Narrow Thorax Research Articles

Novel TRPV6 variant linked with transient neonatal hyperparathyroidism

BackgroundHereditary transient neonatal hyperparathyroidism (TNHP) is a rare autosomal-recessive condition caused by variants in TRPV6 gene which encodes for a transient maternal–fetal calcium transport channel. This is characterized by interference with placental maternal–fetal calcium transport causing fetal calcium deficiency. It primarily manifests as defective bone mineralization, narrow and bell-shaped thorax, bone fractures and short bones at birth. The current study aimed to describe a novel TRPV6 variant linked with TNHP in an Indian family and the review of literature.Case presentationThe proband is a term female neonate with fetal growth restriction born to a third-degree consanguineous couple. She was noted to have diffuse defective bone mineralization, narrow and bell-shaped thoracic cavity, short bones and curved ribs without any bone fractures. The first pregnancy was affected with similar features in the fetus and had been terminated. Parental whole-exome sequencing suggested heterozygous missense variant in exon 12 of the TRPV6 gene (c.1585G > A, p.Asp529Asn) in both the parents. The proband required non-invasive respiratory support for ten days in neonatal intensive care unit. She had low calcium and high parathyroid hormone (PTH) and alkaline phosphatase (ALP) levels. She received calcium, phosphorus and vitamin D supplements for three months leading to normalization of serum PTH and ALP levels. Whole-exome sequencing of the proband suggested a homozygous missense variant in exon 12 of the TRPV6 gene (p.Asp529Asn; ENST00000359396.9) that results in the amino acid substitution of asparagine for aspartic acid at codon 529. To the best of author’s knowledge, this is the twelfth case of TNHP reported in literature. The novel variant of TRPV6 gene present in this family has not been reported earlier.ConclusionOur finding broadens the genotypic spectrum of TNHP.

Cloaked bones in Mucolipidosis II - A periosteal reaction in newborns

On routine, antenatal ultrasound evaluation of a women at 35 weeks gestation showed a fetus (Case 1) with shortening of all the long bones (<5th percentile) with bowing and fuzzy margins. The baby was delivered full term. On physical examination, the baby had a fragile skull, narrow thorax, and short angulated limbs. Postnatal infantogram showed short long bones, periosteal cloaking, fractures, and bell shaped thorax. Another fetus (Case 2) with antenatal ultrasound done elsewhere was suggestive of short and bowed femur. At birth, the baby had angulated limbs. The infantogram shows the periosteal cloaking (thick periosteal reaction) and short long bones similar to the above-mentioned case. Both babies were positive for the I-cell screening test for Mucolipidosis II. Case 1 was confirmed for the same with whole exome sequencing.

Stem chewing lice on Cretaceous feathers preserved in amber

Phthirapteran lice (true lice or parasitic lice) are a major group of ectoparasitic insects living on their bird or mammal hosts during their entire life cycle.1 Due to their highly specialized lifestyles, they are extremely poorly represented in fossil records.2 Molecular clock estimations have speculated extensively about the origin time of parasitic lice,3,4 yet none have been confirmed unequivocally. Herein, we report a new family of stem chewing lice, based on two adult insects associated with several semiplume feathers preserved within a piece of Kachin amber from the mid-Cretaceous. They display some defining characteristics of the Amblycera, an early-diverging lineage of the crown lice group. These features include a wingless body, chewing mouthparts, narrow and small thorax, and short tarsus with elongated euplantulae. Our phylogenetic analysis places the new taxa in the Amblycera, and the discovery thus pushes back the lice fossil records by at least 55 million years. Furthermore, the new specimens show primitive characters such as compressed and club-shaped terminal segments of antennae, maxillary and labial palps, and unmodified femora of hind legs, providing key information for the evolutionary relationship between free-living booklice and parasitic lice. This suggests that some ectoparasitic characters defining the crown lice group might have evolved among amblyceran and non-amblyceran lice in parallel. These newly described fossil specimens imply at least a Cretaceous age of Phthiraptera.

