Secreted ADAMTS-like 2 promotes myoblast differentiation by potentiating WNT signaling.

Myogenesis is the process that generates multinucleated contractile myofibers from muscle stem cells during skeletal muscle development and regeneration. Myogenesis is governed by myogenic regulatory transcription factors, including MYOD1. Here, we identified the secreted matricellular protein ADAMTS-like 2 (ADAMTSL2) as part of a Wnt-dependent positive feedback loop, which augmented or sustained MYOD1 expression and thus promoted myoblast differentiation. ADAMTSL2 depletion resulted in severe retardation of myoblast differentiation in vitro and its ablation in myogenic precursor cells resulted in aberrant skeletal muscle architecture. Mechanistically, ADAMTSL2 potentiated WNT signaling by binding to WNT ligands and WNT receptors. We identified the WNT-binding ADAMTSL2 peptide, which was sufficient to promote myogenesis in vitro. Since ADAMTSL2 was previously described as a negative regulator of TGFß signaling in fibroblasts, ADAMTSL2 now emerges as a signaling hub that could integrate WNT, TGFß and potentially other signaling pathways within the dynamic microenvironment of differentiating myoblasts during skeletal muscle development and regeneration.

Al-Gazali Skeletal Dysplasia Constitutes the Lethal End of ADAMTSL2-Related Disorders.

Lethal short-limb skeletal dysplasia Al-Gazali type (OMIM %601356), also called dysplastic cortical hyperostosis, Al-Gazali type, is an ultra-rare disorder previously reported in only three unrelated individuals. The genetic etiology for Al-Gazali skeletal dysplasia has up until now been unknown. Through international collaborative efforts involving seven clinical centers worldwide, a cohort of nine patients with clinical and radiographic features consistent with short-limb skeletal dysplasia Al-Gazali type was collected. The affected individuals presented with moderate intrauterine growth restriction, relative macrocephaly, hypertrichosis, large anterior fontanelle, short neck, short and stiff limbs with small hands and feet, severe brachydactyly, and generalized bone sclerosis with mild platyspondyly. Biallelic disease-causing variants in ADAMTSL2 were detected using massively parallel sequencing (MPS) and Sanger sequencing techniques. Six individuals were compound heterozygous and one individual was homozygous for pathogenic variants in ADAMTSL2. In one of the families, pathogenic variants were detected in parental samples only. Overall, this study sheds light on the genetic cause of Al-Gazali skeletal dysplasia and identifies it as a semi-lethal part of the spectrum of ADAMTSL2-related disorders. Furthermore, we highlight the importance of meticulous analysis of the pseudogene region of ADAMTSL2 where disease-causing variants might be located. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Advances in acromelic dysplasia caused by FBN1 mutation / 国际儿科学杂志

The mutation of FBN1 gene results in the abnormality of its encoded fibrillin-1 protein, which affects musculoskeletal growth and results in two opposing phenotypes of tall and short stature, with clinical manifestations of Marfan syndrome and acromelic dysplasia.Acromelic dysplasia caused by FBN1 mutation includes acromicric dysplasia(AD), geleophysic dysplasia(GD)and Weill-Marchesani syndrome(WMS). As some FBN1 mutations have been reported to cause both AD and GD.The dysregulation of TGF-β signal pathway is the underlying mechanism of acromelic dysplasia.Currently, there is no specific treatment, mainly symptomatic treatment, early identification, diagnosis and treatment will improve prognosis of patients.This article will review the pathogenesis, clinical phenotype, treatment and follow-up of acromelic dysplasia caused by FBN1 mutation.

