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Laurence-Moon-Bardet-Biedl syndrome (LMBBS) is a rare ciliopathic genetic multisystem disorder. It has several primary and secondary clinical features, which include central obesity, retinitis pigmentosa, mental subnormalities, polydactyly, and renal dysfunction. The majority of children may not show all clinical features at birth, and clinical features can develop progressively over the years. The authors report two children who were followed up for obesity at the pediatric clinic in the local hospital and the ophthalmology clinic at the tertiary care center, respectively, without a diagnosis, and were referred for specialist pediatric evaluation of hypertension detected on their routine checkup and for further management. Both children were investigated and found to have satisfied criteria for LMBBS in association with primary hypertension. Both children were diagnosed late as LMBBS at 12 years and four years of their age although both of them had enough features to have a suspicion of this syndrome.

Craniofacial and limb defects are two of the most common congenital anomalies in the general population. Interestingly, these defects are not mutually exclusive. Many patients with craniofacial phenotypes, such as orofacial clefting and craniosynostosis, also present with limb defects, including polydactyly, syndactyly, brachydactyly, or ectrodactyly. The gene regulatory networks governing craniofacial and limb development initially seem distinct from one another, and yet these birth defects frequently occur together. Both developmental processes are highly conserved among vertebrates, and zebrafish have emerged as an advantageous model due to their high fecundity, relative ease of genetic manipulation, and transparency during development. Here we summarize studies that have used zebrafish models to study human syndromes that present with both craniofacial and limb phenotypes. We discuss the highly conserved processes of craniofacial and limb/fin development and describe recent zebrafish studies that have explored the function of genes associated with human syndromes with phenotypes in both structures. We attempt to identify commonalities between the two to help explain why craniofacial and limb anomalies often occur together.

Between 0.16% and 0.21% of children born are affected with congenital anomalies of the upper extremity (CAUE). The registry and case series with these incidence data are reviewed. There are many syndromes with CAUE as a presenting feature. We review those syndromes with polydactyly, syndactyly, brachydactyly, oligodactyly, or reduction defects as a defining feature.

Congenital anomalies of the upper extremity (CAUE) are seen in a number of syndromes, either as an occasional feature or as a major or even presenting feature. In this chapter, only the syndromes in which the CAUE are defining or major features are included. For each of these syndromes, the genetic basis, including specific genes, if known, is included. The syndromes are reviewed by their involvement of the major types of CAUE: polydactyly, syndactyly, brachydactyly, oligodactyly, or reduction defects. In addition, the genetics of isolated brachydactyly and polydactyly is included.

Introduction Brachydactyly is a bone development abnormality presenting with variable phenotypes and different transmission patterns. Mutations in GDF5 (Growth and Differentiation Factor 5, MIM *601146) account for a significant amount of cases. Here, we report on a three-generation family, where the proband and the grandfather have an isolated brachydactyly with features of both type A1 (MIM # 112500 ) and type C (MIM # 113100 ), while the mother shows only subtle hand phenotype signs. Materials and methods Whole Exome Sequencing (WES) was performed on the two affected individuals. An in-depth analysis of GDF5 genotype-phenotype correlations was performed through literature reviewing and retrieving information from several databases to elucidate GDF5-related molecular pathogenic mechanisms. Results WES analysis disclosed a pathogenic variant in GDF5 (NM_000557.5:c.157dup; NP_000548.2:p.Leu53Profs*41; rs778834209), segregating with the phenotype. The frameshift variant was previously associated with Brachydactyly type C (MIM # 113100 ), in heterozygosity, and with the severe Grebe type chondrodysplasia (MIM # 200700 ), in homozygosity. In-depth analysis of literature and databases allowed to retrieve GDF5 mutations and correlations to phenotypes. We disclosed the association of 49 GDF5 pathogenic mutations with eight phenotypes, with both autosomal dominant and recessive transmission patterns. Clinical presentations ranged from severe defects of limb morphogenesis to mild redundant ossification. We suggest that such clinical gradient can be linked to a continuum of GDF5-activity variation, with loss of GDF5 activity underlying bone development defects, and gain of function causing disorders with excessive bone formation. Conclusions Our analysis of GDF5 pathogenicity mechanisms furtherly supports that mutation and zygosity backgrounds resulting in the same level of GDF5 activity may lead to similar phenotypes. This information can aid in interpreting the potential pathogenic effect of new variants and in supporting an appropriate genetic counseling.