Clinical features and genetic analysis of a case series of skeletal ciliopathies in a prenatal setting

BackgroundShort-rib polydactyly syndrome (SRPS) refers to a group of lethal skeletal dysplasias that can be difficult to differentiate between subtypes or from other non-lethal skeletal dysplasias such as Ellis-van Creveld syndrome and Jeune syndrome in a prenatal setting. We report the ultrasound and genetic findings of four unrelated fetuses with skeletal dysplasias.MethodsSystemic prenatal ultrasound examination was performed in the second or third trimester. Genetic tests including GTG-banding, single nucleotide polymorphism (SNP) array and exome sequencing were performed with amniocytes or aborted fetal tissues.ResultsThe major and common ultrasound anomalies for the four unrelated fetuses included short long bones of the limbs and narrow thorax. No chromosomal abnormalities and pathogenic copy number variations were detected. Exome sequencing revealed three novel variants in the DYNC2H1 gene, namely NM_001080463.2:c.6809G > A p.(Arg2270Gln), NM_001080463.2:3133C > T p.(Gln1045Ter), and NM_001080463.2:c.337C > T p.(Arg113Trp); one novel variant in the IFT172 gene, NM_015662.3:4540-5 T > A; and one novel variant in the WDR19 gene, NM_025132.4:c.2596G > C p.(Gly866Arg). The genotypes of DYNC2H1, IFT172 and WDR19 and the phenotypes of the fetuses give hints for the diagnosis of short-rib thoracic dysplasia (SRTD) with or without polydactyly 3, 10, and 5, respectively.ConclusionOur findings expand the mutation spectrum of DYNC2H1, IFT172 and WDR19 associated with skeletal ciliopathies, and provide useful information for prenatal diagnosis and genetic counseling on rare skeletal disorders.

Thanatophoric dysplasia in nonadherent to antenatal care in low middle income country: a rare case reports.

Thanatophoric dysplasia is a rare, fatal, and sporadic form of skeletal dysplasia caused by a mutation in fibroblast growth factor receptor 3 (FGFR3). It is characterized by a conical thorax, platyspondyly (flat vertebral bodies), and macrocephaly. This disorder can be diagnosed antenatally as early as 13 weeks of gestation. The authors reported a case of thanatophoric dysplasia on USG in a 19 year old young consanguineous female in her second trimester of pregnancy. Ultrasound examination showed a clover leaf-shaped skull, a widened anterior fontanel, a coarse and edematous face, a flattened nasal bridge, a short neck, a low set of ears, shortening of both upper and lower limbs with short fingers, bowed thighs and legs, and a relatively narrow thorax. Lung hypoplasia, polyhydramnios, and hydrops in affected individuals lead to a poor prognosis. Hence, timely intervention should be done to avoid a poor prognosis. However, a mix of sonographic, genetic, histological, and autopsy studies are applied to make the most accurate diagnosis. The authors reported this case due to the rarity of this condition and the need for a systematic and multidisciplinary approach.

CYP26B1-related disorder: expanding the ends of the spectrum through clinical and molecular evidence.

CYP26B1 metabolizes retinoic acid in the developing embryo to regulate its levels. A limited number of individuals with pathogenic variants in CYP26B1 have been documented with a varied phenotypic spectrum, spanning from a severe manifestation involving skull anomalies, craniosynostosis, encephalocele, radio-humeral fusion, oligodactyly, and a narrow thorax, to a milder presentation characterized by craniosynostosis, restricted radio-humeral joint mobility, hearing loss, and intellectual disability. Here, we report two families with CYP26B1-related phenotypes and describe the data obtained from functional studies of the variants. Exome and Sanger sequencing were used for variant identification in family 1 and family 2, respectively. Family 1 reflects a mild phenotype, which includes craniofacial dysmorphism with brachycephaly (without craniosynostosis), arachnodactyly, reduced radioulnar joint movement, conductive hearing loss, learning disability-and compound heterozygous CYP26B1 variants: (p.[(Pro118Leu)];[(Arg234Gln)]) were found. In family 2, a stillborn fetus presented a lethal phenotype with spina bifida occulta, hydrocephalus, poor skeletal mineralization, synostosis, limb defects, and a synonymous homozygous variant in CYP26B1: c.1083C > A. A minigene assay revealed that the synonymous variant created a new splice site, removing part of exon 5 (p.Val361_Asp382del). Enzymatic activity was assessed using a luciferase assay, demonstrating a notable reduction in exogenous retinoic acid metabolism for the variant p.Val361_Asp382del. (~ 3.5 × decrease compared to wild-type); comparatively, the variants p.(Pro118Leu) and p.(Arg234Gln) demonstrated a partial loss of metabolism (1.7× and 2.3× reduction, respectively). A proximity-dependent biotin identification assay reaffirmed previously reported ER-resident protein interactions. Additional work into these interactions is critical to determine if CYP26B1 is involved with other biological events on the ER. Immunofluorescence assay suggests that mutant CYP26B1 is still localized in the endoplasmic reticulum. These results indicate that novel pathogenic variants in CYP26B1 result in varying levels of enzymatic activity that impact retinoic acid metabolism and relate to the distinct phenotypes observed.

