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Summary Background Identification of chromosomal aneuploidies and copy number variants that are associated with fetal structural anomalies has substantial value. Although whole-exome sequencing (WES) has been applied to case series of a few selected prenatal cases, its value in routine clinical settings has not been prospectively assessed in a large unselected cohort of fetuses with structural anomalies. We therefore aimed to determine the incremental diagnostic yield (ie, the added value) of WES following uninformative results of standard investigations with karyotype testing and chromosomal microarray in an unselected cohort of sequential pregnancies showing fetal structural anomalies. Methods In this prospective cohort study, the parents of fetuses who were found to have a structural anomaly in a prenatal ultrasound were screened for possible participation in the study. These participants were predominantly identified in or were referred to the Columbia University Carmen and John Thain Center for Prenatal Pediatrics (New York, NY, USA). Fetuses with confirmed aneuploidy or a causal pathogenic copy number variant were excluded from WES analyses. By use of WES of the fetuses and parents (parent–fetus trios), we identified genetic variants that indicated an underlying cause (diagnostic genetic variants) and genetic variants that met the criteria of bioinformatic signatures that had previously been described to be significantly enriched among diagnostic genetic variants. Findings Between April 24, 2015, and April 19, 2017, 517 sequentially identified pregnant women found to have fetuses with a structural anomaly were screened for their eligibility for inclusion in our study. 71 (14%) couples declined testing, 87 (17%) trios were missing at least one DNA sample (from either parent or the fetus), 69 (13%) trios had a clinically relevant abnormal karyotype or chromosomal microarray finding, 51 (10%) couples did not consent to WES or withdrew consent, and five (1%) samples were not of good enough quality for analysis. DNA samples from 234 (45%) eligible trios were therefore used for analysis of the primary outcome. By use of trio sequence data, we identified diagnostic genetic variants in 24 (10%) families. Mutations with bioinformatic signatures that were indicative of pathogenicity but with insufficient evidence to be considered diagnostic were also evaluated; 46 (20%) of the 234 fetuses assessed were found to have such signatures. Interpretation Our analysis of WES data in a prospective cohort of unselected fetuses with structural anomalies shows the value added by WES following the use of routine genetic tests. Our findings suggest that, in cases of fetal anomalies in which assessment with karyotype testing and chromosomal microarray fail to determine the underlying cause of a structural anomaly, WES can add clinically relevant information that could assist current management of a pregnancy. The unique challenges of WES-based prenatal diagnostics require analysis by a multidisciplinary team of perinatal practitioners and laboratory specialists. Funding Institute for Genomic Medicine (Columbia University Irving Medical Center).

Objective Growing use of clinical exome sequencing (CES) has led to an increased burden of genomic education. Self-guided educational tools can minimize the educational burden for genetic counselors (GCs). The effectiveness of these tools must be evaluated. Methods Parents of patients offered CES were randomized to watch educational videos before their visit or to receive routine care. Parents and GCs were surveyed about their experiences following the sessions. The responses of the video (n = 102) and no-video (n = 105) groups were compared. Results GCs reported no significant differences between parents in the video and no-video groups on genetics knowledge or CES knowledge. In contrast, parents’ scores on genetics knowledge questions were lower in the video than no-video group (p = 0.007). Most parents reported the videos were informative, and the groups did not differ in satisfaction with GCs or decisions to have CES. Conclusion GCs and parents perceived the videos to be beneficial. However, lower scores on genetics knowledge questions highlight the need for careful development of educational tools. Practice implications Educational tools should be developed and assessed for effectiveness with the input of all stakeholders before widespread implementation. Better measures of the effectiveness of these educational tools are needed.

Ataxia-telangiectasia (A-T) is an autosomal recessive chromosome breakage disorder caused by mutations in the ATM gene. Typically, it presents in early childhood with progressive cerebellar dysfunction along with immunodeficiency and oculocutaneous telangiectasia. An increased risk of malignancy is also associated with the syndrome and, rarely, may be the presenting feature in small children. We describe a 17-year-old boy with slurred speech, mild motor delays and learning disability diagnosed with atypical A-T in the setting of T-cell acute lymphoblastic leukemia. Suspicion for A-T was raised after review of a peripheral blood karyotype demonstrating rearrangements involving chromosomes 7 and/or 14. The diagnosis was confirmed after molecular testing identified a novel homozygous missense variant in ATM (c.5585T>A; p.Leu1862His) that resulted in protein instability and abolished serine/threonine protein kinase activity. To our knowledge, this is the first report of concurrent A-T and lymphoid malignancy diagnoses in an older child or adult with only mild neurological disease. Our experience suggests that screening for the disorder should be considered in any individual with lymphoid malignancy and neurological findings, especially as radiation and certain chemotherapy protocols are contraindicated in A-T.

