Molecular basis of unilateral condylar hyperplasia?

Unilateral condylar hyperplasia (UCH) causes progressive asymmetry of the mandible. The aetiology of this growth disorder is unknown. A two-centre prospective study was established, and 10 consecutive adult UCH patients scheduled for high condylectomy were included. The resected condylar tissue was divided into two parts, one for regular histopathology and one for DNA extraction. A panel of eight selected overgrowth genes (AKT1, AKT3, MTOR, PIK3CA, PIK3R2, PTEN, TSC1, TSC2) were sequenced using next-generation sequencing, with coverage of a minimum 500 times in order to be able to detect low-grade mosaicisms. Subsequently, untargeted whole exome sequencing (WES) was performed to detect variants in other genes present in three or more patients. No mutation was detected in any of the overgrowth genes, and untargeted exome sequencing failed to detect any definitively causative variant in any other gene. Ten genes had a rare variant in three or more patients, but these cannot be designated as causative without additional functional studies. The hypothesis that the cause in at least some patients with UCH is a somatic mutation in a gene that controls cell growth could not be confirmed in this study.

Unilateral condylar hyperplasia in hemifacial hyperplasia, is there genetic proof of overgrowth?

Hemifacial hyperplasia (HFH) is characterized by an increase in volume of all affected tissues of half of the face. It is present at birth, subsequently grows proportionally, and stops growing before adulthood. Unilateral condylar hyperplasia (UCH) consists of progressive asymmetric growth of the mandible and develops typically in early adulthood. Both disorders have an unknown aetiology. The overgrowth limited to one body part suggests somatic mosaicism, as this has been found in other similar localized overgrowth disorders. Often this includes a variant in a gene in the (PIK3CA)/PI3K/(PTEN)/AKT1/mTOR pathway. Here we report the case of an HFH patient with asymmetry present at birth, in whom a progressive growth pattern similar to UCH subsequently occurred, causing marked mandibular asymmetry. A condylectomy was successfully performed to stop the progressive growth. Somatic mosaicism for a mutation in PIK3CA was detected in the condylar tissue. This finding might indicate that both HFH and UCH can be caused by variants in genes in the (PIK3CA)/PI3K/(PTEN)/AKT1/mTOR pathway, similar to other disorders that result in asymmetrical bodily overgrowth.

Development and validation of a severity scoring system for Zellweger spectrum disorders.

The lack of a validated severity scoring system for individuals with Zellweger spectrum disorders (ZSD) hampers optimal patient care and reliable research. Here, we describe the development of such severity score and its validation in a large, well-characterized cohort of ZSD individuals. We developed a severity scoring system based on the 14 organs that typically can be affected in ZSD. A standardized and validated method was used to classify additional care needs in individuals with neurodevelopmental disabilities (Capacity Profile [CAP]). Thirty ZSD patients of varying ages were scored by the severity score and the CAP. The median score was 9 (range 6-19) with a median scoring age of 16.0 years (range 2-36 years). The ZSD severity score was significantly correlated with all 5 domains of the CAP, most significantly with the sensory domain (r = 0.8971, P = <.0001). No correlation was found between age and severity score. Multiple peroxisomal biochemical parameters were significantly correlated with the severity score. The presently reported severity score for ZSD is a suitable tool to assess phenotypic severity in a ZSD patient at any age. This severity score can be used for objective phenotype descriptions, genotype-phenotype correlation studies, the identification of prognostic features in ZSD patients and for classification and stratification of patients in clinical trials.

Dihydropyrimidine Dehydrogenase Deficiency: Metabolic Disease or Biochemical Phenotype?

