After maternal exposure to mycophenolate in pregnancy a high number of fetal losses and a specific pattern of birth defects consisting of microtia, cleft lip, and other anomalies have been reported. However, so far, prospective data on pregnancy outcome allowing quantitative risk assessment are missing. We report on 57 prospectively ascertained pregnancies after maternal therapy with mycophenolate (mycophenolate mofetil or mycophenolate sodium) identified by European Teratology Information Services (ETIS) through their risk consultation process. The outcome of these prospective pregnancies was as follows: 16 spontaneous abortions, 12 elective terminations of pregnancy (ETOP) (including two late terminations for multiple malformations consistent with mycophenolate embryopathy), and 29 liveborn infants. The probability of spontaneous abortion was about 45% (95% CI 29 to 66%) estimated using survival analysis technique. Six out of 29 live born infants had major congenital defects: Two with external auditory canal atresia (EACA) (with and without microtia), one with tracheo-esophageal atresia, one with severe hydronephrosis, one with an atrial septal defect (ASD) and one with a myelomeningocele. Thus, at least four fetuses/infants of our prospective case series had a clinical phenotype consistent with mycophenolate embryopathy. Our results confirm a high incidence of major malformations (26%) after first trimester exposure to mycophenolate. Apart from exposure to mycophenololate, the underlying maternal disease and concomitant medication may also have contributed to the other poor pregnancy outcomes such as a high rate of spontaneous abortions, prematurity (62%), and low birth weight (31%). © 2012 Wiley Periodicals, Inc.

The proximal region of the long arm of chromosome 22 is rich in low copy repeats (LCR). Non-allelic homologous recombination (NAHR) between these substrates explains the high prevalence of recurrent rearrangements within this region. We have performed array comparative genomic hybridization in a normally developing girl with growth delay, microcephaly, and truncus arteriosus, and have identified a novel recurrent 22q11 deletion that spans LCR22-4 and partially affects the common 22q11.2 deletion syndrome and the distal 22q11 deletion syndrome. This deletion is atypical as it did not occur by NAHR between any of the major LCRs found on 22q11.2. However, the breakpoint containing regions coincide with highly homologous regions. An identical imbalance was reported previously in a patient with striking phenotypic similarity. Computational gene prioritization methods and biological evidence denote the genes CRKL and MAPK1 as the highest ranking candidates for causing congenital heart disease within the deleted region. © 2012 Wiley Periodicals, Inc.

Although the relationship between meiotic recombination frequency and synaptonemal complex (SC) length has been of interest for a long time, how recombination frequency is related to SC length has not been carefully explored. To address this question, we have measured the meiotic recombination frequency as represented by MLH1 foci in 889 pachytene spermatocytes and measured the length of 19,558 autosomal SCs from 10 human males. A complex relationship between the number of MLH1 foci and total autosomal SC length per cell was observed. A positive correlation with significant correlation coefficients between the two variables was found in eight of the ten donors examined, with three donors showing weak correlation, and five showing moderate correlation. Two donors who did not show any correlation between the two variables were identified for the first time. Moreover, most cells with similar total autosomal SC length showed very different numbers of MLH1 foci both between individuals and even within an individual, and vice versa. Our data provide the first evidence for a complex relationship between the recombination frequency and total length of autosomal SCs per cell in human males. © 2012 Wiley Periodicals, Inc.

To assess psychosocial functioning and quality of life in a representative group of adult and young patients with Shwachman–Diamond syndrome (SDS), all patients 3 years old and over included in the Italian SDS Registry were investigated using an ad-hoc questionnaire for information about demography, education, socialization, rehabilitation therapy, and standardized questionnaires [SF-36, Child Behavior Check-List (CBCL)] for quality of life and behavior. Results were compared with those of a Cystic Fibrosis (CF) patient group, matched for age and sex. Eighty-one percent of patients answered. All but one adult patient lived with their parents, 24% had independent income, and 57% had a driver's license. Different levels (from mild to severe) of cognitive impairment were reported by 76% of the adults and by 65% of the young patients. These data are significantly lower than those of the CF group. Both groups present low scores in the emotional and mental health evaluations at SF-36, but SDS patients reported significantly more limitations in physical functioning (PF) and more body pain (BP) experiences. As reported by parents at CBCL, young SDS patients show more “social problems” (in the clinical area 31% SDS vs. 6% CF), “attention deficits disorder” (29% SDS vs. 0%CF), and “somatic complaints” (24% SDS vs. 12% CF). Psychosocial functioning is impaired in the majority of SDS patients, significantly more than in patients affected by CF. © 2012 Wiley Periodicals, Inc.

We examined factors and experiences associated with parents' use or non-use of genetic counseling services within 5 years of the diagnosis of a birth defect in their child. Eligible parents were identified using birth defects data for births in 2004 in Victoria, Australia, and invited to complete a written questionnaire and optional telephone interview. Participants were asked about sources of genetic information, experiences and satisfaction with obtaining this information, and impressions of genetic services. Reasons given for not attending genetic counseling services included not knowing the service was available, or not feeling a need to attend. Non-users commonly stated they would not consider termination of pregnancy for the type of birth defect experienced or that they obtained information from other sources, such as pediatricians. This study indicates that parents, whose child has been diagnosed with a birth defect, could benefit from being informed about available genetic counseling services. The results show that some non-users of genetics services may have misconceptions about the purpose of genetic counseling and correcting these may increase utilization. This is important in order to ensure all parents receive sufficient information and support after diagnosis of a birth defect in their child. © 2012 Wiley Periodicals, Inc.

A child whose features are consistent with Pallister–Killian syndrome (PKS) did not have detectable tetrasomy 12p due to an additional isochromosome 12p in an unstimulated blood specimen by interphase FISH or array CGH analysis. The diagnosis of PKS was made through these methods solely in a skin biopsy specimen. To determine the sensitivity of our array CGH platform to tetrasomy 12p mosaicism, dilutions of DNA from both the child's skin fibroblasts and a PKS cell line were analyzed. Tetrasomy 12p at 10% mosaicism was identifiable but 5% was below the limit of detection. This result suggests through extrapolation that the tetrasomy 12p is present in <10% of cells in our patient's blood, confirming the tissue-limited mosaicism of PKS. Multiple recent studies show that array CGH provides greater sensitivity than chromosome analysis to detect mosaic abnormalities including that of tetrasomy 12p in blood specimens. However, our case demonstrates that the biology of PKS precludes the exclusive use of array CGH on blood for diagnosis. A tissue sample should continue to be the diagnostic gold standard for PKS. © 2012 Wiley Periodicals, Inc.

Gastroschisis is a congenital abdominal wall defect, thought by many to represent a disruption in intrauterine blood flow, where there is herniation of abdominal organs. Dietary intake is an important environmental factor that has been implicated in the development of many diseases. Omega-6 polyunsaturated fatty acids (PUFAs) are nutrients that are substrates for eicosanoid and cytokine synthesis and prone to oxidation, and play a role in modulating inflammation, immune function, and vascular system development. This pilot case-control study explored the association of dietary intake of the omega-6 PUFA linoleic acid with risk of gastroschisis. Between 2008 and 2011, we recruited 13 pregnant women in mid-gestation who were referred to the UCSD Prenatal Center for evaluation of an abnormal alpha-fetoprotein (AFP) test and subsequently identified as carrying a baby with gastroschisis. Nine controls were selected from a false positive AFP or from the UCSD prenatal clinic. Maternal dietary intake was collected via repeated food record during the last 20 weeks of gestation. Logistic regression was used to test the association between dietary intake of linoleic acid and odds of gastroschisis. Dietary intake of linoleic acid was associated with increased odds of gastroschisis (OR = 1.72; 95% CI: 1.08, 2.74; P = 0.02). A higher maternal intake of omega-6 PUFAs may increase the risk of having a baby with gastroschisis. The mechanism by which this occurs may be via inflammatory processes and oxidative stress leading to a vascular disruption. More research is needed including studies investigating integrated markers of PUFA status or inflammatory markers. © 2012 Wiley Periodicals, Inc.

