Maria Piccione

PORCN mutations in focal dermal hypoplasia: coping with lethality.

The X‐linked dominant trait focal dermal hypoplasia (FDH, Goltz syndrome) is a developmental defect with focal distribution of affected tissues due to a block of Wnt signal transmission from cells carrying a detrimental PORCN mutation on an active X‐chromosome. Molecular characterization of 24 unrelated patients from different ethnic backgrounds revealed 23 different mutations of the PORCN gene in Xp11.23. Three were microdeletions eliminating PORCN and encompassing neighboring genes such as EBP, the gene associated with Conradi‐Hünermann‐Happle syndrome (CDPX2). 12/24 patients carried nonsense mutations resulting in loss of function. In one case a canonical splice acceptor site was mutated, and 8 missense mutations exchanged highly conserved amino acids. FDH patients overcome the consequences of potentially lethal X‐chromosomal mutations by extreme skewing of X‐chromosome inactivation in females, enabling transmission of the trait in families, or by postzygotic mosaicism both in male and female individuals. Molecular characterization of the PORCN mutations in cases diagnosed as Goltz syndrome is particularly relevant for genetic counseling of patients and their families since no functional diagnostic test is available and carriers of the mutation might otherwise be overlooked due to considerable phenotypic variability associated with the mosaic status.

Clinical Significance of Rare Copy Number Variations in Epilepsy A Case-Control Survey Using Microarray-Based Comparative Genomic Hybridization

OBJECTIVE To perform an extensive search for genomic rearrangements by microarray-based comparative genomic hybridization in patients with epilepsy. DESIGN Prospective cohort study. SETTING Epilepsy centers in Italy. PATIENTS Two hundred seventy-nine patients with unexplained epilepsy, 265 individuals with nonsyndromic mental retardation but no epilepsy, and 246 healthy control subjects were screened by microarray-based comparative genomic hybridization. MAIN OUTCOME MEASURES Identification of copy number variations (CNVs) and gene enrichment. RESULTS Rare CNVs occurred in 26 patients (9.3%) and 16 healthy control subjects (6.5%) (P = .26). The CNVs identified in patients were larger (P = .03) and showed higher gene content (P = .02) than those in control subjects. The CNVs larger than 1 megabase (P = .002) and including more than 10 genes (P = .005) occurred more frequently in patients than in control subjects. Nine patients (34.6%) among those harboring rare CNVs showed rearrangements associated with emerging microdeletion or microduplication syndromes. Mental retardation and neuropsychiatric features were associated with rare CNVs (P = .004), whereas epilepsy type was not. The CNV rate in patients with epilepsy and mental retardation or neuropsychiatric features is not different from that observed in patients with mental retardation only. Moreover, significant enrichment of genes involved in ion transport was observed within CNVs identified in patients with epilepsy. CONCLUSIONS Patients with epilepsy show a significantly increased burden of large, rare, gene-rich CNVs, particularly when associated with mental retardation and neuropsychiatric features. The limited overlap between CNVs observed in the epilepsy group and those observed in the group with mental retardation only as well as the involvement of specific (ion channel) genes indicate a specific association between the identified CNVs and epilepsy. Screening for CNVs should be performed for diagnostic purposes preferentially in patients with epilepsy and mental retardation or neuropsychiatric features.

Phenotypic analysis of individuals with Costello syndrome due to HRAS p.G13C

Costello syndrome is characterized by severe failure‐to‐thrive, short stature, cardiac abnormalities (heart defects, tachyarrhythmia, and hypertrophic cardiomyopathy (HCM)), distinctive facial features, a predisposition to papillomata and malignant tumors, postnatal cerebellar overgrowth resulting in Chiari 1 malformation, and cognitive disabilities. De novo germline mutations in the proto‐oncogene HRAS cause Costello syndrome. Most mutations affect the glycine residues in position 12 or 13, and more than 80% of patients share p.G12S. To test the hypothesis that subtle genotype–phenotype differences exist, we report the first cohort comparison between 12 Costello syndrome individuals with p.G13C and individuals with p.G12S. The individuals with p.G13C had many typical findings including polyhydramnios, failure‐to‐thrive, HCM, macrocephaly with posterior fossa crowding, and developmental delay. Subjectively, their facial features were less coarse. Statistically significant differences included the absence of multifocal atrial tachycardia (P‐value = 0.033), ulnar deviation of the wrist (P < 0.001) and papillomata (P = 0.003), and fewer neurosurgical procedures (P = 0.024). Fewer individuals with p.G13C had short stature (height below −2 SD) without use of growth hormone (P < 0.001). The noteworthy absence of malignant tumors did not reach statistical significance. Novel ectodermal findings were noted in individuals with p.G13C, including loose anagen hair resulting in easily pluckable hair with a matted appearance, different from the tight curls typical for most Costello syndrome individuals. Unusually long eye lashes requiring trimming are a novel finding we termed dolichocilia. These distinctive ectodermal findings suggest a cell type specific effect of this particular mutation. Additional patients are needed to validate these findings.