Dihydropyrimidine dehydrogenase (DPD) deficiency is an autosomal recessive disorder of pyrimidine metabolism that impairs the first step of uracil und thymine degradation. The spectrum of clinical presentations in subjects with the full biochemical phenotype of DPD deficiency ranges from asymptomatic individuals to severely affected patients suffering from seizures, microcephaly, muscular hypotonia, developmental delay and eye abnormalities.We report on a boy with intellectual disability, significant impairment of speech development, highly active epileptiform discharges on EEG, microcephaly and impaired gross-motor development. This clinical presentation triggered metabolic workup that demonstrated the biochemical phenotype of DPD deficiency, which was confirmed by enzymatic and molecular genetic studies. The patient proved to be homozygous for a novel c.2059-22T>G mutation which resulted in an in-frame insertion of 21 base pairs (c.2059-21_c.2059-1) of intron 16 of DPYD. Family investigation showed that the asymptomatic father was also homozygous for the same mutation and enzymatic and biochemical findings were similar to his severely affected son. When the child deteriorated clinically, exome sequencing was initiated under the hypothesis that DPD deficiency did not explain the phenotype completely. A deletion of the maternal allele on chromosome 15q11.2-13-1 was identified allowing the diagnosis of Angelman syndrome (AS). This diagnosis explains the patient's clinical presentation sufficiently; the influence of DPD deficiency on the phenotype, however, remains uncertain.

A Duty To Warn Relatives in Clinical Genetics: Arguably 'Fair just and reasonable' in English Law?

The use of 'next-generation' genetic sequencing technology that allows the sequencing of large parts, or even the entirety, of a patient's genome is advancing rapidly in the UK and around the world. This is set to greatly increase the level of health information that will be of relevance to relatives and the latest medical guidance advises that there is a professional duty to consider warning a patient's relatives of a serious genetic risk in limited circumstances. However, the High Court in ABC v St George's Healthcare NHS Trust [2015] EWHC 1394 (QB), recently found that a legal duty on the part of doctors to warn a patient's daughter of a genetic risk of Huntington's Disease without the patient's consent, was not even 'reasonably arguable' and would not be 'fair, just and reasonable'. This article considers the courts' approach to a duty of care towards 'third parties' in this context and concludes that some form of a duty of care to genetic relatives in clinical genetics is at very least arguably 'fair, just and reasonable'.

Frequent intragenic rearrangements of DPYD in colorectal tumours.

Dihydropyrimidine dehydrogenase is a crucial enzyme for the degradation of 5-fluorouracil (5FU). DPYD, which encodes dihydropyrimidine dehydrogenase, is prone to acquire genomic rearrangements because of the presence of an intragenic fragile site FRA1E. We evaluated DPYD copy number variations (CNVs) in a prospective series of 242 stage I-III colorectal tumours (including 87 patients receiving 5FU-based treatment). CNVs in one or more exons of DPYD were detected in 27% of tumours (deletions or amplifications of one or more DPYD exons observed in 17% and 10% of cases, respectively). A significant relationship was observed between the DPYD intragenic rearrangement status and dihydropyrimidine dehydrogenase (DPD) mRNA levels (both at the tumour level). The presence of somatic DPYD aberrations was not associated with known prognostic or predictive biomarkers, except for LOH of chromosome 8p. No association was observed between DPYD aberrations and patient survival, suggesting that assessment of somatic DPYD intragenic rearrangement status is not a powerful biomarker to predict the outcome of 5FU-based chemotherapy in patients with colorectal cancer.

Keloids in Rubinstein-Taybi syndrome: a clinical study.

