Complete loss of vision caused by a giant mucocele of the frontal sinus.

The authors report the case of a 75-year-old man presenting with an exceptionally large giant posttraumatic mucocele of the frontal sinus years after a gunshot blast to the head. The lesion had grown so extensively that the right eye had shrunk and calcified, resulting in total monocular blindness, a complication that has been reported only once. To the best of our knowledge, it is the first time that a giant mucocele of such a large size is reported. We describe how the patient underwent surgical removal of this massive lesion, cranial base reconstruction, and a cosmetic oculoplastic procedure. The etiology, clinical presentation, and possible complications are reviewed, as well as the importance of a regular clinical follow-up and early surgical cure. Although the diagnosis and management of mucoceles are nowadays considered quite standard, the exceptional size of the lesion illustrated here emphasizes the destructive potential of such seemingly indolent lesions. Despite the benign histology of mucoceles, one should never underestimate their morbid potential or be lulled in delaying surgical cure. Large mucoceles should be removed as quickly as possible to prevent such unacceptable complications as permanent visual loss.

Proximal 11p deletion syndrome (P11pDS): additional evaluation of the clinical and molecular aspects.

The combination of multiple exostoses (EXT) and enlarged parietal foramina (foramina parietalia permagna, FPP) represent the main features of the proximal 11p deletion syndrome (P11pDS), a contiguous gene syndrome (MIM 601224) caused by an interstitial deletion on the short arm of chromosome 11. Here we present clinical aspects of two new P11pDS patients and the clinical follow-up of one patient reported in the original paper describing this syndrome. Recognised clinical signs include EXT, FPP, mental retardation, facial asymmetry, asymmetric calcification of coronary sutures, defective vision (severe myopia, nystagmus, strabismus), skeletal anomalies (small hands and feet, tapering fingers), heart defect, and anal stenosis. In addition fluorescence in situ hybridisation and molecular analysis were performed to gain further insight in potential candidate genes involved in P11pDS.

Loss of the BMP Antagonist, SMOC-1, Causes Ophthalmo-Acromelic (Waardenburg Anophthalmia) Syndrome in Humans and Mice.

Ophthalmo-acromelic syndrome (OAS), also known as Waardenburg Anophthalmia syndrome, is defined by the combination of eye malformations, most commonly bilateral anophthalmia, with post-axial oligosyndactyly. Homozygosity mapping and subsequent targeted mutation analysis of a locus on 14q24.2 identified homozygous mutations in SMOC1 (SPARC-related modular calcium binding 1) in eight unrelated families. Four of these mutations are nonsense, two frame-shift, and two missense. The missense mutations are both in the second Thyroglobulin Type-1 (Tg1) domain of the protein. The orthologous gene in the mouse, Smoc1, shows site- and stage-specific expression during eye, limb, craniofacial, and somite development. We also report a targeted pre-conditional gene-trap mutation of Smoc1 (Smoc1(tm1a)) that reduces mRNA to ∼10% of wild-type levels. This gene-trap results in highly penetrant hindlimb post-axial oligosyndactyly in homozygous mutant animals (Smoc1(tm1a/tm1a)). Eye malformations, most commonly coloboma, and cleft palate occur in a significant proportion of Smoc1(tm1a/tm1a) embryos and pups. Thus partial loss of Smoc-1 results in a convincing phenocopy of the human disease. SMOC-1 is one of the two mammalian paralogs of Drosophila Pentagone, an inhibitor of decapentaplegic. The orthologous gene in Xenopus laevis, Smoc-1, also functions as a Bone Morphogenic Protein (BMP) antagonist in early embryogenesis. Loss of BMP antagonism during mammalian development provides a plausible explanation for both the limb and eye phenotype in humans and mice.

Maxillary advancement and transpalatal expansion using internal distraction in a patient with cleft lip and palate.

Correction of sagittal and transverse maxillary discrepancies in patients with cleft lip or palate remains a challenge for craniofacial surgeons. Distraction osteogenesis has revolutionized the conceptualization and approach to the craniofacial malformations and has become a reliable and irreplaceable part of the surgical armamentarium. We are reporting a case of sequential maxillary advancement and transpalatal expansion using internal distraction in a patient with unilateral cleft lip and palate presenting with severe maxillary sagittal and transverse deficiencies.

Isolated bilateral zygomatic arch fracture: an unusual pattern.

Isolated fractures of the zygomatic arch represent 5% to 14% of all zygomatic complex fractures. Bilateral isolated zygomatic arch fractures, which are defined as fractures of both zygomatic arches without any other facial fracture, are extremely rare. In this case report, we present a rare case of this facial fracture pattern.

Phenotypic and molecular assessment of seven patients with 6p25 deletion syndrome: relevance to ocular dysgenesis and hearing impairment.

