Search

Although state estimation using a bad data detector (BDD) is a key procedure employed in power systems, the detector is vulnerable to false data injection attacks (FDIAs). Substantial deep learning methods have been proposed to detect such attacks. However, deep neural networks are susceptible to adversarial attacks or adversarial examples, where slight changes in inputs may lead to sharp changes in the corresponding outputs in even well-trained networks. This article introduces the joint adversarial example and FDIAs (AFDIAs) to explore various attack scenarios for state estimation in power systems. Considering that perturbations added directly to measurements are likely to be detected by BDDs, our proposed method of adding perturbations to state variables can guarantee that the attack is stealthy to BDDs. Then, malicious data that are stealthy to both BDDs and deep learning-based detectors can be generated. Theoretical and experimental results show that our proposed state-perturbation-based AFDIA method (S-AFDIA) can carry out attacks stealthy to both conventional BDDs and deep learning-based detectors, while our proposed measurement-perturbation-based adversarial FDIA method (M-AFDIA) succeeds if only deep learning-based detectors are used. The comparative experiments show that our proposed methods provide better performance than state-of-the-art methods. Besides, the ultimate effect of attacks can also be optimized using the proposed joint attack methods.

Disorders that result from de-arrangement of growth, development and/or differentiation of the appendages (limbs and digit) are collectively called as inherited abnormalities of human appendicular skeleton. The bones of appendicular skeleton have central role in locomotion and movement. The different types of appendicular skeletal abnormalities are well described in the report of "Nosology and Classification of Genetic skeletal disorders: 2019 Revision". In the current article, we intend to present the embryology, developmental pathways, disorders and the molecular genetics of the appendicular skeletal malformations. We mainly focused on the polydactyly, syndactyly, brachydactyly, split-hand-foot malformation and clubfoot disorders. To our knowledge, only nine genes of polydactyly, five genes of split-hand-foot malformation, nine genes for syndactyly, eight genes for brachydactyly and only single gene for clubfoot have been identified to be involved in disease pathophysiology. The current molecular genetic data will help life sciences researchers working on the rare skeletal disorders. Moreover, the aim of present systematic review is to gather the published knowledge on molecular genetics of appendicular skeleton, which would help in genetic counseling and molecular diagnosis.

Brachydactyly (BD) type C is a rare form of familial BD caused by GDF5 mutations. Some of the affected children have severe clinodactyly requiring surgery. The literature is limited to case reports.The current retrospective study included 15 Saudi Arabian families with 42 affected children seen by the author for 25 years. A total of 23 digits (in 23 hands) underwent surgical correction of clinodactyly using a closing wedge osteotomy. The current study reports on the genetics, clinical presentation, radiological features, and midterm outcome of surgery.Genetic analysis was done in 6 families and confirmed the presence of 2 novel missense mutations (p.Met173Val in 3 families and p.Thr203Asn in 3 families) in the GDF5 gene. All cases in the study group demonstrated the classical clinical and radiographic features of BD type C. However, only 1 hand showed all the features of angel-shaped bony defect. The clinodactyly defect was mostly observed in the index or middle fingers. Surgery for the clinodactyly defect was only done if there was finger overlap. Closing wedge osteotomy was done in a total of 23 digits with a satisfactory outcome.This study represents the largest reported series of children undergoing surgery for correction of BD type C clinodactyly with a uniform technique performed by a single surgeon. The closing wedge osteotomy used resulted in good midterm outcomes, although long-term follow-up is lacking.

We report the case of the third patient with Tsukahara-Azuno-Kaiji syndrome. It is characterized by brachydactyly A1, dwarfism, microcephaly, scoliosis, intellectual disability, ptosis, and hearing loss. The first patient was reported in 1989, and the second in 2010. The present patient had many features in common with the previous 2 patients, with a few minor differences. Although this combination of symptoms is very characteristic, the clinicians should know about this syndrome to diagnose it. The syndrome in this patient appeared sporadically, and chromosome G-banding revealed a normal female karyotype of 46XX. However, further genetic research could not be performed. Steady accumulation of information will enable us to discover the true clinical and genetic nature of the disease and to make the diagnosis more easily.

Pycnodysostosis is a rare autosomal recessive condition caused by the mutation of CTSK gene. CTSK regulates the activity of Cathepsin K which is responsible for osteoclast-mediated bone resorption. This mutation causes the bones to become dense, sclerotic, brittle, and thus, prone to fracture. Affected individuals have normal cognitive development and life expectancy, however, the quality of life depends on the early diagnosis of the condition. The patient presents with striking clinical (short stature, brachydactyly) and radiological (frontal and parieto-occipital bossing, open sutures, and fontanelles, acro-osteolysis of terminal phalanges) features making the diagnosis clinico-radiographic. In atypical or mild cases with overlapping features, gene mapping is advocated. A plethora of dental anomalies and characteristic craniofacial dysmorphia puts the dentist in a position to diagnose such a case.

We present five members of a consanguineous Pakistani kinship with the most severe familial tetramelic transverse autopod deficiency reported to date and additionally having some of the common autosomal recessive Robinow syndrome-1 (RRS1) features including short stature, short neck, severe vertebral anomalies of kyphoscoliosis, hemivertebrae, fusion of thoracic vertebrae, broad forehead, and dental crowding. We mapped the locus of this atypical RRS and detected homozygous 8-nucleotide deletion c.1353_1360del (p.(Met452Alafs*4)) in ROR2, the gene responsible for RRS1. We did not find any other variant shared by all affected individuals that could possibly act as a modifier of limb defect. Autopods are affected in RRS1, but severe autopod deficiency is not a characteristic feature. Over 30 biallelic variants dispersed throughout the gene are known in ROR2-related RS, with no genotype-phenotype correlation for specific RRS1 features. Considering together with the sporadic case homozygous for variant p.(Arg442*) and the case homozygous for p.(Arg441Thrfs*16) in a family where heterozygous members have brachydactyly type B1, we propose that homozygous truncating variants that originate at residues 441-452 can cause severe autopod reduction anomalies, suggesting some genotype-phenotype correlation for this particular phenotype.