Hyperphosphatasia with neurologic deficit (Mabry syndrome) was first described in a single family (OMIM#239300) by Mabry et al. [1970]. Although considered rare at the time, more than 20 individuals with the triad of developmental disability, seizures, and hyperphosphatasia have been identified world-wide. The 1-6 mannosyltransferase 2, phosphatidylinositol glycan V (PIGV) gene has been found to be disrupted in some patients with the additional feature of brachytelephalangy. In the present report we identify three patients compound homozygous for PIGV mutations. Two siblings were found to be compound heterozygotes for c.467G > A and c.494C > A in exon 3 of PIGV (the c.494C > A PIGV variant is novel). A third patient with similar phenotype, was a compound heterozygote for the known c.1022C > A/c.1022C > T (p.Ala341Glu/p.Ala341Val) mutation. This patient was also noted to have lysosomal storage in cultured fibroblasts. In contrast, the fourth patient who had no apparent hand abnormality, was found to be heterozygous for a previously unclassified c.1369C > T mutation in exon 4 of the PIGV gene, resulting in a p.Leu457Phe substitution in the catalytic domain of the enzyme. Unless this variant has a dominant negative effect, however, it seems likely that another GPI biosynthesis gene variant may contribute to the disorder, possibly through digenic inheritance. Since slightly fewer than half of the nine cases presented in this report and our previous report [Thompson et al., 2010] have PIGV mutations, we suggest that other genes critical to GPI anchor biosynthesis are likely to be disrupted in some patients. © 2012 Wiley Periodicals, Inc.

Langer–Giedion syndrome (LGS) is a contiguous gene syndrome caused by a hemizygous deletion on chromosome 8q23.3-q24.11 involving TRPS1 and EXT1 genes. We report on a girl with LGS phenotype and a 7.5 Mb interstitial deletion at chromosome 8q23.3-q24.13. Array-comparative genomic hybridization (a-CGH) revealed a deletion encompassing only the EXT1 and not the TRPS1 gene. Even though the deletion of TRPS1 and EXT1 genes is responsible for craniofacial and skeletal features of LGS, there have been previous reports of patients with LGS phenotype and 8q24 deletions leaving the TRPS1 gene intact. To our knowledge, this is the third such case. Our patient differs from previously reported LGS patients without TRPS1 gene deletion in that she has the typical LGS facial dysmorphism and skeletal abnormalities. However, the girl is of normal height and has only a mild developmental delay. Additionally, she has dyslalia and premature adrenarche classified as Tanner stage 3 premature pubarche which have not yet been described as features of LGS. We examine the molecular breakpoints and phenotypes of our patient and previously reported cases. © 2012 Wiley Periodicals, Inc.

The American Journal of Medical Genetics Part A is to be congratulated for taking a leadership role by publishing a number of papers challenging the status quo of prenatal counseling for Down syndrome and of care for children and adults with Down syndrome. Parents want to know about the future abilities and potential of their fetus with Down syndrome, not simply negative medical information that may be outdated. Those providing counseling and those providing medical care could benefit from contact with individuals with Down syndrome outside the medical context. It is imperative that each person with Down syndrome be viewed as a unique individual with particular talents. Medical care providers should work with parents to help the child or adult with Down syndrome reach his/her goals. © 2012 Wiley Periodicals, Inc.

Noonan syndrome (NS) is a common autosomal dominant condition characterized by short stature, congenital heart defects, and dysmorphic facial features caused in approximately 50% of cases by missense mutations in the PTPN11 gene. NS patients are predisposed to malignancies including myeloproliferative disorders or leukemias. We report a female NS patient carrying a PTPN11 germline mutation c.417 G > C (p.E139D), who developed in her second year of life an acute lymphoblastic leukemia (ALL) and after remission, she developed at 4 years of age a juvenile myelomonocytic leukemia (JMML). Molecular genetic analysis of lymphoblastic blasts at the time of the ALL diagnosis revealed the germline mutation in a heterozygous state, while in the myelomonocytic blasts occurring with JMML diagnosis, the mutation p.E139D was found in a homozygous state due to a uniparental disomy (UPD). These findings lead to the suggestion that the pathogenesis of ALL and JMML in our patient is due to different mechanisms including somatically acquired secondary chromosomal abnormalities. © 2012 Wiley Periodicals, Inc.

Periventricular heterotopia (PH), clumps of neurons mislocated beside the ventricle, is caused by failure to initiate migration during embryogenesis. We report on a 32-month-old Japanese girl with a unique subtype of PH, namely ribbon-like PH. The patient presented with severe psychomotor developmental delay, intractable epilepsy, and congenital cataracts and developed West syndrome phenotype. Brain magnetic resonance imaging revealed a unique undulating form of PH, categorized as ribbon-like PH, and other brain malformations including simplified gyri and dysgenesis of the corpus callosum. There was no evidence of prenatal TORCH infection or associated syndrome. Array-based comparative genomic hybridization revealed no chromosomal rearrangements. Genetic analyses of the FLNA, DCX, ARX, LIS1, and TUBA1A genes showed no mutations. Although little is known about ribbon-like PH, the clinical manifestations in our patient clearly differed from those in other reported patients. © 2012 Wiley Periodicals, Inc.

Haploinsufficiency of ANKRD11 encoding ankyrin repeat domain-containing protein 11 was recently reported as the cause of a syndrome due to microdeletion, characterized by intellectual disability with minor facial anomalies and short stature. Most recently, intragenic mutations of ANKRD11 were found in a cohort of patients with KBG syndrome. KBG is an autosomal dominant intellectual disability syndrome characterized by short stature, characteristic facial appearance, macrodontia, and skeletal anomalies. It remains unknown if deletion of the entire ANKRD11 causes KBG syndrome. We present a mother and child with a heterozygous 365 Kb deletion at 16q24.3 containing ANKRD11, ZNF778, and SPG7 genes. The child presented with developmental delay, facial anomalies, hand anomalies, and a congenital heart defect. The mother has short stature, facial anomalies, macrodontia, hand anomalies, and learning disability. Both individuals had many findings reported in KBG syndrome and the family met the suggested diagnostic criteria. However, typical macrodontia with fused incisors, costovertebral anomalies, and delayed bone age were not present. We conclude that microdeletions involving ANKRD11 result in a phenotype similar to that of KBG syndrome. © 2012 Wiley Periodicals, Inc.

We describe a novel inherited disorder consisting of idiopathic massive splenomegaly, cytopenias, anhidrosis, chronic optic nerve edema, and vision loss. This disorder involves three affected patients in a single non-consanguineous Caucasian family, a mother and two daughters, who are half-sisters. All three patients have had splenectomies; histopathology revealed congestion of the red pulp, but otherwise no abnormalities. Electron microscopic studies of splenic tissue showed no evidence for a storage disorder or other ultrastructural abnormality. Two of the three patients had bone marrow examinations that were non-diagnostic. All three patients developed progressive vision loss such that the two oldest patients are now blind, possibly due to a cone-rod dystrophy. Characteristics of vision loss in this family include early chronic optic nerve edema, and progressive vision loss, particularly central and color vision. Despite numerous medical and ophthalmic evaluations, no diagnosis has been discovered. © 2012 Wiley Periodicals, Inc.

Adams–Oliver syndrome (AOS) is a rare condition defined by combination of cutis aplasia and transverse limb abnormalities. Some authors have described a possible association between this syndrome and portal hypertension (PH) due to hepatoportal sclerosis (HPS). We present a boy with AOS who developed a progressive splenomegaly and hypersplenism at the age of 2 months, and was admitted for acute gastrointestinal bleeding (GI) at the age of 9 months. Subsequently, we documented an extrahepatic portal vein obstruction and esophageal varices. After several episodes of cataclysmic upper GI bleeding a mesentero-portal shunt (MPS) was performed at 10 months. The shunt thrombosed, and after three failed attempts of thrombectomy, it was removed. One month later a splenorenal shunt was performed, and this closed spontaneously by 3 years. The patient suffered from ischemic stroke after placing the first shunt, and has spastic diplegia, left frontal lobe epilepsy, hyperactivity and attention deficit disorder, and severe psychomotor delay. At 11 years and he presented with chronic liver failure and hyperammonemia and coagulopathy. We hypothesize that there may be an early embryonic vascular abnormality (vascular disruption) that may explain these vascular phenomena. © 2012 Wiley Periodicals, Inc.