BACKGROUND: Thirty-nine patients have been described with deletions involving chromosome 6p25. However, relatively few of these deletions have had molecular characterization. Common phenotypes of 6p25 deletion syndrome patients include hydrocephalus, hearing loss, and ocular, craniofacial, skeletal, cardiac, and renal malformations. Molecular characterization of deletions can identify genes that are responsible for these phenotypes. METHODS: We report the clinical phenotype of seven patients with terminal deletions of chromosome 6p25 and compare them to previously reported patients. Molecular characterization of the deletions was performed using polymorphic marker analysis to determine the extents of the deletions in these seven 6p25 deletion syndrome patients. RESULTS: Our results, and previous data, show that ocular dysgenesis and hearing impairment are the two most highly penetrant phenotypes of the 6p25 deletion syndrome. While deletion of the forkhead box C1 gene (FOXC1) probably underlies the ocular dysgenesis, no gene in this region is known to be involved in hearing impairment. CONCLUSIONS: Ocular dysgenesis and hearing impairment are the two most common phenotypes of 6p25 deletion syndrome. We conclude that a locus for dominant hearing loss is present at 6p25 and that this locus is restricted to a region distal to D6S1617. Molecular characterization of more 6p25 deletion patients will aid in refinement of this locus and the identification of a gene involved in dominant hearing loss.

Severe neurologic manifestations from cervical spine instability in spondylo-megaepiphyseal-metaphyseal dysplasia.

Spondylo-megaepiphyseal-metaphyseal dysplasia (SMMD; OMIM 613330) is a dysostosis/dysplasia caused by recessive mutations in the homeobox-containing gene, NKX3-2 (formerly known as BAPX1). Because of the rarity of the condition, its diagnostic features and natural course are not well known. We describe clinical and radiographic findings in six patients (five of which with homozygous mutations in the NKX3-2 gene) and highlight the unusual and severe changes in the cervical spine and the neurologic complications. In individuals with SMMD, the trunk and the neck are short, while the limbs, fingers and toes are disproportionately long. Radiographs show a severe ossification delay of the vertebral bodies with sagittal and coronal clefts, missing ossification of the pubic bones, large round "balloon-like" epiphyses of the long bones, and presence of multiple pseudoepiphyses at all metacarpals and phalanges. Reduced or absent ossification of the cervical vertebrae leads to cervical instability with anterior or posterior kinking of the cervical spine (swan neck-like deformity, kyknodysostosis). As a result of the cervical spine instability or deformation, five of six patients in our series suffered cervical cord injury that manifested clinically as limb spasticity. Although the number of individuals observed is small, the high incidence of cervical spine deformation in SMMD is unique among skeletal dysplasias. Early diagnosis of SMMD by recognition of the radiographic pattern might prevent of the neurologic complications via prophylactic cervical spine stabilization. © 2012 Wiley Periodicals, Inc.

Eight years experience from a skeletal dysplasia referral center in a tertiary hospital in Southern India: A model for the diagnosis and treatment of rare diseases in a developing country.

We report on a series of 514 consecutive diagnoses of skeletal dysplasia made over an 8-year period at a tertiary hospital in Kerala, India. The most common diagnostic groups were dysostosis multiplex group (n = 73) followed by FGFR3 (n = 49) and osteogenesis imperfecta and decreased bone density group (n = 41). Molecular confirmation was obtained in 109 cases. Clinical and radiographic evaluation was obtained in close diagnostic collaboration with expert groups abroad through Internet communication for difficult cases. This has allowed for targeted biochemical and molecular studies leading to the correct identification of rare or novel conditions, which has not only helped affected families by allowing for improved genetic counseling and prenatal diagnosis but also resulted in several scientific contributions. We conclude that (1) the spectrum of genetic bone disease in Kerala, India, is similar to that of other parts of the world, but recessive entities may be more frequent because of widespread consanguinity; (2) prenatal detection of skeletal dysplasias remains relatively rare because of limited access to expert prenatal ultrasound facilities; (3) because of the low accessibility to molecular tests, precise clinical-radiographic phenotyping remains the mainstay of diagnosis and counseling and of gatekeeping to efficient laboratory testing; (4) good phenotyping allows, a significant contribution to the recognition and characterization of novel entities. We suggest that the tight collaboration between a local reference center with dedicated personnel and expert diagnostic networks may be a proficient model to bring current diagnostics to developing countries. © 2014 Wiley Periodicals, Inc.

Accuracy and predictability in use of AO three-dimensionally preformed titanium mesh plates for posttraumatic orbital reconstruction: a pilot study.

