Wide Fontanels, Delayed Speech Development and Hoarse Voice as Useful Signs in the Diagnosis of KBG Syndrome: A Clinical Description of 23 Cases with Pathogenic Variants Involving the ANKRD11 Gene or Submicroscopic Chromosomal Rearrangements of 16q24.3.

KBG syndrome is a neurodevelopmental autosomal dominant disorder characterized by short stature, macrodontia, developmental delay, behavioral problems, speech delay and delayed closing of fontanels. Most patients with KBG syndrome are found to have a mutation in the ANKRD11 gene or a chromosomal rearrangement involving this gene. We hereby present clinical evaluations of 23 patients aged 4 months to 26 years manifesting clinical features of KBG syndrome. Mutation analysis in the patients was performed using panel or exome sequencing and array CGH. Besides possessing dysmorphic features typical of the KBG syndrome, nearly all patients had psychomotor hyperactivity (86%), 81% had delayed speech, 61% had poor weight gain, 56% had delayed closure of fontanel and 56% had a hoarse voice. Macrodontia and a height range of -1 SDs to -2 SDs were noted in about half of the patients; only two patients presented with short stature below -3 SDs. The fact that wide, delayed closing fontanels were observed in more than half of our patients with KBG syndrome confirms the role of the ANKRD11 gene in skull formation and suture fusion. This clinical feature could be key to the diagnosis of KBG syndrome, especially in young children. Hoarse voice is a previously undescribed phenotype of KBG syndrome and could further reinforce clinical diagnosis.

Detailed clinical and radiological features of the first patient with Elsahy-Waters syndrome in East Asia.

Elsahy-Waters syndrome (EWS; OMIM#211380) is a rare autosomal recessive disorder that is caused by loss-of-function variants in CDH11, which encodes cadherin 11. EWS is characterized by brachycephaly, midface hypoplasia, characteristic craniofacial morphology, cervical fusion, cutaneous syndactyly in 2-3 digits, genitourinary anomalies, and intellectual disability. To the best of our knowledge, there have been only six patients of molecularly confirmed EWS. We report the first patient of EWS in East Asia in a Japanese man with a novel splice site homozygous variant of CDH11. We reviewed the clinical and molecular findings in previously reported individuals and the present patient. In addition to the previously reported clinical features of EWS, the present patient had unreported findings of atlantoaxial instability due to posterior displacement of dens, thoracic fusion, thoracic butterfly vertebra, sacralization of the lumbar vertebra (L5), and multiple perineural cysts. The spinal findings in this patient could represent a new spectrum of skeletal phenotypes of EWS. It remains to be clarified whether the multiple perineural cysts in the patient were associated with EWS or coincidental. The current observation might contribute to an expanded understanding of the clinical consequences of loss-of-function of cadherin 11.

Medial Metaphyseal Beak Angle as a Predictor for Langenskiöld Stage II of Blount's Disease.

OBJECTIVE: To determine the medial metaphyseal beak (MMB) cut-off angle predicting Langenskiöld stage II of Blount's disease and to study the intra-observer and inter-observer reliabilities of angle measurements and the influence of the experience level of observers. METHODS: A retrospective study was conducted on children aged 2-4 years from January 2000 to December 2017. Children were identified through a computer-based search. Children with Langenskiöld stage II of Blount's disease who had been initially evaluated at our institution were categorized into Blount group and children who were diagnosed with physiologic bowing were categorized into control group. Data on the patients' ages, genders, and affected sides were collected. The MMB angles were measured on standing anteroposterior radiographs of the knees. The angle was formed between one line drawn parallel to the medial cortex of the proximal tibia, and a second line running from the intersection of the first line with the proximal tibial metaphysis through to the most distal point of the MMB. Measurements were independently performed by six observers. All observers repeated the measurements 2 weeks after they were first done. RESULTS: There were 148 legs from 79 children (48 males and 31 females) with an average age of 28.6 months. The average MMB angle of the Blount group was 128.52° ± 5.38° (P-value <0.001) and of the control group was 114.45° ± 4.89°. The average femorotibial angle of the Blount group was 15.48° ± 6.81° (P-value <0.001) and of the control group was 7.71° ± 7.94°. The receiver operating characteristic curve showed that an MMB angle >122° (sensitivity 92.7%; specificity 97.0%) was associated with Langenskiöld stage II. The intraclass correlation coefficient of the intra-observer reliability ranged from 0.93-0.97, and the inter-observer reliability was 0.93. CONCLUSIONS: By using anteroposterior (AP) radiographs of the knee, the MMB angle is a potential radiographic parameter to distinguish between Langenskiöld stage II of Blount's disease and physiologic bowed legs, with an MMB angle >122° predicting Langenskiöld stage II.