ContextX-linked acrogigantism (X-LAG), a condition of infant-onset acrogigantism marked by elevated GH, IGF-1, and prolactin (PRL), is extremely rare. Thirty-three cases, including three kindreds, have been reported. These patients have pituitary adenomas that are thought to be mixed lactotrophs and somatotrophs.Case DescriptionThe patient’s mother, diagnosed with acrogigantism at 21 months, underwent pituitary tumor excision at 24 months. For more than 30 years, stable PRL, GH, and IGF-1 concentrations and serial imaging studies indicated no tumor recurrence. During preconception planning, X-LAG was diagnosed: single-nucleotide polymorphism microarray showed chromosome Xq26.3 microduplication. After conception, single-nucleotide polymorphism microarray on a chorionic villus sample showed the same microduplication in the fetus, confirming familial X-LAG. The infant grew rapidly with rising PRL, GH, and IGF-1 concentrations and an enlarging suprasellar pituitary mass, despite treatment with bromocriptine. At 15 months, he underwent tumor resection. The pituitary adenoma resembled the mother’s pituitary adenoma, with tumor cells arranged in trabeculae and glandular structures. In both cases, many tumor cells expressed PRL, GH, and pituitary-specific transcription factor-1. Furthermore, the tumor expressed other lineage-specific transcription factors, as well as SOX2 and octamer-binding transcription factor 4, demonstrating the multipotentiality of X-LAG tumors. Both showed an elevated Ki-67 proliferation index, 5.6% in the mother and 8.5% in the infant, the highest reported in X-LAG.ConclusionsThis is a prenatally diagnosed case of X-LAG. Clinical follow-up and biochemical evaluation have provided insight into the natural history of this disease. Expression of stem cell markers and several cell lineage-specific transcription factors suggests that these tumors are multipotential.

Hexokinase 1 (HK1) phosphorylates glucose to glucose-6-phosphate, the first rate-limiting step in glycolysis. Homozygous and heterozygous variants in HK1 have been shown to cause autosomal recessive non-spherocytic hemolytic anemia, autosomal recessive Russe type hereditary motor and sensory neuropathy, and autosomal dominant retinitis pigmentosa (adRP). We report seven patients from six unrelated families with a neurodevelopmental disorder associated with developmental delay, intellectual disability, structural brain abnormality, and visual impairments in whom we identified four novel, de novo missense variants in the N-terminal half of HK1. Hexokinase activity in red blood cells of two patients was normal, suggesting that the disease mechanism is not due to loss of hexokinase enzymatic activity.

Background L-serine plays an essential role in neuronal development and function. Although a non-essential amino acid, L-serine must be synthesised within the brain because of its poor permeability by the blood–brain barrier. Within the brain, its synthesis is confined to astrocytes, and its shuttle to neuronal cells is performed by a dedicated neutral amino acid transporter, ASCT1. Methods and results Using exome analysis we identified the recessive mutations, p.E256K, p.L315fs, and p.R457W, in SLC1A4 , the gene encoding ASCT1, in patients with developmental delay, microcephaly and hypomyelination; seizure disorder was variably present. When expressed in a heterologous system, the mutations did not affect the protein level at the plasma membrane but abolished or markedly reduced L-serine transport for p.R457W and p.E256K mutations, respectively. Interestingly, p.E256K mutation displayed a lower L-serine and alanine affinity but the same substrate selectivity as wild-type ASCT1. Conclusions The clinical phenotype of ASCT1 deficiency is reminiscent of defects in L-serine biosynthesis. The data underscore that ASCT1 is essential in brain serine transport. The SLC1A4 p.E256K mutation has a carrier frequency of 0.7% in the Ashkenazi-Jewish population and should be added to the carrier screening panel in this community.

