Short-limbed Dwarfism Research Articles

Case Report Of Short Rib Polydactyly Syndrome

Short rib polydactyly syndrome (SRPS) is a group of skeletal dysplasias manifested by short-limb dwarfism, short ribs with thoracic dysplasia and polydactyly. SRPS is an inherited autosomal-recessive disorder with dif-ferent prenatal sonographic and postnatal clinical, histological and radiologic findings. In this report, we pre-sent a case of SRPS type 3 (Verma-Naumoff) with thoracic hypoplasia, short limbs and postaxial polydactyly in a 30-week fetus. Keywords: Short rib polydactyly syndrome, Verma-Naumoff, Ultrasonography, Narrow thoracic cage

Achondroplasia and Hypochondroplasia

Many women with skeletal dysplasias, such as achondroplasia and hypochondroplasia, choose to become pregnant. These women and their partners should receive pre-conception genetic counseling. Once the woman becomes pregnant, a multidisciplinary team at a tertiary care hospital should mange her antepartum care and birth process. An anesthesia plan should be in place that addressed kyphosis, weight based medications and the possibility of a Cesarean Section. Patients should be monitored for respiratory compromise from the gravid uterus on a smaller body frame. Neonatology must be available to help care for the infant. With a supportive antepartum and postpartum care plan, most women with skeletal dysplasia do well and resume routine OBGYN care after birth. This review contains 5 figures, and 21 references. Keywords: Maternal Achondroplasia, Maternal Hypochondroplasia, Inheritance patterns, short limb dwarfism, high risk pregnancy, autosomal dominant inheritance

Achondroplasia and Hypochondroplasia

Many women with skeletal dysplasias, such as achondroplasia and hypochondroplasia, choose to become pregnant. These women and their partners should receive pre-conception genetic counseling. Once the woman becomes pregnant, a multidisciplinary team at a tertiary care hospital should mange her antepartum care and birth process. An anesthesia plan should be in place that addressed kyphosis, weight based medications and the possibility of a Cesarean Section. Patients should be monitored for respiratory compromise from the gravid uterus on a smaller body frame. Neonatology must be available to help care for the infant. With a supportive antepartum and postpartum care plan, most women with skeletal dysplasia do well and resume routine OBGYN care after birth. This review contains 5 figures, and 21 references. Keywords: Maternal Achondroplasia, Maternal Hypochondroplasia, Inheritance patterns, short limb dwarfism, high risk pregnancy, autosomal dominant inheritance

Achondroplasia and Hypochondroplasia

Many women with skeletal dysplasias, such as achondroplasia and hypochondroplasia, choose to become pregnant. These women and their partners should receive pre-conception genetic counseling. Once the woman becomes pregnant, a multidisciplinary team at a tertiary care hospital should mange her antepartum care and birth process. An anesthesia plan should be in place that addressed kyphosis, weight based medications and the possibility of a Cesarean Section. Patients should be monitored for respiratory compromise from the gravid uterus on a smaller body frame. Neonatology must be available to help care for the infant. With a supportive antepartum and postpartum care plan, most women with skeletal dysplasia do well and resume routine OBGYN care after birth. This review contains 5 figures, and 21 references. Keywords: Maternal Achondroplasia, Maternal Hypochondroplasia, Inheritance patterns, short limb dwarfism, high risk pregnancy, autosomal dominant inheritance

Neurological Manifestations of Achondroplasia.

This review is to delineate the neurological complications seen in patients with achondroplasia. As the understanding of the genetics of this disorder has advanced, the possibility of targets for intervention which might modify the development and management of the neurological complications of this disease may be identified. Achondroplasia is a hereditary short-limbed dwarfism which has been known for millennia. The genetic defect is a gain of function sequence variation in the fibroblast growth factor receptor 3 (FGFR3). This gene normally regulates (inhibits) bone growth thus the gain of function results in abnormal or excessive inhibition of growth. The resulting bone is subject to distortion and the result is that bone impinges on nervous tissue, most commonly at the foramen magnum, spinal canal, and nerve root outlet foramen. Awareness of the range of these complications will, hopefully, allow early and more effective intervention so as to ameliorate the nature and severity of the long-term effects of the neurological complications in patients with achondroplasia.

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.