2p15-p16.1 microdeletions encompassing and proximal to BCL11A are associated with elevated HbF in addition to neurologic impairment

Elevated fetal hemoglobin (HbF) ameliorates the clinical severity of hemoglobinopathies such as β-thalassemia and sickle cell anemia. Currently, the only curative approach for individuals under chronic transfusion/chelation support therapy is allogeneic stem cell transplantation. However, recent analyses of heritable variations in HbF levels have provided a new therapeutic target for HbF reactivation: the transcriptional repressor BCL11A. Erythroid-specific BCL11A abrogation is now actively being sought as a therapeutic avenue, but the specific impact of such disruption in humans remains to be determined. Although single nucleotide polymorphisms in BCL11A erythroid regulatory elements have been reported, coding mutations are scarcer. It is thus of great interest that patients have recently been described with microdeletions encompassing BCL11A. These patients display neurodevelopmental abnormalities, but whether they show increased HbF has not been reported. We have examined the hematological phenotype, HbF levels, and erythroid BCL11A expression in 3 such patients. Haploinsufficiency of BCL11A induces only partial developmental γ-globin silencing. Of greater interest is that a patient with a downstream deletion exhibits reduced BCL11A expression and increased HbF. Novel erythroid-specific regulatory elements in this region may be required for normal erythroid BCL11A expression, whereas loss of separate elements in the developing brain may explain the neurological phenotype.

Abnormalities of the umbilico-portal venous system in Down syndrome: A report of two new patients

Congenital anomalies of the umbilical and portal venous system are rare vascular malformations which are often associated with anomalies of the heart and gastrointestinal tract. Association with chromosomal disorders has been sporadically reported. We now report on two patients with trisomy 21 and congenital anomalies of the umbilico‐portal system. A male fetus showed absence of the intrahepatic portal vein (PV) and ductus venosus with a direct communication between portal sinus and inferior vena cava exhibiting an umbilicosystemic total shunt during the fetal life and a portosystemic total shunt after birth. A female infant showed absence of the intrahepatic PV and a total portocaval shunt. Both patients also had heart defects. As previously documented in other reports, our cases demonstrated that this association may be causally‐related to the chromosomal aberration. In addition, the umbilico‐portal venous system abnormalities seems to be the most frequent congenital vascular malformation in Down syndrome. A presumptive pathogenetic mechanism could be a trisomy 21‐related altered angiogenesis of the vitelloumbilical plexus.

Kabuki make-up (Niikawa-Kuroki) syndrome : clinical and radiological observations in two sicilian children

The Authors describe two patients aged 5 and 8, a female and a male, affected by a condition of polymalformations known as Kabuki make-up or Niikawa-Kuroki syndrome, having a neonatal incidence of 1∶32,000 in Japan. There are two hypothesis about the apparent rarity of the syndrome in the rest of the world, including the Asian Continent: the first is that it exists, but is infrequently recognized outside Japan and the second is that it is really more frequent in those parts of the world, where ethnic exchanges are uncommon, as it happens in Japan.

