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The musculoskeletal (MSK) system begins to form in the third week of intrauterine development. Multiple genes are involved in the complex different processes to form the skeleton, muscles and joints. The embryonic period, from the third to the eighth week of development, is critical for normal development and therefore the time when most structural defects are induced. Many of these defects have a genetic origin, but environmental factors may also play a very important role. This review summarizes the embryology of the different components of the MSK system and their configuration as an organ-system, analyzes the clinical implications resulting from failures in the process of organogenesis, and describes the first approach to diagnosis of skeletal abnormalities using prenatal ultrasound., SCOPUS: ar.j, info:eu-repo/semantics/published

Catel-Manzke syndrome is characterized by hand anomalies, Robin sequence, cardiac defects, joint hyperextensibility, and characteristic facial features. Approximately 40 patients with Catel-Manzke have been reported, all with the pathognomonic bilateral or unilateral hyperphalangy caused by an accessory bone between the second metacarpal and proximal phalanx known as Manzke dysostosis. Here we present the first case of molecularly confirmed Catel-Manzke syndrome with Robin sequence but without Manzke dysostosis.

Objective Facial dysostosis is a group of rare craniofacial congenital disabilities requiring multidisciplinary long-term care. This report presents the phenotypic and genotypic information from South India. Design The study is a case series. Setting This was an international collaborative study involving a tertiary craniofacial clinic and medical genetics unit. Patients, Participants The participants were 9 families with 17 affected individuals of facial dysostosis. Intervention Exome analysis focused on known genes associated with acrofacial and mandibulofacial syndromes. Main Outcome Measure The outcome measure was to report phenotyptic and genetic heterogeneity in affected individuals. Results A Tessier cleft was seen in 7 (41%), lower eyelid coloboma in 12 (65%), ear anomalies in 10 (59%), uniolateral or bilateral aural atresia in 4 (24%), and deafness in 6 (35%). The facial gestalt of Treacher Collins syndrome (TCS) showed extensive phenotypic variations. Pathogenic variants in TCOF1 (Treacher Collins syndrome) were seen in six families, POLR1A (acrofacial dysostosis, Cincinnati type) and EFTUD2 (mandibulofacial dysostosis with microcephaly) in one each. One family (11.1%) had no detectable variation. Five out of six probands with Treacher Collins syndrome had other affected family members (83.3%), including a non-penetrant mother, identified after sequencing. Conclusion Our report illustrates the molecular heterogeneity of mandibulofacial dysostosis in India.

Congenital limb deficiency (CLD), one of the most common congenital anomalies, is characterized by hypoplasia/aplasia of one or more limb bones and can be isolated or syndromic. The etiology in CLD is heterogeneous, including environmental and genetic factors. A fraction remains with no etiological factor identified. We report the study of 44 Brazilian individuals presenting isolated or syndromic CLD, mainly with longitudinal defects. Genetic investigation included particularly next-generation sequencing (NGS) and/or chromosomal microarray. The overall diagnostic yield was 45.7%, ranging from 60.9% in the syndromic to 16.7% in the non-syndromic group. In TAR syndrome, a common variant in 3´UTR of RBM8A, in trans with 1q21.1 microdeletion, was detected, corroborating the importance of this recently reported variant in individuals of African ancestry. NGS established a diagnosis in three individuals in syndromes recently reported or still under delineation (an acrofacial dysostosis, Coats plus and Verheij syndromes), suggesting a broader phenotypic spectrum in these disorders. Although a low rate of molecular detection in non-syndromic forms was observed, it is still possible that variants in non-coding regions and small CNVs, not detected by the techniques applied in this study, could play a role in the etiology of CLD.

Lower eyelid colobomas associated with Treacher Collins syndrome can be challenging to repair because of associated orbital and midfacial dysostosis. Alloplastic implants such as porous polyethylene have been advocated as readily available malar implants to help improve eyelid retraction. The authors report the first case of porous polyethylene implant insidious migration into the orbit with subsequent scleral penetration. A 14-year-old male with Treacher Collins syndrome, presented with a 3-week history of left eye pain, redness, and eyelid swelling unresponsive to topical treatment. He previously had bilateral lower lid coloboma repair with alloplastic implant placement and full-thickness skin grafts. On exam, he had left eye injection and chemosis, with left hypotropia and complete restrictive ophthalmoplegia. Imaging revealed displacement of implant into the orbit with adherence and impingement on the eye globe.

International audience; Introduction: Camel-hump condylo-mandibular dysplasia is a specific form of condyle dysostosis, first described by Delaire. The aim of this study was to describe the clinical and radiographic phenotype of the disease, and to discuss therapeutic options.Case series: Twenty-one patients were analyzed retrospectively. They exhibited the same unilateral facial asymmetry, which was of mandibular origin, with an elevated commissural line and occlusal cant, and a deviated chin on the side of the deformity. The soft tissues and the ears were always normal in terms of their physical appearance. Radiographic analysis generally revealed a short, curved, and anteriorly displaced condyle, with a high and sharp coronoid process. CT scans revealed that the glenoid fossa was empty. Twelve patients exhibited dental abnormalities, consisting mainly of dental inclusions affecting the lower first and/or second molars (10 patients). A good response to functional orthodontic treatment was achieved in eight patients, while 13 patients required a surgical mandibular lengthening procedure.Conclusion: Condylo-mandibular dysplasia is a congenital condyle deformity that needs to be recognized and differentiated from craniofacial microsomia in order to be able to provide patient-specific treatments.

Skeletal dysplasias are a heterogeneous group of disorders ranging from mild to lethal skeletal defects. We investigated two unrelated families with individuals presenting with a severe skeletal disorder. In family NMD02, affected individuals had a dysostosis multiplex-like skeletal dysplasia and severe short stature (-8.5 SD). They manifested increasingly coarse facial features, protruding abdomens, and progressive skeletal changes, reminiscent of mucopolysaccharidosis. The patients gradually lost mobility and the two oldest affected individuals died in their twenties. The affected child in family ID01 had coarse facial features and severe skeletal dysplasia with clinical features similar to mucopolysaccharidosis. She had short stature, craniosynostosis, kyphoscoliosis, and hip-joint subluxation. She died at the age of 5 years. Whole-exome sequencing identified two homozygous variants c.133CT; p.(Arg45Trp) and c.215dupA; p.(Tyr72Ter), respectively, in the two families, affecting an evolutionary conserved gene TMEM251 (NM_001098621.1). Immunofluorescence and confocal studies using human osteosarcoma cells indicated that TMEM251 is localized to the Golgi complex. However, p.Arg45Trp mutant TMEM251 protein was targeted less efficiently and the localization was punctate. Tmem251 knockdown by small interfering RNA induced dedifferentiation of rat primary chondrocytes. Our work implicates TMEM251 in the pathogenesis of a novel disorder and suggests its potential function in chondrocyte differentiation.

