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Background Heterozygous Indian Hedgehog gene (IHH) variants are associated with brachydactyly type A1 (BDA1). However, in recent years, numerous variants have been identified in patients with short stature and more variable forms of brachydactyly. Many are located in the C-terminal domain of IHH (IHH-C), which lacks signaling activity but is critical for auto-cleavage and activation of the N-terminal (IHH-N) peptide. The absence of functional studies of IHH variants, particularly for those located in IHH-C, has led to these variants being classified as variants of uncertain significance (VUS). Objective To establish a simple functional assay to determine the pathogenicity of IHH VUS and confirm that variants in the C-terminal domain affect protein function. Design/Methods In vitro studies were performed for 9 IHH heterozygous variants, to test their effect on secretion and IHH intracellular processing by western blot of cells expressing each variant. Results IHH secretion was significantly reduced in all mutants, regardless of the location. Similarly, intracellular levels of N-terminal and C-terminal IHH peptides were severely reduced in comparison with the control. Two variants present at a relatively high frequency in the general population also reduced secretion but to a lesser degree in the heterozygous state. Conclusions These studies provide the first evidence that variants in the C-terminal domain affect the secretion capacity of IHH and thus, reduce availability of IHH ligand, resulting in short stature and mild skeletal defects. The secretion assay permits a relatively easy test to determine the pathogenicity of IHH variants. All studied variants affected secretion and interestingly, more frequent population variants appear to have a deleterious effect and thus contribute to height variation. [ABSTRACT FROM AUTHOR]

Brachydactyly is a genetic condition leading to shortened or absent digits in hands or feet. It can occur independently or as part of syndromes. This case focuses on Brachydactyly type B, the rarest form. An 8-month-old from the Philippines was referred due to a missing third toe. Examination revealed a hypoplastic left third toe. X-rays confirmed the finding. Treatment options were discussed, including conservative therapy and follow up. Diagnosis involved history, examination, and imaging. Prenatal diagnosis is limited for isolated cases but useful for syndromic forms if a family mutation is known. Prognosis varies depending on the severity and associated syndromes. Currently there is no definitive treatment; management involves genetic counseling and therapy. Due to limited cases, Type B is underreported, highlighting the need for more research into its genetics. [ABSTRACT FROM AUTHOR]

Brachytelephalangy is a congenital condition characterised by the shortening of the distal phalanges, which affects appearance but does not cause severe functional disability. Therefore, most hand surgeons do not consider it to require surgical treatment, and there are limited options to improve the appearance of the affected digits. We present the case of a 55-year-old male patient with congenital brachytelephalangy of the thumb, who underwent a bone lengthening procedure using distraction osteogenesis with the Ilizarov minifixator. The distal phalanx was carefully osteotomised and gradually lengthened up to 5 mm with no adverse events observed. The patient was satisfied with the natural appearance of his thumb after the surgery. This gradual callus distraction method is a radical solution for people with brachytelephalangy, particularly after epiphyseal closure and can manage the external fixator on their own. Level of Evidence: Level V (Therapeutic) [ABSTRACT FROM AUTHOR]

Background: Maternal inactivating GNAS mutations lead to pseudohypoparathyroidism 1A (PHP1A), newly classified as inactivating parathyroid hormone (PTH)/PTHrP-signaling disorder type 2 of maternal inheritance (iPPSD2). Patients present with resistance to PTH and other hormones, subcutaneous ossifications, brachydactyly, short stature, and early-onset obesity. They can be born small for gestational age (SGA) and may present with growth hormone (GH) deficiency. The use of recombinant human GH (rhGH) therapy has been sporadically reported, yet we lack data on the long-term efficacy and safety of rhGH, as well as on adult height. Objective: Our multicenter, retrospective, observational study describes growth in patients treated with rhGH in comparison with untreated iPPSD2/PHP1A controls. Methods: We included 190 patients, of whom 26 received rhGH. Height, weight, body mass index at various time points, and adult height were documented. We analyzed the effect of rhGH on adult height by using linear mixed models. Results: Adult height was available for 11/26 rhGH-treated individuals and for 69/164 controls. Patients treated with rhGH showed a gain in height of 0.7 standard deviation scores (SDS) after 1 year (CI +0.5 to +0.8, P < .001) and of 1.5 SDS after 3 years (CI +1.0 to +2.0, P < .001). Additionally, there was a clear beneficial impact of rhGH on adult height when compared with untreated controls, with a difference of 1.9 SDS (CI +1.1 to +2.7, P < .001). Body mass index SDS did not vary significantly upon rhGH therapy. Conclusion: Recombinant human growth hormone treatment of iPPSD2/PHP1A patients with short stature improves growth and adult height. More studies are needed to confirm long-term efficacy and safety. [ABSTRACT FROM AUTHOR]

Copyright of Journal of the Child / Çocuk Dergisi is the property of Journal of Child and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

A teenage Afghan girl presented with seizure. Clinical features and laboratory investigations revealed elevated serum parathormone, high phosphate levels with low serum calcium. In third‐world countries, diagnosis of rare disorders, such as Albright hereditary osteodystrophy (AHO), can usually be delayed due to scarcity of standard medical and diagnostic services. [ABSTRACT FROM AUTHOR]

Objective: Trichorhinophalangeal syndrome is a rare autosomal dominant disorder characterized by distinctive craniofacial and skeletal abnormalities. This study aimed to delineate the trichorhinophalangeal syndrome phenotype and to compare the clinical and molecular findings between trichorhinophalangeal syndrome types I and II. Materials and Methods: A total of 22 trichorhinophalangeal syndrome patients aged 0.9-45 years from 17 families were enrolled. Nineteen patients were diagnosed with trichorhin ophalangeal syndrome I and 3 with trichorhinophalangeal syndrome II. Genetic analyses were made by TRPS1 sequencing and/or chromosomal microarray analyses. Results: A novel frameshift variant (c.531_532del), a known missense variant, and whole-gene deletions were the pathogenic TRPS1 variants detected in trichorhinophalangeal syndrome I. Three trichorhinophalangeal syndrome II patients had large deletions with variable breakpoints involving the TRPS1-EXT1 interval. All patients had the typical craniofacial findings of trichorhinophalangeal syndrome such as a pear-shaped nose, long philtrum, and thin upper lip, as well as cone-shaped epiphyses. Sparse hair and eyebrows (20/22), short metacarpals and metatarsals (20/22), and small hands (19/22) were common. While craniofacial and limb abnormalities were similar in trichorhinophalangeal syndrome I and II, 3 of 19 trichorhinophal angeal syndrome I patients had mild, and 2 of 3 trichorhinophalangeal syndrome II patients had severe intellectual disability. Three trichorhinophalangeal syndrome II patients including the patient with the EXT1 deletion beginning from exon 2 had exostoses. In trichorhinophal angeal syndrome II, although microdeletion sizes and facial or skeletal features were not correlated, patients with larger deletions had severe intellectual disability. Conclusion: This study has expanded the existing knowledge on the phenotype–genotype spectrum in trichorhinophalangeal syndrome. We suggest including the EXT1 gene partially in the minimal critical region for trichorhinophalangeal syndrome II. [ABSTRACT FROM AUTHOR]

