Mosaic maternal uniparental disomy of chromosome 11 in a patient with Silver-Russell syndrome.

Silver-Russell syndrome (SRS) is a clinically heterogeneous disorder characterised mainly by intrauterine and postnatal growth retardation. While maternal uniparental disomy of chromosome 7 is found in 5-10% of SRS patients, recently genetic and epigenetic mutations affecting the imprinting centres on chromosome 11p15 have been reported in up to 64% of patients. Chromosome 11p15 abnormalities reported in SRS include methylation defects in the imprinting centre 1 (ICR1) and maternally inherited duplications involving all or part of the imprinted region of 11p15. Here we report the first published case of SRS with mosaic maternal uniparental disomy of chromosome 11.

Chondrodysplasia punctata: case report and review of audiological and ENT features.

Chondrodysplasia punctata is a term referring to a clinically heterogeneous group of bone and cartilage dysplasias which cause characteristic epiphyseal stippling. The condition can involve the ear, nose and throat in diverse ways at many levels. We present a case of X-linked brachytelephalangic chondrodysplasia punctata, which illustrates the features of this condition particularly relevant to the audiological physician, otolaryngologist and neonatologist.

Skeletal muscle involvement in infantile systemic hyalinosis.

Infantile Systemic Hyalinosis is a rare autosomal recessive entity, characterised by deposition of hyaline material in skin and bone, often complicated by visceral involvement. The characteristic features are marked delay in motor milestones attributed to severe progressive flexion contractures of proximal and distal joints, and skin and mucosal hypertrophy and thickening, followed by failure to thrive. Pain secondary to osteolytic lesions is also a predominant feature. We report a patient with Infantile Systemic Hyalinosis, confirmed by the clinical findings, who also displayed clear evidence of proximal muscle weakness. Muscle biopsy revealed myopathic changes, which have not been reported previously. We suggest that skeletal muscle is involved in Infantile Systemic Hyalinosis and contributes to the characteristic poor outcome of these patients.

Severe hypophosphatasia: characterization of fifteen novel mutations in the ALPL gene.

Hypophosphatasia is an inherited disorder characterized by defective bone mineralization and deficiency of serum and tissue liver/bone/kidney alkaline phosphatase (L/B/K ALP) activity. We report the characterization of ALPL gene mutations in a series of 11 families from various origins affected by perinatal and infantile hypophosphatasia. Sixteen distinct mutations were found, fifteen of them not previously reported: M45V, G46R, 388-391delGTAA, 389delT, T131I, G145S, D172E, 662delG, G203A, R255L, 876-881delAGGGGA, 962delG, E294K, E435K, and A451T. This confirms that severe hypophosphatasia is due to a large spectrum of mutations in Caucasian populations.

Isolated non-compaction of the ventricular myocardium: prenatal diagnosis and natural history.

Isolated non-compaction of the ventricular myocardium (NCVM) is a rare cardiomyopathy characterized by the persistence of numerous marked ventricular trabeculations and deep intertrabecular recesses with direct vascular supply by the ventricular cavities. We report two cases diagnosed by fetal echocardiography at 27 and 30 weeks' gestation, respectively. Postnatal echocardiography verified the presence of the NCVM seen prenatally. Diagnosis was confirmed at postmortem following neonatal demise in the first case. Surgical intervention for exomphalos and extrahepatic biliary atresia was required in the second case, but there is no clinical abnormality of the cardiovascular system a year after delivery. The uncertainty of prognosis and the familial recurrence described elsewhere indicate the difficulty of counseling and the value of prenatal diagnosis, which is feasible using currently available ultrasonographic equipment.

Trisomy 17p10-p12 resulting from a supernumerary marker chromosome derived from chromosome 17: molecular analysis and delineation of the phenotype.

We report a 5-year-old boy with a small de novo marker chromosome derived from the proximal short arm of chromosome 17. His clinical features include hypotonia, global developmental delay, oval face with large nose and prominent ears, and ligamentous laxity of the fingers. Magnetic resonance imaging of the brain demonstrated mildly delayed myelination. G-band chromosome analysis revealed mosaicism for a small marker chromosome in 85% of the peripheral blood cells analyzed. Fluorescence in situ hybridization and microsatellite polymorphism studies showed that the der(17) was of maternal origin and included genetic material from the 17p10-p12 region, but did not contain the PMP22 gene. One breakpoint mapped within the centromere and the second breakpoint mapped adjacent to the Charcot-Marie-Tooth disease type 1A proximal low-copy repeat (CMT1A-REP). We compare the clinical characteristics of our patient with those previously reported to have a duplication involving the proximal short arm region of chromosome 17 to further delineate the phenotype of trisomy 17pl0-p12.

Maternal contamination at fetal muscle biopsy.

