Short-limbed Dwarfism Research Articles

Antenatal unilateral upper limb acromesomelic dysplasia.

Acromesomelic dysplasia (AMD) is an umbrella term given to a heterogeneous group of progressive skeletal disorders characterized by short limbed dwarfism associated with disproportionate shortening of middle and distal segments of the upper as well as lower limbs. Although specific skeletal anomalies are difficult to diagnose antenatally, but because of their antenatal and postnatal implications and a possibility of reoccurrence in following pregnancies, such skeletal anomalies need to be actively addressed. A combination of radiologic, pathologic, genetic and molecular investigation prenatally as well as postnatally is required to classify a specific congenital skeletal dysplasia. Once the genetic make-up of fetal skeletal dysplasia is deciphered, a meaningful genetic counselling could be offered for future pregnancies of affected families. We describe a case of primigravida diagnosed with fetal unilateral upper limb AMD on antenatal ultrasound done at early second trimester. The radius and ulna of left upper limb were abnormally short (less than 5th centile of the mean for that gestational age). The left hand was also hypoplastic. Rest of the sonographic anomaly scan was normal. To the best of our knowledge, AMD limited to unilateral upper limb diagnosed antenatally as an isolated finding is not described in the medical literature so far.

Surgical outcome after treatment of thoracolumbar spinal stenosis in adults with achondroplasia

PurposeTo describe the complications and the outcome of patients with achondroplasia undergoing thoracolumbar spinal surgery.MethodsRetrospective analysis of prospectively collected data of all patients with achondroplasia undergoing surgery within the years 1992–2021 at the thoracic and/or lumbar spine. The outcome was measured by analyzing the surgical complications and revisions. The patient-rated outcome was assessed with the COMI score from 2005 onwards.ResultsA total of 15 patients were included in this study undergoing a total of 31 surgeries at 79 thoracolumbar levels. 12/31 surgeries had intraoperative complications consisting of 11 dural tears and one excessive intraoperative bleeding. 4/18 revision surgeries were conducted due to post-decompression hyperkyphosis. The COMI score decreased from 7.5 IQR 1.4 (range 7.1–9.8) preoperatively to 5.3 IQR 4.1 (2.5–7.5) after 2 years (p = 0.046).ConclusionPatients with achondroplasia, the most common skeletal dysplasia condition with short-limb dwarfism, are burdened with a congenitally narrow spinal canal and are commonly in need of spinal surgery. However, surgery in these patients is often associated with complications, namely dural tears and post-decompression kyphosis. Despite these complications, patients benefit from surgical treatment at a follow-up of 2 years after surgery.

Thanatophoric Dysplasia: A Case Report and Literature Review

Thanatophoric dysplasia is a lethal skeletal dysplasia characterized by marked underdevelopment of the skeleton and short-limbed dwarfism [1]. The child will present with a short neck, narrow chest, and prominent abdomen. Other anatomical features include a relatively enlarged head with frontal prominence, prominent eyes, hypertelorism, and a depressed nasal bridge. Diagnosis is typically established by ultrasound in the second trimester of pregnancy. In this study, we report a case of this rare entity, emphasizing its anatomical characteristics, anomalies, and clinical profile, along with a relevant literature review.

SLC26A2 Related Diastrophic Dysplasia in 42-Years Ukrainian Women.

Diastrophic dysplasia (DTD) is an uncommon pathology which falls under the group of skeletal dysplasias with its first symptoms observed from birth. The pathology is often featured by short stature and abnormally short extremities (also known as short-limbed dwarfism); the osseous structures of the body (bones and joints) are characterized through defective development in many body regions. More than 300 genes were reported to be involved in DTD etiology with autosomal recessive, autosomal dominant and X-linked manner. We describe clinical case of a 42-year-old woman from the west of Ukraine with diastrophic dysplasia and two pathogenic variants c.1020_1022del (p.Val341del) and c.1957T>A (p.Cys653Ser) identified in SLC26A2 gene. SLC26A2-related diastrophic dysplasia was confirmed based on the presence of pathogenic variants in SLC26A2, which is associated with autosomal recessive forms of skeletal dysplasia, combined with phenotypic symptoms and radiographic findings.

