[Is there more to hypodontia then missing teeth?] / Ernstige hypodontie: meer dan alleen ontbrekende gebitselementen?

Dental care professionals regularly see patients with hypodontia. Hypodontia can be acquired, for example through chemotherapy or radiation at a young age, but is hereditary in most patients. Due to an error (pathogenic variant) in one of the many genes that control odontogenesis, the formation of the tooth germ is disrupted at an early stage. The genes involved are not only crucial for tooth development, but they also play an important role in other physical processes. This article provides background information on hypodontia. Based on an inventory of gastrointestinal complaints in patients with hypodontia and a case description of the simultaneous occurrence of a coagulation disorder and hypodontia, the importance of a broad view of this patient group is illustrated. It is concluded that, in addition to a dental assessment, examination of these patients should include a limited physical examination and the medical history of the patient and his close relatives.

De novo truncating variants in the intronless IRF2BPL are responsible for developmental epileptic encephalopathy.

PURPOSE: Developmental and epileptic encephalopathies (DEEs) are severe clinical conditions characterized by stagnation or decline of cognitive and behavioral abilities preceded, accompanied or followed by seizures. Because DEEs are clinically and genetically heterogeneous, next-generation sequencing, especially exome sequencing (ES), is becoming a first-tier strategy to identify the molecular etiologies of these disorders. METHODS: We combined ES analysis and international data sharing. RESULTS: We identified 11 unrelated individuals with DEE and de novo heterozygous truncating variants in the interferon regulatory factor 2-binding protein-like gene (IRF2BPL). The 11 individuals allowed for delineation of a consistent neurodevelopmental disorder characterized by mostly normal initial psychomotor development followed by severe global neurological regression and epilepsy with nonspecific electroencephalogram (EEG) abnormalities and variable central nervous system (CNS) anomalies. IRF2BPL, also known as enhanced at puberty protein 1 (EAP1), encodes a transcriptional regulator containing a C-terminal RING-finger domain common to E3 ubiquitin ligases. This domain is required for its repressive and transactivating transcriptional properties. The variants identified are expected to encode a protein lacking the C-terminal RING-finger domain. CONCLUSIONS: These data support the causative role of truncating IRF2BPL variants in pediatric neurodegeneration and expand the spectrum of transcriptional regulators identified as molecular factors implicated in genetic developmental and epileptic encephalopathies.

Further audiovestibular characterization of DFNB77, caused by deleterious variants in LOXHD1, and investigation into the involvement of Fuchs corneal dystrophy.

This study focuses on further characterization of the audiovestibular phenotype and on genotype-phenotype correlations of DFNB77, an autosomal recessive type of hearing impairment (HI). DFNB77 is associated with disease-causing variants in LOXHD1, and is genetically and phenotypically highly heterogeneous. Heterozygous deleterious missense variants in LOXHD1 have been associated with late-onset Fuchs corneal dystrophy (FCD). However, up to now screening for FCD of heterozygous carriers in DFNB77 families has not been reported. This study describes the genotype and audiovestibular phenotype of 9 families with DFNB77. In addition, carriers within the families were screened for FCD. Fifteen pathogenic missense and truncating variants were identified, of which 12 were novel. The hearing phenotype showed high inter- and intrafamilial variation in severity and progression. There was no evidence for involvement of the vestibular system. None of the carriers showed (pre-clinical) symptoms of FCD. Our findings expand the genotypic and phenotypic spectrum of DFNB77, but a clear correlation between the type or location of the variant and the severity or progression of HI could not be established. We hypothesize that environmental factors or genetic modifiers are responsible for phenotypic differences. No association was found between heterozygous LOXHD1 variants and the occurrence of FCD in carriers.

Prenatal ultrasound screening for orofacial clefts.

OBJECTIVES: To evaluate the sensitivity and specificity of ultrasound for detecting prenatal facial clefts in low-risk and high-risk populations. METHODS: This study prospectively followed up a non-selected population, namely all pregnant women who underwent routine second-trimester prenatal ultrasound screening in the Utrecht region during the 2-year period from January 2007 to December 2008. RESULTS: A total of 35 924 low-risk and 2836 high-risk pregnant women underwent ultrasound screening. Orofacial clefts were present in 62 cases, an incidence of 1:624. The distribution of clefts was as follows: 18 (29%) cleft lip, 25 (40%) cleft lip with cleft palate, 17 (27%) cleft palate only, one median cleft and one atypical cleft. Of these, 38 (61%) were unilateral and 23 (37%) were bilateral. Thirty-nine per cent (24/62) had associated anomalies, with most chromosomal defects found in the cleft lip with cleft palate and cleft palate only groups. Cleft lip with or without cleft palate was detected prenatally in 38/43 cases, a sensitivity of 88%. No case of cleft palate only was detected prenatally. There were three false-positive cases, of which two were fetuses with multiple congenital deformities. CONCLUSIONS: Ultrasound screening has a high sensitivity for the detection of cleft lip with and without cleft palate in high-risk and low-risk pregnancies in our region, where well-trained sonographers carry out primary screening. The key to a high sensitivity of prenatal ultrasound is likely to be a combination of excellent training of sonographers, referral to specialized centers when a cleft is suspected, routine visualization of the fetal face and advances in ultrasound techniques.