FBN1 gene mutation in a Chinese pedigree of mild Geleophysic dysplasia type 2/Acromicric dysplasia and the exploration of growth-promoting therapy / 中华内分泌代谢杂志

Objective:To summarize the clinical and genetic features of 7 patients with a mild form of Geleophysic dysplasia type 2(GD2)/Acromicric dysplasia(AD) induced by fibrillin 1(FBN1) gene mutation from one Chinese family.Methods:A Chinese pedigree of mild GD2/AD treated at the Pediatric Endocrinology Department at the First Affiliated Hospital of Sun Yat-sen University between August 2017 and May 2022 was collected. Whole-exome genetic sequencing of the FBN1 gene were performed to establish the diagnosis. Additionally, a literature review was further conducted.Results:In this family, among 13 individuals spanning three generations, there were 7 affected cases, including 1 adult female, 1 adult male, and 5 children. All individuals exhibited postnatal growth failure, severe disproportionate short stature, and lacked typical facial features. Exome sequencing and Sanger sequencing confirmed the presence of a heterozygous missense mutation c. 5099A>G(p.Tyr1700Cys) in exon 42 of the FBNI gene in 6 affected individuals(Ⅱ-1, Ⅲ-1 to Ⅲ-5), which was identified as a pathogenic mutation. This mutation was previously reported in a Chinese classical achondroplasia(AD) family. Based on comprehensive genetic analysis, clinical features, and multisystem evaluation, 3 cases were diagnosed with mild type 2 growth hormone deficiency(GD2), and 4 cases were diagnosed with mild AD. Recombinant human growth hormone(rhGH; 1.1-1.4 IU·kg -1·week -1) was applied to all the 5 children, and additional gonadotropin releasing hormone analogue(GnRHa) was administered to the 2 girls in late puberty, resulting in certain growth-promoting effect. Conclusions:The c. 5099A>G(p.Tyr1700Cys) mutation not only leads to the classical type of achondroplasia(AD) as reported in the literature but also causes the non-classical GD2 or AD(mild GD2/AD). Further research is warranted to investigate the long-term therapeutic effects of rhGH treatment.

Case report: A homozygous ADAMTSL2 missense variant causes geleophysic dysplasia with high similarity to Weill-Marchesani syndrome.

Background: Geleophysic dysplasia and Weill-Marchesani syndrome from the acromelic dysplasias group of genetic skeletal disorders share remarkable clinical and genetic overlap. Methods: Ophthalmological, physical, radiological examinations were conducted with a female patient in her early 30 s. Whole exome sequencing followed by Sanger sequencing validation was performed to identify the genetic cause. Results: The patient, born to consanguineous Chinese parents, presented with microspherophakia, lens subluxation, high myopia, short statue, small hands and feet, stiff joints, and thickened skin. A diagnosis of Weill-Marchesani syndrome was initially made for her. However, genetic testing reveals that the patient is homozygous for the c.1966G>A (p.Gly656Ser) variant in ADAMTSL2, and that the patient's healthy mother and daughter are heterozygous for the variant. As mutations in ADAMTSL2 are known to cause autosomal recessive geleophysic dysplasia, the patient is re-diagnosed with geleophysic dysplasia in terms of her genotype and phenotype. Conclusion: The present study describes the clinical phenotype of the homozygous ADAMTSL2 p. Gly656Ser variant, which increases our understanding of the genotype-phenotype correlation in acromelic dysplasias.

Valve Replacement for Progressive Mitral Valve Stenosis Associated with Geleophysic Dysplasia / 日本心臓血管外科学会雑誌