Made available in DSpace on 2020-12-12T02:10:15Z (GMT). No. of bitstreams: 0 Previous issue date: 2020-06-01 Robin sequence with cleft mandible and limb anomalies, known as Richieri-Costa-Pereira syndrome (RCPS), is an autosomal recessive acrofacial dysostosis characterized by mandibular cleft and other craniofacial anomalies and respiratory complications. The aim of this cross-sectional study was to describe the hyoid and head posture of 9 individuals with RCPS using cephalometric measurements and provide a discussion about its implications in obstructive sleep apnea syndrome (OSAS). The study was conducted on lateral cephalograms of patients with RCPS and 9 selected age-matched controls in tertiary cleft center in Brazil. The cephalograms were digitized and analyzed on a software to obtain the vertical and horizontal hyoid position, its relationship with the mandible and the relation of the cranial base and postvertebral line. The t test was used for analysis of means and Levene's test for equality of variances.Cephalometric measurements H-S (vertical distance between hyoid bone and sella) (Supplemental Digital Content, Figure 1, http://links.lww.com/SCS/B247) and H-C4lp (horizontal position of the hyoid in relation to the post-pharyngeal space) showed statistically significant difference compared to controls (P

PURPOSE: Treacher Collins syndrome (TCS) is a rare autosomal dominant mandibulofacial dysostosis, with a prevalence of 0.2-1/10,000. Features include bilateral and symmetrical malar and mandibular hypoplasia and facial abnormalities due to abnormal neural crest cell (NCC) migration and differentiation. To date, three genes have been identified: TCOF1, POLR1C, and POLR1D. Despite a large number of patients with a molecular diagnosis, some remain without a known genetic anomaly. METHODS: We performed exome sequencing for four individuals with TCS but who were negative for pathogenic variants in the known causative genes. The effect of the pathogenic variants was investigated in zebrafish. RESULTS: We identified three novel pathogenic variants in POLR1B. Knockdown of polr1b in zebrafish induced an abnormal craniofacial phenotype mimicking TCS that was associated with altered ribosomal gene expression, massive p53-associated cellular apoptosis in the neuroepithelium, and reduced number of NCC derivatives. CONCLUSION: Pathogenic variants in the RNA polymerase I subunit POLR1B might induce massive p53-dependent apoptosis in a restricted neuroepithelium area, altering NCC migration and causing cranioskeletal malformations. We identify POLR1B as a new causative gene responsible for a novel TCS syndrome (TCS4) and establish a novel experimental model in zebrafish to study POLR1B-related TCS. ispartof: GENETICS IN MEDICINE vol:22 issue:3 pages:547-556 ispartof: location:United States status: published

Skeletal disorders of the fetus are quite common. The incidence is about 5:1000 pregnancies. The disorders affect the extremities or parts of them (dysmelia), the whole skeleton (skeletal dysplasia), the skull (craniosynostosis) and the spine (dysostosis, caudal regression). About half of these diseases are complex. In the majority of cases the complex disorders are caused by single gene mutations or numeric or structural chromosomal aberrations. We explain the classification and diagnostic criteria for prenatal expert and screening ultrasound based on frequent disorders. The main diagnostic challenge concerning malformations of the limbs and craniosynostosis is to find out if they are isolated or symptoms of certain syndromes. In skeletal dysplasia it is clinically important to differentiate lethal entities from non-lethal. Skelettale Erkrankungen des Fetus sind mit 5:1000 Schwangerschaften relativ haufig. Betroffen sein konnen einzelne Abschnitte der Extremitaten (Dysmelien), das ganze Skelett (Skelettdysplasien), der knocherne Schadel (Kraniosynostosen) und die Wirbelsaule (Dysostosen, kaudale Regression). In 50 % bestehen komplexe Krankheitsbilder. Fur die Mehrzahl der Krankheiten sind genetische Ursachen (Einzelgen-Mutationen, numerische und strukturelle chromosomale Aberrationen) bekannt. Anhand haufiger Krankheitsbilder werden diagnostische Kriterien fur die differenzierte Sonografie und das Ultraschall-Screening erlautert.

Richieri-Costa-Pereira syndrome is a rare autosomal recessive acrofacial dysostosis that has been mainly described in Brazilian individuals. The cardinal features include Robin sequence, cleft mandible, laryngeal anomalies and limb defects. A biallelic expansion of a complex repeated motif in the 5' untranslated region of EIF4A3 has been shown to cause this syndrome, commonly with 15 or 16 repeats. The only patient with mild clinical findings harbored a 14-repeat expansion in 1 allele and a point mutation in the other allele. This proband is described here in more details, as well as is his affected sister, and 5 new individuals with Richieri-Costa-Pereira syndrome, including a patient from England, of African ancestry. This study has expanded the phenotype in this syndrome by the observation of microcephaly, better characterization of skeletal abnormalities, less severe phenotype with only mild facial dysmorphisms and limb anomalies, as well as the absence of cleft mandible, which is a hallmark of the syndrome. Although the most frequent mutation in this study was the recurrent 16-repeat expansion in EIF4A3, there was an overrepresentation of the 14-repeat expansion, with mild phenotypic expression, thus suggesting that the number of these motifs could play a role in phenotypic delineation.

Erosive pustular dermatosis of the scalp (EPDS) is an uncommon chronic inflammatory response to scalp trauma that usually resolves with cicatricial alopecia. It most commonly affects elderly patients with a history of actinic damage. Herein, we describe a 16-year-old girl with acrofacial dysostosis type 1 presenting after surgery with crusting purulent scalp lesions, whose clinical presentation and histopathologic findings were consistent with EPDS. A review of the literature on EPDS in children is also detailed.