The aim of this study was to prospectively evaluate the accuracy and predictability of new three-dimensionally preformed AO titanium mesh plates for posttraumatic orbital wall reconstruction.We analyzed the preoperative and postoperative clinical and radiologic data of 10 patients with isolated blow-out orbital fractures. Fracture locations were as follows: floor (N = 7; 70%), medial wall (N = 1; 1%), and floor/medial wall (N = 2; 2%). The floor fractures were exposed by a standard transconjunctival approach, whereas a combined transcaruncular transconjunctival approach was used in patients with medial wall fractures. A three-dimensional preformed AO titanium mesh plate (0.4 mm in thickness) was selected according to the size of the defect previously measured on the preoperative computed tomographic (CT) scan examination and fixed at the inferior orbital rim with 1 or 2 screws. The accuracy of plate positioning of the reconstructed orbit was assessed on the postoperative CT scan. Coronal CT scan slices were used to measure bony orbital volume using OsiriX Medical Image software. Reconstructed versus uninjured orbital volume were statistically correlated.Nine patients (90%) had a successful treatment outcome without complications. One patient (10%) developed a mechanical limitation of upward gaze with a resulting handicapping diplopia requiring hardware removal. Postoperative orbital CT scan showed an anatomic three-dimensional placement of the orbital mesh plates in all of the patients. Volume data of the reconstructed orbit fitted that of the contralateral uninjured orbit with accuracy to within 2.5 cm(3). There was no significant difference in volume between the reconstructed and uninjured orbits.This preliminary study has demonstrated that three-dimensionally preformed AO titanium mesh plates for posttraumatic orbital wall reconstruction results in (1) a high rate of success with an acceptable rate of major clinical complications (10%) and (2) an anatomic restoration of the bony orbital contour and volume that closely approximates that of the contralateral uninjured orbit.

Subtelomeric deletion of chromosome 10p15.3: clinical findings and molecular cytogenetic characterization.

We describe 19 unrelated individuals with submicroscopic deletions involving 10p15.3 characterized by chromosomal microarray (CMA). Interestingly, to our knowledge, only two individuals with isolated, submicroscopic 10p15.3 deletion have been reported to date; however, only limited clinical information is available for these probands and the deleted region has not been molecularly mapped. Comprehensive clinical history was obtained for 12 of the 19 individuals described in this study. Common features among these 12 individuals include: cognitive/behavioral/developmental differences (11/11), speech delay/language disorder (10/10), motor delay (10/10), craniofacial dysmorphism (9/12), hypotonia (7/11), brain anomalies (4/6) and seizures (3/7). Parental studies were performed for nine of the 19 individuals; the 10p15.3 deletion was de novo in seven of the probands, not maternally inherited in one proband and inherited from an apparently affected mother in one proband. Molecular mapping of the 19 individuals reported in this study has identified two genes, ZMYND11 (OMIM 608668) and DIP2C (OMIM 611380; UCSC Genome Browser), mapping within 10p15.3 which are most commonly deleted. Although no single gene has been identified which is deleted in all 19 individuals studied, the deleted region in all but one individual includes ZMYND11 and the deleted region in all but one other individual includes DIP2C. There is not a clearly identifiable phenotypic difference between these two individuals and the size of the deleted region does not generally predict clinical features. Little is currently known about these genes complicating a direct genotype/phenotype correlation at this time. These data however, suggest that ZMYND11 and/or DIP2C haploinsufficiency contributes to the clinical features associated with 10p15 deletions in probands described in this study.

SCRIB and PUF60 Are Primary Drivers of the Multisystemic Phenotypes of the 8q24.3 Copy-Number Variant.

Copy-number variants (CNVs) represent a significant interpretative challenge, given that each CNV typically affects the dosage of multiple genes. Here we report on five individuals with coloboma, microcephaly, developmental delay, short stature, and craniofacial, cardiac, and renal defects who harbor overlapping microdeletions on 8q24.3. Fine mapping localized a commonly deleted 78 kb region that contains three genes: SCRIB, NRBP2, and PUF60. In vivo dissection of the CNV showed discrete contributions of the planar cell polarity effector SCRIB and the splicing factor PUF60 to the syndromic phenotype, and the combinatorial suppression of both genes exacerbated some, but not all, phenotypic components. Consistent with these findings, we identified an individual with microcephaly, short stature, intellectual disability, and heart defects with a de novo c.505C>T variant leading to a p.His169Tyr change in PUF60. Functional testing of this allele in vivo and in vitro showed that the mutation perturbs the relative dosage of two PUF60 isoforms and, subsequently, the splicing efficiency of downstream PUF60 targets. These data inform the functions of two genes not associated previously with human genetic disease and demonstrate how CNVs can exhibit complex genetic architecture, with the phenotype being the amalgam of both discrete dosage dysfunction of single transcripts and also of binary genetic interactions.

Epidemiology of cleft palate in Europe: implications for genetic research.