Objective Here we present the first known examples of brachydactyly from an Andean archaeological context by describing the affected bones, presenting a differential diagnosis, and discussing the cultural implications of there being shortened metapodials in multiple tombs. Materials 3232 well-preserved tubular bones representing an MNI of 250 human adults. Methods Each bone was visually inspected. Measurements were taken with an osteometric board, sliding calipers, and a flexible tape measure. Results Of 1210 metapodials excavated from eight burial contexts, ten were atypically short. Conclusions The ten shortened elements represent an MNI of three individuals with brachydactyly from two tombs. The presence of at least two individuals with brachydactyly in one tomb adds support to a previous suggestion that tombs were used for familial interment. It is plausible that the third individual from a different tomb was related to the other two, and the different burial contexts may reflect postmarital practices. Significance These cases offer insight into tomb use and underscore the importance of identifying rare developmental anomalies in the archaeological record as their presence may indicate genetic relationships within or among archaeological cemeteries. Limitations With commingled contexts and incomplete recovery of skeletal remains, individualizing the brachydactylous elements was not possible. There is also a lack of comparative data from other Andean sites. Suggestions for Further Research Identify more Andean cases of brachydactyly to learn if the relatively frequent involvement of the first digit is more common among Andean skeletal samples than North American, or if it is unique to Marcajirca.

Chung-Jansen Syndrome is a recently identified obesity syndrome, characteristic clinical features of which are global developmental delay, intellectual disability, obesity and dysmorphism (DIDOD). We present a child with the syndrome who also had hypothyroidism and renal involvement in form of small kidneys on one side. The next generation sequencing done in the child showed a nonsense variant in the PHIP gene leading to premature chain termination in the protein on bioinformatic analysis.

Пациенты, пострадавшие от псевдогипопаратиреоза или связанных с ним расстройств, характеризуются такими физическими признаками, как брахидактилия, невысокий рост, коренастое телосложение, ожирение с ранним началом, эктопическая оссификация, задержка неврологического развития, а также резистентностью к гормонам, наиболее выраженной к паратиреоидному гормону. Кроме того, у пациентов может возникать резистентность к другим гормонам, что приводит к манифестному или субклиническому гипотиреозу, гипогонадизму и дефициту гормона роста, нарушению роста без доказательств гормональных отклонений по результатам измерений, диабету 2 типа и проблемам со скелетом с потенциально серьезным ограничением подвижности. Псевдогипопаратиреоз и сопутствующие расстройства — это прежде всего клинический диагноз. Учитывая изменчивость клинического, рентгенологического и биохимического состояния, установление молекулярного диагноза имеет решающее значение для пациентов. Это облегчает лечение, в том числе профилактику осложнений, скрининг и лечение эндокринных дефицитов, поддерживающие мероприятия и соот­ветствующие генетические консультации. На основе первого международного консенсусного заявления по упомянутым расстройствам эта статья предлагает обновленный и готовый к использованию инструмент, который поможет врачам и пациентам определить соответствующие вмешательства и их сроки.Рекомендуется применять скоординированный в течение всей жизни мультидисциплинарный подход, начиная, насколько это возможно, в раннем детстве и продолжая в течение всей взрослой жизни с соответствующим и своевременным переходом от педиатрической ко взрослой медицинской помощи., Patients affected by pseudohypoparathyroidism 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. In addition to these alterations, patients may develop other hormonal resistances, leading to overt or subclinical hypothyroidism, hypogonadism and growth hormone deficiency, impaired growth without measurable evidence for hormonal abnormalities, type 2 diabetes, and skeletal issues with potentially severe limitation of mobility. Pseudohypoparathyroidism 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., Пацієнти, які постраждали від псевдогіпопаратиреозу або пов’язаних з ним розладів, характеризуються такими фізичними ознаками, як брахідактилія, невисокий зріст, кремезна будова тіла, ожиріння з раннім початком, ектопічна осифікація, затримка неврологічного розвитку, а також резистентністю до гормонів, найбільш виражену до паратиреоїдного гормону. Крім того, у пацієнтів може виникати резистентність до інших гормонів, що призводить до маніфестного або субклінічного гіпотиреозу, гіпогонадизму та дефіциту гормону росту, порушення росту без доказів гормональних відхилень за результатами вимірювань, діабету 2 типу та проблем зі скелетом з потенційно серйозним обмеженням рухливості. Псевдогіпопаратиреоз та супутні розлади — це насамперед клінічний діагноз. З огляду на мінливість клінічного, рентгенологічного та біохімічного стану, встановлення молекулярного діагнозу має вирішальне значення для пацієнтів. Це полегшує лікування, зокрема профілактику ускладнень, скринінг і лікування ендокринних дефіцитів, підтримувальні заходи та відповідні генетичні консультації. На основі першої міжнародної консенсусної заяви щодо зазначених розладів ця стаття пропонує оновлений та готовий до використання інструмент, який допоможе лікарям і пацієнтам визначити відповідні втручання та їх терміни.Рекомендується застосовувати скоординований протягом усього життя мультидисциплінарний підхід, починаючи, наскільки це можливо, у ранньому дитинстві та продовжуючи протягом усього дорослого життя з відповідним і своєчасним переходом від педіатричної до дорослої медичної допомоги.