RNA sequencing resolves novel DYNC2H1 variants causing short-rib thoracic dysplasia type 3: Case report.

Intronic variants outside the canonical splice site are challenging to interpret and therefore likely represent an underreported cause of human disease. Autosomal recessive variants in DYNC2H1 are associated with short-rib thoracic dysplasia 3 with or without polydactyly (SRTD3), a clinically heterogeneous disease generally presenting with short ribs, shortened tubular bones, narrow thorax and acetabular roof anomalies. We describe a case of SRTD3 with compound heterozygous frameshift and intronic variants and highlight the essential role of RNA sequencing (RNA-Seq) in variant interpretation. Following inconclusive clinical genetic testing identifying a likely pathogenic frameshift variant and an intronic variant of uncertain significance (VUS) in DYNC2H1 in trans, the family enrolled in the Care4Rare Canada research program, where RNA-Seq studies were performed. The proband presented with post-axial polydactyly of all four limbs, a significantly small chest with a pectus excavatum and anterior flaring of the ribs. RNA-Seq investigations revealed a novel splice junction as a result of the intronic VUS and significantly decreased DYNC2H1 gene expression in the proband. This case demonstrates the diagnostic utility of RNA-Seq for variant interpretation following inconclusive clinical testing, which can ultimately lead to diagnosis for patients with rare disease.

Prenatal whole exome sequencing identified two rare compound heterozygous variants in EVC2 causing Ellis-van Creveld syndrome.

Pathogenic mutations in EVC or EVC2 gene can lead to Ellis-van Creveld (EvC) syndrome, which is a rare autosomal recessive skeletal dysplasia disorder. This study aimed to determine pathogenic gene variations associated with EvC syndrome in fetuses showing ultrasound anomalies. A 32-year-old pregnant woman from Quanzhou, China was investigated. In her pregnancy examination, the fetus exhibited multiple fetal malformations, including a narrow thorax, short limbs, postaxial polydactyly, cardiac malformations, and separation of double renal pelvis. Karyotype, chromosomal microarray analysis and whole exome sequencing were performed for prenatal genetic etiology analysis. Chromosome abnormalities and copy number variants were not observed in the fetus using karyotype and chromosomal microarray analysis. Using whole exome sequencing, two compound heterozygous variants NM_147127.5:c.[2484G>A(p.Trp828Ter)];[871-2_894del] in EVC2 gene were identified in the fetus as pathogenic variants inherited from parents. The study is the first to identify two rare compound variants in EVC2 gene in a Chinese family using whole exome sequencing. The application of whole-exome sequencing would be helpful in fetal etiological diagnosis with ultrasound anomalies.

IFT74 variants cause skeletal ciliopathy and motile cilia defects in mice and humans.

Motile and non-motile cilia play critical roles in mammalian development and health. These organelles are composed of a 1000 or more unique proteins, but their assembly depends entirely on proteins synthesized in the cell body and transported into the cilium by intraflagellar transport (IFT). In mammals, malfunction of non-motile cilia due to IFT dysfunction results in complex developmental phenotypes that affect most organs. In contrast, disruption of motile cilia function causes subfertility, disruption of the left-right body axis, and recurrent airway infections with progressive lung damage. In this work, we characterize allele specific phenotypes resulting from IFT74 dysfunction in human and mice. We identified two families carrying a deletion encompassing IFT74 exon 2, the first coding exon, resulting in a protein lacking the first 40 amino acids and two individuals carrying biallelic splice site mutations. Homozygous exon 2 deletion cases presented a ciliary chondrodysplasia with narrow thorax and progressive growth retardation along with a mucociliary clearance disorder phenotype with severely shorted cilia. Splice site variants resulted in a lethal skeletal chondrodysplasia phenotype. In mice, removal of the first 40 amino acids likewise results in a motile cilia phenotype but with little effect on primary cilia structure. Mice carrying this allele are born alive but are growth restricted and developed hydrocephaly in the first month of life. In contrast, a strong, likely null, allele of Ift74 in mouse completely blocks ciliary assembly and causes severe heart defects and midgestational lethality. In vitro studies suggest that the first 40 amino acids of IFT74 are dispensable for binding of other IFT subunits but are important for tubulin binding. Higher demands on tubulin transport in motile cilia compared to primary cilia resulting from increased mechanical stress and repair needs could account for the motile cilia phenotype observed in human and mice.

