Development, behaviour and sensory processing in Marshall-Smith syndrome and Malan syndrome: phenotype comparison in two related syndromes.

BACKGROUND: Ultrarare Marshall-Smith and Malan syndromes, caused by changes of the gene nuclear factor I X (NFIX), are characterised by intellectual disability (ID) and behavioural problems, although questions remain. Here, development and behaviour are studied and compared in a cross-sectional study, and results are presented with genetic findings. METHODS: Behavioural phenotypes are compared of eight individuals with Marshall-Smith syndrome (three male individuals) and seven with Malan syndrome (four male individuals). Long-term follow-up assessment of cognition and adaptive behaviour was possible in three individuals with Marshall-Smith syndrome. RESULTS: Marshall-Smith syndrome individuals have more severe ID, less adaptive behaviour, more impaired speech and less reciprocal interaction compared with individuals with Malan syndrome. Sensory processing difficulties occur in both syndromes. Follow-up measurement of cognition and adaptive behaviour in Marshall-Smith syndrome shows different individual learning curves over time. CONCLUSIONS: Results show significant between and within syndrome variability. Different NFIX variants underlie distinct clinical phenotypes leading to separate entities. Cognitive, adaptive and sensory impairments are common in both syndromes and increase the risk of challenging behaviour. This study highlights the value of considering behaviour within developmental and environmental context. To improve quality of life, adaptations to environment and treatment are suggested to create a better person-environment fit.

Dermatological manifestations in cardiofaciocutaneous syndrome: a prospective multicentric study of 45 mutation-positive patients.

BACKGROUND: Data on dermatological manifestations of cardiofaciocutaneous syndrome (CFCS) remain heterogeneous and almost without expert dermatological classification. OBJECTIVES: To describe the dermatological manifestations of CFCS; to compare them with the literature findings; to assess those discriminating CFCS from other RASopathies, including Noonan syndrome (NS) and Costello syndrome (CS); and to test for dermatological phenotype-genotype correlations. METHODS: We performed a 4-year, large, prospective, multicentric, collaborative dermatological and genetic study. RESULTS: Forty-five patients were enrolled. Hair abnormalities were ubiquitous, including scarcity or absence of eyebrows and wavy or curly hair in 73% and 69% of patients, respectively. Keratosis pilaris (KP), ulerythema ophryogenes (UO), palmoplantar hyperkeratosis (PPHK) and multiple melanocytic naevi (MMN; over 50 naevi) were noted in 82%, 44%, 27% and 29% of patients, respectively. Scarcity or absence of eyebrows, association of UO and PPHK, diffuse KP and MMN best differentiated CFCS from NS and CS. Oral acitretin may be highly beneficial for therapeutic management of PPHK, whereas treatment of UO by topical sirolimus 1% failed. No significant dermatological phenotype-genotype correlation was determined. CONCLUSIONS: A thorough knowledge of CFCS skin manifestations would help in making a positive diagnosis and differentiating CFCS from CS and NS.

Dermatological manifestations in Noonan syndrome: a prospective multicentric study of 129 patients positive for mutation.

BACKGROUND: Data on dermatological manifestations of Noonan syndrome (NS) remain heterogeneous and are based on limited dermatological expertise. OBJECTIVES: To describe the dermatological manifestations of NS, compare them with the literature findings, and test for dermatological phenotype-genotype correlations with or without the presence of PTPN11 mutations. METHODS: We performed a large 4-year, prospective, multicentric, collaborative dermatological and genetic study. RESULTS: Overall, 129 patients with NS were enrolled, including 65 patients with PTPN11-NS, 34 patients with PTPN11-NS with multiple lentigines (NSML), and 30 patients with NS who had a mutation other than PTPN11. Easy bruising was the most frequent dermatological finding in PTPN11-NS, present in 53·8% of patients. Multiple lentigines and café-au-lait macules (n ≥ 3) were present in 94% and 80% of cases of NSML linked to specific mutations of PTPN11, respectively. Atypical forms of NSML could be associated with NS with RAF1 or NRAS mutations. In univariate analysis, patients without a PTPN11 mutation showed (i) a significantly higher frequency of keratinization disorders (P = 0·001), including keratosis pilaris (P = 0·005), ulerythema ophryogenes (P = 0·0001) and palmar and/or plantar hyperkeratosis (P = 0·06, trend association), and (ii) a significantly higher frequency of scarce scalp hair (P = 0·035) and scarce or absent eyelashes (P = 0·06, trend association) than those with PTPN11 mutations. CONCLUSIONS: The cutaneous phenotype of NS with a PTPN11 mutation is generally mild and nonspecific, whereas the absence of a PTPN11 mutation is associated with a high frequency of keratinization disorders and hair abnormalities.

