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26 January 2025: Articles  China

Neonatal Familiar Cleidocranial Dysplasia: A Case Report

Challenging differential diagnosis, Rare disease

Shimeng Zhao1ADEF*, Tongtong Wang1BDE, Haipeng Yang1BE, Riyan Huang1AE

DOI: 10.12659/AJCR.946322

Am J Case Rep 2025; 26:e946322

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Abstract

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BACKGROUND: Cleidocranial dysplasia (CCD) is a rare (1: 1 000 000) autosomal dominant congenital skeletal dysplasia characterized by widely patent calvarial sutures, clavicular hypoplasia, supernumerary teeth, and short stature. Only a minority of the cases are diagnosed early after birth. We present another case of proven CCD presenting with typical neonatal phenotype to promote awareness of this rare disorder.

CASE REPORT: A male term neonate presented clinically with unusual soft skull, extremely large fontanels, and palpable right clavicular discontinuity. Cranial computed tomography revealed severe calvarian ossification defect leading to widely enlarged sutures. Right-sided clavicular dysplasia with discontinuity in the middle part were shown on a chest X-ray. Whole-exome sequencing and Sanger sequencing of the RUNX2 gene confirmed the diagnosis of CCD following a single-nucleotide mutation (NM_001024630.3: c.569G>A) in the child as well as in his mother. His additional family members in the maternal line had also different degrees of clavicular and cranial hypoplasia or multiple dental anomalies.

CONCLUSIONS: In clinical practice, in a newborn presenting with severe defects in ossification of the skull and widely enlarged sutures and/or hypoplasia or aplasia of the clavicles, CCD should be considered based on a combination of clinical and radiological genetic criteria. Family history and genetic testing are crucial since the mutation follows autosomal dominant inheritance.

Keywords: cleidocranial dysplasia, Neonatology

Introduction

Cleidocranial dysplasia (CCD; MIM 119600) is a rare congenital autosomal dominant skeletal dysplasia (1: 1 000 000) classically characterized by widely patent calvarial sutures, clavicular hypoplasia, hyperdontia and other developmental abnormalities of the teeth, and short stature [1,2]. Owing to the correlation between the diagnostic difficulty of CCD and age, most cases of CCD are diagnosed in later childhood or even in adolescence. Only a few patients have been diagnosed early in the neonatal period [3]. The management of CCD involves a multidisciplinary approach and its early diagnosis is essential to select an optimum plan and therapeutic benefit [4]. We present a case of proven CCD presenting with typical neonatal phenotype to promote awareness of this rare disorder and the importance of early diagnosis due to its nature and implications of autosomal dominant inheritance.

Case Report

A male neonate was born at 40+1 weeks of gestation via transvaginal delivery to a healthy 32-year-old gravida 2, para 2 mother following an uneventful pregnancy. Birth weight was 3460 g (−0.41z), length was 50 cm (−0z), and head circumference was 35 cm (−0.49z). Apgar scores were 10 and 10 at 1 and 5 min, respectively. The mother reported no exposure to drugs or alcohol during pregnancy. The skull was soft with extremely large fontanels, and all of the sutures were very widely spaced, giving the impression of a nearly absent calvarium when palpated shortly after birth, but the infant was clinically stable. A subsequent computed tomography (CT) scan of the brain with three-dimensional (3D) reconstruction at 2 days of age revealed a severe defect in the ossification of the calvaria and widely enlarged sutures (Figure 1A). Furthermore, due to palpable right clavicular discontinuity on physical examination, a right clavicle fracture was initially hypothesized, but X-ray revealed an Ossar substance defect in the middle part of the right clavicle. After immobilization and 8-bandage fixation for 7 days, X-ray re-examination revealed no formation of callus (Figure 1B), so traumatic causes of the discontinuity could be excluded. Based on the combination of the clinical and imaging findings, the diagnosis of clavicular cranial dysplasia (CCD) was very likely.