An extremely preterm infant presented with clinical and radiological features of Robinow syndrome including butterfly vertebrae, posterior rib fusion, brachydactyly, nail hypoplasia, and retromicrognathia resulting in difficult endotracheal intubation in the intensive care setting. Rapid trio exome sequencing detected a novel homozygous likely pathogenic missense variant in the ROR2 gene, NM_004560.3:c.950A>G, p.(Tyr317Cys), for which both parents were heterozygous carriers. In-silico protein modeling predicted a deleterious effect on the function of the protein. We report an extreme premature infant with novel homozygous likely pathogenic variant in the ROR2 gene consistent with autosomal recessive Robinow syndrome. This case expands the phenotypic and genotypic spectrum of this disorder and highlights the benefit of performing rapid exome sequencing early during evaluation to aid in patient management and providing accurate genetic counseling to families.

Background Brachydactyly type B is an autosomal dominant disorder that is characterized by hypoplasia of the distal phalanges and nails and can be divided into brachydactyly type B1 (BDB1) and brachydactyly type B2 (BDB2). BDB1 is the most severe form of brachydactyly and is caused by truncating variants in the receptor tyrosine kinase–like orphan receptor 2 (ROR2) gene. Case presentation Here, we report a five-generation Chinese family with brachydactyly with or without syndactyly. The proband and her mother underwent digital separation in syndactyly, and the genetic analyses of the proband and her parents were provided. The novel heterozygous frameshift variant c.1320dupG, p.(Arg441Alafs*18) in the ROR2 gene was identified in the affected individuals by whole-exome sequencing and Sanger sequencing. The c.1320dupG variant in ROR2 is predicted to produce a truncated protein that lacks tyrosine kinase and serine/threonine- and proline-rich structures and remarkably alters the tertiary structures of the mutant ROR2 protein. Conclusion The c.1320dupG, p.(Arg441Alafs*18) variant in the ROR2 gene has not been reported in any databases thus far and therefore is novel. Our study extends the gene variant spectrum of brachydactyly and may provide information for the genetic counselling of family members.

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.

Protein arginine N-methyltransferase 7 (PRMT7) encodes an arginine methyltransferase central to a number of fundamental biological processes, mutations in which result in an autosomal recessive developmental disorder characterized by short stature, brachydactyly, intellectual developmental disability and seizures (SBIDDS). To date, fewer than 15 patients with biallelic mutations in PRMT7 have been documented. Here we report brothers from a consanguineous Iraqi family presenting with a developmental disorder characterized by global developmental delay, shortened stature, facial dysmorphisms, brachydactyly, and kidney dysfunction. In both affected brothers, whole genome sequencing (WGS) identified a novel homozygous substitution in PRMT7 (ENST00000339507.5), c.1097 G > A (p.Cys366Tyr), considered to account for the majority of the phenotypic presentation. Rare compound heterozygous mutations in the dysplasia-associated perlecan-encoding HSPG2 gene (ENST00000374695.3) were also found (c.10721-2dupA, p.Ser71Asn and c.212 G > A), potentially accounting for the kidney dysfunction. In addition to expanding the known mutational spectrum of variably expressive PRMT7 mutations alongside potential digenic inheritance with HSPG2, this report underlines the diagnostic utility of a WGS-guided analysis in the detection of rare genetic disorders.

Brachydactyly Type D is a congenital condition of the thumb in which there is a short and broad thumbnail. Although the thumb function is often unaffected, some patients seek surgery for cosmetic improvement. This study aimed to describe our method of distraction lengthening to correct nail deformity in brachydactyly Type D. A total of 163 thumbs in 95 patients underwent this surgery between 2018 and 2021.The mean thumbnail length improved from 9 mm to 15 mm, with a mean percentage increase of 62%. The ratio of nail length to width changed from 0.6 to 1.1, which was equal to normal. The mean increased fingernail length/width ratio was 0.5, with a percentage change of 78%. No obvious surgical scar was observed. The thumb function was not significantly affected. We conclude that aesthetic correction of short nail deformity in brachydactyly Type D can be achieved by distraction lengthening with high satisfaction and without functional impairment. Level of evidence: IV

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. Sin financiación 1.361 JCR (2021) Q2, 46/93 Anthropology 0.646 SJR (2021) Q1, 57/448 Anthropology No data IDR 2021 UEM

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.

Objective Pseudohypoparathyroidism and related disorders belong to a group of heterogeneous rare diseases that share an impaired signaling downstream of Gsα-protein-coupled receptors. Affected patients may present with various combination of symptoms including resistance to PTH and/or to other hormones, ectopic ossifications, brachydactyly type E, early onset obesity, short stature and cognitive difficulties. Several years ago we proposed a novel nomenclature under the term of inactivating PTH/PTHrP signaling disorders (iPPSD). It is now of utmost importance to validate these criteria and/or improve the basis of this new classification. Design Retrospective study of a large international series of 459 probands and 85 relatives molecularly characterized. Methods Information on major and minor criteria associated with iPPSD and genetic results were retrieved from patient files. We compared the presence of each criteria according to the iPPSD subtype, age and gender of the patients. Results More than 98% of the probands met the proposed criteria for iPPSD classification. Noteworthy, most patients (85%) presented a combination of symptoms rather than a single sign suggestive of iPPSD and the overlap among the different genetic forms of iPPSD was confirmed. The clinical and molecular characterization of relatives identified familial history as an additional important criterion predictive of the disease. Conclusions The phenotypic analysis of this large cohort confirmed the utility of the major and minor criteria and their combination to diagnose iPPSD. This report shows the importance of having simple and easily recognizable signs to diagnose with confidence these rare disorders and supports a better management of patients.

