Comprehensive multi-omic profiling of somatic mutations in malformations of cortical development.

Malformations of cortical development (MCD) are neurological conditions involving focal disruptions of cortical architecture and cellular organization that arise during embryogenesis, largely from somatic mosaic mutations, and cause intractable epilepsy. Identifying the genetic causes of MCD has been a challenge, as mutations remain at low allelic fractions in brain tissue resected to treat condition-related epilepsy. Here we report a genetic landscape from 283 brain resections, identifying 69 mutated genes through intensive profiling of somatic mutations, combining whole-exome and targeted-amplicon sequencing with functional validation including in utero electroporation of mice and single-nucleus RNA sequencing. Genotype-phenotype correlation analysis elucidated specific MCD gene sets associated with distinct pathophysiological and clinical phenotypes. The unique single-cell level spatiotemporal expression patterns of mutated genes in control and patient brains indicate critical roles in excitatory neurogenic pools during brain development and in promoting neuronal hyperexcitability after birth.

Dislocation of the hip after normal sonographic screening examination: a case report and literature review.

We report the case of a five-month-old girl presenting with a subluxed left hip following normal neonatal clinical examination and serial ultrasound screening. Her only risk factor for developmental dysplasia of the hip (DDH) was breech presentation. She underwent closed reduction with successful concentric reduction. This case demonstrates that hip subluxation can occur after normal ultrasound screening, and has important clinical and medicolegal implications. Consideration should be given to further follow-up in children with overt risk factors for DDH, even after normal ultrasound examination.

Bi-allelic Loss of Human APC2, Encoding Adenomatous Polyposis Coli Protein 2, Leads to Lissencephaly, Subcortical Heterotopia, and Global Developmental Delay.

Lissencephaly is a severe brain malformation in which failure of neuronal migration results in agyria or pachygyria and in which the brain surface appears unusually smooth. It is often associated with microcephaly, profound intellectual disability, epilepsy, and impaired motor abilities. Twenty-two genes are associated with lissencephaly, accounting for approximately 80% of disease. Here we report on 12 individuals with a unique form of lissencephaly; these individuals come from eight unrelated families and have bi-allelic mutations in APC2, encoding adenomatous polyposis coli protein 2. Brain imaging studies demonstrate extensive posterior predominant lissencephaly, similar to PAFAH1B1-associated lissencephaly, as well as co-occurrence of subcortical heterotopia posterior to the caudate nuclei, "ribbon-like" heterotopia in the posterior frontal region, and dysplastic in-folding of the mesial occipital cortex. The established role of APC2 in integrating the actin and microtubule cytoskeletons to mediate cellular morphological changes suggests shared function with other lissencephaly-encoded cytoskeletal proteins such as α-N-catenin (CTNNA2) and platelet-activating factor acetylhydrolase 1b regulatory subunit 1 (PAFAH1B1, also known as LIS1). Our findings identify APC2 as a radiographically distinguishable recessive form of lissencephaly.

Biallelic variants in KIF14 cause intellectual disability with microcephaly.

Kinesin proteins are critical for various cellular functions such as intracellular transport and cell division, and many members of the family have been linked to monogenic disorders and cancer. We report eight individuals with intellectual disability and microcephaly from four unrelated families with parental consanguinity. In the affected individuals of each family, homozygosity for likely pathogenic variants in KIF14 were detected; two loss-of-function (p.Asn83Ilefs*3 and p.Ser1478fs), and two missense substitutions (p.Ser841Phe and p.Gly459Arg). KIF14 is a mitotic motor protein that is required for spindle localization of the mitotic citron rho-interacting kinase, CIT, also mutated in microcephaly. Our results demonstrate the involvement of KIF14 in development and reveal a wide phenotypic variability ranging from fetal lethality to moderate developmental delay and microcephaly.

Biallelic Variants in OTUD6B Cause an Intellectual Disability Syndrome Associated with Seizures and Dysmorphic Features.