OBJECTIVE: To describe the epidemiology of cleft palate (CP) in Europe. DESIGN AND SETTING: A descriptive epidemiological study on 3852 cases of CP, identified (1980 through 1996) from more than 6 million births from the EUROCAT network of 30 registers in 16 European countries. RESULTS: Significant differences in prevalence in Europe between registries and within countries were observed. A total of 2112 (54.8%) CP cases occurred as isolated, 694 (18.0%) were associated with other defects such as multiple congenital anomalies, and 1046 (27.2%) were in recognized conditions. The study confirmed the tendency toward female prevalence (sex ratio [SR] = 0.83), particularly among isolated cases (SR = 0.78) even if SR inversion is reported in some registries. A specific association with neural tube defects (NTDs) in some registers is reported. CONCLUSION: The differences identified in Europe (prevalence, sex, associated anomalies) can be only partially explained by methodological reasons because a common methodology was shared among all registries for case ascertainment and collection, and CP is an easy detectable condition with few induced abortions. The complex model of inheritance and the frequently conflicting results in different populations on the role of genes that constitute risk factors suggest the presence of real biological differences. The association of CP/NTD in an area with a high prevalence of NTDs can identify a group of conditions that can be considered etiologically homogeneous. The epidemiological evaluation can guide genetic research to specify the role of etiological factors in each different population

Subtelomeric 6p deletion: clinical and array-CGH characterization in two patients

We report on two patients with de novo subtelomeric terminal deletion of chromosome 6p. Patient 1 is an 8-month-old female born with normal growth parameters, typical facial features of 6pter deletion, bilateral corectopia, and protruding tongue. She has severe developmental delay, profound bilateral neurosensory deafness, poor visual contact, and hypsarrhythmia since the age of 6 months. Patient 2 is a 5-year-old male born with normal growth parameters and unilateral hip dysplasia; he has a characteristic facial phenotype, bilateral embryotoxon, and moderate mental retardation. Further characterization of the deletion, using high-resolution array comparative genomic hybridization (array-CGH; Agilent Human Genome kit 244 K), revealed that Patient 1 has a 8.1 Mb 6pter-6p24.3 deletion associated with a contiguous 5.8 Mb 6p24.3-6p24.1 duplication and Patient 2 a 5.7 Mb 6pter-6p25.1 deletion partially overlapping with that of Patient 1. Complementary FISH and array analysis showed that the inv del dup(6) in Patient 1 originated de novo. Our results demonstrate that simple rearrangements are often more complex than defined by standard techniques. We also discuss genotype-phenotype correlations including previously reported cases of deletion 6p.

Distraction osteogenesis in the management of severe maxillary hypoplasia in cleft lip and palate patients.

The aim of this study was to systematically review literature reporting on the use of external distraction osteogenesis (DO) and internal DO in the treatment of severe maxillary hypoplasia in cleft and palate patients. Literature research has been performed using the PubMed database of the National Library of Medicine and National Institutes of Health from 1966 to August 2007. We used cleft lip and palate and distraction osteogenesis as key words. Of the 104 articles found, we only considered the Anglo-Saxon literature, which reported on the correction of the maxillary hypoplasia with DO techniques. A total of 32 studies reported on anteroposterior external DO (27 studies on rigid external device and 5 on face mask), 17 studies reported on anteroposterior internal DO, and 3 studies reported on transverse internal DO have been retained for this review. Despite the heterogeneity and methodological limitations of most of the studies, results showed that external DO with rigid external device and internal DO resulted to be a more reliable and accurate technique than the face mask in the management of severe maxillary hypoplasia in patients with cleft lip and palate. The current review demonstrated that external and internal DO in the treatment of severe maxillary hypoplasia in cleft and palate patients (1) is a reproducible and valuable alternative to standard orthognathic surgery procedures, (2) allows for a global improvement in facial aesthetic, (3) allows a maxillary correction in patients during the period of mixed dentition, and (4) allows either for an unchanged or better velopharyngeal function.

Osteogenic sarcoma of the maxillary region in a Mexican mestizo population.

Background and Objectives: This study analyzed maxillary osteosarcoma in a mestizo population, with particular emphasis on the type of treatment and disease-free and overall survival. Methods: This is a retrospective study including all mestizo patients with osteosarcoma of the maxilla seen in a single cancer institution in Mexico during a 20-year period. Results: There were 21 patients. Age ranged from 16 to 76 years (mean, 37.5 y). Mean evolution time to diagnosis was 13 months, with a mean tumor size of 7 x 6 cm(2). Surgery was the initial treatment in 19 patients, 17 of whom received adjuvant treatment. Disease-free survival according to surgical margin and overall survival were not statistically significant. Disease-free survival was 29% at 5 years, and overall survival was 50% and 25% at 5 and 10 years, respectively. Conclusions: Osteosarcomas of the maxilla are infrequent lesions that merit early diagnosis and proper treatment because of their rapid evolution. Treatment is currently based on a well-planned surgery with free surgical margins plus adjuvant radiotherapy and/or chemotherapy.