Development, behaviour and sensory processing in Marshall-Smith syndrome and Malan syndrome: phenotype comparison in two related syndromes.

BACKGROUND: Ultrarare Marshall-Smith and Malan syndromes, caused by changes of the gene nuclear factor I X (NFIX), are characterised by intellectual disability (ID) and behavioural problems, although questions remain. Here, development and behaviour are studied and compared in a cross-sectional study, and results are presented with genetic findings. METHODS: Behavioural phenotypes are compared of eight individuals with Marshall-Smith syndrome (three male individuals) and seven with Malan syndrome (four male individuals). Long-term follow-up assessment of cognition and adaptive behaviour was possible in three individuals with Marshall-Smith syndrome. RESULTS: Marshall-Smith syndrome individuals have more severe ID, less adaptive behaviour, more impaired speech and less reciprocal interaction compared with individuals with Malan syndrome. Sensory processing difficulties occur in both syndromes. Follow-up measurement of cognition and adaptive behaviour in Marshall-Smith syndrome shows different individual learning curves over time. CONCLUSIONS: Results show significant between and within syndrome variability. Different NFIX variants underlie distinct clinical phenotypes leading to separate entities. Cognitive, adaptive and sensory impairments are common in both syndromes and increase the risk of challenging behaviour. This study highlights the value of considering behaviour within developmental and environmental context. To improve quality of life, adaptations to environment and treatment are suggested to create a better person-environment fit.

Do Different Tibial Osteotomy Techniques Affect Sagittal Alignment in Children with Blount Disease?

OBJECTIVE: To determine the radiographic outcomes following dome or wedge-shaped proximal tibial osteotomy in the management of infantile Blount disease with a particular interest in sagittal alignment of the knee joint. METHOD: Medical records of patients with Langenskiöld stage 2 Blount disease (aged ≤5 years) who underwent surgical correction between January 2005 and November 2019 were retrospectively identified. Patients with metabolic bone disease, bone tumors, prior traumatic fractures, congenital anomalies, inadequate plain films, and incomplete medical documents were excluded. Patient characteristics (e.g. age, gender, and body mass index [BMI]) and surgical characteristics (e.g. side, type of surgery, and follow-up times) were recorded. Antero-posterior (AP) and lateral knee radiographs were analyzed. Data were categorized by surgical technique as dome-shaped proximal tibial osteotomy or wedge-shaped proximal tibial osteotomy. The femorotibial angle (FTA) was used to evaluate the correction angle in varus deformities. Sagittal alignment of the lower limbs using the posterior tibial slope (PTS) angle was measured postoperatively at 3, 6, 12, and 24 months, and at the final follow-up visit. RESULTS: The present study included 72 surgeries of 46 patients who had undergone proximal tibial osteotomy. Twenty-nine (63%) were male. The mean age of patients at the time of surgery was 34.50 months (range, 26-47). The mean weight was 23.11 ± 4.98 kg (mean ± SD); the mean height was 95.33 ± 6.36 cm, and the mean BMI was 25.32 ± 4.36 kg/m2 . The mean duration of follow up was 4.77 ± 2.78 years. Sixty-four patients (88.90%) received dome-shaped proximal osteotomy of the tibia, while 8 (11.10%) received wedge-shaped proximal osteotomy of the tibia. The average FTA of the total correction measured was 29.32° ± 7.98°. The demographic data of the two groups were not significantly different for gender, age, BMI, side follow-up times, and the total correction of varus deformities. In the dome-shaped osteotomy group, the mean correction of the FTA was 29.59° ± 7.45°. The mean degree of the PTS angle was 6.50° at 3 months, 6.38° at 6 months, 5.32° at 12 months, 5.17° at 24 months, and 5.53° at the final follow-up visit. In the wedge-shaped proximal tibial osteotomy group, the mean correction of the FTA was 27.25° ± 11.77°. The PTS was 6.00° at 3 months, 7.50° at 6 months, 7.00° at 12 months, 5.40° at 24 months, and 5.57° at the final follow-up visit. No significant difference was observed in the radiological outcome between surgical techniques. CONCLUSION: Dome and wedge-shaped proximal tibial osteotomies did not demonstrate significant differences in the PTS angle in children with Blount disease.