Ubiquitination is a posttranslational modification that regulates many cellular processes including protein degradation, intracellular trafficking, cell signaling, and protein-protein interactions. Deubiquitinating enzymes (DUBs), which reverse the process of ubiquitination, are important regulators of the ubiquitin system. OTUD6B encodes a member of the ovarian tumor domain (OTU)-containing subfamily of deubiquitinating enzymes. Herein, we report biallelic pathogenic variants in OTUD6B in 12 individuals from 6 independent families with an intellectual disability syndrome associated with seizures and dysmorphic features. In subjects with predicted loss-of-function alleles, additional features include global developmental delay, microcephaly, absent speech, hypotonia, growth retardation with prenatal onset, feeding difficulties, structural brain abnormalities, congenital malformations including congenital heart disease, and musculoskeletal features. Homozygous Otud6b knockout mice were subviable, smaller in size, and had congenital heart defects, consistent with the severity of loss-of-function variants in humans. Analysis of peripheral blood mononuclear cells from an affected subject showed reduced incorporation of 19S subunits into 26S proteasomes, decreased chymotrypsin-like activity, and accumulation of ubiquitin-protein conjugates. Our findings suggest a role for OTUD6B in proteasome function, establish that defective OTUD6B function underlies a multisystemic human disorder, and provide additional evidence for the emerging relationship between the ubiquitin system and human disease.

Uner Tan syndrome caused by a homozygous TUBB2B mutation affecting microtubule stability.

The integrity and dynamic properties of the microtubule cytoskeleton are indispensable for the development of the mammalian brain. Consequently, mutations in the genes that encode the structural component (the α/ß-tubulin heterodimer) can give rise to severe, sporadic neurodevelopmental disorders. These are commonly referred to as the tubulinopathies. Here we report the addition of recessive quadrupedalism, also known as Uner Tan syndrome (UTS), to the growing list of diseases caused by tubulin variants. Analysis of a consanguineous UTS family identified a biallelic TUBB2B mutation, resulting in a p.R390Q amino acid substitution. In addition to the identifying quadrupedal locomotion, all three patients showed severe cerebellar hypoplasia. None, however, displayed the basal ganglia malformations typically associated with TUBB2B mutations. Functional analysis of the R390Q substitution revealed that it did not affect the ability of ß-tubulin to fold or become assembled into the α/ß-heterodimer, nor did it influence the incorporation of mutant-containing heterodimers into microtubule polymers. The 390Q mutation in S. cerevisiae TUB2 did not affect growth under basal conditions, but did result in increased sensitivity to microtubule-depolymerizing drugs, indicative of a mild impact of this mutation on microtubule function. The TUBB2B mutation described here represents an unusual recessive mode of inheritance for missense-mediated tubulinopathies and reinforces the sensitivity of the developing cerebellum to microtubule defects.

Surgical treatment for developmental dysplasia of the hip- a single surgeon series of 47 hips with a 7 year mean follow up).

The treatment of developmental dysplasia of the hip (DDH) in children remains controversial. We describe the clinical and radiological outcomes of  47 hips in 43 children treated with open surgery by one surgeon between 2004 and 2008 for DDH. The mean age at operation was 25 months (5 to 113) with a mean follow up of  89 months  (22 to 169). At the latest follow up 40 of the 45 hips where Severin grades were recordable (89%) were graded as excellent or good, Severin class I or II. Clinically significant AVN (grade II to III  according to the Kalamchi and MacEwen classification) was seen in 6  (13%) of the hips. We found a pelvic osteotomy to be a risk factor for AVN  (p 0.02) and age at operation to be a risk factor for poor morphology at final follow up (p 0.03). Over 18 months old a pelvic osteotomy should be performed in selective cases depending on intra-operative stability, but we will now consider doing this as a staged procedure and delaying the osteotomy for a period of time after open reduction to reduce the risk of AVN.

Intra-epiphyseal stress injury of the proximal tibial epiphysis: preliminary experience of magnetic resonance imaging findings.

