ABSTRACT
Congenital adducted thumb has been called variously as congenital clasped thumb, thumb in palm deformity or flexion adduction deformity of the thumb. This condition can be an isolated anomaly or associated with several genetic disorders. The syndromes that include adducted thumb as a cardinal feature such as Dundar Syndrome are few in the literature. This syndrome is an autosomal-recessive very rare disorder characterized by typical facial appearance with dysmorphic features that includes wasted build, hyperextensible, thin and translucent skin with atrophic scarring, severe congenital contractures of fingers and thumbs, club feet, severe kyphoscoliosis, joint instability, muscular hypotonia, and ocular involvement. Heart, kidney, and/or intestinal defects can also be observed. Up to date the syndrome is described in few families in the literature. Here we discuss the syndromes that include adducted thumb as a cardinal feature and also the differential diagnosis of the Dundar Syndrome according to the literature.
Subject(s)
Arthrogryposis , Craniofacial Abnormalities , Ehlers-Danlos Syndrome , Facies , Genetic Diseases, X-Linked , Intellectual Disability , Pterygium , Spastic Paraplegia, Hereditary , Arthrogryposis/genetics , Arthrogryposis/pathology , Arthrogryposis/physiopathology , Craniofacial Abnormalities/genetics , Craniofacial Abnormalities/pathology , Craniofacial Abnormalities/physiopathology , Diagnosis, Differential , Ehlers-Danlos Syndrome/genetics , Ehlers-Danlos Syndrome/pathology , Ehlers-Danlos Syndrome/physiopathology , Eye Abnormalities , Genetic Diseases, X-Linked/genetics , Genetic Diseases, X-Linked/pathology , Genetic Diseases, X-Linked/physiopathology , Humans , Intellectual Disability/genetics , Intellectual Disability/pathology , Intellectual Disability/physiopathology , Joint Instability/congenital , Pterygium/genetics , Pterygium/pathology , Pterygium/physiopathology , Skin Abnormalities , Spastic Paraplegia, Hereditary/genetics , Spastic Paraplegia, Hereditary/pathology , Spastic Paraplegia, Hereditary/physiopathologySubject(s)
Arterio-Arterial Fistula/congenital , Cysts/diagnostic imaging , Fetofetal Transfusion/diagnostic imaging , Heart Defects, Congenital/diagnostic imaging , Pregnancy, Triplet , Uterine Diseases/diagnostic imaging , Diagnosis, Differential , Female , Humans , Pregnancy , Ultrasonography, PrenatalABSTRACT
OBJECTIVE: Congenital diaphragmatic hernia (CDH) is a fetal abnormality affecting diaphragm and lung development with a high mortality rate despite advances in fetal and neonatal therapy. CDH may occur either as an isolated defect or in syndromic form for which the prognosis is worse. Although conventional karyotyping and, more recently, chromosomal microarrays support a substantial role for genetic factors, causal genes responsible for isolated CDH remain elusive. We propose that chromosomal microarray analysis will identify copy number variations (CNVs) associated with isolated CDH. METHODS: We perform a prospective genome-wide screen for CNVs using chromosomal microarrays on 75 fetuses referred with apparently isolated CDH, six of which were later reclassified as non-isolated CDH. RESULTS: The results pinpoint haploinsufficiency of NR2F2 as a cause of CDH and cardiovascular malformations. In addition, the 15q25.2 and 16p11.2 recurrent microdeletions are associated with isolated CDH. By using gene prioritisation and network analysis, we provide strong evidence for several novel dosage-sensitive candidate genes associated with CDH. CONCLUSIONS: Chromosomal microarray analysis detects submicroscopic CNVs associated with isolated CDH or CDH with cardiovascular malformations.
