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.

Chondrodysplasia with multiple dislocations: comprehensive study of a series of 30 cases.

The group of chondrodysplasia with multiple dislocations includes several entities, characterized by short stature, dislocation of large joints, hand and/or vertebral anomalies. Other features, such as epiphyseal or metaphyseal changes, cleft palate, intellectual disability are also often part of the phenotype. In addition, several conditions with overlapping features are related to this group and broaden the spectrum. The majority of these disorders have been linked to pathogenic variants in genes encoding proteins implicated in the synthesis or sulfation of proteoglycans (PG). In a series of 30 patients with multiple dislocations, we have performed exome sequencing and subsequent targeted analysis of 15 genes, implicated in chondrodysplasia with multiple dislocations, and related conditions. We have identified causative pathogenic variants in 60% of patients (18/30); when a clinical diagnosis was suspected, this was molecularly confirmed in 53% of cases. Forty percent of patients remain without molecular etiology. Pathogenic variants in genes implicated in PG synthesis are of major importance in chondrodysplasia with multiple dislocations and related conditions. The combination of hand features, growth failure severity, radiological aspects of long bones and of vertebrae allowed discrimination among the different conditions. We propose key diagnostic clues to the clinician.

A THANATOPHORIC DYSPLASIA TYPE I CASE WITH A FGFR3 P.R248C MUTATION AND SURVIVAL BEYOND THE NEONATAL PERIOD.

A Thanatophoric dysplasia, is a severe congenital anomaly which mostly causes stillbirth or death of the affected baby within hours due to respiratory insufficiency. The diagnosis of TD is typically suspected on ultrasound during the second trimester of pregnancy, when severe shortening of the long bones, frontal bossing, flattened vertebrae, and short ribs that result in a narrow thorax and bell-shaped abdomen, can be seen. Here, we present a case with prenatal ultrasonographic findings suggestive of TD, and highlight the patient's postnatal dysmorphic features and typical radiographic findings. The definitive diagnosis of TD type I (TDI) was made postnatally, when molecular genetic analysis revealed the previously described p.R248C mutation in FGFR3. This case is reported due to its relative long life span and the definitive molecular diagnosis that could be made during hospitalization.

Insights into genotype-phenotype correlations from CREBBP point mutation screening in a cohort of 46 Rubinstein-Taybi syndrome patients.

The genetic basis of Rubinstein-Taybi syndrome (RSTS), a rare, sporadic, clinically heterogeneous disorder characterized by cognitive impairment and a wide spectrum of multiple congenital anomalies, is primarily due to private mutations in CREBBP (approximately 55% of cases) or EP300 (approximately 8% of cases). Herein, we report the clinical and the genetic data taken from a cohort of 46 RSTS patients, all carriers of CREBBP point mutations. Molecular analysis revealed 45 different gene alterations including 31 inactivating (21 frameshift and 10 nonsense), 10 missense and 4 splicing mutations. Bioinformatic tools and transcript analyses were used to predict the functional effects of missense and splicing alterations. Of the 45 mutations, 42 are unreported and 3 were described previously. Recurrent mutations maybe a key tool in addressing genotype-phenotype correlations in patients sharing the same defects (at the genomic or transcript level) and specific clinical signs, demonstrated here in two cases. The clinical data of our cohort evidenced frequent signs such as arched eyebrows, epicanthus, synophrys and/or frontal hypertrichosis and broad phalanges that, previously overlooked in RSTS diagnosis, now could be considered. Some suggested correlations between organ-specific anomalies and affected CREB-binding protein domains broaden the RSTS clinical spectrum and perhaps will enhance patient follow-up and clinical care.

Werner syndrome: clinical evaluation of two cases and a novel mutation.

Werner syndrome (WS) is a premature aging disorder, inherited in an autosomal recessive pattern and caused by the mutation in the WRN gene. In this report we describe two male patients with negative family history who demonstrate characteristic findings of WS, with different mutations, including one novel mutation. The first case was a 47-year-old man who had been suffering from large, ischemic ulcers on both legs for 7 years. Physical examination revealed a thin and short man with severe wasting of all extremities. He had a high-pitched voice, hoarseness, a characteristic bird-like facies, bilateral cataracts, generalized osteoporosis, hypotrichosis, atrophic and poikilodermic skin, flexion contractures of hands, feet and knees, and soft tissue calcifications. Laboratory investigations revealed anemia, high erythrocyte sedimentation rate, low creatinine clearance, and high liver enzymes. Genetic analysis showed a homozygous novel 1bp-deletion in exon 19 of WRN, 2426/27delG, causing frameshift and protein truncation R809SfsX2, which has not been described before. The second case was a 23-year-old man who was referred for large callosities on both feet, present for 7 years. He complained of weakness, weight loss, wasting of muscles, and early graying of hair. The entire skin was thin, wrinkled and dry. Generalized hypotrichosis, scattered ephelid-like macules, sclerotic fingers, calcinosis cutis on ears, hyperpigmentation on elbows were the other alterations of skin. Skeletal survey revealed osteoporosis. Genetic analysis showed a homozygous known pathogenic splice site mutation c.3460-2A>G, causing skipping of Exon 30 in WRN.