Laurence-Moon-Bardet-Biedl syndrome (LMBBS), a rare autosomal recessive genetic disorder, results from consanguineous marriage. It is a congenital ciliopathy manifesting with primary and secondary characteristics. Primary clinical features include rod and cone dystrophy, polydactyly, central obesity, genital abnormalities, and mental retardation, often presenting as poor schooling skills. Secondary clinical features include developmental delay, speech deficit, brachydactyly/syndactyly, dental defects, ataxia, olfactory deficit, diabetes mellitus (DM), and congenital heart disease. Herein, we report a case of a 15-year-old male with clinical manifestations of LMBBS, namely learning disabilities, night blindness, hypogonadism, polydactyly, polysyndactyly, and obesity. Physicians must be familiar with this syndrome, for which an early diagnosis, multidisciplinary approach, and regular follow-ups can profoundly diminish morbidity and mortality in LMBBS patients.

In this case report, we present the case of a 20-year-old male patient who suffered from pain in walking clinically, and in whom an extremely rare type of brachymetatarsia was diagnosed. Although distorted body image is the main reason for consulting a specialist, the patient presented because he was unable to find a proper shoe. The patient had no familial history of brachydactyly, trauma, or a genetic disorder. In this extremely rare case, the decision was made to perform shortening of the normal foot ray with a double osteotomy to the metatarsal and proximal phalanx. At the end of the follow-up period, the patient was walking pain-free and had no limitation in shoe choice.

Different mutations in the Growth/Differentiation Factor 5 gene (GDF5) have been associated with varying types of skeletal dysplasia, including Grebe type chondrodysplasia (GTC), Hunter-Thompson syndrome, Du Pan Syndrome and Brachydactyly type C (BDC). Heterozygous pathogenic mutations exert milder effects, whereas homozygous mutations are known to manifest more severe phenotypes. In this study, we report a GDF5 frameshift mutation (c.404delC) segregating over six generations in an extended consanguineous Pakistani family. The family confirmed that both GTC and BDC are part of the GDF5 mutational spectrum, with severe GTC associated with homozygosity, and with a wide phenotypic variability among heterozygous carriers, ranging from unaffected non-penetrant carriers, to classical BDC and to novel unclassified types of brachydactylies.