Ellis-van Creveld sindrom

Introduction: Ellis-van Creveld syndrome is a rare genetic disorder characterized by short limb dwarfism, additional fingers and/or toes (polydactyly), abnormal development of fingernails and, in over half of the cases, congenital heart defects. Motor development and intelligence are normal. This disorder is inherited as an autosomal recessive condition. Some boys with this condition have been described with undescended testicles (cryptorchidism) or an abnormally located opening of the urine canal in the penis (epispadias). Abnormalities in the chest wall, spine and respiratory system have also been reported. Case report: The boy, aged two (2) years and eight (8) months, lives with parents and two brothers, in good living conditions. From the perinatal anamnesis, we can see that it is the third child from the third monitored pregnancy, delivered naturally at 39.gestational weeks, with normal birth parameters (3980/51/36), Apgar score 9. Immediately after birth, has been spotted complete postaxial polydactyly on both hands and postaxial poly-syndactyly (3,4,5,6) on the left foot, and ultrasound of the hips in early infancy indicated their unusual morphology and delayed bone maturation, which led to further medical investigation and treatment. Conclusion: Ellis-van Creveld syndrome is an extremely rare disease (this is the first registered case in our country). On the basis of this case, we want to express the importance of early diagnosis in order to improve the prognosis of the disease, and necessity of careful monitoring of these patients.

Grebe Syndrome - Case Report With Review of Literature

Grebe syndrome is a rare genetic condition characterized by short limb dwarfism. It is transmitted by autosomal mode of inheritance. There are no associated anomalies and the affected child has normal intelligence and normal life span. This syndrome has a very low incidence and needs to be differentiated from other forms of short limb dwarfism since treatment options may vary. We have described here a severely affected case of the same with review of literature.

Evaluation of FGFR inhibitor ASP5878 as a drug candidate for achondroplasia

Achondroplasia is caused by gain-of-function mutations in FGFR3 gene and leads to short-limb dwarfism. A stabilized analogue of C-type natriuretic peptide (CNP) is known to elongate bone by interacting with FGFR3 signals and thus is a promising drug candidate. However, it needs daily administration by percutaneous injection. FGFR inhibitor compounds are other drug candidates for achondroplasia because they directly fix the mutant protein malfunction. Although FGFR inhibitors elongate the bone of model mice, their adverse effects are not well studied. In this study, we found that a new FGFR inhibitor, ASP5878, which was originally developed as an anti-cancer drug, elongated the bone of achondroplasia model male mice at the dose of 300 μg/kg, which confers an AUC of 275 ng·h/ml in juvenile mice. Although ASP5878 was less effective in bone elongation than a CNP analogue, it is advantageous in that ASP5878 can be administered orally. The AUC at which minimal adverse effects were observed (very slight atrophy of the corneal epithelium) was 459 ng·h/ml in juvenile rats. The positive discrepancy between AUCs that brought efficacy and minimal adverse effect suggests the applicability of ASP5878 to achondroplasia in the clinical setting. We also analyzed effects of ASP5878 in a patient-specific induced pluripotent stem cell (iPSC) model for achondroplasia and found the effects on patient chondrocyte equivalents. Nevertheless, cautious consideration is needed when referring to safety data obtained from its application to adult patients with cancer in clinical tests.

Acrocapitofemoral dysplasia: Novel mutation in IHH in two adult patients from the third family in the literature and progression of the disease

Acrocapitofemoral dysplasia (ACFD) is a rare autosomal recessive skeletal dysplasia characterized by short stature with short limb dwarfism, brachydactyly, and a narrow thorax. Major radiographic features are egg-shaped capital femoral epiphyses with a short femoral neck and cone-shaped epiphyses, mainly in the hands and hips. To date, only four child patients from two families have been reported.We describe two adult patients with ACFD with a novel homozygous c.478C>T (p.Arg160Cys) mutation in IHH in the third family of the literature. The reported cases showed a middle phalanges which fused with distal phalanges in the fifth toes, the typical configuration of metacarpals, radial angulation and extremely short femoral neck. These findings could help the diagnosis of ACFD in adult patients. We hope that this new family will be a helpful guide for predicting and managing the prognosis of diagnosed children.

