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Costello syndrome is a rare congenital anomaly syndrome associated with mental retardation and predisposition to benign and malignant tumors, caused by heterozygous missense mutations in the HRAS oncogene. Previously, all molecularly analyzed mutations appeared de novo, and most arose in the paternal germline. A single patient with somatic mosaicism for a Costello syndrome causing HRAS mutation has been reported. Here we describe the first documented transmission of an HRAS mutation from a parent with somatic mosaicism to a child with typical Costello syndrome. Prior to the identification of the underlying gene mutation in Costello syndrome, this family had been identified clinically. The proband was subsequently found to carry a G12S HRAS germline mutation. Testing of the parents for parental origin identified his father as mosaic for the same HRAS mutation. The mother was found not to carry an HRAS mutation. The causative familial mutation is identified as a c.34G > A, which is the most common mutation in the HRAS gene in patients with Costello syndrome. The father carries the mutation in 7-8% of his alleles. This is the second case of mosaicism observed in Costello syndrome and the first direct molecular evidence of father-to-son transmission of the disease-causing mutation. Our observation underlines the importance of parental evaluation, and may have implications for genetic counseling and clinical practice.

SPONASTRIME dysplasia (SD) is an autosomal recessive skeletal dysplasia of the spondyloepimetaphyseal dysplasia (SEMD) type. The name was derived from "spondylar and nasal alterations with striated metaphyses" [Fanconi et al. 1983; Helv Paediat Acta 38: 267-280]. We follow two previously reported patients with SD [Patients 3, 4 in Langer et al. 1996; Am J Med Genet 63: 20-27]. Since the original publication, additional findings were identified in these patients.

Because Cardio-facio-cutaneous (CFC) syndrome has significant phenotypic overlap with Costello syndrome, it may be difficult to establish the diagnosis on a clinical basis. The recent discoveries of germline HRAS mutations in patients with Costello syndrome and mutations in BRAF, MEK1, and MEK2 in CFC syndrome uncovered the biologic mechanism for the shared phenotypic findings based on the close interaction of the affected gene products within the MAP kinase pathway. We evaluated a series of patients who were either clinically diagnosed with Costello syndrome, or in whom the diagnoses of both Costello and CFC syndromes were considered. After excluding mutations in HRAS, we identified eight changes in BRAF and five in MEK1. Five mutations are novel, and all changes occurred de novo among those triads tested. A review of the clinical abnormalities showed important differences between patients with either a BRAF or MEK1 mutation, and those previously reported with an HRAS mutation. Statistical significance was achieved, despite the relatively small number of patients with BRAF and MEK1 mutations reported here, for polyhydramnios, growth hormone deficiency and the presence of more than one papilloma, which were less common in CFC compared to HRAS mutation positive patients. Although both CFC and Costello syndrome are characterized by cardiac abnormalities in about three-fourths of patients, the pattern of congenital heart defects (CHD), hypertrophic cardiomyopathy (HCM), and tachycardia differs somewhat. CHD, especially pulmonic stenosis associated with a secundum-type atrial septal defect, are more common in CFC than Costello syndrome (P = 0.02). Atrial tachycardia is less frequent in CFC patients with BRAF or MEK1 mutations, compared to Costello syndrome patients with HRAS mutation (P = 0.04). Chaotic atrial rhythm or multifocal atrial tachycardia was observed only in Costello syndrome. Malignant tumors have been viewed as characteristic for Costello syndrome due to HRAS mutations, however, we report here on a MEK1 mutation in a patient with a malignant tumor, a hepatoblastoma. Although this indicates that the presence of a tumor is not specific for Costello syndrome with HRAS mutation, it is noteworthy that the tumor histology differs from those commonly seen in Costello syndrome. Based on these clinical differences we suggest that patients with BRAF and MEK mutations should be diagnosed with CFC syndrome, and the diagnosis of Costello syndrome be reserved for patients with HRAS mutations.