THOC6 is a newly described causal gene for an autosomal recessive intellectual disability (ID) - Beaulieu Boycott Innes syndrome (BBIS) (OMIM # 613680). It is characterized by ID with dysmorphic facies, genitourinary, cardiac anomalies, and dentition problems. Here, we report the first two siblings of BBIS from the Indian subcontinent with previously unreported skeletal anomalies such as Sprengel shoulder, calcaneo valgus deformity, radioulnar dysostosis, and overlapping toes. Whole exome sequencing (WES) identified previously reported three missense variants (p.Trp100Arg, p.Val234Leu, p.Gly275Asp) in THOC6. THOC6 is a subunit of TRanscription and EXport (TREX) complex involved in mRNA transcription, processing, and nuclear export of spliced mRNAs and has a potential role in neurodevelopment. Till date, only 12 patients with BBIS have been reported. This report reviews the phenotypic and genetic data of known BBIS cases in addition to the new phenotypic features, thereby expanding the phenotype of this rare syndrome.

We evaluated a newborn with acrofacial dysostosis in whom a clinical diagnosis of Nager syndrome was entertained. Radiographs revealed hypoplasia of the scapulae and bilateral humeroradial synostosis, with absent ulna on the left and hypoplastic ulna on the right. The finding of bilateral humeroradial synostosis had not been seen in cases of Nager syndrome before and we considered other diagnoses. Humeroradial synostosis has been found in three cases of acrofacial dysostosis Rodriguez type, a syndrome characterized by mandibular hypoplasia, upper and lower extremity phocomelia, and oligodactyly of the upper limbs. More recently, haploinsufficiency of the SF3B4 gene has been identified as the cause of both Nager and Rodriguez syndrome, leading many to believe that Rodriguez syndrome represents a more severe end of a Nager syndrome spectrum. An SF3B4 mutation was found in our patient, prompting a review of the previous known cases of Rodriguez syndrome, which revealed no clustering of SF3B4 mutations, and four cases of Rodriguez syndrome with mutations identical to those in cases of Nager syndrome. Rodriguez syndrome was previously thought of as a lethal acrofacial dysostosis distinct from Nager syndrome. A number of more mild cases, as well as our case, intermediate between the two phenotypes, illustrate that Rodriguez syndrome is a severe manifestation of Nager syndrome, and is not lethal with aggressive medical care.

Introduction: Nager syndrome is a rare condition characterized by craniofacial and upper limb abnormalities. It is commonly mistaken for Treacher Collins syndrome, with which it shares the same craniofacial phenotype. However, patients with Treacher Collins do not exhibit hand anomalies, which are seen in patients with Nager syndrome. This paper reviews the multidisciplinary management of patients with Nager syndrome who were treated at the Australian Craniofacial Unit, Adelaide and the Erasmus Medical Centre, Rotterdam. Methods: The database of both units was scrutinized and the case-notes of the patients with Nager syndrome were reviewed. Data was collected on patient demographics, surgical management, complications, and outcome. Results: Nine patients (6 M:3 F) were identified with Nager syndrome, with a mean age at presentation of 3.7 years (range 8 days to 11.8 years). The mean follow-up time was 2.2 years (2 months to 19 years). SF3B4 mutation was noted in 2 patients and 1 patient had an X:9 translocation. Seven (77.8%) had obstructive sleep apnoea, with 5 patients diagnosed as severe obstructive sleep apnoea. Four patients had pollicization of their index, 2 patients had excision of extra radial digits and 1 patient underwent thumb duplication correction. Craniofacial surgery included mandibular advancement in 5 patients, temporo-mandibular joint reconstruction in 2 patients, and a genioplasty in 1 patient. Conclusion: Nager syndrome is a rare acrofacial dysostosis syndrome that is best managed within the realms of a multidisciplinary team. The authors would advocate early pollicization in patients with thumb anomalies to prevent any impairment in manual dexterity.

Less than one hundred cases of the acrofacial dysostosis, Nager syndrome, have been described. The cardinal features of Nager syndrome are micrognathia, midface retrusion and limb malformations, predominately of the radial ray of upper extremities. Within the past three years haploinsufficiency of SF3B4 has been confirmed as the major cause of Nager syndrome. Different loss-of-function point-mutations in SF3B4 have been found in approximately 2/3 of patients diagnosed with Nager syndrome. Whole gene deletions of SF3B4 have also been suggested to be the cause of Nager syndrome in SF3B4 point mutation negative patients. Only four prenatal cases displaying Nager-like features in the 2nd or 3rd trimester which have been genetically confirmed with SF3B4 point-mutation after birth have been described. We report a case of a 12-week-old fetus with micrognathia, malformed wrists, bilateral club foot and short long bones diagnosed prenatally by chromosomal microarray with a de novo 0.4 Mb deletion at chromosome 1q21.2 involving SF3B4. To our knowledge, this is the first report of Nager syndrome caused by a SF3B4 whole gene deletion. The case presented also shows that high-resolution chromosomal microarray in early pregnancy can confirm Nager syndrome caused by SF3B4-deletion prenatally.

The Richieri-Costa-Pereira syndrome (RCPS) is an autosomal-recessive acrofacial dysostosis caused by mutations in EIF4A3, characterized by mandibular cleft comprising other craniofacial anomalies and limb defects such as cleft palate/Robin Sequence, microstomia, absence of mandibular central incisors, minor ear anomalies, clubfeet and first and 5 ray defects. The findings from this study are useful for better understanding the morphological consequences of disorders of EIF4A3, and having a better picture of the anatomic characteristics of the syndrome for a better therapeutic planning. Twenty-four angular and linear variables were measured to assess anteroposterior and vertical (superior-inferior) position of the cranial base, maxilla, mandible, and facial profile. The cephalometric radiographic analysis was performed on 9 individuals with RCPS, obtained at a mean age of 10.3 years, and compared with randomly selected age-matched 9 controls, without clefts and with well-balanced faces, with mean age of 10.6 years (both groups range 8.1 to 13.7 years). t test was used for analysis of means and Levene test for equality of variances. The syndrome group presented severe mandibular hypoplasia and retrognathism (P = 0.009, P = 0.001), greater facial convexity (N'PnPog and N'SnPog, P

Acrofrontofacionasal Dysostosis type 1 (AFFND1) is an extremely rare, autosomal recessive syndrome, comprising facial and skeletal abnormalities, short stature and intellectual disability. We analyzed an Indian family with two affected siblings by exome sequencing and identified a novel homozygous truncating mutation in the Neuroblastoma-Amplified Sequence (NBAS) gene in the patients' genome. Mutations in the NBAS gene have recently been associated with different phenotypes mainly involving skeletal formation, liver and cognitive development. The NBAS protein has been implicated in two key cellular processes, namely the non-sense mediated decay and the Golgi-to-Endoplasmic Reticulum retrograde traffic. Both functions were impaired in HEK293T cells overexpressing the truncated NBAS protein, as assessed by Real-Time PCR, Western blot analysis, co-immunoprecipitation, and immunofluorescence analysis. We examined the expression of NBAS protein in mouse embryos at various developmental stages by immunohistochemistry, and detected expression in developing chondrogenic and osteogenic structures of the skeleton as well as in the cortex, hippocampus and cerebellum, which is compatible with a role in bone and brain development. Functional genetics in the zebrafish model showed that depletion of endogenous z-nbas in fish embryos results in defective morphogenesis of chondrogenic cranial skeletal elements. Overall, our data point to a conserved function of NBAS in skeletal morphogenesis during development, support the hypothesis of a causative role of the mutated NBAS gene in the pathogenesis of AFFND1 and extend the spectrum of phenotypes associated with defects in this gene.

