Cardioacrofacial dysplasia 1: a case report and literature review

Introduction

Background

PRKACA encodes the protein kinase A (PKA) catalytic subunit α, a core effector molecule in the cAMP/PKA pathway (1). Palencia-Campos et al. first reported that PRKACA gene variants cause a novel autosomal dominant developmental disorder syndrome named cardioacrofacial dysplasia 1 [CAFD1; Online Mendelian Inheritance in Man (OMIM): #619142]. Its primary features include congenital heart defects (particularly atrial septal defects), post-axial polydactyly, skeletal dysplasia, and ectodermal tissue abnormalities (dental and nail hypoplasia) (2). This syndrome is classified within the ciliopathy-associated skeletal dysplasia spectrum. To date, all documented cases in the literature carry the identical c.409G>A (p.Gly137Arg) heterozygous mutation, a pattern that raises the possibility of a recurrent site (2-4). This mutation induces a conformational change in the PKA catalytic subunit, reducing its affinity for the regulatory subunit and thereby causing an abnormal increase in PKA activity—a classic “gain-of-function” mutation mechanism. Enhanced PKA activity excessively phosphorylates the GLI transcription factor family, inhibiting the Hedgehog (Hh) signaling pathway. The Hh pathway is critical for skeletal patterning, cardiac septum development, and ectodermal tissue differentiation during embryonic development (2,5).

Rationale and knowledge gap

The clinical phenotypes of CAFD1 highly overlap with skeletal abnormalities in the ciliopathy spectrum, exhibiting striking similarity to Ellis-van Creveld (EvC) syndrome and Weyers acrofacial dysostosis (WAD) syndrome. All three conditions may present with short limbs, bicuspid aortic valve (BAV), post-axial polydactyly, dental and nail abnormalities, and thickened oral frenula (3). Notably, all five previously reported CAFD1 patients were initially diagnosed as having EvC or WAD syndrome before molecular confirmation, suggesting that clinical differentiation is challenging without genetic testing. However, despite phenotypic similarities, their pathogenic mechanisms differ significantly: PRKACA mutations enhance PKA activity, leading to downregulation of the Hh pathway, whereas EvC and WAD syndrome result from recessive or dominant mutations in the EVC/EVC2 gene, causing loss of function in the basal body Hh signaling complex. Although these pathogenic variants act at different points in the same pathway, they converge on a similar clinical phenotype (2,6). Currently, due to the rarity of cases, systematic research on the phenotypic diversity, diagnostic challenges, and long-term prognosis of CAFD1 remains scarce. Moreover, no literature has conducted an in-depth comparative analysis of the similarities, differences, and boundaries between CAFD1 and EvC/WAD syndrome.

Objective

This paper reports a case of CAFD1 in a pediatric patient, systematically summarizing its clinical, imaging, and molecular characteristics. By comparing this case with five previously reported PRKACA cases and EvC/WAD phenotypes worldwide, we aim to clarify key diagnostic distinctions. We also discuss how gain-of-function PRKACA variants might perturb ciliary Hh signaling pathways, leading to developmental abnormalities. Through case synthesis and literature review, this study aims to deepen understanding of the clinical recognition, molecular pathophysiology, and management strategies for this rare disorder. We present this article in accordance with the CARE reporting checklist (available at https://tp.amegroups.com/article/view/10.21037/tp-2025-aw-752/rc).

Case presentation

All procedures performed in this study were in accordance with the Declaration of Helsinki and its subsequent amendments. This study was approved by the Medical Ethics Committee of Xi’an Children’s Hospital (approval No. 2025004). Written informed consent was obtained from the patient’s parents for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

In August 2024, a 10-year-old Han Chinese male child presenting with short stature and progressive deformity of both knees was referred to the Department of Endocrinology, Genetics, and Metabolism at Xi’an Children’s Hospital. The timeline of the clinical course is shown in Figure 1. The patient was born at term via vaginal delivery with a birth weight of 2.75 kg and length of 45 cm (both <P3), indicating small for gestational age. Prenatal ultrasound revealed limb shortening, but no specific intervention was performed. Early in the neonatal period, he presented with feeding difficulties (milk aspiration and perioral cyanosis during feeding). Consequently, he underwent cardiac evaluation at 8 months of age. Echocardiography at that time revealed a functional single atrium due to a partial atrial septal defect and pulmonary valve stenosis. Surgical repair of the aforementioned congenital heart disease was performed at age 5, yielding favorable therapeutic results.