Ciliopathy syndrome is a congenital abnormality of structure and/or function of cilia, which causes pleiotropic disorder, including liver cirrhosis. This study aimed to describe a unique case of liver cirrhosis with possible aetiology of ciliopathy syndrome. A 44 year-old woman with chief complain of hematemesis had diabetes mellitus, obesity, dyslipidaemia, amenorrhoea and often became unconscious. We found short stature, brachydactyly, hyperpigmented maculae in trunk and four limbs, and hepatosplenomegaly. The laboratory results showed: haemoglobin 7.4 g/dl; albumin 2.42 g/dl; urea 84.8 mg/dl; creatinine 2.4 mg/dl; prolactin 138.8 ng/ml, while HBsAg was negative and anti-HCV was non-reactive. Abdominal ultrasonography showed liver cirrhosis; endoscopy showed grade 3 oesophageal varicose; FibroScan showed 75 kPa; liver biopsy showed hydropic degeneration and cirrhosis; and head CT scan showed chronic lacunar infarction of corona radiata and mega cisterna magna occipital. We reported female with oesophageal varicose rupture, short stature, brachydactyly, obesity, diabetes mellitus, dyslipidaemia, hyperpigmented maculae, liver cirrhosis and mega cisterna magna, which was likely to suffer from ciliopathy syndrome.

Mosaic variegated aneuploidy (MVA) syndrome is a rare, autosomal recessive genetic disease. Here, we report an ultra-rare case of MVA syndrome associated with a CEP57 variant.We retrospectively analyzed the clinical data of a 9-year-old female patient and surveyed her family members. Whole-exome sequencing and karyotype analysis were performed; suspected mutations were verified using Sanger sequencing.The patient presented with intrauterine growth restriction, short stature, microcephaly, facial dysmorphism, brachydactyly, and small teeth, and she showed unsatisfactory response to GH replacement therapy. Laboratory tests revealed high insulin-like growth factor-1 levels. Karyotype analysis of the peripheral blood showed mosaic variegated aneuploidies. Whole-exome and Sanger sequencing revealed a novel homozygous nonsense variant, NM_014679.4: c.312 T G, in CEP57 that leads to translation termination (p.Tyr104*). The parents were heterozygous carriers of the identified variant.This study presents an ultra-rare case of CEP57-driven MVA syndrome, identifying a novel homozygous nonsense variant of CEP57 (p.Tyr104*). Our findings enrich the CEP57 mutational spectrum and emphasize the importance of genetic testing in patients with microcephaly and short stature. Furthermore, we conclude that growth hormone treatment is ineffective in such patients.

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

Context The natriuretic peptide receptor 2 gene (NPR2) is a causative gene of idiopathic short stature (ISS) with an incidence rate of 2% to 6%. The clinical characteristics of patients with NPR2 heterozygous mutations are atypical, and data on the efficacy of recombinant human growth hormone (rhGH) treatment in patients with NPR2 mutations are limited. Objectives This work reports 6 cases with NPR2 mutation and explores the characteristics of patients with an NPR2 mutation and their therapeutic response to rhGH. Design, Settings, and Patients Six Chinese short-stature patients in our hospital with NPR2 mutations by whole-exome sequencing were included. We also searched all previously published NPR2 mutation cases as of August 10, 2020, and information about their medical history, mutations, and rhGH treatment were recorded and summarized. Results The clinical characteristics of patients with an NPR2 heterozygous mutation mainly included short stature, facial anomalies, and skeletal dysplasia. Skeletal dysplasia mainly included brachydactyly (56.2%), shortened metacarpals or metatarsals (particularly fourth to fifth; 26.1%), and clinodactyly (21.7%). rhGH treatment significantly improved the height SD score (SDS) of patients with NPR2 heterozygous mutations (median, –2.1 vs –2.9, P < .001), especially in girls. The height SDS change correlated negatively with initial age of treatment (r = –0.477; P = .034), and height SDS change of patients with NPR2 heterozygous mutations in the carboxyl-terminal guanylyl cyclase catalytic domain was significantly higher than that of the extracellular ligand-binding region domain (median, 1.9 vs 0.6, P = .019). Conclusions ISS patients with skeletal deformities should be tested for an NPR2 mutation. rhGH treatment is beneficial for short-stature patients with NPR2 heterozygous mutations and needs further study.

BackgroundAlthough carpal tunnel syndrome (CTS) is the most common form of peripheral entrapment neuropathy, its pathogenesis remains largely unknown. An estimated heritability index of 0.46 and an increased familial occurrence indicate that genetic factors must play a role in the pathogenesis.Methods and resultsWe report on a family in which CTS occurred in subsequent generations at an unusually young age. Additional clinical features included brachydactyly and short Achilles tendons resulting in toe walking in childhood. Using exome sequencing, we identified a heterozygous variant (c.5009T>G; p.Phe1670Cys) in the fibrillin-2 (FBN2) gene that co‐segregated with the phenotype in the family. Functional assays showed that the missense variant impaired integrin-mediated cell adhesion and migration. Moreover, we observed an increased transforming growth factor-β signalling and fibrosis in the carpal tissues of affected individuals. A variant burden test in a large cohort of patients with CTS revealed a significantly increased frequency of rare (6.7% vs 2.5%–3.4%, pFBN2 variants in patient alleles compared with controls.ConclusionThe identification of a novel FBN2 variant (p.Phe1670Cys) in a unique family with early onset CTS, together with the observed increased frequency of rare and high-impact FBN2 variants in patients with sporadic CTS, strongly suggest a role of FBN2 in the pathogenesis of CTS.

BackgroundWe describe two unrelated patients who display similar clinical features including telangiectasia, ectodermal dysplasia, brachydactyly and congenital heart disease.MethodsWe performed trio whole exome sequencing and functional analysis using in vitro kinase assays with recombinant proteins.ResultsWe identified two different de novo mutations in protein kinase D1 (PRKD1, NM_002742.2): c.1774G>C, p.(Gly592Arg) and c.1808G>A, p.(Arg603His), one in each patient. PRKD1 (PKD1, HGNC:9407) encodes a kinase that is a member of the protein kinase D (PKD) family of serine/threonine protein kinases involved in diverse cellular processes such as cell differentiation and proliferation and cell migration as well as vesicle transport and angiogenesis. Functional analysis using in vitro kinase assays with recombinant proteins showed that the mutation c.1808G>A, p.(Arg603His) represents a gain-of-function mutation encoding an enzyme with a constitutive, lipid-independent catalytic activity. The mutation c.1774G>C, p.(Gly592Arg) in contrast shows a defect in substrate phosphorylation representing a loss-of-function mutation.ConclusionThe present cases represent a syndrome, which associates symptoms from several different organ systems: skin, teeth, bones and heart, caused by heterozygous de novo mutations in PRKD1 and expands the clinical spectrum of PRKD1 mutations, which have hitherto been linked to syndromic congenital heart disease and limb abnormalities.