Subject(s)
DNA Copy Number Variations , Gene Dosage , Hernias, Diaphragmatic, Congenital , Chromosome Aberrations , Comparative Genomic Hybridization/methods , Female , Fetus/metabolism , Genes, Developmental , Genetic Association Studies , Hernia, Diaphragmatic/diagnosis , Hernia, Diaphragmatic/genetics , Humans , Karyotyping/methods , Oligonucleotide Array Sequence Analysis , Pregnancy , Pregnancy Outcome/epidemiology , Prenatal Diagnosis/methods , Severity of Illness IndexABSTRACT
BACKGROUND: Amniotic fluid (AF) cell populations will be applied in perinatology. We aimed to test the feasibility of large-scale cell expansion. STUDY METHODS: We determined the best out of three published expansion protocols for mesenchymal progenitors (AF samples, n = 4) in terms of self-renewal ability. Characterization was performed based on morphology, surface marker analysis, cytogenetic stability, and differentiation potential. The conditions for the best self-renewal ability were further determined in a consecutive series (n = 159). RESULTS: The medium containing fetal bovine serum (FBS), epidermal growth factor, insulin, transferrin, and tri-iodothyronine, combined with seeding on gelatin-coated wells, best stimulated the growth of cells with mesenchymal features, as demonstrated by flow cytometry; however, only osteogenic differentiation was possible. Large-scale testing (n = 44) failed to confirm a robust self-renewal ability. Better results were obtained (n = 88) using optimized FBS or an increased initial cell density. Eventually over 81% of cultures continued growing after the initial medium change and had mesenchymal features but failed differentiation assays. DISCUSSION: Routine in vitro expansion of AF-derived mesenchymal cells remains problematic. Despite an increase in successful cell cultures from 40 up to 80% using optimized serum and an increased cell density, eventually cells failed to demonstrate differentiation abilities. Routine isolation and expansion from unselected AF samples remains a challenge.
Subject(s)
Amniotic Fluid/cytology , Cell Culture Techniques/methods , Mesenchymal Stem Cells/cytology , Animals , Cattle , Cell Count , Cell Differentiation , Cell Proliferation , Culture Media , Female , Humans , Karyotyping , PregnancyABSTRACT
Congenital High Airway Obstruction Syndrome (CHAOS) is a potential lethal condition. We describe a case report of CHAOS, with additional malformations diagnosed at 20 weeks. Autopsy findings are suggestive for Fraser syndrome (cryptophthalmos-syndactyly syndrome; OMIM 219000). The diagnosis was confirmed by mutation analysis of FRAS1.
Subject(s)
Aborted Fetus/pathology , Airway Obstruction/pathology , Fraser Syndrome/diagnosis , Adult , Airway Obstruction/congenital , Airway Obstruction/diagnostic imaging , Autopsy , Female , Fraser Syndrome/complications , Fraser Syndrome/genetics , Humans , Pregnancy , Syndrome , Ultrasonography, PrenatalABSTRACT
Noonan syndrome is a genetically heterogeneous disorder caused by mutations in PTPN11, SOS1, RAF1 and less frequently in KRAS, NRAS or SHOC2. Here, we performed mutation analysis of NRAS and SHOC2 in 115 PTPN11, SOS1, RAF1, and KRAS mutation-negative individuals. No SHOC2 mutations were found, but we identified 3 NRAS mutations in 3 probands. One NRAS mutation was novel. The phenotype associated with germline NRAS mutations is variable. Our results confirm that a small proportion of Noonan syndrome patients carry germline NRAS mutations.
ABSTRACT
Genome-wide array comparative genome hybridization has become the first in line diagnostic tool in the clinical work-up of patients presenting with intellectual disability. As a result, chromosome X-copy number variations are frequently being detected in routine diagnostics. We retrospectively reviewed genome wide array-CGH data in order to determine the frequency and nature of chromosome X-copy number variations (X-CNV) in a cohort of 2222 sporadic male patients with intellectual disability (ID) referred to us for diagnosis. In this cohort, 68 males were found to have at least one X-CNV (3.1%). However, correct interpretation of causality remains a challenging task, and is essential for proper counseling, especially when the CNV is inherited. On the basis of these data, earlier experience and literature data we designed and propose an algorithm that can be used to evaluate the clinical relevance of X-CNVs detected in sporadic male ID patients. Applied to our cohort, 19 male ID patients (0.85%) were found to carry a (likely) pathogenic X-CNV.
Subject(s)
Chromosomes, Human, X/genetics , DNA Copy Number Variations , Intellectual Disability/genetics , Adolescent , Adult , Aged , Child , Child, Preschool , Comparative Genomic Hybridization , Genetic Counseling , Genetic Loci , Genome, Human , Humans , Infant , Intellectual Disability/diagnosis , Male , Middle Aged , Retrospective StudiesABSTRACT
In this report we present two brothers with abnormal neurological development, hypotonia, short stature, pylorus stenosis, pectus excavatum, brachycephaly due to craniosynostosis, frontal bossing, depressed nasal bridge, high arched-wide palate, downslant palpebral fissures, low-set, large ears, thin upper lip and bilateral cryptorchidism. The brothers were born to a couple of second cousins and were the third and fourth pregnancies of the mother. The father, the mother and the eldest sibling were phenotypically and chromosomally normal. The clinical findings of the brothers were found to be similar. These clinical findings were compared with syndromes showing some of the symptoms, namely Apert, FG, Floating-Harbor, Shprintzen-Goldberg and Rett Syndromes. However, when the findings were detailed, we observed that they did not match completely any of the syndromes in a discernable way. The MECP2 gene mutation was analysed because of mental retardation, poor neurological evolution and large ears, but no mutation was found. So these cases are presented as a new syndrome with apparent autosomal recessive inheritance.