De novo heterozygous HRAS point mutations have been reported in more than 81 patients with Costello syndrome (CS), but genotype/phenotype correlation remains incomplete because the majority of patients share a common mutation, G12S, seen in 65/81 (80%). Somatic HRAS mutations have previously been identified in solid tumors, and mutation hot spots related to a gain-of-function effect of the gene product are known. The germline mutations causing CS occur at these hot spots and convey a gain-of-function effect, thus accounting for the greatly increased cancer risk. Diagnostic testing for HRAS mutations is now available and the identification of a mutation in a patient with consistent clinical findings confirms a diagnosis of CS. It is not clear yet if the absence of an HRAS mutation precludes a diagnosis of CS. Because there is a significant overlap in the clinical findings of Costello, cardio-facio-cutaneous, and Noonan syndromes, diagnostic uncertainty remains in patients lacking an HRAS mutation. We report here on a female with findings suggestive of CS in whom mutation analysis performed with standard techniques on white blood cell derived DNA did not show an HRAS mutation. However, analysis of DNA derived from three independently collected buccal swabs showed a sequence change qualitatively consistent with the G12S mutation. Allelic quantitation showed the presence of the mutation in approximately 25%-30% of the sampled buccal cells. In this patient, standard technology failed to identify the disease causing mutation on DNA derived from a blood sample, highlighting the potential pitfalls in the interpretation of negative mutation studies. This is the first reported CS patient mosaic for the common HRAS mutation, likely due to a somatic mutation occurring very early in fetal development.

Fluorescent in situ hybridization (FISH) screening of subtelomeric rearrangements has resulted in the identification of previously unrecognized chromosomal causes of mental retardation with and without dysmorphic features. This article reports the phenotypic and molecular breakpoint characterization in a cohort of 12 patients with subtelomeric deletions of chromosome 9q34. The phenotypic findings are consistent amongst these individuals and consist of mental retardation, distinct facial features and congenital heart defects (primarily conotruncal defects). Detailed breakpoint mapping by FISH, microsatellite and single nucleotide polymorphism (SNP) genotyping analysis has narrowed the commonly deleted region to an approximately 1.2 Mb interval containing 14 known transcripts. The majority of the proximal deletion breakpoints fall within a 400 kb interval between SNP markers C12020842 proximally and C80658 distally suggesting a common breakpoint in this interval.

Costello syndrome is a rare congenital anomaly syndrome with a predisposition to specific tumors, including neuroblastoma, rhabdomyosarcoma, and transitional cell carcinoma of the bladder. The increased risk for solid tumors led to the proposal of a tumor screening protocol. A screening test for neuroblastoma consists of measuring catecholamine metabolites in urine, an assay that may also be used for diagnostic confirmation of a suspected catecholamine secreting tumor. We report eight patients with Costello syndrome with elevated catecholamine metabolites, vanillylmandelic acid (VMA) and/or homovanillic acid (HVA), in urine. Each patient had additional laboratory and/or imaging studies. None of the patients was found to have a neuroblastoma or another catecholamine secreting tumor. In two cases, the assays were performed because the patients were symptomatic with diaphoresis and hypertension, respectively, and in the other six cases the assays were performed in order to screen for neuroblastoma. The pathophysiology for the catecholamine metabolite abnormality in these patients with Costello syndrome remains unclear. However, it appears that in this patient group an elevation above the normal limit, defined as 2 standard deviations (SD) above the mean for age, is more likely to be a variant, rather than a sign of a neuroblastoma. Thus, it may be prudent not to use this assay as a screening test, and to take the frequently elevated results into consideration when interpreting diagnostic assays.

PROBLEM Few studies have focused on grandparent-raised children with behavioral/emotional problems. The present study examined the therapeutic progress of this population. METHODS Data from this descriptive, correlational study were obtained from records of 207 children who received treatment at a child treatment center. Instruments included the Progress Evaluation Scales (PES) and an investigator-constructed tool. FINDINGS Children who had regular paternal contact, were younger when treatment started, and were raised by grandparents with adult partners had significantly more positive change in the PES scores. CONCLUSIONS More thorough clinical assessment of these reconfigured families will lead to improved mental health outcomes for children and will enhance clinical records as sources of research data.

