MED13L-related intellectual disability: involvement of missense variants and delineation of the phenotype.

Molecular anomalies in MED13L, leading to haploinsufficiency, have been reported in patients with moderate to severe intellectual disability (ID) and distinct facial features, with or without congenital heart defects. Phenotype of the patients was referred to "MED13L haploinsufficiency syndrome." Missense variants in MED13L were already previously described to cause the MED13L-related syndrome, but only in a limited number of patients. Here we report 36 patients with MED13L molecular anomaly, recruited through an international collaboration between centers of expertise for developmental anomalies. All patients presented with intellectual disability and severe language impairment. Hypotonia, ataxia, and recognizable facial gestalt were frequent findings, but not congenital heart defects. We identified seven de novo missense variations, in addition to protein-truncating variants and intragenic deletions. Missense variants clustered in two mutation hot-spots, i.e., exons 15-17 and 25-31. We found that patients carrying missense mutations had more frequently epilepsy and showed a more severe phenotype. This study ascertains missense variations in MED13L as a cause for MED13L-related intellectual disability and improves the clinical delineation of the condition.

Amniotic band syndrome: a case report.

Amniotic band syndrome is an uncommon congenital pathological condition that may lead to malformations and foetal-infant death. We report an autoptic case. The patient was a male preterm infant. At 14 weeks of gestation, a routine ultrasonography showed severe craniofacial anomalies and a close contiguity of the foetal head with the amnios. The neonate survived three days, after which an autopsy was carried out. The infant had a frontoparietal meningoencephalocele; a fibrous band was attached to the skin, close to the meningoencephalocele base. Cleft lip and palate, nose deformation and agenesis of the right eye were also present. At the opening of the cranial cavity, occipital hyperostosis was observed. The herniated brain showed anatomical abnormalities that made identification of normal structures difficult. Microscopically, the nervous parenchyma had architectural disorganization and immaturity, and the fibrous band consisted of amniotic membranes. As evident from this case report, amniotic band syndrome may cause severe malformations and foetal-infant death.

SUMO-modified nuclear cyclin D1 bypasses Ras-induced senescence.

Oncogene-induced senescence represents a key tumor suppressive mechanism. Here, we show that Ras oncogene-induced senescence can be mediated by the recently identified haploinsufficient tumor suppressor apoptosis-stimulating protein of p53 (ASPP) 2 through a novel and p53/p19(Arf)/p21(waf1/cip1)-independent pathway. ASPP2 suppresses Ras-induced small ubiquitin-like modifier (SUMO)-modified nuclear cyclin D1 and inhibits retinoblastoma protein (Rb) phosphorylation. The lysine residue, K33, of cyclin D1 is a key site for this newly identified regulation. In agreement with the fact that its nuclear localization is required for its oncogenic activity, we show that nuclear cyclin D1 is far more potent than wild-type (WT) cyclin D1 in bypassing Ras-induced senescence. Thus, this study identifies SUMO modification as a positive regulator of nuclear cyclin D1, and reveals a new way by which cell cycle entry and senescence are regulated.

Growth hormone neurosecretory dysfunction in a boy with hypohidrotic/anhidrotic ectodermal dysplasia: definition of short stature, molecular characterization and long-term hGH replacement treatment to final height.

Anhidrotic/hypohidrotic ectodermal dysplasia is a rare disorder, genetically heterogeneous, commonly X-linked recessive inherited, characterized by hypoplasia up to the absence of the eccrine glands with hypo-anhidrosis and secondary hyperpyrexia, hypodontia and some typical craniofacial features. Some papers have described how these patients may show poor growth, while other recent research shows normal growth. We report a boy with anhidrotic/hypohidrotic ectodermal dysplasia and growth hormone neurosecretory dysfunction, an association not previously reported, and we discuss the possible causes as well as the patient's response to growth hormone treatment until he reached final height.

Congenital hypothyroidism in Young-Simpson syndrome.

We describe a patient with the clinical spectrum of Young-Simpson syndrome. This rare genetic disorder is characterized by congenital hypothyroidism, mental retardation and blepharophimosis. Young-Simpson syndrome is, at present, poorly known to endocrinologists and pediatricians, and should be included in the differential diagnosis of congenital hypothyroidism. It is important to underline that the association of congenital hypothyroidism, blepharophimosis and ptosis allows an exact clinical diagnosis, since the majority of other clinical aspects are common to other disorders.

Contiguous gene deletions involving EFNB1, OPHN1, PJA1 and EDA in patients with craniofrontonasal syndrome.