Subject(s)
Abnormalities, Multiple/diagnosis , Cryptorchidism/diagnosis , Face/abnormalities , Intellectual Disability/diagnosis , Muscle Hypotonia/diagnosis , Abnormalities, Multiple/genetics , Child, Preschool , Cryptorchidism/genetics , Humans , Infant , Intellectual Disability/genetics , Male , Muscle Hypotonia/genetics , SyndromeABSTRACT
Hydrometrocolpos, occurring in approximately 1/6000 newborn girls, can be caused by a stenotic urogenital sinus, a severe cloacal malformation, but also by other conditions such as an imperforate hymen, a midline vaginal septum and vaginal atresia. The prenatal differential diagnosis of this wide spectrum of conditions is not easy and requires a multidisciplinary approach with follow-up scans and MRI to access the severity of the condition. A non-consanguineous couple was referred in the first pregnancy at 30 weeks. The father, 30 years of age, of Kaukasian origin, and the mother of Asian origin, 26 years of age. Ultrasound at 30 weeks revealed ambiguous genitalia (with suspicion of clitoral hypertrophy), a septated structure located behind the bladder compatible with hydrometrocolpos with a uterine malformation (uterus didelphys), a single umbilical artery, mild ascites and growth on the tenth centile. The differential diagnosis included a vaginal atresia, a urogenital sinus and a more severe cloacal malformation. After serial scans, MRI and counselling by an experienced surgeon the preferential diagnosis of a cloacal malformation was made and a late pregnancy termination was performed. Pathological examination revealed: low vaginal atresia with uterus didelphys, anal atresia with rectovaginal fistula and a normal urinary tractus. The differential diagnosis between hydrometrocolpos due to vaginal atresia or due to a more severe cloacal malformation is not straightforward. Care should be taken in decision making and counselling patients with these complex prenatal malformations.
Subject(s)
Abnormalities, Multiple/diagnosis , Anus, Imperforate/diagnosis , Cloaca/abnormalities , Fetal Diseases/diagnosis , Heart Defects, Congenital/diagnosis , Hydrocolpos/diagnosis , Polydactyly/diagnosis , Uterine Diseases/diagnosis , Vaginal Diseases/diagnosis , Abnormalities, Multiple/embryology , Abortion, Eugenic/methods , Adult , Cloaca/diagnostic imaging , Diagnosis, Differential , Female , Heart Defects, Congenital/embryology , Humans , Hydrocolpos/embryology , Polydactyly/embryology , Pregnancy , Pregnancy Trimester, Third , Ultrasonography, Prenatal/methods , Uterine Diseases/embryology , Uterus/abnormalities , Uterus/diagnostic imaging , Uterus/embryology , Vagina/abnormalities , Vagina/diagnostic imaging , Vagina/embryology , Vaginal Diseases/embryologyABSTRACT
Holoprosencephaly (HPE), the most common malformation of the human brain results from abnormal cleavage of the forebrain during the early embryonic developmental stages. The spectrum of malformations in HPE is wide, ranging from the classical cyclopia/proboscis to fairly asymptomatic forms [i.e. a single maxillary central incisor (SMCI)]. HPE may be caused by environmental or genetic factors. ZIC2 (13q32) was the second gene identified in which mutations cause HPE and recently a specific phenotype was ascribed to ZIC2-mutation HPE. Earlier, we reported a boy presenting HPE and deafness. Cytogenetic analyses were normal. Using array-comparative genomic hybridization (aCGH), we found a de novo 129 kb del(13)(q32) encompassing ZIC2 and ZIC5. There is no evidence for the involvement of ZIC5 in human diseases. We reviewed the literature for ZIC2-ZIC5 deletions and their involvement in neural tube defects (NTDs). Interestingly, we found evidence for a specific facial phenotype for ZIC2 gene deletion patients distinct from those with point mutations. In addition, based on the clinical data together with pathology, imaging and functional studies, we suggest an outline for a model explaining the genetic heterogeneity of ZIC2-ZIC5-associated NTDs and propose further studies for validation.