Mutations and polymorphisms in N-acetylgalactosamine-6-sulfate sulfatase gene in Turkish Morquio A patients.

Mucopolysaccharidosis type IVA (MPS IVA) is an autosomal recessive inherited metabolic disease resulting from deficiency of N-acetylgalactosamine-6-sulfatase (GALNS). This lysosomal storage disorder leads to a wide range of clinical variability ranging from severe, through intermediate to mild forms. The classical phenotype of Morquio A disease is characterized by severe bone dysplasia without intellectual impairment. Two severe MPS IVA patients from two unrelated Turkish families have been investigated. The 14 exons and intron-exon junctions of the GALNS gene were sequenced after amplification from genomic DNA. Direct sequencing revealed two homozygous mutations previously described: p.L390X in exon 11 and p.W141R in exon 4. The p L390X mutation was associated with four novel polymorphisms in intron 2, intron 5 and intron 6 and one polymorphism previously described in exon 7. We have analysed the haplotypes associated with the two identified mutations. These molecular findings will permit accurate carrier detection, prenatal diagnosis and counseling for Morquio A syndrome in Turkey.

Confirming genes influencing risk to cleft lip with/without cleft palate in a case-parent trio study.

A collection of 1,108 case-parent trios ascertained through an isolated, nonsyndromic cleft lip with or without cleft palate (CL/P) was used to replicate the findings from a genome-wide association study (GWAS) conducted by Beaty et al. (Nat Genet 42:525-529, 2010), where four different genes/regions were identified as influencing risk to CL/P. Tagging SNPs for 33 different genes were genotyped (1,269 SNPs). All four of the genes originally identified as showing genome-wide significance (IRF6, ABCA4 and MAF, plus the 8q24 region) were confirmed in this independent sample of trios (who were primarily of European and Southeast Asian ancestry). In addition, eight genes classified as 'second tier' hits in the original study (PAX7, THADA, COL8A1/FILIP1L, DCAF4L2, GADD45G, NTN1, RBFOX3 and FOXE1) showed evidence of linkage and association in this replication sample. Meta-analysis between the original GWAS trios and these replication trios showed PAX7, COL8A1/FILIP1L and NTN1 achieved genome-wide significance. Tests for gene-environment interaction between these 33 genes and maternal smoking found evidence for interaction with two additional genes: GRID2 and ELAVL2 among European mothers (who had a higher rate of smoking than Asian mothers). Formal tests for gene-gene interaction (epistasis) failed to show evidence of statistical interaction in any simple fashion. This study confirms that many different genes influence risk to CL/P.

A short rib polydactyly syndrome overlapping both lethal and nonlethal types.

Short rib polydactyly syndrome (SRPS) type II is a rare, autosomal recessively inherited, lethal skeletal dysplasia characterized by polydactyly, short limbs, short and horizontal ribs, a short ovoid tibia and major organ anomalies. We report a patient with a fetus with SRPS type II that presented at the 19th week of pregnancy for amniocentesis because of maternal age. During ultrasound pre-axial synpolydacytly, a short and ovoid tibia, nuchal edema, vertebral irregularities, hypoplastic thorax with short ribs and talipes were detected. All of the extremities were under the 5th percentile. Thorax-abdomen ratio was 0,56. The family was counselled for a diagnosis of lethal SRPS. After termination of pregnancy, radiological and histopathological examination allowed us to reach the diagnosis ofMajewski syndrome (SRPS type II). SRPSs are a continuous spectrum of both lethal and nonlethal forms. Prenatal diagnosis and termination depending on ultrasound findings should be done very precociously considering different phenotypic expressions, even in families previously affected by a lethal SRPS.

A novel loss-of-function mutation in the GNS gene causes Sanfilippo syndrome type D.