Five cases of recognizable "Intra-uterine" dwarfism with cranio-facial dysostosis, disproportionately short arms, and other anomalies were written up by endocrinologist, Dr. Alex Russell in 1954. The syndrome he described went on to be named Russell-Silver syndrome. This report gives further information about the life and medical history of the most pictorially documented boy that Dr. Russell originally described in his seminal paper. The gentleman is now 69 years old and we believe him to be the oldest person known to date to have Russell-Silver syndrome. The article includes information relating to his development of type 2 diabetes mellitus, osteopenia, testosterone deficiency, and hypercholesterolemia. Methylation studies have now confirmed the diagnosis of Russell-Silver syndrome by demonstrating partial hypomethylation at the H19 Locus at IGF2P0 on chromosome 11.

Brachydactyly includes shortening of digits due to abnormal development of phalanges, metacarpals, or both. It can occur either as an isolated malformation or with other anomalies as part of many congenital syndromes. It is included as one of the dysostosis groups affecting the limbs in the nosology and classification of genetic skeletal disorders. However, brachydactyly usually shows a high degree of phenotypic variability. In this study, we successfully identified a novel heterozygous mutation of the parathyroid hormone-like hormone (PTHLH) gene by exome sequencing in a Chinese pedigree with brachydactyly and short stature. The PTHLH gene encodes a parathyroid hormone-related protein (PTHrP) that is involved in the regulation of endochondral bone development, and mutations in this gene cause the type E form of brachydactyly. The mutation p.L15R occurs at a hydrophobic core region of the signal peptide, suggesting that this variation probably changes the signal peptide cleavage site at the in silico prediction. Further in vitro functional analysis showed that this mutation can lead to the retention of an N-terminal signal peptide fragment after the nascent proteins are translated.

We report a 4-year-old boy with sclerosteosis associated with severe digital dysostosis. The initial medical consultation was prompted by bilateral, asymmetrical syndactyly of the index and middle fingers. The left index finger had complicated phalangeal anomalies: hyperphalangy (supernumerary phalanx distal to the middle phalanx) and hypoplasia with bracket epiphyses of the proximal and middle phalanges. Development of facial nerve palsy, hearing impairment and generalized osteosclerosis had occurred between 3 years and 4 years of age, with the subsequent identification of a homozygous SOST mutation. Bilateral second and third fingers syndactyly associated with abnormal patterning of the same fingers should be considered prodromal signs of sclerosteosis.

A 17-year-old adolescent boy presented with progressive lower back pain and fatigue.

Marshall–Smith syndrome (MSS) is a rare syndrome characterized by facial dysostosis, respiratory difficulties, mental retardation, and short height [1]. MSS is thought to be associated with NFIX gene mutation [2]. Spine deformity due to a primary abnormality in bone morphogenesis is also reported in the literature [3]. Untreated progressive spinal deformity in a young MSS patient may cause serious health consequences. Therefore, surgical intervention for progressive kyphoscoliosis in a patient with MSS needs to be conducted at an appropriate time. So far, there has been no report regarding surgical correction of spinal deformity in MSS. However, because of dysostosis, spinal canal dysplasia such as cervical canal stenosis may also present in MSS patients [3–5]. Here, we report an MSS patient who underwent surgical correction of severe kyphoscoliosis and came through a neurological complication resulting from cervical canal stenosis.

Ectodermal dysplasia syndrome is a hereditary disease of ectodermal origin. Appearances of nail dystrophy, alopecia or hypotrichosis, saddle nose deformity, and palmoplantar hyperkeratosis are usually associated with a lack of sweat glands as well as partial or complete absence of teeth. These manifestations are usually corrected only with oral rehabilitation by mounting dentures. In this study, plastic rehabilitation was developed to correct the special features of patients with ectodermal dysplasia. Four men and 1 woman with ectodermal dysplasia syndrome were treated. Four patients showed dysostosis of the midface, and rhinoplasty with costal bone was performed, whereas cosmetic operation aiming to repair soft tissue defects was adopted for the last patient. After plastic corrections, all 5 patients were satisfied with the results and had no social embarrassment.

Diaphanospondylodysostosis (DSD) and ischiospinal dysostosis (ISD) are both rare skeletal dysplasias consisting of abnormal axial skeletal development but normal appendicular skeletal development. Both disorders recently have been found to result from mutations in the BMPER gene. We report a patient with one deletion and one mutation of the BMPER gene who has features most consistent with DSD but who has survived to age 9 years. Survival suggests that DSD and ISD reflect a spectrum of severity of one disease process.

Shwachman-Bodian-Diamond syndrome (OMIM 260400) was identified in 1964 by pediatricians Harry Shwachman, a leader in cystic fibrosis, and Louis K. Diamond, a hematologist, along with pediatrician and morbid anatomist Martin Bodian. Initially the syndrome's clinical presentation included exocrine pancreatic insufficiency (lipomatous replacement of the pancreas) and neutropenia. In 1967 skeletal changes of metaphyseal chondrodysplasia were also described, completing the triad of findings; these abnormalities are present in all affected children and should be viewed as an integral feature of the syndrome, also called Shwachman-Diamond syndrome.

We report on the findings of a novel heterozygous de novo SF3B4 mutation in a long-surviving patient with clinical features of Rodriguez syndrome including severe acrofacial dysostosis, phocomelia with pre- and post-axial limb defects, fibular agenesis, rib, and shoulder girdle anomalies. Since SF3B4 mutations have been recently associated with Nager syndrome, this suggests that at least some cases of Rodriguez syndrome are either allelic to or represent unusually severe manifestations of Nager syndrome. Although clinical overlap is obvious, this is somewhat surprising given the presumed autosomal recessive inheritance of Rodriguez syndrome. Investigation of other Rodriguez syndrome patients is needed to clarify the genetic mechanism and possible heterogeneity in patients with clinical features of Rodriguez syndrome.

