Identification of single gene deletions at 15q13.3: further evidence that CHRNA7 causes the 15q13.3 microdeletion syndrome phenotype.

The 15q13.3 microdeletion syndrome (OMIM #612001) is characterized by a wide range of phenotypic features, including intellectual disability, seizures, autism, and psychiatric conditions. This deletion is inherited in approximately 75% of cases and has been found in mildly affected and normal parents, consistent with variable expressivity and incomplete penetrance. The common deletion is approximately 2 Mb and contains several genes; however, the gene(s) responsible for the resulting clinical features have not been clearly defined. Recently, four probands were reported with small deletions including only the CHRNA7 gene. These patients showed a wide range of phenotypic features similar to those associated with the larger 15q13.3 microdeletion. To further correlate genotype and phenotype, we queried our database of >15,000 patients tested in the Mayo Clinic Cytogenetics Laboratory from 2008 to 2011 and identified 19 individuals (10 probands and 9 family members) with isolated heterozygous CHRNA7 gene deletions. All but two infants displayed multiple features consistent with 15q13.3 microdeletion syndrome. We also identified the first de novo deletion confined to CHRNA7 as well as the second known case with homozygous deletion of CHRNA7 only. These results provide further evidence implicating CHRNA7 as the gene responsible for the clinical findings associated with 15q13.3 microdeletion.

Unusual cardiac malformations in conjoined twins: thoracopagus twins with conjoined pentalogy of Cantrell and an omphalopagus twin with atretic ventricles.

Two unrelated cases of conjoined twins were found to have cardiac malformations that apparently have not been reported previously. In one case, thoracopagus twins had an extensive thoracoabdominal wall defect that resulted in ectopia cordis of a conjoined heart along with evisceration of the shared liver and intestine along with one spleen. These malformations, accompanied by defects in the sternum, diaphragm, and supraumbilical abdominal wall, constitute a conjoined pentalogy of Cantrell. In the second case, the heart of one of omphalopagus twins consisted of a solid ventricular mass with only a minute aortic cavity but no atrioventricular communication-an ineffective heart that could develop only in a conjoined or chorioangiopagus twin. In both cases, a common atrium lay in the primitive (embryologic) position caudal to the ventricles.

Meier-Gorlin syndrome: report of eight additional cases and review.

The Meier-Gorlin syndrome or ear, patella, short stature syndrome (MIM 224690) is a rare autosomal recessive disorder, characterized by the association of bilateral microtia, aplasia/hypoplasia of the patellae, and severe pre- and postnatal growth retardation. Twenty-one cases have been reported in literature thus far. Here we report on eight patients from seven families and compare them with previously described cases. One of the present cases had previously undescribed genital anomalies. There is a difference in facial characteristics between patients reported in early infancy and those described at older age; follow-up of patients is needed to substantiate this changing facial phenotype. We recommend radiographic survey of the patellae in patients at older age to investigate the weight of absent or hypoplastic patellae in the diagnosis of the syndrome.

Severe end of Opitz trigonocephaly (C) syndrome or new syndrome?

We report on four unrelated cases of an Opitz trigonocephaly (C)-like syndrome with a highly characteristic combination of facial anomalies including prominent metopic suture, exophthalmos, hypertelorism, cleft lip and palate, flexion deformities of the upper limbs and multiple other anomalies. We also review two very similar published cases formerly considered to have the C syndrome. Although there is overlap, a clinical distinction from the Opitz trigonocephaly and other syndromes seems possible, and thus a specific causal entity may be postulated.

Aberrant retropharyngeal internal carotid artery in a child with spondyloepimetaphyseal dysplasia and cleft palate.

In a patient with spondyloepimetaphyseal dysplasia and cleft palate, the course of the internal carotid artery was aberrant. Prompt identification of this anomaly is critical, because operative fatality can occur if the defect is unrecognized. This case illustrates the occurrence of this vascular anomaly and focuses on options for radiologic identification and evaluation of the defect.

Peroxisomal bifunctional enzyme complex deficiency with associated retinal findings.

Peroxisomal bifunctional enzyme complex deficiency is a recently recognized abnormality of fatty acid metabolism. We herein present the association of a flecked retina with peroxisomal bifunctional enzyme deficiency, a clinical association not previously reported. We suggest the finding of a flecked retina in an infant presenting with hypotonia, seizures, and failure to thrive is highly suggestive of this diagnosis.

Sagittal craniosynostosis, Dandy-Walker malformation, and hydrocephalus: a unique multiple malformation syndrome.

The Dandy-Walker malformation and craniosynostosis have each been described as isolated occurrences and as components of multiple malformation syndromes. The purpose of this report is to delineate the characteristics of a multiple malformation syndrome of Dandy-Walker malformation and sagittal craniosynostosis. The inheritance pattern appears to be autosomal dominant.

Early prenatal diagnosis: the first 100 cases of chorionic villus sampling at Ochsner Foundation Hospital.

Chorionic villus sampling is an exciting addition to prenatal diagnosis. With this procedure, accomplished quickly and with minimal discomfort at 9 to 11 weeks of pregnancy, information can be obtained about the fetal chromosomal complement. In addition, the fetus can be tested for a variety of disorders, such as sickle-cell disease, Tay-Sachs, and cystic fibrosis. The majority of fetal studies are normal, and such early prenatal testing provides relief of anxiety and opportunity for early maternal-fetal bonding.

Flanking markers bracket the neurofibromatosis type 2 (NF2) gene on chromosome 22.