Coffin–Siris syndrome is a rare disorder, which can be difficult to recognize. A broad spectrum of nonspecific clinical features is associated with Coffin–Siris syndrome, and the expression of these features is diverse. We describe two cases with Coffin–Siris syndrome with mutations in the ARID1A gene, with dissimilar presentation and clinical course. [ABSTRACT FROM AUTHOR]

Congenital anonychia is a relatively rare abnormality of nail development affecting all or some of the finger and toe nails, characterized by either complete absence of nails or hypoplasia of nails. We report a rare case of congenital anonychia with brachydactyly with unique congenital abnormalities of heart-shaped tongue, congenital hypoglossal nerve palsy, and staghorn calculus. To our knowledge, these associations have never been described before and do not fall under any known syndromic entity. [ABSTRACT FROM AUTHOR]

Introduction: Saul Wilson syndrome (SWS) is a rare congenital syndrome characterized by a variety of symptoms, mostly skeletal changes. Saul and Wilson were the first to describe children with extremely short stature and craniofacial dysmorphism. Case report: We present a case of a 15-years-old boy with clinical and radiological characteristics of SWS. Genetic examination identified a pathogenic heterozygous variant in the COG4 gene. Magnetic resonance imaging revealed a critical stenosis of the cranio-cervical junction (CCJ) which required surgical treatment to attempt sufficient neurological decompression. The patient underwent decompression of CCJ under general anesthesia. There was no significant radiological and clinical improvement during the postoperative period. Conclusions: SWS is presented as an extremely rare congenital disease in children. The clinical condition of our patient confined surgical possibilities, therefore further treatment in such patients should be appropriately evaluated. [ABSTRACT FROM AUTHOR]

Background: With the introduction of genetic tests such as chromosomal microarray analysis (CMA) and exome sequencing (ES) into fetal medical practices, genotype–phenotype correlations in intrauterine-onset disorders have substantially improved. The BMP2 gene, located on the long arm of chromosome 20 plays a role in bone and cartilage development and is associated with Brachydactyly type A2, an autosomal dominant disease characterized by malformations of the middle phalanx of the index finger and abnormalities of the second toe. However, the BMP2 gene has so far never been reported as a candidate gene for Brachydactyly type D (BDD) affecting only the thumbs. Methods and results: Here, we report one family possessing a maternally inherited 6.3 Mb microduplication of 20p13p12.2 including the BMP2 gene with discordant phenotypes between the mother and the fetus. The mother was affected with BDD alongside mild facial dysmorphism and learning difficulties, while the female fetus showed BDD, severe symmetric intrauterine growth restriction combined with oligohydramnios. The CMA and Trio ES tests were implemented. Trio ES ruled out other possible monogenic causes for the family. After reviewing cases and literature with duplications within this genomic region, we found that they are extremely rare and most of the cited cases were too small for comparison. The disturbance of the BMP2 gene could explain BDD, but the other clinical presentations in the mother and fetus are not yet fully understood. Conclusion: This study provides important evidence for the current understanding of genotype–phenotype association of this 6.3 Mb size duplication in the 20p13p12.2 region. This duplication is a unique CNV occurring so far only in this family. Further cases and research are needed to understand the discordance in the phenotypes between the mother and fetus and establish the relationship between BMP2 gene and BDD. [ABSTRACT FROM AUTHOR]

Introduction: To analyze the prevalence of brachydactyly type A3 (BDA3) in children with short stature and the effect on growth hormone (GH) therapy. Methods: We analyzed the medical records of pediatric patients from July 2009 to July 2021. We included children with short stature defined as their height standard deviation score (HtSDS) < -2 and normal short height as their HtSDS between -2 and -1. We calculated the prevalence of BDA3 in different groups and compared the differences in children's characteristics and the therapeutic effect of GH therapy between the BDA3 and no BDA3 groups. Results: A total of 752 cases were included. The overall prevalence of BDA3 was 23.1%; with a female predominance (30.8% vs. 16.1%, P < 0.01). BDA3 was more prevalent in the short stature group (27.2%) than in the normal short stature group (16.7%) and growth hormone deficiency group (16.5%). Birth length, birth weight, HtSDS, and mid-parental height of children with BDA3 were lower than those without BDA3, but there were no significant differences. In patients with Turner syndrome and idiopathic short stature, the HtSDS of the BDA3 group was significantly lower than that of the no BDA3 group (P < 0.01). During four years of GH therapy, the HtSDS improvement per year in the BDA3 group were 0.79 ± 0.29, 0.50 ± 0.31, 0.20 ± 0.30, and 0.10 ± 0.22, which were not significantly different from those in the no BDA3 group. At the end of treatment, there were no significant differences in the duration of treatment and total HtSDS improvement between these two groups. Conclusions: BDA3 is more commonly seen in children with short stature with a female predominance. BDA3 occurrence is independent of the GH pathway and does not affect the therapeutic effect of GH on short stature children. [ABSTRACT FROM AUTHOR]

Epidermolysis bullosa (EB) encompasses a phenotypically and genetically heterogeneous group of inherited skin disorders characterized by blistering and erosions of the skin with minimal trauma. Dystrophic EB (DEB), both dominant and recessive, can be associated with several extracutaneous manifestations, including musculoskeletal deformities. Congenital deformities of the feet have rarely been reported in the literature. We describe an infant with dominant DEB and congenital absence of the skin who presented with congenital brachydactyly of the bilateral great toes. [ABSTRACT FROM AUTHOR]