TBL1XR1 mutations in Pierpont syndrome are not restricted to the recurrent p.Tyr446Cys mutation.

Pierpont syndrome is a rare and sporadic syndrome, including developmental delay, facial characteristics, and abnormal extremities. Recently, a recurrent de novo TBL1XR1 variant (c.1337A > G; p.Tyr446Cys) has been identified in eight patients by whole-exome sequencing. A dominant-negative effect of this mutation is strongly suspected, since patients with TBL1XR1 deletion and other variants predicting loss of function do not share the same phenotype. We report two patients with typical Pierpont-like syndrome features. Exome sequencing allowed identifying a de novo heterozygous missense TBL1XR1 variant in both patients, different from those already reported: p.Cys325Tyr and p.Tyr446His. The localization of these mutations and clinical features of Pierpont-like syndrome suggest that their functional consequences are comparable with the recurrent mutation previously described, and provided additional data to understand molecular mechanisms of TBL1XR1 anomalies.

Systematic molecular and cytogenetic screening of 100 patients with marfanoid syndromes and intellectual disability.

The association of marfanoid habitus (MH) and intellectual disability (ID) has been reported in the literature, with overlapping presentations and genetic heterogeneity. A hundred patients (71 males and 29 females) with a MH and ID were recruited. Custom-designed 244K array-CGH (Agilent®; Agilent Technologies Inc., Santa Clara, CA) and MED12, ZDHHC9, UPF3B, FBN1, TGFBR1 and TGFBR2 sequencing analyses were performed. Eighty patients could be classified as isolated MH and ID: 12 chromosomal imbalances, 1 FBN1 mutation and 1 possibly pathogenic MED12 mutation were found (17%). Twenty patients could be classified as ID with other extra-skeletal features of the Marfan syndrome (MFS) spectrum: 4 pathogenic FBN1 mutations and 4 chromosomal imbalances were found (2 patients with both FBN1 mutation and chromosomal rearrangement) (29%). These results suggest either that there are more loci with genes yet to be discovered or that MH can also be a relatively non-specific feature of patients with ID. The search for aortic complications is mandatory even if MH is associated with ID since FBN1 mutations or rearrangements were found in some patients. The excess of males is in favour of the involvement of other X-linked genes. Although it was impossible to make a diagnosis in 80% of patients, these results will improve genetic counselling in families.

The Renpenning syndrome spectrum: new clinical insights supported by 13 new PQBP1-mutated males.

Since the first reports of polyglutamine-binding protein 1 (PQBP1) mutations in Renpenning syndrome and related disorders, the spectrum of PQBP1-linked clinical manifestations has been outlined from rare published case reports. The phenotypic description is often obtained from medical archives, and therefore, heterogeneous. Moreover, some aspects such as brain imaging or cognitive and behavioral functioning are rarely described. In this study, 13 PQBP1-mutated French patients were subjected to a standardized clinical, cognitive and behavioral assessment. Physical measurements of their relatives were also collected. We report on a recognizable clinical and radiological phenotype. All patients presented with microcephaly, leanness and mild short stature, relative to familial measurements. Three new clinical features are described: upper back progressive muscular atrophy, metacarpophalangeal ankylosis of the thumb and velar dysfunction. The specific facial dysmorphic features included at least four of the following signs: long triangular face, large ridged nose, half-depilated eyebrows, dysplastic or protruding ears and rough slightly sparse hair. An over-aged appearance was noticed in elderly patients. Cortical gyrification was normal based on available magnetic brain imaging of six patients. PQBP1-linked microcephaly (or Renpenning syndrome) is an X-linked mental retardation syndrome, which has clinically recognizable features.