Craniofrontonasal syndrome (CFNS [MIM 304110]) is an X-linked malformation syndrome characterized by craniofrontonasal dysplasia and extracranial manifestations in heterozygous females. In the majority of patients CFNS is caused by mutations in the EFNB1 gene (MIM 300035). We identified three girls with classical CFNS and mild developmental delay harboring de novo deletions of the EFNB1 gene. Applying haplotype analysis, Southern blot hybridization and array-comparative genomic hybridization, deletion of EFNB1 was found to be part of contiguous gene deletions in the patients. In one patient the deletion interval includes the genes for oligophrenin-1 (OPHN1 [MIM 300127]) and praja 1 (PJA1 [MIM 300420]). In the second patient the deletion includes OPHN1, PJA1 and the gene for ectodysplasin A (EDA [MIM 300451]). In the third patient EFNB1 gene deletion may include deletion of regulatory regions 5' of OPHN1. Previously, the OPHN1 gene has been shown to be responsible for recessive X-linked mental retardation. Although it is too early to predict the future cognitive performance of the two infant patients with contiguous gene deletions of OPHN1-EFNB1-PJA1, mild learning disabilities have been recognized in the older, third patient. It is important for genetic counseling to be aware that their male offspring may not only be carriers of CFNS but may also be affected by mental retardation and anhidrotic ectodermal dysplasia.

S100A2 gene is a direct transcriptional target of p53 homologues during keratinocyte differentiation.

The p53 paralogues p73, p63 and their respective truncated isoforms have been shown to be critical regulators of developmental and differentiation processes. Indeed, both p73- and p63-deficient mice exhibit severe developmental defects. Here, we show that S100A2 gene, whose transcript and protein are induced during keratinocyte differentiation of HaCaT cells, is a direct transcriptional target of p73beta and DeltaNp63alpha and is required for proper keratinocyte differentiation. Transactivation assays reveal that p73beta and DeltaNp63alpha exert opposite transcriptional effects on S100A2 gene. While DeltaNp63alpha is found in vivo onto S100A2 regulatory regions predominantly in proliferating cells, p73beta is recruited in differentiating cells. Silencing of p73 impairs the induction of S100A2 during the differentiation of HaCaT cells. Moreover, silencing of p73 or S100A2 impairs the proper expression of keratinocyte differentiation markers. Of note, p53 family members do not trigger S100A2 gene expression in response to apoptotic doses of cisplatin and doxorubicin.

Mutant p53 gain of function: reduction of tumor malignancy of human cancer cell lines through abrogation of mutant p53 expression.

Mutations in the TP53 tumor suppressor gene are the most frequent genetic alteration in human cancers. These alterations are mostly missense point mutations that cluster in the DNA binding domain. There is growing evidence that many of these mutations generate mutant p53 proteins that have acquired new biochemical and biological properties. Through this gain of function activity, mutant p53 is believed to contribute to tumor malignancy. The purpose of our study was to explore mutant p53 as a target for novel anticancer treatments. To this aim, we inhibited mutant p53 expression by RNA interference in three different cancer cell lines endogenously expressing mutant p53 proteins, and evaluated the effects on the biological activities through which mutant p53 exerts gain of function. We found that depletion of mutant p53 reduces cell proliferation, in vitro and in vivo tumorigenicity, and resistance to anticancer drugs. Our results demonstrate that mutant p53 knocking down weakens the aggressiveness of human cancer cells, and provides further insight into the comprehension of mutant p53 gain of function activity in human tumor.

Meiotic origin of two ring chromosomes 18 in a girl with developmental delay.

We report on the cytogenetic, fluorescence in situ hybridization (FISH), and molecular results obtained for a patient with a mild and nonspecific pattern of minor anomalies and developmental delay. In the proband's karyotype one chromosome 18 was replaced by a ring chromosome 18 in all metaphases, with deletion of the terminal regions. Furthermore, 56% of the metaphases contained a supernumerary small ring chromosome. Microdissection followed by FISH analysis demonstrated that the small ring chromosome consisted of material from the pericentromeric region of chromosome 18. The karyotype was defined as 46,XX,r(18)(p11.3q23)[88]/47,XX,r(18)(p11.3q23)+r(18)(p11.22q12.2)[112]. Thus, the patient has a deletion at 18pter and at 18qter, and a mosaic partial trisomy of the pericentromeric region of chromosome 18. We undertook molecular analysis using DNA samples of the patient and her parents in order to clarify the origin and possible mode of formation of the chromosome abnormalities. Our results show a paternal origin of the structurally normal chromosome 18 and a maternal origin for both ring chromosomes 18. Interestingly, the smaller ring chromosome did not arise postzygotically from the larger ring, since the two ring chromosomes contain genetic material derived from the two different maternal chromosomes 18. The abnormalities appear to have arisen during a meiotic division, and it could be speculated that both ring chromosomes 18 arose simultaneously due to complex pairing and recombination events. After fertilization, the small ring chromosome was lost in a subset of cells, thus leading to mosaicism.

Spectrum and distribution of MECP2 mutations in 64 Italian Rett syndrome girls: tentative genotype/phenotype correlation.

We report a direct DNA sequencing analysis of the MECP2 gene undertaken on a further 64 Italian patients with Rett syndrome by using a LICOR 4200 Automated Sequencer. All of the girls entering the study had a consistent clinical diagnosis for this disorder. All coding regions and the flanking intronic splice site sequences were amplified as three non-overlapping fragments by using both forward and reverse primers. The results were then compared to the MECP2 reference sequences published in GenBank. Mutations of the MECP2 gene were identified in 64 of 75 (85.33%) unrelated sporadic Rett syndrome girls. Genotype/phenotype correlation studies, in particular in groups of patients with the same mutation, did not offer definitive and interesting data.