Adult achondroplasia patient with extensive long segment severe C1 to C6 segment spinal canal stenosis: Unique presentation

Achondroplasia represents the common variety of skeletal dysplasia causing short-limb dwarfism. It may be associated with congenial craniovertebral junction anomaly, including atlantoaxial dislocation, Os odointoideum or basilar invagination or acquired as a result of the previous foramen magnum region surgery. However, long segment cervical compression from the first cervical vertebra region to sixth cervical region, such extensive compression producing myelopathy is not reported, and current case represents first case in the western literature. He was managed surgically with a good outcome. Perioperative management along with brief review of pertinent literature along with the management of such case is discussed in brief. Anesthetic management of such patient with coexisting extensive cervical compression presents unique challenges in view of the multisystem involvement along with preexisting anatomical and physiological constraints.

Clinical, histopathological and genetic characterisation of oculoskeletal dysplasia in the Northern Inuit Dog.

Seven Northern Inuit Dogs (NID) were diagnosed by pedigree analysis with an autosomal recessive inherited oculoskeletal dysplasia (OSD). Short-limbed dwarfism, angular limb deformities and a variable combination of macroglobus, cataracts, lens coloboma, microphakia and vitreopathy were present in all seven dogs, while retinal detachment was diagnosed in five dogs. Autosomal recessive OSD caused by COL9A3 and COL9A2 mutations have previously been identified in the Labrador Retriever (dwarfism with retinal dysplasia 1—drd1) and Samoyed dog (dwarfism with retinal dysplasia 2—drd2) respectively; both of those mutations were excluded in all affected NID. Nine candidate genes were screened in whole genome sequence data; only one variant was identified that was homozygous in two affected NID but absent in controls. This variant was a nonsense single nucleotide polymorphism in COL9A3 predicted to result in a premature termination codon and a truncated protein product. This variant was genotyped in a total of 1,232 dogs. All seven affected NID were homozygous for the variant allele (T/T), while 31/116 OSD-unaffected NID were heterozygous for the variant (C/T) and 85/116 were homozygous for the wildtype allele (C/C); indicating a significant association with OSD (p = 1.41x10-11). A subset of 56 NID unrelated at the parent level were analysed to determine an allele frequency of 0.08, estimating carrier and affected rates to be 15% and 0.6% respectively in NID. All 1,109 non-NID were C/C, suggesting the variant is rare or absent in other breeds. Expression of retinal mRNA was similar between an OSD-affected NID and OSD-unaffected non-NID. In conclusion, a nonsense variant in COL9A3 is strongly associated with OSD in NID, and appears to be widespread in this breed.

The Protective Role of Natriuretic Peptide Receptor 2 against High Salt Injury in the Renal Papilla

Mutations in natriuretic peptide receptor 2 (Npr2) gene cause a rare form of short-limbed dwarfism, but its physiological effects have not been well studied. Human and mouse genetic data suggest that Npr2 in the kidney plays a role in salt homeostasis. Herein, we described anatomic changes within renal papilla of Npr2 knockout (Npr2-/-) mice. Dramatic reduction was found in diuresis, and albuminuria was evident after administration of 1% NaCl in drinking water in Npr2-/- and heterozygous (Npr2+/-) mice compared with their wild-type (Npr2+/+) littermates. There was indication of renal epithelial damage accompanied by high numbers of red blood cells and inflammatory cells (macrophage surface glycoproteins binding to galectin-3) and an increase of renal epithelial damage marker (T-cell Ig and mucin domain 1) in Npr2-/- mice. Addition of 1% NaCl tended to increase apoptotic cells (cleaved caspase 3) in the renal papilla of Npr2-/- mice. Invitro, genetic silencing of the Npr2 abolished protective effects of C-type natriuretic peptide, a ligand for Npr2, against death of M-1 kidney epithelial cells exposed to 360 mmol/L NaCl. Finally, significantly lower levels of expression of the NPR2 protein were detected in renal samples of hypertensive compared with normotensive human subjects. Taken together, these findings suggest that Npr2 is essential to protect renal epithelial cells from high concentrations of salt and prevent kidney injury.

