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.

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.

Public health monitoring of developmental disabilities with a focus on the autism spectrum disorders.

Developmental disabilities (DDs) are conditions characterized by physical, cognitive, psychological, sensory, adaptive, and/or communication impairments manifested during development. Approximately 17% of individuals in the United States 18 years and younger have a DD, and for most children the cause of their condition is unknown. Of particular interest are the autism spectrum disorders (ASDs), characterized by unusual social, communication, and behavioral development. Previously autism was thought to be a rare condition, but the number of children receiving services for an ASD has increased dramatically in the last decade. Concerns about increases in DDs, particularly ASDs, their causes, and the high costs of intervention have highlighted the need for systematic public health monitoring. Service provider data, such as annual reporting of special education services or of state DD programs, do not provide a complete estimate of the rates for DDs, including ASDs. Unlike genetic metabolic disorders or congenital hearing loss (HL) for which newborn screening programs can provide accurate prevalence rates, there are currently no genetic or biologic markers for the ASDs to enable consistent and early identification of affected children. Centers for Disease Control and Prevention's (CDC) Metropolitan Atlanta Developmental Disabilities Surveillance Program (MADDSP) is a model for population monitoring of ASDs/DDs that has been implemented in other states. This article discusses the role of ASD/DD tracking in public health, as well as the challenges of ASD/DD tracking, including case definition and identification, associated conditions, linkages, and data access.

Molecular mechanisms in neurologic disorders.

Although many pediatric neurologic disorders, such as epilepsy and mental retardation, are the result of a combination of genetic and environmental factors, many others are the result of mutations of single genes. Most of these single gene traits are inherited in autosomal dominant, autosomal recessive, or X-linked fashion. The diversity of mutations that are responsible for these diseases produces variability in phenotypic expression. However, there are other important features of many neurologic disorders that cannot be explained by standard models of mendelian inheritance. This review focuses on recently described mechanisms, such as genomic imprinting, germline mosaicism, mitochondrial inheritance, and triplet repeat expansion. The diagnostic evaluation, prognostic significance, and recurrence risk for specific neurogenetic disorders is correlated with these underlying disease mechanisms.

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.

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.

Improving access to and utilization of genetic services in Arizona's Hispanic population.

This abstract presents a model project aimed to train community lay health workers about genetics, increase cultural competency of genetic services providers, and provide local access to genetic services in primarily Hispanic communities in the state of Arizona. Health Start, a community-based prenatal outreach program, served as the basis for providing genetic education and services. A genetics training curriculum was developed and training of community lay health workers was provided. Cultural and Spanish language training was provided for all genetic services providers. Pediatric genetics outreach clinics were established in eight communities. Community-based lay health workers eagerly incorporate genetic information into their public health knowledge base, but this may not lead to acceptance of these personnel by local health care providers as sources of referrals for specialized health services such as genetics. Cultural competence training of genetic service providers is enthusiastically accepted and utilized in the provision of locally accessible genetics clinics.

Evaluation of mental retardation: recommendations of a Consensus Conference: American College of Medical Genetics.

A Consensus Conference utilizing available literature and expert opinion sponsored by the American College of Medical Genetics in October 1995 evaluated the rational approach to the individual with mental retardation. Although no uniform protocol replaces individual clinician judgement, the consensus recommendations were as follows: 1. The individual with mental retardation, the family, and medical care providers benefit from a focused clinical and laboratory evaluation aimed at establishing causation and in providing counseling, prognosis, recurrence risks, and guidelines for management. 2. Essential elements of the evaluation include a three-generation pedigree: pre-, peri-, and post-natal history, complete physical examination focused on the presence of minor anomalies, neurologic examination, and assessment of the behavioral phenotype. 3. Selective laboratory testing should, in most patients, include a banded karyotype. Fragile X testing should be strongly considered in both males and females with unexplained mental retardation, especially in the presence of a positive family history, a consistent physical and behavioral phenotype and absence of major structural abnormalities. Metabolic testing should be initialed in the presence of suggestive clinical and physical findings. Neuroimaging should be considered in patients without a known diagnosis especially in the presence of neurologic symptoms, cranial contour abnormalities, microcephaly, or macrocephaly. In most situations MRI is the testing modality of choice. 4. Sequential evaluation of the patient, occasionally over several years, is often necessary for diagnosis, allowing for delineation of the physical and behavioral phenotype, a logical approach to ancillary testing and appropriate prognostic and reproductive counseling.