Mutation update for the CSB/ERCC6 and CSA/ERCC8 genes involved in Cockayne syndrome.

Cockayne syndrome is an autosomal recessive multisystem disorder characterized principally by neurological and sensory impairment, cachectic dwarfism, and photosensitivity. This rare disease is linked to mutations in the CSB/ERCC6 and CSA/ERCC8 genes encoding proteins involved in the transcription-coupled DNA repair pathway. The clinical spectrum of Cockayne syndrome encompasses a wide range of severity from severe prenatal forms to mild and late-onset presentations. We have reviewed the 45 published mutations in CSA and CSB to date and we report 43 new mutations in these genes together with the corresponding clinical data. Among the 84 reported kindreds, 52 (62%) have mutations in the CSB gene. Many types of mutations are scattered along the whole coding sequence of both genes, but clusters of missense mutations can be recognized and highlight the role of particular motifs in the proteins. Genotype-phenotype correlation hypotheses are considered with regard to these new molecular and clinical data. Additional cases of molecular prenatal diagnosis are reported and the strategy for prenatal testing is discussed. Two web-based locus-specific databases have been created to list all identified variants and to allow the inclusion of future reports (www.umd.be/CSA/ and www.umd.be/CSB/).

Evidence that liver microsomes of human neonates desaturate essential fatty acids.

delta 6- and delta 5-Desaturation of essential fatty acids of n-6 and n-3 series are required for the biosynthesis of polyunsaturated fatty acids (PUFAs), which are precursors of eicosanoids and constituents of membrane phospholipids. This pathway could be of special importance during the perinatal period, when PUFAs accretion in the central nervous system is very active. However, experimental evidence of delta 6- and delta 5-desaturase activities in man is very scarce, and no data are available for newborns. We report the delta 6- and delta 5-desaturase activities detected in human liver microsomes from three neonates who died from associated malformations. Radiochemical assays of delta 6- and delta 5-desaturase activities performed with reverse phase HPLC analysis of the products in the n-6 series ranged from 4.8-13.6 to 3.2-16.4 pmol substrate converted.min-1.mg-1 microsomal proteins, respectively. In the n-3 series delta 6-desaturase activity ranged from 5.3 to 12.8 pmol.min-1.mg-1. The relationships between enzyme activities and substrate concentrations suggest excess substrate inhibition for n-6 and not for n-3 fatty acids. These results demonstrate significant delta 6- and delta 5-desaturase activities in human liver of neonates, but this activity was lower than previously reported in adult humans and in mammals, especially rodents.

A broad spectrum of clinical presentations in congenital disorders of glycosylation I: a series of 26 cases.

INTRODUCTION: Congenital disorders of glycosylation (CDG), or carbohydrate deficient glycoprotein syndromes, form a new group of multisystem disorders characterised by defective glycoprotein biosynthesis, ascribed to various biochemical mechanisms. METHODS: We report the clinical, biological, and molecular analysis of 26 CDG I patients, including 20 CDG Ia, two CDG Ib, one CDG Ic, and three CDG Ix, detected by western blotting and isoelectric focusing of serum transferrin. RESULTS: Based on the clinical features, CDG Ia could be split into two subtypes: a neurological form with psychomotor retardation, strabismus, cerebellar hypoplasia, and retinitis pigmentosa (n=11), and a multivisceral form with neurological and extraneurological manifestations including liver, cardiac, renal, or gastrointestinal involvement (n=9). Interestingly, dysmorphic features, inverted nipples, cerebellar hypoplasia, and abnormal subcutaneous fat distribution were not consistently observed in CDG Ia. By contrast, the two CDG Ib patients had severe liver disease, enteropathy, and hyperinsulinaemic hypoglycaemia but no neurological involvement. Finally, the CDG Ic patient and one of the CDG Ix patients had psychomotor retardation and seizures. The other CDG Ix patients had severe proximal tubulopathy, bilateral cataract, and white matter abnormalities (one patient), or multiorgan failure and multiple birth defects (one patient). CONCLUSIONS: Owing to the remarkable clinical variability of CDG, this novel disease probably remains largely underdiagnosed. The successful treatment of CDG Ib patients with oral mannose emphasises the paramount importance of early diagnosis of PMI deficiency.

Determination of a safe INR for joint injections in patients taking warfarin.