Figure 1 Clinical event flow chart.

Polydactyly of the hands (axial polydactyly) was present at birth and surgically corrected at age 7. Although growth caught up after cardiac surgery (approximately 5–6 cm per year), stature remains significantly below average. Over the past 5 years, the parents noted progressive deformity of both knees, accompanied by gait abnormalities and activity-related pain, ultimately requiring crutches.

Physical examination revealed marked body disproportion: height 125 cm [−2.45 standard deviation (SD), <P3], weight 28 kg (−1 SD, ≈P15). Truncal-limb ratio characteristics showed brachydactyly (arm length 112 cm; sitting height 78 cm), with the trunk appearing excessively long relative to the limbs. Craniofacial examination revealed increased interpupillary distance, broad nasal bridge with alar flaring, and thickened lips. Dental examination confirmed universal microdontia and increased interdental spacing, with caries present in 4 of 15 teeth. Oral examination focused on searching for a multi-palatal frenulum, which is frequently seen in EvC syndrome, but none was found in this case.

Examination of the extremities revealed surgical scars on the ulnar side of both palms, consistent with a history of polydactyly resection, accompanied by bilateral nail hypoplasia. Typical skeletal features included severe bilateral genu varum, with an estimated tibiofibular distance of 18 cm in the standing position and a tibiofemoral angle of approximately 35° degrees. Knee joint range of motion was 5° to 130°, with no erythema, swelling, or tenderness, and good ligamentous stability. Genital examination revealed Tanner stage I development, a penile length of approximately 3.5 cm, and bilateral testicular volumes of 2 mL each (Figure 2). The patient exhibited syndrome-related findings, including short stature, limb deformities, ectodermal dysplasia, and congenital heart disease. Therefore, primary clinical differential diagnoses considered were osteodysplastic syndromes, specifically EvC syndrome and Wells syndrome. Imaging evaluation was performed to clarify the skeletal phenotype characteristics and guide genetic testing. Standing lower extremity radiographs revealed bilateral tibial plateau depression with valgus deformity and bone erosion (Figure 3A,3B). Left-hand radiographs showed shortening and thickening of the 2nd–4th metacarpal and metatarsal bones, along with brush-like changes at the epiphyses, which are characteristic findings of myeloid ciliopathy. Bone age assessment using the Grulich-Pere method was approximately 10 years, consistent with chronological age (Figure 3C). Metabolic evaluation was performed to exclude causes of acquired bone dysplasia. Complete blood count, liver and kidney function, electrolytes, lipid profile, and blood glucose were all within normal ranges. Bone metabolism markers—serum calcium (2.38 mmol/L), serum phosphorus (1.77 mmol/L), and alkaline phosphatase (201 U/L)—showed no abnormalities. Thyroid function and parathyroid hormone levels were normal. No metabolic abnormalities were detected by urinary tandem mass spectrometry.

Figure 2 Clinical features of the patient with cardioacrofacial dysplasia 1. (A) Anterior view showing short stature, short limbs, and marked genu valgum. (B) Posterior view demonstrating genu valgum and relatively long trunk. (C) Oral examination revealing hypodontia with conical teeth. (D) Hands showing postaxial polydactyly and partial syndactyly. (E) Feet showing postaxial polydactyly. All identifying features have been obscured in accordance with the patient’s parents’ consent.

Figure 3 Initial radiographic findings. (A) Lower extremity standing radiographs demonstrate bilateral genu valgum. (B) Anteroposterior and lateral knee radiographs show bilateral genu valgum with lateral femoral condylar depression and irregularity of the tibial plateau. (C) Left-hand radiograph shows a bone age of approximately 10 years; the 2nd–4th metacarpals and middle phalanges are shortened and thickened, with brush-like metaphyseal changes at the epiphyseal ends.

Postoperative follow-up echocardiography showed no residual atrial shunt, normal systolic and diastolic function in both ventricles (ejection fraction 67%), mild mitral and tricuspid regurgitation, and good mobility of the pulmonary valve. The electrocardiogram showed a sinus rhythm.

