Airway Involvement in Conradi–Hünermann–Happle Syndrome: A Novel Clinical Manifestation

We report the first documented case of airway involvement in Conradi–Hünermann–Happle syndrome (CDPX2), an X-linked dominant form of chondrodysplasia punctata caused by pathogenic variants in EBP. A 2-month-old female with genetically confirmed CDPX2 developed severe subglottic stenosis and persistent respiratory distress requiring CPAP; cross-sectional imaging demonstrated extensive laryngotracheal calcifications. Serial endoscopic balloon dilations successfully restored airway patency, enabled weaning from respiratory support, and avoided tracheostomy, expanding the recognized clinical spectrum of CDPX2 and highlighting the potential role of minimally invasive airway intervention in selected cases. Chondrodysplasia punctata (CDP) represents a heterogeneous group of skeletal dysplasias defined radiographically by punctate calcifications within epiphyseal cartilage and periarticular soft tissues [1]. Stippled foci arise from abnormal calcium deposition during endochondral ossification and may result from defects in cholesterol or peroxisomal metabolism, abnormalities of vitamin K metabolism, chromosomal disorders, teratogenic exposures, or idiopathic causes. Several clinical subtypes have been described, with variable inheritance patterns and severity (Table 1) [1, 2]. CDP X-linked recessive type (CDPX1) Also known as: Brachytelephalangic Type; ARSE-related Unknown Skeletal abnormalities are detectable by US between the 2nd or 3rd trimesters Nasomaxillary hypoplasia with a depressed nasal bridge and flat, short nose (Binder phenotype) Growth restriction, both pre- and postnatally Hypoplastic distal phalanges with short nails Cervical spinal cord compression (rare) Mild intellectual disability Airway involvement/calcification (rare) CDP X-linked Dominant Type (CDPX2) Also known as: Conradi–Hünermann (Happle) syndrome; EBP-related Group 1B: Inborn error of metabolism (abnormal cholesterol synthesis) 1 in 400,000 live births Affected fetuses may show abnormalities detectable by US Flattened face with depressed nasal bridge Skin changes along Blaschko lines, including transient congenital ichthyosiform erythroderma, linear hyperkeratosis, follicular atrophoderma, coarse lusterless hair, and cicatricial alopecia Cataracts Asymmetric limb shortening and short stature Scoliosis 1 in 100,000 Prenatal US can detect features between 16 and 22 weeks gestation RCDP1: PEX7 (6q23) RCDP2: GNPAT (1q42) RCDP3: AGPS (2q31) RCDP4: FAR1 (11p15) RCDP5: PEX5 (12p13) Flattened facial profile with depressed nasal bridge Rhizomelic shortening of the proximal limbs Cataracts Ichthyosiform skin lesions Severe developmental delay with abnormal cerebral myelination Joint contractures Unknown Limb shortening detectable on prenatal US at 16–21 weeks Moderate to severe growth failure Mesomelic or rhizomesomelic limb shortening Brachytelephalangy with brachydactyly Severe nasomaxillary hypoplasia (Binder phenotype) Occasionally short, broad thorax Greenberg Dysplasia, LBR-related (GRBGD) Also known: Hydrops-ectopic calcification-moth-eaten skeletal dysplasia Approximately two dozen reported cases Prenatal US can detect features from ~17 weeks gestation Polyhydramnios and hydrops fetalis Narrow thorax with rhizomelic limb shortening Broad, relatively long hands; sometimes postaxial polydactyly Severe facial hypoplasia with retracted midface and depressed nasal bridge Extraskeletal anomalies: pulmonary hypoplasia, intestinal malrotation, extramedullary hematopoiesis Rare; occurs in a minority of fetuses exposed to warfarin Detectable on US during the 2nd trimester 1 sr trimester exposure: hydrops, IUGR Severe nasal hypoplasia; choanal atresia Brachydactyly, especially distal phalanges CNS: hydrocephalus, midline brain malformations Eye anomalies: cataract, corneal opacity, optic atrophy, microphthalmia Other: cleft lip/palate, cardiac defects, renal obstruction, laryngotracheal abnormalities ~60% unaffected, 20% miscarriage, 20% liveborn Neonatal management require airway support; severe skeletal disease worsens prognosis Unknown; occurs in a minority of SLE pregnancies Detectable on US during the 2nd trimester Intrauterine and postnatal growth restriction Nasomaxillary hypoplasia (variable, may be mild) Short limbs; brachydactyly Neonatal lupus manifestations (skin rashes, heart block) less common Risk of preeclampsia and prematurity may impact outcome Cervical myelopathy Usually viable AV block; may cause fetal demise (5%–20%) Neonatal respiratory failure (thoracic hypoplasia and airway stenosis) Zellweger Syndrome (ZWS) Also known as cerebro-hepato-renal syndrome; PBD-A 1 in 50,000–500,000 Prenatal detection in the 1st trimester (10–14 weeks) in at-risk pregnancies Expressionless facies, large fontanelles, high forehead, flat occiput, hypoplastic supraorbital ridges, hypertelorism, epicanthic folds Cryptorchidism, hypospadias, prominent clitoris Cataracts, retinal pigment changes, Brushfield spots, optic disc hypoplasia CNS: polymicrogyria, heterotopia, callosal hypoplasia, severe hypotonia Hepatosplenomegaly, jaundice, renal cortical cysts Talipes equinovarus, camptodactyly, single palmar crease, PDA, VSD Severe neurological impairment; most affected infants rarely survive beyond the first year Hepatosplenomegaly and renal microcysts may persist postnatally Long-term survivors have been reported Only 3 families reported Detectable in the 1st trimester US Early-onset severe