Ali Al Kaissi

Mutations in lectin complement pathway genes COLEC11 and MASP1 cause 3MC syndrome

3MC syndrome has been proposed as a unifying term encompassing the overlapping Carnevale, Mingarelli, Malpuech and Michels syndromes. These rare autosomal recessive disorders exhibit a spectrum of developmental features, including characteristic facial dysmorphism, cleft lip and/or palate, craniosynostosis, learning disability and genital, limb and vesicorenal anomalies. Here we studied 11 families with 3MC syndrome and identified two mutated genes, COLEC11 and MASP1, both of which encode proteins in the lectin complement pathway (collectin kidney 1 (CL-K1) and MASP-1 and MASP-3, respectively). CL-K1 is highly expressed in embryonic murine craniofacial cartilage, heart, bronchi, kidney and vertebral bodies. Zebrafish morphants for either gene develop pigmentary defects and severe craniofacial abnormalities. Finally, we show that CL-K1 serves as a guidance cue for neural crest cell migration. Together, these findings demonstrate a role for complement pathway factors in fundamental developmental processes and in the etiology of 3MC syndrome.

The diagnosis and management of patients with idiopathic osteolysis

Idiopathic osteolysis or disappearing bone disease is a condition characterized by the spontaneous onset of rapid destruction and resorption of a single bone or multiple bones. Disappearing bone disorder is a disease of several diagnostic types. We are presenting three patients with osteolysis who have different underlying pathological features. Detailed phenotypic assessment, radiologic and CT scanning, and histological and genetic testing were the baseline diagnostic tools utilized for diagnosis of each osteolysis syndrome. The first patient was found to have Gorham-Stout syndrome (non-heritable). The complete destruction of pelvic bones associated with aggressive upward extension to adjacent bones (vertebral column and skull base) was notable and skeletal angiomatosis was detected. The second patient showed severe and aggressive non-hereditary multicentric osteolysis with bilateral destruction of the hip bones and the tarsal bones as well as a congenital unilateral solitary kidney and nephropathy. The third patient was phenotypically and genotypically compatible with Winchester syndrome resulting in multicentric osteolysis (autosomal recessive). Proven mutation of the (MMP2-Gen) was detected in this third patient that was associated with 3MCC deficiency (3-Methylcrontonyl CoA Carboxylase deficiency). The correct diagnoses in our 3 patients required the exclusion of malignant osteoclastic tumours, inflammatory disorders of bone, vascular disease, and neurogenic arthropathies using history, physical exam, and appropriate testing and imaging. This review demonstrates how to evaluate and treat these complex and difficult patients. Lastly, we described the various management procedures and treatments utilized for these patients.

Craniocervical junction malformation in a child with Oromandibular-limb hypogenesis-Möbius syndrome

We report a male child with Oromandibular-limb hypogenesis (OMLH), the main features being bilateral sixth and seventh nerve palsies, limb anomalies and hypoplasia of the tongue. Additional features were shortness of the neck associated with torticollis. Radiographs of the cervical spine were non-contributory, but 3D computed tomography (CT) scanning of this area identified: a) congenital hypoplasia of the atlas; b) the simultaneous development of occiput-atlas malformation/developmental defect. To our knowledge, this is the first clinical report assessing the cervico-cranium malformation in a child with OMLH-Möbius syndrome.

Asymmetrical skull, ptosis, hypertelorism, high nasal bridge, clefting, umbilical anomalies, and skeletal anomalies in sibs: is Carnevale syndrome a separate entity?

A group of syndromes, consisting of Malpuech syndrome, Michels syndrome, Carnevale syndrome, OSA syndrome, and Mingarelli syndrome share the combination of symptoms of highly arched eyebrows, ptosis, and hypertelorism, and vary in other symptoms such as asymmetry of the skull, eyelid, and anterior chamber anomalies, clefting of lip and palate, umbilical anomalies, and growth and cognitive development. It has been suggested that they are in fact part of the same entity. Here, we describe a brother and sister with the same constellation of symptoms, and compare these with the various entities. We conclude that the present patients resemble most patients with Carnevale and Mingarelli syndrome, and the case reported by Guion‐Almeida, and that these patients form together most probably the same entity. We suggest the name Carnevale syndrome as this author described this combination of symptoms for the first time. Malpuech and Michels syndromes are probably separate entities, although they may still be allelic. Pattern of inheritance of Carnevale syndrome is most likely autosomal recessive.