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.

Copy number changes of the microcephalin 1 gene (MCPH1) in patients with autism spectrum disorders.

Autism spectrum disorder (ASD) represents a set of neurodevelopmental disorders with a strong genetic aetiology. Chromosomal rearrangements have been detected in 5-10% of the patients with ASD, and recent applications of array comparative genomic hybridisation (aCGH) are identifying further candidate regions and genes. In this study, we present four patients who implicate microcephalin 1 (MCPH1) in band 8p23.1 as an ASD susceptibility gene. Patient 1 was a girl with a syndromic form of autistic disorder satisfying the Autism Diagnostic Interview-Revised (ADI-R), Autism Diagnostic Observation Schedule (ADOS) and Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) criteria. Oligonucleotide aCGH (oaCGH) showed that she had a classic inv dup del(8)(qter-> p23.1::p23.1-> p21.2) containing at least three candidate genes; MCPH1 and DLGAP2 within the 6.9-Mb terminal deletion and NEF3 within the concomitant 14.1-Mb duplication. Three further patients with MCPH1 copy number changes were found using single-nucleotide polymorphism (SNP) array analysis in a cohort of 54 families with ASD patients. Our results show that ASD can be a component of the classical inv dup del(8) phenotype and identify changes in copy number of MCPH1 as a susceptibility factor for ASD in the distal short arm of chromosome 8.

A case with laryngeal atresia and partial trisomy 9 due to maternal 9;16 translocation.

A newborn with a partial trisomy 9 and a partial trisomy 16q is described. The child died shortly after birth because of laryngeal atresia. The chromosome anomaly was the result of a 3:1 segregation of a maternal translocation t(9;16) (q22;q24). The pertinent literature on both partial trisomy 9 and partial trisomy 16q is reviewed. All cases with partial trisomy 9 were either de novo or the result of a maternal translocation, possibly indicating the influence of imprinting on this chromosomal abnormality. The relationship between the laryngeal atresia and other features in the patient and the chromosome anomalies remains uncertain.

The Peters'-Plus syndrome: description of 16 patients and review of the literature.

Peters'-Plus syndrome is characterized by Peters' anomaly, a typical face, cleft lip and palate, short limb dwarfism, and developmental retardation. We report the follow-up of six patients in the original report, 10 yet unreported patients, and review 26 patients that have been reported in the literature. The spectrum of the syndrome is broadened by data from affected sibs which indicate that a wider range of anterior chamber cleavage disorders may be present, a cleft lip or palate need not be present, and developmental retardation may be mild or even absent. An increased foetal loss in families with Peters'-Plus syndrome may indicate intrauterine death of some foetuses affected by the syndrome. The pattern of inheritance is autosomal recessive.

Delayed diagnosis and underreporting of congenital anomalies associated with oral clefts in the Netherlands: a national validation study.

OBJECTIVE: Since 1997, the 15 Dutch cleft palate teams have reported their patients with oral clefts to the national oral cleft registry (NVSCA). During the first visit of the patient to the team - which is usually within the first year of life - the oral cleft and associated congenital anomalies are recorded through a unique recording form by a plastic surgeon/orthodontist/paediatrician. In this study, we evaluated the quality of data on congenital anomalies associated with clefts. METHODS: We drew a random sample of 250 cases registered in the national database with oral clefts from 1997 through 2003; of these, 13 were excluded. Using two independent reregisters derived from two-phased medical data review, we analysed whether associated anomalies were correctly diagnosed and recorded. RESULTS: The agreement on associated anomalies between the NVSCA and medical data ranged from moderate to poor (kappa 0.59 to 0). Seventy-seven percent of the craniofacial anomalies were underreported in the NVSCA: 30% due to delayed diagnosis and 47% due to deficient recording. Additionally, 80% of the associated anomalies of other organ systems were underreported: 52% due to delayed diagnosis and 28% due to deficient recording. The reporting of final diagnoses was somewhat better; however, 54% were still underreported (24% delayed diagnosis and 30% deficient recording). The rate of overreporting was 1.6% or lower. CONCLUSION: Congenital anomalies associated with clefts are underreported in the NVSCA because they are under diagnosed and deficiently recorded during the first consultations with the cleft palate teams. Our results emphasise the need for routine and thorough examination of patients with clefts. Team members should be more focussed on co-occurring anomalies, and early genetic counselling seems warranted in most cases. Additionally, our findings underline the need for postnatal follow-up and ongoing registration of associated anomalies; reregistration in the NVSCA at a later age is recommended.

