Anaesthesia and orphan disease: management of a case of Nicolaides-Baraitser syndrome undergoing cleft palate surgery.

BACKGROUND: Nicolaides-Baraitser syndrome (NCBRS) is a rare disease caused by mutations in the SMRCA2 gene, which affects chromatin remodelling and leads to a wide range of symptoms including microcephaly, distinct facial features, recurrent seizures, and severe mental retardation. Until now, less than 100 cases have been reported. CASE PRESENTATION: A 22-month old male infant with NCBRS underwent elective cleft palate surgery. The anaesthetists were challenged by the physiological condition of the patient: narrow face, very small mouth, mild tachypnea, slight sternal retractions, physical signs of partial monosomy 9p, and plagiocephalus, midface hypoplasia, V-shaped cleft palate, enhanced muscular hypotension, dysplastic kidneys (bilateral, estimated GFR: approx. 40 ml/m2), nocturnal oxygen demand, and combined apnea. In addition, little information was available about interaction of the NCBRS displayed by the patient and anaesthesia medications. CONCLUSIONS: The cleft palate was successfully closed using the bridge flap technique. Overall, we recommend to perform a trial video assisted laryngoscopy in the setting of spontaneous breathing with deep inhalative anaesthesia before administration of muscle relaxation to detect any airway difficulties while remaining spontaneoues breathing and protective reflexes.

Epilepsy in Nicolaides-Baraitser Syndrome: Review of Literature and Report of 25 Patients Focusing on Treatment Aspects.

Nicolaides-Baraitser syndrome (NCBRS), caused by a mutation in the SMARCA2 gene, which goes along with intellectual disability, congenital malformations, especially of face and limbs, and often difficult-to-treat epilepsy, is surveyed focusing on epilepsy and its treatment. Patients were recruited via "Network Therapy of Rare Epilepsies (NETRE)" and an international NCBRS parent support group. Inclusion criterion is NCBRS-defining SMARCA2 mutation. Clinical findings including epilepsy classification, anticonvulsive treatment, electroencephalogram (EEG) findings, and neurodevelopmental outcome were collected with an electronic questionnaire. Inclusion of 25 NCBRS patients with epilepsy in 23 of 25. Overall, 85% of the participants (17/20) reported generalized seizures, the semiology varied widely. EEG showed generalized epileptogenic abnormalities in 53% (9/17), cranial magnetic resonance imaging (cMRI) was mainly inconspicuous. The five most frequently used anticonvulsive drugs were valproic acid (VPA [12/20]), levetiracetam (LEV [12/20]), phenobarbital (PB [8/20]), topiramate (TPM [5/20]), and carbamazepine (CBZ [5/20]). LEV (9/12), PB (6/8), TPM (4/5), and VPA (9/12) reduced the seizures' frequency in more than 50%. Temporary freedom of seizures (>6 months) was reached with LEV (4/12), PB (3/8), TPM (1/5, only combined with PB and nitrazepam [NZP]), and VPA (4/12). Seizures aggravation was observed under lamotrigine (LTG [2/4]), LEV (1/12), PB (1/8), and VPA (1/12). Ketogenic diet (KD) and vagal nerve stimulation (VNS) reduced seizures' frequency in one of two each. This first worldwide retrospective analysis of anticonvulsive therapy in NCBRS helps to treat epilepsy in NCBRS that mostly shows only initial response to anticonvulsive therapy, especially with LEV and VPA, but very rarely shows complete freedom of seizures in this, rather genetic than structural epilepsy.

Congenital radioulnar synostosis presenting in adulthood - a case report.

Congenital radioulnar synostosis is a rare developmental skeletal malformation of the upper limb, characterized by the fusion of the proximal ends of the radius and ulna from birth. The failure of prenatal longitudinal segmentation of the adjacent radius and ulna results in a fibrous bony bridge between the radius and ulna. We present a 23-year-old female who presented with pain and restricted mobility of the left elbow joint for 7 years. A plain X-ray was performed for the patient, revealing a diagnosis of congenital radio-ulnar synostosis. Careful evaluation of the anatomical relations and spatial orientation of bony structures is required for the diagnosis and treatment of such cases.

Movement disorders rounds: Atypical cases in two Chinese families with novel variants in ATP1A3.

ATP1A3-related dystonia is a disorder with high heterogeneous spectrum of clinical manifestations caused by mutations in ATP1A3 gene. Here, 2 atypical cases carring 2 de-novo ATP1A3 variants with RDP-CAPOS overlapping phenotype or continuous hemi-dystonia are described.