Townes–Brocks syndrome (TBS) is a well-described genetic syndrome characterized by anal, ear, and thumb anomalies and variable expressivity. Over 60 nonsense and frameshift mutations have been identified in SALL1, the zinc finger transcription factor causing TBS, and are proposed to cause disease via a dominant negative mechanism. In contrast, only four deletions have been described, with mild phenotypes reported as a result of haploinsufficiency. We report on a family with features of TBS in whom a novel 149 kb deletion spanning the SALL1 gene was identified by high resolution cytogenetics SNP microarray. We review the available genotype–phenotype information for all known truncating mutations and deletions. Taken together, they do not support the correlation of SALL1 deletions with a milder TBS phenotype and highlight a need for more robust clinical phenotyping combined with investigation of mutational mechanism. © 2012 Wiley Periodicals, Inc.

We report on a consanguineous couple with two affected sons who presented with primary microcephaly and moderate to severe intellectual disabilities. A SNP array uncovered two overlapping regions of copy-neutral absence of heterozygosity (AOH) in both sibs. This led to sequencing of WDR62, a gene that codes for a spindle pole protein recently identified as a cause of primary microcephaly. A homozygous missense mutation in WDR62, p.E400K, was found in both boys and segregated with the condition in this family. WDR62 is one of seven genes responsible for autosomal recessive primary microcephaly (MCPH), and appears to be one of the most frequently involved in MCPH following ASPM. Studies of ASPM and WDR62 should perhaps be pursued in all cases of primary microcephaly with or without gross brain malformations. © 2012 Wiley Periodicals, Inc.

In most Western countries, information on prenatal screening for Down syndrome is provided in the first-trimester of pregnancy. The purpose of this study was to examine whether this information should additionally be provided before pregnancy to improve the informed decision-making process. In an empirical study, we obtained data from pregnant women with respect to their preferences regarding information on prenatal screening preconceptionally. Questionnaire data (n = 510) showed that 55.7% of responding women considered participating in prenatal screening for Down syndrome before pregnancy. 28.0% of women possessed information on prenatal screening preconceptionally. 84.6% preferred not to receive information preconceptionally in retrospect. In an ethical analysis, we elaborated on these preferences by weighing pros and cons. We considered two arguments against the provision of information on prenatal screening preconceptionally: women's preference to receive information in a step-by-step manner, and the risk of providing a directive message. We identified three reasons supporting its provision preconceptionally: the likelihood of making an informed decision could, firstly, be increased by “unchaining” the initial information from possible subsequent decisions, and, secondly, by providing women sufficient time to deliberate. Thirdly, the probability of equal access to prenatal screening may increase. To conclude with, we propose to incorporate an information offer on prenatal screening for Down syndrome in preconception care consultations. By offering information, instead of providing information, prospective parents are enabled to either accept or decline the information, which respects both their right to know and their right not-to-know. © 2012 Wiley Periodicals, Inc.

Mutations in ACTA2 (smooth muscle cell—specific isoform of α-actin) lead to a predisposition to thoracic aortic aneurysms and other vascular diseases. More recently, the ACTA2 R179H mutation has been described in individuals with global smooth muscle dysfunction. We report a patient heterozygous for the mutation in ACTA2 R179H who presented with megacystis at 13 weeks gestational age and, at birth, with prune-belly sequence. He also had deep skin dimples and creases on his palms and soles, a finding not previously described but possibly related to ACTA2. To our knowledge, this is the first report of the R179H mutation in ACTA2 in a child with prune-belly sequence. We think the R179H mutation in ACTA2 should be included in the differential diagnosis of individuals presenting with the sequence without an identified mechanical obstruction. Furthermore, as ACTA2 R179H has been reported in patients with severe vasculomyopathy and premature death, we recommend that molecular testing for this mutation be considered in fetuses presenting with fetal megacystis with a normal karyotype, particularly if the bladder diameter is 15 mm or more, to allow expectant parents to make an informed decision. © 2012 Wiley Periodicals, Inc.

The prevalence of the 22q11.2 duplication is unknown in children with cardiovascular malformations (CVMs). As most individuals with the duplication are detected in the search for other conditions, especially the 22q11.2 deletion, CVMs associated with the duplication are subject to referral bias. We circumvented this bias by investigating the prevalence of the 22q11.2 duplication in a population-based cohort of children with CVMs. The study population was defined as children born in 2000–2008, who were registered in the Danish National Patient Registry with a diagnosis of CVM from one of the two national university departments of pediatric cardiology. Sensitive multiplex ligation-dependent probe amplification was performed on dried blood spot samples from each individual's neonatal screening test. The study population consisted of 2,952 children with CVMs, 2,424 of whom were eligible for genetic testing; 13 individuals (0.5% [0.3–0.9%]) carried the duplication. Nine individuals (69%) had not previously been tested for a copy number variation on chromosome 22q11.2 in the clinical setting for children with CVMs. We conclude that 22q11.2 duplication is rare in children with CVMs, and is primarily found in malformations that are also associated with the 22q11.2 deletion. © 2012 Wiley Periodicals, Inc.

Hydrops fetalis is an excessive accumulation of fetal fluid. Hydrops is traditionally classified into either immune or non-immune hydrops (NIHF), but in practice, nowadays in the Western world >90% of hydrops is of non-immune origin. The basis of the disorder is an imbalance in the regulation of fetal fluid movement between the vascular and interstitial space. We previously suggested a diagnostic flow-chart for NIHF. In this short review we describe the main mechanisms leading to NIHF. © 2012 Wiley Periodicals, Inc.

The deletion of the long arm of chromosome 18 causes a contiguous gene deletion syndrome with a highly variable phenotype, usually related to the extent of the deleted region. The most commonly reported clinical features include: decreased growth, microcephaly, facial abnormalities, hypotonia, developmental delay, intellectual disability, congenital aural atresia with hearing impairment and limb anomalies. Here we report on a familial terminal deletion of 18q23 region transmitted from a mother to two daughters, resulting in a remarkable phenotypic variability. The deletion was first detected by conventional cytogenetic analysis in one daughter and subsequently characterized using fluorescence in situ hybridization (FISH) and array-CGH. FISH analysis using subtelomeric 18p and 18q probes confirmed the 18qter deletion in the three patients, and FISH with a whole chromosome painting probe specific for chromosome 18 excluded rearrangements with other chromosomes. Array-CGH analysis allowed us to precisely define the extent of the deletion, which spans 4.8 Mb from 71,236,891 to 76,093,303 genomic positions and includes GALR1 and MBP genes, among others. High-resolution analysis of the deletion, besides a detailed clinical assessment, has provided important data for phenotype–genotype correlation and genetic counseling in this family. Furthermore, this study adds valuable information for phenotype–genotype correlation in 18q- syndrome and might facilitate future search for candidate genes involved in each phenotypic trait. © 2012 Wiley Periodicals, Inc.

Taybi–Linder syndrome, also known as microcephalic osteodysplastic primordial dwarfism types I and III, is a rare disorder with presumed autosomal recessive inheritance. It is characterized by intrauterine growth retardation, distinctive bone dysplasia, and central nervous system malformations. We present two siblings with Taybi–Linder syndrome, with an emphasis on the neurological profile in this disease, which includes brain malformations, intractable epilepsy, sensory deficits, profound cognitive deficits, and neuroendocrine dysfunction. We also present distinctive correlative neuroimaging (MRI) and electroencephalographic (EEG) findings. Increased knowledge of the neurological profile of Taybi–Linder syndrome may be helpful for clinicians and genetic counselors managing these patients. © 2012 Wiley Periodicals, Inc.