Subject(s)
Holoprosencephaly/genetics , Nuclear Proteins/genetics , Transcription Factors/genetics , Adolescent , Chromosome Deletion , Comparative Genomic Hybridization , DNA-Binding Proteins , Genetic Heterogeneity , Humans , Male , Mutation , Neural Tube Defects/genetics , PhenotypeABSTRACT
Hydrolethalus syndrome is a severe lethal disorder most commonly found in Finland. We present a lethal case of complex congenital malformation in a Romanian family who showed multiple signs described in hydrolethalus syndrome. Our case presented the specific characteristics: macrocephaly, midline cleft-lip, cleft palate, polydactyly of both hands and feet but without occipitoschisis, considered as the pathognomonic sign of the syndrome. Sequencing analysis of HYLS1 did not identify the point mutation present in the Finnish cases or other mutations in this gene.
Subject(s)
Abnormalities, Multiple/genetics , Hand Deformities, Congenital/genetics , Heart Defects, Congenital/genetics , Hydrocephalus/genetics , Proteins/genetics , Brain/abnormalities , Cleft Lip/genetics , Cleft Palate/genetics , Clubfoot/genetics , Craniofacial Abnormalities/genetics , Fatal Outcome , Humans , Infant, Newborn , Kidney Diseases, Cystic/congenital , Kidney Diseases, Cystic/genetics , Male , Polydactyly/genetics , Romania , SyndromeABSTRACT
Rubinstein-Taybi syndrome (RTS) is a rare autosomal dominant genetic disorder and is characterized by mental retardation, distinctive facial features, broad and often angulated thumbs and great toes. We report on a 7 year old boy with classical Rubinstein-Taybi syndrome. His facial and clinical features were very typical, including broad thumbs with radial angulation and broad great toes. Rigorous genetic analysis of the CREBBP and EP300 genes using DNA sequencing and multiple ligation-dependent probe amplification (MLPA) revealed no causative mutation in this boy, only a hitherto unreported but paternally inherited heterozygous sequence alteration, c.506 1+9C>T in IVS 30-31, which most likely represents a normal variant (NetGene 2 splice prediction software). We question if this boy could have a hitherto undetectable mutation type.
Subject(s)
CREB-Binding Protein/genetics , DNA Mutational Analysis , E1A-Associated p300 Protein/genetics , Rubinstein-Taybi Syndrome/genetics , Alleles , Child , Consanguinity , Genetic Carrier Screening , Humans , Karyotyping , Male , Phenotype , Rubinstein-Taybi Syndrome/diagnosis , Sequence Analysis, DNAABSTRACT
BACKGROUND: In 1967, Cross et al. [J Pediatr 1967;70:398-406] reported four siblings with intellectual disability, microcephaly, neurologic and ocular disorders, and hypopigmentation involving skin and hair. This novel entity, known as oculocerebral hypopigmentation syndrome (OCHS) or Cross syndrome (OMIM 257800), is assumed to be autosomal recessive. However, its genetic cause is still unknown. CASE REPORT: A 4-year-old girl is reported with OCHS, a history of recurrent infections and vertebral fusion of L4-L5. Central nervous system and cardiac imaging as well as metabolic screening were normal. Microscopic hair investigations did not show any melanin deposit defects. RESULTS: Using molecular cytogenetics, we detected a de novo interstitial del(3)(q27.1q29) of the paternal chromosome. To our knowledge, this is the first molecular genetics finding in a patient with OCHS. Here we discuss the genotype-phenotype correlations and suggest candidate genes for this disorder. CONCLUSION: Investigating further patients would enable fine-mapping the OCHS locus and identifying its putative gene.