The effect of mono- versus multi-segment musculoskeletal models of the foot on simulated triceps surae lengths in pathological and healthy gait.

BACKGROUND: Estimating muscle-tendon complex (MTC) lengths is important for planning of soft tissue surgery and evaluating outcomes, e.g. in children with cerebral palsy (CP). Conventional musculoskeletal models often represent the foot as one rigid segment, called a mono-segment foot model (mono-SFM). However, a multi-segment foot model (multi-SFM) might provide better estimates of triceps surae MTC lengths, especially in patients with foot deformities. RESEARCH QUESTION: What is the effect of a mono- versus a multi-SFM on simulated ankle angles and triceps surae MTC lengths during gait in typically developing subjects and in children with CP with equinus, cavovarus or planovalgus foot deformities? METHODS: 50 subjects were included, 10 non-affected adults, 10 typically developing children, and 30 children with spastic CP and foot deformities. During walking trials, marker trajectories were collected for two marker models, including a mono- and multi-segment foot; respectively Newington gait model and Oxford foot model. Two musculoskeletal lower body models were constructed in OpenSim with either a mono- or multi-SFM based on the corresponding marker models. Normalized triceps surae MTC lengths (soleus, gastrocnemius medialis and lateralis) and ankle angles were calculated and compared between models using statistical parametric mapping RM-ANOVAs. Root mean square error values between simulated MTC lengths were compared using Wilcoxon signed-rank and rank-sum tests. RESULTS: Mono-SFM simulated significantly more ankle dorsiflexion (7.5 ± 1.2°) and longer triceps surae lengths (difference; soleus:2.6 ± 0.29 %, gastrocnemius medialis:1.7 ± 0.2 %, gastrocnemius lateralis:1.8 ± 0.2%) than a multi-SFM. Differences between models were larger in children with CP compared to typically developing children and larger in the stance compared to the swing phase of gait. Largest differences were found in children with CP presenting with planovalgus (4.8 %) or cavovarus (3.8 %) foot deformities. SIGNIFICANCE: It is advisable to use a multi-SFM in musculoskeletal models when simulating triceps surae MTC lengths, especially in individuals with planovalgus or cavovarus foot deformities.

Striking phenotypic overlap between Nicolaides-Baraitser and Coffin-Siris syndromes in monozygotic twins with ARID1B intragenic deletion.

The chromatin remodeling AT-Rich interaction domain containing 1B protein (ARID1B) also known as BAF-associated factor, 250-KD, B (BAF250B) codified by the ARID1B gene (MIM#614556), is a small subunit of the mammalian SWI/SNF or BAF complex, an ATP-dependent protein machinery which is able to activate or repress gene transcription, allowing protein access to histones through DNA relaxed conformation. ARID1B gene mutations have been associated with two hereditary syndromic conditions, namely Coffin-Siris (CSS, MIM#135900) and Nicolaides-Baraitser syndromes (NCBRS, MIM#601358), characterized by neurodevelopment delay, craniofacial dysmorphisms and skeletal anomalies. Furthermore, intellectual impairment and central nervous system (CNS) alterations, comprising abnormal corpus callosum, have been associated with mutations in this gene. Moreover, ARID1B anomalies resulted to be involved in neoplastic events and Hirschprung disease. Here we report on two monozygotic male twins, displaying clinical appearance strikingly resembling NCBRS and CSS phenotype, who resulted carriers of a novel 6q25.3 microdeletion, encompassing only part of the ARID1B gene. The deleted segment was not inherited from the only parent tested and afflicted the first exons of the gene, coding for protein disordered region. We also provide, for the first time, a review of previously published ARID1B mutated patients with NCBRS and CSS phenotype and a computer-assisted dysmorphology analysis of NCBRS and ARID1B related CSS individuals, through the Face2Gene suite, confirming the existence of highly overlapping facial gestalt of both conditions. The present findings indicate that ARID1B could be considered a contributing gene not only in CSS but also in NCBRS phenotype, although the main gene related to this latter condition is the SMARCA2 gene (MIM#600014), another component of the BAF complex. So, ARID1B study should be considered in such individuals.

Naviculectomy for two ambulatory children with intractable congenital vertical talus: redefining the indications of an old technique.

