A maturation pathway. Accumulation of a truncated farnesylated prelamin A form, called progerin, is a hallmark of the severe premature ageing syndrome, Hutchinson-Gilford progeria. Progerin elicits toxic effects in cells, leading to chromatin damage and cellular senescence and ultimately causes skin and endothelial defects, bone resorption, lipodystrophy and accelerated ageing. Knowledge of the mechanism underlying prelamin A turnover is critical for the development of clinically effective protein inhibitors that can avoid accumulation to toxic levels without impairing lamin A/C expression, which is essential for normal biological functions. Little is known about specific molecules that may target farnesylated prelamin A to elicit protein degradation. Here, we report the discovery of rapamycin as a novel inhibitor of progerin, which dramatically and selectively decreases protein levels through a mechanism involving autophagic degradation. Rapamycin treatment of progeria cells lowers progerin, as well as wild-type prelamin A levels, and rescues the chromatin phenotype of cultured fibroblasts, including histone methylation status and BAF and LAP2α distribution patterns. Importantly, rapamycin treatment does not affect lamin C protein levels, but increases the relative expression of the prelamin A endoprotease ZMPSTE24. Thus, rapamycin, an antibiotic belonging to the class of macrolides, previously found to increase longevity in mouse models, can serve as a therapeutic tool, to eliminate progerin, avoid farnesylated prelamin A accumulation, and restore chromatin dynamics in progeroid laminopathies.

Pelvic ultrasonography in patients with Turner syndrome: Age-related findings in different karyotypes

Real-time ultrasonography was performed in 142 patients with Turner syndrome, aged 0.57 to 21 years, with different karyotypes (45,X [4896], X mosaicism [17%], and X structural abnormalities [35%]). Ovarian and uterine volumes were calculated and the data collected in a mixed longitudinal and cross-sectional mode. Thirty-eight patients were followed longitudinally during pubertal age (10 to 18 years bone age) for ovarian data. Patients with Turner syndrome were divided into two groups according to the presence or absence of detectable ovaries. Patients with Turner syndrome with detectable ovaries showed the first increase in ovarian volume at about 9 years of bone age; this increase was continuous and more evident only after 14 years of age and appeared later than in control subjects. When followed longitudinally during puberty, the ovaries showed a hormonal function in some cases. Girls with X mosaicism had the highest percentage of bilateral detectable ovaries and the greatest total ovarian volume; about 50% of them had spontaneous breast appearance and 38.5% had spontaneous menarche. They showed also the lowest gonadotropin levels, when bilateral ovaries were present during puberty. On the contrary, patients with the 45,X karyotype had the lowest percentage of detectable ovaries, ovarian volume, and spontaneous breast appearance. In our patients with Turner syndrome, uterine measures increased significantly with age and this was more evident in subjects with detectable ovaries after 13 years of bone age. Compared with control subjects, they showed significantly lower uterine measures, and patients with X mosaicism had greater and more progressive increments. In conclusion, pelvic ultrasonography in Turner syndrome is particularly useful in detecting ovaries and their possible increase in volume. These data, linked with karyotype pattern and gonadotropin levels, have prognostic value in predicting the future sexual development of these patients.

A de novo nonsense mutation of PAX6 gene in a patient with aniridia, ataxia, and mental retardation

Claudio Graziano, Angela V. D’Elia, Laura Mazzanti, Filomena Moscano, Simonetta Guidelli Guidi, Emanuela Scarano, Daniela Turchetti, Emilio Franzoni, Giovanni Romeo, Giuseppe Damante, and Marco Seri* U.O. di Genetica Medica, Dipartimento di Medicina Interna, Cardioangiologia ed Epatologia, Università degli Studi di Bologna, Bologna, Italy Dipartimento di Scienze e Tecnologie Biomediche, Università degli Studi di Udine, Udine, Italy Clinica Pediatrica, Dipartimento di Pediatria, Università degli Studi di Bologna, Bologna, Italy U.O. di Neuropsichiatria Infantile, Dipartimento di Pediatria, Università degli Studi di Bologna, Bologna, Italy Ottica Fisiopatologica, Policlinico S. Orsola-Malpighi, Bologna, Italy

Hearing loss in Turner syndrome: Results of a multicentric study

The purpose of this article was to evaluate otological diseases in 173 patients (pts) with Turner syndrome (TS). Study design: One hundred and seventy-three pts, mean chronological age (CA) 12±6.2 yr. Patients were submitted to different therapies: GH, estrogen therapy (EE), no therapy (no tx). Seventy-nine pts (CA 11 yr) had no otological diseases. Conductive hearing loss (CHL) occurred in 38.7% (CA 11 yr) and otoscopy was: persistent secretory otitis media in 55.2%, chronic otitis media in 10.4%, pars flaccida retraction pocket in 19.4%, mostly bilateral. Cholesteatoma was present in 15%. Sensorineurinal hearing loss (SNHL) occurred in 15.6% (CA 16 yr), 11 of whom were affected by high tone loss, and 15 by loss in midfrequencies (dip between 0.5-3 kHz), bilateral in 93%. Degree of hearing loss (HL) was mild [20–40 decibel hearing level (dBHL)] in 15%, moderate (45–60 dBHL) in 31%, severe (65–80 dBHL) in 8%, profound (dBHL>85) in 2%. We found a significant association between CHL and karyotype 45, X (p<0.025), congenital cranio-facial abnormalities, prevalently with low-set ears (p<0.04), narrow and/or high arched palate (p<0.018), and micrognathia (p<0.004). Our study confirms that the high prevalence of middle ear infections and CHL in TS are probably due to growth disturbances of the structures from the first and second branchial arches. We did not find any association between EE, GH, and HL. We recommend a regular audiological follow-up, especially during childhood, to prevent important middle ear anatomic sequele and to identify HL at an early stage, as the impact on social functioning may be significant.

