Neglected Bilateral Clubfoot Clubhand Deformity.

Introduction: Neglected bilateral clubfoot clubhand deformity is a mesomelic type of dysplasia that is characterized by disproportionate shortness of the middle segment of all limbs and is a form of short-limb dwarfism. Affected individuals are clinically of normal stature with particularly short mesomelic segments with nearly symmetric limb abnormalities. Case Report: The patient was a 20-year-old male Indian who came to outpatient department for cosmetic purpose. Upper limb abnormalities include short forearm, and elbow joints which are broad and deformed with limited flexion-extension range of motion and decreased pronosupination of the forearms. The hands are normal in appearance. The foot is also affected and deformed. The fibulae are malformed and long in relation to the tibiae. Both bones, tibia, and fibula are dysplastic. The atypical foot deformity seen in this patient is characterized by a severe equinovarus component. He is able to do his activities of daily living and can do activities such as gripping, holding a pen/cup, opening a door, and writing on paper comfortably. He is able to walk normally without any support. This patient has normal stature, normal systemic examination, and normal chromosomes. Conclusion: The neglected bilateral clubfoot clubhand deformity a type of mesomelic dysplasia was the most likely diagnosis in our patient. Disorders involving Nievergelt syndrome and mesomelic dwarfism were considered but none were likely possibilities. Our patient had the malformed fibulae and tibiae, and the severe equinovarus deformity of the feet. There were triangular shaped ulnae which were deficient distally, and the radii were bowed. Unlike Nievergelt syndrome, our patient did not have a severe deformity of hands and fingers. He is functionally sound and able to do his activities of daily living and can do activities such as gripping, holding a pen/cup, opening a door, and writing on paper comfortably. He is able to walk normally without any support. These features have not been previously described in literature leading to our diagnosis of neglected bilateral clubfoot clubhand deformity.

Variant-specific pathophysiological mechanisms of AFF3 differently influence transcriptome profiles.

BACKGROUND: We previously described the KINSSHIP syndrome, an autosomal dominant disorder associated with intellectual disability (ID), mesomelic dysplasia and horseshoe kidney, caused by de novo variants in the degron of AFF3. Mouse knock-ins and overexpression in zebrafish provided evidence for a dominant-negative mode of action, wherein an increased level of AFF3 resulted in pathological effects. METHODS: Evolutionary constraints suggest that other modes-of-inheritance could be at play. We challenged this hypothesis by screening ID cohorts for individuals with predicted-to-be damaging variants in AFF3. We used both animal and cellular models to assess the deleteriousness of the identified variants. RESULTS: We identified an individual with a KINSSHIP-like phenotype carrying a de novo partial duplication of AFF3 further strengthening the hypothesis that an increased level of AFF3 is pathological. We also detected seventeen individuals displaying a milder syndrome with either heterozygous Loss-of-Function (LoF) or biallelic missense variants in AFF3. Consistent with semi-dominance, we discovered three patients with homozygous LoF and one compound heterozygote for a LoF and a missense variant, who presented more severe phenotypes than their heterozygous parents. Matching zebrafish knockdowns exhibit neurological defects that could be rescued by expressing human AFF3 mRNA, confirming their association with the ablation of aff3. Conversely, some of the human AFF3 mRNAs carrying missense variants identified in affected individuals did not rescue these phenotypes. Overexpression of mutated AFF3 mRNAs in zebrafish embryos produced a significant increase of abnormal larvae compared to wild-type overexpression further demonstrating deleteriousness. To further assess the effect of AFF3 variation, we profiled the transcriptome of fibroblasts from affected individuals and engineered isogenic cells harboring + / + , KINSSHIP/KINSSHIP, LoF/ + , LoF/LoF or KINSSHIP/LoF AFF3 genotypes. The expression of more than a third of the AFF3 bound loci is modified in either the KINSSHIP/KINSSHIP or the LoF/LoF lines. While the same pathways are affected, only about one third of the differentially expressed genes are common to the homozygote datasets, indicating that AFF3 LoF and KINSSHIP variants largely modulate transcriptomes differently, e.g. the DNA repair pathway displayed opposite modulation. CONCLUSIONS: Our results and the high pleiotropy shown by variation at this locus suggest that minute changes in AFF3 function are deleterious.