Congenital vertical talus is a rare and complex foot anomaly. Serial casting with or without minimally invasive surgery is a universal management strategy especially for children in the first year of life. Nevertheless, extensive surgical treatment of late-presenting, neglected and multiple operated children with congenital vertical talus may be required with guarded results. The results of naviculectomy as a more conservative intervention and directed exclusively at ambulatory children with intractable congenital vertical talus have not been reported. We present the radioclinical outcomes of two ambulatory children with intractable congenital vertical talus treated by naviculectomy/midtarsal resection and limited soft tissue release. One child had an isolated congenital vertical talus whereas the other had a non-isolated etiology. Generally, naviculectomy/midtarsal resection revealed a positive benefit-risk profile in children with intractably severe congenital vertical talus on the short-term. We reported favorable results in terms of foot appearance, function and radiology. We believe that a less invasive procedure like naviculectomy/midtarsal resection is an encouraging technique to investigate in children with intractable congenital vertical talus.

Conjoined twins presenting with foot deformities: insights to management and challenges.

Conjoined twins are a rare outcome of conception associated with numerous anomalies involving multiple organ systems. Musculoskeletal abnormalities like vertebral anomalies, sacral agenesis, foot deformities and hip dysplasia have been described in literature. We describe two cases of pyopagus twins with congenital talipes equinovarus and congenital vertical talus deformity which have not been described previously in this type of conjoined twins. The orthopaedist should look actively for such deformities in this patient population and be wary of the difficulties associated with their management.

Management of pediatric foot deformities: an imaging review.

Abnormalities of foot alignment can be a cause of significant morbidity in children, and some require complex surgical intervention to improve functionality and decrease pain. Imaging plays a key role in management decisions. We address some of the most common surgical strategies for selected diagnoses including pes planus, congenital vertical talus, pes cavus, and clubfoot, with a focus on imaging findings.

Metatarsalgia in Metatarsus Adductus Patients: A Rational Approach.

Metatarsus adductus (MA) is a congenital condition resulting in adduction of the forefoot at the tarsometatarsal joint, medial metatarsal deviation, supination of the hindfoot through the subtalar joint, and plantarflexed first ray. The exact underlying pathophysiology remains elusive. There is increasing evidence highlighting the importance of recognizing MA as an associated deformity that complicates management of hallux valgus (HV). Unfortunately, metatarsalgia and lesser toe pathology is also common in this population. We present a review regarding the epidemiology, pathomechanics, and a comprehensive surgical treatment algorithm to optimize the management of patients with MA, HV, lesser toe deformity, and metatarsalgia.

Chronological dynamic changes in cortico-subcortical imbalance of cerebral blood flow in a boy with CAPOS syndrome.

BACKGROUND: Cerebellar ataxia, Areflexia, Pes cavus, Optic atrophy and Sensorineural hearing loss (CAPOS) syndrome is a known ATP1A3-related disorder, but little has been elucidated regarding its pathophysiology. We now report two new patients, a Japanese boy and his mother with a pathogenic mutation (c.2452G>A) in ATP1A3, who were diagnosed with CAPOS syndrome. METHODS: After febrile illnesses at 7 months of age, and again at 22 months of age, the boy had a reduced level of consciousness, truncal ataxia and eye movement-disorders. The patient's 32-year-old mother may have experienced an episode of acute encephalopathy in her childhood and sustained sensorineural hearing loss. In the present study, we demonstrated chronological dynamic changes in cerebral blood flow (CBF) in the son, using serial single-photon emission computed tomography (SPECT). RESULTS: The serial CBF-SPECT findings using statistical methods showed progressive hyperperfusion in the frontal lobes, basal ganglia and thalamus, and hypoperfusion in the occipital and temporal lobes during the acute and subacute phases. Thereafter, the dynamic changes of CBF improved in the chronic but hypoperfusion in thalamus appeared to the chronic phase. CONCLUSION: The abnormal cortico-subcortical CBF may contribute to an acute encephalopathy-like condition in the acute stage of CAPOS syndrome. CAPOS syndrome is not often reported, and is possibly an under-recognized syndrome in clinically mild cases.

Multifaceted Hoxa13 function in urogenital development underlies the Hand-Foot-Genital Syndrome.