BACKGROUND: Rubinstein-Taybi syndrome (RSTS) is a multiple congenital anomalies-intellectual disability syndrome. One of the complications is keloid formation. Keloids are proliferative fibrous growths resulting from excessive tissue response to skin trauma. OBJECTIVES: To describe the clinical characteristics of keloids in individuals with RSTS reported in the literature and in a cohort of personally evaluated individuals with RSTS. PATIENTS AND METHODS: We performed a literature search for descriptions of RSTS individuals with keloids. All known individuals with RSTS in the Netherlands filled out three dedicated questionnaires. All individuals with (possible) keloids were personally evaluated. A further series of individuals with RSTS from the U.K. was personally evaluated. RESULTS: Reliable data were available for 62 of the 83 Dutch individuals with RSTS and showed 15 individuals with RSTS (24%) to have keloids. The 15 Dutch and 12 U.K. individuals with RSTS with keloids demonstrated that most patients have multiple keloids (n > 1: 82%; n > 5: 30%). Mean age of onset is 11·9 years. The majority of keloids are located on the shoulders and chest. The mean length × width of the largest keloid was 7·1 × 2·8 cm, and the mean thickness was 0·7 cm. All affected individuals complained of itching. Generally, treatment results were disappointing. CONCLUSIONS: Keloids occur in 24% of individuals with RSTS, either spontaneously or after a minor trauma, usually starting in early puberty. Management schedules have disappointing results. RSTS is a Mendelian disorder with a known molecular basis, and offers excellent opportunities to study the pathogenesis of keloids in general and to search for possible treatments.

Somatic mosaicism in a mother of two children with Pitt-Hopkins syndrome.

Pitt-Hopkins syndrome (PTHS) is a neurodevelopmental disorder characterized by intellectual disability, unusual face and breathing abnormalities and can be caused by haploinsufficiency of TCF4. The majority of cases are sporadic. Somatic mosaicism was reported infrequently. We report on a proband with typical manifestations of PTHS and his younger brother with a less striking phenotype. In both, a heterozygous frameshift mutation (c.1901_1909delinsA, p.Ala634AspfsX67) was found in exon 19 of TCF4. The same mutation was found at low levels in DNA extracted from the mother's blood, urine and saliva. This report of familial recurrence with somatic mosaicism in a healthy mother has important consequences for genetic counseling. We suggest careful studies in parents of other patients with PTHS to determine the frequency of germline and somatic mosaicism for TCF4 mutations.

Development and behaviour in Marshall-Smith syndrome: an exploratory study of cognition, phenotype and autism.

BACKGROUND: Marshall-Smith syndrome (MSS) is an infrequently described entity characterised by failure to thrive, developmental delay, abnormal bone maturation and a characteristic face. In studying the physical features of a group of patients, we noticed unusual behavioural traits. This urged us to study cognition, behavioural phenotype and autism in six patients. METHODS: Information on development, behavioural characteristics, autism symptoms, and adaptive and psychological functioning of six MSS children was collected through in-person examinations, questionnaires, semi-structured interviews of parents and neuropsychological assessments. RESULTS: Participants showed moderate to severe delays in mental age, motor development and adaptive functioning, with several similarities in communication, social interactions and behaviour. There was severe delay of speech and motor milestones, a friendly or happy demeanour and enjoyment of social interactions with familiar others. They exhibited minimal maladaptive behaviours. Deficits in communication and social interactions, lack of reciprocal social communication skills, limited imaginary play and the occurrence of stereotyped, repetitive behaviours were noted during assessments. CONCLUSIONS: Systematic collection of developmental and behavioural data in very rare entities such as MSS allows recognition of specific patterns in these qualities. Clinical recognition of physical,developmental and behavioural features is important not only for diagnosis, prognosis and counselling of families, but also increases our understanding of the biological basis of the human physical and behavioural phenotype.

A microdeletion at 12q24.31 can mimic beckwith-wiedemann syndrome neonatally.

We report on a patient who was initially suspected to have Beckwith-Wiedemann syndrome because of recurrent neonatal hypoglycaemias, macroglossia and overgrowth, but in whom no 11p15 abnormality could be found. Follow-up showed continued overgrowth and disturbed glucose homeostasis, a marked developmental delay, and severe behavioural problems especially caused by anxieties. Array comparative genomic hybridization analysis showed a de novo 12q24.31 interstitial deletion, which was confirmed by fluorescence in situ hybridization. The deleted region contains amongst others: HNF1 homeobox A (HNF1A) which is important for the regulation of gene expression in the liver and involved in maturity-onset diabetes of the young type 3 and insulin resistance; acyl-CoA dehydrogenase short chain (ACADS) which encodes an enzyme important in mitochondrial fatty acid beta-oxidation and can cause short-chain acyl-CoA dehydrogenese (SCAD) deficiency, and purinergic receptor P2X7 (P2RX7) which encodes a ligand-gated ion channel, and of which polymorphisms are found with increased frequency in patients with psychiatric disorders, especially anxieties. We conclude the present patient has a hitherto undescribed contiguous gene syndrome, which can initially resemble Beckwith-Wiedemann syndrome.

