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Meier-Gorlin syndrome is a rare autosomal recessive genetic condition whose primary clinical hallmarks include small stature, small external ears and small or absent patellae. Using marker-assisted mapping in multiple families from a founder population and traditional coding exon sequencing of positional candidate genes, we identified three different mutations in the gene encoding ORC4, a component of the eukaryotic origin recognition complex, in five individuals with Meier-Gorlin syndrome. In two such individuals that were negative for mutations in ORC4, we found potential mutations in ORC1 and CDT1, two other genes involved in origin recognition. ORC4 is well conserved in eukaryotes, and the yeast equivalent of the human ORC4 missense mutation was shown to be pathogenic in functional assays of cell growth. This is the first report, to our knowledge, of a germline mutation in any gene of the origin recognition complex in a vertebrate organism.

� Abstract: Despite an abundance of information available for dealing with patients with BRCA-1 and BRCA-2 mutations, little guidance is available to assist the surgeon in dealing with the genetically high-risk patient recently diagnosed with breast cancer. A retrospective review was undertaken of 170 patients who underwent genetic counseling and testing over a 3-year period from March 2000 to March 2003. Forty-three of the 170 patients tested were diagnosed with breast cancer prior to genetic testing. Nine patients (20.9%) tested positive for a deleterious mutation. Fifty-eight percent underwent genetic counseling prior to definitive cancer surgery. Five of the 25 patients who underwent lumpectomy tested positive for a deleterious mutation. Testing results became available during systemic therapy or radiation was delayed until results were known. After counseling, all five patients testing positive went on to bilateral prophylactic mastectomy and reconstruction. None had radiation therapy. Because of a strong family history, eight patients elected to undergo prophylactic mastectomy and reconstruction prior to obtaining genetic test results; and despite compelling histories, all eight tested negative for a mutation. Treatment algorithms are developed to manage patients that are first discovered to be at high risk for a BRCA-1 or BRCA-2 mutation at the time they are diagnosed with breast cancer. Patients diagnosed with breast cancer who are discovered to be at high risk for a genetic mutation should undergo counseling prior to definitive surgery. This maximizes the time that patients have to consider options for prophylaxis and monitoring should their test be positive. It also prevents women who would otherwise be candidates for breast preservation from undergoing unnecessary radiation therapy should they chose prophylactic mastectomy in the face of a positive test. �

FG syndrome is a rare X-linked recessive form of mental retardation, first described by Opitz and Kaveggia in 1974. Based on over 50 reported cases, FG syndrome is associated with agenesis of the corpus callosum, minor facial anomalies (high, broad forehead with frontal cowlick, ocular hypertelorism, down-slanted palpebral fissures, and small cupped auricles), relative macrocephaly, broad thumbs and halluces, and prominent fetal fingertip pads. Affected individuals manifest neonatal hypotonia and severe constipation, which usually resolves during mid-childhood. The hypotonia with joint hyperlaxity evolves into spasticity with joint contractures in later life. Affability, hyperactivity, and excessive talkativeness are noted frequently in patients with FG syndrome. Recently, we described three additional families (six additional patients) with FG syndrome who support the localization of a gene for the FG syndrome in chromosome region Xq12-q21 [Graham JM Jr, Tackels D, Dibbern K, Superneau D, Rodgers C, Corning K, Schwartz CE. 1998. Am J Med Genet 80:145-156.]. Using these same families and one additional sporadic case of FG syndrome, we compared behavioral and personality characteristics of 6 FG boys with other boys with syndromic and nonsyndromic mental retardation: eight with Down syndrome, seven with Prader-Willi syndrome, eight with nonspecific mental retardation, and 13 with Williams syndrome. Using the Vineland Adaptive Behavior Scales, the Reiss Personality Profiles, and the Achenbach Child Behavior Checklist, parents were asked to characterize the behavior and personality of their boys from ages 4 to 10 years. When compared with Williams syndrome, the FG boys had fewer internalizing behaviors and were significantly less anxious and withdrawn but had similar socially oriented, attention-seeking behaviors. On the Reiss Profile, FG boys were also quite similar to Williams syndrome boys. On the Vineland Scales, FG boys demonstrated significant relative strengths in their socialization skills, consistent with their personality, tending to confirm previous descriptions of their personalities.