Stress induced injuries affecting the physeal plate or cortical bone in children and adolescents, especially young athletes, have been well described. However, there are no reports in the current English language literature of stress injury affecting the incompletely ossified epiphyseal cartilage. We present four cases of stress related change to the proximal tibial epiphysis (PTE) along with their respective magnetic resonance imaging (MRI) appearances ranging from subtle oedema signal to a pseudo-tumour like appearance within the epiphyseal cartilage. The site and pattern of intra-epiphyseal injury is determined by the type of tissue that is affected, the maturity of the skeleton and the type of forces that are transmitted through the tissue. We demonstrate how an awareness of the morphological spectrum of MRI appearances in intra-epiphyseal stress injury and the ability to identify concomitant signs of stress in other nearby structures can help reduce misdiagnosis, avoid invasive diagnostic procedures like bone biopsy and reassure patients and their families.

Ponseti casting for club foot - above- or below-knee?: A prospective randomised clinical trial.

We undertook a randomised clinical trial to compare treatment times and failure rates between above- and below-knee Ponseti casting groups. Eligible children with idiopathic clubfoot, treated using the Ponseti method, were randomised to either below- or above-knee plaster of Paris casting. Outcome measures were total treatment time and the occurrence of failure, defined as two slippages or a treatment time above eight weeks. A total of 26 children (33 feet) were entered into the trial. The above-knee group comprised 17 feet in 13 children (ten boys and three girls, median age 13 days (1 to 40)) and the below-knee group comprised 16 feet in 13 children (ten boys and three girls, median age 13 days (5 to 20)). Because of six failures (37.5%) in the below-knee group, the trial was stopped early for ethical reasons. The rate of failure was significantly higher in the below-knee group (p = 0.039). The median treatment times of six weeks in the below-knee and four weeks in the above-knee group differed significantly (p = 0.01). This study demonstrates that the use of a below-knee plaster of Paris cast in conjunction with the Ponseti technique leads to unacceptably high failure rates and significantly longer treatment times. Therefore, this technique is not recommended.

The role of community screening for developmental dysplasia of the hip at the 8-month baby check.

BACKGROUND: Screening for developmental dysplasia of the hip (DDH) after the neonatal period is controversial. Due to recent changes in the screening policy in England & Wales, routine clinical screening for DDH at the 8-month baby check is no longer recommended. RESULTS: This paper looks at the effectiveness of screening for DDH by health visitors in the Flintshire area. A total of 525 8-month baby checks were performed in our area in 2007. Thirty babies were referred to their general practitioner of which six were referred on to a specialist children's orthopaedic surgeon. None of these required treatment for DDH. One patient who was screened by the health visitor but not referred was later diagnosed with DDH. CONCLUSION: Screening for DDH at 8 months using clinical examination by a trained health visitor has a high false-positive rate. This paper therefore supports the current UK National Screening Committee position.

Late dislocation of the hip following normal neonatal clinical and ultrasound examination.

We present a case of late dislocation of the hip in a 30-month-old girl. Her hip was clinically stable at birth and an ultrasound scan at six weeks was normal. She had no additional risk factors for developmental dysplasia. She underwent anterior open reduction with a femoral osteotomy.

The ferguson medial approach for open reduction of developmental dysplasia of the hip. A clinical and radiological review of 49 hips.

The results of the Ferguson medial approach for open reduction of developmental dysplasia of the hip (DDH) were reviewed for 49 hips with a follow-up of more than 48 months. The mean age at operation was 12.3 months (6 to 23). The mean length of clinical and radiological follow-up was 82 months (48 to 148). Three redislocations occurred. Group I avascular necrosis according to the classification of Kalamchi and MacEwen was seen in four hips, group II in two hips and group III in one hip; 92% of the hips were classified as Severin class I and II. The acetabular index and centre edge (CE) angles were within normal limits at final follow-up, but were still significantly different from the unaffected side. We conclude that the Ferguson procedure is safe and reliable for low dislocations in children aged six to 18 months.

Medullary carcinoma of the thyroid metastatic to breast.

Medullary carcinoma of the thyroid commonly spreads to the lymphatics and later on in the disease process, to distant sites such as lung, liver and bone. Spread to the breast is rare (only two previous reported cases) and presents a major diagnostic dilemma. We report a case of metastatic medullary carcinoma of the thyroid which presented as a primary breast nodule with ipsilateral axillary lymphadenopathy. Clearly it was important to distinguish this tumour from a breast primary as each are managed differently. Both cytological and radiological investigations were inconclusive but excision biopsy was diagnostic.