Hand-Foot-Genital syndrome is a rare condition caused by mutations in the HOXA13 gene and characterized by limb malformations and urogenital defects. While the role of Hoxa13 in limb development has been extensively studied, its function during the development of the urogenital system remains elusive mostly due to the embryonic lethality of Hoxa13 homozygous mutant mice. Using a conditional inactivation strategy, we show that mouse fetuses lacking Hoxa13 function develop megaureters, hydronephrosis and malformations of the uterus, reminiscent of the defects characterizing patients with Hand-Foot-Genital syndrome. Our analysis reveals that Hoxa13 plays a critical role in Müllerian ducts fusion and in ureter remodeling by regulating the elimination of the caudal common nephric duct, eventually preventing the separation from the nephric duct. Our data also reveal a specific role for Hoxa13 in the urogenital sinus, which is in part mediated by Gata3, as well as Hoxa13 requirement for the proper organization of the ureter. Finally, we provide evidence that Hoxa13 provides positional and temporal cues during the development of the lower urogenital system, a sine qua non condition for the proper function of the urinary system.

Hallux valgus and metatarsus adductus measurements: inter-reader reliability and correlations on radiographs and MRI.

AIM: To assess inter-reader reliability of metatarsus adductus (MA) using the traditional method and Engel's angle (EA) on radiography and magnetic resonance imaging (MRI) and assess correlations with hallux valgus (HV). METHODS AND MATERIALS: Ninety consecutive patients with radiographs and MRI of the foot were included. Two readers measured HV angle (HVA), traditional metatarsus adductus angle (MAA), and EA on radiographs and HVA and EA on MRI. Three- and two-way mixed model analyses were used for reader agreements. Ninety-five percent bootstrap confidence intervals were calculated. The linear mixed model was used for association between HVA and EA/MAA. RESULTS: Mean age and male to female ratio was 54.2±15.4 and 0.4:1, respectively. Mean HVA and EA were 20.6±9.4 and 21.2±8, 21.2±8.3 and 22.4±7.5 on radiographs and MRI, respectively. Mean MAA was 18.5±5.7 on radiographs. Inter-reader agreement was good for EA (ICC=0.73, 0.6) and moderate for MAA (ICC=0.41). Positive correlations between HVA, MAA, and EA on radiographs and MRI were found, but none were statistically significant (p=0.44 and 0.87). CONCLUSION: Engel's angle is more reproducible. Although positive correlations exist between the degrees of HV and MA, they are not statistically significant.

Further characterization of CAPOS/CAOS syndrome with the Glu818Lys mutation in the ATP1A3 gene: A case report.

A 38-year-old female patient experienced recurrent episodes of neurological deterioration during febrile illness at the age of 7 and 8 months, and 2, 4, and 37 years. Acute symptoms comprised unconsciousness, headache, abnormal ocular movements, flaccid paralysis with areflexia, ataxia, dysphagia, and movement disorders. Each episode of neurological deterioration was followed by partial recovery with residual symptoms of progressive disturbance of visual acuity with optic atrophy and hearing loss, moderate intellectual disability, strabismus, ophthalmoplegia, as well as fluctuating degree of gait ataxia, chorea, tremor, and myoclonus. In addition, electrocardiography revealed incomplete right bundle branch block. The genetic testing revealed a de novo heterozygous mutation of c.2452G > A (p.Glu818Lys) in the ATP1A3 gene, which was compatible with the clinical phenotype of CAPOS (cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss)/CAOS syndrome. Here we discuss the significance of clinical features of a patient, overlapping with those of alternating hemiplegia of childhood, along with a literature review.

Homozygous CHST11 mutation in chondrodysplasia, brachydactyly, overriding digits, clino-symphalangism and synpolydactyly.

BACKGROUND: Carbohydrate sulfotransferase 11 (CHST11) is a membrane protein of Golgi that catalyses the transfer of sulfate to position 4 of the N-acetylgalactosamine residues of chondroitin. Chondroitin sulfate is the predominant proteoglycan in cartilage, and its sulfation is important in the developing growth plate of cartilage. A homozygous deletion encompassing part of the gene and the embedded miRNA MIR3922 had been detected in a woman with hand/foot malformation and malignant lymphoproliferative disease. Chst11-deficient mouse has severe chondrodysplasia, congenital arthritis and neonatal lethality. We searched for the causative variant for the unusual combination of limb malformations with variable expressivity accompanied by skeletal defects in a consanguineous Pakistani kindred. METHODS: We performed detailed clinical investigations in family members. Homozygosity mapping using SNP genotype data was performed to map the disease locus and exome sequencing to identify the underlying molecular defect. RESULTS: The limb malformations include brachydactyly, overriding digits and clino-symphalangism in hands and feet and syndactyly and hexadactyly in feet. Skeletal defects include scoliosis, dislocated patellae and fibulae and pectus excavatum. The disease locus is mapped to a 1.6 Mb region at 12q23, harbouring a homozygous in-frame deletion of 15 nucleotides in CHST11. Novel variant c.467_481del (p.L156_N160del) is deduced to lead to the deletion of five evolutionarily highly conserved amino acids and predicted as damaging to protein by in silico analysis. Our findings confirm the crucial role of CHST11 in skeletal morphogenesis and show that CHST11 defects have variable manifestations that include a variety of limb malformations and skeletal defects.