This paper focuses on the influence of consanguinity on the occurrence of orofacial clefts. All patients with orofacial clefts registered at King Faisal Specialist Hospital and Research Center, Riyadh since June 1999 until December 2009 were included in this study. Patients were classified in two distinct groups: cleft lip with or without cleft palate (CL ± P) and isolated cleft palate (CP). Chi-squared test was used to test independence of variables. Intracluster correlation coefficient was estimated to assess the degree of concordance between siblings. Among 1,171 total patients, CL ± P was found to be more common (64.0%). Males were more likely to be affected with CL ± P (M:F = 1.5:1) and females were more likely to be affected with CP (M:F = 0.9:1; P < 0.0001). About a third of patients had a family history of clefts; family history was more likely to be positive for patients with CL ± P than for patients with CP (33.6% vs. 22.0%; P < 0.0001). Consanguineous relationships were seen in 56.8% of our patients' parents. Family history was more likely to be positive for patients whose parents were consanguineous than those who were non-consanguineous (34.2% vs. 25.8%; P = 0.003), both for the CL ± P and CP groups. Recurrence among siblings did not differ between those born to consanguineous versus non-consanguineous parents. Recurrence of clefts in offspring was higher among parents affected by cleft compared to those who were not affected (51.4% vs. 11.4%; P < 0.0001), both for CL ± P and CP groups. Education about anticipated genetic consequences of consanguinity is important for populations with a high degree of consanguinity. © 2012 Wiley Periodicals, Inc.

We report on a child with dextrocardia, atrial septal defect (ASD), severe developmental delay, hypotonia, 13 pairs of ribs, left preauricular choristoma, hirsutism, and craniofacial abnormalities. Prenatal cytogenetic evaluation showed karyotype 46,XY,?dup(8p)ish del(8)pter. Postnatal array CGH demonstrated a 6.8 Mb terminal deletion at 8p23.3–p23, an interstitial 31.1 Mb duplication within 8p23.1–p11, and a terminal duplication of 0.24 Mb at 22q13.33, refining the karyotype to 46,XY,der(8)dup(8)(p23.1p11.1)t(8;22)(p23.1;q13.1).ish der(8)dup(8)(p23.1p11.1)t(8;22)(p23.1;q13.1) (D8S504-,MS607 + ,ARSA + ,D8Z1 + , RP115713 + +). Previous reports of distal 8p deletion, 8p duplication, and distal 22q duplication have shown similar manifestations, including congenital heart disease, intellectual impairment, and multiple minor anomalies. We correlate the patient's clinical findings with these particular areas of copy number. This case study supports the use of aCGH to identify subtle chromosomal rearrangement in infants with cardiac malformation as their most significant or only apparent birth defect. Additionally, it illustrates why aCGH is essential in the description of chromosome rearrangements, even those seemingly visible via routine karyotype. This method shows that there is often greater complexity submicroscopically, essential to an adequate understanding of a patient's genotype and phenotype. © 2012 Wiley Periodicals, Inc.

The 4q deletion syndrome is a rare chromosome deletion syndrome with a wide range of clinical phenotypes. There is limited clinical phenotype and molecular correlation for congenital heart defects (CHDs) reported so far for this region primarily because many cases are large deletions, often terminal, and because high-resolution array has not been reported in the evaluation of this group of patients. CHDs are reported in about 60% of patients with 4q deletion syndrome, occurring in the presence or absence of dHAND deletion, implying the existence of additional genes in 4q whose dosage influences cardiac development. We report an 8-month-old patient with a large mid-muscular to outlet ventricular septal defect (VSD), moderate-sized secundum-type atrial septal defect (ASD), thickened, dysplastic pulmonary valve with mild stenosis and moderate pulmonic regurgitation, and patent ductus arteriosus (PDA). Illumina CytoSNP array analysis disclosed a de novo, heterozygous, interstitial deletion of 11.6 Mb of genomic material from the long arm of chromosome 4, at 4q32.3–q34.3 (Chr4:167236114–178816031; hg18). The deleted region affects 37 RefSeq genes (hg18), including two provisional microRNA stemloops. Three genes in this region, namely TLL1 (Tolloid-like-1), HPGD (15-hydroxyprostaglandin dehydrogenase), and HAND2 (Heart and neural crest derivatives-expressed protein 2), are known to be involved in cardiac morphogenesis. This report narrows the critical region responsible for CHDs seen in 4q deletion syndrome. © 2012 Wiley Periodicals, Inc.

Hypochondroplasia (HCH) is the mildest phenotype among fibroblast growth factor receptor 3 (FGFR3)-associated skeletal dysplasias. Affected individuals usually presents with mild short stature in preschool age. It was uncommon that a diagnosis of HCH is made in young affected children. Recently, however, prenatal ultrasound (US) has increased likelihood of detecting in utero mild short limbs. There have been a few reports on the early diagnosis of HCH in the neonatal period preceded by a suspicion of skeletal dysplasia on fetal US. However, the proper diagnosis of HCH is hampered by absence of the radiological criteria relevant to age, particularly those in the neonatal period. We report on the clinical and radiological findings in two HCH children with a FGFR3 mutation. In both children, fetal US showed short femora and relatively increased biparietal diameter (BPD). However, postnatal assessment failed to make a specific diagnosis in the neonatal period. The correct diagnosis of HCH was accomplished by reassessment after exacerbation of postnatal short stature. In retrospective radiological review, the radiological findings relevant to HCH were discernible more easily in the neonatal period than at age of 3 years. © 2012 Wiley Periodicals, Inc.

A 9-year-old boy with the classical type of Ehlers–Danlos syndrome (EDS) developed a symptomatic aneurysm of the superior mesenteric artery. His EDS diagnosis had been confirmed biochemically and genetically. Vascular complications are known to be associated with the vascular type of EDS, but this is the first report of a child with classical EDS who developed a major vascular complication. Clinicians should be aware that severe vascular complications albeit rare, can also occur in classical EDS. © 2012 Wiley Periodicals, Inc.

Noonan syndrome (NS) is the most common non-chromosomal syndrome seen in children and is characterized by short stature, dysmorphic facial features, chest deformity, a wide range of congenital heart defects and developmental delay of variable degree. Mutations in the Ras/mitogen-activated protein kinase (MAPK) signaling pathways cause about 70% of NS cases with a KRAS mutation present in about 2%. In a cohort of 65 clinically confirmed NS patients of Japanese origin, we screened for mutations in the RAS genes by direct sequencing. We found a novel mutation in KRAS with an amino acid substitution of asparagine to serine at codon 116 (N116S). We analyzed the biological activity of this mutant by ectopic expression of wild-type or mutant KRAS. NS-associated KRAS mutation resulted in Erk activation and active Ras–GTP levels, and exhibited mild cell proliferation. In addition, kras-targeted morpholino knocked-down zebrafish embryos caused heart and craniofacial malformations, while the expression of mutated kras resulted in maldevelopment of the heart. Our findings implicate that N116S change in KRAS is a hyperactive mutation which is a causative agent of NS through maldevelopment of the heart. © 2012 Wiley Periodicals, Inc.

We report on a fetus with an isolated short femur detected by ultrasound and a de novo interstitial deletion of chromosome 15. The deletion was diagnosed prenatally by karyotype and further mapped by fluorescence in situ hybridization (FISH) and array comparative genomic hybridization (array-CGH) to bands 15q15.3 to 15q21.3 with a size of 11.11 Mb. Fetal autopsy showed characteristic minor anomalies, urinary abnormalities, and delayed bone maturation, but neither craniosynostosis, nor congenital heart defects as observed in previously reported cases. Despite the existence of ultrasound abnormalities, all five cases reported so far were diagnosed after birth. This is the first case of an interstitial deletion involving chromosomal band 15q15.3-q21.3 diagnosed prenatally and characterized at the molecular level. Our observation suggests the absence of imprinted genes in the area of 15q15–q22 and strengthens the hypothesis that a critical region for craniosynostosis may be mapped outside the deleted region in the present patient. © 2012 Wiley Periodicals, Inc.

Von Recklinghausen neurofibromatosis (NF1) is an autosomal dominant disorder with a prevalence about 1/3,000 (1/2,000–1/5,000 in various population-based studies). About 30–50% of cases are sporadic, resulting from a new mutation. NF1 is fully penetrant by mid-childhood, stigmata, and medical problems (neurological, dermatological, endocrine, ophthalmological, oncological) are highly variable. Advanced paternal age (APA) has been known to increase the risk of new germline mutations that contribute to the presence of a variety of genetic diseases in the human population. The trend in developed countries has been toward higher parental age due to various reasons. In a cross-sectional study, in two university hospital centers, data on parental age of 103 children (41 female) born between 1976 and 2005 with sporadic NF1 were analyzed. Parental age at birth was compared with the Czech general population matched to birth year. The mean NF1 sporadic case paternal age at birth was 32.0 years (95% CI 30.7–33.3 years) compared with 28.8 years (95% CI 28.6–29.1 years) in the general population (P < 0.001). The mean maternal age at birth was 27.4 years (95% CI 26.3–28.5 years) compared with 25.8 years (95% CI 25.5–26.0 years) in the general population (P < 0.05). The case-control difference in the father's age was higher than it was for the mother's age. Sporadic NF1 cases accounted for 35.6% of our entire NF1 cohort. We confirmed an association of advanced parental and particularly paternal age with the occurrence of sporadic NF1. © 2012 Wiley Periodicals, Inc.