Whole-exome sequencing and Sanger sequencing of the RUNX2 gene confirmed CCD with single-nucleotide mutation (NM_001024630.3: c.569G>A). The parents were examined via Sanger detection, and the mother presented the same genomic alterations (Figure 1C). The older sister of the neonate presented similar skull and collarbone findings in infancy. We successfully recovered her cranial CT and chest X-ray images taken at birth and found that the CT scan also revealed a defect in ossification of the temporal, parietal, and occipital bones and widely enlarged sutures (Figure 2A), and her chest X-ray revealed discontinuity of the left clavicle and bilateral hypoplasia of clavicles Figure 2B). Unfortunately, the diagnosis of CCD in the girl was overlooked in her neonatal period, despite the typical combination of skull and clavicular malformation in imaging. Furthermore, additional family members in the maternal line had also different degrees of clavicular and cranial hypoplasia or multiple dental anomalies, but no other skeletal anomalies, like short terminal phalanges, spinal malalignment, genu valgus, and pes planus [5], were found. The genealogical tree is shown in Figure 3.

The neonate was discharged home 8 days after delivery, without others complications. We recommended that the parents take the baby for a regular physical examination, but the appointment was not kept.

Discussion

For the infant boy we presented, there were 3 outstanding features: (1) Severe ossification defect of the skull with widely enlarged sutures. In all CCD infants a generalized delay in skull ossification can be observed in variable degrees, up to extreme cases with almost completely missing parietal bones at birth [8]. In contrast to congenital hypothyroidism [5], levels of serum alkaline phosphatase, calcium, free thyroxine (fT4), and thyroid-stimulating hormone (TSH) are usually normal in CCD patients. The almost complete lack of calcification of the skull suggests that CCD involves a high risk of brain injury during vaginal delivery. Surprisingly, no evidence can be found in the literature of a causal association between decreased skull ossification and the risk of neonatal brain damage during normal vaginal delivery in neonates with CCD, and caesarean section is not always recommended [8]. With increasing age, the unossified areas are replaced by numerous Wormian, dysplastic bones. Repeated X-ray and 3D CT reconstructions of the skull is regarded from a technical point of view as the best method for follow-up evaluation of ossification, but the total central nervous system radiation exposure in childhood is important and the indication for CT re-examination must be considered critically. (2) Hypoplasia or aplasia of the clavicles. The abnormalities of the clavicles vary in severity from a minor unilateral defect to bilateral absence and are often diagnosed as fracture or congenital pseudoarthrosis. In our case, clavicular dysplasia was initially misdiagnosed as a clavicular fracture, but he had no obvious traumatic birth history and no pain from the discontinuity. Interestingly, the upper limb showed unrestricted spontaneous movements. Eighty percent of cases of this type of clavicular dysplasia occur on the right side [6]. (3) Features of appearance. The infant presented a prominent forehead and wide nasal bridge with an ocular hypertelorism. Facial signs of CCD in the neonatal period are not obvious; some patients exhibit characteristic facial features that include brachycephaly, prominent forehead, depressed nasal bridge, hypertelorism with possible exophthalmos, and a small maxilla with mandibular prognathism with age [1]

CCD is characterized by defective endochondral and intramembranous bone formation caused by of the runt-related transcription factor 2 (RUNX2) gene, which is located on the short arm of chromosome 6 [9]. A wide range of mutations are known, with high penetrance and significant variability but weak phenotype-genotype correlation [9]. The RUNX2 gene encodes the synthesis of the RUNX2 protein, also called CBFA1 (core-binding factor subunit alpha-1), which is involved in osteoblastic differentiation and skeletal morphogenesis [10]. RUNX2 induces and regulates the expression of genes involved in bone matrix formation and remodelling by modifying chromatin or interacting with coregulator proteins [11]. The anomalies in CCD involve the entire skeleton because of membranous as well as endochondral bone formation. However, it is not clear why the skull and collarbone are most affected.