Skeletal maturation and long-bone growth patterns of patients with progeria: a retrospective study.

BACKGROUND: Hutchinson-Gilford progeria syndrome (termed progeria in this Article) is a rare sporadic genetic disorder. One early clinical manifestation of progeria is abnormal skeletal growth, yet this growth has not been fully characterised. We aimed to characterise the skeletal maturation and long-bone growth patterns of patients with the clinical phenotype of progeria. METHODS: For this retrospective study, we reviewed skeletal surveys of patients (aged <20 years) with progeria obtained over a 9·5-year period. Most surveys included radiographs of the hands and long bones (humeri, radii, ulnas, tibias, and fibulas). Bone ages of these patients were estimated by the standards of Greulich and Pyle. Following the established methods for studying long-bone growth, the study cohort was separated into two overlapping age groups: longitudinal bone length measurements were made between physes for the childhood group (aged 12 years or younger) and from the upper margins of the proximal to the lower margin of the distal ossified epiphyses for the adolescent group (aged 10 years or older). Bone age estimates and bone length measurements were plotted against the chronological age of patients and compared with reference standards. Statistical analyses were based on mixed models. FINDINGS: 85 patients with progeria and 250 skeletal surveys were included in our study. For both sexes, bone age estimates showed a more advanced skeletal maturation rate throughout all chronological ages than the normal rate of 1 (p<0·0001), with the rate of maturation being 1·09 (SE 0·02) for boys and 1·14 (0·02) for girls. Longitudinal long-bone lengths began to deviate from normal standards by age 1-2 years. Growth curves for these long bones plateaued at about half the normal eventual bone length, and the half-life (the time taken to grow to half the eventual bone length) was also about half the time compared with normal standards. INTERPRETATION: Our study established growth curves that might serve as reference standards for skeletal maturation and long-bone growth of patients with the clinical phenotype of progeria. FUNDING: The Progeria Research Foundation, the US National Heart, Lung and Blood Institute, the Dana-Farber Cancer Institute Stop&Shop Pediatric Brain Tumor Program, the US National Center for Research Resources, US National Institutes of Health.

Trevor's disease of the distal radioulnar joint in two children with achondroplasia.

Two children with achondroplasia who developed an abnormal bony outgrowth at the distal radioulnar joint (DRUJ), indistinguishable from an osteochondroma on histology, but the radiographic appearance, location, and asymmetry suggested the rare diagnosis of dysplasia epiphysealis hemimelica (DEH or "Trevor's disease"). One child experienced symptomatic relief with surgical excision and one was observed clinically due to lack of significant symptoms. These are the first presented cases of DEH in achondroplasia, both affecting the DRUJ. Due to the infrequency of DEH, more research is needed to better understand the potential connection to achondroplasia. For management, we suggest shared surgical decision making based on symptoms.

Improved Gait Parameters After Orthotic Treatment in Children with Infantile Tibia Vara.

The aim of this study was to investigate the modification of gait kinematics before and after orthotic treatment in patients with ITV. Vicon instrumented gait analysis was performed on three patients with ITV, pre and post treatment. Orthoses were applied a total of eighteen participants with ITV who were 25-38 months. 34 extremities were treated and radiographic evidence evaluated before and after orthotic treatment. Treatment duration for orthotic treatment ranged between 11 and 41 (25.9 ± 10.0) months. Only three patients were evaluated in gait analysis due to application difficulties. Three patients kinematic and kinetic instrumented gait analysis were found flatfoot, varus and internal rotation of the foot, hip flexion and external rotation. Study were reported an improvement in gait kinematics after orthotic treatment, in patients with ITV.

Beyond the adrenals: Organ manifestations in inherited primary adrenal insufficiency in children.