Coloboma and various ocular abnormalities have been described in CHARGE syndrome, although the severity of visual impairment varies from case to case. We conducted a multicenter study to clarify the ophthalmic features of patients with molecularly confirmed CHARGE syndrome. Thirty-eight eyes in 19 patients with CHARGE syndrome and confirmed CHD7 mutations treated at four centers were retrospectively studied. Colobomata affected the posterior segment of 35 eyes in 18 patients. Both retinochoroidal and optic disk colobomata were bilaterally observed in 15 patients and unilaterally observed in 3 patients. The coloboma involved the macula totally or partially in 21 eyes of 13 patients. We confirmed that bilateral large retinochoroidal colobomata represents a typical ophthalmic feature of CHARGE syndrome in patients with confirmed CHD7 mutations; however, even eyes with large colobomata can form maculas. The anatomical severity of the eye defect was graded according to the presence of colobomata, macula defect, and microphthalmos. A comparison of the severity in one eye with that in the other eye revealed a low-to-moderate degree of agreement between the two eyes, reflecting the general facial asymmetry of patients with CHARGE syndrome. The location of protein truncation and the anatomical severity of the eyes were significantly correlated. We suggested that the early diagnosis of retinal morphology and function may be beneficial to patients, since such attention may determine whether treatment for amblyopia, such as optical correction and patching, will be effective in facilitating the visual potential or whether care for poor vision will be needed. © 2012 Wiley Periodicals, Inc.

Deletion of chromosome 22q11.2 is considered one of the most frequent genetic causes of cardiovascular malformations. It is frequently associated with conotruncal malformations, but may also be present among patients with nonconotruncal malformations. The aim of the present study was to establish the prevalence of the 22q11.2 deletion in an unselected population-based cohort of children with various cardiovascular malformations. The study population was defined as children born in 2000–2008 who were registered in the Danish National Patient Registry with a diagnosis of cardiovascular malformation from one of the two national departments of pediatric cardiology. Sensitive multiplex ligation-dependent probe amplification was performed on dried blood spot samples from each individual's neonatal screening test. Of 2,952 children with cardiovascular malformations, 2,478 were eligible for genetic testing. A total of 46 individuals (1.9% [1.4–2.5%]) carried the deletion, with the highest prevalence among individuals registered with interrupted aortic arch (22% [11–40]). The most frequent diagnoses among individuals carrying the deletion were tetralogy of Fallot (n = 15) and ventricular septal defect (n = 15). One in four cases had not been diagnosed in the usual clinical setting. The prevalence of 22q11.2 deletions in an unselected population-based cohort of children with cardiac malformations was 1.9% [1.4–2.5%]. Genetic testing of every individual registered with a conotruncal malformation would have achieved a diagnostic sensitivity of 70% in the present cohort. Prospective studies outlining testing recommendations in children with ventricular septal defect are warranted. © 2011 Wiley Periodicals, Inc.

Recently, a revised Ghent nosology has been established for the diagnosis of Marfan syndrome (MFS) that puts more weight on the aortic root aneurysm and ectopia lentis. We compared the application of the Ghent and revised Ghent nosologies in adult Korean patients for whom there is suspicion of MFS. From January 1995 to June 2010, we enrolled 106 patients older than 20 years for whom there was suspicion of MFS, and who had undergone genetic analysis of the fibrillin-1 gene (FBN1). Of 106 patients, 86 patients (81%) fulfilled the criteria of the Ghent nosology, and 84 patients (79%) met the criteria of the revised Ghent nosology. The two patients who met the Ghent nosology criteria, but not the criteria of the revised Ghent nosology were diagnosed with Loeys–Dietz syndrome and MASS phenotype. The level of agreement between both nosologies was very high (κ = 0.94, 95% confidence interval: 0.86 to 1.0). Marfan-like syndromes were diagnosed in 30% (6/20 patients) with negative Ghent and revised Ghent criteria and no FBN1 mutations. These results suggest that adult Korean patients who fulfill the old Ghent criteria almost all fulfill the new criteria for the diagnosis of MFS. © 2011 Wiley Periodicals, Inc.

Dynamic MRIs showing changes over time in 2 patients with progressive cerebellar tonsillar ectopia who have a disorder of brain overgrowth. See article by Mirzaa et al. in this issue.

The macrocephaly-capillary malformation syndrome (M-CM), which we here propose to rename the megalencephaly-capillary malformation syndrome (MCAP; alternatively the megalencephaly-capillary malformation-polymicrogyria syndrome), and the more recently described megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome (MPPH) are two megalencephaly (MEG) disorders that involve a unique constellation of physical and neuroimaging anomalies. We compare the features in 42 patients evaluated for physical and neuroimaging characteristics of MCAP and MPPH and propose a more global view of these syndromes based on classes of developmental abnormalities that include primary MEG and growth dysregulation, developmental vascular anomalies (primarily capillary malformations), distal limb anomalies (such as syndactyly and polydactyly), cortical brain malformations (most distinctively polymicrogyria, PMG), and variable connective tissue dysplasia. Based on these classes of developmental abnormalities, we propose that MCAP diagnostic criteria include progressive MEG with either vascular anomalies or syndactyly. In parallel, we propose that MPPH diagnostic criteria include progressive MEG and PMG, absence of the vascular anomalies and syndactyly characteristic of MCAP, and absence of brain heterotopia. © 2012 Wiley Periodicals, Inc.

We describe a newborn girl with multiple congenital anomalies and abnormal phenotype comprising underdeveloped corpus callosum with ventriculomegaly, chorioretinal atrophy, pulmonary arterial hypertension, annular pancreas, horseshoe kidney, asymmetric limb and chest anomalies, spinal segmentation defects, hypertrichosis, and unusual face with large anterior fontanel, high anterior hairline, broad forehead, mildly underdeveloped midface, hypertelorism, depressed nasal bridge, short and upturned nose, large mouth, retrognathia, and large and malformed ears. Work-up included cytogenetic studies of lymphocytes and skin fibroblasts, subtelomere Multiplex Ligation-dependent Probe Amplification (MLPA), whole-genome oligo-array, and molecular analysis of SETBP1 and NSDHL: no abnormalities were found. Mucopolysaccharide urinary excretion was elevated. Results of metabolic studies for sterol and peroxisomal abnormalities in fibroblasts were normal. Additional electronic microscopy studies in skin fibroblasts did not show evidence for storage in fibroblasts or lysosomal changes. Nosologic considerations allowed exclusion of Schinzel–Giedion and Urioste syndrome. This condition seems not to have been described before; a segregating Mendelian mutation is assumed. © 2011 Wiley Periodicals, Inc.

Hearing loss is the most prevalent sensory perception deficit in humans, affecting 1/500 newborns, can be syndromic or nonsyndromic and is genetically heterogeneous. Nearly 80% of inherited nonsyndromic bilateral sensorineural hearing loss (NBSNHI) is autosomal recessive. Although many causal genes have been identified, most are minor contributors, except for GJB2, which accounts for nearly 50% of all recessive cases of severe to profound congenital NBSNHI in some populations. More than 60% of children with a NBSNHI do not have an identifiable genetic cause. To identify genetic contributors, we genotyped 659 GJB2 mutation negative pediatric probands with NBSNHI and assayed for copy number variants (CNVs). After identifying 8 mild-moderate NBSNHI probands with a Chr15q15.3 deletion encompassing the Stereocilin (STRC) gene amongst this cohort, sequencing of STRC was undertaken in these probands as well as 50 probands and 14 siblings with mild-moderate NBSNHI and 40 probands with moderately severe-profound NBSNHI who were GJB2 mutation negative. The existence of a STRC pseudogene that is 99.6% homologous to the STRC coding region has made the sequencing interpretation complicated. We identified 7/50 probands in the mild-moderate cohort to have biallelic alterations in STRC, not including the 8 previously identified deletions. We also identified 2/40 probands to have biallelic alterations in the moderately severe-profound NBSNHI cohort, notably no large deletions in combination with another variant were found in this cohort. The data suggest that STRC may be a common contributor to NBSNHI among GJB2 mutation negative probands, especially in those with mild to moderate hearing impairment. © 2011 Wiley Periodicals, Inc.