Sonographic Correlation of Fetal Foot Length as a Reliable Parameter for Estimation of Gestational Age in 2ND and 3RD Trimester

Objective : To sonographic correlation fetal foot length as a reliable parameter for estimation of gestational age in 2 nd and 3 rd trimester. Study Design : An analytical cross-sectional prospective study was performed. Settings : The study was performed in Meer Children and family clinic, Tajpora Lahore. Period: An analytical cross-sectional study was conducted from 15 October, 2021 to 15 January, 2021. Material & Methods : The present study is conducted in the in the Meer Children and Family Clinic Tajpura Lahore .In pregnant women attending the OPD during 2 nd and 3 rd trimester for routine checkups. The present study done in 60 normal pregnant women who were sure about their last menstrual period, have regular menstrual cycle, not experienced any vaginal bleeding. Ultrasonographic fetal foot length measurements was done without previous knowledge of gestational age and then the gestational age confirmed by biparietal diameter, abdominal circumference and head circumference . Results : The present study is conducted in 63 pragnent women between 15 to 35 weeks of gestational age attending the OPD for 2 nd and 3 rd trimester routine checkups the in the Meer Children and Family Clinic Tajpura Lahore . Sonographically we calculated foot length from 15 to 35 weeks of gestation. In our study to Early age at which fetal foot length could be seen and measured sonographically was found to be 15 weeks of gestation age. In 27 weeks of gestational age and mean foot length 83.67 with std. deviation 5.718 and std. Error Mean -720 and the mean value of foot length by gestational age is 93.33 with std. deviation and std. error mean 338.740 and 42.677 respectivly. Along with foot length bipraietal diameter(BPD),Abdominal circumference(AC),head circumference(HC) also measured for comparison. Conclusion : In the normal growing fetus the fetal foot length increases with increasing gestational age. Fetal foot length is a good parameter for gestational age especially in cases of femur achondroplasia, dolichocephaly or brachycephaly and in cases who are not sure about their L.M.P. Fetal foot length is used as an investigational implement to measured of gestational age in the late second and third trimesters of pregnancy. Fetal foot length was especially useful when other parameters did not correctly estimate gestational age, e.g., in cases of short-limb dwarfism hydrocephalus or anencephaly. Keywords: Gestational age, Fetal foot length, Ultrasonographically age estimation DOI: 10.7176/JHMN/93-04 Publication date: September 30 th 2021

Prevention of guanylyl cyclase-B dephosphorylation rescues achondroplastic dwarfism.

Activating mutations in the fibroblast growth factor receptor 3 (FGFR3) or inactivating mutations in guanylyl cyclase–B (GC-B), also known as NPR-B or Npr2, cause short-limbed dwarfism. FGFR3 activation causes dephosphorylation and inactivation of GC-B, but the contribution of GC-B dephosphorylation to achondroplasia (ACH) is unknown. GC-B7E/7E mice that express a glutamate-substituted version of GC-B that cannot be inactivated by dephosphorylation were bred with mice expressing FGFR3-G380R, the most common human ACH mutation, to determine if GC-B dephosphorylation is required for ACH. Crossing GC-B7E/7E mice with FGFR3G380R/G380R mice increased naso-anal and long (tibia and femur), but not cranial, bone length twice as much as crossing GC-B7E/7E mice with FGFR3WT/WT mice from 4 to 16 weeks of age. Consistent with increased GC-B activity rescuing ACH, long bones from the GC-B7E/7E/FGFR3G380R/G380R mice were not shorter than those from GC-BWT/WT/FGFR3WT/WT mice. At 2 weeks of age, male but not female FGFR3G380R/G380R mice had shorter long bones and smaller growth plate hypertrophic zones, whereas female but not male GC-B7E/7E mice had longer bones and larger hypertrophic zones. In 2-week-old males, crossing FGFR3G380R/G380R mice with GC-B7E/7E mice increased long bone length and hypertrophic zone area to levels observed in mice expressing WT versions of both receptors. We conclude that preventing GC-B dephosphorylation rescues reduced axial and appendicular skeleton growth in a mouse model of achondroplasia.