Primary adrenal insufficiency (PAI) in children is mostly due to genetic defects. The understanding of the molecular genetics of the causes of adrenal insufficiency in the pediatric population has made significant progress during the last years. It has been shown that inherited PAI can lead to certain clinical manifestations and health problems in children beyond the adrenals. Organ dysfunctions associated with different forms of PAI in children include a wide range of organs such as gonads, brain, heart, bone, growth, bone marrow, kidney, skin, parathyroid, and thyroid. Diagnosing the correct genetic cause of PAI in children is therefore crucial to adequately control long-term treatment and follow-up in such patients.

Neurofibromatosis tipos 1 y 2 / Neurofibromatosis type 1 and 2

La neurofibromatosis (NF) comprende un grupo de enfermedades genéticas de herencia autosómica dominante, que se clasifican de la siguiente manera: neurofibromatosis tipo 1 (NF1), neurofibromatosis tipo 2 (NF2) y schwannomatosis (también conocida como neurofibromatosis tipo 3). Esta última es una enfermedad muy infrecuente, con una prevalencia aproximada de 1/126 000 personas, por lo que solo profundizaremos las dos primeras. La NF1, también conocida como la enfermedad de Von Recklinghausen, es la más frecuente de las tres y afecta principalmente la piel y el sistema nervioso periférico. Se caracteriza por la presencia de máculas "café con leche", pecas axilares o inguinales, nódulos de Lisch (hamartomas en el iris) y neurofibromas (tumores de la vaina de nervios periféricos). Otras manifestaciones menos frecuentes, aunque de mayor gravedad, incluyen gliomas del nervio óptico, meningiomas, neurofibromas malignos, escoliosis y displasia de la tibia. Su diagnóstico se suele realizar al nacimiento o durante los primeros años de vida, y se estima que un 50% de quienes la padecen presenta dificultades cognitivas. No hay datos concluyentes sobre la mortalidad en los pacientes con NF1, aunque se sabe que la expectativa de vida es menor que en la población general. La NF2 tiene una prevalencia considerablemente menor que la NF1 y su inicio es más tardío, afectando principalmente a adultos jóvenes. La presentación clínica típica se caracteriza por acúfenos, hipoacusia y ataxia en contexto de la presencia de schwannomas vestibulares bilaterales. Otros hallazgos menos frecuentes incluyen schwannomas de nervios periféricos, meningiomas, ependimomas o astrocitomas. La esperanza de vida es de unos 36 años, con una supervivencia media desde el momento del diagnóstico de 15 años. (AU)

Neurofibromatosis (NF) includes a group of genetic diseases with an autosomal-dominant inheritance pattern, and they are classified as follows: Neurofibromatosis type 1 (NF1), neurofibromatosis type 2 (NF2) and Schwannomatosis (also known as neurofibromatosis type 3). This last one is a very rare disease, with an approximate prevalence of 1/126000, so we will only deepen in the first two. NF1, also known as von Recklinghausen disease, is the most frequent, and mainly affects the skin and peripheral nervous system. Its typical manifestations are the presence of café-au-lait macules, axillary or inguinal freckles, Lisch nodules (hamartomas in the iris) and neurofibromas (peripheral nerve sheath tumors). Less frequent manifestations, although more serious, include optic nerve gliomas, meningiomas, malignant neurofibromas, scoliosis and tibial dysplasia. The diagnosis is usually made at birth or during the first years of life, and approximately 50% of patients present cognitive difficulties. There is no conclusive data on mortality in patients with NF1, although it is known that life expectancy is lower than in general population. NF2 has a considerably lower prevalence than NF1, and its onset is later in life, mainly affecting young adults. Its typical clinical presentation is characterized by tinnitus, hearing loss and ataxia in the context in the presence of bilateral vestibular schwannomas. Less frequent findings include peripheral nerve schwannomas, meningiomas, ependymomas or astrocytomas. Life expectancy is about 36 years old, with a median survival from the moment of diagnosis of 15 years. (AU)

A novel transgenic murine model with persistently brittle bones simulating osteogenesis imperfecta type I.