Introduction Variegate porphyria (VP; OMIM 176200) is one of the acute hepatic porphyrias, and it is characterized by the partial deficiency of protoporphyrinogen oxidase (PPOX). The unusual homozygous variant with mutations on both alleles of PPOX is distinguished with general heterozygous VP by several typical points such as severe defect in PPOX enzyme activity, early onset of photosensitivity before puberty, and skeletal deformity. Material and method In this study, we describe a very rare case of autosomal recessive form of true homozygous VP found in a Chinese patient with consanguineous parents. Sanger sequencing of the PPOX gene showed a novel homozygous variant located at the first base of exon 8 of the gene, i.e., NM_000309.3c.808G > T. To investigate aberrant splicing induced by the mutant, wild-type exon 8 and mutant exon 8 were expressed in pET01 vector as minigene in cultured-cells and analyzed by RT-PCR. Results The wildtype PPOX showed an expected band in the gel electrophoresis after RT-PCR. The PPOX c.808G > T only showed a band similar to the band size of the vector only control. This result suggested c.808G > T mutant is an exonic mutation inducing aberrant splicing of pre-mRNA of the PPOX gene. Conclusion This study showed a very rare case of homozygous VP with autosomal recessive homoallelic pattern. In comparison with previous cases of homozygous VP presenting brachydactyly, it is notable that our patient did not have any skeletal deformities.

Background Brachydactyly type A1 (BDA1) is an autosomal dominant disorder characterized by uniform shortening of the middle phalanges in all digits. It is associated with variants in the Indian Hedgehog (IHH) gene, which plays a key role in endochondral ossification. To date, heterozygous pathogenic IHH variants involving several codons, which are restricted to a specific region of the N-terminal active fragment of IHH, have been reported. The purpose of this study was to identify the pathogenic variant in a Japanese family with BDA1 and to evaluate its pathogenesis with regard to previous reports. Methods The proband, a 9-year-old boy, his siblings, and his father had shortened digits and a short stature of variable severity. Based on physical examinations, radiographic findings and family history, they were diagnosed with BDA1. This family is the first case of an isolated malformation in Japan. Sanger sequencing of IHH was performed on these individuals and on the proband’s unaffected mother. The significance of the variants was assessed using three-dimensional analysis methods. Results Sanger sequencing showed a novel IHH heterozygous variant, NM_002181.4:c.544_549delTCAAAG(p.Ser182Lys183del) [NC_000002.12:g.219057461_219057466del].. These two residues are located outside the cluster region considered a hotspot of pathogenic variants. Three-dimensional modelling showed that S182 and K183 are located on the same surface as other residues associated with BDA1. Analysis of residue interactions across the interface between IHH and its interacting receptor protein revealed the presence of hydrogen bonds between them. Conclusions We report a novel variant, NM_002181.4:c.544_549delTCAAAG (p.Ser182Lys183del) [NC_000002.12:g.219057461_219057466del] in a Japanese family with BDA1. Indeed, neither variations in codons 182 or 183 nor with such two-amino-acid deletions in IHH have been reported previously. Although these two residues are located outside the cluster region considered a hotspot of pathogenic variants, we speculate that this variant causes BDA1 through impaired interactions between IHH and target receptor proteins in the same manner as other pathogenic variants located in the cluster region. This report expands the genetic spectrum of BDA1.

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., We firstly identified a new subtype of brachydactyly in a large Chinese family carrying the similar duplication involving in regulatory region of SOX9 (17q24.3), which is important for the future gene diagnosis.

Robinow syndrome, a rare genetic disorder, is characterized by skeletal dysplasia with, among other anomalies, extremity and hand anomalies. There is locus heterogeneity and both dominant and recessive inheritance. A detailed description of associated extremity and hand anomalies does not currently exist due to the rarity of this syndrome. This study seeks to document the hand anomalies present in Robinow syndrome to allow for improved rates of timely and accurate diagnosis. A focused assessment of the extremities and stature was performed using clinical examination and standard photographic images. A total of 13 patients with clinical and molecular diagnosis consistent with dominant Robinow syndrome or recessive Robinow syndrome were evaluated. All patients had limb shortening, the most common of which was mesomelia; however, rhizomelia and micromelia were also seen. These findings are relevant to clinical characterization, particularly as Robinow syndrome has classically been defined as a "mesomelic disorder." A total of eight distinct hand anomalies were identified in 12 patients with both autosomal recessive and dominant forms of Robinow syndrome. One patient did not present with any hand differences. The most common hand findings included brachydactyly, broad thumbs, and clinodactyly. A thorough understanding of the breadth of Robinow syndrome-associated extremity and hand anomalies can aid in early patient identification, improving rates of timely diagnosis and allowing for proactive management of sequelae.