The patient was an 8-years- and 4-months old girl. At the age of one, she visited a previous doctor with hepatomegaly and liver dysfunction. As a result of the examination, she was diagnosed with geleophysic dysplasia. Other than the heart, she was followed in genetics, ophthalmology, orthopedics, endocrinology, and otolaryngology. At 3 years and 5 months, she was first examined by the cardiology department and was found to have mild mitral regurgitation and aortic valve stenosis, and was followed up once a year. The patient was referred to our hospital at 7 years and 11 months, and the cardiac catheterization performed at 8 years and 2 months showed mild mitral valve regurgitation, but the mean pressure gradient was 16 mmHg and the mitral valve area was 0.60 cm2 (MVAi 0.97 cm2/m2), and mitral valve stenosis was observed. The left atrial pressure was as high as 25 mmHg and the average pulmonary artery pressure was as high as 36 mmHg, and pulmonary hypertension was also observed. Intraoperative findings demonstrated that the mitral valve had a marked thickening of the leaflet, the papillary muscles and chordae were also thickened, and the effective valve opening area was narrowed. The leaflet and subvalvular tissue were resected as much as possible and mechanical valve replacement was performed. Postoperatively, the patient recovered satisfactorily and was discharged on the 16th postoperative day. Pathological findings showed no major disturbance in the layered structure of the papillary muscle or the leaflet itself, but it was highly thickened due to mucous degeneration of the leaflet. We report our experience with the rare case described above.

Geleophysic dysplasia caused by a mutation in FBN1: A case report.

BACKGROUND: Geleophysic dysplasia (GD) presents the characterized clinical manifestations of acromelic dysplasia, including extremely short stature, short limbs, small hands and feet, stubby fingers and toes, joint stiffness and others. It is clinically distinct from the other acromelic dysplasia in terms of symptoms such as cardiac valvular abnormalities, progressive hepatomegaly and tracheal stenosis. CASE SUMMARY: We report on a Chinese 9-year-old girl with GD with the c.5243G>T (p.C1748F) mutation in FBN1 (fibrillin 1, OMIM 134797). She was born in Guangxi Zhuang Autonomous Region of China. The patient presented with typical clinical features of GD and recurrent respiratory tract infections over 6 years. Laboratory studies and chest computed tomography (CT) scan indicated bronchopneumonia. Her echocardiography revealed mild mitral valve thickening with regurgitation. Laryngopharyngeal CT and electronic bronchoscopy revealed severe glottic stenosis. Echocardiography examination displayed mild mitral valve thickening and regurgitation. Ophthalmic examination did not reveal myopia or lens dislocation. Treated with ceftriaxone sodium and methylprednisolone sodium succinate for injection as well as methylprednisolone orally, patient's symptoms had improved. CONCLUSION: GD is a rare genetic condition that can cause life-threatening cardiovascular and respiratory problems. This study also found that the identified genotype of GD could be related to different clinical phenotypes.

A Review of Three Chinese Cases of Acromicric/Geleophysic Dysplasia with FBN1 Mutations.

OBJECTIVE: This study aims to explore the clinical features and molecular diagnosis of FBN1-related acromelic dysplasia in Chinese patients. METHODS: The clinical and genetic features of three FBN1-related acromicric dysplasia (AD)/geleophysic dysplasia (GD) Chinese patients from two families were reviewed, and comprehensive medical evaluations were performed. Targeted next-generation sequencing was used to detect genetic mutations associated with short statures, including FBN1. Sanger sequencing was used to determine the de novo mutation origin. RESULTS: Patient 1 presented with short stature, short and stubby hands and feet, mild facial dysmorphism, hepatomegaly, delayed bone age and beak-like femoral heads. Patient 2 and this patient's father merely presented with short stature, wide and short hands, and beak-like femoral heads. One novel mutation, c.5272G>T(p.D1758Y), and one known mutation, c.5183C>T(p.A1728V), were identified in these patients. CONCLUSION: The clinical features varied among these patients. The variant c.5272G>T(p.D1758Y) is a novel mutation.

Acromelic dysplasias: how rare musculoskeletal disorders reveal biological functions of extracellular matrix proteins.

