Camptodactyly-arthropathy-coxa vara-pericarditis syndrome (CACP) is a rare autosomal recessive disease caused by mutation in proteoglycan 4 (PRG4) gene on chromosome 1q25-q31. We faced a dilemma and delay in diagnosis in two sisters. The elder sister had pericardial effusion with constrictive pericarditis, underwent pericardiectomy and received empirical treatment for suspected tuberculosis. After 2 years, she developed bilateral knee swelling with restriction of movement. At the same time, her younger sister also presented with bilateral knee swelling which aroused the suspicion of genetic disease. The whole-genome sequencing revealed homozygous PRG4 mutation suggestive of CACP syndrome.

BACKGROUND Congenital hypoplasia of the thumb type IV, also known as floating thumb, is a condition in which 2 small phalanges are attached to the hand with a thin skin bridge. Surgical management options for this condition vary from amputation to flap reconstruction. MATERIAL AND METHODS This retrospective study analyzed 11 infants with congenital hypoplasia of the thumb type IV who underwent surgical reconstruction using a modified vascularized polydactylous hallux flap. The study included 6 male and 5 female infants, aged 6 to 24 months. Functional evaluations and radiographic studies were conducted postoperatively. RESULTS All 11 patients underwent the complete surgical protocol. Successful vascular and nerve anastomoses were performed during the initial procedure, ensuring sufficient blood supply and neural connectivity to the transferred toes. The second operation showed promising outcomes, including improvements in thumb opposition, grasp strength, and overall function. Postoperative assessments demonstrated satisfactory radiographic alignment and no major complications during the follow-up period. CONCLUSIONS The modified vascularized polydactylous hallux flap reconstruction is a viable surgical option for managing congenital hypoplasia of the thumb type IV in infants. This technique effectively restores thumb opposition, grasp strength, and overall hand function, with satisfactory radiographic alignment and minimal complications. The study findings support the efficacy and safety of this surgical approach in addressing this rare congenital anomaly.

Coffin-Siris syndrome (CSS) is a rare autosomal dominant inheritance disorder characterized by distinctive facial features, hypoplasia of the distal phalanx or nail of the fifth and additional digits, developmental or cognitive delay of varying degree, hypotonia, hirsutism/hypertrichosis, sparse scalp hair and varying kind of congenital anomalies. CSS can easily be misdiagnosed as other syndromes or disorders with a similar clinical picture because of their genetic and phenotypic heterogeneity. We describde the genotype-phenotype correlation of one patient from a healthy Chinese family with a novel genotype underlying CSS, who was first diagnosed in the ophthalmology department as early-onset high myopia (eoHM). Comprehensive ophthalmic tests as well as other systemic examinations were performed on participants to confirm the phenotype. The genotype was identified using whole exome sequencing, and further verified the results among other family members by Sanger sequencing. Real-time quantitative PCR (RT-qPCR) technology was used to detect the relative mRNA expression levels of candidate genes between proband and normal family members. The pathogenicity of the identified variant was determined by The American College of Medical Genetics and Genomics (ACMG) guidelines. STRING protein-protein interactions (PPIs) network analysis was used to detect the interaction of candidate gene-related proteins with high myopia gene-related proteins. The patient had excessive eoHM, cone-rod dystrophy, coarse face, excessive hair growth on the face, sparse scalp hair, developmental delay, intellectual disability, moderate hearing loss, dental hypoplasia, patent foramen ovale, chronic non-atrophic gastritis, bilateral renal cysts, cisterna magna, and emotional outbursts with aggression. The genetic assessment revealed that the patient carries a de novo heterozygous frameshift insertion variant in the ARID1B c.3981dup (p.Glu1328ArgfsTer5), which are strongly associated with the typical clinical features of CSS patients. The test results of RT-qPCR showed that mRNA expression of the ARID1B gene in the proband was approximately 30% lower than that of the normal control in the family, suggesting that the variant had an impact on the gene function at the level of mRNA expression. The variant was pathogenic as assessed by ACMG guidelines. Analysis of protein interactions in the STRING online database revealed that the ARID1A protein interacts with the high myopia gene-related proteins FGFR3, ASXL1, ERBB3, and SOX4, whereas the ARID1A protein antagonizes the ARID1B protein. Therefore, in this paper, we are the first to report a de novo heterozygous frameshift insertion variant in the ARID1B gene causing CSS with excessive eoHM. Our study extends the genotypic and phenotypic spectrums for ARID1B-CSS and supplies evidence of significant association of eoHM with variant in ARID1B gene. As CSS has high genetic and phenotypic heterogeneity, our findings highlight the importance of molecular genetic testing and an interdisciplinary clinical diagnostic workup to avoid misdiagnosis as some disorders with similar manifestations of CSS.

Anorectal malformations (ARMs) represent a wide spectrum of congenital anomalies of the anus and rectum, of which more than half are syndromic. Their etiology is highly heterogeneous and still poorly understood. We report a 4-year-old girl who initially presented with an isolated ARM, and subsequently developed a global developmental delay as part of an ARID1B-related Coffin-Siris syndrome (CSS). A co-occurrence of ARMs and CSS in an individual by chance is unexpected since both diseases are very rare. A review of the literature enabled us to identify 10 other individuals with both CSS and ARMs. Among the ten individuals reported in this study, 8 had a variant in ARID1A, 2 in ARID1B, and 1 in SMARCA4. This more frequent than expected association between CSS and ARM indicates that some ARMs are most likely part of the CSS spectrum, especially for ARID1A-related CSS.

