Expansion and further delineation of the SETD5 phenotype leading to global developmental delay, variable dysmorphic features, and reduced penetrance.

Diagnostic exome sequencing (DES) has aided delineation of the phenotypic spectrum of rare genetic etiologies of intellectual disability (ID). A SET domain containing 5 gene (SETD5) phenotype of ID and dysmorphic features has been previously described in relation to patients with 3p25.3 deletions and in a few individuals with de novo sequence alterations. Herein, we present additional patients with pathogenic SETD5 sequence alterations. The majority of patients in this cohort and previously reported have developmental delay, behavioral/psychiatric issues, and variable hand and skeletal abnormalities. We also present an apparently unaffected carrier mother of an affected individual and a carrier mother with normal intelligence and affected twin sons. We suggest that the phenotype of SETD5 is more complex and variable than previously presented. Therefore, many features and presentations need to be considered when evaluating a patient for SETD5 alterations through DES.

Increased Frequency of Clonal Hematopoiesis of Indeterminate Potential in Bloom Syndrome Probands and Carriers.

Background: Bloom Syndrome (BSyn) is an autosomal recessive disorder caused by biallelic germline variants in BLM, which functions to maintain genomic stability. BSyn patients have poor growth, immune defects, insulin resistance, and a significantly increased risk of malignancies, most commonly hematologic. The malignancy risk in carriers of pathogenic variants in BLM (BLM variant carriers) remains understudied. Clonal hematopoiesis of indeterminate potential (CHIP) is defined by presence of somatic mutations in leukemia-related genes in blood of individuals without leukemia and is associated with increased risk of leukemia. We hypothesize that somatic mutations driving clonal expansion may be an underlying mechanism leading to increased cancer risk in BSyn patients and BLM variant carriers. Methods: To determine whether de novo or somatic variation is increased in BSyn patients or carriers, we performed and analyzed exome sequencing on BSyn and control trios. Results: We discovered that both BSyn patients and carriers had increased numbers of low-frequency, putative somatic variants in CHIP genes compared to controls. Furthermore, BLM variant carriers had increased numbers of somatic variants in DNA methylation genes compared to controls. There was no statistical difference in the numbers of de novo variants in BSyn probands compared to control probands. Conclusion: Our findings of increased CHIP in BSyn probands and carriers suggest that one or two germline pathogenic variants in BLM could be sufficient to increase the risk of clonal hematopoiesis. These findings warrant further studies in larger cohorts to determine the significance of CHIP as a potential biomarker of aging, cancer, cardiovascular disease, morbidity and mortality.

Second-trimester markers of fetal size in schizophrenia: a study of monozygotic twins.

OBJECTIVE: Since the second prenatal trimester is the critical period of massive neural cell migration to the cortex, and fingertip dermal cells migrate to form ridges during this same period, the authors sought to determine whether there are differences in fingertip ridge count in pairs of monozygotic twins discordant for schizophrenia, possibly indicating that a prenatal anatomical insult affected the twins differently. METHOD: The fingertip dermal ridges of 30 pairs of monozygotic twins (23 pairs in which the twins were discordant for schizophrenia and seven pairs in which both twins were normal) were counted by two persons trained in anthropometric research. Intrapair differences in the counts were then measured, and the differences among the pairs of normal twins were compared with the differences among the pairs discordant for schizophrenia. RESULTS: The twins discordant for schizophrenia had significantly greater absolute intrapair differences in total finger ridge count and significantly greater percent intrapair differences than the normal twins; i.e., their fingerprints were significantly less "twin-like." CONCLUSIONS: The study suggests that various second-trimester prenatal disturbances in the epigenesis of one twin in a pair discordant for schizophrenia may be related to the fact that only one of the twins expresses his or her genetic predisposition toward schizophrenia. This is consistent with a "two-strike" etiology of schizophrenia: a genetic diathesis plus a second-trimester environmental stressor.

Fryns syndrome: an autosomal recessive disorder associated with craniofacial anomalies, diaphragmatic hernia, and distal digital hypoplasia.