Background: Mutations in LMNA, encoding lamin A/C, lead to a variety of diseases known as laminopathies including dilated cardiomyopathy (DCM) and skeletal abnormalities. Though previous studies have investigated the dysregulation of gene expression in cells from patients with DCM, the role of epigenetic (gene regulatory) mechanisms, such as DNA methylation, has not been thoroughly investigated. Furthermore, the impact of family-specific LMNA mutations on DNA methylation is unknown. Here, we performed reduced representation bisulfite sequencing on ten pairs of fibroblasts and their induced pluripotent stem cell (iPSC) derivatives from two families with DCM due to distinct LMNA mutations, one of which also induces brachydactyly. Results: Family-specific differentially methylated regions (DMRs) were identified by comparing the DNA methylation landscape of patient and control samples. Fibroblast DMRs were found to enrich for distal regulatory features and transcriptionally repressed chromatin and to associate with genes related to phenotypes found in tissues affected by laminopathies. These DMRs, in combination with transcriptome-wide expression data and lamina-associated domain (LAD) organization, revealed the presence of inter-family epimutation hotspots near differentially expressed genes, most of which were located outside LADs redistributed in LMNA-related DCM. Comparison of DMRs found in fibroblasts and iPSCs identified regions where epimutations were persistent across both cell types. Finally, a network of aberrantly methylated disease-associated genes revealed a potential molecular link between pathways involved in bone and heart development. Conclusions: Our results identified both shared and mutation-specific laminopathy epimutation landscapes that were consistent with lamin A/C mutation-mediated epigenetic aberrancies that arose in somatic and early developmental cell stages. [ABSTRACT FROM AUTHOR]

Brachymetacarpia, a form of brachydactyly, is one of the so‐called rare diseases because of its low prevalence. Although it is a well‐known malformation today, which occasionally requires surgical correction, it is not, or hardly, reported in the palaeopathological literature. The case presented here includes an individual exhumed from the Mudejar cemetery in Uceda (Guadalajara, Spain) dated between the 13th and 14th centuries. It was in an acceptable state of preservation, except for the skull, missing except for the mandible. Its sex was determined as female and the age as a young adult. On examining the hands, the short length of both the 4th and 5th metacarpals and the shortening of the distal phalanx of one of the thumbs were noteworthy. No anomaly was observed in the bones of the feet, which were only partially recovered. Due to the characteristics of the shortening and bones affected, it was considered that the case probably corresponded to type E of brachydactyly in the Bell and Temtamy classifications and to subtype E2 in the Hertzog classification. No data were found in the bones or teeth, suggesting their inclusion in any of the multiple clinical syndromes with this abnormality. [ABSTRACT FROM AUTHOR]

Variants of the diphthamide biosynthesis I (DPH1, OMIM*603527) are associated with developmental delay, short stature, and sparse hair syndrome (DEDSSH/DPH1 syndrome) (OMIM# 616901). Another name is Loucks‐Innes syndrome. DPH1 syndrome is an ultrarare and severe neurodevelopmental disorder. Less than 20 patients were reported from different ethnicities. Here, we described the first Chinese adult with genetically confirmed DPH1 syndrome. We summarized previously reported patients in the literature and found that developmental delay, unusual skull shape, sparse hair, and facial dysmorphism were consistently present in all DPH1 syndrome patients. Dysplastic toenails and dental abnormalities are age‐dependent characteristics of DPH1 syndrome. Our patient was the first reported patient with documented growth hormone deficiency. Dental and endocrine checkup should be considered in the routine follow‐up of DPH1 syndrome patients. [ABSTRACT FROM AUTHOR]

Acrodysostosis is a rare syndrome of peripheral dysostosis, neurodevelopment delay, and skeletal abnormalities. The most common bone changes are peripheral dysostosis with severe brachydactyly of the lesser toes. The first ray of the feet is often not affected or may present hyperplasia resulting in an unbalanced transverse arch of the forefoot, with potential negative effects on function. Additionally, the insufficiency of the lesser toes may be associated with complex congenital hallux valgus deformities. Surgical approaches include growth plate epiphysiodesis, bulk reduction procedures, bone shortening, osteotomies, or amputation. Here, we report a case of a 14-year-old girl with acrodysostosis and severe discrepancy of the first ray and hallux valgus deformity simultaneously treated by a modified scarf osteotomy. Levels of Evidence: Level V: Case report [ABSTRACT FROM AUTHOR]

Background: Brachydactylies are a group of inherited conditions, characterized mainly by the presence of shortened fingers and toes. Based on the patients' phenotypes, brachydactylies have been subdivided into 10 subtypes. In this study, we have identified a family with two members affected by brachydactyly type A2 (BDA2). BDA2 is caused by mutations in three genes: BMPR1B, BMP2 or GDF5. So far only two studies have reported the BDA2 cases caused by mutations in the BMPR1B gene. Methods: We employed next‐generation sequencing to identify mutations in culpable genes. Results and Conclusion: In this paper, we report a case of BDA2 resulting from the presence of a heterozygous c.1456C>T, p.Arg486Trp variant in BMPR1B, which was previously associated with BDA2. The next generation sequencing analysis of the patients' family revealed that the mutation occurred de novo in the proband and was transmitted to his 26‐month‐old son. Although the same variant was confirmed in both patients, their phenotypes were different with more severe manifestation of the disease in the adult. [ABSTRACT FROM AUTHOR]

Pseudohypoparathyroidism is a rare disease of the endocrine gland. Its diagnosis should not be dismissed when hypocalcemia is accompanied by hyperphosphatemia and high levels of parathyroid hormone even if kidney failure and vitamin D deficiency do not occur. Although genetic studies provide a definitive diagnosis, biochemical tests that show hormonal resistance and phenotypic characteristics allow us to establish a diagnosis. Literature is limited in Latin America and few cases have been described. Here we report an 18-year-old male suffering pseudohypoparathyroidism and we discuss clinical characteristics, biochemical and radiographic findings, as well as treatment. [ABSTRACT FROM AUTHOR]