From Whole Gene Deletion to Point Mutations of EP300‐Positive Rubinstein–Taybi Patients: New Insights into the Mutational Spectrum and Peculiar Clinical Hallmarks

Rubinstein–Taybi syndrome (RSTS) is a rare congenital neurodevelopmental disorder characterized by growth deficiency, skeletal abnormalities, dysmorphic features, and intellectual disability. Causative mutations in CREBBP and EP300 genes have been identified in ∼55% and ∼8% of affected individuals. To date, only 28 EP300 alterations in 29 RSTS clinically described patients have been reported. EP300 analysis of 22 CREBBP‐negative RSTS patients from our cohort led us to identify six novel mutations: a 376‐kb deletion depleting EP300 gene; an exons 17–19 deletion (c.(3141+1_3142‐1)_(3590+1_3591‐1)del/p.(Ile1047Serfs*30)); two stop mutations, (c.3829A>T/p.(Lys1277*) and c.4585C>T/p.(Arg1529*)); a splicing mutation (c.1878‐12A>G/p.(Ala627Glnfs*11)), and a duplication (c.4640dupA/p.(Asn1547Lysfs*3)). All EP300‐mutated individuals show a mild RSTS phenotype and peculiar findings including maternal gestosis, skin manifestation, especially nevi or keloids, back malformations, and a behavior predisposing to anxiety. Furthermore, the patient carrying the complete EP300 deletion does not show a markedly severe clinical picture, even if a more composite phenotype was noticed. By characterizing six novel EP300‐mutated patients, this study provides further insights into the EP300‐specific clinical presentation and expands the mutational repertoire including the first case of a whole gene deletion. These new data will enhance EP300‐mutated cases identification highlighting distinctive features and will improve the clinical practice allowing a better genotype–phenotype correlation.

Reduced spontaneous growth hormone secretion in patients with Turner's syndrome

Pirazzoli P, Mazzanti L, Bergamaschi R, Perri A, Scarano E, Nanni S, Zucchini S, Gualandi S, Cicognani A, Cacciari E. Reduced spontaneous growth hormone secretion in patients with Turners syndrome. Acta Pædiatr 1999; 88: 610‐3. Stockholm. ISSN 0803‐5253

Developmental syndromes: growth hormone deficiency and treatment.

Developmental syndromes are characterized by numerous phenotypical signs and malformations. In most of them such as Turner, Noonan, Prader-Willi, Silver-Russel, Williams, Kabuki, Leri-Weill syndrome and skeletal dysplasias, short stature is a common feature. Growth defect is very often related to a defect in cellular growth, but some unknown abnormality in GH action is possible. Recently, the greater availability of recombinant GH has expanded the interest towards GH secretion and therapy also in developmental syndromes. We recognize syndromes associated with GH deficiency (GHD), showing a developmental midline defect such as Pallister-Hall syndrome, septo-optic dysplasia, but many of these conditions do not have a convincing link with GHD. Moreover, some conditions, in particular the well-studied Turner syndrome, that do not have a real GHD, have proven to benefit from GH therapy at supra-physiological doses obtaining a higher final height than the expected one according to the natural history. This has expanded the indications for GH therapy. The aim of our paper is to review the literature on GH secretion, on the effects and costs-benefits of GH therapy in many dysmorphic syndromes, presenting some results of GH secretion and therapy obtained in our experience.

Correlations of phenotype and genotype in relation to morphologic remodelling of the aortic root in patients with Turner’s syndrome

BACKGROUND Patients with Turners syndrome are at risk of aortic dilation and dissection. Currently, it is not known whether such dilation is related to associated cardiovascular abnormalities, or to the genetic anomaly itself. METHODS We studied echocardiographically 107 patients with genetically proven Turners syndrome, with heterogeneous underlying karyotypes, and without associated cardiac lesions. Their average age was 19.6 plus or minus 8.4 years. We compared the finding with those from 71 age-matched healthy female volunteers. The diameter of the aorta was measured at the level of the basal attachments of the aortic valvar leaflets, the sinuses of Valsalva, the sinutubular junction, and its ascending component. RESULTS Compared to control subjects, the patients with Turners syndrome had larger diameters of the aorta at the level of the sinuses of Valsalva, at 23.4+/-4.8 versus 25.5+/-4.1 millimetres (p = 0.0014), the sinutubular junction, at 19.9+/-3.8 versus 23.3+/-4.1 millimetres (p < 0.0001), and the ascending aorta, at 22.3+/-4.9 versus 24.6+/-4.4 millimetres (p = 0.0011). Dilation of the sinutubular junction, found in just over one-quarter of the patients, was more common than dilation of the ascending aorta, the latter found in less than one-tenth. The patients with Turners syndrome, therefore, presented with remodelling of the aortic root, with relative dilation of the sinutubular junction. The underlying karyotype influenced both the dimensions of the sinutubular junction (p = 0.0054), and the ascending aorta (p = 0.0064), so that patients with the karyotype 45X had larger aortas. The karyotype was the strongest predictor by multivariate analysis for dilation at both these sites (p = 0.0138 and 0.0085, respectively). CONCLUSIONS Dilation at the sinutubular junction is frequent in patients with Turners syndrome, and is more common than dilation of the ascending aorta. The syndrome is associated with a remodelling of the aortic root, with prominent dilation of the sinutubular junction. There seems to be a relation between aortic dilation and the underlying genotype.