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.

Background: High blood pressure is the primary risk factor for cardiovascular death worldwide. Autosomal dominant hypertension with brachydactyly clinically resembles salt-resistant essential hypertension and causes death by stroke before 50 years of age. We recently implicated the gene encoding phosphodiesterase 3A ( PDE3A ); however, in vivo modeling of the genetic defect and thus showing an involvement of mutant PDE3A is lacking. Methods: We used genetic mapping, sequencing, transgenic technology, CRISPR-Cas9 gene editing, immunoblotting, and fluorescence resonance energy transfer. We identified new patients, performed extensive animal phenotyping, and explored new signaling pathways. Results: We describe a novel mutation within a 15 base pair (bp) region of the PDE3A gene and define this segment as a mutational hotspot in hypertension with brachydactyly. The mutations cause an increase in enzyme activity. A CRISPR/Cas9-generated rat model, with a 9-bp deletion within the hotspot analogous to a human deletion, recapitulates hypertension with brachydactyly. In mice, mutant transgenic PDE3A overexpression in smooth muscle cells confirmed that mutant PDE3A causes hypertension. The mutant PDE3A enzymes display consistent changes in their phosphorylation and an increased interaction with the 14-3-3θ adaptor protein. This aberrant signaling is associated with an increase in vascular smooth muscle cell proliferation and changes in vessel morphology and function. Conclusions: The mutated PDE3A gene drives mechanisms that increase peripheral vascular resistance causing hypertension. We present 2 new animal models that will serve to elucidate the underlying mechanisms further. Our findings could facilitate the search for new antihypertensive treatments.

Synpolydactyly type 1 (SPD1, OMIM 186000) is inherited as autosomal dominant and is caused byHOXD13mutations. The condition is rare and is known for its phenotypic heterogeneity. In the homozygous state, the phenotype is generally more severe and is characterized by three main features: a more severe degree of syndactyly, a more severe degree of brachydactyly, and the frequent loss of the normal tubular shape of the metacarpals/metatarsals. Due to the phenotypic heterogeneity and the phenotypic overlap with other types of syndactyly, no pathognomonic feature has been described for the homozygous phenotype of SPD1. In the current communication, the author reviews the literature on the phenotypes of SPD1 in homozygous patients. The review documents that not all homozygous patients show a severe hand phenotype. The review also defines the “relatively long and medially deviated big toe with/without cupping of the forefoot” as a pathognomonic feature in the phenotype. Illustration of this feature is done through a demonstrative clinical report in a multigeneration family with SPD1 andHOXD13polyalanine repeat expansion. Finally, the pathogenesis of the clinical features is reviewed.

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.

We report a family with a spectrum of short stature, craniofacial dysmorphism, and digital anomalies in a father and 2 daughters, with the youngest (proband) displaying a severe phenotype. Clinically, autosomal dominant Robinow syndrome (ADRS) was diagnosed. Whole-exome sequencing identified a heterozygous pathogenic BMP2 variant in the father and his daughters. The phenotype of short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies related to BMP2 haploinsufficiency has some facial and digital resemblance to ADRS. Although this variant segregated in the affected members, it failed to explain the severe phenotype of the proband. A reanalysis of the girl's raw data confirmed 2 disorders: a de novo likely pathogenic DVL1 variant implicated in ADRS and the familial BMP2 variant. A close interplay of high-throughput sequencing and deep phenotyping unraveled the complexities of the blended phenotype in the proband.

Monogenic nephrotic syndrome (NS) is associated with a resistance to initial glucocorticoid therapy and causative variants, which may be found in several genes influencing podocyte stability and kidney development. The TTC21B gene, which encodes the retrograde intraflagellar transport protein IFT139, is found mostly in association with ciliopathies in humans. The role of this protein in podocyte cytoskeleton stability was confirmed later and the mutated TTC21B also may be associated with proteinuric diseases, such as nephrotic syndrome. Our patient manifested as an infant with brachydactyly, nephrotic-range proteinuria, and renal tubular acidosis, and a kidney biopsy revealed focal segmental glomerulosclerosis (FSGS). Multiple phalangeal cone-shaped epiphyses of the hand were seen on X-ray. Next-generation sequencing revealed the well-described p.Pro209Leu heterozygous variant and a novel heterozygous p.Cys14Arg variant in the TTC21B gene. Our finding confirmed that the causative variants in the TTC21B gene may contribute to a spectrum of clinical features, such as glomerular proteinuric disease with tubulointerstitial involvement and skeletal abnormalities.

Background The literature on laminopathy with ventricular phenotype is extensive. However, the pathogenicity of LMNA variations in atrial lesions still lacks research. Objective To characterize the atrial phenotype and possible mechanisms in a large Chinese family with heart-hand syndrome carrying LMNA missense variant in rod 2B domain (c.1003C>T p.R335W). Methods Clinical characteristics were collected based on the pedigree investigation. Comprehensive functional analyses, including molecular dynamic simulation, cellular, and animal functional assays, determined the pathogenicity in atrial myopathy. Results In the pedigree investigation, 6/13 of the mutation carriers showed heterogeneous cardiac phenotypes, and eight carriers also had brachydactyly. In silico molecular dynamics simulations predicted increased binding energy of R335W mutant lamin A. Atrial cardiomyocytes (HL-1, hiPSC-derived atrial cardiomyocytes) expressing R335W showed abnormal nuclear morphology, compromised DNA repair, and dysfunctional contraction. Adult zebrafish expressing mutant lamin A showed increased P wave duration in the electrocardiogram, decreased A peak velocity in echocardiography, and atrial lesions under the transmission electron microscope. Conclusion The LMNA p.R335W mutation leads to a familial heart-hand syndrome characterized by an overlapping phenotype of prominent atrial lesions and brachydactyly. The unstable lamin dimerization and impaired DNA repair are possible mechanisms underlying cardiac phenotypes. Our findings consolidated the genetic role in the course of atrial arrhythmias and cardiac aging, which is helpful to the diagnosis and treatment of cardiac laminopathy.