INTRODUCTION: With an increase in life expectancy in 'developed' countries, the number of elderly patients receiving joint injections for arthritis is increasing. There are legitimate concerns about an increased risk of thromboembolism if anticoagulation is stopped or reversed for such an injection. Despite being a common dilemma, the literature on this issue is scarce. METHODS: We undertook 2,084 joint injections of the knee and shoulder in 1,714 patients between August 2008 and December 2013. Within this cohort, we noted 41 patients who were taking warfarin and followed them immediately after joint injection in the clinic or radiology department, looking carefully for complications. Then, we sought clinical follow-up, correspondence, and imaging evidence for 4 weeks, looking for complications from these joint injections. We recorded International Normalised Ratio (INR) values before injection. RESULTS: No complications were associated with the procedure after any joint injection. The radiologists who undertook ultrasound-guided injections to shoulders re-scanned the joints looking for haemarthroses: they found none. A similar outcome was noted clinically after injections in the outpatient setting. CONCLUSION: With a mean INR of 2.77 (range, 1.7-5.5) and a maximum INR within this group of 5.5, joint injections to the shoulder and knee can be undertaken safely in primary or secondary care settings despite the patient taking warfarin.

Expression of FMR1, FXR1, and FXR2 genes in human prenatal tissues.

We analyzed the distribution of FMR1, FXR1, FXR2 mRNA, and FMRP in whole normal human embryos and in the brains of normal and fragile X fetuses. The distributions of mRNA for the 3 genes in normal whole embryos and in the brains of normal male and female carrier fetuses were similar, with large amounts of mRNA in the nervous system and in several non-nervous system tissues. No FMR1 (mRNA and protein) was detected and no evident neuropathologic abnormalities found in the brains of male carrier fetuses, suggesting that the FMR1 product (FMRP) may have no crucial function in early stages of nervous system development. FXR1 and FXR2 mRNA had the same distribution and similar intensity in the brains of normal and pathologic fetuses (female and male carriers). The coexpression in the same tissues of FMR1, FXR1, and FXR2, associated with the normal expression of FXR1 and FXR2 and the absence of obvious neuropathological abnormalities in pathological brains, supports the notion that the FXR1 and FXR2 proteins partially compensate for FMRP function. However, the absence of significant overexpression of FXR1 and FXR2 in pathological brains suggests that these genes do not compensate for the lack of FMR1 expression. Alternatively, FMR1, FXR1, and FXR2 proteins may not have compensatory functions, but instead may regulate functions by hetero or homo oligomerization, as suggested by other studies. Thus, a dominant negative effect of abnormal multimeric protein complexes lacking FMRP (e.g. by modification of FXR1 and FXR2 protein functions) may result in the fragile X syndrome phenotype.

Storage of medium-chain triglycerides in adipose tissue of orally fed infants.

The effect of the fatty acid content of the diet on that of adipose tissue was studied in 5 newborn infants studied prior to feeding and 30 infants fed ad libitum from birth with either human milk or a commercial formula as the sole nutrient. Significant positive linear correlations of dietary intake on adipose tissue content of fatty acids were found for both long- and medium-chain fatty acids (MCFA). Infants stored up to 12% of MCFAs in their subcutaneous fat. The technique of direct transesterification improved the recovery of the volatile MCFAs and could explain the finding that medium-chain triglyceride storage in adipose tissue is more extensive than in previous reports. This study documents that MCFAs are not used solely as a source of energy: they can be reesterified or serve for chain elongation, before being deposited in fat stores.

The Mediterranean-type diet: is there a need for further modification?

The effects on plasma lipoproteins of four fat-modified diets were assessed in 11 nuns in a contemplative order in the Mediterranean region of Spain. Diet 1 [high polyunsaturated fatty acid (PUFA), low monounsaturated fatty acid (MUFA), low ratio of PUFAs to saturated fatty acids (P:S)] and diet 3 (low PUFA, high MUFA, low P:S) induced significant, directly comparable reductions in total plasma (12% and 13%, respectively) and low-density-lipoprotein (LDL) cholesterol (24% and 19%, respectively). Diet 2 [high PUFA, high MUFA, low saturated fatty acid (SFA), high P:S] induced greater decrements (23% and 30% in total plasma and LDL cholesterol, respectively). Diet 4 (low PUFA, low MUFA, high SFA, low P:S) induced a significant increase in LDL cholesterol of 11%. No significant changes in high-density-lipoprotein cholesterol were observed with these diets. Because the effects of PUFAs and MUFAs are comparable, no recommendations on modifying the habitual, high-MUFA-containing Mediterranean diet need be made other than, perhaps, a reduction in the overall intake of SFAs.