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.

The effects of peer ridicule on depression and self-image among adolescent females with Turner syndrome.

PURPOSE: This study attempted to examine the effects of body image, height dissatisfaction, and peer ridicule on depression and self-image among adolescent females with Turner syndrome. METHODS: A prospective, cross-sectional survey examined 59 subjects' responses to standardized measures of depression, self-image, body image, height perception, and teasing. RESULTS: Descriptive statistics found the mean age of subjects to be 14.8 years (range: 13-19). Approximately 30% reported cardiac defects and 17% indicated kidney anomalies. Only five experienced spontaneous menses and 61% indicated they were receiving estrogen replacement therapy. Linear regression analyses examined the effects of body image, height perceptions, and peer ridicule on depression and self-image scores. The first regression analysis found a five-step model to account for 39% of the variance, with peer ridicule of general appearance being the most important variable. The second linear regression (R2 = .3248, P < .0004) also found peer teasing of general appearance to be significantly associated with self-image scores. Discrepancy scores between ideal versus current body shape or height, as well as teasing about these issues, appeared to be unrelated to depression and self-image among our subjects. CONCLUSION: These data suggest that peer ridicule is a domain that requires ongoing assessment by health care providers, as it appears to be an important contributor to mental health problems. Social skill interventions that emphasize strategies to manage teasing, assertively respond to negative statements, and teach effective coping skills are key variables to minimize the emotional discomfort these young women may experience.

Health care utilization and perceptions of health among adolescents and adults with Turner syndrome.

We surveyed women aged 12 years and older who are members of the Turner Syndrome Society of the United States in regard to their health history, current health status, and health care utilization practices to identify the range of health problems and health care practices in this group. The mean age at diagnosis was 10.8 years, and an endocrinologist (41%) or pediatrician (35%) was most likely to make the initial diagnosis. Individuals over age 35 years were diagnosed with Turner syndrome and begun on estrogen replacement therapy at a significantly older age than those who were in younger age groups. Seventy-five percent of the respondents had required some type of surgical procedure, and 14% had been hospitalized within the previous year. Ninety-four percent of women rated their overall health as good to excellent, while 6% rated it fair to poor. In the 12-17-year age group, 89% of the young women were either currently taking or had previously taken growth hormone. The prevalence of major depressive symptoms was slightly higher than the general population for adolescents but similar to the general population for adults. For adult respondents, ratings of fair to poor health were significantly associated with increased outpatient visits. Growth hormone use was significantly associated with increased visits in the adolescent population. Based on these data, it appears that the clinical care of individuals with Turner syndrome has improved, but that they continue to have relatively high hospitalization rates and utilization of subspecialty services. Despite these health problems, most respondents demonstrated good adjustment as determined by standardized mental health measures.

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.

Ehlers-Danlos syndrome, type VIII presenting with periodontitis and prolonged bleeding time.

We report on a case of Ehlers-Danlos syndrome, probable type VIII (EDS VIII) in a 6-year-old girl with severe periodontitis, extensive bruising of the shins, abnormal bleeding time, and thin body habitus. The structure and biosynthesis of types I and III colagen were normal. Desmopressin (DDAVP) was found to correct the bleeding time, and the patient underwent an uneventful dental procedure after DDAVP therapy. The finding of childhood or juvenile periodontitis should prompt consideration of a diagnosis of EDS, particularly type VIII, and alert the clinician to the possibility of a treatable bleeding abnormality.

Clinical and molecular characterization of patients with distal 11q deletions.

