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Biomedical subjects

A E Lin

Publications and source records attributed to A E Lin.

At least 19 recordsLinked to original sources
PubMed2001

Exclusion of growth factor gene mutations as a common cause of Sotos syndrome.

Sotos syndrome is characterized by somatic overgrowth, i.e., macrocephaly and tall stature. Because the cause and pathogenesis of Sotos syndrome remain unknown, we selected nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and neurotrophin 3 (NT-3) as possible genes mutated in Sotos syndrome. In seven patients with the classic phenotype, we excluded mutations in these growth factor genes. It is possible that these three genes are not involved in the cause of Sotos syndrome, or alternatively, mutations could not be identified in the small number of patients studied.

Abnormalities, Multiple↗
PubMed2000

Cardiovascular malformations and other cardiovascular abnormalities in neurofibromatosis 1.

Although it is well recognized that a peripheral vasculopathy may occur in patients with neurofibromatosis 1 (NF1), it is unclear whether cardiovascular abnormalities are more common. We reviewed the frequency of cardiovascular abnormalities, in particular, cardiovascular malformations (CVMs), among 2322 patients with definite NF1 in the National Neurofibromatosis Foundation International Database from 1991-98. Cardiovascular malformations were reported in 54/2322 (2.3%) of the NF1 patients, only 4 of whom had Watson syndrome or NF1-Noonan syndrome. There was a predominance of Class II "flow" defects [Clark, 1995: Moss and Adams' Heart Disease in Infants, Children, and Adolescents Including the Fetus and Young Adult. p 60-70] (43/54, 80%) among the NF1 patients with CVMs. Pulmonic stenosis, that was present in 25 NF1 patients, and aortic coarctation, that occurred in 5, constitute much larger proportions of all CVMs than expected. Of interest was the paucity of Class I conotruncal defects (2 patients with tetralogy of Fallot), and the absence of atrioventricular canal, anomalous pulmonary venous return, complex single ventricle and laterality defects. Besides the 54 patients with CVMs, there were 27 patients with other cardiac abnormalities (16 with murmur, 5 with mitral valve prolapse, 1 with intracardiac tumor, and 5 with electrocardiogram abnormalities). No patient in this study had hypertrophic cardiomyopathy. There were 16 patients who had a peripheral vascular abnormality without an intracardiac CVM, plus an additional 4 patients among those with a CVM who also had a peripheral vascular abnormality.

Aortic Coarctation↗
PubMed2000

Exclusion of the branchio-oto-renal syndrome locus (EYA1) from patients with branchio-oculo-facial syndrome.

In addition to craniofacial, auricular, ophthalmologic, and oral anomalies, the distinctive phenotype of the branchio-oculo-facial (BOF) syndrome (MIM 113620) includes skin defects in the neck or infra/supra-auricular region. These unusual areas of thin, erythematous wrinkled skin differ from the discrete cervical pits, cysts, and fistulas of the branchio-oto-renal (BOR) syndrome (MIM 113650). Although the BOF and BOR syndromes are sufficiently distinctive that they should not be confused, both can be associated with nasolacrimal duct stenosis, deafness, prehelical pits, malformed pinna, and renal anomalies. Furthermore, a reported father and son [Legius et al., 1990, Clin Genet 37:347-500] had features of both conditions. It was not clear whether they had an atypical presentation of either BOR or BOF syndrome, or represented a private syndrome. In light of these issues, we selected the BOR locus (EYA1) as a possible gene mutation for the BOF syndrome. In five BOF patients, there were no mutations detected in the EYA1 gene, suggesting that it is not allelic to the BOR syndrome.

Branchio-Oto-Renal Syndrome↗
PubMed2000

Genetic aspects of atrioventricular septal defects.

Formation of the atrioventricular canal (AVC) results from complex interactions of components of the extracellular matrix. In response to signaling molecules, endothelial/mesenchymal transformations are crucial to normal development of the AVC. Atrioventricular septal defects (AVSDs) can result from arrest or interruption of normal endocardial cushion development. The presence of AVSDs has been associated with chromosome abnormalities, laterality or left-right axis abnormalities, and a variety of syndromes. An AVSD susceptibility gene has been identified in a large kindred with many affected members. Studies of transcription factors and signaling molecules in heart development over the past decade are paving the way for our understanding of the heterogeneous mechanisms of causation of AVSDs.