Caudal regression syndrome and popliteal webbing in connection with maternal diabetes mellitus: a case report and literature review

IntroductionMost cases of caudal regression are sporadic or associated with gestational/maternal diabetes. The condition is thought to be part of a spectrum including imperforate anus, sacral agenesis and sirenomelia. Infants of diabetic mothers have two to three times the average incidence of congenital anomalies.Case PresentationWe report on a 7-year-old boy from non-consanguineous family in Austria was born with features of caudal regression syndrome. A constellation of malformation complex such as caudal regression syndrome and anorectal malformation complex were evident at birth. Of great interest was the abnormal articulation between the pelvis and the remaining abnormal spine. Spinal-pelvic instability, dislocation of the hip, and knee-flexion contracture associated with popliteal webbing were the major orthopaedic abnormalities.ConclusionWe showed that an offspring of a diabetic mother was at significant risk of developing caudal regression syndrome. Our present patient demonstrated type1 of Welch and Aterman classification. There was total sacral agenesis associated with subtotal lumbar agenesis. The lowest vertebrae were resting above an iliac amphiathrosis. We strongly encourage primary care providers to discuss the consequences of maternal diabetes mellitus as part of routine anticipatory guidance for antenatal/prenatal management. Careful diabetic control in the preconceptional period and the first eight weeks of pregnancy may lower the chances of congenital anomalies.

Musculo-Skeletal Abnormalities in Patients with Marfan Syndrome

Background A leptosomic body type is tall and thin with long hands. Marfanoid features may be familial in nature or pathological, as occurs in congenital contractual arachnodactyly (Beals syndrome) and Shprintzen-Goldberg syndrome mimicking some of the changes of Marfan syndrome, although not accompanied by luxation of lens and dissecting aneurysm of aorta. Methods In this article we collected eight patients who were consistent with the diagnosis of Marfan syndrome via phenotypic and genotypic characterization. Results Our patients manifested a constellation of variable presentations of musculo-skeletal abnormalities ranging from developmental dysplasia of the hip, protrusio acetabuli, leg length inequality, patellar instability, scoliosis, to early onset osteoarthritis. Each abnormality has been treated accordingly. Conclusion This is the first paper which includes the diagnosis and the management of the associated musculo-skeletal abnormalities in patients with Marfan syndrome, stressing that patients with Marfan syndrome are exhibiting great variability in the natural history and the severity of musculo-skeletal abnormalities.

Osteochondritis dissecans and Osgood Schlatter disease in a family with Stickler syndrome

PurposeStickler syndrome is among the most common autosomal dominant connective tissue disorders but is often unrecognised and therefore not diagnosed by clinicians. Despite much speculation, the cause of osteochondrosis in general and osteochondritis dissecans (OCD) and Osgood Schlatter syndrome (OSS) in particular remain unclear. Etiological understanding is essential. We describe a pair of family subjects presented with OCD and OSS as a symptom complex rather than a diagnosis.MethodsDetailed clinical and radiographic examinations were undertaken with emphasis on the role of MRI imaging. Magnetic resonance imaging may allow early prediction of articular lesion healing potential in patients with Stickler syndrome.ResultsThe phenotype of Stickler syndrome can be diverse and therefore misleading. The expectation that the full clinical criteria of any given genetic disorder such as Stickler syndrome will always be present can easily lead to an underestimation of these serious inheritable disorders. We report here two family subjects, a male proband and his aunt (paternal sister), both presented with the major features of Stickler syndrome. Tall stature with marfanoid habitus, astigmatism/congenital vitreous abnormality and submucus cleft palate/cleft uvula, and enlarged painful joints with early onset osteoarthritis. Osteochondritis dissecans (OCD) and Osgood Schlatter syndrome (OSS) were the predominating joint abnormalities.ConclusionWe observed that the nature of the articular and physeal abnormalities was consistent with a localised manifestation of a more generalised epiphyseal dysplasia affecting the weight-bearing joints. In these two patients, OCD and OSS appeared to be the predominant pathologic musculoskeletal consequences of an underlying Sticklers syndrome. It is empirical to consider generalised epiphyseal dysplasia as a major underlying causation that might drastically affect the weight-bearing joints.