Duchenne muscular dystrophy (DMD) can be diagnosed by fetal muscle biopsy and immunohistochemical staining showing the absence of dystrophin. We report a case of fetal muscle biopsy in which the needle gun was successfully fired within the fetal gluteal muscle but the sample was contaminated by maternal tissue. This was attributed to the design of the biopsy needle, allowing transient opening of the biopsy core as the needle penetrated the maternal rectus sheath, muscle, and myometrium. Histology showed tissue suggestive of maternal origin, confirmed by DNA analysis. Repeat sampling revealed fetal muscle with normal dystrophin expression. We recommend that care be taken during needle insertion to avoid maternal contamination, and tests be used to confirm the fetal source of the sample.

Partial trisomy 3q causing mild Cornelia de Lange phenotype.

A brother and sister are reported with developmental delay and facial features suggestive of the Cornelia de Lange syndrome. Cytogenetic analysis showed them to be trisomic for the region 3q25.1-26.2 because of the inheritance of an unbalanced interchromosomal insertion from their father, who was a balanced insertion carrier. The clinical phenotype and cytogenetic analysis (including chromosome painting studies) in relation to the possible localisation of the Cornelia de Lange gene are discussed.

Velocardiofacial syndrome in a mother and daughter: variability of the clinical phenotype.

We report a mother and daughter with features of the velocardiofacial (VCF) syndrome and monosomy for 22q11 identified using molecular techniques. The mother had surgery as a child for a cleft palate and a congenital heart defect, and her facial features were consistent with the diagnosis. The daughter had developmental delay, absent speech, scoliosis, and similar facial features, but no cleft palate or congenital heart defect. These cases illustrate the considerable intrafamilial variability of the phenotype of VCF syndrome. The clinical and molecular diagnosis of this syndrome is discussed. The phenotypic variability of the VCF syndrome means that many cases may be undiagnosed.

Exclusion of candidate genes from a role in cleft lip with or without cleft palate: linkage and association studies.

Candidate genes and marker loci for cleft lip/palate (CL/P) were tested using linkage analyses and association studies. Eight British families with apparent autosomal dominant inheritance of non-syndromic CL/P participated in the linkage analyses while the association analyses involved 61 unrelated British white people with CL/P and 60 controls. The report of an association between RARA (17q21) and unrelated Australian persons with CL/P (p = 0.016) was not confirmed in British CL/P persons (chi 2 = 0.954, p > 0.1). There was also no evidence of linkage between RARA and the eight CL/P families (Z = -3.211, theta = 0.001). Linkage was excluded between familial CL/P and F13A1 (map position 6p24-25) with an observed maximum lod score of Z = -2.052 at theta = 0.05. No association was found between alleles at VIM (10p13) and the British CL/P subjects (chi 2 = 0.110, p > 0.5). Multipoint analysis excluded linkage between familial CL/P and the markers D1S65 and D1S58 which flank the Van der Woude syndrome locus with a maximum lod score of Z = -4.0. This suggests that the genetic defect underlying VWS is not the same as in non-syndromic CL/P. There was no evidence of linkage between CRTL1 (5q15) and the eight CL/P families (Z = -3.466, theta = 0.05).

No evidence of linkage between the transforming growth factor-alpha gene in families with apparently autosomal dominant inheritance of cleft lip and palate.

Eight families have been identified with cleft lip, with or without cleft palate (CL/P), inherited in an apparently autosomal dominant manner. Transforming growth factor-alpha (TGFA) has been tested as a candidate gene for clefting in these families. Negative lod scores were generated in an autosomal dominant model with 80% penetrance (Z = -3.152 at theta = 0.05 and Z = -2.49 at theta = 0.05 with only affected subjects scored). After testing with a reduced penetrance of 28%, less negative lod scores were generated (Z = -0.157 at theta = 0.00), but there was still no evidence of linkage. An autosomal recessive model with a penetrance of 35% was also tested. Regardless of the model used there was little evidence of linkage between TGFA and the CL/P phenotype, which is in contrast to the previously published findings of an association between TGFA and CL/P in unrelated subjects.

Confirmation of an association between RFLPs at the transforming growth factor-alpha locus and non-syndromic cleft lip and palate.

Three RFLPs at the TGFA locus were studied in 60 unrelated British Caucasian subjects with non-syndromic cleft lip/palate and 60 controls. A highly significant association between the TaqI RFLP and the occurrence of clefting was found (chi 2 = 15.04, p = less than 0.001). No significant association was found with the two other RFLPs studied (BamHI and RsaI). Haplotypes derived from the three RFLPs at the TGFA locus also showed an over-representation of the C2A2B2 haplotype in cases compared to controls. Analyses of genotypes according to type of cleft and the presence or absence of a family history of clefting were also carried out. These results provide further support for the role of TGFA as a gene of major effect in the development of orofacial clefts in humans.