Background & objectives: Multiple suphphatase deficiency (MSD) is an autosomal recessive disorder affecting the post translational activation of all enzymes of the sulphatase family. To date, approximately 30 different mutations have been identified in the causative gene, sulfatase modifying factor 1 (SUMF1). We describe here the mutation analysis of a case of MSD. Methods: The proband was a four year old boy with developmental delay followed by neuroregression. He had coarse facies, appendicular hypertonia, truncal ataxia and ichthyosis limited to both lower limbs. Radiographs showed dysostosis multiplex. Clinical suspicion of MSD was confirmed by enzyme analysis of four enzymes of the sulphatase group. Results: The patient was compound heterozygote for a c.451A>G (p.K151E) substitution in exon 3 and a single base insertion mutation (c.690_691 InsT) in exon 5 in the SUMF1 gene. The bioinformatic analysis of the missense mutation revealed no apparent effect on the overall structure. However, the mutated 151-amino acid residue was found to be adjacent to the substrate binding and the active site residues, thereby affecting the substrate binding and/or catalytic activity, resulting in almost complete loss of enzyme function. Conclusions: The two mutations identified in the present case were novel. This is perhaps the first report of an insertion mutation in SUMF1 causing premature truncation of the protein.

Crouzon syndrome is a dominantly inherited disorder characterized by craniosynostosis and facial dysostosis, caused by mutations in the fibroblast growth factor receptor 2 (FGFR2) gene; it belongs to a class of disorders that mostly arise as de novo mutations and exhibit a near-exclusive paternal origin of mutation and elevated paternal age (“paternal age effect”). However, even if this is the major mode of origin of mutations in paternal age-effect disorders, germline mosaicism may also occur. Here we describe the first molecularly documented evidence of germline and somatic mosaicism for FGFR2 mutation, identified in the mother of a child with Crouzon syndrome caused by a heterozygous c.1007A>G (p.Asp336Gly) substitution. Levels of maternal somatic mosaicism for this mutation, estimated by pyrosequencing, ranged from 3.3% in hair roots to 14.1% in blood. Our observation underlines the importance of parental molecular testing for accurate genetic counseling of the risk of recurrence for Crouzon, and other paternal age-effect syndromes. © 2010 Wiley-Liss, Inc.

BACKGROUND: Craniosynostosis can be caused by both genetic and environmental factors, the relative contributions of which vary between patients. Genetic testing identifies a pathogenic mutation or chromosomal abnormality in ∼ 21% of cases, but it is likely that further causative mutations remain to be discovered. OBJECTIVE: To identify a shared signature of genetically determined craniosynostosis by comparing the expression patterns in three monogenic syndromes with a control group of patients with non-syndromic sagittal synostosis. METHODS: Fibroblasts from 10 individuals each with Apert syndrome (FGFR2 substitution S252W), Muenke syndrome (FGFR3 substitution P250R), Saethre-Chotzen syndrome (various mutations in TWIST1) and non-syndromic sagittal synostosis (no mutation detected) were cultured. The relative expression of ∼ 47,000 transcripts was quantified on Affymetrix arrays. RESULTS: 435, 45 and 46 transcripts were identified in the Apert, Muenke and Saethre-Chotzen groups, respectively, that differed significantly from the controls. Forty-six of these transcripts were shared between two or more syndromes and, in all but one instance, showed the same direction of altered expression level compared with controls. Pathway analysis showed over-representation of the shared transcripts in core modules involving cell-to-cell communication and signal transduction. Individual samples from the Apert syndrome cases could be reliably distinguished from non-syndromic samples based on the gene expression profile, but this was not possible for samples from patients with Muenke and Saethre-Chotzen syndromes. CONCLUSIONS: Common modules of altered gene expression shared by genetically distinct forms of craniosynostosis were identified. Although the expression profiles cannot currently be used to classify individual patients, this may be overcome by using more sensitive assays and sampling additional tissues.

Craniofacial anomalies account for approximately one-third of all congenital birth defects reflecting the complexity of head and facial development. Craniofacial development is dependent upon a multipotent, migratory population of neural crest cells, which generate most of the bone and cartilage of the head and face. In this review, we discuss advances in our understanding of the pathogenesis of a specific array of craniofacial anomalies, termed facial dysostoses, which can be subdivided into mandibulofacial dysostosis, which present with craniofacial defects only, and acrofacial dysostosis, which encompasses both craniofacial and limb anomalies. In particular, we focus on Treacher Collins syndrome, Acrofacial Dysostosis-Cincinnati Type as well as Nager and Miller syndromes, and animal models that provide new insights into the molecular and cellular basis of these congenital syndromes. We emphasize the etiologic and pathogenetic similarities between these birth defects, specifically their unique deficiencies in global processes including ribosome biogenesis, DNA damage repair, and pre-mRNA splicing, all of which affect neural crest cell development and result in similar tissue-specific defects. WIREs Dev Biol 2017, 6:e263. doi: 10.1002/wdev.263 For further resources related to this article, please visit the WIREs website.

The acrofacial dysostoses (AFD) are a genetically heterogeneous group of inherited disorders with craniofacial and limb abnormalities. Rodriguez syndrome is a severe, usually perinatal lethal AFD, characterized by severe retrognathia, oligodactyly and lower limb abnormalities. Rodriguez syndrome has been proposed to be a severe form of Nager syndrome, a non-lethal AFD that results from mutations in SF3B4, a component of the U2 small nuclear ribonucleoprotein particle (U2 snRNP). Furthermore, a case with a phenotype intermediate between Rodriguez and Nager syndromes has been shown to have an SF3B4 mutation. We identified heterozygosity for SF3B4 mutations in Rodriguez syndrome, confirming that the phenotype is a dominant disorder that is allelic with Nager syndrome. The mutations led to reduced SF3B4 synthesis and defects in mRNA splicing, primarily exon skipping. The mutations also led to reduced expression in growth plate chondrocytes of target genes, including the DLX5, DLX6, SOX9, and SOX6 transcription factor genes, which are known to be important for skeletal development. These data provide mechanistic insight toward understanding how SF3B4 mutations lead to the skeletal abnormalities observed in the acrofacial dysostoses., Author Summary The acrofacial dysostoses (AFD) are inherited disorders with abnormalities of the facial and limb bones. Rodriguez syndrome is a severe type of AFD that is usually lethal in the immediate perinatal period. Rodriguez syndrome has been proposed to be a severe form of Nager syndrome, a non-lethal AFD that results from mutations in SF3B4, a component of mRNA splicing machinery needed for proper maturation of primary transcripts. Furthermore, a case with a phenotype intermediate between Rodriguez and Nager syndromes has been shown to have an SF3B4 mutation. We found that mutations in SF3B4 produce Rodriguez syndrome, further demonstrating that it is allelic with Nager syndrome. The consequences of the mutations include abnormal splicing and reduced expression in growth plate chondrocytes of genes that are important for proper development of the skeleton, providing mechanistic insight toward understanding how SF3B4 mutations lead to the skeletal abnormalities observed in the acrofacial dysostoses.