Despite the clinical significance of balanced chromosomal abnormalities (BCAs), their characterization has largely been restricted to cytogenetic resolution. We explored the landscape of BCAs at nucleotide resolution in 273 subjects with a spectrum of congenital anomalies. Whole-genome sequencing revised 93% of karyotypes and demonstrated complexity that was cryptic to karyotyping in 21% of BCAs, highlighting the limitations of conventional cytogenetic approaches. At least 33.9% of BCAs resulted in gene disruption that likely contributed to the developmental phenotype, 5.2% were associated with pathogenic genomic imbalances, and 7.3% disrupted topologically associated domains (TADs) encompassing known syndromic loci. Remarkably, BCA breakpoints in eight subjects altered a single TAD encompassing MEF2C, a known driver of 5q14.3 microdeletion syndrome, resulting in decreased MEF2C expression. We propose that sequence-level resolution dramatically improves prediction of clinical outcomes for balanced rearrangements and provides insight into new pathogenic mechanisms, such as altered regulation due to changes in chromosome topology. info:eu-repo/semantics/publishedVersion

Reports of the use of whole-exome sequencing in clinical practice are limited. We report our experience with whole-exome sequencing in 115 patients in a single center and evaluate its feasibility and clinical usefulness in clinical care. Whole-exome sequencing was utilized based on the judgment of three clinical geneticists. We describe age, gender, ethnicity, consanguinity, indication for testing, family history, insurance, laboratory results, clinician interpretation of results, and impact on patient care. Most patients were children (78.9%). The most common indications for testing were birth defects (24.3%) and developmental delay (25.2%). We identified four new candidate human disease genes and possibly expanded the disease phenotypes associated with five different genes. Establishing a diagnosis led to discontinuation of additional planned testing in all patients, screening for additional manifestations in eight, altered management in fourteen, novel therapy in two, identification of other familial mutation carriers in five, and reproductive planning in six. Our results show that whole-exome sequencing is feasible, has clinical usefulness, and allows timely medical interventions, informed reproductive choices, and avoidance of additional testing. Our results also suggest phenotype expansion and identification of new candidate disease genes that would have been impossible to diagnose by other targeted testing methods. Genet Med 16 12, 922–931.

Objective: To investigate prenatal ultrasonographic findings associated with megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS). Methods: A PubMed search was performed using the terms ‘MMIHS', ‘MMIH' and ‘prenatal diagnosis'. Results: A total of 50 cases were analyzed. Prenatal diagnosis was achieved in 26% of cases. In 54% of patients with a correct antenatal diagnosis there was a previously affected sibling. Fetal megacystis with or without hydroureteronephrosis was the most common initial ultrasonographic finding (88%). While megacystis eventually complicated all fetal presentations, isolated bilateral hydronephrosis and isolated dilated stomach were noted (in 10 and 2% of cases, respectively) prior to megacystis. The initial sonographic abnormality was most commonly detected (in 70% of patients) in the second trimester. Amniotic fluid was normal in 69% and increased in 27% of cases. Gastrointestinal abnormalities were noted in 24% of pregnancies. Conclusion: MMIHS should be prenatally suspected when fetal megacystis is associated with a normal or increased amount of amniotic fluid and normal external genitalia, especially in the setting of a suggestive family history. Associated gastrointestinal findings support this diagnosis. Isolated bilateral hydronephrosis may precede the development of megacystis. Due to preserved renal function and a general absence of oligohydramnios, no rationale exists for vesicoamniotic shunt placement.

We present a case of an otherwise healthy infant with a localized patch of phylloid hypopigmentation bordered by terminal hairs on the back. We believe that this is a unique clinical entity and propose the term "phylloid terminal hair nevus." We believe that this is a localized form of phylloid hypomelanosis that is not associated with extracutaneous abnormalities.