Linked homozygous BMPR1B and PDHA2 variants in a consanguineous family with complex digit malformation and male infertility.

In affected members of a consanguineous family, a syndrome, which is concurrence of set of medical signs, is often observed and commonly assumed to have arisen from pleiotropy, i.e., the phenomenon of a single gene variant affecting multiple traits. We detected six sibs afflicted with a unique combination of digit malformation that includes brachydactyly, symphalangism and zygodactyly plus infertility in males owing to azoospermia, sperm immotility or necrospermia, which we hypothesised to have arisen from a defect in a single gene. We mapped the disease locus and by exome sequencing identified in patients homozygous missense variants bone morphogenetic protein receptor type IB (BMPR1B) c.640C>T (p.(Arg214Cys)) and alpha-2 pyruvate dehydrogenase (PDHA2) c.679A>G (p.(Met227Val)). Structural protein modelling, protein sequence conservation and in silico analysis indicate that both variants affect protein function. BMPR1B is known to be responsible for autosomal dominant brachydactyly and autosomal recessive acromesomelic chondrodysplasia. Our findings show that also recessive complex digit malformation can be caused by BMPR1B variant and not all biallelic BMPR1B variants cause acromesomelic dysplasia. PDHA2 is a novel candidate gene for male infertility; the protein product is a mitochondrial enzyme with highest expression in ejaculated sperm. Our findings are a unique example of two linked variants, ~ 711 Kb apart, in different genes that together manifest as a novel syndrome. They demonstrate that exome sequencing and not candidate gene approach should be employed in disease gene hunt, defining new diseases and genetic testing, to rule out the coincidental presence of two variants contributing together to the phenotype, which may be discerned as a novel disease.

The CAPOS mutation in ATP1A3 alters Na/K-ATPase function and results in auditory neuropathy which has implications for management.

Cerebellar ataxia, areflexia, pes cavus, optic atrophy and sensorineural hearing impairment (CAPOS) is a rare clinically distinct syndrome caused by a single dominant missense mutation, c.2452G>A, p.Glu818Lys, in ATP1A3, encoding the neuron-specific alpha subunit of the Na+/K+-ATPase α3. Allelic mutations cause the neurological diseases rapid dystonia Parkinsonism and alternating hemiplegia of childhood, disorders which do not encompass hearing or visual impairment. We present detailed clinical phenotypic information in 18 genetically confirmed patients from 11 families (10 previously unreported) from Denmark, Sweden, UK and Germany indicating a specific type of hearing impairment-auditory neuropathy (AN). All patients were clinically suspected of CAPOS and had hearing problems. In this retrospective analysis of audiological data, we show for the first time that cochlear outer hair cell activity was preserved as shown by the presence of otoacoustic emissions and cochlear microphonic potentials, but the auditory brainstem responses were grossly abnormal, likely reflecting neural dyssynchrony. Poor speech perception was observed, especially in noise, which was beyond the hearing level obtained in the pure tone audiograms in several of the patients presented here. Molecular modelling and in vitro electrophysiological studies of the specific CAPOS mutation were performed. Heterologous expression studies of α3 with the p.Glu818Lys mutation affects sodium binding to, and release from, the sodium-specific site in the pump, the third ion-binding site. Molecular dynamics simulations confirm that the structure of the C-terminal region is affected. In conclusion, we demonstrate for the first time evidence for auditory neuropathy in CAPOS syndrome, which may reflect impaired propagation of electrical impulses along the spiral ganglion neurons. This has implications for diagnosis and patient management. Auditory neuropathy is difficult to treat with conventional hearing aids, but preliminary improvement in speech perception in some patients suggests that cochlear implantation may be effective in CAPOS patients.