Abnormalities, Multiple↗
PubMed1999

Cardiovascular malformations: changes in prevalence and birth status, 1972-1990.

Through an ongoing hospital-based active malformation surveillance program, we identified cardiovascular malformations (CVMs) in 3.3 per 1,000 liveborn and stillborn infants, and fetuses from pregnancies terminated electively during a 15-year period. We excluded the children of mothers who had planned delivery elsewhere, but were transferred for care of anomalies that had been detected in prenatal screening. Birth status changed markedly during the study with a significant increase in elective terminations of fetuses with a CVM from 0 to 22% (P < 0.01 based on a test for trend). The proportion of liveborn infants with CVMs decreased from 90% to 73% (P < 0.01); the frequency of stillbirths did not change. During the study period, there was a significant increase in the prevalence of CVMs in all births (P < 0.01) and elective terminations (P < 0.01). The increase in liveborn prevalence was not statistically significant (P = 0.08). Stillborn prevalence was unchanged. The number of mothers having prenatal ultrasonography (P < 0.01 for trend) and amniocentesis (P < 0.01 for trend) increased steadily. There were significant increases in the proportion of mothers having any ultrasound examination (P < 0.01 for trend), the number of initial ultrasound examinations occurring in the second trimester (P < 0.01 for trend), and the proportion of mothers having amniocentesis (P < 0.01 for trend). There was a significant increasing trend in the proportion of mothers who were 35 years and older (10% in 1972-1974, 26% in 1988-1990, P < 0.01). This hospital-based active surveillance program suggests that more frequent elective terminations had a significant effect on overall birth prevalence of CVMs. This trend would not have been detected by most other surveillance systems which determine prevalence of common birth defects from birth certificates and other forms of administrative reporting, and exclude elective terminations of pregnancy.

Abortion, Induced↗
PubMed1999

Cardiac anomalies in the Simpson-Golabi-Behmel syndrome.

Diverse cardiac abnormalities have been reported in patients with the Simpson-Golabi-Behmel syndrome (SGBS), and it is suspected that they are related to the apparently high incidence of early death. To clarify the incidence and significance of the various cardiac abnormalities, we reviewed 101 SGBS patients (89 from the literature, 12 new). All were male, except for one clearly affected female patient with translocation X;1 [Punnett, 1994: Am J Med Genet 50: 391-393]. Ninety-six of 99 (97%) patients had the classic phenotype of macrosomia and typical "coarse" face. Thirty-six patients (36%) had a cardiac abnormality, of whom 26 (26%) had a cardiovascular malformation (CVM). After excluding 24 patients with insufficient clinical data, these percentages among the 77 informative cases were 47% and 34%, respectively. When grouped according to a mechanistic classification, most cases (20/ 26, or 77%) were class II CVMs (attributed to altered embryonic intracardiac flow). Other cardiac abnormalities included cardiomyopathy (n = 4) and electrocardiogram (ECG) conduction or rhythm abnormalities (n = 12); three of the affected patients (25%) also had a CVM. Among 92 informative cases, there were 29 (32%) deaths, a figure that excludes seven elective terminations. Among the 25 patients younger than 3 years, death was associated with a cardiac abnormality in six (23%). GPC3 mutation analysis using Southern blot testing and polymerase chain reaction amplification was performed for 37 of 101 (37%) patients. A mutation was detected in 26 of the 37 patients tested (70%), 12 of whom (46%) had a cardiac abnormality. We conclude that cardiac abnormalities of any type are common in SGBS (almost one-half of informative cases), with CVMs seen in one-third of cases. The heterogeneous ECG abnormalities in this survey must be viewed with caution, since they may represent a genuine component of the syndrome or reporting bias. Determining the true prevalence and natural history of cardiac abnormalities in SGBS will require a larger number of patients and more consistent prospective cardiac evaluations. There are sufficient data to recommend a baseline echocardiogram and ECG in SGBS patients. Data are insufficient to define a cardiac phenotype/molecular correlation.

Adolescent↗
PubMed1999

Circumferential abdominal skin defect possibly due to umbilical cord encirclement.