Craniofacial and dental abnormalities, clavical hypoplasia or aplasia, and delayed closure of cranial sutures are the main features of CCD [12]. Phenotypically apparent maxillofacial maldevelopment and dental problems become apparent later in infancy; therefore, the typical signs in the neonatal period are in the skull and/or clavicle. Proper diagnosis is frequently missed or misdiagnosed as a ricket, clavicular fracture, congenital pseudarthrosis of the clavicle, achondroplasia, congenital osteogenesis disorder, hypophosphatasia (perinatal and infantile forms), osteogenesis imperfecta congenita (type 1), and Yunis-Varon syndrome [13,14]. Identification of RUNX2 gene mutation confirms the diagnosis that leads to a rational follow-up focusing on the typical problems in the child’s physical development (eg, sleep apnea, scoliosis, irregular hands and motor skills, ear infections/hearing loss, weak bone density, growth problems). However, mutations are detected in only 65% of all patients with a clinical diagnosis of CCD. The diagnosis should be established on the basis of a combination of clinical and radiological genetic criteria.

Early diagnosis of CCD is not only important to initiate an early and adequate interdisciplinary treatment, but also to prevent early complications in neonates as for example respiratory distress [14]. CCD is often comparatively mild; apart from dental complications, affected persons usually have little disability, and the prognosis mainly depends on prevention and early treatment of complications.

Conclusions

In clinical practice, in a newborn presenting with severe defects in ossification of the skull and widely enlarged sutures and/or hypoplasia or aplasia of the clavicles, CCD should be considered based on a combination of clinical and radiological genetic criteria. Family history and genetic testing are crucial since the mutation follows autosomal dominant inheritance.

References:

1.. Mundlos S, Cleidocranial dysplasia: Clinical and molecular genetics: J Med Genet, 1999; 36(3); 177-82

2.. Cunningham ML, Seto ML, Hing AV, Cleidocranial dysplasia with severe parietal bone dysplasia: C-terminal RUNX2 mutations: Birth Defects Res A Clin Mol Teratol, 2006; 76(2); 78-85

3.. Kim JH, Kim SJ, Kim HH, Kim JK, Sporadic cleidocranial dysplasia in a newborn: A 4-year follow-up study: Neonatal Med, 2020; 27; 192-96

4.. Mahajan PS, Mahajan AP, Mahajan PS, A rare case of cleidocranial dysplasia presenting with failure to thrive: J Nat Sci Biol Med, 2015; 6(1); 232-35

5.. Garg RK, Agrawal P, Clinical spectrum of cleidocranial dysplasia: A case report: Cases J, 2008; 1; 377

6.. Franceschi R, Stringari G, Soli F, Newborn with cleidocranial dysplasia: Skeletal Radiol, 2022; 51(12); 2351-52

7.. Ramos Mejía R, Rodríguez Celin M, Fano V, Clinical, radiological, and auxological characteristics of patients with cleidocranial dysplasia followed in a pediatric referral hospital in Argentina: Arch Argent Pediatr, 2018; 116(4); e560-66

8.. Nakano Y, Ebata A, Yamaoka D, Intraparenchymal hemorrhage in a neonate with cleidocranial dysplasia: Pediatr Int, 2022; 64(1); e14665

9.. Jaruga A, Hordyjewska E, Kandzierski G, Tylzanowski P, Cleidocranial dysplasia and RUNX2-clinical phenotype-genotype correlation.: Clin Genet, 2016; 90(5); 393-402

10.. Mundlos S, Otto F, Mundlos C, Mutations involving the transcription factor CBFA1 cause cleidocranial dysplasia: Cell, 1997; 89(5); 773-79

11.. Komori T, Runx2, an inducer of osteoblast and chondrocyte differentiation: Histochem Cell Biol, 2018; 149; 313-32

12.. Back SJ, Pollock AN, Cleidocranial dysostosis: Pediatr Emerg Care, 2013; 29(7); 867-69

13.. Tsuji M, Suzuki H, Suzuki S, Moriyama K, Three-dimensional evaluation of morphology and position of impacted supernumerary teeth in cases of cleidocranial dysplasia: Congenit Anom (Kyoto), 2020; 60(4); 106-14

14.. Ringe KI, Schirg E, Galanski M, Cleidocranial dysplasia (CCD) causing respiratory distress syndrome in a newborn infant. A case report: J Radiol Case Rep, 2010; 4(4); 9-12

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American Journal of Case Reports eISSN: 1941-5923
American Journal of Case Reports eISSN: 1941-5923