MLL2 mutation detection in 86 patients with Kabuki syndrome: a genotype-phenotype study.

Recently, pathogenic variants in the MLL2 gene were identified as the most common cause of Kabuki (Niikawa-Kuroki) syndrome (MIM#147920). To further elucidate the genotype-phenotype correlation, we studied a large cohort of 86 clinically defined patients with Kabuki syndrome (KS) for mutations in MLL2. All patients were assessed using a standardized phenotype list and all were scored using a newly developed clinical score list for KS (MLL2-Kabuki score 0-10). Sequencing of the full coding region and intron-exon boundaries of MLL2 identified a total of 45 likely pathogenic mutations (52%): 31 nonsense, 10 missense and four splice-site mutations, 34 of which were novel. In five additional patients, novel, i.e. non-dbSNP132 variants of clinically unknown relevance, were identified. Patients with likely pathogenic nonsense or missense MLL2 mutations were usually more severely affected (median 'MLL2-Kabuki score' of 6) as compared to the patients without MLL2 mutations (median 'MLL2-Kabuki score' of 5), a significant difference (p < 0.0014). Several typical facial features such as large dysplastic ears, arched eyebrows with sparse lateral third, blue sclerae, a flat nasal tip with a broad nasal root, and a thin upper and a full lower lip were observed more often in mutation positive patients.

Clinical and molecular characterization of Diastrophic Dysplasia in the Portuguese population.

SLC26A2-related dysplasias encompass a spectrum of diseases: from lethal achondrogenesis type 1B (ACG1B; MIM #600972) and atelosteogenesis type 2 (AO2; MIM #256050) to classical diastrophic dysplasia (cDTD; MIM #222600) and recessive multiple epiphyseal dysplasia (rMED; MIM #226900). This study aimed at characterizing clinically, radiologically and molecularly 14 patients affected by non-lethal SLC26A2-related dysplasias and at evaluating genotype-phenotype correlation. Phenotypically, eight patients were classified as cDTD, four patients as rMED and two patients had an intermediate phenotype (mild DTD - mDTD, previously 'DTD variant'). The Arg279Trp mutation was present in all patients, either in homozygosity (resulting in rMED) or in compound heterozygosity with the known severe alleles Arg178Ter or Asn425Asp (resulting in DTD) or with the mutation c.727-1G>C (causing mDTD). The 'Finnish mutation', c.-26+2T>C, and the p.Cys653Ser, both frequent mutations in non-Portuguese populations, were not identified in any of the patients of our cohort and are probably very rare in the Portuguese population. A targeted mutation analysis for p.Arg279Trp and p.Arg178Ter in the Portuguese population allows the identification of approximately 90% of the pathogenic alleles.

Clinical and molecular diagnosis of the skeletal dysplasias associated with mutations in the gene encoding Fibroblast Growth Factor Receptor 3 (FGFR3) in Portugal.

Mutations in the gene that encodes Fibroblast Growth Factor Receptor 3 (FGFR3) are associated with Achondroplasia (MIM 100800), Hypochondroplasia (MIM 146000), Muenke Syndrome (MIM 602849), Thanatophoric Dysplasia (MIM 187600, MIM 187601) and Lacrimo-Auriculo-Dento-Digital Syndrome (MIM 149730).Here we report a clinical and molecular study in a large cohort of 125 Portuguese patients with these skeletal disorders. The identification of the P250R mutation allowed the confirmation of the Muenke Syndrome in 9 out of the 52 cases referred. Two known mutations were found in the Thanatophoric Dysplasia referred cases. No mutations were identified in the LADD syndrome patient. In Achondroplasia and Hypochondroplasia, genetic heterogeneity was present amongst the 70 clinically diagnosed patients with 5 different mutations identified. As in other studies, complex phenotypic heterogeneity amongst patients carrying the same gene defect was observed. In several cases, the new amino acids encoded, as a consequence of mutations, were related to the severity of patients' phenotype. The presence of 10 misdiagnosed cases emphasizes the importance of performing mutation analysis of the hotspot regions responsible for both dysplasias (Ach and Hch). For patients with an unquestionable clinical diagnosis, lacking the most common mutations, a complete screening of FGFR3 is necessary.

Molecular studies in Portuguese patients with Smith-Lemli-Opitz syndrome and report of three new mutations in DHCR7.