In guanosine diphosphate (GDP)-mannose pyrophosphorylase A (GMPPA), we identified a homozygous nonsense mutation that segregated with achalasia and alacrima, delayed developmental milestones, and gait abnormalities in a consanguineous Pakistani pedigree. Mutations in GMPPA were subsequently found in ten additional individuals from eight independent families affected by the combination of achalasia, alacrima, and neurological deficits. This autosomal-recessive disorder shows many similarities with triple A syndrome, which is characterized by achalasia, alacrima, and variable neurological deficits in combination with adrenal insufficiency. GMPPA is a largely uncharacterized homolog of GMPPB. GMPPB catalyzes the formation of GDP-mannose, which is an essential precursor of glycan moieties of glycoproteins and glycolipids and is associated with congenital and limb-girdle muscular dystrophies with hypoglycosylation of α-dystroglycan. Surprisingly, GDP-mannose pyrophosphorylase activity was unchanged and GDP-mannose levels were strongly increased in lymphoblasts of individuals with GMPPA mutations. This suggests that GMPPA might serve as a GMPPB regulatory subunit mediating feedback inhibition of GMPPB instead of displaying catalytic enzyme activity itself. Thus, a triple-A-like syndrome can be added to the growing list of congenital disorders of glycosylation, in which dysregulation rather than mere enzyme deficiency is the basal pathophysiological mechanism.

Severe congenital neutropenia type IV (SCN IV) is a syndrome of severe neutropenia, cardiac and urogenital defects, prominent superficial veins, facial dysmorphism, failure to thrive (FTT), and intermittent thrombocytopenia, caused by a glucose-6-phosphatase catalytic subunit 3 (G6PC3) gene mutation. SCN IV has been linked to glycogen storage disease type 1b as both disorders involve disruption of the glucose-6-phosphatase/glucose-6-phosphate transporter complex, leading to arrested neutrophil maturation. Emerging evidence suggests that neutrophil function plays an important role in intestinal integrity, evidenced by inflammatory bowel disease in certain neutropenic patients. Here, we report 3 unrelated Hispanic males from the Dominican Republic with classic features of SCN IV found to share an identical inherited canonical splice-site mutation of the G6PC3 gene (c.218+1GA). All 3 patients presented with severe FTT and gastrointestinal manifestations. Two of the patients had significant improvement in growth and resolution of gastrointestional symptoms with initiation of granulocyte colony-stimulating factor. We hypothesize that the gene variant described represents a founder mutation in the Dominican Republic, the first to be described in this geographical region. We discuss the potential associations between neutropenia and gastrointestinal disease with FTT and the role of granulocyte colony-stimulating factor in improving neutrophil count and intestinal integrity and growth.

Purpose: To describe a case of a child with a known history of pigmentary mosaicism suggestive of Hypomelanosis of Ito presenting with unilateral leukocoria, who was ultimately diagnosed with retinoblastoma. Methods: A report of a 16-month-old girl with pigmentary mosaicism and unilateral retinoblastoma. Results: A previously healthy 16-month-old girl with a diagnosis of a mosaic hypopigmentation at the age of 6 months based on a linear and whorled pattern of skin hypopigmentation along the lines of Blaschko, presented with unilateral strabismus, leukocoria, retinal detachment, and sub-retinal exudation. Hypomelanosis of Ito and other similar neuro- cutaneous syndromes are known to be associated with abnormal retinal pigmentation, vascular abnormalities, and retinal detachment. Examination included a fluorescein angiogram, ultrasonography, and an MRI of the brain and orbits that demonstrated features consistent with retinoblastoma. Given these findings and a flat electroretinogram, the eye was enucleated with final pathologic confirmation of retinoblastoma. Conclusions: Previously unreported presentation of unilateral retinoblastoma in a child with pigmentary mosaicism.

Various inactivating mutations in guanine nucleotide−binding protein, alpha−stimulating activity polypeptide1 (GNAS1) gene have been described with poor phenotype correlation. Pseudohypoparathyroidism type 1a (PHP1a) results from an inactivating mutation in the GNAS1 gene. Hormone resistance occurs not only to parathyroid hormone (PTH), but typically also to other hormones which signal via G protein coupled receptors including thyroid stimulating hormone (TSH), gonadotropins, and growth hormone releasing hormone. In addition, the phenotype of Albright hereditary osteodystrophy (AHO) is observed, which may include short stature, round facies, brachydactyly, obesity, ectopic soft tissue or dermal ossification (osteoma cutis) and psychomotor retardation with variable expression. We present a 2−year−old boy with PHP 1A who initially presented at age 3 weeks with congenital hypothyroidism. By 17 months of age, he manifested osteoma cutis, psychomotor retardation, obesity, brachydactyly and resistance to PTH with normocalcemia and mild hyperphosphatemia. Genetic analysis revealed a novel mutation in exon 13 of GNAS1 in our patient. This mutation, c.1100_1101insA, resulted in a frameshift and premature truncation of bases downstream. This mutation was also found in the mother of this patient who was also noted to have short stature, obesity, brachydactyly and non progressive osteoma cutis, but no hormone resistance. We report a novel heterozygous mutation causing PHP1A with PTH and TSH resistance and AHO which has not been described previously. PHP1A is also a rare presentation of congenital hypothyroidism. Conflict of interest:None declared.