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.

Microdeletions within 1q24 have been associated with growth deficiency, varying intellectual disability, and skeletal abnormalities. The candidate locus responsible for the various phenotypic features of this syndrome has previously been predicted to lie in the area of 1q24.3, but molecular evidence of the causative gene remains elusive. Here, we report two additional patients carrying the smallest reported 1q24 deletion to date. Patient 1 exhibited intrauterine growth retardation, shortening of the long bones, frontal bossing, microstomia, micrognathia, and a language acquisition delay. Her mother, Patient 2, displayed a broad forehead and nasal bridge, thick supraorbital ridges, and toe brachydactyly, along with learning disability and language acquisition delay. The microdeletion encompasses a 94 Kb region containing exon 14 and portions of the surrounding introns of the gene encoding dynamin 3 (DNM3), resulting in an in-frame loss of 38 amino acids. This microdeletion site also contains a long non-coding RNA (DNM3OS) and three microRNAs (miR-214, miR-199A2, and miR-3120). Following culture of patient-derived and control fibroblasts, molecular analyses were performed to determine expression levels of genes affected by the heterozygous deletion. Results show decreased expression of DNM3OS and miR-214-3p in patient fibroblasts cultured in an osteogenic induction medium. Overall, our data provide further evidence to support a functional role for non-coding RNAs in regulating the skeletal phenotype, and the potential of a functionally-impaired DNM3 protein causing the non-skeletal disease pathogenesis.

Background The aim of the study was to present a new operative technique for aesthetic and anatomic reconstruction of polysyndactyly of the fifth toe fused with the fourth toe. Methods Surgery was performed in 86 feet in 73 patients with polysyndactyly of the fifth toe fused with the fourth toe. The operation involved polydactyly excision, syndactyly release using an improved dorsal asymmetric gullwing flap for web space reconstruction without skin grafting, and simultaneous correction of valgus deformity and brachydactyly of the toes. The web shape (height and width),scar contracture, and aesthetic outcomes (foot contour and morphology of the reconstructed fifth toe) were assessed using the criterion of D'Arcangelo, Vancouver Scar Scale score, and older children and parent-based satisfactory questionnaire, respectively. Results The patients were followed up for 12 to 36 months. The reconstructed web spaces were slightly deeper than normal, with an hourglass shape and a physiological slope. Valgus deformity was completely corrected without recurrence. The reconstructed fifth toes appeared to be visually lengthened. On the basis of the criterion of D'Arcangelo, the height and width of the webs were good in 76, fair in 10, and poor in none of the feet. The mean Vancouver Scar Scale score was 1.5. All parents and patients were satisfied with the appearance and function. Conclusions Our new operative procedure could achieve aesthetic and anatomic reconstruction of polysyndactyly of the fifth toe fused with the fourth toe with good shape of the reconstructed web space without skin grafting, favorable appearance and axis alignment of the reconstructed fifth toes, and good foot contour.

C-type natriuretic peptide (CNP), its endogenous receptor, natriuretic peptide receptor-B (NPR-B), as well as its downstream mediator, cyclic guanosine monophosphate (cGMP) dependent protein kinase II (cGKII), have been shown to play a pivotal role in chondrogenic differentiation and endochondral bone growth. In humans, biallelic variants inExome sequencing was performed in two girls with severe short stature due to acromesomelic limb shortening, brachydactyly, mild to moderate platyspondyly and progressively increasing metaphyseal alterations of the long bones. Functional characterisation was undertaken for the identified variants.Two homozygousIn conclusion, we have clinically and molecularly characterised a new acromesomelic dysplasia, acromesomelic dysplasia, PRKG2 type (AMDP).