Smith-Lemli-Opitz syndrome (SLO) is an autosomal recessive disorder characterised by craniofacial dysmorphism, mental retardation, multiple congenital anomalies, and increased levels of 7-dehydrocholesterol (7-DHC) in body tissues and fluids. SLO is caused by mutations in the DHCR7 gene which encodes 7-dehydrocholesterol reductase, the last enzyme of cholesterol biosynthesis pathway. In our investigation, we screened 682 dysmorphic/mentally retarded Portuguese patients for abnormal levels of 7-DHC in blood by UV spectrometry. We identified six unrelated patients with SLO (0.87% of total). Mutational analysis of the DHCR7 gene led to the identification of seven distinct mutations, three of which are new (F174S, H301R, and Q98X). The common IVS8-1G > C and T93M variants together with the H301R accounted for 70% of the all SLO alleles in our population. Our findings contribute to the variegate array of pathological changes in the DHCR7 gene among different European populations.

Eleven novel APC mutations identified in Portuguese FAP families.

Germline mutations of the adenomatous polyposis coli (APC) gene are responsible for familial adenomatous polyposis (FAP), an autosomal dominant predisposition to colorectal cancer. In the present study we screened all of the exons of the APC gene in individuals belonging to 85 Portuguese FAP families. We here report eleven novel mutations which are predominantly frameshifts or single base substitutions, resulting in premature stop codons. Hum Mutat 16:178, 2000.

Manifestations and treatment of Schimke immuno-osseous dysplasia: 14 new cases and a review of the literature.

UNLABELLED: Schimke immuno-osseous dysplasia (SIOD) is a rare autosomal recessive spondylo-epiphyseal dysplasia. The characteristic features of SIOD include 1) short stature with hyperpigmented macules and an unusual facies, 2) proteinuria with progressive renal failure, 3) lymphopenia with recurrent infections, and 4) cerebral ischaemia. Although 25 patients have been reported with this disorder, the clinical course and phenotype of SIOD are not well characterized. This report summarizes the clinical findings, course and treatment of reported patients and includes 14 additional patients with SIOD. We emphasize the high incidence of cerebral ischaemia and ocular abnormalities, define the high incidence of thyroid dysfunction and blood cytopenia, and confirm the absence of effective and durable medical therapies. CONCLUSION: Schimke immuno-osseous dysplasia is a multi-system autosomal recessive disorder with variable expression that affects the skeletal, renal, immune, vascular, and haematopoietic systems. Medical therapy is limited especially for more severely affected individuals.

Anencephaly with spinal dysraphism, cleft lip and palate and limb reduction defects.

We report three unrelated fetuses presenting with anencephaly, spinal dysraphism, cleft lip and palate and limb reduction defects. Review of the literature suggests that this association may be more commonly found than previously recognized and may indicate severe disturbance in early embryogenesis.

Examination of fetuses after induced abortion for fetal abnormality--a follow-up study.

In the North-Western Region we offer a service to examine fetuses aborted after the diagnosis of fetal abnormalities. Many obstetricians use this service. We examined 343 mid-trimester fetuses over the last 5 years: 215 following an abnormal scan and 128 abnormal amniotic fluid or villus findings. When necessary, investigations were performed. A post-mortem examination was always required. As a result of fetal investigation, the scan diagnosis was modified or refined in 91 cases (42.3 per cent). In three of these cases no fetal abnormality was found. For the fetuses diagnosed as abnormal by amniocentesis or chorionic villus biopsy, in one (0.8 per cent) the pre-termination diagnosis was not confirmed. The results were similar to those of our previous 5-year study except (a) diagnosis of neural tube defects was rarely based on amniocentesis in the present study (2/62, 3.2 per cent) compared with the previous one (32/103, 31 per cent), and (b) renal abnormalities were more often diagnosed in the pre-termination scan in the present study. We conclude that the examination of aborted mid-trimester fetuses by dysmorphologists continues to improve diagnosis, allowing more accurate genetic counselling for the families.

Postaxial acrofacial dysostosis syndrome with vertebral segmentation defects.

We report a fetus with severe mandibulofacial dysostosis (MFD), postaxial hand defects, talipes equinovarus and extensive vertebral segmentation defects. This constellation may represent a distinct postaxial acrofacial dysostosis syndrome.

Schinzel-Giedion syndrome. A patient with hypothyroidism and diabetes insipidus.

The Schinzel-Giedion is an autosomal recessive syndrome characterized by midface retraction, hypertrichosis, multiple skeletal anomalies, cardiac and renal malformations and mental retardation. We describe a female child with this syndrome and a clinical status complicated by hypernatremic dehydration, hypothyroidism and diabetes insipidus at the age of 10 months.