Variant-specific pathophysiological mechanisms of AFF3 differently influence transcriptome profiles.

Background: We previously described the KINSSHIP syndrome, an autosomal dominant disorder associated with intellectual disability (ID), mesomelic dysplasia and horseshoe kidney,caused by de novo variants in the degron of AFF3. Mouse knock-ins and overexpression in zebrafish provided evidence for a dominant-negative (DN) mode-of-action, wherein an increased level of AFF3 resulted in pathological effects. Methods: Evolutionary constraints suggest that other mode-of-inheritance could be at play. We challenged this hypothesis by screening ID cohorts for individuals with predicted-to-be deleterious variants in AFF3. We used both animal and cellular models to assess the deleteriousness of the identified variants. Results: We identified an individual with a KINSSHIP-like phenotype carrying a de novo partial duplication of AFF3 further strengthening the hypothesis that an increased level of AFF3 is pathological. We also detected seventeen individuals displaying a milder syndrome with either heterozygous LoF or biallelic missense variants in AFF3. Consistent with semi-dominance, we discovered three patients with homozygous LoF and one compound heterozygote for a LoF and a missense variant, who presented more severe phenotypes than their heterozygous parents. Matching zebrafish knockdowns exhibit neurological defects that could be rescued by expressing human AFF3 mRNA, confirming their association with the ablation of aff3. Conversely, some of the human AFF3 mRNAs carrying missense variants identified in affected individuals did not complement. Overexpression of mutated AFF3 mRNAs in zebrafish embryos produced a significant increase of abnormal larvae compared to wild-type overexpression further demonstrating deleteriousness. To further assess the effect of AFF3 variation, we profiled the transcriptome of fibroblasts from affected individuals and engineered isogenic cells harboring +/+, DN/DN, LoF/+, LoF/LoF or DN/LoF AFF3 genotypes. The expression of more than a third of the AFF3 bound loci is modified in either the DN/DN or the LoF/LoF lines. While the same pathways are affected, only about one-third of the differentially expressed genes are common to these homozygote datasets, indicating that AFF3 LoF and DN variants largely modulate transcriptomes differently, e.g. the DNA repair pathway displayed opposite modulation. Conclusions: Our results and the high pleiotropy shown by variation at this locus suggest that minute changes in AFF3 function are deleterious.

A de novo heterozygous HOXA11 variant in a patient with mesomelic dysplasia with urogenital abnormalities.

Mesomelic dysplasias are a genetically and clinically heterogeneous group of diseases with more than 10 types defined. This article presents an 18-year-old female patient with normal intelligence and a multisystem phenotype including disproportionate short stature, scoliosis, mesomelic limb shortening, radial bowing, short fourth to fifth metacarpals and metatarsals, fusions in the carpal/tarsal bones, operated pes equinovarus, primary amenorrhea, uterine hypoplasia, vesicoureteral reflux, and chronic kidney disease. Whole-exome sequencing revealed a de novo heterozygous c.881T>G (p.Met294Arg) variant in HOXA11 (NM_005523.6) gene. The variant was located in the homeodomain of HOXA11 and predicted to alter DNA-binding ability of the protein. In silico analyses indicated that the variant could promote the alterations in the protein-protein interaction. The possible functional effect of the variant was supposed as dominant-negative. Hoxa11-mutant mice have been reported to exhibit homeotic transformations in the thoracic and sacral vertebrae, zeugopodal phenotype in forelimb and hindlimb, and urogenital abnormalities. Although mice models were reported as mesomelic dysplasia and urogenital abnormalities (MDUGA), this phenotype has not yet been reported in humans. This was the first case with MDUGA putatively related to a de novo variant in HOXA11.