FG syndrome is a rare X-linked recessive form of mental retardation, first described by Opitz and Kaveggia in 1974 in five related males with mental retardation, disproportionately large heads, imperforate anus, and congenital hypotonia. Partial agenesis of the corpus callosum was noted in at least one of the initial cases and has been seen in a number of subsequently-reported cases. The associated congenital hypotonia with joint hyperlaxity tends to progress to contractures with spasticity and unsteady gait in later life. The presence of subtle facial abnormalities and the characteristic behavior in midchildhood facilitate diagnosis at this age, particularly when there are other affected male relatives in the maternal family. Recently, Briault et al. [1997] mapped a gene for FG syndrome to the Xq12-q21.31 region. We describe three additional families (six additional patients) with FG syndrome on whom we have conducted linkage analysis. Our findings support the localization of a gene for the FG syndrome in Xq12-q21. In addition, we have noted skewed X-inactivation in carrier females, as well as new associated findings in affected males of sagittal craniosynostosis and split hand malformation.

Nonsense-mediated mRNA decay (NMD) is of universal biological significance1-3. It has emerged as an important global RNA, DNA and translation regulatory pathway4. By systematically sequencing 737 genes (annotated in the Vertebrate Genome Annotation database) on the human X chromosome in 250 families with X-linked mental retardation, we identified mutations in the UPF3 regulator of nonsense transcripts homolog B (yeast) (UPF3B) leading to protein truncations in three families: two with the Lujan-Fryns phenotype5,6 and one with the FG phenotype7. We also identified a missense mutation in another family with nonsyndromic mental retardation. Three mutations lead to the introduction of a premature termination codon and subsequent NMD of mutant UPF3B mRNA. Protein blot analysis using lymphoblastoid cell lines from affected individuals showed an absence of the UPF3B protein in two families. The UPF3B protein is an important component of the NMD surveillance machinery8,9. Our results directly implicate abnormalities of NMD in human disease and suggest at least partial redundancy of NMD pathways.

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.

Item does not contain fulltext 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.

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.

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. © 1993 Wiley-Liss, Inc.

We describe a mother and daughter with typical cri du chat syndrome. Previous investigators have noted the lack of information about the reproductive fitness of patients with this disorder. This report demonstrates that females with cri du chat syndrome are fertile, can gestate and likewise deliver affected offspring, which has significant management and counseling implications.

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.

SummaryThe effect of educational activities, distance from a genetic centre, and presence of satellite clinics on the growth in genetic services in three regions served (south Alabama, west Florida and southeast Mississippi) was examined. Comparisons of growth trends between the three regions were made in the context of regional differences in clinical and educational variables. Multiple regression analyses of growth in clinical services with these variables were also performed. Results demonstrated that growth in clinical services is greatly enhanced when educational activities are offered in concert with the establishment of a satellite clinic.

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.

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.

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.

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.

Diagnosis of the Whistling-Face syndrome (WF) usually follows the observation of microstomia and a stigmatic facies associated with ulnar deviation of fingers and joint contractures. Muscle atrophy and myopathy, although reported in WF, receive insufficient emphasis. More recently, cardiomyopathy and malignant hyperthermia have been observed in WF patients. Our clinical studies and review bring support to the conclusion that the spectrum of WF includes; skeletal weakness, hypertrophic cardiomegaly with WPW conduction abnormalities (unresponsive to quinidine), and elevated serum CPK, GOT, and LDH. Hypertrophic cardiomyopathy with enlarged myofilaments due to abundant amyloid-like material, and skeletal myopathy with scattered fiber atrophy and focal areas of fatty deposition and myelin fibers, are also part of WF. Consequently, individuals with primary hypertrophic cardiomyopathy or a history of malignant hyperthermia should also be assessed for clinical features of WF and vice versa. Because WF presents with clinical variability and is an autosomal dominant disorder of prenatal onset, a family history of any of the features described above may be pertinent in genetic counseling and prenatal assessment of families with WF syndrome.

Neurofibromatosis (NF) has been categorized as type I (von Recklinghausen) or type II (formerly “Central NF”), and other categories have been proposed (III-VII). Our investigations concern a large kindred with NF II that spans 7 generations and includes over 300 members. Affected individuals do not fulfill the diagnostic criteria of NF I. Their symptoms and signs are direct byproducts of the emergence of nervous system neoplasia. Clinical and histologic data from 28 patients (14 males, 14 females) indicate that the most prevalent neoplasms are acoustic neuromas (AN) (15 cases) followed by meningiomas (MEN) (8 cases) and ependymomas (2 cases). MEN, if present, are diagnosed during puberty or shortly after (earliest onset 16 years) and tend to be multiple. Individuals developing symptoms later (latest onset 6th decade) tend to be free of MEN, and instead develop AN which most often are bilateral. None of the affected developed optic glioma or pheochromocytoma. Molecular studies of MEN and AN tissue were indicative of a loss of genes on chromosome 22 (Seizinger et al, 1986), a strong clue to the chromosomal location of the defect. Molecular studies of this kindred by the same investigators are in process to determine whether the NP II gene is on chromosome 22.