To confirm the molecular diagnosis, whole-exome sequencing (WES, coverage depth ≥200×) was performed on peripheral blood samples from the patient and both parents. A heterozygous mutation c.409G>A (p.Gly137Arg) was identified in the PRKACA gene (NM_002730.3). Neither parent carried this mutation, confirming it as a de novo variant. This mutation is classified as pathogenic in the ClinVar database (RCV001006445.1, https://www.ncbi.nlm.nih.gov/clinvar/RCV001006445.1/) and is associated with Omphalocele-Microcephaly-Anencephaly Syndrome Type 1 (OMIM: #619142; https://omim.org/entry/619142). Based on American College of Medical Genetics and Genomics (ACMG) guidelines (7), this mutation was determined to be pathogenic (Figure 4). Diagnosis: cardio-amelodysplasia type 1 due to a molecularly confirmed PRKACA c.409G>A (p.Gly137Arg) mutation.

Figure 4 Whole-exome sequencing results for the proband and his parents. The proband harbors a heterozygous PRKACA variant c.409G>A (p.Gly137Arg) located within the catalytic subunit-encoding region (highlighted in gray). Neither parent carries this variant, confirming a de novo mutation.

Treatment and follow-up

Due to progressive genu varum deformity with significant functional limitation, surgical intervention was deemed necessary in addition to conservative treatments such as conventional orthotic therapy and physical therapy. In January 2025, a robot-assisted bilateral proximal tibial epiphyseal fusion was performed under general anesthesia combined with a local nerve block. Preoperative cardiac evaluation was approved based on stable echocardiography results. The postoperative course was uneventful, with standard prophylactic antibiotics, pain management, and edema control implemented. Radiographs on postoperative day 3 showed good positioning of the bilateral proximal tibial metal fixation devices and near-maintained joint reduction.

At the February 2025 follow-up (1-month postoperatively), the patient had regained independent ambulation and was able to attend school normally, reporting only mild activity-related lower limb discomfort. Follow-up radiographs demonstrated stable morphology of the proximal tibia, favorable implant positioning, and satisfactory joint alignment, with no signs of complications (Figure 5). Orthopedic follow-up will continue to monitor symmetrical bone growth and progressive restoration of mechanical axis alignment.

Figure 5 Postoperative radiographs of both lower limbs. (A-D) Radiographs obtained on postoperative day 3 after bilateral genu valgum correction demonstrate abnormal proximal tibial morphology with metallic internal fixation in situ. The patellae are laterally displaced, while overall joint alignment remains satisfactory without other remarkable abnormalities. (E) Radiograph taken 1 month postoperatively shows similar findings, with stable fixation and maintained alignment.

Long-term management requires a multidisciplinary approach: ongoing orthopedic evaluation of lower limb alignment, cardiac monitoring of valve function, dental management of caries and missing teeth, and genetic counseling for the family (including explanation that the mutation is de novo and that parental germline chimeras may exist).

Discussion

Key findings

We report a case from China with PRKACA c.409G>A (p.Gly137Arg), presenting with typical features of CAFD1: congenital heart malformations (partial atrial septal defect, functional single atrium, pulmonary valve stenosis), post-axial polydactyly, disproportionate short stature (limbs shorter than trunk), severe genu valgum, and hypoplasia of teeth and nails. His clinical features highly concord with the phenotype of five previously reported cases worldwide, all harboring the identical de novo or mosaic mutation. While overlapping with the phenotypes of EvC and Weyers syndrome, the distinct genetic mechanisms suggest clinical differentiation based on external features is challenging, making molecular testing crucial for diagnosis.

Strengths and limitations

This report documents a molecularly confirmed CAFD1 case with systematic characterization, with systematic clinical, imaging, and genetic characterization, as well as short-term postoperative follow-up data after orthopedic intervention. However, due to the extreme rarity of this condition and the limited number of published cases, comprehensive phenotypic mapping and functional validation of the p.Gly137Arg variant remain incomplete. Future multicenter collaborative studies and mechanistic research are warranted to elucidate genotype-phenotype correlations.