Variants in the degron of AFF3 are associated with intellectual disability, mesomelic dysplasia, horseshoe kidney, and epileptic encephalopathy.

The ALF transcription factor paralogs, AFF1, AFF2, AFF3, and AFF4, are components of the transcriptional super elongation complex that regulates expression of genes involved in neurogenesis and development. We describe an autosomal dominant disorder associated with de novo missense variants in the degron of AFF3, a nine amino acid sequence important for its binding to ubiquitin ligase, or with de novo deletions of this region. The sixteen affected individuals we identified, along with two previously reported individuals, present with a recognizable pattern of anomalies, which we named KINSSHIP syndrome (KI for horseshoe kidney, NS for Nievergelt/Savarirayan type of mesomelic dysplasia, S for seizures, H for hypertrichosis, I for intellectual disability, and P for pulmonary involvement), partially overlapping the AFF4-associated CHOPS syndrome. Whereas homozygous Aff3 knockout mice display skeletal anomalies, kidney defects, brain malformations, and neurological anomalies, knockin animals modeling one of the microdeletions and the most common of the missense variants identified in affected individuals presented with lower mesomelic limb deformities like KINSSHIP-affected individuals and early lethality, respectively. Overexpression of AFF3 in zebrafish resulted in body axis anomalies, providing some support for the pathological effect of increased amount of AFF3. The only partial phenotypic overlap of AFF3- and AFF4-associated syndromes and the previously published transcriptome analyses of ALF transcription factors suggest that these factors are not redundant and each contributes uniquely to proper development.

Concomitant rhomboid-shaped tibiae and fibulae, finger-like projections, and orthopedic management in a new variant of nievergelt syndrome: A case report.

INTRODUCTION: The rare Nievergelt syndrome (NS) is the most severe form of mesomelic dysplasia and is characterized by disproportionate shortness of the limbs. The aim of this case report was to describe the clinical and radiological features of a rare case of NS. PRESENTATION OF CASE: Here we describe a female patient originally presenting with bilateral hand, lower leg, and foot deformities at the age of 10 years old. In addition to the characteristic features of NS, this patient presented with finger-like projections on her heels, bilateral hand anomalies, and atypical facial features. She underwent concomitant bilateral tibial lengthening and deformity correction using external fixators due to severe bilateral lower leg deformities with shortness. At 10 years of age, this patient was able to walk independently with significant improvement in her ambulation. DISCUSSION: There is a clear gap in the literature regarding the orthopedic management of mesomelic limb deformities due to NS. No studies have been designed to illustrate surgical planning in the management of orthopedic deformities in this rare syndrome. CONCLUSION: Limb lengthening and deformity correction using an external fixator can be considered as a salvage method or alternative to amputation for patients with severe mesomelic limb deformities due to NS.

Expanding the Clinical Spectrum of Phenotypes Caused by Pathogenic Variants in PLOD2.