We report on a newborn black male twin with a distinctive circumferential abdominal skin defect who was identified through the Active Malformation Surveillance Program at the Brigham and Women's Hospital. There were no other malformations, and amniotic disruption was not present. Although it cannot be proven, we believe that this skin defect may have been caused by in utero encirclement of the abdomen by an umbilical cord.

Abdomen↗
PubMed1998

Adams-Oliver syndrome associated with cardiovascular malformations.

We describe two families with Adams-Oliver syndrome (AOS), an autosomal dominant malformation syndrome (MIM No. 10030), in which cardiovascular malformations (CVMs) have been reported previously. In the first family, twin boys and their mother had the typical digital and scalp defects of AOS with various obstructive CVMs of the left heart (bicuspid aortic valve, Shone's complex). At least three other relatives not examined personally are reported to have related CVMs (aortic valve stenosis, hypoplastic left heart syndrome). In the second family, a girl had typical AOS digital and scalp defects and a bicuspid aortic valve. At least three other relatives are reported to be mildly affected. Tetralogy of Fallot had been previously reported as the most common CVM in AOS [Zapata HH, Sletten LJ, Pierport MEM (1995). J Med Genet 47:80-84.]. However, with the addition of these new patients and two other literature reports, we emphasize that approximately 20% have a CVM, frequently obstructive lesions of the left heart. Cardiology consultation should be offered to most patients with AOS.

Abnormalities, Multiple↗
PubMed1998

CHARGE association: an update and review for the primary pediatrician.

CHARGE association is a nonrandom pattern of congenital anomalies that occurs together more frequently than one would expect on the basis of chance. This common multiple anomaly condition has an estimated prevalence of 1:10,000. The number of children diagnosed with CHARGE association is increasing, owing presumably to greater awareness of this condition and advances in the care of complex, chronically ill children, resulting in improved survival and outcome. This review of CHARGE association presents diagnostic criteria that may define a concise, recognizable syndrome with a single pathogenetic basis. This review also summarizes our current understanding of the management for this complex and chronic multiple congenital anomaly condition and discusses the pathogenetic basis for this condition.

Abnormalities, Multiple↗
PubMed1998

Further delineation of aortic dilation, dissection, and rupture in patients with Turner syndrome.

OBJECTIVE: Although cardiovascular malformations (CVMs) are well-recognized congenital anomalies in Turner syndrome, aortic dilation and dissection are less common and less familiar. Most of the relevant literature is limited to single cases reports or small series. We sought to increase the information available about the frequency and characteristics of aortic dilation in patients with Turner syndrome. DESIGN: A 1-page survey of cardiac abnormalities, including aortic dilation, was mailed to approximately 1000 (1040 verified) members of the Turner Syndrome Society as an enclosure in the June 1997 newsletter. We also conducted a literature review. PARTICIPANTS: A total of 245 patients or families of patient members of the Turner Syndrome Society responded to the survey ( approximately 24% response rate). RESULTS: A CVM was reported in 120 of 232 (52%) respondents to this questionnaire. Obstructive lesions of the left side of the heart predominated and included bicuspid aortic valve (38%) and coarctation (41%). Aortic dilation was reported in at least 15 of 237 respondents (6.3%; 95% confidence interval: 3.6%-10.3%); 2 of 15 (13%) had dissection. Twelve of 15 (80%) patients had an associated risk factor for aortic dilation such as a CVM or hypertension. The 3 (20%) patients who did not have a CVM or hypertension were all younger than 21 years. In the entire group with aortic dilation, 10 of 15 (67%) patients were younger than 21 years. All patients with aortic dilation had involvement of the ascending aorta, and 2 had additional involvement of the descending aorta distal to a repaired coarctation. An update of the literature revealed 68 patients with aortic dilation, dissection, or rupture. An associated CVM or hypertension was reported in 53 of 59 (90%) informative patients. At least 6 (10%) had no predisposing risk factor (information was inadequate for 9 of 68 patients). The following patterns of aortic involvement were identified: ascending +/- descending aorta with coarctation (14); ascending +/- descending aorta without coarctation (39); descending aorta with coarctation (3); descending thoracic or abdominal aorta without coarctation (4); and unspecified (8). Dissection or rupture was reported in 42/68 (62%). Two reported patients died suddenly from aortic dissection in the third trimester of assisted pregnancy. At least 20 (29%) patients were younger than 21 years. One of the 6 (17%) patients with isolated aortic dilation was in this younger group. CONCLUSIONS: More information is needed about the frequency and natural history of aortic dilation in Turner syndrome. This work contributes new patient data and increases the literature review. Despite the well-recognized limitations of self-reporting, this survey detected aortic dilation with or without dissection in approximately 6% of patients with Turner syndrome. Although rare, this is a potentially catastrophic occurrence, warranting greater awareness among health professionals. In this study and the literature, the vast majority of patients with aortic dilation have an associated risk factor such as a CVM, typically bicuspid aortic valve or coarctation, or systemic hypertension. These patients represent a higher risk group that should be followed appropriately, usually under the direction of a cardiologist. Patients undergoing assisted pregnancy also should be evaluated closely. It is generally accepted that at the time of diagnosis of Turner syndrome, all patients should have a complete cardiology evaluation including echocardiography. The small number of patients with aortic dilation without a CVM, who would not be under the long-term care of a cardiologist, makes it prudent to screen all patients with Turner syndrome for this potentially lethal abnormality. The specific timing for this screening is controversial. Our recommendations for prospective imaging do not represent a rigid standard of care.