Skeletal ciliopathy: pathogenesis and related signaling pathways.

Cilia are tiny organelles with conserved structures and components in eukaryotic cells. Ciliopathy is a set of diseases resulting from cilium dysfunction classified into first-order and second-order ciliopathy. With the advancement of clinical diagnosis and radiography, numerous skeletal phenotypes, including polydactyly, short limbs, short ribs, scoliosis, a narrow thorax, and numerous anomalies in bone and cartilage, have been discovered in ciliopathies. Mutation in genes encoding cilia core components or other cilia-related molecules have been found in skeletal ciliopathies. Meanwhile, various signaling pathways associated with cilia and skeleton development have been deemed to be significant for the occurrence and progression of diseases. Herein, we review the structure and key components of the cilium and summarize several skeletal ciliopathies with their presumable pathology. We also emphasize the signaling pathways involved in skeletal ciliopathies, which may assist in developing potential therapies for these diseases.

Genetic variations in the DYNC2H1 gene causing SRTD3 (short-rib thoracic dysplasia 3 with or without polydactyly).

Background and aims: Short-rib thoracic dysplasia 3 with or without polydactyly (SRTD3) represents a type of severe fetal skeletal dysplasia (SD) characterized by shortened limbs, narrow thorax with or without polydactyly, which is caused by the homozygous or compound heterozygous mutations in the DYNC2H1 gene. SRTD3 is a recessive disorder, identification of the responsible genetic variation would be beneficial to an accurate prenatal diagnosis and well-grounded counseling for the affected families. Material and methods: Two families having experienced recurrent fetal SDs were recruited and submitted to a multiplatform genetic investigation. Whole-exome sequencing (WES) was performed with samples collected from the probands. Sanger sequencing and fluorescent quantitative PCR (qPCR) were conducted as validation assays for suspected variations. Results: WES identified two compound heterozygous variations in the DYNC2H1(NM_001080463.2) gene, namely c.2386C>T (p.Arg796Trp) and c.7289T>C (p.Ile2430Thr) for one; and exon (64-83)del and c.8190G>T (p.Leu2730Phe) for the other, respectively. One variant in them, exon (64-83)del, was novelly identified. Conclusion: The study detected two compound heterozygous variation in DYNC2H1 including one novel deletion: exon (64-83) del. Our findings clarified the cause of fetal skeletal dysplasia in the subject families, provided guidance for their future pregnancies, and highlighted the value of WES in diagnosis of skeletal dysplasia with unclear prenatal indications.

Routine Screening for Fetal Limb Abnormalities in the First Trimester

Objective: To evaluate the routine screening for fetal limb abnormalities in the first trimester. Study Design: Prospective study Place and Duration of Study: Department of Radiology and Department of Obstetrics & Gynaecology, Khirpur Medical College, Khairpur Mir’s from 1st October 2020 to 30th September 2022. Methodology: The study enrolled all pregnant women in visiting the Gynaecology OPD for routine check-up. All the cases were referred to ultrasound diagnostic for screening of fetal limb abnormalities. The total sample size of the study was assigned as 1000 fetuses from 980 women as 10 women had twin pregnancies. Limb reduction shortcomings included transverse-limb reduction deficit as well as longitudinal-limb reduction deficit as seen through absent radius and also club hand, absent fibula phocomelia. The diagnosis of the limb shortening was based on the length of long bone if <5th percentile. Lethal skeletal dysplasia suspicion was based on narrow thorax and long bone abnormalities. Results: The mean age of the pregnant women was 27.6±5.3 year. Around 26% of the women were nulliparous. The fetal limb anomaly was presented in 0.9% of the total cases. Within these, 0.7% was those women with single fetus while 0.2% had twin pregnancy. There were 60% of the women who were identified with fetal anomaly on their first screening visit within 1st trimester transverse limb anomaly was observed in 2 case within first trimester whereas 2 cases of club foot were identified in first trimester and one in third trimester. Conclusion: The fetal limb anomaly can be feasibly screened within first trimester. It has a prevalence of 0.9% with transverse limb deficiencies and club foot to be presented in highest frequency. Keywords: Fetal limb abnormalities, First trimester, Prevalence

Jeune syndrome: Case report

Jeune syndrome, also known as asphyxiating thoracic dystrophy, was first described by Jeune et al in a couple of siblings back in 1955. He described 2 boys with certain distinctive characteristics, particularly a severely narrow thorax [1]. We now know it is a rare genetic condition presented in only 1 per 1000 000 130 000 live births in the USA [1].