Jacobsen syndrome is caused by segmental aneusomy for the distal end of the long arm of chromosome 11. Typical features include mild to moderate psychomotor retardation, trigonocephaly, facial dysmorphism, cardiac defects, and thrombocytopenia, though none of these features are invariably present. To define the critical regions responsible for these abnormalities, we studied 17 individuals with de novo terminal deletions of 11q. The patients were characterized in a loss-of-heterozygosity analysis using polymorphic dinucleotide repeats. The breakpoints in the complete two-generation families were localized with an average resolution of 3.9 cM. Eight patients with the largest deletions extending from 11q23.3 to 11qter have breakpoints, between D11S924 and D11S1341. This cytogenetic region accounts for the majority of 11q- patients and may be related to the FRA11B fragile site in 11q23.3. One patient with a small terminal deletion distal to D11S1351 had facial dysmorphism, cardiac defects, and thrombocytopenia, suggesting that the genes responsible for these features may lie distal to D11S1351. Twelve of 15 patients with deletion breakpoints as far distal as D11S1345 had trigonocephaly, while patients with deletions distal to D11S912 did not, suggesting that, if hemizygosity for a single gene is responsible for this dysmorphic feature, the gene may lie distal to D11S1345 and proximal to D11S912.

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.

Deaths associated with renal agenesis: a population-based study of birth prevalence, case ascertainment, and etiologic heterogeneity.

We report on deaths associated with renal agenesis among 211,704 consecutive births. Sources included birth and death certificates and an active birth defects surveillance system. Medical review and classification of cases were performed for 1985-1990 events. Sixty-one cases of renal agenesis were identified, and review of records was possible for 59 of the 61 cases. Of these 59 cases, 36 (61%) were confirmed, 5 (8%) were questionable, and 18 (31%) were incorrectly coded. The prevalence of confirmed cases is thus estimated at 17/100,000 births (14.2/100,000 births, excluding elective terminations and fetal deaths). Records incorrectly coded were most often those with multicystic dysplasia. Approximately one-third of cases was found by the birth defects surveillance system alone, confirming the utility of this data source for prevalence estimates. Isolated renal agenesis accounted for 44% of confirmed cases; other diagnoses included VATER association (19%), unrecognized multiple malformation syndromes (17%), exstrophy of the cloaca sequence (14%), and chromosome disorders (6%). Based on these data, prevalence rates for ICD code 753.0 and death include overascertainment of cases from erroneous coding of multicystic dysplasia and underascertainment of cases with unilateral renal agenesis associated with other malformations. Population-based ascertainment of cases by active surveillance methods and rigorous diagnostic coding standards are required to improve the accuracy of these rates. Targeted investigations of distinct subclassifications will be necessary to identify specific etiologic factors.

Contribution of genetic disorders to neonatal mortality in a regional intensive care setting.

We examined the contribution of chromosomal abnormalities, mendelian disorders, and birth defects to mortality in a regional neonatal intensive care unit by medical record review of neonatal deaths in that unit. Of a total of 296 infant deaths during the 5-year period June 1986 to May 1991, 69 (23.3%) had a genetic disorder. By diagnostic category, 18.8% had a chromosomal abnormality, 10.1% had a mendelian condition, 42% had a single primary defect in development, and 29% had an unrecognized pattern of malformation. The rate of autopsy and genetic evaluation differed markedly between these diagnostic categories. A comparison was made of underlying cause of death determined from medical records with underlying cause as classified by vital statistics nosologic procedures. No death certificate was on file for two of the deaths; for the remaining 67, 27 (40.3%) had an erroneous or misleading underlying cause of death as determined from vital statistics. The important contribution of genetic disorders to neonatal mortality in this high-risk population and the relative underrecognition of these disorders by vital statistics sources indicate that efforts aimed at reducing neonatal mortality will require a full range of preventive health activities, including preconception, prenatal and perinatal assessment, and counseling. Improved data collection techniques need to be developed to understand the contribution of this group of conditions to total neonatal mortality.

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.