Schinzel-Giedion syndrome (SGS) is a severe multisystem disorder characterized by distinctive facial features, profound intellectual disability, refractory epilepsy, cortical visual impairment, hearing loss, and various congenital anomalies. SGS is attributed to gain-of-function (GoF) variants in the SETBP1 gene, with reported variants causing canonical SGS located within a 12 bp hotspot region encoding SETBP1 residues aa868-871 (degron). Here, we describe a case of typical SGS caused by a novel heterozygous missense variant, D874V, adjacent to the degron. The female patient was diagnosed in the neonatal period and presented with characteristic facial phenotype (midface retraction, prominent forehead, and low-set ears), bilateral symmetrical talipes equinovarus, overlapping toes, and severe bilateral hydronephrosis accompanied by congenital heart disease, consistent with canonical SGS. This is the first report of a typical SGS caused by a, SETBP1 non-degron missense variant. This case expands the genetic spectrum of SGS and provides new insights into genotype-phenotype correlations.

To date 11 patients with Coffin-Siris syndrome type 7 (OMIM 618027) have been described since the first literature report. All reported patients carried de novo variants with presumed dominant negative effect, which localized in the PHD1/PHD2 domains of DPF2. Here we report on the first familial case of Coffin-Siris syndrome type 7. The index patient presented during the 1st year of life with failure to thrive and ectodermal anomalies. The genetic analysis using whole exome sequencing showed a likely pathogenic missense variant in the PHD1 region. The family analysis showed that the mother as well as the older brother of the index patient also carried the detected DPF2 variant in heterozygous state. The mother had a history of school difficulties but no history of failure to thrive and was overall mildly affected. The brother showed developmental delay with autistic features, ectodermal anomalies and overlapping morphologic features but did not have a history of growth failure problems. To our knowledge this is the first report of an inherited likely pathogenic variant in DPF2, underlining the variability of the associated phenotype as well as the importance of considering inherited DPF2 variants during the variant filtering strategy of whole exome data.

OBJECTIVE: Coffin-Siris Syndrome (CSS) is a congenital disorder characterized by delayed growth, dysmorphic facial features, hypoplastic nails and phalanges of the fifth digit, and dental abnormalities. Tooth agenesis has been reported in CSS patients, but the mechanisms regulating this syndromic tooth agenesis remain largely unknown. This study aims to identify the pathogenic mutation of CSS presenting tooth genesis and explore potential regulatory mechanisms.
METHODS: We utilized whole-exome sequencing to identify variants in a CSS patient, followed by Sanger validation. In silico analysis including conservation analysis, pathogenicity predictions, and 3D structural assessments were carried out. Additionally, single-cell RNA sequencing and fluorescence in situ hybridization (FISH) were applied to explore the spatio-temporal expression of Sox4 expression during murine tooth development. Weighted Gene Co-expression Network Analysis (WGCNA) was employed to examine the functional role of SOX4.
RESULTS: A novel de novo SOX4 missense mutation (c.1255C > G, p.Leu419Val) was identified in a Chinese CSS patient exhibiting tooth agenesis. Single-cell RNA sequencing and FISH further verified high expression of Sox4 during murine tooth development, and WGCNA confirmed its central role in tooth development pathways. Enriched functions included cell-substrate junctions, focal adhesion, and RNA splicing.
CONCLUSIONS: Our findings link a novel SOX4 mutation to syndromic tooth agenesis in CSS. This is the first report of SOX4 missense mutation causing syndromic tooth agenesis.
CONCLUSIONS: This study not only enhances our understanding of the pathogenic mutation for syndromic tooth agenesis but also provides genetic diagnosis and potential therapeutic insights for syndromic tooth agenesis.

We experienced an atypical case of radial longitudinal deficiency that did not fit into any classifications, including Blauth. The patient had a bilateral hypoplastic thumb, in which the index and middle fingers were missing in the right hand. We performed surgeries in four stages: centralization of the right hand, opponensplasty of the right thumb, opponensplasty of the left thumb, and distraction lengthening of the right ulnar. Twenty-five years after the initial treatment, the patient was satisfied with the treatment and had no significant difficulty with activities of daily living.

暂无摘要。

Campotodactyly-artrhropathy-coxa vara-pericarditis (CACP) syndrome is a very rare autosomal recessive genetic disorder. It is characterized by flexion contracture of the fifth finger (camptodactyly); noninflammatory arthropathy; decreased angle between the shaft and the head of the femur (coxa vara) and pericarditis. Its association with mitral stenosis has not yet been reported. Hereby we report this unique association with CACP syndrome.
An eleven-year-old girl presented with non-productive cough, dyspnea, and orthopnea. She was diagnosed CACP syndrome at the age of seven and a biallelic frameshift mutation in the PRG4 gene was determined. The physical examination revealed pectus excavatum, camptodactyly, genu valgum, tachypnea and orthopnea. The functional capacity was NYHA III-IV. She had 2/6 soft pansystolic murmur at 4th left intercostal space and a rumbling diastolic murmur at apex. Echocardiography revealed an enlarged left atrium, severe stenotic mitral valve with a mean diastolic transmitral gradient of 22.5 mmHg, mild mitral regurgitation and mild apical pericardial effusion. The patient had mitral comissurotomy and partial pericardiectomy operation. Her post-operative transmitral gradient decreased to 6.9 mmHg and the pulmonary pressure was 30 mmHg. Her functional capacity increased to NYHA I-II.
The main defect is the proteoglycan 4 protein which acts like a lubricant in articular and visceral surfaces. Therefore, the leading clinical feature is arthropathy. Cardiac involvement other than clinically mild pericarditis is not usually expected. Three types of proteoglycans (decorin, biglycan, and versican) are present in the mitral valve. This could be the reason of mitral valve involvement in rare cases as like ours. It is important that these patients undergo echocardiographic examination regularly.