We report five new cases of rhabdomyosarcoma (RMS) in Costello syndrome. These cases, combined with those previously reported, increase the number of solid tumors to 17 (10 RMSs, 3 neuroblastomas, 2 bladder carcinomas, 1 vestibular schwannoma, 1 epithelioma), in at least 100 known Costello syndrome patients. Despite possible ascertainment bias, and the incomplete identification of all Costello syndrome patients, the tumor frequency could be as high as 17%. This is comparable to the 7-21% frequency of solid tumors in Beckwith-Wiedemann syndrome (BWS), and may justify tumor screening. Based on the recommendations for screening BWS patients, we propose a screening protocol consisting of ultrasound examination of the abdomen and pelvis every 3-6 months until age 8-10 years for RMS and abdominal neuroblastoma; urine catecholamine metabolite analysis every 6-12 months until age 5 years for neuroblastoma; and urinalysis for hematuria annually for bladder carcinoma after age 10 years. These recommendations may need to be modified, as new information becomes available. Potential criticism of the tumor screening protocol concerns the lack of evidence for improved outcome, and possible overestimation of the tumor risk. The ability of RMSs to occur at various sites complicates tumor screening, but 8 of the 10 RMSs in Costello syndrome patients originated from the abdomen, pelvis and urogenital area. Prior diagnosis of Costello syndrome is a prerequisite for the implementation of any screening protocol. The diagnosis of Costello syndrome should also be considered in individuals with RMS and physical findings suggestive of Costello syndrome.

We report on a man with neurofibromatosis type 1 (NF1) and Leri-Weill dyschondrosteosis (LWD). His father had NF1. His mother had LWD plus additional findings of Turner syndrome (TS): high arched palate, bicuspid aortic valve, aortic stenosis, and premature ovarian failure. The proband's karyotype was 46,X,dic(X;Y)(p22.3;p11.32). Despite having almost the same genetic constitution as 47,XXY Klinefelter syndrome, he was normally virilized, although slight elevation of serum gonadotropins indicated gonadal dysfunction. His mother's karyotype was mosaic 45,X[17 cells]/46,X,dic(X;Y)(p22.3;p11.32)[3 cells].ish dic(X;Y)(DXZ1 + ,DYZ1 + ). The dic(X;Y) chromosome was also positive for Y markers PABY, SRY, and DYZ5, but negative for SHOX. The dic(X;Y) chromosome was also positive for X markers DXZ1 and a sequence

One female and two male patients with multiple lateral meningoceles are presented. They do not have neurofibromatosis or Marfan syndrome and share findings with the two previously described patients with multiple lateral meningoceles. The original report by Lehman et al. [1977: J Pediatr 90:49-54] was titled "familial osteosclerosis," because osteosclerosis was present in the proposita and her mother; the patient described by Philip et al. [1995: Clin Dysmorphol 4:347-351] also had increased bone density of the skull base and the sutures. Thickened calvaria were present in one of our patients; two had a prominent metopic suture. Other shared findings include multiple lateral meningoceles, Wormian bones, malar hypoplasia, downslanted palpebral fissures, a high narrow palate, and cryptorchidism in males. In addition, our patients showed ligamentous laxity, keloid formation, hypotonia, and developmental delay. A short umbilical cord was noted in two patients. One had a hypoplastic posterior arch of the atlas and an enlarged sella, as reported by Lehman et al. [1977]. Our patients appear to have the same syndrome as previously reported. We suggest it be called "lateral meningocele syndrome," because of this unique finding.