Blastogenesis dominant 1: a sequence with midline anomalies and heterotaxy.

Lateralization defect is a heterogeneous condition with different modes of transmission (autosomal recessive, dominant or X-linked). Here, we report on 3 additional families that contribute to the description of phenotypic anomalies of the autosomal dominant type. Phenotypic anomalies include: lateralization defects, cardiac malformations, diaphragmatic hernia, urologic and neurologic anomalies. We suggest calling this sequence BGD1 for blastogenesis dominant 1 because the deleterious effect probably occurs during blastogenesis and involves not only lateralization but other defects as well.

Meier-Gorlin syndrome: report of eight additional cases and review.

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.

Frequent severe liver iron overload after stem cell transplantation and its possible association with invasive aspergillosis.

Iron overload is associated with free radical generation and tissue damage. Our main objective was to ascertain the frequency and severity of iron overload in a group of 59 patients who died after conventional-intensity autologous (n=24) or allogeneic (n=35) haematopoietic stem cell transplantation (HSCT). A second objective was to investigate associations between liver-iron concentration and causes of transplant-related mortality. The median age was 41 years (range, 19-66), 41 were males and 18 females. In total, 26 patients had acute leukaemia or MDS, 10 CML, 17 lymphoma, four myeloma and two aplastic anaemia. The median hepatic iron concentration (HIC) was 138 micromol/g dry weight (7.7 mg/g; range 31-631 micromol/g). In total, 4/32 (12%) patients with HIC <150 micromol/g and 10/27 (37%) with hepatic iron > or =150 micromol/g showed invasive aspergillosis at autopsy (P=0.035). This was significant in multivariate analysis (RR 9.0; 95% CI 1.6-50.3, P=0.012). In conclusion, severe iron overload is frequent in patients who die following HSCT and is associated with invasive aspergillosis.

Mobilization of peripheral blood progenitor cells by cyclophosphamide and rhGM-CSF in multiple myeloma.

Fifteen consecutive patients with multiple myeloma (MM) scheduled for peripheral blood progenitor cell (PBPC) transplantation, were randomly selected to receive cyclophosphamide (CY) (4 g/m2) alone (group I) or associated with recombinant human granulocyte-macrophage colony stimulating factor (rhGM-CSF) (5 micrograms/kg/day) (group II). The mean time of neutropenia after CY administration was 9.8 +/- 4.3 days in group I and 6.4 +/- 1.2 days in group II (P = 0.0228). One hundred and eight aphereses were performed (7.1 +/- 1.8 aphereses per patient in group I and 6.4 +/- 2.8 aphereses per patient in group II). rhGM-CSF administration after CY allowed a higher collection of CD34+ cells in apheresis products (1.42 +/- 1.68 x 10(6) CD34+ cells/kg) in comparison to without factor administration (0.47 +/- 0.52 x 10(6) CD34+ cells/kg) (P = 0.0165). The mean number of cells infused per patient was 6.56 +/- 4.02 x 10(8) MNC/kg and 7.64 +/- 3.00 x 10(4) CFU-GM/kg in group I and 6.25 +/- 4.03 x 10(8) MNC/kg and 8.16 +/- 9.73 x 10(4) CFU-GM/kg in group II. The mean time to recover 0.5 x 10(9) granulocytes/I, 20 and 50 x 10(9) platelets/I in peripheral blood (PB) was 17.2 +/- 7.4, 13.4 +/- 3.7 and 16.5 +/- 6.9 days respectively, in group I and 13.3 +/- 1.7, 11.6 +/- 1.6 and 15 +/- 6.3 days, in group II. rhGM-CSF administration after CY treatment for PBPC mobilization in MM patients reduces the neutropenic period after CY and enhances apheresis CD34+ cell collection.