Say-Barber-Biesecker-Young-Simpson syndrome and Genitopatellar syndrome: Lumping or splitting?

The Say-Barber-Biesecker-Young-Simpson variant of Ohdo syndrome (SBBYSS) and Genitopatellar syndrome (GTPTS) are 2 rare but clinically well-described diseases caused by de novo heterozygous sequence variants in the KAT6B gene. Both phenotypes are characterized by significant global developmental delay/intellectual disability, hypotonia, genital abnormalities, and patellar hypoplasia/agenesis. In addition, congenital heart defects, dental abnormalities, hearing loss, and thyroid anomalies are common to both phenotypes. This broad clinical overlap led some authors to propose the concept of KAT6B spectrum disorders. On the other hand, some clinical features could help to differentiate the 2 disorders. Furthermore, it is possible to establish a genotype-phenotype correlation when considering the position of the sequence variant along the gene, supporting the notion of the 2 disorders as really distinct entities.

Clinical and molecular characterization of Rubinstein-Taybi syndrome patients carrying distinct novel mutations of the EP300 gene.

Rubinstein-Taybi syndrome (RSTS) is a rare congenital neurodevelopmental disorder characterized by postnatal growth deficiency, skeletal abnormalities, dysmorphic features and cognitive deficit. Mutations in two genes, CREBBP and EP300, encoding two homologous transcriptional co-activators, have been identified in ˜55% and ˜3-5% of affected individuals, respectively. To date, only eight EP300-mutated RSTS patients have been described and 12 additional mutations are reported in the database LOVD. In this study, EP300 analysis was performed on 33 CREBBP-negative RSTS patients leading to the identification of six unreported germline EP300 alterations comprising one deletion and five point mutations. All six patients showed a convincing, albeit mild, RSTS phenotype with minor skeletal anomalies, slight cognitive impairment and few major malformations. Beyond the expansion of the RSTS-EP300-mutated cohort, this study indicates that EP300-related RSTS cases occur more frequently than previously thought (˜8% vs 3-5%); furthermore, the characterization of novel EP300 mutations in RSTS patients will enhance the clinical practice and genotype-phenotype correlations.

Interleukin (IL)-6 and receptor activator of nuclear factor (NF)-kappaB ligand (RANKL) are increased in the serum of a patient with primary pachydermoperiostosis.

Primary pachydermoperiostosis (PDP) is a rare syndrome, characterized by digital clubbing, periostosis, and pachydermia. We have evaluated biochemical bone turnover markers, including components of interleukin-6 (IL-6) and osteoprotegerin/receptor activator of nuclear factor (NF)-kappaB ligand (OPG/RANKL) systems, in an 18-year-old man affected by primary PDP. The acute phase of the disease was characterized in our patient by high serum levels of IL-6 and RANKL. The observed high serum levels of these parameters are associated with increased values in markers of bone resorption (degradation products of C-terminal telopeptides of type-I collagen and urinary hydroxyproline/creatinine ratio) and reduced serum levels of bone alkaline phosphatase, a marker of bone formation. Serum levels of osteotrophic hormones were in the normal range. Our data suggest that, despite the radiographic findings, the acute phase of primary PDP is characterized by increased bone resorption, probably mediated by IL-6 and RANKL.

Mutation analysis of the NSD1 gene in a group of 59 patients with congenital overgrowth.

Sotos syndrome is characterized by pre- and post-natal overgrowth, typical craniofacial features, advanced bone age, and developmental delay. Some degree of phenotypic overlap exists with other overgrowth syndromes, in particular with Weaver syndrome. Sotos syndrome is caused by haploinsufficiency of the NSD1 (nuclear receptor SET domain containing gene 1) gene. Microdeletions involving the gene are the major cause of the syndrome in Japanese patients, whereas intragenic mutations are more frequent in non-Japanese patients. NSD1 aberrations have also been described in some patients diagnosed as Weaver syndrome. Some authors have suggested a certain degree of genotype-phenotype correlation, with a milder degree of overgrowth, a more severe mental retardation, and a higher frequency of congenital anomalies in microdeleted patients. Data on larger series are needed to confirm this suggestion. We report here on microdeletion and mutation analysis of NSD1 in 59 patients with congenital overgrowth. Fourteen novel mutations, two previously described and one microdeletion were identified. All patients with a NSD1 mutation had been clinically classified as "classical Sotos," although their phenotype analysis demonstrated that some major criteria, such as overgrowth and macrocephaly, could be absent. All patients with confirmed mutations shared the typical Sotos facial gestalt. A high frequency of congenital heart defects was present in patients with intragenic mutations, supporting the relevance of the NSD1 gene in the pathogenesis of this particular defect.

Relevance of the chlorophyll phytyl chain on lamellar phase formation and organisation.

A series of modified chlorophylls (chlorophyll a, pyrochlorophyll a, Zn-pheophytin a and Zn-pheophorbide a) have been inserted into lamellar phases of sodium bis-(2-ethylhexyl)-sulfosuccinate (AOT). The role played by the different functional groups in affecting the bilayer formation and organisation has been investigated by means of the NMR quadrupolar splitting technique. Evidence is reported for the first time on the capacity of the phytyl chain of the chlorophylls to anchor the tetrapyrroles into the bilayer, favouring at the same time the regular formation of the lamellae.