Thyroid dyshormonogenesis continues to be a significant cause of congenital hypothyroidism. Over time, forms of thyroid dyshormonogenesis can result in goiter, which can lead to difficult management decisions as the pathologic changes can both mimic or lead to thyroid cancer.Herein we describe the cases of two brothers diagnosed with congenital hypothyroidism, with initial findings consistent with thyroid dyshormonogenesis. One brother eventually developed multinodular goiter with complex pathology on biopsy, resulting in thyroidectomy.Whole exome sequencing revealed the brothers carry a novel frameshift mutation in thyroperoxidase; the mutation, while not previously described, was likely both deleterious and pathogenic.These cases highlight the complex pathology that can occur within thyroid dyshormonogenesis, with similar appearance to possible thyroid cancer, leading to complex management decisions. They also highlight the role that a genetic diagnosis can play in interpreting the impact of dyshormonogenesis on nodular thyroid development, and the need for long-term follow-up in these patients.

Bohring-Opitz syndrome (BOS) was first described by Bohring et al. [1999]. The authors reported four cases which had several features in common, including a prominent metopic suture, hypertelorism, exophthalmos, cleft lip and palate, limb anomalies, as well as difficulty feeding with severe developmental delays. In almost 50% of cases that meet the clinical criteria for BOS, de novo frameshift and nonsense mutations in the ASXL1 gene have been detected, suggesting that loss of function of this gene is a major cause. We report on the clinical characterization of one young female patient who was evaluated because of severe developmental delays, failure to thrive, and multiple minor anomalies and was clinically diagnosed with BOS. Whole exome sequencing analysis detected one novel disruptive frameshift mutation in the ASXL1 gene and we were also able to confirm the presence of two CFTR mutations associated with her chronic pancreatitis with acute severe breakthrough attacks requiring multiple ICU admissions. This latter complication of pancreatitis further contributed to the complexity of the clinical presentation and represents an independent genetic finding. Our case report emphasizes the importance of highly specific phenotypic characterization of patients with complex phenotypes before proceeding with molecular studies. That approach will lead to more accurate molecular data interpretation and better clinical genetic diagnosis, particularly for those patients with rare, difficult-to-diagnose disorders.

Common FTO variants are associated with obesity. However, it has recently been shown that homozygous FTO c.947G>A variant, which predicts p.R316Q, and c.956C>T, which predicts p.S319F, are associated with a malformation syndrome inherited in an autosomal recessive pattern. We present a similar homozygous FTO c.965G>A variant that predicts p.R322Q, associated with a lethal malformation syndrome in a consanguineous Yemeni family. Functional studies showed that the p.R316Q, p.S219F, and p.R322Q variants render the FTO protein inactive. We further expand on the phenotype of homozygous FTO loss-of-function mutations to include eye abnormalities, gingival overgrowth, craniosynostosis, and cutaneous photosensitivity.

We report cutis verticis gyrata in a patient with Noonan syndrome. While cutis vertices gyrata has been shown to have a strong association with chromosomal abnormalities, especially Turner syndrome, this infant represents only the second reported instance of cutis verticis gyrata occurring in a patient with Noonan syndrome.

Previous reports of cognitive functioning in children with the 22q11 Deletion Syndrome have reported marked variability in IQ and achievement subtest scores. Studies have begun to explore neuropsychological function in 22q11 DS however results are inconsistent and the profile incomplete. We assessed 40 children ages 5–12 with 22q11 DS. Consistent with past results, visual-spatial memory was significantly lower than verbal memory. Differentially lowered scores were found only in visual attention, working memory and motor function. Contrary with some past results quantitative, verbal ability, and visual spatial memory scores were within 1 SD from the standardization sample mean. Motor behavior, not typically discussed with regard to 22q11 DS school-age children, may be critical to incorporate in neurocognitive studies of children with 22q11 DS. Implications of these findings are considered with regard to past results.