Short stature is a frequent disorder in the pediatric population and can be caused by multiple factors. In the last few years, the introduction of Next Generation Sequencing (NGS) in the molecular diagnostic workflow led to the discovery of mutations in novel genes causing short stature including heterozygous mutations in ACAN gene. It encodes for aggrecan, a primary proteoglycan component specific for the structure of the cartilage growth plate, articular and intervertebral disc. We report a novel ACAN heterozygous pathogenic variant in a family with idiopathic short stature, early-onset osteoarthritis and osteoarthritis dissecans (SSOAOD). We also performed a literature review summarizing the clinical characteristic of ACAN's patients. The probands are two Caucasian sisters with a family history of short stature and osteoarthritis dissecans. They showed dysmorphic features such as mild midface hypoplasia, brachydactyly and broad thumbs, especially the great toes. The same phenotype was presented in the mother who had had short stature and suffered from intervertebral disc disease. DNA sequencing identified a heterozygous pathogenic variation (c.4390delG p.Val1464Ter) in the sisters, with a maternal inheritance. The nonsense mutation, located on exon 12, results in premature truncation and presumed loss of protein function. In terms of treatment, our patients underwent recombinant human growth hormone replacement therapy, associated with gonadotropin releasing hormone therapy, in order to block early growth cessation and therefore reach a better final height. Our case suggests that SSOAOD ACAN related should be considered in the differential diagnosis of children with autosomal dominant short stature and family history of joints disease.

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.

Grange syndrome (OMIM 602531) is an autosomal recessive condition characterized by severe early onset vascular occlusive disease and variable penetrance of brachydactyly, syndactyly, bone fragility, and learning disabilities. Grange syndrome is caused by homozygous or compound heterozygous loss-of-function variants in the YYA1P1 gene. We report on the case of a 53-year old female with novel homozygous missense variants in YYA1P1 (c.1079C>T, p.Pro360Leu), presenting with a history of brachysyndactyly, hypertension, and ischemic stroke. Imaging studies revealed stenosis of the bilateral internal carotid with extensive collateralization of cerebral vessels in a moyamoya-like pattern, along with stenosis in the splenic, common hepatic, celiac, left renal, and superior mesenteric arteries. Functional studies conducted with the patient's dermal fibroblasts suggest that the p.Pro360Leu variant decreases the stability of the YY1AP1 protein. This is the first report of a missense variant associated with Grange syndrome characterized by later onset of vascular disease and a lack of developmental delay and bone fragility.

Orofaciodigital syndrome 1 (OFD-1) is a rare, X-linked, dominantly inherited disorder caused by an OFD1 mutation that can cause polycystic kidneys. A 37-year-old woman on hemodialysis therapy was admitted to our hospital for trans-catheter arterial embolization therapy for enlarged polycystic kidneys. Lobulated tongue and brachydactyly were noticed, prompting an OFD1 sequencing analysis. Sequencing revealed a causal four-base-pair deletion in exon 13, both in the patient and in her mother, whose renal function had been retained. The peripheral leukocyte X chromosome inactivation pattern was skewed in the patient but not in her mother, suggesting some role in their phenotypic difference.

Background: Deletions of the interstitial 2q36 are uncommon and associated with varying phenotypes. However, the list of currently known phenotypes is still far complete for an understanding of the...

Supplemental Digital Content is available in the text, Background Brachydactyly, a developmental disorder, refers to shortening of hands/feet due to small or missing metacarpals/metatarsals and/or phalanges. Isolated brachydactyly type E (BDE), characterized by shortened metacarpals and/or metatarsals, consists in a small proportion of patients with Homeobox D13 (HOXD13) or parathyroid-hormone-like hormone (PTHLH) mutations. BDE is often accompanied by other anomalies that are parts of many congenital syndromes. In this study, we investigated a Chinese family presented with BDE combined with pectus carinatum and short stature. Methods A four-generation Chinese family was recruited in June 2016. After informed consent was obtained, venous blood was collected, and genomic DNA was extracted by standard procedures. Whole-exome sequencing was performed to screen pathogenic mutation, array comparative genomic hybridization (Array-CGH) analysis was used to analyze copy number variations, and quantitative real-time polymerase chain reaction (PCR), stride over breakpoint PCR (gap-PCR), and Sanger sequencing were performed to confirm the candidate variation. Results A 3.06-Mb deletion (chr12:25473650–28536747) was identified and segregated with the phenotype in this family. The deletion region encompasses 23 annotated genes, one of which is PTHLH which has been reported to be causative to the BDE. PTHLH is an important regulator of endochondral bone development. The affected individuals showed bilateral, severe, and generalized brachydactyly with short stature, pectus carinatum, and prematurely fusion of epiphyses. The feature of pectus carinatum has not been described in the PTHLH-related BDE patients previously. Conclusions The haploinsufficiency of PTHLH might be responsible for the disease in this family. This study has expanded the knowledge on the phenotypic presentation of PTHLH variation.