Dihydropyrimidine dehydrogenase deficiency caused by a novel genomic deletion c.505_513del of DPYD.

Dihydropyrimidine dehydrogenase (DPD) deficiency is an autosomal recessive disorder of the pyrimidine degradation pathway. In a patient presenting with convulsions, psychomotor retardation and Reye like syndrome, strongly elevated levels of uracil and thymine were detected in urine. No DPD activity could be detected in peripheral blood mononuclear cells. Analysis of the gene encoding DPD (DPYD) showed that the patient was homozygous for a novel c.505_513del (p.169_171del) mutation in exon 6 of DPYD.

Novel and recurrent TRPV4 mutations and their association with distinct phenotypes within the TRPV4 dysplasia family.

BACKGROUND: Mutations in TRPV4, a gene that encodes a Ca(2+) permeable non-selective cation channel, have recently been found in a spectrum of skeletal dysplasias that includes brachyolmia, spondylometaphyseal dysplasia, Kozlowski type (SMDK) and metatropic dysplasia (MD). Only a total of seven missense mutations were detected, however. The full spectrum of TRPV4 mutations and their phenotypes remained unclear. OBJECTIVES AND METHODS: To examine TRPV4 mutation spectrum and phenotype-genotype association, we searched for TRPV4 mutations by PCR-direct sequencing from genomic DNA in 22 MD and 20 SMDK probands. RESULTS: TRPV4 mutations were found in all but one MD subject. In total, 19 different heterozygous mutations were identified in 41 subjects; two were recurrent and 17 were novel. In MD, a recurrent P799L mutation was identified in nine subjects, as well as 10 novel mutations including F471del, the first deletion mutation of TRPV4. In SMDK, a recurrent R594H mutation was identified in 12 subjects and seven novel mutations. An association between the position of mutations and the disease phenotype was also observed. Thus, P799 in exon 15 is a hot codon for MD mutations, as four different amino acid substitutions have been observed at this codon; while R594 in exon 11 is a hotspot for SMDK mutations. CONCLUSION: The TRPV4 mutation spectrum in MD and SMDK, which showed genotype-phenotype correlation and potential functional significance of mutations that are non-randomly distributed over the gene, was presented in this study. The results would help diagnostic laboratories establish efficient screening strategies for genetic diagnosis of the TRPV4 dysplasia family diseases.

Phenotypic variability in 49 cases of ESCO2 mutations, including novel missense and codon deletion in the acetyltransferase domain, correlates with ESCO2 expression and establishes the clinical criteria for Roberts syndrome.

BACKGROUND: Roberts syndrome (RBS) and SC phocomelia are caused by mutations in ESCO2, which codes for an acetyltransferase involved in the regulation of sister chromatid cohesion. Of 26 mutations described to date, only one missense mutation has been reported and all others are predicted to be truncating mutations. Genotype-phenotype analysis has been hampered by limited numbers of patients with clinical information available. OBJECTIVE: To provide unpublished clinical data for 31 patients with proven ESCO2 mutations and combine this series with previously reported clinical and mutation data on 18 cases. Methods Genotype-phenotype correlations and functional effects of two novel ESCO2 mutations were analysed. In situ hybridisation on human embryos at Carnegie stages 14, 17 and 21 was performed to study ESCO2 expression during development. RESULTS AND CONCLUSIONS: Using the cohort of 49 patients, the clinical criteria for RBS were delineated to include: growth retardation; symmetric mesomelic shortening of the limbs in which the upper limbs are more commonly and severely affected than the lower limbs; characteristic facies with microcephaly. The severity of malformations of the facies correlates with the severity of limb reduction. The occurrence of corneal opacities may be associated with specific mutations. Two new mutations, both in the ESCO2 acetyltransferase domain, are described and their acetylation effects in vitro demonstrated. In situ hybridisation on human embryos showed ESCO2 expression in the brain, face, limb, kidney and gonads, which corresponds to the structures affected in RBS.