Ciliary phenotyping in renal epithelial cells in a cranioectodermal dysplasia patient with WDR35 variants.

Background: Cranioectodermal dysplasia (CED) is a skeletal autosomal recessive ciliopathy. The characteristic clinical features of CED are facial dysmorphisms, short limbs, narrow thorax, brachydactyly, ectodermal abnormalities, and renal insufficiency. Thus far, variants in six genes are known to be associated with this disorder: WDR35, IFT122, IFT140, IFT144, IFT52, and IFT43. Objective: The goal of this study was to perform cilium phenotyping in human urine-derived renal epithelial cells (hURECs) from a CED patient diagnosed with second-stage chronic kidney disease (CKD) and three unrelated and unaffected pediatric controls. Methods: Genetic analysis by WDR35 screening was performed in the affected individual. Cilium frequency and morphology, including cilium length, height, and width, were evaluated by immunofluorescence (IF) experiments in hURECs using two markers visualizing the ciliary axoneme (Acet-Tub and ARL13B) and the base of the cilium (PCNT). The IF results were analyzed using a confocal microscope and IMARIS software. Results: WDR35 analysis revealed the presence of a known nonsense p. (Leu641*) variant and a novel missense variant p. (Ala1027Thr). Moreover, comparative genomic hybridization analysis showed that the patient carries a microdeletion on chromosome 7q31.1. Ciliary phenotyping performed on hURECs showed morphological differences in the patient's cilia as compared to the three controls. The cilia of the CED patient were significantly wider and longer. Conclusion: The obtained results suggest that CED-related second-stage CKD might be associated with cilia abnormalities, as identified in renal epithelial cells from a CED patient harboring variants in WDR35. This study points out the added value of hURECs in functional testing for ciliopathies.

De novo heterozygous variants in KIF5B cause kyphomelic dysplasia.

Kyphomelic dysplasia is a heterogeneous group of skeletal dysplasias characterized by severe bowing of the limbs associated with other variable findings, such as narrow thorax and abnormal facies. We searched for the genetic etiology of this disorder. Four individuals diagnosed with kyphomelic dysplasia were enrolled. We performed whole-exome sequencing and evaluated the pathogenicity of the identified variants. All individuals had de novo heterozygous variants in KIF5B encoding kinesin-1 heavy chain: two with c.272A>G:p.(Lys91Arg), one with c.584C>A:p.(Thr195Lys), and the other with c.701G>T:p.(Gly234Val). All variants involved conserved amino acids in or close to the ATPase activity-related motifs in the catalytic motor domain of the KIF5B protein. All individuals had sharp angulation of the femora and humeri, distinctive facial features, and neonatal respiratory distress. Short stature was observed in three individuals. Three developed postnatal osteoporosis with subsequent fractures, two showed brachycephaly, and two were diagnosed with optic atrophy. Our findings suggest that heterozygous KIF5B deleterious variants cause a specific form of kyphomelic dysplasia. Furthermore, alterations in kinesins cause various symptoms known as kinesinopathies, and our findings also extend the phenotypic spectrum of kinesinopathies.

Compound heterozygous variants in DYNC2H1 in a foetus with type III short rib-polydactyly syndrome and situs inversus totalis

BackgroundShort-rib thoracic dysplasia 3 with or without polydactyly (SRTD3, OMIM: 613091) is an autosomal recessive disorder. SRTD3 presents clinically with a narrow thorax, short ribs, shortened tubular bones, and acetabular roof abnormalities. Clinical signs of SRTD3 vary among individuals. Pathogenic variants of DYNC2H1 (OMIM: 603297) have been reported to cause SRTD3.MethodsWe performed a detailed clinical prenatal sonographic characterization of a foetus with SRTD3. Trio whole-exome sequencing was used to identify causative variants in the family. The identified variants in the families were validated by Sanger sequencing and mass spectrometry. Multiple computational tools were used to predict the harmfulness of the two variants. A minigene splicing assay was carried out to evaluate the impact of the splice-site variant.ResultsWe evaluated prenatal sonographic images of the foetus with SRTD3, including abnormal rib curvature, narrow thorax, bilateral hypoplastic lungs, bilateral polydactyly, syndactyly, and foetal visceral situs inversus with mirror-image dextrocardia. We revealed novel compound variants of DYNC2H1 (NM_001377.3:c.11483T > G (p.Ile3828Arg) and c.2106 + 3A > T). Various statistical methods predicted that the variants would cause harmful effects on genes or gene products. The minigene assay findings suggested that c.2106 + 3A > T caused the skipping over exon 14, producing an exon 14 loss in the protein.ConclusionThis study identified a foetus with SRTD3 with situs inversus totalis with mirror-image dextrocardia in a Chinese family, revealing two novel compound heterozygous dynein cytoplasmic 2 heavy chain 1 (DYNC2H1) variants, expanding the phenotypic spectrum of SRTD3. The minigene study of c.2106 + 3A > T was predicted to cause an inframe exclusion of exon 14, which was predicted to have important molecular functions. Our findings strongly supported the use of WES in prenatal diagnosis and helped to understand the correlation of genotype and phenotypes of DYNC2H1. The specific sonographic findings and the molecular diagnosis helped add experience to further our expertise in prenatal counselling for SRTD3.