SUN-LB008 Clinical Phenotype and Genotype Analysis of Short Stature Patients with Skeletal Dysplasia

Background: Skeletal dysplasia is a frequent cause of congenital disproportionate short stature, and genetic defects of cartilage extracellular matrix (ECM) affect growth plate structure and functions. However, precise diagnosis remains difficult due to high heterogeneity of phenotypes. Objective: We sought to identify phenotype spectrum and genetic causes for Chinese patients with skeletal related short stature. Patients and Methods: 86 short stature patients clinically diagnosed or suspected of skeletal dysplasia from 2013 to 2018 were included, and clinical information were systematically collected. Next generation sequencing (NGS) was informed and conducted in all these patients, and pathogenicity of candidate genes were analyzed based on clinical data. Results: 45 of the 86 patients had confirmed mutations, and 46.7% of them (21 to 45) were identified with heterozygous mutations relevant of cartilage extracellular matrix. 19 variants of 5 genes were identified including 9 of COL2A1, 1 of COL9A1, 4 of COL10A1, 4 of COMP and 3 of FBN1. The age at diagnosis was 9.47±5.46 years, and the height SDS was -4.78±1.65. The phenotypic spectrum ranged from proportionate short stature with mild upper limb deformity to typical, severe disproportionate manifestations. Deformities of limbs and vertebral anomalies were more frequently encountered presentations. Patients with COL2A1 mutations were more likely to show facial features, pectus carinatum, scoliosis and epiphyseal dysplasia while those with COL10A1 variants mainly presented genu varum and scoliosis. 5 probands (2 COL10A1, 3 COL2A1) were maternal inherited and 12 of 14 affected family members were female. Individuals with COMP variants had the severest height loss (medium height, -6.24 SDS; range, -7.56 to -5.97) and showed typical short-limb dwarfism, irregular epiphyses and dysfunction of joints in early ages. None of the patients with FBN1 mutations had significant facial features or spinal deformity, but bowing of limbs, brachydactyly and decreased joint mobility were visible. 4 of 20 individuals underwent rhGH therapy but had limited effects. Facial dysmorphism was a significant feature to exclude patients with FGFR3 mutations, while limb and spine deformities were frequently encountered in both ECM and FGFR3 patients. Conclusion: NGS is an efficient tool to identify genetic cause of skeletal dysplasia due to its clinical and molecular heterogeneity, and variants of genes encoding cartilage extracellular matrix are the most common cause. Sources of Research Support: The National Key Research and Development Program of China” (No. 2016YFC0901501) and CAMS Innovation Fund for Medical Science (CAMS-2016-I2M-1-002). Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. s presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.

Clinical features and gene mutation analysis of COMP in eight patients with pseudoachondroplasia

The clinical features and the mutation of cartilage oligomer matrix protein (COMP) gene were analyzed in 8 patients with pseudoachondroplasia (PSACH). The clinical data and the peripheral blood from 5 male and 3 female probands, their pedigree members, and 250 unrelated volunteers were collected. Eight patients who were sporadic cases, had been detected mutation of COMP gene by DNA sequencing. PSACH is a skeletal disorder characterized by short stature, joint laxity, and early-onset osteoarthritis. The heights of 8 patients were significantly lower than the average level by 3 standard deviations, with short limbs and deformities of legs. Radiographs showed flattening of vertebrae with anterior beaking or tonguing in children and osteoarthritis in adults. As to the patients with short limb dwarfism, short toes, and abnormal radiography findings, PSACH should be suspected and could be confirmed by detection of COMP gene mutation. Key words: Pseudoachondroplasia; Clinical features; Cartilage oligomer matrix protein; Gene mutation

A CASE OF THANATOPHORIC DYSPLASIA TYPE I: THE FIRST CLINICOPATHOLOGIC REPORT FROM ETHIOPIA

ABSTRACTThanatophoric dysplasia (TD) is a short-limb neonatal dwarfism syndrome that is usually lethal in the perinatal period1. It is characterized by markedly underdeveloped skeleton and short-limb dwarfism. TD is caused by a mutation of the fibroblast growth factor receptor 3 gene (FGFR3), which is located on the short arm of chromosome 42,3.This study reports a neonate born at Tikur Anbessa Teaching Hospital with features of thanatophoric dysplasia which was proven radiologically and pathomorphologically. The mother presented to the hospital at 39 +1 weeks of gestational age with ultrasound diagnosis of achondroplasia. She developed cephalopelvic disproportion and underwent caesarian section. Outcome was an alive anomalous female neonate with a weight of 2900 gms of 4, 2, 2 & 0 in the 1st, 5th, 10th & 20th minute APGAR scores, respectively. The neonate expired due to severe respiratory distress despite resuscitation. The parturient died following pulmonary thromboembolism diagnosed on her second postoperative day.CONCLUSION: Thanatophoric dysplasia is a lethal skeletal anomaly which should be diagnosed and managed in the second trimester of pregnancy. Missing this case in the mid-trimester costed note only the physical, psychological and the economic burden but also the life of the mother. KEY WORDS: Thanatophoric dysplasia, fibroblast growth factor receptor 3 gene (FGFR3) (Ethiopian Journal of Reproductive Health 2018; 10; 3: 65-70)