Copyright of Gaceta Médica Boliviana is the property of Universidad Mayor de San Simon, Facultad de Medicina and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Brachydactyly type A (BDA) is defined as short middle phalanges of the affected digits and is subdivided into four types (BDA1‐4). To date, the molecular cause is unknown. However, there is some evidence that pathogenic variants of HOXD13 could be associated with BDA3 and BDA4. Here, we report a Chinese autosomal dominant BDA3 pedigree with a novel HOXD13 mutation. The affected individuals presented with an obviously shorter fifth middle phalanx. The radial side of the middle phalanx was shorter than the ulnar side, and the terminal phalanx of the fifth finger inclined radially and formed classical clinodactyly. Interestingly, the index finger was normal. The initial diagnosis was BDA3. However, the distal third and fourth middle phalanges were also slightly affected, resulting in mild radial clinodactyly. Both feet showed shortening of the middle phalanges, which were fused to the distal phalanges of the second to the fifth toes, as reported in BDA4. Therefore, this pedigree had combined BDA3 and atypical BDA4. By direct sequencing, a 13 bp deletion within exon 1 of HOXD13 (NM_000523.4: c.708_720del13; NP_000514.2: p.Gly237fs) was identified. The 13 bp deletion resulted in a frameshift and premature termination of HOXD13. This study provides further evidences that variants in HOXD13 cause BDA3‐BDA4 phenotypes. [ABSTRACT FROM AUTHOR]

Pseudohypoparathyroidism is a rare disease of the endocrine gland. Its diagnosis should not be dismissed when hypocalcemia is accompanied by hyperphosphatemia and high levels of parathyroid hormone even if kidney failure and vitamin D deficiency do not occur. Although genetic studies provide a definitive diagnosis, biochemical tests that show hormonal resistance and phenotypic characteristics allow us to establish a diagnosis. Literature is limited in Latin America and few cases have been described. Here we report an 18-year-old male suffering pseudohypoparathyroidism and we discuss clinical characteristics, biochemical and radiographic findings, as well as treatment. [ABSTRACT FROM AUTHOR]

Background: Brachydactyly (BD) is a rare autosomal dominant inherited disease characterized by shortness of the fingers and/or toes, which has been classified into the subtypes A–E. However, the exact cause and mechanism of BD remain to be illuminated. Here, we aim to reveal the clinical and genetic characteristics of a subtype of BD, brachydactyly‐anonychia. Methods: In this study, a large Chinese family with three members affected by brachydactyly‐anonychia was investigated. Both whole‐exome sequencing and microarray‐based comparative genomic hybridization (CGH) were performed on this family and the results of copy number variation (CNV) were verified by quantitative real‐time PCR (qPCR). Results: All the affected individuals showed short fingers and toes as well as missing nails; and the absence of middle phalanges in figure II‐V of the upper and lower extremities was observed by X‐ray examination. A duplication involving in the region of 17q24.3 was detected by CGH. The results of qPCR also represented this duplication in 17q24.3 in all the patients. Conclusion: In summary, our findings suggest that 17q24.3 duplication is the genetic cause of brachydactyly‐anonychia in this family, which support the prior report that brachydactyly‐anonychia is associated with 17q24.3 duplication, and further indicates the pathogenic correlation between BD and CNVs. [ABSTRACT FROM AUTHOR]

Background: Autosomal dominant hypertension with brachydactyly type E syndrome caused by pathogenic variants in the PDE3A gene was first reported in 2015. To date, there are only a few reports of this kind of syndrome. Other patients still lack a genetic diagnosis. Case presentation: Whole-exome sequencing was performed in an 18-year-old female proband with a clinical diagnosis of hypertension with brachydactyly syndrome. Quantitative real-time PCR was used to identify pathogenic copy number variations (CNVs). After bioinformatics analysis and healthy control database filtering, we revealed a heterozygous missense PDE3A variant (c.1346G > A, p.Gly449Asp). The variant was absent in the ExAC database and located in a highly evolutionarily conserved cluster of reported PDE3A pathogenic variants. Importantly, this variant was predicted to affect protein function by both SIFT (score = 0) and PolyPhen-2 (score = 1). After Sanger sequencing, the variant was determined to be absent in the healthy parents of the proband as well as 800 ethnically and geographically matched healthy controls. Conclusion: We present a report linking a de novo PDE3A variant to autosomal dominant hypertension with brachydactyly type E syndrome. [ABSTRACT FROM AUTHOR]

Weill-Marchesani syndrome (WMS) is a rare disorder displaying short stature, brachydactyly and joint stiffness, and ocular features including microspherophakia and ectopia lentis. Brachydactyly and joint stiffness appear less commonly in patients with WMS4 caused by pathogenic ADAMTS17 variants. Here, we investigated a large family with WMS from Newfoundland, Canada. These patients displayed core WMS features, but with proportionate hands that were clinically equivocal for brachydactyly. Whole exome sequencing and autozygosity mapping unveiled a novel pathogenic missense ADAMTS17 variant (c.3068 G > A, p.C1023Y). Sanger sequencing demonstrated variant co-segregation with WMS, and absence in 150 population matched controls. Given ADAMTS17 involvement, we performed deep phenotyping of the patients' hands. Anthropometrics applied to hand roentgenograms showed that metacarpophalangeal measurements of affected patients were smaller than expected for their age and sex, and when compared to their unaffected sibling. Furthermore, we found a possible sub-clinical phenotype involving markedly shortened metacarpophalangeal bones with intrafamilial variability. Transfection of the variant ADAMTS17 into HEK293T cells revealed significantly reduced secretion into the extracellular medium compared to wild-type. This work expands understanding of the molecular pathogenesis of ADAMTS17, clarifies the variable hand phenotype, and underscores a role for anthropometrics in characterizing sub-clinical brachydactyly in these patients. [ABSTRACT FROM AUTHOR]