Treatment of Varus Deformities of the Lower Limbs in Patients with Achondroplasia and Hypochondroplasia

Angular deformities of the lower limbs are a common clinical problem encountered in pediatric orthopaedic practices particularly in patients with osteochondrodysplasias. The varus deformity is more common than the valgus deformity in achondroplasia and hypochondroplasia patients because of the unusual growth of the fibulae than that of the tibiae. We retrospectively reviewed six patients (four patients with achondroplasia and two patients with hypochondroplsia) with relevant limb deformities due to the above-mentioned entities. All patients manifested significant varus deformity of the lower limbs. Detailed phenotypic characterization, radiologic and genetic testing was carried out as baseline diagnostic tool. We described the re-alignment procedures, which have been applied accordingly. Therefore, bilateral multi-level procedures, multi-apical planning and limb lengthening have been successfully applied. While recognition of the underlying syndromic association in patients who are manifesting angular deformities is the baseline for proper orthopaedic management, this paper demonstrates how to evaluate and treat these complex patients.

Familial vertebral segmentation defects, Sprengel anomaly, and omovertebral bone with variable expressivity.

A 10‐year‐old boy was found to have an unusual presentation of the Sprengel anomaly, omovertebral bones, and segmentation defects of the vertebral column at the cervical, thoracic, and sacral level. In addition, he showed hypertelorism, downslanting palpebral fissures, ptosis, webbing, and hypoplasia of the thenar and hypothenar areas. He had moderate mental delay. In addition to the segmentation defects and omovertebral bones, radiological studies showed a small pelvis and 11 pairs of ribs. Some of the features were present in the mother, and minimal symptoms were present in the father. The parents were consanguineous. A paternal cousin had segmentation defects, omovertebral bones, and a Sprengel deformity as well, although with milder presentation than the proband. We were unable to find a similar combination of manifestations in literature. The familial occurrence is best compatible with autosomal dominant inheritance, showing wide variability of expression. It is possible that the more notable signs in the proband can be explained by homozygosity for the disorder.

Distinctive spine abnormalities in patients with Goldenhar syndrome: tomographic assessment

PurposeGoldenhar syndrome consists of a combination of unilateral auricular appendages, auricular fistulas, and ocular epibulbar dermoids combined with a unilateral underdevelopment of the craniofacial structures and vertebral abnormalities. We aimed to elicit the underlying spine pathology in a group of patients via tomographic assessment.Materials and MethodsHemifacial microsomia, cranial asymmetry, multiple ear tags, skin tags around the mouth and microtia were the most prominent facial features encountered in six patients with Goldenhar syndrome. Torticollis and cervico-thoracic scoliosis were the major deformities encountered in all patients. Thoraco-lumbar scoliosis and kyphoscoliosis were of lesser occurrence. Tomographic studies have been applied to all patients to delineate the underlying pathology.ResultsDiverse spectrum of distinctive spine anomalies has been identified. Malsegmentation of the skull base associated with diffuse fusion with the upper cervical vertebrae was the most common spine pathology. Bilateral failure of segmentation, unilateral unsegmented bar and failure of vertebral formation were of lesser occurrence. Strikingly, we observed that the side of the hemifacial microsomia is strongly correlated with that of the craniocervical and the cervical vertebral abnormalities.ConclusionThe importance of this paper is threefold; first, little information is available in the literature regarding the magnitude and the diversity of spine pathology in patients with Goldenhar syndrome. Second, is to alert spine specialists that conventional radiographic assessment of the craniocervical area is an insufficient modality to assess children with syndromic associations. Third, a rotation and flexion deformity of the neck associated with facial asymmetry and/or plagiocephaly should be considered as a syndromic entity rather than a simple physiological deformation.