Clinical spectrum of SIX3-associated mutations in holoprosencephaly: correlation between genotype, phenotype and function.

BACKGROUND: Holoprosencephaly (HPE) is the most common structural malformation of the human forebrain. There are several important HPE mutational target genes, including the transcription factor SIX3, which encodes an early regulator of Shh, Wnt, Bmp and Nodal signalling expressed in the developing forebrain and eyes of all vertebrates. OBJECTIVE: To characterise genetic and clinical findings in patients with SIX3 mutations. METHODS: Patients with HPE and their family members were tested for mutations in HPE-associated genes and the genetic and clinical findings, including those for additional cases found in the literature, were analysed. The results were correlated with a mutation-specific functional assay in zebrafish. RESULTS: In a cohort of patients (n = 800) with HPE, SIX3 mutations were found in 4.7% of probands and additional cases were found through testing of relatives. In total, 138 cases of HPE were identified, 59 of whom had not previously been clinically presented. Mutations in SIX3 result in more severe HPE than in other cases of non-chromosomal, non-syndromic HPE. An over-representation of severe HPE was found in patients whose mutations confer greater loss of function, as measured by the functional zebrafish assay. The gender ratio in this combined set of patients was 1.5:1 (F:M) and maternal inheritance was almost twice as common as paternal. About 14% of SIX3 mutations in probands occur de novo. There is a wide intrafamilial clinical range of features and classical penetrance is estimated to be at least 62%. CONCLUSIONS: Our data suggest that SIX3 mutations result in relatively severe HPE and that there is a genotype-phenotype correlation, as shown by functional studies using animal models.

Behavioural phenotype in Börjeson-Forssman-Lehmann syndrome.

BACKGROUND: Börjeson-Forssman-Lehmann syndrome (BFLs) is an X-linked inherited disorder characterised by unusual facial features, abnormal fat distribution and intellectual disability. As many genetically determined disorders are characterised not only by physical features but also by specific behaviour, we studied whether a specific behavioural phenotype exists in BFLs. METHODS: We studied in detail the behaviour of four molecularly proven BFLs patients, and reviewed available literature on BFLs specifically for behavioural characteristics. RESULTS: Behaviour in persons with BFLs is in general friendly, but can be challenging with externalising and thrill-seeking features. Social skills are good. However, variation among patients is wide. Three patients from a single family showed expressed hypersexual behaviour. This was not present in other patients. CONCLUSION: In BFLs a specific behavioural phenotype exists and in behaviour general is challenging besides a friendly habit. Within single families more problematic behaviour may occur. Further behavioural and molecular analysis of a larger group of patients is warranted to determine whether a genotype-behavioural phenotype correlation exists.

Arterial tortuosity syndrome: clinical and molecular findings in 12 newly identified families.

Arterial tortuosity syndrome (ATS) is a rare autosomal recessive connective tissue disease, characterized by widespread arterial involvement with elongation, tortuosity, and aneurysms of the large and middle-sized arteries. Recently, SLC2A10 mutations were identified in this condition. This gene encodes the glucose transporter GLUT10 and was previously suggested as a candidate gene for diabetes mellitus type 2. A total of 12 newly identified ATS families with 16 affected individuals were clinically and molecularly characterized. In addition, extensive cardiovascular imaging and glucose tolerance tests were performed in both patients and heterozygous carriers. All 16 patients harbor biallelic SLC2A10 mutations of which nine are novel (six missense, three truncating mutations, including a large deletion). Haplotype analysis suggests founder effects for all five recurrent mutations. Remarkably, patients were significantly older than those previously reported in the literature (P=0.04). Only one affected relative died, most likely of an unrelated cause. Although the natural history of ATS in this series was less severe than previously reported, it does indicate a risk for ischemic events. Two patients initially presented with stroke, respectively at age 8 months and 23 years. Tortuosity of the aorta or large arteries was invariably present. Two adult probands (aged 23 and 35 years) had aortic root dilation, seven patients had localized arterial stenoses, and five had long stenotic stretches of the aorta. Heterozygous carriers did not show any vascular anomalies. Glucose metabolism was normal in six patients and eight heterozygous individuals of five families. As such, overt diabetes is not related to SLC2A10 mutations associated with ATS.