Acromelic dysplasias are a group of rare musculoskeletal disorders that collectively present with short stature, pseudomuscular build, stiff joints, and tight skin. Acromelic dysplasias are caused by mutations in genes (FBN1, ADAMTSL2, ADAMTS10, ADAMTS17, LTBP2, and LTBP3) that encode secreted extracellular matrix proteins, and in SMAD4, an intracellular coregulator of transforming growth factor-ß (TGF-ß) signaling. The shared musculoskeletal presentations in acromelic dysplasias suggest that these proteins cooperate in a biological pathway, but also fulfill distinct roles in specific tissues that are affected in individual disorders of the acromelic dysplasia group. In addition, most of the affected proteins directly interact with fibrillin microfibrils in the extracellular matrix and have been linked to the regulation of TGF-ß signaling. Together with recently developed knockout mouse models targeting the affected genes, novel insights into molecular mechanisms of how these proteins regulate musculoskeletal development and homeostasis have emerged. Here, we summarize the current knowledge highlighting pathogenic mechanisms of the different disorders that compose acromelic dysplasias and provide an overview of the emerging biological roles of the individual proteins that are compromised. Finally, we develop a conceptual model of how these proteins may interact and form an "acromelic dysplasia complex" on fibrillin microfibrils in connective tissues of the musculoskeletal system.

O-Fucosylation of ADAMTSL2 is required for secretion and is impacted by geleophysic dysplasia-causing mutations.

ADAMTSL2 mutations cause an autosomal recessive connective tissue disorder, geleophysic dysplasia 1 (GPHYSD1), which is characterized by short stature, small hands and feet, and cardiac defects. ADAMTSL2 is a matricellular protein previously shown to interact with latent transforming growth factor-ß binding protein 1 and influence assembly of fibrillin 1 microfibrils. ADAMTSL2 contains seven thrombospondin type-1 repeats (TSRs), six of which contain the consensus sequence for O-fucosylation by protein O-fucosyltransferase 2 (POFUT2). O-fucose-modified TSRs are subsequently elongated to a glucose ß1-3-fucose (GlcFuc) disaccharide by ß1,3-glucosyltransferase (B3GLCT). B3GLCT mutations cause Peters Plus Syndrome (PTRPLS), which is characterized by skeletal defects similar to GPHYSD1. Several ADAMTSL2 TSRs also have consensus sequences for C-mannosylation. Six reported GPHYSD1 mutations occur within the TSRs and two lie near O-fucosylation sites. To investigate the effects of TSR glycosylation on ADAMTSL2 function, we used MS to identify glycan modifications at predicted consensus sequences on mouse ADAMTSL2. We found that most TSRs were modified with the GlcFuc disaccharide at high stoichiometry at O-fucosylation sites and variable mannose stoichiometry at C-mannosylation sites. Loss of ADAMTSL2 secretion in POFUT2-/- but not in B3GLCT-/- cells suggested that impaired ADAMTSL2 secretion is not responsible for skeletal defects in PTRPLS patients. In contrast, secretion was significantly reduced for ADAMTSL2 carrying GPHYSD1 mutations (S641L in TSR3 and G817R in TSR6), and S641L eliminated O-fucosylation of TSR3. These results provide evidence that abnormalities in GPHYSD1 patients with this mutation are caused by loss of O-fucosylation on TSR3 and impaired ADAMTSL2 secretion.

Geleophysic dysplasia: novel missense variants and insights into ADAMTSL2 intracellular trafficking.

Geleophysic dysplasia (GPHYSD1, MIM231050; GPHYSD2, MIM614185; GPHYSD3, MIM617809) is an autosomal disorder characterized by short-limb dwarfism, brachydactyly, cardiac valvular disease, and laryngotracheal stenosis. Mutations in ADAMTSL2, FBN1, and LTBP3 genes are responsible for this condition. We found that three previously described cases of GPHYSD diagnosed clinically were homozygote or compound heterozygotes for five ADAMTSL2 variants, four of which not being previously reported. By electron microscopy, skin fibroblasts available in one case homozygote for an ADAMTSL2 variant showed a defective intracellular localization of mutant ADAMTSL2 protein that did not accumulate within lysosome-like intra-cytoplasmic inclusions. Moreover, this mutant ADAMTSL2 protein was less secreted in medium and resulted in increased SMAD2 phosphorylation in transfected HEK293 cells.