The 22q11 chromosomal deletion syndrome (22q11 DS) is associated with learning disabilities and a complex neuropsychological profile. Previous findings have suggested that executive attention deficits might underlie other neurocognitive anomalies. We administered the child Attention Network Test (ANT) to 52 children ages 5.0 to 11.5, 32 22q11 DS children (19 girls) and 20 controls (13 girls) and assessed the efficiency of segregated executive, orienting, and alerting networks. We hypothesized that 22q11 DS children have impaired executive network efficiency as compared to control siblings. The internal validity of the child ANT was confirmed for this population. Analysis of variance results showed significant main effects for flanker and cue types and no interaction effect in either 22q11 DS children or control siblings. Compared to control siblings, 22q11 DS children had significantly larger (less efficient) executive network scores, significantly increased errors on only incongruent trials, and a significant correlation between executive network scores and accuracy. The implications of these findings for future neurocognitive studies of 22q11 DS children are considered.

Objective. The objective of this study was to review the problem of lumbar gibbus in children with storage diseases and bone dysplasias utilizing plain films and MR imaging. Materials and methods. Clinical histories and radiographic images in five patients with storage diseases [four mucopolysaccharidosis (MPS) and one mucolipidosis] and two with achondroplasia were reviewed. The International Skeletal Dysplasia Registry (Los Angeles, Calif.), surveyed for all patients with lumbar gibbus and skeletal dysplasias, provided 12 additional cases. Results. All patients had localized gibbus of the upper lumbar spine, characterized by anterior wedging and posterior displacement of the vertebrae at the apex of the curve, producing a beaked appearance. The curve, exaggerated in the sitting or standing position, was most severe in the two patients with MPS-IV (one of whom died). Both developed severe neurologic signs and symptoms requiring surgical intervention. In four patients, MR images demonstrated the apex of the curve to be at or below the conus. Two patients demonstrated anterior herniation of the intervertebral discs at the apex of the curve, though the signal intensity of the intervertebral discs was normal. Conclusion. Lumbar gibbus has important neurologic and orthopedic implications, and is most severe in patients with MPS. The etiology of the gibbus with vertebral beaking is multifactorial and includes poor truncal muscle tone, weight-bearing forces, growth disturbance and anterior disc herniation. The curve is generally at or below the conus. Neurologic complications are unusual, although orthopedic problems can arise. Due to their longer survival, patients with achondroplasia or Morquio's disease are more vulnerable to eventual gibbus-related musculoskeletal complications.

Mutations in the RASA-1 gene underlie several related disorders of vasculogenesis. Capillary malformation-arteriovenous malformation (CM-AVM) is one such entity and was recently encountered in a neonate who demonstrated its clinical and radiologic features. A single mutation in the RASA-1 gene was detected. A novel flow reduction strategy was employed to a large AVM affecting the patient’s upper limb. The imaging findings, surgical procedure and patient’s improved post-operative state are described.

We report on two patients with overlapping small interstitial deletions involving regions 14q12 to 14q13.1. Both children had severe developmental delay, failure to thrive, microcephaly, and distinctive facial features, including abnormal spacing of the eyes, epicanthal folds, sloping forehead, low-set ears, rounded eyebrows with triangular media aspect and outer tapering, depressed and broad nasal bridge, small mouth, a long philtrum, and a prominent Cupid's bow. Brain MRI of both children showed partial agenesis of the corpus callosum. Our first patient had bilateral hypoplastic optic nerves causing blindness, mild hearing impairment, sinus arrhythmia, abnormal temperature regulation, frequent apneic episodes, myoclonic jerks, and opisthotonus. Our second patient had a seizure disorder confirmed by EEG, sleep apnea, chronic interstitial lung disease, and several episodes of pneumonia and gastroenteritis. Cytogenetic analysis showed a normal karyotype in Patient 1 and a unique apparently balanced three-way translocation in Patient 2 involving chromosomes 4, 14, and 11. High resolution SNP Oligonucleotide Microarray Analysis (SOMA) revealed a deletion in the proximal region of chromosome 14q overlapping with the deletion of our first patient, and no copy number changes in chromosomes 4 and 11. Here, we review and compare published cases with a deletion involving the 14q12-22.1 chromosomal region in an effort to correlate phenotype and genotype. We also examine the underlying genomic architecture to identify the possible mechanism of the chromosomal abnormality. Our review found a patient with a mirror duplication of our first patient's deletion, confirming the existence of an underlying genomic structural instability in the region. © 2011 Wiley-Liss, Inc.