Subject(s)
Abnormalities, Multiple/genetics , Chromosomes, Human, Pair 3/genetics , Craniofacial Abnormalities/genetics , Pigmentation Disorders/genetics , Child, Preschool , Chromosome Mapping , Female , Genetic Association Studies , Humans , Intellectual Disability/genetics , Microcephaly/geneticsABSTRACT
First trimester spontaneous abortions occur in 15 to 20% of all clinically recognized pregnancies. Chromosomal -anomalies are responsible for more than 50% of spontaneous abortions. The majority (90%) of these chromosomal anomalies are numerical, particularly autosomal trisomies (involving chromosomes 13,16, 18, 21, 22), polyploidy and monosomy X. At birth chromosomal anomalies are still an important cause of congenital malformations occurring in 0,55% of newborns (autosomal: 0,40%, sex chromosomal: 0,15%). Autosomal trisomies result from maternal -meiotic nondisjunction of gametogenesis and the risk increases with maternal age. Polyploidy (triploidy (3nâ=â69) or tetraploidy (4nâ=â92)), results from a contribution of one or more extra haploid chromosome sets at fertilization. Unlike the risk for autosomal trisomies, the risk for polyploidies and for monosomy X (Turner syndrome) does not increase with maternal age. In the prenatal period the ultrasonographic diagnosis of some autosomal trisomies such as trisomy 13 and 18 is feasible based on the frequently seen major malformations while the diagnosis of trisomy 21 often remains challenging due to the absence of major malformations in >â50% of cases. For Turner syndrome (monosomy X), the lethal form will present with cystic hygroma colli and hydrops but the non lethal form is difficult to recognize by -ultrasound in the second trimester. The 5 frequently encountered chromosomal anomalies (Trisomy 13, 18, 21, Turner syndrome and Triploidy) referred here as the 5T's have specific hand features which will be discussed.
ABSTRACT
A good pregnancy outcome is partly determined by a women's preconceptional health and healthy lifestyle. The access to prenatal care is good nowadays but the incidence of congenital malformations, preterm births, low birth weight and maternal mortality has not significantly declined over the years. Although most women of reproductive age have a gynecological examination every two years in Belgium, they are not often counseled before starting a pregnancy. The American College of Obstetricians and Gynecologists (ACOG) states that optimizing a woman's health before and between pregnancies must be an ongoing process. The most vulnerable period for fetal defects is between 4 and 10 weeks of gestation, the period of embryogenesis, meaning that counseling for a healthy life style and reducing high-risk conditions should start preferably before conception.
Subject(s)
Counseling , Preconception Care/methods , Belgium , Communicable Disease Control , Contraception , Female , Genetic Counseling , Humans , Life Style , Pregnancy , Pregnancy, High-Risk , Risk FactorsABSTRACT
We describe a 3-year-old girl with pure 17q25.3 duplication and a complex clinical presentation comprising psychomotor/mental retardation, growth retardation and most dysmorphic features of partial duplication 17q syndrome with, additionally, a striking distal arthrogryposis. The duplication size was maximum 2.46 MB, being thus, to the best of our knowledge, the smallest 17q25.3 duplicated portion ever reported. This defect could only be detected by microarray assays, stressing once again the pertinence of this tool in detecting cryptic rearrangements. From the findings in the present patient and in the previously reported cases with duplication within the 17q21-7q25 region, it appears that the clinical features collected from the group of patients without a complementary monosomy illustrate better the trisomy 17q phenotype, and that most dysmorphic features of the 17q duplication syndrome might largely be related to the very terminal segment extending from 17q25.3 to 17qter.
Subject(s)
Abnormalities, Multiple/genetics , Arthrogryposis/genetics , Chromosomes, Human, Pair 17 , Developmental Disabilities/genetics , Face/abnormalities , Gene Duplication , Adult , Child, Preschool , Comparative Genomic Hybridization , Female , Humans , Male , Oligonucleotide Array Sequence Analysis , PedigreeABSTRACT
Partial 3p duplications are very rare. Often they are reported in translocations involving other chromosomes, whereas deletions encompassing the VHL gene in 3p25.3 predispose to Van-Hippel Lindau syndrome. We report here a paternally-inherited microduplication of 3p25.3 detected by array comparative genomic hybridisation (aCGH) in a 17 year-old male patient presenting with mental retardation and multiple congenital anomalies (MR/MCA), epilepsy and ectomorphic habitus. He has no tumour and there is no history of familial cancer. We refined the duplication by Multiplex Ligation-dependent Probe Amplification (MLPA) to a 251 kb region encompassing the VHL and IRAK2 genes. The duplication is likely to be causal. Interestingly, duplication of IRAK2 can cause epilepsy. Disruption of the GHRL gene can explain the ectomorphic habitus. To our knowledge, this is the smallest 3p duplication encompassing the VHL region. Its prognosis is unknown and a long-term follow-up is essential for an early diagnosis of malignancy.