Copyright of Turkish Journal of Endocrinology & Metabolism is the property of Aves Yayincilik Ltd. STI and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Patients affected by pseudohypoparathyroidism (PHP) or related disorders are characterized by physical findings that may include brachydactyly, a short stature, a stocky build, early-onset obesity, ectopic ossifications, and neurodevelopmental deficits, as well as hormonal resistance most prominently to parathyroid hormone (PTH). In addition to these alterations, patients may develop other hormonal resistances, leading to overt or subclinical hypothyroidism, hypogonadism and growth hormone (GH) deficiency, impaired growth without measurable evidence for hormonal abnormalities, type 2 diabetes, and skeletal issues with potentially severe limitation of mobility. PHP and related disorders are primarily clinical diagnoses. Given the variability of the clinical, radiological, and biochemical presentation, establishment of the molecular diagnosis is of critical importance for patients. It facilitates management, including prevention of complications, screening and treatment of endocrine deficits, supportive measures, and appropriate genetic counselling. Based on the first international consensus statement for these disorders, this article provides an updated and ready-to-use tool to help physicians and patients outlining relevant interventions and their timing. A life-long coordinated and multidisciplinary approach is recommended, starting as far as possible in early infancy and continuing throughout adulthood with an appropriate and timely transition from pediatric to adult care. [ABSTRACT FROM AUTHOR]

BACKGROUND Hypertension and brachydactyly syndrome (HTNB), also called Bilginturan syndrome, is a rare autosomal dominant disorder characterized by severe salt-independent hypertension, a short stature, brachydactyly, and death from stroke before the age of 50 years when untreated. The purpose of the present study was to identify a PDE3A mutation leading to HTNB associated with vertebral artery malformation in a Chinese family. METHODS Peripheral blood samples were collected from all subjects for DNA extraction. Next-generation sequencing and Sanger sequencing were performed to identify the PDE3A mutation. A comparative overview was performed in the probands with HTNB caused by PDE3A mutations. RESULTS Genetic analysis identified a missense mutation in PDE3A , c.1346G>A, in the proband with HTNB. This mutation, resulting in p.Gly449Asp, was located in a highly conserved domain and predicted to be damaging by different bioinformatics tools. Cosegregation analyses showed that the proband inherited the identified mutation from her father. Antihypertensive therapy was effective for the proband. Comparative overview of HTNB probands with 9 different PDE3A mutations revealed phenotypic heterogeneity. CONCLUSIONS Genetic screening can significantly improve the diagnosis of HTNB patients at an early age. Our study not only adds to the spectrum of PDE3A mutations in the Chinese population and extends the phenotype of HTNB patients to include vertebral malformation but also improves the awareness of pathogenesis in HTNB patients. We emphasize the importance of antihypertensive treatment and long-term follow-up to prevent stroke and adverse cardiovascular events. [ABSTRACT FROM AUTHOR]

Copyright of Acta Oto-Laryngologica is the property of Taylor & Francis Ltd and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Biallelic and pathogenic variants in the RTTN gene, encoding the centrosomal protein Rotatin, are associated with variable degrees of neurodevelopmental abnormalities, microcephaly, and extracranial malformations. To date, no reported case has reached their third decade. Herein, we report on a consanguineous family with three adult members, age 43, 57, and 60 years respectively, with primary microcephaly, developmental delay, primordial dwarfism, and brachydactyly segregating a homozygous splice site variant NM_173630.3:c.5648–5T>A in RTTN. The variant RTTN allele results in a nonhypomorphic skipping of exon 42 and a frameshift [(NP_775901.3:p.Ala1883Glyfs*6)]. Brain MRI of one affected individual showed markedly reduced volume of cerebral lobes and enlarged sulci but without signs of neural migration defects. Our assessment of three adult cases with a biallelic RTTN variant shows that a predicted shortened Rotatin, lacking the C‐terminal end, are associated with stationary clinical features into the seventh decade. Furthermore, our report adds brachydactyly to the phenotypic spectrum in this pleiotropic entity. [ABSTRACT FROM AUTHOR]

Background: Brachydactyly type A1 (BDA1, OMIM 112500) is a rare inherited malformation characterized primarily by shortness or absence of middle bones of fingers and toes. It is the first recorded disorder of the autosomal dominant Mendelian trait. Indian hedgehog (IHH) gene is closely associated with BDA1, which was firstly mapped and identified in Chinese families in 2000. Previous studies have demonstrated that BDA1-related mutant IHH proteins affected interactions with its receptors and impaired IHH signaling. However, how the altered signaling pathway affects downstream transcriptional regulation remains unclear. Results: Based on the mouse C3H10T1/2 cell model for IHH signaling activation, two recombinant human IHH-N proteins, including a wild type protein (WT, amino acid residues 28–202) and a mutant protein (MT, p.E95k), were analyzed. We identified 347, 47 and 4 Gli1 binding sites in the corresponding WT, MT and control group by chromatin immunoprecipitation and the overlapping of these three sets was poor. The putative cis regulated genes in WT group were enriched in sensory perception and G-protein coupled receptor-signaling pathway. On the other hand, putative cis regulated genes were enriched in Runx2-related pathways in MT group. Differentially expressed genes in WT and MT groups indicated that the alteration of mutant IHH signaling involved cell-cell signaling and cellular migration. Cellular assay of migration and proliferation validated that the mutant IHH signaling impaired these two cellular functions. Conclusions: In this study, we performed integrated genome-wide analyses to characterize differences of IHH/Gli1 downstream regulation between wild type IHH signaling and the E95K mutant signaling. Based on the cell model, our results demonstrated that the E95K mutant signaling altered Gli1-DNA binding pattern, impaired downstream gene expressions, and leaded to weakened cellular proliferation and migration. This study may help to deepen the understanding of pathogenesis of BDA1 and the role of IHH signaling in chondrogenesis. [ABSTRACT FROM AUTHOR]

Bone morphogenetic proteins (BMPs) are secreted cytokines that were initially discovered on the basis of their ability to induce bone. Several decades of research have now established that these proteins function in a large variety of physiopathological processes. There are about 15 BMP family members, which signal via three transmembrane type II receptors and four transmembrane type I receptors. Mechanistically, BMP binding leads to phosphorylation of the type I receptor by the type II receptor. This activated heteromeric complex triggers intracellular signaling that is initiated by phosphorylation of receptor‐regulated SMAD1, 5, and 8 (also termed R‐SMADs). Activated R‐SMADs form heteromeric complexes with SMAD4, which engage in specific transcriptional responses. There is convergence along the signaling pathway and, besides the canonical SMAD pathway, BMP‐receptor activation can also induce non‐SMAD signaling. Each step in the pathway is fine‐tuned by positive and negative regulation and crosstalk with other signaling pathways. For example, ligand bioavailability for the receptor can be regulated by ligand‐binding proteins that sequester the ligand from interacting with receptors. Accessory co‐receptors, also known as BMP type III receptors, lack intrinsic enzymatic activity but enhance BMP signaling by presenting ligands to receptors. In this review, we discuss the role of BMP receptor signaling and how corruption of this pathway contributes to cardiovascular and musculoskeletal diseases and cancer. We describe pharmacological tools to interrogate the function of BMP receptor signaling in specific biological processes and focus on how these agents can be used as drugs to inhibit or activate the function of the receptor, thereby normalizing dysregulated BMP signaling. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland. [ABSTRACT FROM AUTHOR]