UNLABELLED: A novel loss-of-function mutation in the GNS gene causes Sanfilippo syndrome type D: Mucopolysaccharidosis type IIID (MIM 252940) is the least common form of the four subtypes of Sanfilippo syndrome. It is an autosomal recessive lysosomal disorder caused by a deficiency of the N-acetylglucosamine-6-sulphatase (GlcNAc-6S sulphatase, GNS), a hydrolase, which is one of the enzymes involved in heparan sulfate catabolism leading to lysosomal storage. The clinical features of this disorder are progressive neurodegeneration with relatively mild somatic symptoms. Twenty patients have been described in the literature and only seven causative mutations in the GNS gene encoding GlcNAc-6S sulphatase have been reported to date. We present the clinical and molecular results of a newly diagnosed Turkish patient with MPS IIID. We identified the novel homozygous single base pair insertion, c.1226GinsG, which leads to a frame-shift and a premature truncation of the GNS protein (p.R409Rfs21X). CONCLUSION: This novel mutation provides further evidence that loss-of-function is the underlying pathophysiological mechanism of this rare phenotype.

Molecular characterisation of six patients with prolidase deficiency: identification of the first small duplication in the prolidase gene and of a mutation generating symptomatic and asymptomatic outcomes within the same family.

Prolidase deficiency (PD) is a rare autosomal recessive connective tissue disorder caused by mutations in the prolidase gene. The PD patients show a wide range of clinical outcomes characterised mainly by intractable skin ulcers, mental retardation and recurrent respiratory infections. Here we describe five different PEPD mutations in six European patients. We identified two new PEPD mutant alleles: a 13 bp duplication in exon 8, which is the first reported duplication in the prolidase gene and a point mutation resulting in a change in amino acid E412, a highly conserved residue among different species. The E412K substitution is responsible for the first reported phenotypic variability within a family with severe and asymptomatic outcomes.

Prenatal diagnosis of Wolf-Hirschhorn syndrome (4p-) in association with congenital diaphragmatic hernia, cystic hygroma and IUGR.

Wolf-Hirschhorn syndrome (WHS) is a rare distinct clinical entity caused by a deletion of the short arm of chromosome 4. We report a case in which intrauterine growth restriction (IUGR), severe oligohydramnios, left-sided congenital diaphragmtic hernia (CDH), and cystic hygroma were detected by prenatal ultrasound examination at 27 weeks of gestation. A 29-year-old gravida 3, para 2, woman was referred at 26 weeks' gestation with suspicion of IUGR and cystic hygroma. Sonographic examination revealed IUGR with severe oligohydramnios, increased nuchal fold with cystic hygroma (left-sided diaphragmatic defect of Bochdalek type), and congenital diaphragmatic hernia. Chromosome analysis revealed a 46, XX, del(4)(p15.2) karyotype. Autopsy confirmed the ultrasound findings. Congenital diaphragmatic hernia (CDH) has rarely been described to be associated with WHS. CDH and cystic hygroma can lead to a diagnosis of this syndrome very early in life. We recommend genetic evaluation of a fetus with cystic hygroma, IUGR and CDH taking into consideration 4p deletion syndrome.

Novel truncating and missense mutations of the KCC3 gene associated with Andermann syndrome.

BACKGROUND: Andermann syndrome (OMIM 218000) is an autosomal recessive motor-sensory neuropathy associated with developmental and neurodegenerative defects. The cerebral MRI reveals a variable degree of agenesis of the corpus callosum. Recently, truncating mutations of the KCC3 gene (also known as SLC12A6) have been associated with Andermann syndrome. METHODS: The authors assessed clinically and genetically three isolated cases from Germany and Turkey with symptoms consistent with Andermann syndrome. RESULTS: The authors detected four novel mutations within the KCC3 gene in their patients: two different truncating mutations in the first patient, a homozygous truncating mutation in the second, and a homozygous missense mutation in the third patient. In contrast to the classic phenotype of the Andermann syndrome linked to truncating KCC3 mutations the phenotype and the course of the disease linked to the missense mutation appeared to be different (i.e., showing additional features like diffuse and widespread white matter abnormalities). CONCLUSIONS: Not only truncating but also missense mutations of the KCC3 gene are associated with Andermann syndrome. Different types of KCC3 mutations may determine different clinical phenotypes.

Neonatal Marfan syndrome caused by an exon 25 mutation of the fibrillin-1 gene.