Autosomal dominant craniosynostosis of the sutura metopica.

Trigonocephaly due to craniosynostosis of the sutura metopica was found in two sibs with normal intelligence. Both were microcephalic. The father had a sloping forehead and possibly partial metopic craniosynostosis. The paternal grandfather had a bony ridge at the upper half of the metopic suture without significant head deformity. A paternal sister was possibly also affected. None of the affected persons showed significant other anomalies. Craniosynostosis of the metopic suture may be an autosomal dominantly inherited disorder, not associated with functional brain or other abnormalities.

A cephalometric study in Rubinstein-Taybi syndrome.

A roentgencephalometric study to compare the facial morphology of 18 individuals affected with Rubinstein-Taybi syndrome and 25 of their parents was performed. The main findings in the affected individuals were shortening of facial height and depth, cranial base length, a marked decrease in size of the mandible, and a steep cranial base. A change with age was found for some dimensions. The pattern variability indices were high, indicating an abnormal craniofacial profile. The correlations between most patients were high, although this was less expressed for the younger patients. The parents had a normal pattern profile and pattern profile variability indices. The correlation between parents and their affected children was low. This study suggests that pattern profile analysis of cephalometric measurements may be a useful diagnostic tool in Rubinstein-Taybi syndrome. However, comparable studies of large groups of patients, especially of a younger age, are needed for further ascertainment of normal values in individuals with Rubinstein-Taybi syndrome at different stages of facial development.

Rubinstein-Taybi syndrome in The Netherlands.

This study reports the physical and radiographic characteristics of 45 patients with Rubinstein-Taybi syndrome living in The Netherlands. All had broad halluces, but only 39 patients had broad thumbs. Microcephaly was present in 35% of patients. In addition to the well-known characteristics, persistent fetal pads, a shawl scrotum, and a high frequency of fractures were found in several patients. Morbidity was mainly determined by the mental handicap, constipation, and recurrent upper respiratory infections, probably due to abnormal anatomy in the craniofacial region. Easy collapsible laryngeal walls may cause problems in sleep and anaesthesia.

Metacarpophalangeal pattern profile analysis in Rubinstein-Taybi syndrome.

Metacarpophalangeal pattern profile (MCPP) was determined in 49 radiographs of 40 patients with Rubinstein-Taybi syndrome. Two recognizable hand profiles were seen, depending on the configuration of the thumb and on age. Patients with a straight thumb showed a short first proximal phalanx, and short third medial phalanx. Patients with a radially deviated thumb had a short first proximal phalanx. Depending on age, a relatively large (infancy) or markedly short (older patients) first distal phalanx was found. The similarity between the patients was high. A third group of patients did not show a particular hand profile, but only small hand bones. The pattern variability indices were high in all groups of patients. MCPP analysis in Rubinstein-Taybi syndrome seems to be a powerful, but not pathognomonic, diagnostic tool.

Identification of two new nucleotide mutations (HPRTUtrecht and HPRTMadrid) in exon 3 of the human hypoxanthine-guanine phosphoribosyltransferase (HPRT) gene.

Mutations in the X-linked hypoxanthine-guanine phosphoribosyl transferase gene (HPRT) result in deficiencies of HPRT enzyme activity, which may cause either a severe form of gout or Lesch-Nyhan syndrome depending on the residual enzyme activity. Mutations leading to these diseases are heterogeneous and include DNA base substitutions, DNA deletions, DNA base insertions and errors in RNA splicing. Identification of mutations has been performed at the RNA and DNA level. Sequencing genomic DNA of the HPRT gene offers the possibility of direct diagnostic analysis independent on the expression of the mature HPRT mRNA. We describe a Dutch and a Spanish family, in which the Lesch-Nyhan syndrome and a severe partial HPRT-deficient phenotype, respectively, were diagnosed. Direct sequencing of the exons coding for the HPRT gene was performed in both families. Two new exon 3 mutations have been identified. At position 16676, the normally present G was substituted by an A in the Dutch kindred (HPRTUtrecht), and led to an arginine for glycine change at residue 70. At position 16680, the G was substituted by a T in the Spanish family (HPRTMadrid); this substitutes a valine for glycine at residue 71. These new mutations are located within one of the clusters of hotspots in exon 3 of the HPRT gene in which HPRTYale and HPRTNew Haven have previously been identified.