Neurofibromatosis 2 or bilateral acoustic neurofibromatosis (NF2) is a severe autosomal dominant disorder characterized by the development of multiple tumors of the nervous system, including meningiomas, gliomas, neurofibromas, ependymomas, and particularly acoustic neuromas. Polymorphic DNA markers have revealed frequent loss of one copy of chromosome 22 in the tumor types associated with NF2. Family studies have demonstrated that the primary defect in NF2 is linked to DNA markers on chromosome 22, suggesting that it involves inactivation of a tumor suppressor gene. We have employed a combination of multipoint linkage analysis and examination of deletions in primary tumor specimens to precisely map the NF2 locus between flanking polymorphic DNA markers on chromosome 22. The 13-cM region bracketed by these markers corresponds to 13% of the genetic length of the long arm of chromosome 22 and is expected to contain less than 5 x 10(6) bp of DNA. The delineation of flanking markers for NF2 should permit accurate presymptomatic and prenatal diagnosis for the disorder and greatly facilitate efforts to isolate the defective gene on the basis of its location.

Neurofibromatosis 2: clinical and DNA linkage studies of a large kindred.

At least eight provisional categories of neurofibromatosis have been proposed. Among these, neurofibromatosis 1 (von Recklinghausen's disease or peripheral neurofibromatosis) and neurofibromatosis 2 (central or bilateral acoustic neurofibromatosis) have been established as distinct disorders. We studied 15 affected male and 8 affected female members of one large kindred with neurofibromatosis 2. None of the patients met the diagnostic criteria for neurofibromatosis 1. Between the ages of 15 and 53 years, the patients had multiple central nervous system tumors of various types--mainly, bilateral acoustic neuromas. Two or more tumors eventually developed in 20 of the patients; 9 had evidence of only bilateral acoustic neuromas. Meningiomas and ependymomas were more common among the young patients; those who initially presented with acoustic neuromas were nearly a decade older. Intracranial nontumoral calcifications were present in most patients and were also found in symptom-free children. The presence of such lesions is probably a prodromic feature of neurofibromatosis 2. Simultaneous analysis of D22S1 and IGLV DNA markers for coinheritance with neurofibromatosis 2 indicates that the locus for the disease is near the center of the long arm of chromosome 22 (22q11.1----22q13.1). The eventual isolation of this disease gene may reveal a cause of the most common intracranial tumors in humans.

Angiomas and von Recklinghausen neurofibromatosis.

The notion that vascular alterations represent a major feature of the pathogenesis of neurofibromatosis (NF) has been supported by an increasing number of observations. We present data about skin Morgan angiomas in the general US white population and a cohort of patients with NF-1 and their unaffected relatives. Among patients with NF-1, angiomas were significantly more common, but not so among unaffected relatives. The striking nature of skin angiomas in some patients is illustrated by a mother-daughter pair with innumerable lesions of early onset. The mother also had a large venous angioma and a constriction of the siphon of an internal carotid artery.

Genetic linkage of bilateral acoustic neurofibromatosis to a DNA marker on chromosome 22.

Bilateral acoustic neurofibromatosis (BANF) is a severe autosomal dominant disorder involving development of multiple tumours of the nervous system including meningiomas, gliomas, neurofibromas and particularly bilateral acoustic neuromas. We have used genetic linkage analysis with DNA markers to establish that the defective gene causing BANF is on chromosome 22, and is therefore distinct from the gene for the von Recklinghausen form of neurofibromatosis, which maps to chromosome 17. Linked DNA markers will be particularly valuable in BANF, facilitating early detection of tumours and thereby permitting more effective surgical intervention. In view of the reported loss of genes on chromosome 22 in meningiomas and acoustic neuromas, the genetic localization of the primary BANF defect strongly supports the concept that the disease locus encodes a 'tumour suppressor' gene. Isolation of this gene should provide insights into the pathogenesis of acoustic neuromas and other nervous system tumours, as well as into the control of proliferation and differentiation of neural crest cells.

Myopathy in Marinesco-Sjogren syndrome.

Progressive muscular weakness, hypotonia and atrophy are among the cardinal signs of the Marinesco-Sjogren syndrome but have not been extensively investigated. Our study focused on 6 related patients who are members of an inbred population. Muscle biopsies revealed myopathic alterations with variation of fiber size, rounding, degeneration and regeneration of fibers, internalization of nuclei and endomysial fat and fibrosis. Most patients had elevated serum creatine kinase levels. One patient revealed endstage neuromuscular disease and had normal serum creatine kinase levels. Of particular interest was the finding of conspicuous myopathy in 2 young children. Thus far, it has not been appreciated that myopathy represents an early sign of the Marinesco-Sjogren syndrome.

Abnormal centromere-chromatid apposition (ACCA) and Peters' anomaly.

Abnormal centromere-chromatid apposition (ACCA) was noted in a patient with Peters' anomaly. Previous reports of ACCA emphasized its association with tetraphocomelia and other congenital malformations (Roberts, SC Phocomelia, Pseudothalidomide Syndromes). This report expands the array of congenital malformations associated with ACCA and emphasizes the diagnostic importance of ocular defects for the ascertainment of additional cases of ACCA and its possible relationship with abnormal cell division.

Similarity of effects--experimental hyperthermia as a teratogen and maternal febrile illness associated with oromandibular and limb defects.

Experimental hyperthermia in pregnancy causes oromandibular and limb anomalies. In humans, hyperthermia has been suspected of being teratogenic. Two patients were investigated; both had limb defects and one had oromandibular anomalies. Their mothers had a febrile illness at about the 10th wk of gestation. The similarity of defects produced by experimental hyperthermia and those reported here is striking.

Brief clinical report: a sixth report (eighth case) of craniosynostosis-radial aplasia (Baller-Gerold) syndrome.

We report a patient with craniosynostosis, radial aplasia, imperforate anus, and several associated congenital anomalies. It is concluded that she has the Baller-Gerold syndrome. Parenteral consanguinity supports the suggestion that this condition is inherited in an autosomal recessive manner.