Background Dominant deafness-onychodystrophy (DDOD) syndrome is a rare disorder mainly characterized by severe deafness, onychodystrophy and brachydactyly. We previously identified c.1516C > T (p.Arg506X) in ATP6V1B2 as cause of DDOD syndrome, accounting for all cases of this genetic disorder. Clinical follow-up of DDOD syndrome patients with cochlear implantation revealed the language rehabilitation was unsatisfactory although the implanted cochlea worked well, which indicates there might be learning and memory problems in DDOD syndrome patients. However, the underlying mechanisms were unknown. Methods atp6v1b2 knockdown zebrafish and Atp6v1b2 c.1516C > T knockin mice were constructed to explore the phenotypes and related mechanism. In mutant mice, auditory brainstem response test and cochlear morphology analysis were performed to evaluate the auditory function. Behavioral tests were used to investigate various behavioral and cognitive domains. Resting-state functional magnetic resonance imaging was used to evaluate functional connectivity in the mouse brain. Immunofluorescence, Western blot, and co-immunoprecipitation were performed to examine the expression and interactions between the subunits of V-ATPases. Findings atp6v1b2 knockdown zebrafish showed developmental defects in multiple organs and systems. However, Atp6v1b2 c.1516C > T knockin mice displayed obvious cognitive defects but normal hearing and cochlear morphology. Impaired hippocampal CA1 region and weaker interaction between the V1E and B2 subunits in Atp6v1b2Arg506X//Arg506X mice were observed. Interpretation Our study extends the phenotypic range of DDOD syndrome. The impaired hippocampal CA1 region may be the pathological basis of the behavioral defects in mutant mice. The molecular mechanism underlying V-ATPases dysfunction involves a weak interaction between subunits, although the assembly of V-ATPases can still take place.

Cartilage hair hypoplasia (CHH), anauxetic dysplasia 1, and anauxetic dysplasia 2 are rare metaphyseal dysplasias caused by biallelic pathogenic variants in RMRP and POP1, which encode the components of RNAse-MRP endoribonuclease complex (RMRP) in ribosomal biogenesis pathway. Nucleolus and neural progenitor protein (NEPRO), encoded by NEPRO (C3orf17), is known to interact with multiple protein subunits of RMRP. We ascertained a 6-year-old girl with skeletal dysplasia and some features of CHH. RMRP and POP1 did not harbor any causative variant in the proband. Parents-child trio exomes revealed a candidate biallelic variant, c.435G>C, p.(Leu145Phe) in NEPRO. Two families with four affected individuals with skeletal dysplasia and a homozygous missense variant, c.280C>T, p.(Arg94Cys) in NEPRO, were identified from literature and their published phenotype was compared in detail to the phenotype of the child we described. All the five affected individuals have severe short stature, brachydactyly, skin laxity, joint hypermobility, and joint dislocations. They also have short metacarpals, broad middle phalanges, and metaphyseal irregularities. Protein modeling and stability prediction showed that the mutant protein has decreased stability. Both the reported variants are in the same domain of the protein. Our report delineates the clinical and radiological characteristics of an emerging ribosomopathy caused by biallelic variants in NEPRO.

Author(s): Fasham, James; Arno, Gavin; Lin, Siying; Xu, Mingchu; Carss, Keren J; Hull, Sarah; Lane, Amelia; Robson, Anthony G; Wenger, Olivia; Self, Jay E; Harlalka, Gaurav V; Salter, Claire G; Schema, Lynn; Moss, Timothy J; Cheetham, Michael E; Moore, Anthony T; Raymond, F Lucy; Chen, Rui; Baple, Emma L; Webster, Andrew R; Crosby, Andrew H; NIHR Bioresource Rare Diseases Consortium

We report the case of a young woman who presented at age 10 years with height on the tenth centile, brachydactyly type E and mild developmental delay. Biochemistry and hormonal profiles were normal. Differential diagnoses considered included Albright hereditary osteodystrophy without hormone resistance (a.k.a pseudopseudohypoparathyroidism), 2q37 microdeletion syndrome and acrodysostosis. She had a normal karyotype and normal FISH of 2q37. Whole genome sequencing (WGS) identified a mutation in the ANKRD11 gene associated with KBG syndrome. We review the clinical features of the genetic syndromes considered, and suggest KBG syndrome be considered in patients presenting with syndromic brachydactyly type E, especially if short stature and developmental delay are also present.

Osteogenesis imperfecta (OI) is mainly characterized by bone fragility and Ehlers-Danlos syndrome (EDS) by connective tissue defects. Mutations in COL1A1 or COL1A2 can lead to both syndromes. OI/EDS overlap syndrome is mostly caused by helical mutations near the amino-proteinase cleavage site of type I procollagen. In this study, we identified a Thai patient having OI type III, EDS, brachydactyly, and dentinogenesis imperfecta. His dentition showed delayed eruption, early exfoliation, and severe malocclusion. For the first time, ultrastructural analysis of the tooth affected with OI/EDS showed that the tooth had enamel inversion, bone-like dentin, loss of dentinal tubules, and reduction in hardness and elasticity, suggesting severe developmental disturbance. These severe dental defects have never been reported in OI or EDS. Exome sequencing identified a novel de novo heterozygous glycine substitution, c.3296G > A, p.Gly1099Glu, in exon 49 of COL1A2. Three patients with mutations in the exon 49 of COL1A2 were previously reported to have OI with brachydactyly and intracranial hemorrhage. Notably, two of these three patients did not show hyperextensible joints and hypermobile skin, while our patient at the age of 5 years had not developed intracranial hemorrhage. Here, we demonstrate that the novel glycine substitution in the carboxyl region of alpha2(I) collagen triple helix leads to OI/EDS with brachydactyly and severe tooth defects, expanding the genotypic and phenotypic spectra of OI/EDS overlap syndrome. Keywords: Bone-like dentin, Collagen defect, Dentinogenesis imperfecta, Joint laxity, Skeletal fragility, Skin hypermobility

Brachydactyly type E, which can be an isolated finding or part of a syndrome in combination with other clinical anomalies, involves metacarpals and metatarsals with or without short phalanges. Herein we report two unrelated Turkish females who presented with brachydactyly type E and vitamin D deficiency in the absence of marked alterations in serum calcium, phosphate, and parathyroid hormone. After excluding disease-causing variants in two candidate genes, PTHLH and PDE4D, we identified different pathogenic variants in TRPS1, the gene mutated in patients with tricho-rhino-phalangeal syndrome (TRPS). In one of the patients, who displayed severe brachydactyly and short stature, we identified a novel heterozygous missense pathogenic variant in exon 6 (c.2783A>G, p.Tyr928Cys), located within the GATA DNA-binding domain. The second patient, who had relatively milder brachydactyly and was of normal height, carried a heterozygous nonsense pathogenic variant in exon 4 (c. 1870C>T, p.Arg624Ter), which has been previously described. Both pathogenic variants segregated in affected family members. The patients additionally showed sparse hair and a bulbous nose, consistent with the clinical features of TRPS. Our findings, in addition to identifying the genetic cause of brachydactyly in two unrelated kindreds, emphasize the role of pathogenic TRPS1 variants in the development of brachydactyly type E and highlight the GATA DNA-binding region of TRPS1 protein with respect to phenotype-genotype correlation.