Fibrochondrogenesis is a severe, recessively inherited skeletal dysplasia shown to result from mutations in the gene encoding the proα1(XI) chain of type XI collagen, COL11A1. The first of two cases reported here was the affected offspring of first cousins and sequence analysis excluded mutations in COL11A1. Consequently, whole-genome SNP genotyping was performed to identify blocks of homozygosity, identical-by-descent, wherein the disease locus would reside. COL11A1 was not within a region of homozygosity, further excluding it as the disease locus, but the gene encoding the proα2(XI) chain of type XI collagen, COL11A2, was located within a large region of homozygosity. Sequence analysis identified homozygosity for a splice donor mutation in intron 18. Exon trapping demonstrated that the mutation resulted in skipping of exon 18 and predicted deletion of 18 amino acids from the triple helical domain of the protein. In the second case, heterozygosity for a de novo 9 bp deletion in exon 40 of COL11A2 was identified, indicating that there are autosomal dominant forms of fibrochondrogenesis. These findings thus demonstrate that fibrochondrogenesis can result from either recessively or dominantly inherited mutations in COL11A2. © 2012 Wiley Periodicals, Inc.

Mutations in the CLDN14 gene are known to cause autosomal recessive (AR) non-sydromic hearing loss (NSHL) at the DFNB29 locus on chromosome 21q22.13. As part of an ongoing study to localize and identify NSHL genes, the ARNSHL segregating in four Pakistani consanguineous families were mapped to the 21q22.13 region with either established or suggestive linkage. Given the known involvement of CLDN14 gene in NSHL, DNA samples from hearing-impaired members from the four families were sequenced to potentially identify causal variants within this gene. Three novel CLDN14 mutations, c.167G>A (p.Trp56*), c.242G>A (p.Arg81His), and c.694G>A (p.Gly232Arg), segregate with hearing loss (HL) in three of the families. The previously reported CLDN14 mutation c.254T>A (p.Val85Asp) was observed in the fourth family. None of the mutations were detected in 400 Pakistani control chromosomes and all were deemed damaging based on bioinformatics analyses. The non-sense mutation c.167G>A (p.Trp56*) is the first stop codon mutation in CLDN14 gene to be identified to cause NSHL. The c.242G>A (p.Arg81His) and c.694G>A (p.Gly232Arg) mutations were identified within the first extracellular loop and the carboxyl-tail of claudin-14, respectively, which highlights the importance of the extracellular domains and phosphorylation of cytoplasmic tail residues to claudin function within the inner ear. The HL due to novel CLDN14 mutations is prelingual, severe-to-profound with greater loss in the high frequencies. © 2012 Wiley Periodicals, Inc.

Floating-Harbor syndrome (FHS) is characterized by characteristic facial dysmorphism, short stature with delayed bone age, and expressive language delay. To date, the gene(s) responsible for FHS is (are) unknown and the diagnosis is only made on the basis of the clinical phenotype. The majority of cases appeared to be sporadic but rare cases following autosomal dominant inheritance have been reported. We identified a 4.7 Mb de novo 12q15-q21.1 microdeletion in a patient with FHS and intellectual deficiency. Pangenomic 244K array-CGH performed in a series of 12 patients with FHS failed to identify overlapping deletions. We hypothesized that FHS is caused by haploinsufficiency of one of the 19 genes or predictions located in the deletion found in our index patient. Since none of them appeared to be good candidate gene by their function, a high-throughput sequencing approach of the region of interest was used in eight FHS patients. No pathogenic mutation was found in these patients. This approach failed to identify the gene responsible for FHS, and this can be explained by at least four reasons: (i) our index patient could be a phenocopy of FHS; (ii) the disease may be clinically heterogeneous (since the diagnosis relies exclusively on clinical features), (iii) these could be genetic heterogeneity of the disease, (iv) the patient could carry a mutation in a gene located elsewhere. Recent descriptions of patients with 12q15-q21.1 microdeletions argue in favor of the phenocopy hypothesis. © 2012 Wiley Periodicals, Inc.

Rett syndrome (RTT; OMIM 312750) is an X-linked dominant neurodevelopmental disorder leading to cognitive and motor impairment, epilepsy, and autonomic dysfunction in females. Since the discovery that RTT is caused by mutations in MECP2, large retrospective genotype–phenotype correlation studies have been performed. A number of general genotype–phenotype relationships were confirmed and specific disorder profiles were described. Nevertheless, conflicting results are still under discussion, partly due to the variability in classification of mutations, assessment tools, and structure of the data sets. The aim of this study was to investigate relationships between genotype and specific clinical data collected by the same experienced physician in a well-documented RTT cohort, and evaluate its prognostic value in counseling young parents with a newly diagnosed RTT girl regarding her future outcome. The Maastricht–Leuven Rett Syndrome Database is a register of 137 molecularly confirmed clinical RTT cases, containing both molecular and clinical data on examination and follow up by the same experienced physician. Although the general genotype–phenotype relationships were confirmed, the clinical severity was still found to be very variable. We therefore recommend caution in using genotype–phenotype data in the prognosis of outcome for children in Rett syndrome. Early diagnosis, early intervention, and preventive management are imperative for better outcomes and better quality of daily life for RTT females and their families. © 2011 Wiley Periodicals, Inc.

Nevoid basal cell carcinoma syndrome (NBCCS) is characterized by developmental defects and tumorigenesis. The clinical manifestations of NBCCS have been reported in large epidemiological studies from the United States, the United Kingdom, and Australia, but not from an Asian country. We conducted a nationwide survey and identified 311 NBCCS patients in Japan. We investigated the detailed clinical manifestations of 157 patients ranging in age from 9 months to 77 years old (mean: 33.1 years). We then compared the frequency and age of onset for various tumors developed in Japanese NBCCS patients with patients from the three countries listed above in which NBCCS studies were previously conducted. Our most significant finding was the low frequency of basal cell carcinoma (BCC) in Japanese patients. Frequency of BCC in patients over 20 years of age was 51.4%, a much lower rate compared to the United States, Australia, and the United Kingdom (91%, 85%, and 73%, respectively). The mean age of BCC onset was 37.4 years of age, a much older age compared to the above-mentioned countries. These findings suggest that differences in ethnicity and/or environmental factors affect the incidence of BCC. Because the age of BCC onset is generally higher in Japanese NBCCS patients, careful skin examination over a prolonged period of time is warranted. © 2012 Wiley Periodicals, Inc.

Mowat–Wilson syndrome (MWS) is caused by a heterozygous mutation or deletion of the ZEB2 gene. It is characterized by a distinctive facial appearance in association with intellectual disability (ID) and variable other features including agenesis of the corpus callosum, seizures, congenital heart defects, microcephaly, short stature, hypotonia, and Hirschsprung disease. The current study investigated the behavioral phenotype of MWS. Parents and carers of 61 individuals with MWS completed the Developmental Behavior Checklist. Data were compared with those for individuals selected from an epidemiological sample of people with ID from other causes. The behaviors associated with MWS included a high rate of oral behaviors, an increased rate of repetitive behaviors, and an under-reaction to pain. Other aspects of the MWS behavioral phenotype are suggestive of a happy affect and sociable demeanor. Despite this, those with MWS displayed similarly high levels of behavioral problems as those with intellectual disabilities from other causes, with over 30% showing clinically significant levels of behavioral or emotional disturbance. These findings have the potential to expand our knowledge of the role of the ZEB2 gene during neurodevelopment. Furthermore, they are a foundation for informing interventions and management options to enhance the independence and quality of life for persons with MWS. © 2012 Wiley Periodicals, Inc.