Fryns syndrome is an autosomal recessive, genetically determined condition with variable expression, which includes abnormal facial features, diaphragmatic hernia, distal limb abnormalities, and malformations of the cardiovascular, gastrointestinal, genitourinary, and central nervous systems. Five cases of children with Fryns syndrome, including an example of familial recurrence and a case of long-term survival, are described. This report brings to 25 the number of cases reported in the literature and further serves to illustrate the clinical variability of this disorder.

Contribution of heritable disorders to mortality in the pediatric intensive care unit.

OBJECTIVES: To determine the percentage of patients dying in the pediatric intensive care unit (PICU) who have heritable disorders and to compare vital statistics classification of underlying cause of death with underlying heritable disorder identified from medical record review. DESIGN: Retrospective medical record review. SETTING: The PICU of a university-affiliated hospital. METHODS: Medical records were reviewed for all deaths occurring in the PICA over a 5-year period. Further review, including hospital course, clinical findings, and the presence or absence of a genetic evaluation, was accomplished for those patients found to have a chromosome abnormality, recognized syndrome, single major malformation, or unrecognized syndrome. Underlying cause of death classification obtained from the Center for Health Statistics, Arkansas Department of Health was reviewed to determine the frequency with which the underlying heritable disorder was recorded. RESULTS: Fifty-one of 268 (19%) deaths during the study period were in patients with heritable disorders. Of these 51 patients, eight (16%) had chromosome abnormalities, 17 (33%) had a recognized syndrome, 15 (29%) had a single primary defect in development, and 11 (22%) had an unrecognized syndrome. Genetic evaluation was carried out on 45% of patients, with the frequency of evaluation differing between categories of patients with heritable conditions. When underlying cause of death from vital statistics classification was reviewed, 21 of 51 (41%) records did not include the underlying heritable disorder. CONCLUSIONS: Heritable disorders are a frequent cause of mortality in the PICU. Vital statistics classification of underlying cause of death in this population often fails to identify heritable disorders, leading to an underascertainment of these conditions in mortality statistics. Improved cause of death classification procedures will be necessary to target public health interventions to etiology-specific populations.

Craniosynostosis and lid anomalies: report of a girl with Michels syndrome.

We report on a 2-year-old girl with Michels syndrome, a condition characterized by mental deficiency, craniosynostosis, blepharophimosis, ptosis, and epicanthus inversus. The phenotypic findings are compared with those of previously reported cases.

Malformations and minor anomalies in non-trisomic, autosomal aneuploidy.

We examined the medical records of 43 individuals with non-trisomic, autosomal aneuploidy evaluated by the Arkansas Genetics Program. Birthweight and the presence of malformations and minor anomalies by organ system were analyzed on each patient. Low birthweight was present in 28% (N = 12) of the patients, 72% (N = 31) of the subjects had a malformation, and 93% (N = 40) had a minor anomaly. Of the entire sample, the most common site of a malformation or minor anomaly was the limbs (79%). The most common site of a malformation was the head (21%), eyes (21%), or heart (26%). If a malformation was present, the head was significantly more likely (P < .04) than another body system to be the site of an additional malformation or minor anomaly. A malformation or minor anomaly of the ears was significantly more likely (P < .03) to be present when there was an associated eye anomaly than when no anomaly of the eye was identified. These data have implications for chromosome screening of individuals with malformations or minor anomalies and for the clinical evaluation of those found to have non-trisomic autosomal aneuploidy.

Autosomal dominant benign neonatal seizures.

Eight individuals in two generations of a family experienced seizures neonatally or in early infancy. Evaluation in two of these infants documented an EEG pattern suggestive of seizure activity without discernible pathogenesis of their seizures. Subsequently, affected individuals had a normal neurodevelopmental outcome, although one person had later epilepsy. The benign course of this disorder and its association with adult epilepsy agree with previously reported cases from the literature.