Acute type A aortic dissection repair in an octogenarian with achondroplasia: a case report

BackgroundAchondroplasia is an inherited disorder and the most common type of short-limbed dwarfism in human beings, affecting more than 250,000 individuals worldwide. To the best of our knowledge, no study has reported a correlation between achondroplasia and aortic dissection. Here, we report a rare case of acute type A aortic dissection repair in a patient with achondroplasia.Case presentationAn 82-year-old Japanese female with achondroplasia was admitted to our hospital because of acute-onset severe chest pain migration to her back accompanied by numbness and pain in the right lower limb. A computed tomography scan revealed acute type A aortic dissection with right leg ischemia because of an occlusion of the right common iliac artery. We successfully performed hemiarch repair.ConclusionsThis report presents the first case of a patient at such an advanced age with dwarfism and cardiac surgery and the second case to illustrate successful acute aortic dissection repair in achondroplasia. Of note, all procedures were performed without specialized equipment. Overall, this report adds to the experience of successful cardiac surgery in this unique patient population.

Short rib-polydactyly syndrome (Saldino-Noonan type) undetected by standard prenatal genetic testing

Abstract Short rib-polydactyly syndrome (SRPS) is an extremely rare lethal skeletal dysplasia characterized by organ abnormalities, polydactyly, shortened tubular bones and a constricted thoracic cage [Saldino RM. Lethal short-limbed dwarfism: achondrogenesis and thanatophoric dwarfism. Am J Roentgenol. 1971;112:185–97]. In this case, we describe a neonate born with Type I SRPS (Saldino-Noonan type). Prenatal ultrasounds were suspicious for skeletal dysplasia, but prenatal genetic testing was negative. Postnatally, the infant was found to have severely hypoplastic lungs, a large patent ductus arteriosus, hydrops fetalis, polydactyly and a saddle nose. Postnatal DNA sequencing confirmed the diagnosis of SRPS and revealed a compound heterogeneous mutation in a gene involved in primary cilia synthesis. Ultimately, the infant was withdrawn from life support at 7 days due to severe respiratory decompensation from the lung hypoplasia.

Whole-Exome Sequencing Reveals a Recurrent D401N Mutation in the COMP gene that Causes Multiple Epiphyseal Dysplasia

Multiple epiphyseal dysplasia (MED) is a rare osteochondrodysplasia characterized by moderate short limb dwarfism and earlyonset osteoarthrosis. By whole-exome sequencing (WES), we identified a dominantly inherited mutation (c.1201G>A; p.D401N) in cartilage oligomeric matrix protein (COMP) in a large four-generation Chinese family. Immunofluorescence analysis revealed mutant COMP secretion was severely impaired. Our result expands the mutational spectrum of COMP and provides strong evidence for the genotype-phenotype correlation of COMP pathogenicity in MED.

Surgical treatment for lumbar canal stenosis in adult achondroplasia

Introduction: Achondroplasia is the most common form of human short-limbed dwarfism caused by mutations in theFGFR3 gene, with an incidence of 1 in 30,000 live births annually in global.Achondroplasia is characterized by foramen magnum stenosis, thoracolumbar kyphosis, spinal stenosis, shortened pedicles, genu varum, and short stature. Methods: We report a female, 51 years old, with lumbar canal stenosis due to degenerative disc disease and achondroplasia. We decided to perform decompression (laminectomy) and posterior stabilization. Post-operatively, we observed the general condition of the patient, neurovascular complication, Visual Analogue Scale (VAS), Oswestry Disability Index (ODI), implant position and spinal structure condition. Results: There was no neurovascular complication following the surgery. Mean VAS score of the leg pain improved from 5 to 2. ODI scores also improved consecutively from 18 out of 45 (40%) to 8 out of 45 (17,7%). The sensory function at the L5 and S1 dermatome region of the right leg was improved, as well as the radiological evaluation. Conclusion: Decompression followed by posterior stabilization in a one-stepsurgery isan effective surgical modality to treat lumbar canal stenosis in achondroplastic patients. However, pedicle screw instrumentation in patients with achondroplasia and short stature can be challenging. Safe insertion requires technical experience and knowledge of the achondroplastic pedicle morphometry, which differs markedly from that of the normal spine.

Increased intracellular proteolysis reduces disease severity in an ER stress-associated dwarfism.