Management of progressive spine deformity in a child with pseudoachondroplasia

Short-limbed dwarfism, knock knees and joint hypermobility are the classical clinical criteria encountered in patients with pseudoachondroplasia. Progressive kyphoscoliosis was the main clinical presentation in our patients with pseudoachondroplasia. Preoperative spine radiographs in an 13-years-old-girl showed severe kyphoscoliotic deformity (kyphosis - 70o and scoliosis of Cobbs angle – 55o ). Keywords: Pseudoachondroplasia; COMP gene mutation.

An induced pluripotent stem cell line (GZHMCi004-A) derived from a fetus with heterozygous G380R mutation in FGFR3 gene causing achondroplasia

Achondroplasia (ACH; MIM #100800) is an autosomal dominant genetic disease caused by gain-of-function mutations in FGFR3 gene and results in short-limb dwarfism. Here, we generated an induced pluripotent stem cell line GZHMCi004-A derived from umbilical cord blood mononuclear cells (UCBMCs) of a fetus with heterozygous G380R mutation in FGFR3 gene. This iPSC line is a valuable in vitro model to study the pathological mechanism and the treatment of ACH.

Canine DVL2 variant contributes to brachycephalic phenotype and caudal vertebral anomalies

A frameshift deletion variant in the Wnt pathway gene dishevelled 2 (DVL2) is associated with a truncated, kinked tail (“screw tail”) in English Bulldogs, French Bulldogs and Boston Terriers. These breeds are also characterized by distinctive morphological traits, including a wide head, flat face and short-limbed dwarfism, which are characteristic of Robinow syndrome in humans, caused by defects in genes such as DVL1 and DVL3. Based on these phenotypic and genetic similarities, it has previously been hypothesized that the canine DVL2 variant results in a syndromic phenotype called the Robinow-like syndrome. In our study, we investigated the distribution of the DVL2 variant in 1954 dogs from 15 breeds, identifying breeds with allele variation and enabling the dissection of the genotype–phenotype correlation for the first time. With CT examinations in American Staffordshire Terriers, we confirmed that the DVL2 allele is associated with caudal vertebral malformations and a brachycephalic phenotype. We also hypothesize that the variant may be linked to additional health conditions, including brachycephalic obstructive airway syndrome and congenital heart defects. Altogether, our study strengthens the role of DVL2 as one of the contributors to the “bulldog type” morphology and features on the spectrum of human Robinow syndrome.

Evaluation of FGFR inhibitor ASP5878 as a drug candidate for achondroplasia

Achondroplasia is caused by gain-of-function mutations in FGFR3 gene and leads to short-limb dwarfism. A stabilized analogue of C-type natriuretic peptide (CNP) is known to elongate bone by interacting with FGFR3 signals and thus is a promising drug candidate. However, it needs daily administration by percutaneous injection. FGFR inhibitor compounds are other drug candidates for achondroplasia because they directly fix the mutant protein malfunction. Although FGFR inhibitors elongate the bone of model mice, their adverse effects are not well studied. In this study, we found that a new FGFR inhibitor, ASP5878, which was originally developed as an anti-cancer drug, elongated the bone of achondroplasia model male mice at the dose of 300 μg/kg, which confers an AUC of 275 ng·h/ml in juvenile mice. Although ASP5878 was less effective in bone elongation than a CNP analogue, it is advantageous in that ASP5878 can be administered orally. The AUC at which minimal adverse effects were observed (very slight atrophy of the corneal epithelium) was 459 ng·h/ml in juvenile rats. The positive discrepancy between AUCs that brought efficacy and minimal adverse effect suggests the applicability of ASP5878 to achondroplasia in the clinical setting. We also analyzed effects of ASP5878 in a patient-specific induced pluripotent stem cell (iPSC) model for achondroplasia and found the effects on patient chondrocyte equivalents. Nevertheless, cautious consideration is needed when referring to safety data obtained from its application to adult patients with cancer in clinical tests.

A SMOC2 variant inhibits BMP signaling by competitively binding to BMPR1B and causes growth plate defects.