Neonatal Marfan syndrome caused by an exon 25 mutation of the Fibrillin-1 gene: We describe a male infant with severe arachnodactyly, hypermobility of the fingers, flexion contractures of elbows, wrists, hips, and knees, microretrognathia, crumpled ears, rockerbottom feet, loose redundant skin, and lens dislocations. Cardiac valve insufficiency and aortic dilatation resulted in cardiac failure, decompensated with digitalisation and death occurred at the age of 4 months. This case represents the severe end of the clinical spectrum of Marfan syndrome, namely neonatal Marfan syndrome. Molecular diagnostic analyses confirmed a de novo exon 25 mutation in the FBN1 gene.

Alkaptonuria caused by compound heterozygote mutations.

Alkaptonuria is a rare autosomal recessive disorder of inborn errors of metabolism. It is characterised by the deposition of "ochronotic pigment" especially in connective tissue as a result of deficieny of the "homogentisic acid oxidase" enzyme which has a role in the catabolism of tyrosine and phenylalanine. A compound heterozygote alkaptonuria patient, with manifestations in adulthood, without infantile and childhood signs is presented. The described alkaptonuria mutations are reported for the first time in the Turkish population.

Genetic and mutational analyses of a large multiethnic Bardet-Biedl cohort reveal a minor involvement of BBS6 and delineate the critical intervals of other loci.

Bardet-Biedl syndrome (BBS) is a rare autosomal recessive disorder characterized primarily by obesity, polydactyly, retinal dystrophy, and renal disease. The significant genetic and clinical heterogeneity of this condition have substantially hindered efforts to positionally clone the numerous BBS genes, because the majority of available pedigrees are small and the disorder cannot be assigned to any of the six known BBS loci. Consequently, the delineation of critical BBS intervals, which would accelerate the discovery of the underlying genetic defect(s), becomes difficult, especially for loci with minor contributions to the syndrome. We have collected a cohort of 163 pedigrees from diverse ethnic backgrounds and have evaluated them for mutations in the recently discovered BBS6 gene (MKKS) on chromosome 20 and for potential assignment of the disorder to any of the other known BBS loci in the human genome. Using a combination of mutational and haplotype analysis, we describe the spectrum of BBS6 alterations that are likely to be pathogenic; propose substantially reduced critical intervals for BBS2, BBS3, and BBS5; and present evidence for the existence of at least one more BBS locus. Our data also suggest that BBS6 is a minor contributor to the syndrome and that some BBS6 alleles may act in conjunction with mutations at other BBS loci to cause or modify the BBS phenotype.

A variant of Cenani-Lenz type syndactyly.

Cenani-Lenz syndrome is a form of complete syndactyly resembling the spoon hand in Apert syndrome. It is often associated with disorganization of phalanges, the fusion of metacarpals and mesomelic shortness of the arm. We describe an additional case of Cenani-Lenz type of syndactylism in a 16 month-old girl who also has rib and vertebral abnormalities and mixed type hearing loss, that have not been seen before in a single patient.

Peroxisomal disorders: clinical and biochemical studies in 15 children and prenatal diagnosis in 7 families.

We describe the main clinical and biochemical findings in 15 patients with peroxisomal disorders, together with the results of 11 prenatal investigations for Zellweger syndrome. The initial laboratory diagnosis depended in most cases on demonstration of elevated very long chain fatty acids in plasma, but follow-up studies using cultured fibroblasts were essential for complete classification. The patient group comprises nine cases of Zellweger syndrome, one of neonatal adrenoleucodystrophy, two of infantile Refsum disease, one of bifunctional protein deficiency, and two of rhizomelic chondrodysplasia punctata. The study illustrates the clinical and biochemical variability of this group of patients and the detailed studies that are required for classification.

A Rapp-Hodgkin like syndrome in three sibs: clinical, dental and dermatoglyphic study.

Rapp-Hodgkin ectodermal dysplasia is an autosomal dominant disorder characterized by distinctive craniofacies, cleft lip or palate, oligodontia or anodontia, hypoplasia of the nails, and a decrease in or absence of the sweat glands and hair follicles. We have identified a family in which three children display clinical features similar to Rapp-Hodgkin syndrome. The father and two other sisters of the patient had normal facial features, but had short stature and had dental anomalies, the latter suggestive of ectodermal dysplasia. The overall clinical, dental, and dermatoglyphic findings of these patients are discussed in relation to reports of families with Rapp-Hodgkin syndrome.