We present a boy followed from age 5-13 years who is the fifth reported case of ter Haar syndrome. This is a recently-named entity comprising congenital glaucoma, hypertelorism, congenital heart defects and kyphoscoliosis, skeletal dysplasia, and developmental delay. These patients were originally thought to have an autosomal-recessive form of Melnick-Needles syndrome, and were only identified as having a distinct syndrome with the report of the fourth case. Probable autosomal-recessive inheritance is based on consanguinity in 4 of 5 cases. Ocular, cardiac, and craniofacial findings distinguish ter Haar syndrome as a distinct entity. Our patient is the longest survivor at present, suggesting that there is heterogeneity in this syndrome or, alternatively, that aggressive therapy of the congenital heart defects has significant effect.

We describe a mother and son with multiple, non-progressive, congenital contractures, camptodactyly and absent flexion creases, expressionless face, blepharophimosis, microstomia, and short stature. Although these cases share similarities with the autosomal-recessive Schwartz-Jampel and Marden-Walker syndromes, they have a different mode of inheritance and lack myotonia, one of the most characteristic findings of the Schwartz-Jampel syndrome. Our cases most closely resemble those previously reported as distal arthrogryposis type IIb, although in our patients the proximal joints are severely affected and extraocular involvement is absent. Hearing loss is present in one and cleft palate in the other of our patients; these findings were previously described in arthrogryposis syndromes other than type IIb. We suggest extending the spectrum of distal arthrogryposis to include these manifestations, since there appears to be significantly overlap between the different syndromes.

We describe a previously unrecognized syndrome in two unrelated patients with congenital cataracts, sensorineural deafness, distinctive facial appearance, skeletal changes, postnatal short stature, and mental retardation.

Stephen P. Robertson,* Zandra A. Jenkins, Timothy Morgan, Lesley Ades, Salim Aftimos, Odile Boute, Torunn Fiskerstrand, Sixto Garcia-Minaur, Arthur Grix, Andrew Green, Vazken Der Kaloustian, Ray Lewkonia, Brenda McInnes, Mieke M. van Haelst, Grazia Macini, Tamas Illes, Geert Mortier, Ruth Newbury-Ecob, Linda Nicholson, Charles I. Scott, Karolina Ochman, Izabela Brozek, Deborah J. Shears, Andrea Superti-Furga, Mohnish Suri, Margo Whiteford, Andrew O.M. Wilkie, and Deborah Krakow Department of Paediatrics and Child Health, Dunedin School of Medicine, Dunedin, New Zealand Department of Medical Genetics, The Children’s Hospital at Westmead, Sydney, Australia Discipline of Paediatrics and Child Health, University of Sydney, Sydney, Australia Northern Regional Genetics Service, Auckland, New Zealand Genetics Service, Jeanne de Flandre Hospital, Lille, France Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway Genetics Service, Western General Hospital, Edinburgh, United Kingdom Permanente Medical Group, Sacramento, California Department of Medical Genetics, Our Lady’s Hospital for Sick Children, Dublin, Ireland Division of Medical Genetics, McGill University, Montreal Children’s Hospital, Montreal, Canada Department of Medical Genetics, Alberta Children’s Hospital, Calgary, Canada Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands Department of Orthopedic Surgery, University of Pecs, Pecs, Hungary Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium Clinical Genetics Service, United Bristol Hospitals Trust, Bristol, United Kingdom Division of Medical Genetics, DuPont Hospital for Children, Wilmington, Delaware Department of Biology and Genetics, Medical University of Gdansk, Gdansk, Poland Clinical and Molecular Genetics Unit, Institute for Child Health, London, United Kingdom Department of Paediatrics and Adolescent Medicine, University of Freiburg, Freiburg, Germany Clinical Genetics Service, City Hospital, Nottingham, United Kingdom Ferguson-Smith Centre for Medical Genetics, Glasgow, United Kingdom Weatherall Institute of Molecular Medicine, The John Radcliffe, Oxford, United Kingdom Cedars Sinai Medical Research Institute, Los Angeles, California