Mutations in the human receptor tyrosine kinase ROR2 are associated with Robinow syndrome (RRS) and brachydactyly type B1. Amongst others, the shortened limb phenotype associated with RRS is recapitulated in Ror2(−/−) mutant mice. In contrast, Ror1(−/−) mutant mice are viable and show no limb phenotype. Ror1(−/−);Ror2(−/−) double mutants are embryonic lethal, whereas double mutants containing a hypomorphic Ror1 allele (Ror1(hyp)) survive up to birth and display a more severe shortened limb phenotype. Both orphan receptors have been shown to act as possible Wnt coreceptors and to mediate the Wnt5a signal. Here, we analyzed genetic interactions between the Wnt ligand, Wnt9a, and Ror2 or Ror1, as Wnt9a has also been implicated in skeletal development. Wnt9a(−/−) single mutants display a mild shortening of the long bones, whereas these are severely shortened in Ror2(−/−) mutants. Ror2(−/−);Wnt9a(−/−) double mutants displayed even more severely shortened long bones, and intermediate phenotypes were observed in compound Ror2;Wnt9a mutants. Long bones were also shorter in Ror1(hyp/hyp);Wnt9a(−/−) double mutants. In addition, Ror1(hyp/hyp);Wnt9a(−/−) double mutants displayed a secondary palate cleft phenotype, which was not present in the respective single mutants. Interestingly, 50% of compound mutant pups heterozygous for Ror2 and homozygous mutant for Ror1 also developed a secondary palate cleft phenotype.

PRMT7 encodes for an arginine methyltransferase that methylates arginine residues on various protein substrates and has been shown to play a role in various developmental processes. Mutations in PRMT7 have been recently shown to be implicated in a phenotype with intellectual disability, short stature and brachydactyly, and considered to be a phenocopy of pseudohypoparathyroidism. We report a patient with short stature, psychomotor delay, hearing loss and brachydactyly, for whom whole exome sequencing detected two mutations in PRMT7 and parental segregation studies detected biallelic mutation inheritance. Few patients with biallelic PRMT7 mutations have been reported so far in the literature. We report a new patient and review all reported cases to date to delineate the clinical manifestations that may help in diagnosis this disorder, known as Short Stature, Brachydactyly, Intellectual Developmental Disability, and Seizures syndrome, allowing appropriate management and genetic counselling.

Pseudoachondroplasia (PSACH; MIM 177170) is a rare disease which was characterized by disproportionate short stature, deformity of the lower limbs, brachydactyly, loose joints, and ligamentous laxity. It is an autosomal dominant osteochondrodysplasia presented in childhood, and usually resolved with age, but osteoarthritis is progressive and severe. Genetic testing using the whole exome sequencing and Sanger sequencing was performed for the patients, a 30-year-old woman and her affected son, who is only 8 years old. A heterozygous mutationin exon 15 of COMP (c.1675G > A, p.Glu559Lys, NM 000095.2) was identified. The Polyphen-2 predicted that the mutation may damage the COMP protein function. This study suggested that the heterozygous mutations in COMP were responsible for PSACH and demonstrated the genotype-phenotype relationship between mutations in COMP and clinical characteristics of PSACH.

A 19-year-old Japanese woman was referred to us with the complaints of arthralgia and meralgia following human papillomavirus (HPV) vaccination. She received HPV vaccination at the age of 15 years and three years later, she developed intermittent arthralgia, meralgia, and numbness in limbs. There were no orthostatic dysregulation symptoms. She had hypertelorism, and brachydactyly in both the hands, and revealed mild cubitus varus deformity with lateral instability. X-ray examination disclosed hypoplasia of the humeral capitellum and trochlea in elbow joints. G-banded chromosomes were shown to be composed of 48, XXXX. She was, therefore, diagnosed with XXXX syndrome, which explained the reason for her limb symptoms. Although some girls with HPV vaccination complain of various symptoms including limb pain and numbness, exact underlying cause of these symptoms needs to be ascertained carefully for reaching a final diagnosis.