Identification of two new mutations in TRPS 1 gene leading to the tricho-rhino-phalangeal syndrome type I and III†

Identification of Two New Mutations in TRPS 1 Gene Leading to the Tricho-Rhino-Phalangeal Syndrome Type I and III Maria Piccione, Marcello Niceta, Vincenzo Antona,* Antonella Di Fiore, Filomena Cariola, Mattia Gentile, and Giovanni Corsello Unit a Operativa di Pediatria e Terapia Intensiva Neonatale, Dipartimento Materno Infantile, Universit a degli Studi di Palermo, Palermo, Italy Dipartimento di Genetica Medica I.R.C.C.S. ‘Saverio de Bellis’, Castellana Grotte (BA), Italy

Down syndrome and breastfeeding

Aim: The aim of the study was to investigate the frequency of breastfeeding among children with Down syndrome. Methods: The mothers of 560 children with Down syndrome attending four university hospitals in Italy were interviewed and the neonatal clinical records retrieved. Information was collected on the type of infant feeding and on why some mothers had not breastfed their children. Two groups of healthy children whose feeding habits had been previously investigated were recruited as control subjects (1601 and 714, respectively). A paediatrician in each hospital was interviewed about the neonatal admission policy of children with Down syndrome. Results: Among the 560 Down children, 246 (44%) were admitted to the neonatal unit. Compared with the two control groups, children with Down syndrome were significantly more frequently bottle‐fed (57% vs 15% and 24%, respectively, odds ratio 7.5, 95% CI 6.0–9.4 and 4.2, 95% CI 3.3–5.4. respectively). Only 30% of infants admitted to the neonatal unit were breastfed. The main reasons reported by the mothers for not having breastfed were infants’illness in infants who had been admitted to the neonatal unit and frustration or depression, perceived milk insufficiency and difficulty with suckling for those babies who had not been admitted to the unit. The paediatricians reported that the admission of a baby with Down syndrome to the neonatal unit could sometimes take place not for medical reasons, but for diagnostic work‐up or for a more appropriate diagnosis and to maintain communication with the family.

PTEN hamartoma tumor syndromes in childhood: description of two cases and a proposal for follow-up protocol.

PTEN hamartoma tumor syndromes (PHTS) are a spectrum of hamartomatous overgrowth syndromes associated with germ‐line mutations in the tumor suppressor PTEN gene located on 10q23.3. It is widely accepted that two of these disorders, Cowden syndrome and Bannayan–Riley–Ruvalcaba syndrome, are allelic conditions. Because PTEN mutations are not identifiable in every case of the PHTS phenotype, the inability to detect a mutation within the PTEN gene does not invalidate the clinical diagnosis of Cowden syndrome, or Bannayan–Riley–Ruvalcaba syndrome, in patients who meet diagnostic criteria for these disorders. PTEN mutations are associated with an increased risk for developing breast, thyroid, endometrial, and sometimes renal cancers. Thus, cancer surveillance is the cornerstone of PHTS patient management. Although a consensus cancer surveillance protocol has not been formally instituted, all PTEN mutation carriers should adopt the cancer surveillance strategies proposed for patients with Cowden syndrome. In addition, because gastrointestinal and vascular complications can be more severe in Bannayan–Riley–Ruvalcaba syndrome than in Cowden syndrome, patients with Bannayan–Riley–Ruvalcaba syndrome should be monitored from this point of view too. In this study, we report on two cases with Bannayan–Riley–Ruvalcaba phenotype that showed two different PTEN mutations. We also propose practice recommendations for management of PHTS patients.

The first case of myoclonic epilepsy in a child with a de novo 22q11.2 microduplication

Chromosome 22, particularly the q11.2 sub‐band, has long been recognized as responsible for multiple congenital anomaly disorders. In particular, its susceptibility to subtle microdeletions or, more rarely, microduplications has been attributed to the presence of several low‐copy repeats spanning the region as mediators of nonallelic homologous recombination that result in 22q11.2 rearrangements. While recent data suggest that the frequency of 22q11.2 microduplications could be approximately half of all deletions, now only 50 unrelated cases have been reported thus far. However, it is reasonable to suppose that microduplications of 22q11.2 may be largely undetected as a result of a less‐distinct, unpredictable, and/or milder phenotype ranging from normal to mild learning difficulties with/without other multiple defects. We report on the first case of myoclonic epilepsy in a 10‐year‐old boy carrying a de novo 22q11.2 microduplication. Emphasizing that this rare association could be one of the many unrecognized aspects underlying this new emerging syndrome and once again its clinical heterogeneity, we suggest further investigation of the function of the RAB36 gene and propose that in the screening of individuals with developmental delay, minor behavioral problems mild dysmorphology and seizures, investigation of 22q11.2 microduplications should be considered.