Skin fibroblasts of patients with geleophysic dysplasia due to FBN1 mutations have lysosomal inclusions and losartan improves their microfibril deposition defect.

BACKGROUND: Geleophysic dysplasia (GPHYSD) is a disorder characterized by dysmorphic features, stiff joints and cardiac involvement due to defects of TGF-ß signaling. GPHYSD can be caused by mutations in FBN1, ADAMTLS2, and LTBP3 genes. METHODS AND RESULTS: Consistent with previous reports, we found intracellular inclusions of unknown material by electron microscopy (EM) in skin fibroblasts of two GPHYSD individuals carrying FBN1 mutations. Moreover, we found that the storage material is enclosed within lysosomes and is associated with the upregulation of several lysosomal genes. Treatment of GPHYSD fibroblasts carrying FBN1 mutations with the angiotensin II receptor type 1 inhibitor losartan that inhibits TGF-ß signaling did not reduce the storage but improved the extracellular deposition of fibrillin-1 microfibrils. CONCLUSION: Losartan is a promising candidate drug for treatment of GPHYSD due to FBN1 defects.

Limb- and tendon-specific Adamtsl2 deletion identifies a role for ADAMTSL2 in tendon growth in a mouse model for geleophysic dysplasia.

Geleophysic dysplasia is a rare, frequently lethal condition characterized by severe short stature with progressive joint contractures, cardiac, pulmonary, and skin anomalies. Geleophysic dysplasia results from dominant fibrillin-1 (FBN1) or recessive ADAMTSL2 mutations, suggesting a functional link between ADAMTSL2 and fibrillin microfibrils. Mice lacking ADAMTSL2 die at birth, which has precluded analysis of postnatal limb development and mechanisms underlying the skeletal anomalies of geleophysic dysplasia. Here, detailed expression analysis of Adamtsl2 using an intragenic lacZ reporter shows strong Adamtsl2 expression in limb tendons. Expression in developing and growing bones is present in regions that are destined to become articular cartilage but is absent in growth plate cartilage. Consistent with strong tendon expression, Adamtsl2 conditional deletion in limb mesenchyme using Prx1-Cre led to tendon anomalies, albeit with normal collagen fibrils, and distal limb shortening, providing a mouse model for geleophysic dysplasia. Unexpectedly, conditional Adamtsl2 deletion using Scx-Cre, a tendon-specific Cre-deleter strain, which does not delete in cartilage, also impaired skeletal growth. Recombinant ADAMTSL2 is shown here to colocalize with fibrillin microfibrils in vitro, and enhanced staining of fibrillin-1 microfibrils was observed in Prx1-Cre Adamtsl2 tendons. The findings show that ADAMTSL2 specifically regulates microfibril assembly in tendons and that proper microfibril composition in tendons is necessary for tendon growth. We speculate that reduced bone growth in geleophysic dysplasia may result from external tethering by short tendons rather than intrinsic growth plate anomalies. Taken together with previous work, we suggest that GD results from abnormal microfibril assembly in tissues, and that ADAMTSL2 may limit the assembly of fibrillin microfibrils.

Fibrillin protein pleiotropy: Acromelic dysplasias.

The fibrillins are large extracellular matrix molecules that polymerize to form microfibrils. Fibrillin microfibrils are distinctive architectural elements that are both ubiquitous in the connective tissue space and also unique, displaying tissue-specific patterns. Mutations in the genes for fibrillin-1 (FBN1) result in multiple distinct pleiotropic disorders. Most of the more than 3000 mutations known today in FBN1 cause the Marfan syndrome. Marfan mutations can occur in any of the 56 domains that compose fibrillin-1. In contrast, rare mutations in FBN1 that are confined to only certain domains cause several different types of acromelic dysplasia. These genetic disorders demonstrate that specific domains of fibrillin-1 perform roles important to musculoskeletal growth. Many of the phenotypes of acromelic dysplasias are the opposite of those found in Marfan syndrome. Knowledge of the functions and structural organization of fibrillin molecules within microfibrils is required to understand how one protein and one gene can be the basis for multiple genetic disorders.