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Background: Tricho-rhino-phalangeal syndrome (TRPS) is a rare autosomal dominant genetic disorder characterized by distinctive craniofacial and skeletal abnormalities, while non-ossifying fibroma (NOF) is a common benign bone tumour in children and adolescents. To date, no case of TRPS coexisting with NOF has been reported. This report presents a 12-year-old girl who had the characteristic features of tricho-rhino-phalangeal syndrome and non-ossifying fibroma with a fibula fracture. Case presentation: A 12-year-old girl was admitted to the Department of Endocrinology and Diabetes for evaluation of brachydactyly and a right fibula fracture. Clinical examination revealed sparse scalp hair, a characteristic bulbous pear-shaped nose, and brachydactyly with significant shortening of the fourth metatarsal. Neither intellectual disability nor multiple exostoses were observed. Radiography of both hands showed brachydactyly and cone-shaped epiphyses of the middle phalanges of the digits of both hands with deviation of the phalangeal axis. Genetic analysis of TRPS1 identified a heterozygous germline sequence variant (p.Ala932Thr) in exon 6 in the girl and her father. Approximately 1 month before being admitted to our department, the girl experienced a minor fall and suffered a fracture of the proximal fibula in the right lower limb. The pathological cytological diagnosis of the osteolytic lesion was NOF. Ten months following the surgery, the lesion on the proximal fibula of the girl disappeared. Conclusions: In conclusion, the present study is the first to report a rare case of NOF with a pathologic fracture in the fibula of a girl with TRPS. The identification of a missense mutation, (p.Ala932Thr), in exon 6 of TRPS1 in this kindred further suggested that the patient had type I TRPS and indicated that mutations in this exon may be correlated with more pronounced features of the syndrome. Radiological techniques and genetic analysis played key roles in the definitive diagnosis. [ABSTRACT FROM AUTHOR]

1q24q25 deletions cause a distinctive phenotype including proportionate short stature, microcephaly, brachydactyly, dysmorphic facial features and intellectual disability. We present a mother and son who have a 672 kb microdeletion at 1q24q25. They have the typical skeletal features previously described but do not have any associated intellectual disability. We compare the genes within our patients' deletion to those in the deletions of previously reported cases. This indicates two genes that may be implicated in the intellectual disability usually associated with this deletion syndrome; PIGC and C1orf105. In addition, our cases provide supporting evidence to recent published work suggesting that the skeletal features may be linked to the microRNAs miR199 and miR214, encoded within intron 14 of the Dynamin‐3 gene. [ABSTRACT FROM AUTHOR]

KBG syndrome is characterized by short stature, distinctive facial features, and developmental/cognitive delay and is caused by mutations in ANKRD11, one of the ankyrin repeat‐containing cofactors. After the advent of whole exome sequencing, the number of clinical reports with KBG diagnosis has increased, leading to a revision of the phenotypic spectrum associated with this syndrome. Here, we report a female child showing clinical features of the KBG syndrome in addition to a caudal appendage at the coccyx with prominent skin fold and a peculiar calcaneus malformation. Exons and exon–intron junctions targeted resequencing of SH3PXD2B and MASP1 genes, known to be associated with prominent coccyx, gave negative outcome, whereas sequencing of ANKRD11 whose mutations matched the KBG phenotype of the proband showed a de novo heterozygous frameshift variant c.4528_4529delCC in exon 9 of ANKRD11. This report contributes to expand the knowledge of the clinical features of KBG syndrome and highlights the need to search for vertebral anomalies and suspect this condition in the presence of a prominent, elongated coccyx. [ABSTRACT FROM AUTHOR]

Summary: Objective: Mutations in the aggrecan gene (ACAN) have been identified in two autosomal dominant skeletal dysplasias, spondyloepiphyseal dysplasia, Kimberley type (SEDK), and osteochondritis dissecans, as well as in a severe recessive dysplasia, spondyloepimetaphyseal dysplasia, aggrecan type. Next‐generation sequencing (NGS) has aided the identification of heterozygous ACAN mutations in individuals with short stature, minor skeletal defects and mild facial dysmorphisms, some of whom have advanced bone age (BA), poor pubertal spurt and early growth cessation as well as precocious osteoarthritis. Design and methods: This study involves clinical and genetic characterization of 16 probands with heterozygous ACAN variants, 14 with short stature and mild skeletal defects (group 1) and two with SEDK (group 2). Subsequently, we reviewed the literature to determine the frequency of the different clinical characteristics in ACAN‐positive individuals. Results: A total of 16 ACAN variants were located throughout the gene, six pathogenic mutations and 10 variants of unknown significance (VUS). Interestingly, brachydactyly was observed in all probands. Probands from group 1 with a pathogenic mutation tended to be shorter, and 60% had an advanced BA compared to 0% in those with a VUS. A higher incidence of coxa valga was observed in individuals with a VUS (37% vs 0%). Nevertheless, other features were present at similar frequencies. Conclusions: ACAN should be considered as a candidate gene in patients with short stature and minor skeletal defects, particularly those with brachydactyly, and in patients with spondyloepiphyseal dysplasia. It is also important to note that advanced BA and osteoarticular complications are not obligatory conditions for aggrecanopathies/aggrecan‐associated dysplasias. [ABSTRACT FROM AUTHOR]