BACKGROUND: First described by Holt and Oram in 1960 in a four-generation family with atrial septal defects and thumb abnormalities, is an inherited disorder characterized by abnormalities of the upper limbs and heart. This syndrome is characterized by upper extremity malformations involving radial, thenar, or carpal bones. An abnormal carpal bone is present in all affected individuals and may be the only evidence of disease. About 75% of individuals with Holt–Oram syndrome (HOS) have a congenital heart malformation which may include an atrial or ventricular septal defect or heart block. In rare cases, the syndrome can affect other organs and systems which can be life threatening. CASE REPORT: Here, we present a newborn with clinical and radiologic features of HOS consisting of bilateral asymmetric hypoplastic thumbs, generalized brachydactyly, limited bilateral supination due to radioulnar synostosis, and associated with complex heart disease and hypoplastic tricuspid valve. CONCLUSION: In our case HOS is associated with complex congenital heart defects including atrial septal defect, ventricular septal defect with hypoplastic tricuspid valve. Based on the listed literature we didn’t find any other case where tricuspid valve was affected.

Pathogenic variants in ZMYND11, which acts as a transcriptional repressor, have been associated with intellectual disability, behavioural abnormalities and seizures. Only 11 affected individuals have been reported to‐date, and the phenotype associated with pathogenic variants in this gene have not been fully defined.\ud \ud Here, we present 16 additional patients with predicted pathogenic heterozygous variants in ZMYND11, including four individuals from the same family, to further delineate and expand the genotypic and phenotypic spectrum of ZMYND11‐related syndromic intellectual disability. The associated phenotype includes developmental delay, particularly affecting speech, mild‐moderate intellectual disability, significant behavioural abnormalities, seizures, and hypotonia. There are subtle shared dysmorphic features, including prominent eyelashes and eyebrows, depressed nasal bridge with bulbous nasal tip, anteverted nares, thin vermilion of the upper lip and wide mouth. Novel features include brachydactyly and tooth enamel hypoplasia.\ud \ud Most identified variants are likely to result in premature truncation and/or nonsense mediated decay. Two ZMYND11 variants located in the final exon ‐ p.(Gln586*) (likely escaping nonsense‐mediated decay) and p.(Cys574Arg) ‐ are predicted to disrupt the MYND‐type zinc finger motif and likely interfere with binding to its interaction partners. Hence, the homogeneous phenotype likely results from a common mechanism of loss‐of‐function.

We describe the case of a 23-year-old African American male who presented to the emergency department complaining of unremitting dyspepsia for the last four months. His blood pressure was incidentally found to be 230/157 mm Hg. The initial admitting diagnosis in the intensive care unit was hypertensive "emergency" as he had also displayed acute kidney injury that was deemed to be superimposed on chronic kidney disease. While the diagnostic work-up of his hypertension was inconclusive, physical examination was impressive for the presence of brachydactyly of the bilateral hands, especially the fourth digits. His feet appeared grossly normal. X-rays (XRs) of the bilateral hands revealed absent distal phalanges and fused middle and distal phalanges of the second digits. XRs of the bilateral feet showed similar findings in addition to the absence or hypoplasia of the lateral cuneiform bones. His family medical history was unknown as the patient was adopted and did not have contact with his biological parents. Given these findings in the setting of uncontrolled hypertension in a young adult, he was diagnosed with hypertension with brachydactyly syndrome.

BackgroundBrachydactyly type A1(BDA-1) is an autosomal dominant disorder which is caused by heterozygous pathogenic variants in a specific region of the N-terminal active fragment of Indian Hedgehog (IHH). The disorder is mainly characterized by shortening or missing of the middle phalanges. In this study, Our purpose is to identify the pathogenic variations associated with BDA-1 involved in a five-generation Chinese family.MethodsA BDA-1 family with 8 affected and 14 unaffected family members was recruited. Whole exome sequencing (WES) was performed to identify the pathogenic variant in the proband, and which was later confirmed and segregated by Sanger sequencing. The significance of variants were assessed using several molecular and bioinformatics analysis methods.ResultsWe uncovered a novel heterozygous missense variant c.299A > G (p.D100G) at the mutational hotspot ofIHHgene following whole-exome sequencing of a Chinese family with BDA-1. The variant co-segregated with BDA-1 in the pedigree, showed 100% penetrance for phalange phenotype with variable expressivity.ConclusionsIn conclusion, this study reports a five-generation Chinese family with BDA-1 due to a novel pathogenic variant (c.299A > G (p.D100G)) of IHH and expands the clinical and genetic spectrum of BDA-1.