Comparison with similar research

We systematically searched PubMed, OMIM, Human Gene Mutation Database (HGMD), and Chinese databases (China National Knowledge Infrastructure, Wanfang, VIP) using the keywords “PRKACA”, “atrial septal defect”, “polydactyly”, “congenital malformation”, and “atrial defects-polydactyly-multiple congenital malformation syndrome” (updated to June 2025). Three studies reporting five cases of cardioacrocervical dysplasia 1 were identified (2-4). Table 1 summarizes the core phenotypic and genetic characteristics of all six cases (including the present case). All cases harbored the identical c.409G>A mutation, with four cases representing de novo mutations and two cases inherited via parental mosaicism. This “single mutation site” phenomenon is extremely rare and may reflect a tendency for mutation recurrence or reporting bias.

CAFD1 shows significant clinical overlap with EvC syndrome and WAD, both caused by mutations in the EVC/EVC2 gene in the 4q16.2 region (8). EvC follows an autosomal recessive inheritance pattern and is characterized by limb shortening, polydactyly of the hindlimbs, nail and tooth abnormalities, and congenital heart disease (9). WAD follows an autosomal dominant inheritance pattern, with relatively mild clinical symptoms including hypodontia, nail hypoplasia, and mild short stature, but typically without cardiac malformations (10). Among the six reported cases of CAFD1, five were initially diagnosed with EvC and one with WAD, highlighting the difficulty of clinical differential diagnosis when molecular testing is not performed. In patients with an EvC-like phenotype who test negative for EVC/EVC2, screening for the PRKACA gene should be considered.

Explanations of findings

Highly consistent phenotypic strains suggest the existence of a unified molecular pathophysiological mechanism. The catalytic subunit Cα of PKA, encoded by the PRKACA gene, is a key regulator of cAMP signaling, and its activity is dynamically controlled by regulatory subunits (11). The p.Gly137Arg substitution occurs at a critical interface where PKA binds to regulatory subunits, weakening this interaction and causing sustained PKA activation—a classic “gain-of-function” change (12). Enhanced PKA activity promotes excessive phosphorylation of GLI transcription factors, thereby suppressing Hh pathway output (12,13). Differences exist in the molecular mechanisms of EvC/WAD and CAFD1—EVC/EVC2 mutations directly disrupt ciliary Hh signaling (14), while PRKACA mutations suppress Hh upstream pathways via PKA hyperactivation—but both ultimately result in diminished Hh pathway signaling (15). The Hh pathway controls skeletal patterning and ventricular septum development during embryogenesis, explaining the overlapping phenotypes of limb shortening, polydactyly, and cardiac malformations (16). To date, only the p.Gly137Arg mutation has been identified in all reported cases, strongly suggesting this residue is critical. Future structural biology studies are expected to elucidate its precise mechanism of action.

Implications and actions needed

Clinical recommendations: given the multisystemic nature of CAFD1, a multidisciplinary approach is recommended, including regular orthopedic evaluation of lower limb skeletal alignment, cardiac valve function monitoring, and dental management. For severe skeletal deformities such as genu varum, orthopedic management strategies for EvC syndrome may be referenced. Although novel mutations predominate, genetic counseling should consider the possibility of parental germline mosaicism.

Research directions: future studies should focus on establishing cellular and animal models to validate the impact of PRKACA mutations on PKA/Hh signaling pathways and explore targeted interventions regulating PKA activity. Expanding case collection and implementing long-term follow-up are necessary to systematically delineate the full clinical spectrum and natural history of this syndrome.

Conclusions

This case adds a Chinese pediatric example of PRKACA c.409G>A (p.Gly137Arg) with classic skeletal and ectodermal features. Clinicians encountering similar phenotypes are advised to pursue WES testing for definitive diagnosis. Further work that links pathway changes to measurable clinical endpoints will be most informative.

Acknowledgments

We would like to thank the patient and his family for their participation.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://tp.amegroups.com/article/view/10.21037/tp-2025-aw-752/rc

Peer Review File: Available at https://tp.amegroups.com/article/view/10.21037/tp-2025-aw-752/prf

Funding: This study was supported by the Central Special Lottery Public Welfare Fund under the Rare Disease Diagnosis and Treatment Capacity Building Project, which provided free genetic testing for the affected children.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-2025-aw-752/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the Declaration of Helsinki and its subsequent amendments. This study was approved by the Medical Ethics Committee of Xi’an Children’s Hospital (approval No. 2025004). Written informed consent was obtained from the patient’s parents for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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