Mutations in OTX2 are mostly identified in patients with anophthalmia/microphthalmia with variable severity. The OTX2 homeobox gene plays a crucial role in craniofacial morphogenesis during early embryo development. We report for the first time a patient with a mandibular dysostosis caused by a 120 kb deletion including the entire coding sequence of OTX2, identified by array CGH. No ocular malformations were identified after extended ophthalmologic examination. Our data refine the clinical spectrum associated with OTX2 mutations and suggests that OTX2 haploinsufficiency should be considered as a possible cause for isolated mandibular dysostosis. © 2016 Wiley Periodicals, Inc.

Acrofacial dysostosis syndrome of Rodriguez is characterized by severe mandibular underdevelopment, upper limb phocomelia with absent fingers, absent fibulae, cleft palate, microtia, and abnormal pulmonary function. First reported in three siblings it was assumed to be an autosomal recessive condition. However, subsequent publication reported a further five simplex occurrences and a living patient with a heterozygous mutation in the SF3B4 gene. Exome sequencing was performed on four fetuses with this disorder, including one of the originally described affected siblings. We identified two heterozygous frameshift mutations in the SF3B4 gene in three of the four fetuses investigated. The observed mutation was apparently de novo in one fetus for whom parental DNA was available. Thus, Acrofacial dysostosis syndrome of Rodriguez is an autosomal dominant condition and the recurrences identified in the initial report were likely due to gonadal mosaicism. © 2016 Wiley Periodicals, Inc.

Auriculo-condylar syndrome (ACS) is a rare condition affecting first branchial arch structures. The types of hearing loss and temporal bone findings in ACS have not been reported. We describe a 14-year-old male with constricted pinnae, mandibular dysostosis, glossoptosis, a high-arched palate, hearing loss, and cholesteatoma. Computed tomography imaging demonstrated malleoincudal joint ankylosis. The fused malleoincudal complex was removed during mastoidectomy for cholesteatoma. Electron microscopy and histopathology of the joint suggested the fusion was congenital. This is the first report of ossicular fusion and cholesteatoma in ACS and the most detailed in vivo evidence of disruption of embryogenesis during malleoincudal joint formation. Laryngoscope, 2012

Mutations in the RNU4ATAC gene cause microcephalic osteodysplastic primordial dwarfism type I. It encodes U4atac, a small nuclear RNA that is a component of the minor spliceosome. Six distinct mutations in 30 patients diagnosed as microcephalic osteodysplastic primordial dwarfism type I have been described. We report on three additional patients from two unrelated families presenting with a milder phenotype of microcephalic osteodysplastic primordial dwarfism type I and metopic synostosis. Patient 1 had two novel heterozygous mutations in the 3' prime stem-loop, g.66G > C and g.124G > A while Patients 2 and 3 had a homozygous mutation g.55G > A in the 5' prime stem-loop. Although they manifested the known spectrum of clinical features of microcephalic osteodysplastic primordial dwarfism type I, they lacked evidence of severe developmental delay and neurological symptoms. These findings expand the mutational and phenotypic spectrum of this syndrome.

The availability of microarray technology has led to the recent recognition of copy number abnormalities of distal chromosome 22q11.2 that are distinct from the better-characterized deletions and duplications of the proximal region. This report describes five unrelated individuals with copy number abnormalities affecting distal chromosome 22q11.2. We report on novel phenotypic features including diaphragmatic hernia and uterine didelphys associated with the distal microdeletion syndrome; and frontomedial polymicrogyria and callosal agenesis associated with the distal microduplication syndrome. We describe the third distal chromosome 22q11.2 microdeletion patient with Goldenhar syndrome. Patients with distal chromosome 22q11.2 copy number abnormalities exhibit inter- and intra-familial phenotypic variability, and challenge our ability to draw meaningful genotype-phenotype correlations.

Summary Objects The first aim of this study was to determine the incidence of craniosynostosis, metopic synostosis and sagittal synostosis in the Netherlands from 1997 to 2007. The second aim was to study whether a shift in the proportion of different subtypes of craniosynostosis had taken place in the Netherlands during the study period. Methods Patients of all six units performing craniofacial procedures in the Netherlands that met the inclusion criteria participated in the study ( n =927). A logistic regression in a weight sample was used to assess the differences in both the proportion and the incidence of different subtypes of craniosynostosis each year. The angle of the metopic ridge was compared using a regression analysis. Results The incidence of craniosynostosis increased from 2.6 per 10 000 live births in 1997 to 6.4 in 2007. The incidence of metopic synostosis showed a significant increase of 6% each year ( p =0.029). We observed a significant change in the proportion of metopic synostosis, with a mean percentage of 20% during 1997–2000 and 27% during 2001–2007 ( p =0.046). The incidence of sagittal synostosis annually increased by 3% ( p =0.89). We did not find a significant change regarding the proportion of sagittal synostosis during 2000–2001. No significant difference in the severity of metopic synostosis was found between 1997–2000 and 2001–2004. Conclusion The incidence of craniosynostosis, metopic synostosis and sagittal synostosis is 6.4; 1.9; and 2.8 per 10,000 live births, respectively. Both the incidence and the proportion of metopic synostosis have significantly increased over the study period, concluding that metopic synostosis is on the rise.