Premature ovarian failure (POF) and fragile X premutation females: from POF to to fragile X carrier identification, from fragile X carrier diagnosis to POF association data.

Early menopause in the fragile X carriers has been well documented in several reports. All surveys demonstrated that 13-25% of fragile X carriers experienced premature ovarian failure (POF), defined as menopause before the age of 40 years. In 1995 we started screening two groups of subjects as a part of a Fragile X Research Program: 1) women previously diagnosed as fragile X carriers from the register of our center and 2) women with POF and without a family history of fragile X or other forms of mental retardation. In this study we report the preliminary data collected from 75 fragile X families; in 30 of them, POF was present in one or several subjects, all of whom had a fragile X premutation. None of the women with a full mutation experienced POF in our series of patients. We also identified 89 families without a family history of fragile X or mental retardation, and there were 108 subjects who experienced POF, of which 6.5% had a fragile X premutation. This is 70-fold higher than the background prevalence of fragile X premutation in the Italian population and suggests an association with POF. These data confirm the results of other surveys.

Synpolydactyly phenotypes correlate with size of expansions in HOXD13 polyalanine tract.

Synpolydactyly (SPD) is a dominantly inherited congenital limb malformation. Typical cases have 3/4 finger and 4/5 toe syndactyly, with a duplicated digit in the syndactylous web, but incomplete penetrance and variable expressivity are common. The condition has recently been shown to be caused by expansions of an imperfect trinucleotide repeat sequence encoding a 15-residue polyalanine tract in HOXD13. We have studied 16 new and 4 previously published SPD families, with between 7 and 14 extra residues in the tract, to analyze the molecular basis for the observed variation in phenotype. Although there is no evidence of change in expansion size within families, even over six generations, there is a highly significant increase in the penetrance and severity of phenotype with increasing expansion size, affecting both hands (P = 0.012) and feet (P < 0. 00005). Affected individuals from a family with a 14-alanine expansion, the largest so far reported, all have a strikingly similar and unusually severe limb phenotype, involving the first digits and distal carpals. Affected males from this family also have hypospadias, not previously described in SPD, but consistent with HOXD13 expression in the developing genital tubercle. The remarkable correlation between phenotype and expansion size suggests that expansion of the tract leads to a specific gain of function in the mutant HOXD13 protein, and has interesting implications for the role of polyalanine tracts in the control of transcription.

[Idiopathic congenital hemihypertrophy: a report on 6 cases]. / Emipertrofia congenita idiopatica: descrizione di sei casi.

Idiopathic hemihypertrophy is a specific entity not distinguishable from the numerous other causes of limb overgrowth. In our investigation of six new cases in Valdarno no genetic or other aetiological factors could be recognized. Management of these cases is confined to orthopaedic support. Three cases with ipsilateral benign nephromegaly are presented. Idiopathic hemihypertrophy is often associated with mild mental retardation, genito-urinary anomalies and an oncogenic potential. Regular clinical surveillance for abdominal tumours is recommended.

[Synpolydactyly: unusual features and variable expression in 5 generations of an Italian family]. / Sinpolidattilia: caratteri peculiari ed espressività variabile in cinque generazioni di una famiglia italiana.

The Authors report a family with synpolydactyly (or syndactyly type II) present in eleven out of thirty four members in five generations. Affected members do not show any other anomalies so that chromosomal or other genetic syndromes may be excluded. The possible mode of inheritance, the variability in expression, the penetrance in five generations are discussed. The peculiar bone deformities of hands and feet already reported by Cross et Al. are confirmed. The Authors presume that the present report is the first observation of synpolydactyly in an Italian family.

The anterior segment anomalies in the Warburg syndrome. A study of new cases.

The Warburg syndrome is a primary lethal neurodysplasia recently defined with autosomal recessive inheritance. The clinical diagnosis is based on the association of brain alterations with ocular defects, among which the anterior segment anomalies and the retinal dysplasia appear to be the most significant. The authors report a clinical and histopathological study on personal observations.

[Velo-cardio-facial syndrome (Shprintzen syndrome)]. / Sindrome velo-cardio-faciale (Sindrome di Shprintzen).

A patient with the velo-cardio-facial syndrome is described. The most frequent features include cleft palate, cardiac anomalies, typical facies, and learning disabilities. Less frequent findings include microcephaly, mental retardation, small stature, slender hands and digits, minor auricolar anomalies, and inguinal hernia. There were four instances of familial transmission in the 39 patients of the literature.

[Blepharophimosis, ptosis and epicanthus inversus]. / Blefarofimosi, ptosi ed epicanto inverso.

Blepharophimosis, ptosis and epicanthus inversus is a rare well-documented autosomal dominant disorder. Described here is a family with typical features of this syndrome in eleven cases in five generations. Syndrome is discussed and blepharophimosis underlined. Blepharophimosis is also a minor defect in the contest of complex malformation syndromes having different aetiology (mendelian inheritance, chromosomal abnormality, toxic agents). The Authors believe that blepharophimosis, for its clinical evidence, is an important guide sign.