VP16.14: Diagnosis of short rib polydactyly syndrome type IV (Beemer‐Langer syndrome): a case report

Short rib-polydactyly syndrome (SRPS) is a rare congenital autosomal recessive inherited disease classified in four subtypes. Prenatal ultrasonography findings and postnatal examinations may help classify in one of four subtypes. We present a case of an infant who presented multiple congenital anomalies and the postnatal radiography helped to classify the SRPS as type IV (Beemer-Langer). A 23-year-old was referred for prenatal ultrasound which showed cystic hygroma, small omphalocele and choledocal cyst. Chromosomal analysis revealed a normal male karyotype. Morphological scan revealed small thorax, short ribs, micromelic shortening of limbs with the tibia slightly longer than the fibula, unilateral clubfoot, hidrocephalus and renal hiperechogenicity. Magnetic Resonance performed at 35 weeks revealed micrognathia and mesenteric lymphangioma. The infant delivered at 38 weeks of gestation and died within 60 minutes due to respiratory failure. Postmortem radiography showed marked shortening of all long bones, strikingly narrow thorax with short and horizontal ribs, highly placed clavicles, small scapulae, small ilia and the tibia was longer then the fibula. Identification of the SRPS subtype can be difficult due to overlap of clinical and pathologic findings. This case may help understanding Beemer-Langer type's phenotypic features such as micrognathia, cleft lip, hydrops, hydrocephalus and omphalocele. The most common radiological findings include narrow thorax with short ribs, short tubular bones, highly placed clavicle, small scapulae and ilia and bowing of radius and ulna with the tibia being longer than the fibula. The prognosis of Beemer-Langer syndrome is poor as infants usually die shortly after birth because of respiratory failure secondary to marked pulmonary hypoplasia.

OEIS Syndrome: Omphalocele, Exstrophy of the Cloaca, Imperforate Anus, and Spinal Defects

OEIS Syndrome: Omphalocele, Exstrophy of the Cloaca, Imperforate Anus, and Spinal Defects

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

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

Radiological and histopathological features of short rib‑polydactyly syndrome typeIII andidentification of two novel DYNC2H1 variants.

Short rib‑polydactyly syndrome typeIII (SRPS3) is a lethal perinatal skeletal disorder consisting of polydactyly and multi‑system organ abnormalities. To further assess the pathogenicity of twopairs of compound heterozygotes and to search for novel molecular etiology, X‑rays and hematoxylin and eosin staining were conducted in threecases: Two retrospective samples and a newly identified patient with SRPS3. In addition, next‑generation sequencing was used to evaluate a fetus with SRPS3. Typical radiological features of the threecases included a long, narrow thorax with short ribs, shortened long bones, spurs at the metaphysis of the long bones and congenital bowing of the femurs. The present study also observed atypical histopathological changes, together with the absence of proliferation and abundance of retaining cartilage in the primary spongiosum. In addition, twonovel compound heterozygous variants were identified in the dynein cytoplasmic2 heavy chain1 (DYNC2H1) gene of the fetus: NM_001080463.1, c.6591_6593delTGG (chr11:103055738‑103055740); NM_001080463.1, c.7883T>C (chr11:103070000). The findings of the present study provided further confirmation of the pathogenicity of twocompound heterozygous variants in two retrospective samples and identified novel compound heterozygous variants. These findings may improve our knowledge of the histopathological and radiological changes in patients with SRPS3 and the relative effects of DYNC2H1 variants. The findings of the present study may facilitate the clinical and molecular diagnosis of SRPS3.