Impairment of chondrogenesis and microfibrillar network in Adamtsl2 deficiency.

Mutations in the a disintegrin and metalloproteinase with thrombospondin motif-like 2 ( ADAMTSL2) gene are responsible for the autosomal recessive form of geleophysic dysplasia, which is characterized by short stature, short extremities, and skeletal abnormalities. However, the exact function of ADAMTSL2 is unknown. To elucidate the role of this protein in skeletal development, we generated complementary knockout (KO) mouse models with either total or chondrocyte Adamtsl2 deficiency. We observed that the Adamtsl2 KO mice displayed skeletal abnormalities reminiscent of the human phenotype. Adamtsl2 deletion affected the growth plate formation with abnormal differentiation and proliferation of chondrocytes. In addition, a TGF-ß signaling impairment in limbs lacking Adamtsl2 was demonstrated. Further investigations revealed that Adamtsl2 KO chondrocytes failed to establish a microfibrillar network composed by fibrillin1 and latent TGF-ß binding protein 1 fibrils. Chondrocyte Adamtsl2 KO mice also exhibited dwarfism. These studies uncover the function of Adamtsl2 in the maintenance of the growth plate ECM by modulating the microfibrillar network.-Delhon, L., Mahaut, C., Goudin, N., Gaudas, E., Piquand, K., Le Goff, W., Cormier-Daire, V., Le Goff, C. Impairment of chondrogenesis and microfibrillar network in Adamtsl2 deficiency.

Geleophysic dysplasia: 48 year clinical update with emphasis on cardiac care.

Geleophysic dysplasia is a rare skeletal dysplasia often complicated by progressive cardiac disease. Information about long-term outcomes is limited. A clinical update of the oldest surviving patient described with geleophysic dysplasia type 1 is provided. Special note is made in relation to the cardiac disease and interventions. Genetic testing of ADAMTSL2 revealed a previously reported missense mutation as well as a novel nonsense mutation, which can be added to the list of causative mutations in geleophysic dysplasia.

A report of three families with FBN1-related acromelic dysplasias and review of literature for genotype-phenotype correlation in geleophysic dysplasia.

Acromelic dysplasia is a heterogeneous group of rare skeletal dysplasias characterized by distal limb shortening. Weill-Marchesani syndrome (WMS), Geleophysic dysplasia (GD) and Acromicric dysplasia (AD) are clinically distinct entities within this group of disorders and are characterized by short stature, short hands, stiff joints, skin thickening, facial anomalies, normal intelligence and skeletal abnormalities. Mutations of the Fibrillin-1 (FBN1) gene have been reported to cause AD, GD and related phenotypes. We reported three families with acromelic short stature. FBN1 analysis showed that all affected individuals carry a heterozygous missense mutation c.5284G > A (p.Gly1762Ser) in exon 42 of the FBN1 gene. This mutation was previously reported to be associated with GD. We reviewed the literature and compared the clinical features of the patients with FBN1 mutations to those with A Distintegrin And Metalloproteinase with Thrombospondin repeats-like 2 gene (ADAMTSL2) mutations. We found that tip-toeing gait, long flat philtrum and thin upper upper lip were more consistently found in GD patients with ADAMTSL2 mutations than in those with FBN1 mutations. The results have shed some light on the phenotype-genotype correlation in this group of skeletal disorders. A large scale study involving multidisciplinary collaboration would be needed to consolidate our findings.

A chinese boy with geleophysic dysplasia caused by compound heterozygous mutations in ADAMTSL2.