Trichorhinophalangeal syndrome (TRPS) is rare genetic disorder with autosomal dominant inheritance. The TRPS1 gene is located on the long arm of the eighth chromosome (8q24.12). The phenotype is variable and presents a wide clinical spectrum. Most cases are characterised by thin, sparse scalp hair, distinctive facial dysmorphism, and various skeletal abnormalities, especially of the hands and feet. Characteristic facial features may include a "pear-shaped" nose, micrognathia, dental anomalies, prominent ears, elongated philtrum, and thin upper vermillion border. In most cases, affected individuals exhibit skeletal abnormalities including brachydactyly and clinodac-tyly, short metacarpals phalanges, short feet and metatarsals, and pectus carinatum and hip joint malformations. Additionally, patients may exhibit short stature. This report presents four cases of TRPS (three sporadic and one familial). Clinical presentation included typical facial features and vari-ous skeletal abnormalities. Some TRPS symptoms may mimic growth hormone deficiency and other endocrine disturbances. The aim of this article is to deliver TRPS symptomatology. The treatment of TRPS is symptomatic and supportive and requires the coordination of several specialists, including paediatricians, endocrinologists, orthopaedic surgeons, dermatologists, and medical rehabilitation and den-tal specialists. In some cases, recombinant growth hormone therapy may be necessary. Genetic counselling may be of benefit for affect-ed individuals and their families.Zespół włosowo-nosowo-paliczkowy jest rzadką chorobą uwarunkowaną genetycznie, w większości przypadków o autosomalnie do-minującym sposobie dziedziczenia. Gen TRPS1 jest zlokalizowany na długim ramieniu chromosomu 8 – 8q24(8q24.12). Fenotyp jest zróżnicowany i prezentuje szerokie spektrum objawów klinicznych. Do charakterystycznych cech fenotypowych zalicza się rzadkie włosy, dysmorfię twarzoczaszki oraz zaburzenia kostno-szkieletowe, zwłaszcza w obrębie dłoni i stóp. Do typowych cech dysmorficz-nych twarzy należą: "gruszkowaty nos", mikrognacja, anomalie zębowe, wydatne uszy, wydłużona rynienka nosowa i wąska czerwień wargowa. W większości przypadków występują anomalie szkieletowe, takie jak klino- i brachydaktylia, skrócenie paliczków śródręcza i śródstopia, kurza klatka piersiowa oraz malformacje stawu biodrowego. Część pacjentów ma niedobór wzrostu. Artykuł przygotowano na podstawie serii czterech przypadków klinicznych (trzy sporadyczne i jeden rodzinny). Wszystkie dzieci pre-zentowały typowe dla TRPS cechy dysmorfii twarzoczaszki oraz różne anomalie układu kostno-szkieletowego. Przyczyną skierowania na Oddział Endokrynologii Dziecięcej było podejrzenie różnych endokrynopatii, w tym niedobór hormonu wzrostu, zaburzeń gospo-darki wapniowo-fosforanowej czy zespołu Turnera. Celem pracy jest przybliżenie symptomatologii TRPS. Leczenie jest objawowe i wymaga skoordynowanej współpracy wielu specjalistów, w tym lekarza pediatry, endokrynologa, ortopedy, dermatologa, specjalisty rehabilitacji medycznej czy chirurga szczękowego. Część pacjentów z niskorosłością i niedoborem GH może wymagać terapii substytu-cyjnej rGH. Doradztwo genetyczne może przynieść korzyści dotkniętym TRPS osobom i ich rodzinom.

Patient: Male, 9-year-old Final Diagnosis: Weill-Marchesani syndrome Symptoms: Joint stiffnes • myopia • short stature Medication: — Clinical Procedure: — Specialty: Endocrinology and Metabolic • Genetics Objective: Rare disease Background: Short stature is the second most common reason for referral to a pediatric endocrinology clinic. Numerous genetic causes have been identified. Weill-Marchesani syndrome (WMS) is one of the rare genetic disorders that cause short stature. It is caused by homozygous mutations in the FBN1 gene, ADAMTS10 gene, ADAMTS17 gene, or LTBP2 gene. Despite genetic heterogeneity, WMS is clinically homogeneous. It is characterized by short stature, brachydactyly, joint stiffness, ocular abnormalities, mainly microspherophakia and glaucoma, and occasionally cardiac defects. Case Report: A 9-year-old boy had bilateral narrow-angle glaucoma with lens subluxation, elevated intraocular pressure, and severe myopia since early childhood. He had phenotypic dysmorphic features and radiological findings consistent with WMS. He underwent lensectomy and scleral-fixated intraocular lens implantation as well as drug treatment to control the intraocular pressure. He was a slow grower, and his growth parameters showed disproportionate short stature with brachydactyly and joint stiffness. Growth hormone provocation tests were subnormal with a peak value of 7.89 ng/mL. Conclusions: The constellation of clinical presentation, radiological findings, and the molecular examination confirmed a homozygous familial variant of the ADAMTS10 gene identified by carrier gene testing. This known familial variant creates a premature termination codon classified as a likely pathogenic cause of WMS. In this syndrome, glaucoma treatment is considered the greatest challenge. The disease-causing mechanism in WMS is not known but thought to be due to abnormal actin distribution and organization in fibroblasts as a result of impaired connections between extracellular matrix components and the cytoskeleton.

Background Rare diseases are pathologies that affect less than 1 in 2000 people. They are difficult to diagnose due to their low frequency and their often highly heterogeneous symptoms. Rare diseases have in general a high impact on the quality of life and life expectancy of patients, which are in general children or young people. The advent of high-throughput sequencing techniques has improved diagnosis in several different areas, from pediatrics, achieving a diagnostic rate of 41% with whole genome sequencing (WGS) and 36% with whole exome sequencing, to neurology, achieving a diagnostic rate between 47 and 48.5% with WGS. This evidence has encouraged our group to pursue a molecular diagnosis using WGS for this and several other patients with rare diseases. Results We used whole genome sequencing to achieve a molecular diagnosis of a 7-year-old girl with a severe panvascular artery disease that remained for several years undiagnosed. We found a frameshift variant in one copy and a large deletion involving two exons in the other copy of a gene called YY1AP1. This gene is related to Grange syndrome, a recessive rare disease, whose symptoms include stenosis or occlusion of multiple arteries, congenital heart defects, brachydactyly, syndactyly, bone fragility, and learning disabilities. Bioinformatic analyses propose these mutations as the most likely cause of the disease, according to its frequency, in silico predictors, conservation analyses, and effect on the protein product. Additionally, we confirmed one mutation in each parent, supporting a compound heterozygous status in the child. Conclusions In general, we think that this finding can contribute to the use of whole genome sequencing as a diagnosis tool of rare diseases, and in particular, it can enhance the set of known mutations associated with different diseases.

Acral clinical and radiographic characteristics of a further patient with Coffin-Siris syndrome (CSS), which is caused by mutations in the ARID1B gene, encoding a subunit of the BAF-complex, are here described. Metacarpophalangeal profile pattern analysis (MCPPPA) of the present proband and other two known ARID1B mutated individuals has been performed for the first time, demonstrating hands brachydactyly. In this novel study, the utility of an accurate appendicular radiographic examination and MCPPPA in this congenital condition is highlighted. The MCPPPA could be considered in the clinical practice, to better study the hand skeletal morphology in patients with a syndrome characterized by limb defects, including CSS. This article is protected by copyright. All rights reserved.