Mosaic trisomy 17 in amniocytes: phenotypic outcome, tissue distribution, and uniparental disomy studies.

Mosaicism for trisomy 17 in amniocyte cultures is a rare finding, whilst postnatal cases are exceptional. In order to gain insight into the possible effects of the distribution of the trisomic line and of uniparental disomy (UPD) on embryofoetal development, we have performed follow-up clinical, cytogenetic and molecular investigations into three newly detected prenatal cases of trisomy 17 mosaicism identified in cultured amniotic fluid. In the first case, the pregnancy ended normally with the birth of a healthy girl, and analysis of newborn lymphocytes and of multiple extra-embryonic tissues was indicative of confined placental mosaicism. The second case was also associated with a normal pregnancy outcome and postnatal development, and only euploid cells were found in peripheral blood after birth. However, maternal isodisomy 17 consequent to a meiosis II error and loss of a chromosome 17 homologue was detected in peripheral lymphocytes postnatally. In the third case, pathological examination after termination of pregnancy showed growth retardation and minor dysmorphisms, and the trisomic line was detected in foetal skin fibroblasts. In addition, biparental derivation of chromosome 17 was demonstrated in the euploid lineage. These results, together with previously reported data, indicate that true amniotic trisomy 17 mosaicism is more commonly of extra-embryonic origin and associated with normal foetal development. Phenotypic consequences may arise when the trisomic line is present in foetal tissues. Case 2 also represents the first observation of maternal UPD involving chromosome 17; the absence of phenotypic anomalies in the child suggests that chromosome 17 is not likely to be subject to imprinting in maternal gametes.

Linkage of DFNB1 to non-syndromic neurosensory autosomal-recessive deafness in Mediterranean families.

Recent studies show a susceptibility locus (DFNB1) responsible for non-syndromic neurosensory autosomal-recessive deafness (NSRD) mapping to the pericentromeric region of chromosome 13q. In order to better understand the frequency with which DFNB1 is the gene for deafness in our patient population and the role of DFNB1 in Caucasians, we performed a genetic linkage study with four microsatellite markers linked to DFNB1 in a total of 48 independent Mediterranean families, of which 30 and 18 were of Italian and Spanish descent, respectively. A maximum two-point lod score of 7.28 was found with marker D13S115 at a recombination frequency of theta 0.1. Significant lod scores were also obtained for D13S143, D13S292 and D13S175. Genetic heterogeneity was confirmed using the HOMOG program which indicated absence of linkage to DFNB1 in approximately 21% of the sample. This study clearly demonstrates that DFNB1 plays an important role in 79% of Mediterranean families with NSRD. Furthermore, results from multipoint analysis predict that the DFNB1 gene maps between markers D13S175 and D13S115 which are separated by approximately 14.2 cM.

The Williams syndrome: an Italian collaborative study.

Williams syndrome (WS) is a multiple congenital anomalies/mental retardation syndrome caused by a microdeletion on the long arm of chromoome 7 including the elastin gene. Possibly it is a contiguous gene syndrome with autosomal dominant transmission. Seventy-seven WS patients from 11 Italian Pediatric-Dysmorphology-Genetics Units were collected by means of a questionnaire designed to draw a comprehensive clinical picture, to define the frequency of different traits and associations thereof, to better understand the clinical evolution, to improve the prognosis and to ameliorate the follow-up. The most important signs for diagnosis, based on their relative frequencies, are: mental retardation with characteristic outgoing behaviour and hoarse voice; facial findings like stellate iris, periorbital fullness and thick lips; congenital heart disease. The frequency of the clinical signs reported in our patients are on the whole concordant with those found in the literature; the only significant differences concern low stature, hallus valgus, hypoplastic nails, joint contractures and ear infections. The multisystemic nature of this syndrome requires a coordinated and integrated approach in order to avoid fragmentary interventions.

Novel findings in a patient with Weaver or a Weaver-like syndrome.

We report on a young male patient with an overgrowth syndrome, who had normal birth weight. He had a number of manifestations typical of the Weaver syndrome (WS), such as advanced bone age, peculiar craniofacial appearance, and camptodactyly. He also showed severe mental and speech retardation and demineralisation of the bones of the hands and feet. The latter can be considered as unreported manifestations of WS, or the patient could represent an example of a new WS-like syndrome.

Prenatal diagnosis of femur-fibula-ulna complex by ultrasonography in a male fetus at 24 weeks of gestation.

We present a case of ultrasonographic prenatal diagnosis at 24 weeks of femur-fibula-ulna (FFU) complex. To our knowledge, this is the first report of an early prenatal diagnosis of FFU.

Expression of the autosomal folate-sensitive fragile sites in ten kindreds with Martin-Bell syndrome.

The authors analyse the expression of all the folate-sensitive fra sites in a sample of 24 male patients with Martin-Bell syndrome (MBS) and their 12 mothers distributed in 10 kindreds. The cytogenetic results are compared with that of a control group, constituted by 8 unrelated normal subjects. Except for the fra Xq27, there was no autosomal folate-sensitive fra site significantly more expressed in patients with MBS than in the control group. On the basis of the present cytogenetic sample of about 6 500 R-banded mitoses, a list of all the in vitro folate-sensitive fra sites and their relative frequencies is given.