Osteogenesis imperfecta (OI) type I caused by the null allele of COL1A1 gene is in the majority in clinical OI cases. Currently, heterozygous Mov-13 mice generated by virus insertion in the first intron of col1a1 is the exclusive model to modulate OI type I, in spite of the gradually recovered bone mineral and mechanical properties. A newly designed heterozygous col1a1±365 OI mouse was produced in the present study by partial exons knockout (exon 2-exon 5, 365 nt of mRNA) using CRISPR/Cas9 system. The deletion resulted in generally large decrease in type I collagen synthesis due to frameshift mutation and premature chain termination, closely mimicking the pathogenic mechanism in affected individuals. And the strain possessed significantly sparse mineral scaffolds, bone loss, lowered mechanical strength and broken bone metabolism by 8 and 20 weeks compared to their littermates, suggesting a sustained skeletal weakness. Notably, the remarkable down-regulation of Yes-associated protein (YAP), one of the key coactivator in Hippo signaling pathway, was first found both in the femur and adipose derived mesenchymal stem cells (ADSCs) under osteogenic differentiation of col1a1±365 mice, which might be responsible for the reduced osteogenic potential and brittle bones. Still, further research was needed in order to illuminate the underlying mechanism.

Dynll1 is essential for development and promotes endochondral bone formation by regulating intraflagellar dynein function in primary cilia.

Mutations in subunits of the cilia-specific cytoplasmic dynein-2 (CD2) complex cause short-rib thoracic dystrophy syndromes (SRTDs), characterized by impaired bone growth and life-threatening perinatal respiratory complications. Different SRTD mutations result in varying disease severities. It remains unresolved whether this reflects the extent of retained hypomorphic protein functions or relative importance of the affected subunits for the activity of the CD2 holoenzyme. To define the contribution of the LC8-type dynein light chain subunit to the CD2 complex, we have generated Dynll1-deficient mouse strains, including the first-ever conditional knockout (KO) mutant for any CD2 subunit. Germline Dynll1 KO mice exhibit a severe ciliopathy-like phenotype similar to mice lacking another CD2 subunit, Dync2li1. Limb mesoderm-specific loss of Dynll1 results in severe bone shortening similar to human SRTD patients. Mechanistically, loss of Dynll1 leads to a partial depletion of other SRTD-related CD2 subunits, severely impaired retrograde intra-flagellar transport, significant thickening of primary cilia and cilia signaling defects. Interestingly, phenotypes of Dynll1-deficient mice are very similar to entirely cilia-deficient Kif3a/Ift88-null mice, except that they never present with polydactyly and retain relatively higher signaling outputs in parts of the hedgehog pathway. Compared to complete loss of Dynll1, maintaining very low DYNLL1 levels in mice lacking the Dynll1-transcription factor ASCIZ (ATMIN) results in significantly attenuated phenotypes and improved CD2 protein levels. The results suggest that primary cilia can maintain some functionality in the absence of intact CD2 complexes and provide a viable animal model for the analysis of the underlying bone development defects of SRTDs.

A comparative evaluation of tibial metaphyseal-diaphyseal angle changes between physiologic bowing and Blount disease.

The purpose of this study was to estimate the rate of spontaneous improvement in tibial metaphyseal-diaphyseal angle (TMDA) in physiologic bowing in comparison to that in Blount disease and to provide reference values of TMDA for monitoring patients with highly suspected to have Blount disease.We retrospectively reviewed patients with physiologic bowing meeting the following criteria:(1) TMDA greater than 9° before 36 months of age at initial evaluation;(2) two or more standing long bone radiographs available; and(3) follow-up conducted up to resolution of deformity.Patients with Blount disease had(1) more than 2 standing long bone radiographs obtained before 36 months of age and(2) underwent no treatment during the period in which these images were obtained.TMDA measurements were obtained from 174 patients with physiologic bowing and 32 patients with Blount disease. Rates of TMDA improvement were adjusted by multiple factors using a linear mixed model, with sex and laterality as fixed effects and age and individual patients as the random effects.In the physiologic bowing group, TMDA improved significantly, by 3° per 6 months and by 6° per year. Changes in TMDA were not significant in the Blount disease group.Knowing the rate of TMDA change can be helpful for physicians seeking to monitor infants with suspected as having Blount disease with a high TMDA and to avoid unnecessary repeat radiographic evaluations.

Osteogenesis Imperfecta: A Pediatric Orthopedic Perspective.