Purpose: To demonstrate the accuracy and sensitivity of Representational Oligonucleotide Microarray Analysis (ROMA) to describe copy number changes in patients with chromosomal abnormalities. Methods: ROMA was performed using BglII digested DNA from two cases with cytogenetically detected deletions and one case with an unbalanced terminal rearrangement detected only by subtelomeric FISH. Hybridization was to an 85,000-probe oligonucleotide microarray, providing an average resolution of 35 kb. FISH was used to confirm some of the ROMA findings. Results: By ROMA, a del(13)(q14.3q21.2) was shown to be noncontiguous, with deletions extending from 53.08 to 61.40 Mb and from 72.88 to 74.83 Mb. The 10-Mb deletion contained only six known genes. FISH confirmed the noncontiguous nature of the deletion, as well as a small amplification in 6q that was also found in the patient's mother. A del(4)(q12q21.2) was found by ROMA to be 23 Mb in length, from 58.8 to 81.9 Mb on chromosome 4, in agreement with the cytogenetically assigned breakpoints. ROMA showed that an unbalanced “subtelomeric” rearrangement involved a 6-Mb deletion of 22q and an 8-Mb duplication of 16q. Conclusions: ROMA can define cytogenetic aberrations with extraordinary precision. Unexpected findings included the interrupted nature of the deletion in 13q and the large size of the imbalances in the “subtelomeric” rearrangement. Together with the information from the human genome sequence and proteomics, the ability to define rearrangements with “ultra-high” resolution will improve the ability to provide accurate prognosis both prenatally and postnatally to parents of offspring with chromosomal aberrations.

We describe three siblings with congenital myopathy, bullous eruption of the skin, secretory diarrhea, apparent zinc deficiency, failure to thrive, deafness, and microcephaly. The parents are not consanguineous and there are no other affected relatives. This new syndrome, which follows an apparent autosomal recessive pattern, appears to be distinct from known syndromes of secretory diarrhea, myopathy, deafness, microcephaly, and zinc deficiency.

We present transvaginal ultrasonographic findings of a fetus with Dandy-Walker malformation and associated massive obstructive hydrocephalus at 13 weeks' gestation. First-trimester ultrasonographic diagnosis of Dandy-Walker malformation is uncommon with only two such occurrences having been reported previously. These cases and recent reports of single gene transmission of this condition in some families emphasize the importance of first-trimester transvaginal ultrasound assessment especially in women with previously affected fetuses.

We describe the first case of a baby with maternal uniparental disomy of chromosome 2. Growth failure, hypothyroidism, and hyaline membrane disease were present at birth, and the first year of life was complicated by bronchopulmonary dysplasia. At age 14 months, motor and intellectual development were normal, but growth remained below the 10th centile. The baby was investigated for uniparental disomy because trisomy 2 mosaicism had been detected in a second trimester amniocentesis. This is the first reported case in which amniotic fluid chromosome mosaicism has been associated with uniparental disomy. Implications for prenatal diagnosis are considered.

3 páginas, 1 figura., Here, we report a family with one child affected by mild DEB. At birth, blistering and denuded areas were present together with the syndactyly of the second and third toes. By the age of 11 mo, blistering was significantly reduced but the blisters healed with hyperpigmented and hypopigmented scars and milia. Both parents and an older sibling were clinically unaffected, and there was no family history of consanguinity or of a blistering disorder or skin fragility.