Pentalogy of Cantrell and ectopia cordis, a familial developmental field complex.

The association of sternal fusion defects with various cardiac, diaphragmatic, and anterior body wall defects represents a developmental field complex that includes the Pentalogy of Cantrell and ectopia cordis. No familial cases have been reported previously. We present 3 consecutively born brothers with extensive diaphragmatic defects, 2 who had the Pentalogy of Cantrell. One of the 2 also had ectopia cordis.

Variable presentation of Rothmund-Thomson syndrome.

The recent finding that a subset of patients with Rothmund-Thomson syndrome (RTS) have mutations of a helicase gene has prompted reexamination of the phenotypes of individuals diagnosed with this disorder. We report on two patients with variable presentations of RTS. Initial presenting symptoms included growth deficiency and absent thumbs in one patient and osteogenic sarcoma and poikiloderma in the second patient. The growth-deficient patient was diagnosed with growth hormone deficiency and had a subnormal response to growth hormone supplementation. Neither malformations nor growth deficiency were present in the patient with osteogenic sarcoma, and her only other manifestation of RTS was poikiloderma. The diagnosis of RTS should be considered in all patients with osteogenic sarcoma, particularly if associated with skin changes.

Chromosome instability in ICF syndrome: formation of micronuclei from multibranched chromosomes 1 demonstrated by fluorescence in situ hybridization.

We report on a new patient with immunodeficiency, centromeric heterochromatin instability, and facial anomalies (the ICF syndrome). Studies with traditional cytogenetic methods demonstrate that aberrations in this syndrome primarily involve the centromeric regions of chromosomes 1 and 16. We applied fluorescence in situ hybridization (FISH) using "painting" probes for chromosomes 1 and 16 to document the progression of centromeric instability from simple decondensation aberrations to the subsequent formation of complex multibranched chromosomes 1, and finally to the interphase aberrations of nuclear projections and micronuclei involving both chromosomes 1 and 16. The loss of the large multibranched chromosome 1 configurations from the cells as micronuclei suggests that the centromeric aberrations subsequently interfere with normal chromosome movement at anaphase in ICF syndrome. Circular areas of counterstained chromatin were observed by FISH in the micronuclei corresponding to the intertwined segments of centromeric heterochromatin seen involving multibranched chromosomes 1 in the patient's G-banded chromosome study. The current hypothesis of recessive inheritance for this disorder suggests that the chromosomal aberrations are not a causative event in this syndrome; however, the chromosome aberrations are clearly an important basic diagnostic criterion.

Blepharophimosis: a causally heterogeneous malformation frequently associated with developmental disabilities.

We report on 22 individuals referred for genetic evaluation because of blepharophimosis. Fourteen of these patients had the blepharophimosis syndrome: 5 familial and 9 sporadic. Mental retardation or developmental delay was seen in 8 of the 12 children in whom this could be assessed. Eight of 22 children had a malformation syndrome other than the blepharophimosis syndrome. All 8 of these children were mentally retarded or developmentally delayed. Two of these 8 had recognized disorders (branchio-oto-renal syndrome and a ring 4 chromosome); the remaining 6 had unrecognized malformation syndromes. Based on this information, it is suggested that children with blepharophimosis be evaluated carefully for underlying conditions and that they be observed for developmental disabilities because of the frequent association.

Laterality defects in conjoined twins: implications for normal asymmetry in human embryogenesis.

We evaluated six pairs of conjoined twins: four pairs were dicephalus, and two were of the ischiopagus type. In three of the four dicephalus pairs, the right twin had an abnormality of laterality that included a right aortic arch, reversed great vessel orientation, bilateral right-sided isomerism of the lungs, asplenia, and situs inversus of the viscera. The left twin had normal great vessel orientation and situs solitus in each case. The finding that was unique in these three dicephalus twin pairs was their fused hearts, which were similar in orientation and configuration. The fourth dicephalus twin pair had one normally rotated heart, which was located in the midline and had normally placed chambers and great vessels. Each twin of this pair had normal visceral situs. In the two pairs of ischiopagus twins, each pair had two separate hearts, with normal cardiac structure and great vessel relationships. The viscera expressed normal laterality. Documentation of a defect in laterality in the right twin in three conjoined twin pairs with fusion of the hearts, combined with the presence of normal laterality in three pairs without cardiac fusion, has implications regarding the mechanisms leading to laterality of the human embryo. We suggest that rotation of the heart initiates the embryo's process of lateralization and that the laterality defects of the viscera seen in the right twin are a result of their abnormal cardiac rotation.