Osteogenesis imperfecta is a genetically and phenotypically heterogeneous disorder related to a defect or deficiency in the production of type I collagen. It is characterized by brittle bones, fractures, spine and extremity deformity, and a host of extraskeletal manifestations. Type I collagen is present in bone, tendons, ligaments, skin, dentin, and the sclera of the eye and other connective tissues. Osteogenesis imperfecta includes a multitude of disease manifestations that may be present at birth or develop over time and vary depending on the severity of the disease. This article describes the disease presentation and management considerations from a pediatric orthopedic perspective.

Exploring the behavioral and cognitive phenotype of KBG syndrome.

KBG syndrome is a neurodevelopmental disorder, caused by dominant mutations in ANKRD11, that is characterized by developmental delay/intellectual disability, mild craniofacial dysmorphisms, and short stature. Behavior and cognition have hardly been studied, but anecdotal evidence suggests higher frequencies of ADHD-symptoms and social-emotional impairments. In this study, the behavioral and cognitive profile of KBG syndrome will be investigated in order to examine if and how cognitive deficits contribute to behavioral difficulties. A total of 18 patients with KBG syndrome and a control group consisting of 17 patients with other genetic disorders with comparable intelligence levels, completed neuropsychological assessment. Age-appropriate tasks were selected, covering overall intelligence, attention, memory, executive functioning, social cognition and visuoconstruction. Results were compared using Cohen's d effect sizes. As to behavior, fewer difficulties in social functioning and slightly more attentional problems, hyperactivity, oppositional defiant behavior and conduct problems were found in the KBG syndrome group. Regarding cognitive functioning, inspection of the observed differences shows that patients with KBG syndrome showed lower scores on sustained attention, cognitive flexibility, and visuoconstruction. In contrast, the KBG syndrome group demonstrated higher scores on visual memory, social cognition and emotion recognition. The cognitive profile of KBG syndrome in this sample indicates problems in attention and executive functioning that may underlie the behavior profile which primarily comprises impulsive behavior. Contrary to expectations based on previous (case) reports, no deficits were found in social cognitive functioning. These findings are important for counseling purposes, for tailored education planning, and for the development of personalized intervention.

Novel ANKRD11 gene mutation in an individual with a mild phenotype of KBG syndrome associated to a GEFS+ phenotypic spectrum: a case report.

BACKGROUND: KBG syndrome is a very rare autosomal dominant disorder, characterized by macrodontia, distinctive craniofacial findings, skeletal findings, post-natal short stature, and developmental delays, sometimes associated with seizures and EEG abnormalities. So far, there have been over 100 cases of KBG syndrome reported. CASE PRESENTATION: Here, we describe two sisters of a non-consanguineous family, both presenting generalized epilepsy with febrile seizures (GEFS+), and one with a more complex phenotype associated with mild intellectual disability, skeletal and dental anomalies. Whole exome sequencing (WES) analysis in all the family members revealed a heterozygous SCN9A mutation, p.(Lys655Arg), shared among the father and the two probands, and a novel de novo loss of function mutation in the ANKRD11 gene, p.(Tyr1715*), in the proband with the more complex phenotype. The reassessment of the phenotypic features confirmed that the patient fulfilled the proposed diagnostic criteria for KBG syndrome, although complicated by early-onset isolated febrile seizures. EEG abnormalities with or without seizures have been reported previously in some KBG cases. The shared variant, occurring in SCN9A, has been previously found in several individuals with GEFS+ and Dravet syndrome. CONCLUSIONS: This report describe a novel de novo variant in ANKRD11 causing a mild phenotype of KGB syndrome and further supports the association of monogenic pattern of SCN9A mutations with GEFS+. Our data expand the allelic spectrum of ANKRD11 mutations, providing the first Brazilian case of KBG syndrome. Furthermore, this study offers an example of how WES has been instrumental allowing us to better dissect the clinical phenotype under study, which is a multilocus variation aggregating in one proband, rather than a phenotypic expansion associated with a single genomic locus, underscoring the role of multiple rare variants at different loci in the etiology of clinical phenotypes making problematic the diagnostic path. The successful identification of the causal variant in a gene may not be sufficient, making it necessary to identify other variants that fully explain the clinical picture. The prevalence of blended phenotypes from multiple monogenic disorders is currently unknown and will require a systematic re-analysis of large WES datasets for proper diagnosis in daily practice.

Terminal osseous dysplasia with pigmentary defects (TODPD) in a Turkish girl with new skin findings.