The rise of anatomical abnormalities in anurans over recent years has increased the interest in producingmore and better information about the abnormalities observed in specimens within natural environments that are currently being altered. The aimof this work was to identify and describe la osseous abnormalities found in Rhinella arenarum. Four samplings were conducted between March 2009 and February 2010 in the Claro river, located in San Francisco in the Ayacucho Department in the province of San Luis. Specimens of R. arenarum with visible abnormalities were observed and collected manually. They were euthanized in the laboratory, preserved in 10% formaldehyde, and stored in the Herpetological Collection Unit of the National University of San Luis (CHUNSL). The Alizarin-Alzian technique was also applied to the specimens. Photographs of the abnormalities were taken, and observations were made with a stereoscopic microscope. The following abnormalities were identified and described: femur ectromelia, tibial and fibular ectromelia, ectrodactylia and brachydactyly. Further work could focus on determining the causes of the abnormalities observed in this species, conducting an integrated study, and attempting to link this with the worldwide phenomenon of amphibious declination. [ABSTRACT FROM AUTHOR]

Protein arginine methyltransferase 7 (PRMT7) is a member of a family of enzymes that catalyze the transfer of methyl groups from S‐adenosyl‐l‐methionine to nitrogen atoms on arginine residues. Arginine methylation is involved in multiple biological processes, such as signal transduction, mRNA splicing, transcriptional control, DNA repair, and protein translocation. Currently, 7 patients have been described harboring compound heterozygous or homozygous variants in the PRMT7 gene, causing a novel intellectual disability syndrome, known as SBIDDS syndrome (Short Stature, Brachydactyly, Intellectual Developmental Disability, and Seizures). We report on 3 additional patients from 2 consanguineous families with severe/moderate intellectual disability, short stature, brachydactyly and dysmorphisms. Exome sequencing revealed 2 novel homozygous mutations in PRMT7. Our findings expand the clinical and molecular spectrum of homozygous PRMT7 mutations, associated to the SBIDDS syndrome, showing a possible correlation between the type of mutation and the severity of the phenotype. [ABSTRACT FROM AUTHOR]

Acrodysostosis is a very rare congenital multisystem condition characterized by skeletal dysplasia with severe brachydactyly, midfacial hypoplasia, and short stature, varying degrees of intellectual disability, and possible resistance to multiple G protein-coupled receptor signalling hormones. Two distinct subtypes are differentiated: acrodysostosis type 1 resulting from defects in protein kinase type 1-α regulatory subunit and acrodysostosis type 2 caused by mutations in phosphodiesterase 4D (PDE4D). Most cases are sporadic. We report on a rare multigenerational familial case of acrodysostosis type 2 due to a novel autosomal dominantly inherited PDE4D mutation. A 3.5-year-old boy presented with short stature, midfacial hypoplasia, severe brachydactyly, developmental delay, and behavioural problems. Laboratory investigations revealed mild thyrotropin resistance. His mother shared some characteristic features, such as midfacial hypoplasia and severe brachydactyly, but did not show short stature, intellectual disability or hormonal resistance. Genetic analysis identified the identical, novel heterozygous missense mutation of the PDE4D gene c.569C>T (p.Ser190Phe) in both patients. This case illustrates the significant phenotypic variability of acrodysostosis even within one family with identical mutations. Hence, a specific clinical diagnosis of acrodysostosis remains challenging because of great interindividual variability and a substantial overlap of the two subtypes as well as with other related Gsα-cAMP-signalling-linked disorders. [ABSTRACT FROM AUTHOR]

TRPV4 encodes a polymodal calcium-permeable plasma membrane channel. Dominant pathogenic mutations in TRPV4 lead to a wide spectrum of abnormal phenotypes. This is the first report of biallelic TRPV4 mutations and we describe two compound heterozygous siblings presenting with a complex phenotype including severe neuromuscular involvement. In light of previously well described dominant inheritance for TRPV4-related neuromuscular disease, our study suggests a role for compound heterozygosity and loss-of-function as a potential novel disease mechanism for this group of disorders. Profound intellectual disability was also noted in both affected children, suggesting that TRPV4 may be necessary for normal brain development. [ABSTRACT FROM AUTHOR]

Exome sequencing has led to the comprehension of the molecular bases of several forms of neurodevelopmental disorders, a clinically heterogeneous group of diseases characterized by intellectual disability (ID) and autism spectrum disorder (ASD). De novo mutations in POGZ has been causally linked to isolated ASD and syndromic ID, only recently. Here we report on a 15 year-old girl in whom exome sequencing allowed to identify a de novo POGZ truncating mutation as the molecular cause underlying a complex phenotype apparently not fitting any recognized syndrome. We describe the evolution of her clinical features with age, and review published clinical data of patients with POGZ mutations to systematically analyze the clinical spectrum associated with mutations. Our finding expands the clinical and molecular spectrum of POGZ mutations. Revision of the literature indicate that moderate to severe ID, microcephaly, variable CNS malformations, reduced growth, brachytelephalangy, and facial dysmorphism represent recurrent features associated with POGZ mutations. [ABSTRACT FROM AUTHOR]

The treatment of a brachymetacarpia using a distraction osteogenesis was mostly single, unilateral pattern. In case of multiple brachymetacarpia, singlestage lengthening or rapid distraction lengthening with a bone graft were usually used. Multiple brachymetacarpia treated by distraction osteogenesis is rarely reported. We report a case of a 15-year-old female presented with bilateral multiple brachymetacarpia treated by distraction osteogenesis simultaneously without complications. Also, we have evaluated the clinical results and factors which influence the clinical results. [ABSTRACT FROM AUTHOR]

Chromosome 2q37 deletion syndrome is a rare chromosomal disorder characterized by mild to moderate developmental delay, brachydactyly of the third to fifth digits or toes, short stature, obesity, hypotonia, a characteristic facial appearance, and autism spectrum disorder. Here, we report on a patient with 2q37 deletion presenting with dilated cardiomyopathy (DCMP). Congenital heart malformations have been noted in up to 20% of patients with 2q37 deletions. However, DCMP has not been reported in 2q37 deletion patients previously. The patient exhibited the characteristic facial appearance (a flat nasal bridge, deep-set eyes, arched eyebrows, and a thin upper lip), developmental delay, mild mental retardation, peripheral nerve palsy, and Albright hereditary osteodystrophy (AHO)-like phenotypes (short stature and brachydactyly). Conventional chromosomal analysis results were normal; however, microarray-based comparative genomic hybridization revealed terminal deletion at 2q37.1q37.3. In addition, the patient was confirmed to have partial growth hormone (GH) deficiency and had shown a significant increase in growth rate after substitutive GH therapy. Chromosome 2q37 deletion syndrome should be considered in the differential diagnosis of patients presenting with AHO features, especially in the presence of facial dysmorphism. When patients are suspected of having a 2q37 deletion, high-resolution cytogenetic analysis is recommended. [ABSTRACT FROM AUTHOR]