Deletion at chromosome 16p13.3 as a cause of Rubinstein-Taybi syndrome: clinical aspects.

In the accompanying paper, a chromosomal localization of the Rubinstein-Taybi syndrome by cytogenetic investigations with fluorescence in situ hybridization techniques at chromosome 16p13.3 is described. We investigated 19 of these patients and their parents (a) to ascertain the parental origin of the chromosome with the deletion in families where such a deletion was detected, (b) to disclose whether uniparental disomy plays a role in etiology, and (c) to compare clinical features in patients with a deletion to those in individuals in whom deletions were not detectable. Molecular studies showed a copy of chromosome 16 from each parent in all 19 patients. Uniparental disomy was also excluded for five other chromosome arms known to be imprinted in mice. None of the probes used for determining the origin of the deleted chromosome proved to be informative. The clinical features were essentially the same in patients with and without visible deletion, with a possible exception for the incidence of microcephaly, angulation of thumbs and halluces, and partial duplication of the halluces. A small deletion at 16p13.3 may be found in some patients with Rubinstein-Taybi syndrome. Cytogenetically undetectable deletions, point mutations, mosaicism, heterogeneity, or phenocopy by a nongenetic cause are the most probable explanations for the absence of cytogenetic or molecular abnormalities in other patients with Rubinstein-Taybi syndrome.

Genotype-phenotype correlation in adult-onset acid maltase deficiency.

We performed a clinical, biochemical, and genetic study in 16 patients from 11 families with adult-onset acid maltase deficiency. All patients were compound heterozygotes and carried the IVS1(-13T --> G) transversion on one allele; the second allele harbored either a deletion of a T at position 525 in exon 2 (7 probands, 64%) or a deletion of exon 18 (1 proband, 9%). Deterioration of handicap was related to age, and decrease in vital capacity to duration of the symptomatic stage. Respiratory insufficiency was never the first manifestation. The levels of activity of serum creatine kinase and of alpha-glucosidase in peripheral blood cells or muscle were helpful for the diagnosis, but did not have prognostic value. The adult form of acid maltase deficiency appears to be both clinically and genetically rather homogeneous; decrease of alpha-glucosidase activity is the final common pathway leading to destruction of muscle fibers and progression of muscle weakness over a period of years.

Osteoporosis-pseudoglioma syndrome, a disorder affecting skeletal strength and vision, is assigned to chromosome region 11q12-13.

Osteoporosis-pseudoglioma syndrome (OPS) is an autosomal recessive disorder characterized by severe juvenile-onset osteoporosis and congenital or juvenile-onset blindness. The pathogenic mechanism is not known. Clinical, biochemical, and microscopic analyses suggest that OPS may be a disorder of matrix homeostasis rather than a disorder of matrix structure. Consequently, identification of the OPS gene and its protein product could provide insights regarding common osteoporotic conditions, such as postmenopausal and senile osteoporosis. As a first step toward determining the cause of OPS, we utilized a combination of traditional linkage analysis and homozygosity mapping to assign the OPS locus to chromosome region 11q12-13. Mapping was accomplished by analyzing 16 DNA samples (seven affected individuals) from three different consanguineous kindreds. Studies in 10 additional families narrowed the candidate region, supported locus homogeneity, and did not detect founder effects. The OPS locus maps to a 13-cM interval between D11S1298 and D11S971 and most likely lies in a 3-cM region between GSTP1 and D11S1296. At present, no strong candidate genes colocalize with OPS.

Rubinstein-Taybi syndrome caused by submicroscopic deletions within 16p13.3.

The Rubinstein-Taybi syndrome (RTS) is a well-defined complex of congenital malformations characterized by facial abnormalities, broad thumbs and big toes, and mental retardation. The breakpoint of two distinct reciprocal translocations occurring in patients with a clinical diagnosis of RTS was located to the same interval on chromosome 16, between the cosmids N2 and RT1, in band 16p13.3. By using two-color fluorescence in situ hybridization, the signal from RT1 was found to be missing from one chromosome 16 in 6 of 24 patients with RTS. The parents of five of these patients did not show a deletion of RT1, indicating a de novo rearrangement. RTS is caused by submicroscopic interstitial deletions within 16p13.3 in approximately 25% of the patients. The detection of microdeletions will allow the objective conformation of the clinical diagnosis in new patients and provides an excellent tool for the isolation of the gene causally related to the syndrome.