Terminal osseous dysplasia with pigmentary defects (TODPD; MIM #300244) is an extremely rare, X-linked dominant, in utero male-lethal disease, characterized by skeletal dysplasia of the limbs, pigmentary defects of the skin, and recurrent digital fibromatosis of childhood. Delayed/abnormal ossification of bones of the hands and feet, joint contractures, and dysmorphic facial features may accompany. A single recurrent mutation (c.5217 G>A) of the FLNA gene which causes cryptic splicing was identified as the cause of the disease. We here present the first TODPD case from Turkey with full-blown phenotype who exhibit unique additional findings, hypopigmented patch on the lower extremity following Blaschko's lines and smooth muscle hamartoma of the scalp in review of all the previously reported TODPD cases.

CREB activation in hypertrophic chondrocytes is involved in the skeletal overgrowth in epiphyseal chondrodysplasia Miura type caused by activating mutations of natriuretic peptide receptor B.

Natriuretic peptide receptor B (NPRB) produces cyclic guanosine monophosphate (cGMP) when bound by C-type natriuretic peptide (CNP). Activating mutations in NPRB cause a skeletal overgrowth disorder, which has been named epiphyseal chondrodysplasia, Miura type (ECDM; OMIM #615923). Here we explored the cellular and molecular mechanisms for the skeletal overgrowth in ECDM using a mouse model in which an activating mutant NPRB is specifically expressed in chondrocytes. The mutant mice (NPRB[p.V883M]-Tg) exhibited postnatal skeletal overgrowth and increased cGMP in cartilage. Both endogenous and transgene-derived NPRB proteins were localized at the plasma membrane of hypertrophic chondrocytes. The hypertrophic zone of growth plate was thickened in NPRB[p.V883M]-Tg. An in vivo BrdU-labeling assay suggested that some of the hypertrophic chondrocytes in NPRB[p.V883M]-Tg mice continued to proliferate, although wild-type (WT) chondrocytes stopped proliferating after they became hypertrophic. In vitro cell studies revealed that NPRB activation increased the phosphorylation of cyclic AMP-responsive element binding protein (CREB) and expression of cyclin D1 in matured chondrocytes. Treatment with cell-permeable cGMP also enhanced the CREB phosphorylation. Inhibition of cyclic adenosine monophosphate (cAMP)/protein kinase A pathway had no effects on the CREB phosphorylation induced by NPRB activation. In immunostaining of the growth plates for the proliferation marker Ki67, phosphorylated CREB and cyclin D1, most signals were similarly observed in the proliferating zone in both genotypes, but some cells in the hypertrophic zone of NPRB[p.V883M]-Tg were also positively stained. These results suggest that NPRB activation evokes its signal in hypertrophic chondrocytes to induce CREB phosphorylation and make them continue to proliferate, leading to the skeletal overgrowth in ECDM.

Biallelic disruption of PKDCC is associated with a skeletal disorder characterised by rhizomelic shortening of extremities and dysmorphic features.

BACKGROUND: During mouse embryonic development the protein kinase domain containing, cytoplasmic (Pkdcc) gene, also known as Vlk, is expressed in several tissues including the ventral midbrain, with particularly strong expression in branchial arches and limb buds. Homozygous Pkdcc knockout mice have dysmorphic features and shortened long bones as the most obvious morphological abnormalities. The human PKDCC gene has currently not been associated with any disorders. OBJECTIVE: To use clinical diagnostic exome sequencing (DES) for providing genetic diagnoses to two apparently unrelated patients with similar skeletal abnormalities comprising rhizomelic shortening of limbs and dysmorphic features. METHODS: Patient-parents trio DES was carried out and the identified candidate variants were confirmed by Sanger sequencing. RESULTS: Each patient had a homozygous gene disrupting variant in PKDCC considered to explain the skeletal phenotypes shared by both. The first patient was homozygous for the nonsense variant p.(Tyr217*) (NM_1 38 370 c.651C>A) expected to result in nonsense-mediated decay of the mutant transcripts, whereas the second patient was homozygous for the splice donor variant c.639+1G>T predicted to abolish the donor splice site by three in silico splice prediction algorithms. CONCLUSIONS: Biallelic gene disrupting variants in PKDCC in humans, just like in mice, cause dysmorphic features and rhizomelic shortening of limbs.