Subject(s)
Abnormalities, Multiple/genetics , Chromosomes, Human, Pair 3/genetics , Epilepsy/genetics , Gene Duplication , Intellectual Disability/genetics , Interleukin-1 Receptor-Associated Kinases/genetics , Von Hippel-Lindau Tumor Suppressor Protein/genetics , Adolescent , Ghrelin/genetics , Humans , Male , Oligonucleotide Array Sequence Analysis , SomatotypesABSTRACT
BACKGROUND: The 10q24 chromosomal region has previously been implicated in split hand foot malformation (SHFM). SHFM3 was mapped to a large interval on chromosome 10q. The corresponding dactylaplasia mouse model was linked to the syntenic locus on chromosome 19. It was shown that the two existing Dac alleles result from MusD-insertions upstream of or within Dactylin (Fbxw4). However, all efforts to find the underlying cause for the human SHFM3 have failed on the analysis of all the genes within the linkage region. Intriguingly a submicroscopic duplication within the critical locus on chromosome 10q24 was associated with the phenotype. METHODS AND RESULTS: As a part of screening for genomic rearrangements in cases with unexplained syndromic limb defects, a cohort of patients was analysed by array comparative genomic hybridisation (CGH). A 10q24 microduplication was detected in two individuals with distal limb deficiencies associated with micrognathia, hearing problems and renal hypoplasia. In addition, in a family with two affected siblings, a somatic/gonadal mosaicism for the microduplication was detected in the apparently healthy mother. Using a high resolution oligoarray further delineation of the duplication size was performed. CONCLUSIONS: The detected 10q24 genomic imbalance in our syndromic patients has a similar size to the duplication in the previously reported individuals with an isolated form of SHFM, thus extending the clinical spectrum of SHFM3. These findings clearly demonstrate the importance of array CGH in the detection of the aetiology of complex, clinically heterogeneous entities.
Subject(s)
Chromosomes, Human, Pair 10 , F-Box Proteins/genetics , Foot Deformities, Congenital/genetics , Hand Deformities, Congenital/genetics , Limb Deformities, Congenital/genetics , Micrognathism/genetics , Chromosome Mapping , Chromosomes, Artificial, Bacterial , Cohort Studies , Comparative Genomic Hybridization , Female , Gene Duplication , Gene Rearrangement , Humans , In Situ Hybridization, Fluorescence , Male , Oligonucleotide Array Sequence Analysis , Polymerase Chain Reaction , SyndromeABSTRACT
A recent pilot study found that curcumin, in certain patients with monoclonal gammopathy of undetermined significance (MGUS), decreases the paraprotein load and the urinary N-telopeptide of type 1 collagen bone turnover marker. While this result is encouraging, the easy availability of the food component turmeric, containing curcumin, may lead to intake by MGUS patients without medical supervision. Curcumin is generally considered safe. Nevertheless, it is known that curcumin inhibits interleukin-12 production in dendritic cells, thereby dampening the Th1 response. It is also well established that Th1 cells are protective against invading pathogens and tumors. The present study describes a case in which bronchitis developed upon turmeric intake for gastrointestinal complaints. While one case does not provide proof of curcumin toxicity, a thorough literature overview suggests that turmeric may have an immunosuppressive effect, notably in patients with a compromised immune system. A warning against the use of turmeric or curcumin without medical supervision in immunocompromised patients seems therefore very opportune. Patients with MGUS, in whom the levels of non-affected immunoglobulins are reduced, should be carefully monitored for toxicity when curcumin is administered.
ABSTRACT
Branchio-oculo-facial syndrome (BOFS) is a rare disorder characterized by maldevelopment of the first and second branchial arches, skin defects, facial dysmorphism, auricular, ophthalmological and oral abnormalities. A high clinical variability has been reported. Recently, mutations in TFAP2A were found to underlie this condition. A small duplication on 5q13 was detected in 2 family members with mild BOFS features. Molecular cytogenetic delineation of the duplication demonstrated that only 7 genes are affected: LOC100289045, RGNEF, UTP15, ANKRA2, FUNDC2P1, BTF3 and FOXD1. The latter is expressed in the developing branchial arches and involved in cranio-facial development. Zebrafish embryos with combined inhibition of the expression of foxd1l and tfap2a show optic axis defects. We identified a novel locus associated with a mild BOFS-like phenotype. The functional in vivo experiments suggest an interaction between FOXD1 and TFAP2A.