Endochondral ossification is the major process of long bone formation, and chondrogenesis is the final step of this process. Several studies have indicated that bone morphogenetic proteins (BMPs) are required for chondrogenesis and regulate multiple growth plate features. Abnormal BMP pathways lead to growth plate defects, resulting in osteochondrodysplasia. The SPARC-related modular calcium binding 2 (SMOC2) gene encodes an extracellular protein that is considered to be an antagonist of BMP signaling. In this study, we generated a mouse model by knocking-in the SMOC2 mutation (c.1076T>G), which showed short-limbed dwarfism, reduced, disorganized, and hypocellular proliferative zones and expanded hypertrophic zones in tibial growth plates. To determine the underlying pathophysiological mechanism of SMOC2 mutation, we used knock-in mice to investigate the interaction between SMOC2 and the BMP-SMAD1/5/9 signaling pathway in vivo and in vitro. Eventually, we found that mutant SMOC2 could not bind to COL9A1 and HSPG. Furthermore, mutant SMOC2 inhibited BMP signaling by competitively binding to BMPR1B, which lead to defects in growth plates and short-limbed dwarfism in knock-in mice.

TO COMPARE ESTIMATION OF GESTATIONAL AGE BY FOETAL TRANSCEREBELLAR DIAMETER WITH BIPARIETAL DIAMETER`, FEMUR LENGTH, ABDOMINAL CIRCUMFERENCE, HEAD CIRCUMFERENCE AT DEPARTMENT OF OBSTETRICS AND GYNAECOLOGY AT SMS MEDICAL COLLEGE, JAIPUR

Background: Ultrasonographic assessment of gestational age by using different foetal parameter such as BPD, FL, AC are highly reliable in first and second trimester in pregnancy. In third trimester reliability of any single parameter has limitations.
 Methods: This was a hospital based comparative cross-sectional study done in the Department of Obstetrics and Gynaecology, S.M.S. Medical College and attached hospitals, Jaipur, Rajasthan. The period of study was from June 2018 to October 2019.
 Results: The mean TCD at 15 weeks and 40 weeks was 15.00 ± 0.00mm and 53.33±1.155mm respectively. The mean BPD at 16 weeks and 40 weeks was 33.50±0.70mm and 93±1.528mm respectively. The mean HC at 15 weeks and 40 weeks was 111.00±1,41mm and 340±2.00mm respectively. The mean FL at 15 weeks and 40 weeks was 18.50±0.70mm and 77.67±1.528mm respectively. The mean AC at 15 weeks and 40 weeks was 99.00±1.41mm and 365.33±8.32mm respectively.
 Conclusion: We conclude that foetal transcerebellar diameter can thus be used as an alternative foetal parameter to assess gestational age and can be used in cases of wrong dates or when other routine parameters are not conclusive or did not accurately predict gestational age for e.g. in cases of hydrocephalus, brachycephaly, dolicocephaly, intrauterine growth restriction, achondroplasia or short limb dwarfism.
 Keywords: Gestational age, Linear regression, BPD

Achondroplasia: a case report and the review of the basics

The achondroplasia is a variant of short-limbed dwarfism. The word achondroplasia literally means without cartilage formation. However, in achondroplasia the problem is not in formation of cartilage but, in its conversion to bone (i.e. ossification). This deficient ossification is particularly seen in the long bones of arm and leg. The characteristic external appearance of people born with achondroplasia is short stature. The average height of an adult male with achondroplasia is 131 centimetres (4 feet, 4 inches), and the average height for adult females is 124 centimetres (4 feet, 1 inch). The trunk is of average size but the leg and upper arm is of short length. It is because the femur and humerus are relatively shorter in length. The range of movement at elbow is limited. The head is enlarged called macrocephaly and is with a prominent forehead. People with Achondroplasia are generally of normal intelligence. They have bowed legs and abnormal curvature of spine giving rise to lordosis or kyphosis. They may develop spinal stenosis, which is associated with pain, tingling and weakness in leg. This may cause difficulty in walking. The other health problems associated with Achondroplasia are episodes of apnoea, obesity and recurrent ear infection. The purpose of this study is to evaluate the cardinal phenotypic features in patient of Achondroplasia. It is also to assess the body physique, anthropometric measurements and to study the typical radiological signs in such patients as the main tool of diagnosis.