Post-translational protein modifications exponentially expand the functional complement of proteins encoded by the human genome. One such modification is the covalent addition of a methyl group to arginine or lysine residues, which is used to regulate a substantial proportion of the proteome. Arginine and lysine methylation are catalyzed by protein arginine methyltransferase (PRMTs) and protein lysine methyltransferase proteins (PKMTs), respectively; each methyltransferase has a specific set of target substrates. Here, we report a male with severe intellectual disability, facial dysmorphism, microcephaly, short stature, brachydactyly, cryptorchidism and seizures who was found to have a homozygous 15,309 bp deletion encompassing the transcription start site of PRMT7, which we confirmed is functionally a null allele. We show that the patient's cells have decreased levels of protein arginine methylation, and that affected proteins include the essential histones, H2B and H4. Finally, we demonstrate that patient cells have altered Wnt signaling, which may have contributed to the skeletal abnormalities. Our findings confirm the recent disease association of PRMT7, expand the phenotypic manifestations of this disorder and provide insight into the molecular pathogenesis of this new condition. [ABSTRACT FROM AUTHOR]

Unlabelled: Myhre syndrome (OMIM 139210) is a rare developmental disorder inherited as an autosomal dominant trait and caused by a narrow spectrum of missense mutations in the SMAD4 gene. The condition features characteristic face, short stature, skeletal anomalies, muscle pseudohypertrophy, restricted joint mobility, stiff and thick skin, and variable intellectual disability. While most of the clinical features manifest during childhood, the diagnosis may be challenging during the first years of life. We report on the evolution of the clinical features of Myhre syndrome during childhood in a subject with molecularly confirmed diagnosis. The clinical records of 48 affected patients were retrospectively analysed to identify any early clinical signs characterizing this disorder and to better delineate its natural history. We also note that pericarditis and laryngotracheal involvement represent important life-threatening complications of Myhre syndrome that justify the recommendation for cardiological and ENT follow-up for these patients.Conclusion: Short length/stature, short palpebral fissures, and brachydactyly with hyperconvex nails represent signs/features that might lead to the correct diagnosis in the first years of life and direct to the proper molecular analysis. We underline the clinical relevance of pericarditis and laryngotracheal stenosis as life-threatening complications of this disorder and the need for careful monitoring, in relation to their severity.What Is Known: • The clinical and radiological signs of the disease in children older than 7-8 years. • Pericarditis, sometimes occurring with constrictive pericardium requiring pericardiectomy, has been reported as a recurrent feature but has not been adequately stressed in previous literature. What is New: • Short length/stature, short palpebral fissures, brachydactyly with hyperconvex nails represent clinical signs that might lead to diagnosis in the first years of life. • Review of the literature showed that pericarditis and laryngotracheal complications represent major recurrent issues in patients with Myhre syndrome. [ABSTRACT FROM AUTHOR]

Pseudoachondroplasia (PSACH; MIM no. 177170) is an autosomal dominant osteochondrodysplasia characterized by short-limb short stature, brachydactyly and early-onset osteoarthropathy. Typically, at approximately two years of age, the rate of growth falls below the standard growth curve, causing a moderately severe form of disproportionate short-limb short stature. The current study described the clinical and radiographic observations of six Chinese patients with PSACH, and identified two de novo novel missense mutations [p.Asp326Asn (c.976G>A) and c.1585A>G (p.Thr529Ala)] in cartilage oligomeric matrix protein (COMP) in the patients. The current study expanded the mutation spectrum of the COMP gene, and contributes to the understanding of phenotype/ genotype of COMP-associated diseases. [ABSTRACT FROM AUTHOR]

Congenital limb deformities are very rare conditions and the knowledge about etiology, pathogenesis, clinical presentation and treatment is still poor. Moreover, many defects are still not reported in veterinary literature. This report documents clinical and radiographic findings in three dogs with congenital deformity involving the distal extremities. Case 1 was affected with bilateral aphalangia of the pedes, case 2 presented a combination of brachydactyly and syndactyly, whereas in case 3 a unilateral ectrodactyly was observed. To the authors' knowledge, brachydactyly, as well as aphalangia, are very uncommon anomalies and have been rarely documented. Moreover, association between syndactyly and brachydactyly has still not been reported. [ABSTRACT FROM AUTHOR]

Acromesomelic dysplasia, Grebe type is a very rare skeletal dysplasia characterized by severe dwarfism with marked micromelia and deformation of the upper and lower limbs, with a proximodistal gradient of severity. CDMP1 gene mutations have been associated with Grebe syndrome, Hunter-Thompson syndrome, Du Pan syndrome and brachydactyly type C. The proband is a 4-year-old boy, born of consanguineous Pakistani parents. Radiographic imaging revealed features typical of Grebe syndrome: severe shortening of the forearms with an acromesomelic pattern following a proximodistal gradient, with distal parts more severely affected than medial parts; hypoplastic hands, with the phalangeal zone more affected than the metacarpal zone; and severe hypoplastic tibial/femoral zones in both limbs. After molecular analyses, the p.Arg377Trp variant in a homozygous pattern was identified in the CDMP1 gene in the affected child. In silico and structural analyses predicted the p.Arg377Trp amino acid change to be pathogenic. Of the 34 mutations described in the CDMP1 gene, four different missense mutations have been associated with Grebe syndrome. The CDMP1 gene encodes growth differentiation factor 5 (GDF5), which plays a role in regulation of limb patterning, joint formation and distal bone growth. Homozygous mutations in the mature domain of GDF5 result in severe limb malformations such as the Grebe type or the Hunter-Thompson type of acromesomelic chondrodysplasia. The p.Arg377Trp mutation is located within the recognition motif at the processing site of GDF5 where the sequence RRKRR changes to WRKRR. The genotype-phenotype correlation allowed not only confirmation of the clinical diagnosis but also appropriate genetic counselling to be offered to this family. [ABSTRACT FROM AUTHOR]