The short-limbed dwarfism metaphyseal chondrodysplasia type Schmid (MCDS) is linked to mutations in type X collagen, which increase ER stress by inducing misfolding of the mutant protein and subsequently disrupting hypertrophic chondrocyte differentiation. Here, we show that carbamazepine (CBZ), an autophagy-stimulating drug that is clinically approved for the treatment of seizures and bipolar disease, reduced the ER stress induced by 4 different MCDS-causing mutant forms of collagen X in human cell culture. Depending on the nature of the mutation, CBZ application stimulated proteolysis of misfolded collagen X by either autophagy or proteasomal degradation, thereby reducing intracellular accumulation of mutant collagen. In MCDS mice expressing the Col10a1.pN617K mutation, CBZ reduced the MCDS-associated expansion of the growth plate hypertrophic zone, attenuated enhanced expression of ER stress markers such as Bip and Atf4, increased bone growth, and reduced skeletal dysplasia. CBZ produced these beneficial effects by reducing the MCDS-associated abnormalities in hypertrophic chondrocyte differentiation. Stimulation of intracellular proteolysis using CBZ treatment may therefore be a clinically viable way of treating the ER stress–associated dwarfism MCDS.

Endoplasmic reticulum retention of xylosyltransferase 1 (XYLT1) mutants underlying Desbuquois dysplasia type II.

Desbuquois syndrome is a heterogeneous rare type of skeletal dysplasia with a prevalence of less than 1 in 1,000,000 individuals. It is characterized by short-limbed dwarfism, dysmorphic facial features, and severe joint laxity. Two types have been recognized depending on the presence of distinctive carpal and phalangeal features. Mutations in the calcium activated nucleotidase 1 (CANT1) have been found to be responsible for type I and lately, for the Kim type of Desbuquois dysplasia. In addition, a number of Desbuquois dysplasia type II patients have been attributed to mutations in xylosyltransferase 1, encoded by the XYLT1 gene, an enzyme that catalyzes the transfer of UDP-xylose (a marker of cartilage destruction) to serine residues of an acceptor protein, essential for the biosynthesis of proteoglycans. We report here a patient with features consistent with Desbuquois dysplasia II including short long bones, flat face, mild monkey wrench appearance of the femoral heads. Whole exome sequencing revealed a novel homozygous duplication of a single nucleotide in XYLT1 gene (c.2169dupA). This variant is predicted to result in a frame-shift and stop codon p.(Val724Serfs*10) within the xylosyltransferase catalytic domain. Immunoflourescence staining of HeLa cells transfected with mutated XYLT1 plasmids constructs of the current as well as the previously reported missense mutations (c.1441C>T, p.(Arg481Trp) and c.1792C>T, p.(Arg598Cys)), revealed aberrant subcellular localization of the enzyme compared to wild-type, suggesting endoplasmic reticulum retention of these mutants as the likely mechanism of disease.

Growth of maxillo-facial region and related anomalies.

Since maxillo-facial region is quite complex, growth and developmental defect cause various anomalies. It is known that 70% of whole genetic disorders have any symptom or abnormal condition in maxilla-facial region. Cleft lip and/or palate is the most popular congenital anomaly and is seen in 0.2% of general population. Cases with Treacher Collins syndrome and Robin sequence are with respiratory problem due to the small mandible or mandibular retrusion. Achondroplasia is a genetic disease with short-limbed dwarfism due to abnormal proliferation or differentiation of chondrocytes. Interestingly, in this disease, growth of condylar cartilage is not impaired and causes mandibular prognathism. In this review, various diseases caused by the abnormality in growth and development of maxilla-facial region are discussed.

Utility of Adoption a Molecular Method for Diagnosis of Short Limb Dwarfism

Background and objectives: Mutation analysis in Egyptian children with clinical diagnosis of short limb dwarfism (Achondroplasia). In addition, to adopt a molecular method for both prenatal and postnatal diagnosis. Materials and methods: Eight sporadic cases of short limb dwarfism were studied. A mutation analysis was done by PCR/RFLP (Polymerase chain reaction/Restriction fragment length polymorphism). Results of RFLP were confirmed using sequencing of PCR products. Results: The G380R mutation was positive in all eight probands (100%) and negative in all parents (0%). Results of RFLP were confirmed using sequencing that revealed substitution of guanine by adenine at the nucleotide (nt. 1138). Interpretation and conclusions: All cases had the G-A transition at nt. 1138 of the FGFR3 gene. Our conclusion is that vast majority of Egyptian achondroplasia patients have the same mutation. Mutation analysis is useful for both prenatal and postnatal diagnosis.