Terminal deletions of the long arm of chromosome 7: five new cases.

Twenty-two cases of terminal deletions of the long arm of chromosome 7 have been reported. We present 5 new cases, 3 of which were ascertained due to fetal holoprosencephaly, one due to anencephaly, and one due to multiple structural defects in a 15-year-old boy. The presence of holoprosencephaly in 3 of the 5 cases reported herein and in 2 previously reported cases suggests that this manifestation may be commonly observed in individuals with deletion 7q.

Duplication and deletion of chromosome band 2(p21p22) resulting from a familial interstitial insertion (2;11)(p21;p15).

Routine amniocentesis for advanced maternal age led to the prenatal diagnosis of a fetus with a karyotype of a 46,XX,del(2)(p21p22). At delivery the baby had holoprosencephaly as the major clinical finding, which has been associated with a deletion of band 2p21 in several other case reports. Chromosome studies of the parents showed a normal 46,XY karyotype in the father, and a balanced interstitial insertion 46,XX dir ins (11;2)(p15.1;p21p22) in the mother. Subsequent chromosome studies of other relatives documented a 23-year-old half-brother of the proposita with a partial trisomy for the segment deleted in the proposita. The half-brother showed the derivative chromosome 11 from the mother, resulting in a 46,XY,der(11)dup(2)(p21p22) karyotype. Major clinical findings include short stature, mild developmental delay, and behavior abnormalities. A half-sister of the proposita is also a balanced carrier of the dir ins (11;2) (p15.1;p21p22.2). The association of the deletion chromosome band 2p21 and the clinical finding of holoprosencephaly is further supported by the findings in this family.

Chromosome 10qter deletion syndrome: a review and report of three new cases.

We report on three patients with terminal deletions of chromosome 10q and compare them to 15 previously reported patients. A similar facial appearance with a prominent beaked nose, large and/or malformed ears, and a pattern of major abnormalities including severe mental retardation, cardiac anomalies, and anogenital anomalies are reviewed. We feel the manifestations of del 10qter are sufficiently distinct to suggest this diagnosis on clinical examination.

Clinical and biochemical spectrum of patients with RSH/Smith-Lemli-Opitz syndrome and abnormal cholesterol metabolism.

RSH/Smith-Lemli-Opitz (RSH/SLO) syndrome is an autosomal recessive malformation syndrome recently shown to be associated with a severe deficiency of cholesterol biosynthesis and markedly elevated plasma and tissue levels of 7-dehydrocholesterol (7-DHC), the immediate precursor of cholesterol in the Kandutsch-Russell biosynthetic pathway. Because these biochemical abnormalities permit a reassessment of RSH/SLO on biochemical criteria rather than less specific physical criteria, we review here the clinical and biochemical characteristics of our first 80 patients with abnormally increased levels of 7-DHC. The study population included 68 index patients and 12 additional relatives identified by quantification of 7-DHC and cholesterol in plasma, amniotic fluid, or cultured fibroblasts, lymphoblasts, or amniocytes. As demonstrated in other clinical syndromes when redefined biochemically, we have found a wider range of clinical expression of RSH/SLO than previously recognized. These newly recognized atypical RSH/SLO patients included several with no malformations other than syndactyly of the toes and, at the other extreme, patients with frank holoprosencephaly or multiple visceral anomalies who died in utero. Syndactyly of toes 2 and 3 was the most common malformation, occurring in all but one of 80 patients. The best biochemical predictor of clinical severity was the plasma cholesterol level, which decreased with increasing clinical severity. However, at least 10% of patients, including one newborn infant, had normal cholesterol levels at the time of diagnosis and would have been missed without specific quantification of 7-DHC. Not unexpectedly, several patients carrying a clinical diagnosis of RSH/SLO were found to have normal levels of all plasma sterols and apparently normal cholesterol biosynthesis in cultured cells. A comparison of the frequency of anomalies in our biochemically identified patients with similar data from previously reported clinical series suggests that up to 25% of reports of RSH/SLO in the literature may describe genetic conditions other than RSH/SLO with 7-DHC-emia.