CRELD2 Is a Novel LRP1 Chaperone That Regulates Noncanonical WNT Signaling in Skeletal Development.

Cysteine-rich with epidermal growth factor (EGF)-like domains 2 (CRELD2) is an endoplasmic reticulum (ER)-resident chaperone highly activated under ER stress in conditions such as chondrodysplasias; however, its role in healthy skeletal development is unknown. We show for the first time that cartilage-specific deletion of Creld2 results in disrupted endochondral ossification and short limbed dwarfism, whereas deletion of Creld2 in bone results in osteopenia, with a low bone density and altered trabecular architecture. Our study provides the first evidence that CRELD2 promotes the differentiation and maturation of skeletal cells by modulating noncanonical WNT4 signaling regulated by p38 MAPK. Furthermore, we show that CRELD2 is a novel chaperone for the receptor low-density lipoprotein receptor-related protein 1 (LRP1), promoting its transport to the cell surface, and that LRP1 directly regulates WNT4 expression in chondrocytes through TGF-β1 signaling. Therefore, our data provide a novel link between an ER-resident chaperone and the essential WNT signaling pathways active during skeletal differentiation that could be applicable in other WNT-responsive tissues. © 2020 American Society for Bone and Mineral Research. © 2020 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research..

Mutation analysis of the fibroblast growth factor receptor 3 gene in fetuses with thanatophoric dysplasia, type I

Objective: To analyze the fibroblast growth factor receptor 3 gene (FGFR3) mutations in fetuses with thanatophoric dysplasia type I (TD1) and to provide additional data for genotype-phenotype analyses. Materials and Methods: Eight cases of severe fetal short-limb dwarfism detected by antenatal ultrasonography were referred to this center. Before the termination of pregnancy, cordocentesis was performed for FGFR3 gene-sequencing analysis. Postmortem radiographic examination was performed in each instance for definitive diagnosis. Results: By FGFR3 gene sequencing, the authors identified six cases with missense mutations and two cases with stop codon mutations in the FGFR3 gene. Among the 6 FGFR3 missense mutations, four cases revealed a heterozygous p.Arg248Cys mutation, one case had a heterozygous p. Tyr373Cys mutation, and one case had a heterozygous p.Ser348Cys mutation. Discussion: The present data confirm the existence of hotspot FGFR3 mutations of TD1 and suggest that considerable overlap may occur between genotypes and phenotypes among FGFR3-related skeletal dysplasias.

Clinical characteristics of pseudoachondroplasia and analysis of COMP gene mutation

Objective This article reported the clinical characteristics and gene mutations of two pseudoachondroplasia cases, and made a literature review in order to improve clinicians′ understanding of the disease. Methods Clinical features of two patients who were short stature accompanied with skeletal deformities were summarized, and they accepted whole exome sequencing. We also reviewed literature to summarize the clinical characteristics and known gene research progress of all reported Chinese pseudoachondroplasia cases. Results The two patients′ clinical characteristics were short limbdwarfism with skeletal deformity. Genetic results showed that there were two heterozygous mutations in the cartilage oligomeric matrix protein (COMP) gene of the two patients, c. 1417_1419delGAC and c. 1552G>A, respectively. Up to March 2019, a total of 58 cases of pseudoachondroplasia have been reported in China. The median height of these patients is -5.03 SDS. The clinical features include abnormal gait, short limbs, short fingers/toes, scoliosis, bracelet sign, ankle sign and other skeletal deformities. COMP is the pathogenic gene and mutations mainly located in calmodulin-like domains. The hotspot mutation is c. 1417_1419delGAC. Conclusions Pseudoachondroplasia is a kind of rare genetic disease characterized by short stature and skeletal deformities. The clinical and genetic characteristics of the disease were summarized, which may improve the early diagnosis rate. Key words: Pseudoachondroplasia; Cartilage oligomeric matrix protein; Gene mutation; Molecular mechanism