Osteogenesis imperfecta (OI) is a strikingly heterogeneous group of disorders with a broad range of phenotypic variations. It is also one of the differential diagnoses in bent bone dysplasias along with campomelic dysplasia and thanatophoric dysplasia and can usually be distinguished by decreased bone mineralization and bone fractures. Bent bone dysplasias also include syndromes such as kyphomelic dysplasia (MIM:211350) and mesomelic dysplasia Kozlowski-Reardon (MIM249710), both of which have been under debate regarding whether or not they are a real entity or simply a phenotypic manifestation of another dysplasia including OI. Bruck syndrome type 2 (BRKS2; MIM:609220) is a rare form of autosomal recessive OI caused by biallelic PLOD2 variants and is associated with congenital joint contractures with pterygia. In this report, we present six patients from four families with novel PLOD2 variants. All cases had multiple fractures. Other features ranged from prenatal lethal severe angulation of the long bones as in kyphomelic dysplasia and mesomelic dysplasia Kozlowski-Reardon through classical Bruck syndrome to moderate OI with normal joints. Two siblings with a kyphomelic dysplasia-like phenotype who were stillborn had compound heterozygous variants in PLOD2 (p.Asp585Val and p.Ser166*). One infant who succumbed at age 4 months had a bent bone phenotype phenotypically like skeletal dysplasia Kozlowski-Reardon (with mesomelic shortening, camptodactyly, retrognathia, cleft palate, skin dimples, but also with fractures). He was homozygous for the nonsense variant (p.Trp561*). Two siblings had various degrees of Bruck syndrome caused by the homozygous missense variant, p.His687Arg. Furthermore a boy with a clinical presentation of moderate OI had a possibly pathogenic homozygous variant p.Trp588Cys. Our experience of six patients with biallelic pathogenic variants in PLOD2 expands the phenotypic spectrum in the PLOD2-related phenotypes. © 2017 American Society for Bone and Mineral Research.

A unique phenotype of 2q24.3-2q32.1 duplication: early infantile epileptic encephalopathy without mesomelic dysplasia.

The voltage-gated sodium channel genes and HOXD genes are clustered on chromosome 2q, and duplication of this region is associated with 2 clinical phenotypes: early-onset epilepsy and mesomelic dysplasia Kantaputra type, respectively. We report a case involving 2q24.3-2q32.1 duplication encompassing both the voltage-gated sodium channel and HOXD gene clusters, which were detected by a comparative genomic hybridization array. The associated clinical features were early-infantile-onset epilepsy, hypoplastic left heart syndrome, and global developmental delay. However, no features of mesomelic dysplasia were found. A fluorescent in situ hybridization study showed that the noncontiguous insertion of the duplicated chromosome 2q segment into chromosome 6q was inherited from the father, who has a balanced insertional translocation. The unique genotype-phenotype correlation in the present case suggests that dosage-sensitive effects might apply only to the voltage-gated sodium channel genes.

Compound heterozygous deletions in pseudoautosomal region 1 in an infant with mild manifestations of langer mesomelic dysplasia.

Haploinsufficiency of SHOX on the short arm pseudoautosomal region (PAR1) leads to Leri-Weill dyschondrosteosis (LWD), and nullizygosity of SHOX results in Langer mesomelic dysplasia (LMD). Molecular defects of LWD/LMD include various microdeletions in PAR1 that involve exons and/or the putative upstream or downstream enhancer regions of SHOX, as well as several intragenic mutations. Here, we report on a Japanese male infant with mild manifestations of LMD and hitherto unreported microdeletions in PAR1. Clinical analysis revealed mesomelic short stature with various radiological findings indicative of LMD. Molecular analyses identified compound heterozygous deletions, that is, a maternally inherited ∼46 kb deletion involving the upstream region and exons 1-5 of SHOX, and a paternally inherited ∼500 kb deletion started from a position ∼300 kb downstream from SHOX. In silico analysis revealed that the downstream deletion did not affect the known putative enhancer regions of SHOX, although it encompassed several non-coding elements which were well conserved among various species with SHOX orthologs. These results provide the possibility of the presence of a novel enhancer for SHOX in the genomic region ∼300 to ∼800 kb downstream of the start codon.

Short stature homeoboxcontaining gene and idiopathic short stature.

The term idiopathic short stature (ISS) refers to patients who are short due to various unknown reasons. Although it is clear that multiple factors contribute to final height, genetic factors play a crucial role. Mutations of a human homeobox gene, short stature homeobox-containing (SHOX) gene, have been shown to be associated with the short stature phenotype in patients with Turner syndrome, most patients with Leri-Weill dyschondrosteosis and some cases of ISS. The prevalence of SHOX anomalies in subjects previously recognized as having ISS has been estimated at 2.4% in a large series of ISS individuals. This review focuses on the functional properties of the SHOX gene and its linkage to ISS.