Cardiovascular malformations in Smith-Lemli-Opitz syndrome.

We reviewed 215 patients (59 new, 156 from the literature) with Smith-Lemli-Opitz syndrome (SLOS), and found that 95 (44%) had a cardiovascular malformation (CVM). Classifying CVMs by disordered embryonic mechanisms, there were 5 (5.3%) class 1 (ectomesenchymal tissue migration abnormalities), 56 (58.9%) class II (abnormal intracardiac blood flow), 25 (26.3%) class IV (abnormal extracellular matrix), and 5 (5.3%) class V (abnormal targeted growth). Comparing the frequencies of individual CVMs in this series with a control group (the Baltimore-Washington Infant Study), there were 6 individual CVMs which showed a significant difference from expected values. When frequencies of CVMs in SLOS were analyzed by mechanistic class, classes IV and V were significantly more frequent, and class I significantly less frequent, than the control group. Although CVMs in SLOS display mechanistic heterogeneity, with an overall predominance of class II CVMs, the developmental error appears to favor alteration of the cardiovascular developmental mechanisms underlying atrioventricular canal and anomalous pulmonary venous return. This information should assist the clinical geneticist evaluating a patient with possible SLOS, and should suggest research direction for the mechanisms responsible for the SLOS phenotype.

Radiological features in Brachmann-de Lange syndrome.

Brachmann-de Lange syndrome (BDLS) is a well-delineated disorder consisting variably of pre- and postnatal growth deficiency, microbrachycephaly, characteristic face, hypertrichosis, visceral anomalies, and limb defects consisting primarily of variable limb reduction defects, micromelia, and elbow abnormalities. The course is usually marked by initial hypertonicity, low-pitched weak cry, feeding problems, and behavioral problems with marked mental deficiency. In classical cases there is rarely any difficulty in making the diagnosis, but for mildly affected cases, it may be difficult to feel secure about the diagnosis. In an effort to increase the precision of diagnosis for mildly affected cases, we reviewed roentgenograms in 21 cases of Brachmann-de Lange syndrome, as well as previously published descriptions of the radiological manifestations. Unusual radiologic manifestations were related primarily to the limb anomalies, and these were often asymmetric. These manifestations included digital abnormalities, which ranged from acheiria to oligodactyly, hypoplasia of the thumb and first metacarpal, clinodactyly of the fifth finger, or ectrodactyly. Long bone abnormalities included ulnar a/hypoplasia, dysplasia of the radial head, or fusion of the elbow. When there was a single forearm bone, there was often fusion at the elbow and oligodactyly, which made it difficult to determine whether the radius or ulna was absent. Other radiologic manifestations included 13 ribs with precocious sternal fusion, and micrognathia. We suggest that these radiologic manifestations could increase diagnostic precision in mildly affected cases.

Congenital diaphragmatic hernia in the Brachmann-de Lange syndrome.

We present 12 children with typical Brachmann-de Lange syndrome and congenital diaphragmatic hernia. Affected children were more likely to be of low birth weight and to have major upper limb malformations. Hernia repair was attempted in 4 of these children, and only one survived past 12 months. Newborn infants with congenital diaphragmatic hernia should be examined carefully for evidence of the Brachmann-de Lange syndrome because diagnosis of this condition may influence their clinical management and prognosis.