Objective To investigate the incidence of aortic root dilatation in pectus excavatum. Design Retrospective medical record review and echocardiographic reanalysis. Setting Morgan Stanley Children's Hospital of New York–Presbyterian. Participants Surgical candidates with pectus excavatum (n = 37) and age-matched controls (n = 44) referred for an echocardiogram from 1994 to 2002. Interventions Two-dimensional and color Doppler transthoracic echocardiograms. Outcome Measures The aortic annulus and root were measured and z scores were calculated and compared. Medical records were reviewed for genetic evaluation. Results Patients with pectus excavatum and age-matched controls were reanalyzed. There was no difference in age, weight, height, or body surface area between patients and controls. There were no differences in the mean aortic annulus diameter, mean aortic annulus z score, or mean aortic root measurements. However, the aortic root z score was significantly higher in the pectus excavatum group compared with the controls: 0.9 (SD, 1.06) vs 0.0 (SD, 1.25) ( P = .001). There were more patients with an aortic root z score of 2 or greater in the pectus excavatum group (9 of 37 patients) than in the control group (0 of 43 controls), with a calculated odds ratio of 29.7 (95% confidence interval, 1.10-1.59). Genetic evaluation was performed in 5 patients with a pectus excavatum and dilated aortic root; 2 of them received diagnoses of Marfan syndrome. Conclusions Aortic root dilatation is more common in patients with pectus excavatum than in a control population. Echocardiographic screening may be useful in the identification of aortic root dilatation in patients with isolated pectus excavatum.

We report on an infant with the syndrome of Thrombocytopenia with Absent Radii (TAR) with severe lower-limb involvement. Amegakaryocytic thrombocytopenia was detected at 6 days when the platelet count was 11,000/microL. The platelet count increased steadily to 100,000/microL at 3 years. The patient required bilateral above-knee amputations for femorotibial synostoses. We recommend postponement of all elective operations until platelet counts are normal.

Four new cases are reported in which mosaicism for a supernumerary chromosome interpreted as an isochromosome for 12p [i(12p)] is present. In 2 cases seen in early childhood the mosaicism was present at a low level in peripheral blood and was documented in one case to be present with a higher frequency in fibroblast cultures from skin. These cases have clinical features compatible with those in previously reported cases of the Teschler-Nicola/Killian syndrome, many of whom have now been found to be mosaic for a similar i(12p) chromosome in fibroblast cultures. One case was diagnosed prenatally from amniotic fluid culture. The fourth case was a neonatal death, in which fibroblast cultures were established from muscle and increased activity of LDH-B was demonstrated, supporting the theory that the origin of the additional chromosome was from 12p. Loss of the cell line with the supernumerary chromosome occurs after long-term fibroblast culture. Previously unpublished studies showing increased LDH-B activity in case 1 of Pallister-Mosaic syndrome originally reported in 1977 are also reported. It is of interest that our 2 cases which did not survive birth and one previously published case diagnosed prenatally had diaphragmatic herniae.

Background Leri-Weill syndrome (LWS) is a genetic disorder caused by deletions or mutations in the SHOX gene or by deletions downstream of the gene and is classically characterized by short stature, mesomelic shortening of forearms and legs, and Madelung deformity. Correct identification of short stature homeobox-containing gene (SHOX) deficiency in children with growth problems is vital for appropriate initiation of growth hormone therapy. Method We report a phenotypically normal 23 day old male infant born to a father diagnosed with Leri-Weill syndrome at age 12 years with a documented SHOX deletion on his X chromosome. The patient’s fetal long bones had been found to be about three weeks delayed in growth on prenatal ultrasound during the second trimester. Results The infant underwent genetic evaluation at 23 days of life and was found to have a SHOX deletion on Yp11.32 identified using single nucleotide polymorphism microarray (SNP) analysis and confirmed by FISH using a SHOX gene probe. Conclusion We report the case of a male infant diagnosed with Leri-Weill syndrome with an unusual documented inheritance between father and son due to crossover between X and Y chromosomes during paternal meiosis. Our case is the youngest patient in literature documented by FISH analysis to have an X to Y chromosome transfer and the first of these patients diagnosed prior to onset of short stature or Madelung deformity. Our patient was identified prior to growth failure and can now be monitored for growth abnormalities with the ability to implement growth augmentation therapy without delay. Our case highlights the importance of advising affected SHOX patients of risks to future offspring and supports screening off-spring of parents carrying SHOX abnormalities regardless of sex.