Diplopodia is a rare congenital disorder that has not been extensively discussed in textbooks, and case reports appear to be the main source of information. Although the exact cause of diplopodia remains unknown, the presence of extra digits as well as metatarsals and tarsals allows it to be differentiated from pedal polydactyly. Syndactyly refers to the congenital fusion of the digits. Concomitant bilateral syndactyly and diplopodia is extremely unusual, and in this report we describe a case of right diplopodia and left polydactyly combined with bilateral manual syndactyly in a 15-year-old girl who was ultimately treated with through-the-knee amputation. Radiological examination of the right leg revealed tibial hypoplasia and the right foot displayed 8 digits with corresponding metatarsals and tarsals, whereas the left leg revealed 2 extra digits on the medial aspect of the foot with corresponding metatarsal and tarsal bones. Anatomical dissection of the right foot revealed that it was divided into halves consisting of 8 toes with corresponding metatarsals and tarsals, as well as tibial hypoplasia and absence of the great toe. Diplopodia associated with tibial hypoplasia and syndactyly can be treated surgically, and the present case report details the clinical, radiological, and anatomical elements of this rare deformity.

Fronto-orbital advancement is a procedure commonly performed in craniofacial centers for coronal and metopic suture synostosis. Several variations of the technique have been reported.To describe our modifications to the anterior cranioplasty procedure and the results of our surgical series.Using our craniofacial database, we retrospectively analyzed the records of all patients undergoing fronto-orbital advancement for craniosynostosis. The same team of neurosurgeons and plastic surgeons performed all procedures. Demographic data, operative time, blood loss, length of stay, and clinical outcome were analyzed.Of 248 patients treated for craniosynostosis, a total of 70 patients underwent fronto-orbital advancement. Nineteen presented with metopic, 26 with unilateral coronal, 17 with bilateral coronal, and 8 with multiple synostosis. Median age at surgery was 6.5 months. Mean operative time was 210 minutes; mean blood loss was 167 mL; and length of stay was 4.5 days. A positive correlation was found between operative time and blood loss (r = 0.1, P.01) and age at surgery and blood loss (r = 0.3, P.0001). There was a minor morbidity rate of 2.9%. A good reconstruction was obtained in all patients using our en bloc fronto-orbital advancement without any midline osteotomies at a mean follow-up of 15 months.A team approach and the application of a standardized surgical technique should make it safer to operate in young children, shorten the surgical time, and lead to a reduction in blood loss. Reconstructing the frontal bone as an entire unit yielded excellent correction for coronal and metopic synostosis.

We reported on 16 new Brazilian patients and review findings in 12 previously reported cases (25 apparently unrelated Brazilian families) from Hospital of Rehabilitation of Craniofacial Anomalies, presenting with Richieri-Costa-Pereira syndrome. All patients display a unique pattern of anomalies consisting of microstomia, micrognathia, abnormal fusion of mandible, cleft palate/Robin sequence, absence of central lower incisors, minor ears anomalies, hypoplastic first ray, abnormal tibiae, hypoplastic halluces, and clubfeet. Learning disability was also a common finding. The sex-ratio showed deviation toward to female (1.8F:1M). Recurrence in sibs was observed in nine instances and consanguinity in 11, supporting the hypothesis of autosomal recessive inheritance. Nineteen of the 25 families lived in São Paulo State, seven of them (10 affected individuals) from an isolated region named "Vale do Ribeira." The geographic barrier of this region associated with the high incidence of the consanguineous matting suggested that this condition is caused by a rare mutation with a founder effect. With the exception of one patient in France, all known cases are of Brazilian origin. The causative gene of this rare syndrome remains unknown.

In 1938, Saul Jarcho and Paul Levin from Johns Hopkins Hospital reported cases of thoracic insufficiency due to vertebral and rib anomalies. Nearly 30 years later, in 1966, Norman Lavy and associates from Indiana University reported a similar syndrome in a family from Puerto Rico. Lavy's description was followed by a report by John E. Moseley from New York City, where the name spondylothoracic dysplasia (dysostosis) was first used. For more than half a century, there has been confusion regarding the distinction between these two phenotypically similar syndromes that cause thoracic insufficiency. Spondylocostal dysostosis (SCD), or Jarcho-Levin syndrome, causes mild to moderate respiratory insufficiency, is panethnic and has been linked to genes such as DLL3, which is known to be associated with the Notch pathway. In contrast, spondylothoracic dysostosis (STD), or Lavy-Moseley syndrome, results in more severe respiratory compromise, is largely linked to Puerto Rican cohorts and is thought to be associated to the MESP2 gene, also a Notch pathway gene. Long-term studies of Puerto Rican cohorts with STD contradicts the previously held belief that individuals affected with STD have markedly diminished life expectancy with as many as 25% surviving into later childhood and adult life.

Syndromic craniosynostosis is known to be associated with various obstructive respiratory disorders including sleep apnoea. We performed early midfacial distraction using a transfacial pinning technique in five syndromic craniosynostotic patients with obstructive respiratory disorders. Here, we report good results, indications and usefulness of this procedure. The subjects were five young children aged 7 months to 2 years who had respiratory disorders since birth due to midface hypoplasia. All subjects underwent midfacial distraction to avoid tracheotomy. The method involved Le Fort III osteotomy followed by the use of our original transfacial pinning system. This system consisted of devices connecting (1) transfacial pins penetrating the bilateral zygomatic bones and (2) Kirschner wires, which were passed through plates fixed on the bilateral temporal bones. The maxilla was distracted anteriorly at least 20 mm. Distraction was evaluated by comparing the pre- and postoperative polysomnography (PSG) and cephalograms. All patients had markedly improved respiratory conditions after distraction, and a tracheotomy was avoided. Postoperative PSG and cephalograms also showed great improvements compared with preoperative findings. A transfacial pinning system was considered useful and can be the most suitable method for early midfacial distraction in syndromic craniosynostosis with obstructive respiratory disorders.

Craniosynostosis, the premature fusion of one or more cranial sutures, is a common malformation of the skull that can result in facial deformity and increased intracranial pressure. Syndromic craniosynostosis is present in ∼15% of craniosynostosis patients and often is clinically diagnosed by neurocranial phenotype as well as various other skeletal abnormalities. The most common genetic mutations identified in syndromic craniosynostosis involve the fibroblast growth factor receptor (FGFR) family with other mutations occurring in genes for transcription factors TWIST, MSX2, and GLI3, and other proteins EFNB1, RAB23, RECQL4, and POR, presumed to be involved either upstream or downstream of the FGFR signaling pathway. Both syndromic and nonsyndromic craniosynostosis patients require early diagnosis and intervention. The premature suture fusion can impose pressure on the growing brain and cause continued abnormal postnatal craniofacial development. Currently, treatment options for craniosynostosis are almost exclusively surgical. Serious complications can occur in infants requiring either open or endoscopic repair and therefore the development of nonsurgical techniques is highly desirable although arguably difficult to design and implement. Genetic studies of aberrant signaling caused by mutations underlying craniosynostosis in in vitro calvarial culture and in vivo animal model systems have provided promising targets in designing genetic and pharmacologic strategies for systemic or adjuvant nonsurgical treatment. Here we will review the current literature and provide insights to future possibilities and limitations of therapeutic applications. © 2010 Wiley-Liss, Inc.