Geleophysic dysplasia, belonging to the group of acromelic dysplasia, is a rare genetic disease. Two genes, FBN1 and ADAMTSL2, were known to be linked to this disorder. The disorder presents as extreme short stature, short limbs, small hands and feet, stubby fingers and toes, joint stiffness, toe walking, skin thickening, progressive cardiac valvular thickening and characteristic facial features, including a round face with full cheeks. Here, we report the first Chinese case with geleophysic dysplasia type 1 based on clinical and genetic features. The boy was admitted because of severe physical growth retardation and mild motor retardation. Comprehensive medical evaluations were performed including metabolic studies, endocrine function examination, bone X-rays and echocardiography. Much delayed bone age and geleophysic dysplasia were found. Targeted next-generation sequencing was used to detect genetic mutations associated with skeletal dysplasia. Sanger sequencing was used to confirm the mutations in the patient. PCR amplification, cloing, and sequencing was used to determine the de novo mutation origin. Two compound heterozygous mutations were confirmed in the ADAMTSL2 gene of the patient. The c.340G > A (p.Glu114Lys) mutation was a de novo heterozygous mutation, and our results suggested that it was located on the paternal allele. While the c.234-2A > G inherited from his mother was a novel pathogenic heterozygous splicing mutation. Growth hormone deficiency had been observed in the patient. His growth velocity was improved by growth hormone supplementation. In conclusion, we have identified a novel splicing mutation of ADAMTSL2 carried by a Chinese boy with geleophysic dysplasia type 1. The patient was treated effectively with growth hormone supplementation.

Rapidly progressive mitral valve stenosis in patients with acromelic dysplasia.

Acromelic dysplasias are a group of skeletal dysplasias characterised by short-limbed short stature with other distinctive phenotypic features including small hands and feet and stiff joints. Geleophysic dysplasia is an acromelic dysplasia that is associated with characteristic facial features, progressive cardiac valvular thickening, and tracheal stenosis. Owing to overlapping clinical features with other types of short-limbed skeletal dysplasias, it is important to make a precise diagnosis as they have different cardiac morbidity and mortality. We present the cases of three patients with geleophysic dysplasia and progressive mitral valve disease to emphasise the natural history of this disorder and provide guidance regarding cardiac health supervision in these individuals.

Mutations in LTBP3 cause acromicric dysplasia and geleophysic dysplasia.

BACKGROUND: Acromelic dysplasias are a group of disorders characterised by short stature, brachydactyly, limited joint extension and thickened skin and comprises acromicric dysplasia (AD), geleophysic dysplasia (GD), Myhre syndrome and Weill-Marchesani syndrome. Mutations in several genes have been identified for these disorders (including latent transforming growth factor ß (TGF-ß)-binding protein-2 (LTBP2), ADAMTS10, ADAMSTS17 and fibrillin-1 (FBN1) for Weill-Marchesani syndrome, ADAMTSL2 for recessive GD and FBN1 for AD and dominant GD), encoding proteins involved in the microfibrillar network. However, not all cases have mutations in these genes. METHODS: Individuals negative for mutations in known acromelic dysplasia genes underwent whole exome sequencing. RESULTS: A heterozygous missense mutation (exon 14: c.2087C>G: p.Ser696Cys) in latent transforming growth factor ß (TGF-ß)-binding protein-3 (LTBP3) was identified in a dominant AD family. Two distinct de novo heterozygous LTPB3 mutations were also identified in two unrelated GD individuals who had died in early childhood from respiratory failure-a donor splice site mutation (exon 12 c.1846+5G>A) and a stop-loss mutation (exon 28: c.3912A>T: p.1304*Cysext*12). CONCLUSIONS: The constellation of features in these AD and GD cases, including postnatal growth retardation of long bones and lung involvement, is reminiscent of the null ltbp3 mice phenotype. We conclude that LTBP3 is a novel component of the microfibrillar network involved in the acromelic dysplasia spectrum.