Outcome measures are important assessment tools to evaluate clinical genetics services. Research suggests that perceived personal control (PPC) is an outcome valued by clinical genetics patients and clinicians. The PPC scale was developed in Hebrew to capture three dimensions of PPC: Cognitive, decisional, and behavioral control. This article reports on the first psychometric validation of the English translation of the PPC scale. Previous research has shown that the Hebrew and Dutch translations have good psychometric properties. However, the psychometric properties of the English translation have not been tested, and there is disagreement about the factor structure, with implications for how to score the measure. A total of 395 patients attending a clinical genetics appointment in the United Kingdom completed several measures at baseline, and a further 241 also completed measures at 2–4 weeks follow-up. The English language PPC has (a) a one-factor structure, (b) convergent validity with internal health locus of control (IHLC), satisfaction with life (SWL), depression, and authenticity, (c) high internal consistency (α = 0.83), and (d) sensitivity to change, being able to identify moderate changes in PPC following clinic attendance (Cohen's d = 0.40). These properties suggest the English language PPC measure is a useful tool for both clinical genetics research and for use as a Patient Reported Outcome Measure (PROM) in service evaluation. © 2011 Wiley Periodicals, Inc.

The availability of tests to detect genetic conditions prenatally has expanded considerably in recent decades. These advances allow women and couples choices; the choice of whether or not to undergo prenatal screening or diagnosis and therefore the choice whether to continue or terminate a pregnancy. Following prenatal testing many people choose to terminate an affected pregnancy, however little is known about the experiences of parents who choose to continue such a pregnancy. This exploratory qualitative study involved in-depth interviews with five mothers and four fathers who experienced a pregnancy where a genetic diagnosis was, or could have been, detected prenatally. Transcripts of the interviews were analyzed using thematic analysis. While the participants' experiences of genetic diagnoses and prenatal choices varied, findings revealed three major categories triggering new life trajectories for all of these parents: knowledge of reproductive risk and receiving a genetic diagnosis; adapting to diagnosis and new life path; and attitudes to prenatal diagnosis and disability. Parents reported that while dealing with their own attitudes and getting on with their “new world,” positive and negative attitudes of others impacted on these parents' experiences. A conceptual model arising from the major themes is offered as a way of thinking about this paradigm. Parents who continue a pregnancy where a genetic condition is detected or suspected prenatally, can be supported appropriately by health professionals while adjusting to their new life path. © 2011 Wiley Periodicals, Inc.

Physicians and parents report a need for pediatricians to have additional training in delivering a diagnosis of Down syndrome (DS). This study tested a web-based tutorial to assess its effectiveness in improving physicians' perceived comfort with both ambiguous and more medically factual situations as they deliver diagnoses of DS. Based on this web tutorial that integrated prenatal and postnatal information into virtual patient scenarios, the study assessed pediatrics residents' knowledge and comfort in delivering a diagnosis of DS pre and postnatally. A separate survey, given at the same time, asked for residents' perception of their need for this training. Ninety-one volunteer residents from 10 pediatric training programs across the country participated. The tutorial yielded significant improvement in knowledge and a significant decrease in perceived level of discomfort in both ambiguous situations and more medically certain contexts related to a DS diagnosis. In addition, across all pediatric resident groups (by year, gender, and performance on the knowledge test and the comfort scale), residents strongly agreed that this type of training was beneficial for themselves, other residents, practicing physicians, and other medical professionals. This study suggests that web-based, interactive, multi-media training may be an effective tool for improving resident physician comfort with both ambiguous and more medically certain situations in delivering a diagnosis of DS to families. © 2012 Wiley Periodicals, Inc.

Basal cell nevus syndrome (BCNS), also known as Gorlin syndrome (OMIM #109400) is a well-described rare autosomal dominant condition due to haploinsufficiency of PTCH1. With the availability of comparative genomic hybridization arrays, increasing numbers of individuals with microdeletions involving this locus are being identified. We present 10 previously unreported individuals with 9q22.3 deletions that include PTCH1. While 7 of the 10 patients (7 females, 3 males) did not meet strict clinical criteria for BCNS at the time of molecular diagnosis, almost all of the patients were too young to exhibit many of the diagnostic features. A number of the patients exhibited metopic craniosynostosis, severe obstructive hydrocephalus, and macrosomia, which are not typically observed in BCNS. All individuals older than a few months of age also had developmental delays and/or intellectual disability. Only facial features typical of BCNS, except in those with prominent midforeheads secondary to metopic craniosynostosis, were shared among the 10 patients. The deletions in these individuals ranged from 352 kb to 20.5 Mb in size, the largest spanning 9q21.33 through 9q31.2. There was significant overlap of the deleted segments among most of the patients. The smallest common regions shared among the deletions were identified in order to localize putative candidate genes that are potentially responsible for each of the non-BCNS features. These were a 929 kb region for metopic craniosynostosis, a 1.08 Mb region for obstructive hydrocephalus, and a 1.84 Mb region for macrosomia. Additional studies are needed to further characterize the candidate genes within these regions. © 2011 Wiley Periodicals, Inc.

We report on clinical and cytogenetic studies in a 7-year-old child with moderate intellectual disability, short stature, mild dysmorphism, and hearing loss. R-chromosome banding showed a de novo autosomal marker originating from the 17p chromosome segment in all cells analyzed. Array comparative genome hybridization (aCGH) was used to determine the gene content and proximal and distal breakpoints of the small supernumerary marker chromosome (SMC). These breakpoints mapped to the centromere of chromosome 17 and the 17p11.2 region, respectively. Unexpectedly, aCGH analysis also revealed a de novo deletion of 800 kb encompassing six genes in the 17q23.2 region, including MED13 (also known as THRAP1). We compared our patient with other reported cases of SMC(17), to determine the respective contributions of the duplication and the deletion to the phenotype. We cannot entirely exclude a minor role for the SMC(17), but we suggest that MED13 haploinsufficiency was responsible for the phenotype of the patient particularly the cataract, hearing loss and semicircular canal dysplasia. Moreover, this report highlights the usefulness of aCGH for the specification of gene content in cases of abnormality, facilitating the establishment of accurate phenotype–genotype correlations and the detection of other, complex rearrangements. © 2011 Wiley Periodicals, Inc.

We report on the fifth case, and oldest reported patient, of an individual affected with mosaic tetrasomy 5p resulting from an isochromosome 5p [i(5)(p10)] marker chromosome. A syndrome of mosaic tetrasomy 5p is defined, and includes the following features seen in the reported cases: developmental delay, seizures, ventriculomegaly (other brain anomalies), small stature/growth delay and mosaic pigmentary skin changes. Other findings include various dysmorphic facial features as well as hand and foot anomalies. This syndrome is likely more common than suggested in the literature, as the clinical presentation can be variable, and the chromosome anomaly is unlikely to be found on routine karyotype of peripheral blood lymphocytes. The i(5)(p10) marker chromosome is found only as a mosaic anomaly, with levels ranging from 0% to 10% in cultured lymphocytes to 12–85% in cultured skin fibroblasts. Microarray analysis performed on unstimulated lymphocytes from the patient in this report did not detect any evidence of the chromosome abnormality, indicating that this methodology may not be useful as a diagnostic tool in this disorder. Diagnosis of the mosaic tetrasomy 5p syndrome will rely on good clinical assessment, and appropriate cytogenetic studies, including analysis of skin fibroblasts. A child with unexplained developmental delay, seizures, hypotonia, and ventriculomegaly with or without dysmorphic features should be assessed carefully for pigmentary changes of the skin. If a diagnosis of mosaic 5p tetrasomy is suspected, karyotype of cultured fibroblasts in addition to routine cytogenetic analysis, to look for this marker chromosome is warranted. © 2012 Wiley Periodicals, Inc.