Genetic syndromes and prenatally detected renal anomalies.

Renal anomalies are frequently detected on the routine second trimester scan offered to all pregnant women in the UK. These anomalies may be isolated but can also be associated with other congenital anomalies. Many combinations of ultrasound scan findings constitute recognised genetic entities. Knowledge of these conditions is essential for adequate management of the pregnancy and subsequent balanced parental counselling. This short review discusses the common genetic syndromes associated with the renal abnormalities identified on the antenatal ultrasound scan, and also provides an overview of renal symptoms in chromosome imbalances and after teratogenic influences.

A Malay boy with the Cornelia de Lange syndrome: clinical and molecular findings.

The Cornelia de Lange syndrome is a multiple congenital anomaly syndrome characterised by dysmorphic facial features, hirsutism, severe growth and developmental delays, and malformed upper limbs. The prevalence is estimated to be one per 10,000. Recently, several independent groups proved that Cornelia de Lange syndrome is caused by mutations in the NIPBL gene, the human homologue of the Drosophila Nipped-B gene. Here, we present the first clinical case report of a Malay child, a 9-year-old boy with the Cornelia de Lange syndrome. We also report the molecular investigation of the NIPBL gene in this patient.

[Possible teratogenic effects of thiamazole]. / Mogelijke teratogene invloed van thiamazol.

A newborn male presented with choanal atresia and minor dysmorphic facial features. At 4 years of age he showed delayed speech and language development. His mother had been treated with thiamazole for pre-existing hyperthyroidism during the first 3 months of pregnancy. It is possible that the maternal use of thiamazole caused the congenital anomalies. Embryopathy caused by maternal thiamazole use during pregnancy has been described several times before and is mainly characterised by choanal atresia, oesophageal atresia, minor dysmorphic facial features, growth retardation and delayed psychomotor development. Because the use of propylthiouracil during pregnancy has not been associated with similar effects, it is the treatment of choice for hyperthyroidism during pregnancy. For pregnant women or women who wish to become pregnant, thiamazole should be prescribed only ifpropylthiouracil cannot be used.

Mutation screening in Borjeson-Forssman-Lehmann syndrome: identification of a novel de novo PHF6 mutation in a female patient.

BACKGROUND: Börjeson-Forssman-Lehmann syndrome (BFLS; MIM 301900) is an infrequently described X linked disorder caused by mutations in PHF6, a novel zinc finger gene of unknown function. OBJECTIVE: To present the results of mutation screening in individuals referred for PHF6 testing and discuss the value of prior X-inactivation testing in the mothers of these individuals. RESULTS: 25 unrelated individuals were screened (24 male, one female). Five PHF6 mutations were detected, two of which (c.940A-->G and c.27_28insA) were novel. One of these new mutations, c.27_28insA, was identified in a female BFLS patient. This was shown to be a de novo mutation arising on the paternal chromosome. This is the first report of a clinically diagnosed BFLS female with a confirmed PHF6 mutation. In addition, the X-inactivation status of the mothers of 19 males with suggested clinical diagnosis of BFLS was determined. Skewed (> or =70%) X-inactivation was present in five mothers, three of whom had sons in whom a PHF6 mutation was detected. The mutation positive female also showed skewing. CONCLUSIONS: The results indicate that the success of PHF6 screening in males suspected of having BFLS is markedly increased if there is a positive family history and/or skewed X-inactivation is found in the mother.