We expand the Kosaki overgrowth syndrome (KOGS) phenotype by over 70% to include 24 unreported KOGS symptoms, in a first male patient, the third overall associated with the PDGFRB c.1751C>G p.(Pro584Arg) mutation. Eighteen of these symptoms are unique to our patient, the remaining six are shared with other patients. Of the 24 unreported features overall, 6 show marked phenotype evolution and varying time of onset. The triangular face detected at 14 months and long palpebral fissures with lateral ectropion at 4 years are present in other members of the cohort. The remaining 4 are unique to Patient 5: pronounced macrocephaly from birth, increasingly triangular anterior skull from 14 months, camptodactyly, emerging at 4 years and worsening joint contractures from 6 years. Compilation of all new symptoms reported here with published clinical data further identifies at least 18 clinical parameters common to all cases to date, encompassing both known KOGS-associated PDGFRB mutations. We therefore propose a set of 18 core KOGS symptoms, with 16 present in early childhood. These results should also impact diagnostic/prognostic scope, intervention and outcome potential for KOGS patients, particularly for developmentally progressive conditions such as scoliosis and myofibroma. =C2=A9 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

The Alagille syndrome (AGS), a congenital disorder affecting liver, heart, skeleton and eye in association with a typical face, is an autosomal dominant disease with nearly complete penetrance and variable expression. AGS is caused by mutations in the developmentally important JAG1 gene. In our mutation screening, where 61 mutations in JAG1 were detected, we identified five cases where mosaicism is present. Our results point to a significant frequency of mosaicism for JAG1 mutations in AGS of more than 8.2%. Because mosaicism may be associated with a very mild phenotype, the appropriate diagnosis of AGS and consequently the determination of the recurrence risk can be complicated.

Uniparental disomy (UPD) is defined as the inheritance of both homologous chromosomes from only one parent. So far, maternal UPD 7 has been described in 28 cases. Here, we report 4 new cases, present clinical information of 5 cases previously reported by us, and review the clinical and molecular findings of all 32 cases. We found a phenotype characterized by pre- and postnatal growth retardation, occipitofrontal head circumference in the lower normal range, a triangular face, and retarded bone maturation. Findings of the facial gestalt included a high and broad forehead and a pointed chin. A broad mouth with down-turned corners, prominent ears, cafe-au-lait spots, hemihypotrophy, or clinodactyly were rarely present. Psychomotor development was delayed in 6 cases. The clinical findings strikingly resemble the phenotype of the heterogeneous Silver-Russell syndrome (SRS). Other anomalies were less frequently found than in SRS. Molecular investigations revealed 11 cases with isodisomy and 17 cases with heterodisomy. In 4 cases this information was not available. From the allelic distribution of the microsatellites investigated, 9 cases might be the consequence of an error at maternal meiosis I, and 6 cases might be due to non-disjunction at maternal meiosis II. Three of the 17 heterodisomic cases had trisomy 7 in chorionic villi, in the remaining cases no prenatal diagnosis through chorionic villus sampling was reported. Conclusion Maternal UPD 7 should be investigated in children with pre- and postnatal growth retardation and a facial gestalt characterized by a high and broad forehead and a pointed chin, as well as in confined placental mosaicism for trisomy 7.

Background: Smith-Lemli-Opitz syndrome (MIM 270400) is an autosomal recessive malformation and mental retardation syndrome that ranges in clinical severity from minimal dysmorphism and mild mental retardation to severe congenital anomalies and intrauterine death. Smith-Lemli-Opitz syndrome is caused by mutations in the Delta7 sterol-reductase gene (DHCR7; EC 1.3.1.21), which impair endogenous cholesterol biosynthesis and make the growing embryo dependent on exogenous ( maternal) sources of cholesterol. We have investigated whether apolipoprotein E, a major component of the cholesterol transport system in human beings, is a modifier of the clinical severity of Smith-Lemli-Opitz syndrome. Method: Common apo E, DHCR7, and LDLR genotypes were determined in 137 biochemically characterised patients with Smith-Lemli-Opitz syndrome and 59 of their parents. Results: There was a significant correlation between patients' clinical severity scores and maternal apo E genotypes (p = 0.028) but not between severity scores and patients' or paternal apo E genotypes. In line with their effects on serum cholesterol levels, the maternal apo epsilon2 genotypes were associated with a severe Smith-Lemli-Opitz syndrome phenotype, whereas apo E genotypes without the epsilon2 allele were associated with a milder phenotype. The correlation of maternal apo E genotype with disease severity persisted after stratification for DHCR7 genotype. There was no association of Smith-Lemli-Opitz syndrome severity with LDLR gene variation. Conclusions: These results suggest that the efficiency of cholesterol transport from the mother to the embryo is affected by the maternal apo E genotype and extend the role of apo E and its disease associations to modulation of embryonic development and malformations.

Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive disorder of cholesterol biosynthesis caused by mutations in the DHCR7 gene. Thirty-seven ethnic Polish patients with SLOS underwent mutation analysis. The mutation frequencies in Polish patients were significantly different from those observed in Western European populations. Two mutations, W151X (22/68 alleles, 32%) and V326L (19/68 alleles, 28%), accounted for 60% of all observed in our cohort. Two missense mutations L68P and L360P have not been reported previously. In total, we report 15 DHCR7 mutations identified in Polish patients. By comparing clinical severity scores and the biochemical and molecular data, a genotype-phenotype correlation was attempted. In compound heterozygotes with one null mutation, the phenotype severity depends on the localization and type of the second mutation: mild phenotypes are correlated with mutations affecting the putative transmembrane domains TM1-TM6 or CT regions and severe phenotypes with mutations localized in TM7 and 4L region. The phenotypic differences of patients with the same genotype suggest that severity of the disease may be affected by other factors.

We report two new patients, a boy and a girl, who show variable but specific manifestations of CFC syndrome. The patients differ in general appearance, severity of skin changes, cardiac involvement and in behaviour. The girl shows some additional clinical features such as easy bruising and altered sensation of the distal part of the limbs, which have never been observed in CFC syndrome, but have been described in a few patients with Noonan syndrome. We discuss our observations in relation to previous cases of CFC syndrome and the possible relationships between the Noonan and CFC syndromes. There is no doubt that the CFC and Noonan syndromes share many manifestations and it is extremely difficult if not impossible unequivocally to distinguish between these two syndromes.

Cohen syndrome is a rare autosomal recessive disorder with a variable clinical picture mainly characterized by developmental delay, mental retardation, microcephaly, typical facial dysmorphism, progressive pigmentary retinopathy, severe myopia, and intermittent neutropenia. A Cohen syndrome locus was mapped to chromosome 8q22 in Finnish patients, and, recently, mutations in the gene COH1 were reported in patients with Cohen syndrome from Finland and other parts of northern and western Europe. Here, we describe clinical and molecular findings in 20 patients with Cohen syndrome from 12 families, originating from Brazil, Germany, Lebanon, Oman, Poland, and Turkey. All patients were homozygous or compound heterozygous for mutations in COH1. We identified a total of 17 novel mutations, mostly resulting in premature termination codons. The clinical presentation was highly variable. Developmental delay of varying degree, early-onset myopia, joint laxity, and facial dysmorphism were the only features present in all patients; however, retinopathy at school age, microcephaly, and neutropenia are not requisite symptoms of Cohen syndrome. The identification of novel mutations in COH1 in an ethnically diverse group of patients demonstrates extensive allelic heterogeneity and explains the intriguing clinical variability in Cohen syndrome.

This study reports clinical, biochemical and histopathological findings associated with a novel homozygous MPV17 mutation in four patients with mitochondrial depletion syndrome. The severe course of the disease, which started in the first weeks of life, was dominated by a failure to thrive, hypotonia and liver dysfunction, with relatively mild neurological involvement. All affected infants died by 1year of age. Laboratory findings included progressive liver failure (hypertransaminasaemia, icterus, and coagulopathy), recurrent hypoglycaemia, lactic acidaemia, hyperferritinaemia, and increased transferrin saturation. Histological and ultrastructural analyses uncovered significant lipid accumulation in hepatocytes and myocytes. A severe decrease in the mitochondrial/nuclear DNA (mtDNA/nDNA) ratio was found post-mortem in the livers (and in one muscle specimen) of both examined patients. Oxidative phosphorylation system (OXPHOS) Western blotting revealed low levels of complexes I, III and IV subunits. The highlights of our findings are as follows: (i) The novel p.Pro64Arg mutation is the second recurrent MPV17 mutation reported. The phenotype associated with the p.Pro64Arg mutation differs from the phenotype of the relatively common p.Arg50Gln mutation, suggesting the existence of a genotype-phenotype correlation. (ii) Tissues collected from patients during autopsy may be useful for both mtDNA/nDNA ratio assessment and OXPHOS Western blotting. =C2=A9 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive disorder caused by reduced activity of 7-dehydrocholesterol (7DHC) reductase, resulting in a decreased level of cholesterol and increased concentrations of 7DHC and 8DHC in body fluids and tissues. Ten pregnancies at 25% risk of SLOS underwent prenatal testing. Diagnostic studies included DHCR7 mutation analysis in chorionic villus samples, amniotic fluid sterol analysis and serial measurements of oestriol (EA pregnanetriol (PT), 7-dehydropregnanetriol (7DHPT) and 8-dehydroesteriol (8DHE(3)) concentrations in maternal urine samples obtained between 9 and 20 weeks of gestation. All tests were diagnostic and revealed nine unaffected foetuses (two normal homozygotes and seven DHCR7 heterozygotes) and one affected foetus. In the affected pregnancy, 7DHC and 8DHC in amniotic fluid were 9.87 and 3.7 mu g/ ml, respectively [reference range (RR) 0.0026 +/- 0.0015 mu g/ml and not detectable, respectively] and maternal urinary steroid analyses showed increased ratios of 7DHPT/PT and 8DHE(3)/E-3 of 0.74 and 1.7, respectively (RR 0-0.0147 and 0-0.019). In the heterozygous foetuses, 7DHPT/PT and 8DHE(3)/E-3 ratios did not exceed those found in 48 normal controls. This is the first series of prenatal diagnostic testing for SLOS where non-invasive biochemical testing was performed in tandem with invasive diagnostic testing. We conclude that steroid measurements in maternal urine are a reliable means of prenatal diagnosis for SLOS.