15q24 deletion syndrome is a recently-described chromosomal disorder, characterized by developmental delay, growth deficiency, distinct facial features, digital abnormalities, loose connective tissue, and genital malformations in males. To date, 19 patients have been reported. We report on a 13-year-old boy with this syndrome manifesting childhood myelodysplastic syndrome (MDS). He had characteristic facial features, hypospadias, and mild developmental delay. He showed neutropenia and thrombocytopenia for several years. At age 13 years, bone marrow examination was performed, which showed a sign suggestive of childhood MDS: mild dysplasia in the myeloid, erythroid, and megakaryocytic cell lineages. Array comparative genomic hybridization (array CGH) revealed a de novo 3.4 Mb 15q24.1q24.3 deletion. Although MDS has not been described in patients with the syndrome, a boy was reported to have acute lymphoblastic leukemia (ALL). The development of MDS and hematological malignancy in the syndrome might be caused by the haploinsufficiency of deleted 15q24 segment either alone or in combination with other genetic abnormalities in hematopoietic cells. Further hematological investigation is recommended to be beneficial if physical and hematological examination results are suggestive of hematopoietic disturbance in patients with the syndrome. © 2011 Wiley Periodicals, Inc.

The 12q14 microdeletion syndrome is characterized by microcephaly, short stature, osteopoikilosis, weight deficiency, and learning disabilities. We report on a mother and daughter with a 12q14 microdeletion. To our knowledge these are the first reported familial cases with the syndrome. We also discuss the genes in the deleted area that may be contributing to the phenotype. © 2011 Wiley Periodicals, Inc.

Aberrant methylation at different imprinted loci has been reported for several congenital imprinting disorders, that is, Silver–Russell syndrome (SRS), but the coincidental occurrence of aberrant methylation and uniparental disomy (UPD) has not yet been described. We report on a patient initially diagnosed with SRS carrying a segmental maternal UPD of chromosome 7 [upd(7q)mat]. By further screening the patient's DNA for methylation defects on other chromosomes we identified a hypomethylation of the paternally methylated DLK1/GTL2 locus in 14q32, an epigenotype typically associated with the upd(14)mat phenotype. Detailed clinical analysis confirmed the molecular finding in the patient indicating that the 14q32 epimutation was clinically preponderant. The parallel occurrence of upd(7q)mat and a DLK1/GTL2 hypomethylation in the same patient is a unique finding. Indeed, both disturbances might have occurred coincidentally, but it can also be hypothesized that the upd(7q)mat as the initial genomic mutation represents a trans-acting mutation causing an aberrant methylation in 14q32. © 2012 Wiley Periodicals, Inc.

Interstitial deletions of the distal part of chromosome 2p are rare, with only six reported cases involving regions from 2p23 to 2pter. Most of these were cytogenetic investigations. We describe a 14-year-old boy with an 8.97 Mb deletion of 2p23.3–24.3 detected by array comparative genomic hybridization (array CGH) who had intellectual disability (ID), unusual facial features, cryptorchidism, skeletal myopathy, dilated cardiomyopathy (DCM), and postnatal overgrowth (macrocephaly and tall stature). We compared the clinical features of the present case to previously described patients with an interstitial deletion within this chromosomal region and conclude that our patient exhibits a markedly different phenotype. Additional patients are needed to further delineate phenotype–genotype correlations © 2012 Wiley Periodicals, Inc.

Vici syndrome is a rare congenital multisystem disorder characterized by agenesis of the corpus callosum, hypotonia, developmental delay, hypopigmentation, cataract, cardiomyopathy, and immunological abnormalities. Recurrent infections, mainly affecting the respiratory tract, have been reported in the majority of cases, representing an important risk factor for morbidity and mortality. The immunological phenotype of patients is extremely variable, ranging from a combined immunodeficiency to nearly normal immunity. We report on a new patient with Vici syndrome, in whom we have extensively investigated immunological features. Despite a mild impairment of the cellular compartment, a defect of humoral immunity was found, requiring treatment with intravenous immunoglobulin. A wider knowledge of immune system abnormalities of Vici syndrome will help to plan strategies for treatment and prevention of infections, such as immunoglobulin replacement and antimicrobial prophylaxis, resulting in improved survival rates. © 2011 Wiley Periodicals, Inc.

Since its first description by Vici et al. [1988], further reports have continued to broaden the clinical phenotype of this rare multisystem disorder. Main features of agenesis of corpus callosum (ACC), hypopigmentation, immunodeficiency/recurrent infections, cataracts, severe failure to thrive, and profound psychomotor delay have been reported in all cases. An additional feature is the recent evidence for neuromuscular involvement. We describe a female infant with the above core features in whom an initial rapid neurological deterioration and associated transient left ventricular hypertrophy and liver dysfunction was followed by relative clinical stability after ten months of age. This case further underlines the clinical phenotype of Vici syndrome as an early onset neurodegenerative disorder with hypopimentation, recurrent infections and muscle findings indicating myopathic and neurogenic features. © 2011 Wiley Periodicals, Inc.

The term “phacomatosis” refers to a growing number of sporadic genetic skin disorders characterized by the combination of two or more different nevi and possibly resulting from non-allelic twin spotting. While phacomatosis pigmentovascularis (PPV) and pigmentokeratotica represent the most common patterns, some patients do not fit with either condition and are temporarily classified as unique phenotypes. We report on an 8-year-old boy with striking right hemihypoplasia, resulting in limb asymmetry and fixed dislocation of right hip. Skin on the affected side showed three distinct nevi: (i) A whorled, hairless nevus of the scalp in close proximity with (ii) epidermal hyperpigmentation following lines of Blaschko on the neck and right upper limb, and (iii) multiple telangiectatic nevi of the right lower limb and hemiscrotum. Didymosis atricho-melanotica was proposed for the combination of adjacent patchy congenital alopecia and linear hyperpigmentation, while phacomatosis atricho-pigmento-vascularis appears to define the entire cutaneous phenotype, thus implying the involvement of three neighboring loci influencing the development of distinct constituents of the skin. Given the striking asymmetry of the observed phenotype, the effect of mosaicism (either genomic or functional) for a mutation in a single gene with pleiotropic action and influenced by the lateralization pattern of early development cannot be excluded. © 2012 Wiley Periodicals, Inc.

Mucopolysaccharidosis type II (MPS II, Hunter syndrome) is an X-linked lysosomal storage disease caused by a deficiency of iduronate-2-sulfatase (IDS). Two affected girls with moderate and severe forms of MPS II with normal karyotypes and increased urinary dermatan sulphate and heparin sulphate excretion and marked deficiencies of IDS activity are reported. Molecular studies showed that case 1 has a heterozygous mutation c.1568A > G (p.Y523C) associated with almost totally skewed inactivation of the normal maternal X chromosome, and case 2 has a heterozygous deletion that includes exons 1–4 of IDS (minimal deletion range c.1–103_184del). The multi-exon deletion correlated with early onset of the disease and severe phenotype with intellectual disability, whereas the missense mutation was associated with moderate developmental delay. Although genotype–phenotype correlation in MPS II is difficult, gene deletions seem to correlate with more severe clinical manifestation of the disease. Enzyme replacement therapy (ERT) in these two females resulted in disease stabilization in both. © 2012 Wiley Periodicals, Inc.

We identified a novel missense mutation, c.424G>C (p.Val142Leu) in PRPS1 in a patient with uric acid overproduction without gout but with developmental delay, hypotonia, hearing loss, and recurrent respiratory infections. The uric acid overproduction accompanying this combination of symptoms suggests that the patient presented with phosphoribosylpyrophosphate (PRPP) synthetase superactivity, but recurrent infections have not been associated with superactivity until now. However, recurrent infections are a prominent feature of patients with Arts syndrome, which is caused by PRPS1 loss-of-function mutations, indicating that the patient reported here has an intermediate phenotype. Molecular modeling predicts that the p.Val142Leu change affects both allosteric sites that are involved in inhibition of PRPS1 and the ATP-binding site, which suggests that this substitution can result both in a gain-of-function and loss-of-function of PRPP synthetase. This finding is in line with the normal PRPP synthetase activity in fibroblasts and the absence of activity in erythrocytes of the present patient. We postulate that the overall effect of the p.Val142Leu change on protein activity is determined by the cell type, being a gain-of-function in proliferating cells and a loss-of-function in postmitotic cells. Our results show that missense mutations in PRPS1 can cause a continuous spectrum of features ranging from progressive non-syndromic postlingual hearing impairment to uric acid overproduction, neuropathy, and recurrent infections depending on the functional sites that are affected. © 2012 Wiley Periodicals, Inc.