Adolescent↗
PubMed1997

Vitamin K deficiency embryopathy: a phenocopy of the warfarin embryopathy due to a disorder of embryonic vitamin K metabolism.

Three unrelated infants presented with radiographic punctate calcifications, nasal hypoplasia, and abnormalities of the spine. Additional anomalies included cupped ears in 2 patients and one each with Dandy-Walker malformation with hydrocephaly, congenital cataracts, and peripheral pulmonary artery stenosis. The mothers of these 3 patients had chronic conditions associated with intestinal malabsorption requiring total parenteral nutrition for varying periods of time. The underlying causes of malabsorption were celiac disease, short bowel syndrome secondary to surgical resection, and jejuno-ileal bypass, respectively. Bleeding diathesis occurred in one mother requiring vitamin K supplementation during the second and third trimesters of pregnancy. We speculate that the chondrodysplasia punctata and other abnormalities in these children were caused by an acquired maternal vitamin K deficiency manifested during early pregnancy. However, the involvement of other vitamin deficiencies cannot be excluded. Thus, vitamin K deficiency of the embryo secondary to maternal malabsorption appears to be a third vitamin K-related mechanism leading to chondrodysplasia punctata in addition to warfarin embryopathy and epoxide reductase deficiency (pseudo-warfarin embryopathy).

Abnormalities, Drug-Induced↗
PubMed1997

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.

Female↗
PubMed1996

Clinical approach to genetic cardiomyopathy in children.

BACKGROUND: Cardiomyopathy (CM) remains one of the leading cardiac causes of death in children, although in the majority of cases, the cause is unknown. To have an impact on morbidity and mortality, attention must shift to etiology-specific treatments. The diagnostic evaluation of children with CM of genetic origin is complicated by the large number of rare genetic causes, the broad range of clinical presentations, and the array of specialized diagnostic tests and biochemical assays. METHODS AND RESULTS: We present a multidisciplinary diagnostic approach to pediatric CM of genetic etiology. We specify criteria for abnormal left ventricular systolic performance and structure that suggest CM based on established normal echocardiographic measurements and list other indications to consider an evaluation for CM. We provide a differential diagnosis of genetic conditions associated with CM, classified as inborn errors of metabolism, malformation syndromes, neuromuscular diseases, and familial isolated CM disorders. A diagnostic strategy is offered that is based on the clinical presentation: biochemical abnormalities, encephalopathy, dysmorphic features or multiple malformations, neuromuscular disease, apparently isolated CM, and pathological specimen findings. Adjunctive treatment measures are recommended for severely ill patients in whom a metabolic cause of CM is suspected. A protocol is provided for the evaluation of moribund patients. CONCLUSIONS: In summary, we hope to assist pediatric cardiologists and other subspecialists in the evaluation of children with CM for a possible genetic cause using a presentation-based approach. This should increase the percentage of children with CM for whom a diagnosis can be established, with important implications for treatment, prognosis, and genetic counseling.

Brain Diseases↗