Poland syndrome is a sporadic, congenital unilateral absence of the sternocostal head of the pectoralis major muscle that can occur with other ipsilateral chest wall and limb derangements. The chest wall deficiency is primarily cosmetic, its incidence is unknown, male patients may be affected more than female patients, the right side is affected more than the left, and associated comorbidities may exist. Chest wall repair depends on anatomical type and gender.Sixty-three patients with Poland syndrome were divided into two treatment groups by chest wall anatomy and gender. Surgical repair was based on this division. Seventy-six operations were performed by the senior author (A.E.S.) during a 30-year period, and long-term outcomes are presented. Corrective methods included use of custom-made chest wall prostheses, mammary prostheses, latissimus dorsi muscle transfers, transverse rectus abdominis musculocutaneous flaps, sternal/rib reconstruction, or a combination of methods. Follow-up ranged from 1 to 21 years.Two anatomical forms of the disorder are described, each with unique surgical requirements. The simple deformity was effectively repaired with a latissimus dorsi muscle transfer plus, in female patients, a sublatissimus mammary prosthesis. Repair of the complex deformity, in addition to the latissimus transfer, selectively included musculoskeletal chest wall realignment. Custom-made chest wall prostheses carried a higher risk of complications.Poland syndrome of the chest wall exists in two forms: the more common simple variety and a complex form (as originally described by Poland). Repair of the chest wall can be effectively tailored to these anatomical types, gender, and patient preference.

Objective To describe the clinical, speech, hearing, and imaging findings in three members of a Brazilian family with Saethre-Chotzen syndrome (SCS) who presented some unusual characteristics within the spectrum of the syndrome. Design Clinical evaluation was performed by a multidisciplinary team. Direct sequencing of the polymerase chain reaction–amplified coding region of the TWIST1 gene, routine and electrophysiological hearing evaluation, speech evaluation, and imaging studies through computed tomography (CT) scan and magnetic resonance imaging (MRI) were performed. Results TWIST1 gene analysis revealed a Pro136His mutation in all patients. Hearing evaluation showed peripherial and mixed hearing loss in two of the patients, one of them with severe unilateral microtia. Computed tomography scan showed structural middle ear anomalies, and MRI showed distortion of the skull contour as well as some of the brain structures. Conclusions We report a previously undescribed TWIST1 gene mutation in patients with SCS. There is evidence that indicates hearing loss (conductive and mixed) can be related both with middle ear (microtia, high jugular bulb, and enlarged vestibules) as well as with brain stem anomalies. Here we discuss the relationship between the gene mutation and the clinical, imaging, speech, and hearing findings.

Background: Patients with Apert, Crouzon, and Pfeiffer syndromes who have severe midfacial hypoplasia are treated by Le Fort III midface advancement. The purpose of this study was to examine long-term (10-year) midface skeletal stability and growth following Le Fort III midface advancement in growing children. Methods: A review of 192 patients with syndromic craniosynostosis treated by classic (nondistracted) Le Fort III advancement osteotomy between 1973 and 1998 was performed. Twenty-five patients met the inclusion criteria (age at surgery < 11 years and availability of cephalograms of diagnostic quality before treatment, after surgery, and at 1-, 5-, and 10-year follow-up). The mean age at the time of surgery was 5.8 years and the diagnosis was either Crouzon (n = 10), Apert (n = 9), or Pfeiffer (n = 6) syndrome. Results: After surgery, point A advanced sagittally 10.72 mm and moved downward 3.77 mm. At 1 year, point A moved forward 0.10 mm and downward 0.47 mm. At 5 years, point A moved back 0.18 mm, whereas at 10 years it advanced 0.12 mm. During the same periods, however, pogonion came forward 5.72 mm and 7.32 mm, respectively. Conclusions: Le Fort III midface advancement in growing children with syndromic craniosynostosis is stable after the first year postoperatively. There is minimal horizontal growth of the midface between postoperative years 5 and 10, although the mandible continues to grow. Due to the differential growth rate of the midface and mandible, the facial profile becomes concave, thereby necessitating secondary midface surgery at the completion of skeletal growth.

To try and identify potential parental risk factors for isolated non-syndromic metopic craniosynostosis, we did a telephone survey of parents of children who attended the craniofacial centre at Birmingham Children's Hospital (BCH), UK, from 1995 to 2004. We calculated the prevalence of a number of potential risk factors and compared them with those of the general population. A total of 103 children with syndromic or non-syndromic isolated metopic craniosynostosis were seen, of which 81 (79%) had non-syndromic, isolated metopic craniosynostosis (M:F ratio 3:1). The response rate to the telephone survey was 72%. The prevalences of maternal epilepsy and the use of valproate, antenatal maternal complications (hypertension or pre-eclampsia, haemorrhage, and urinary tract infection), and fertility treatment in our sample were significantly higher than among the general population ( p = 0.01 or less in all cases). The likely roles of maternal epilepsy and taking valproate in the aetiology of isolated non-syndromic metopic craniosynostosis are further consolidated by our study. The finding that antenatal complications are possible risk factors for craniosynostosis has not to our knowledge been published previously.

Brachyphalangy, polydactyly and tibial aplasia/hypoplasia syndrome (OMIM 609945) is a rare congenital disorder. Only seven patients have been reported to date, and the etiology of this syndrome is unknown. Autosomal dominant inheritance with variable expression has been suggested based on the presence of minor features in some parents and the fact that neither parental consanguinity nor pairs of affected siblings were observed. We report on the first patient with this syndrome who was born to consanguineous parents. Neither the mother nor the father, who were first cousins, had clinical features suggestive of a manifestation of brachyphalangy, polydactyly and tibial aplasia/hypoplasia syndrome. The patient had no siblings, and the family history was unremarkable. Clinical problems included brachydactyly of hands and feet, splaying of fingers and toes, preaxial polydactyly of feet, bilateral tibial aplasia, shortened radius and ulna, and characteristic facial dysmorphic signs. The detailed description of this patient adds to our knowledge of the clinical manifestations of brachyphalangy, polydactyly and tibial aplasia/hypoplasia syndrome and will eventually also contribute to the elucidation of the underlying gene defects.