limb shortening Absent ossification of the cranial vault (thick membranous tissue instead) Narrow thorax from short ribs Conradi–Hünermann–Happle syndrome (CDPX2) is an X-linked dominant form of CDP caused by pathogenic variants in the EBP (emopamil-binding protein) gene, which is essential for cholesterol biosynthesis [3]. CDPX2 almost exclusively affects females because it is typically lethal in males. CDPX2 is characterized by asymmetric skeletal abnormalities, cataracts, and cutaneous lesions distributed along Blaschko's lines (lines representing pathways of ectodermal cell migration during fetal development). To date, airway involvement has not been reported in the CDPX2 subtype of CDP. We report a 2-month-old female with a prenatal diagnosis of CDPX2 who developed persistent respiratory distress requiring continuous positive airway pressure (CPAP). Imaging revealed severe subglottic stenosis, which was successfully managed with endoscopic balloon dilations. This case highlights that, while CDP-related airway obstruction is often severe and frequently fatal, localized stenosis may be amenable to intervention, leading to meaningful improvement in respiratory outcomes. A female infant was delivered at 35 + 1 weeks' gestation following a pregnancy complicated by intrauterine growth restriction and short, long bones on prenatal ultrasound. Amniocentesis with whole exome sequencing identified a de novo, likely pathogenic, variant in EBP (c.310T>C, p.Y104H), consistent with X-linked dominant CDP. At birth, she had respiratory distress requiring CPAP. She had brachycephaly with frontal bossing, microretrognathia, short neck, and broad nasal bridge. Limb examination revealed asymmetric rhizomelic shortening (right upper limb shorter than the left). Hand findings included clinodactyly and brachydactyly of the fifth digits. Additional findings included congenital cataracts with iris neovascularization and generalized erythroderma with ichthyosiform scaling. Radiographic evaluation demonstrated stippled calcifications throughout multiple cartilaginous structures consistent with CDPX2 (Figure 1A). At 2 months of age, pediatric respiratory medicine at our institution was consulted because the patient remained dependent on CPAP at 7 cmH2O. Cross-sectional CT imaging demonstrated extensive calcification of the laryngeal and tracheal cartilages, most pronounced at the thyroid and cricoid, with significant subglottic narrowing (smallest diameter 3 × 2 mm2) and additional focal narrowing of the distal trachea (Figure 1B,C). Transfer to our institution for emergent pediatric otolaryngological assessment was arranged. The patient underwent three serial endoscopic airway balloon dilations for severe subglottic stenosis. In the first procedure, laryngoscopy revealed posterolateral subglottic narrowing. She could not be intubated with a 3.0 uncuffed endotracheal tube (ETT). A 2.9 mm telescope passed the stenosis with no further narrowing of the distal airway. Scar incision and balloon dilation were done resulting in improved patency (Figure 1D). A second look was performed 2 weeks later due to ongoing CPAP dependence. There was some persistent narrowing; therefore, repeat incision and balloon dilation were performed (Figure 1E). The third bronchoscopy demonstrated interval improvement of the subglottic stenosis. Releasing incision and balloon dilation were performed, after which intubation with a 3.5 ETT was successful without significant leak (Figure 1F). All procedures were performed using a 6 mm balloon inflated to 24 ATM for 30–60 s. There was minimal bleeding following dilation. The patient was successfully weaned from CPAP to low-flow oxygen and then subsequently to room air. She was discharged home in stable condition without respiratory support. CDP is primarily a skeletal dysplasia with stippled calcifications in the epiphyses, but deposits can also involve costal, laryngeal, and tracheobronchial cartilage. Although rare, airway calcification may cause severe fixed obstruction, leading to substantial morbidity and mortality. Prior reports of other CDP subtypes describe infants with diffuse airway involvement who developed critical narrowing refractory to both medical and surgical interventions. Table S1 (online-only) summarizes the 10 published cases of chondrodysplasia punctata with airway involvement reported to date. All patients were male, and most had either a clinical or molecular diagnosis of CDPX1, the X-linked recessive form caused by pathogenic variants in ARSE (arylsulfatase E). One patient had CDP in the context of systemic lupus erythematosus, and one report did not specify the subtype. To our knowledge, this is the first documented case of the X-linked dominant form of CDP caused by the EBP mutation (Conradi–Hünermann–Happle syndrome) to manifest with airway involvement. This expands the clinical spectrum of CDPX2 and highlights the importance of considering airway manifestations in this condition. When CDP is suspected and respiratory compromise is evident, cross-sectional imaging is a valuable, non-invasive adjunct to microlaryngoscopy and bronchoscopy for assessing the severity of airway narrowing and detecting multilevel involvement. Three-dimensional reconstruction may be useful for delineating the airway anatomy because it enables precise assessment of airway caliber, localization of the most critical stenotic segments, and anticipation of technical challenges during intubation, endoscopic or surgical interventions [4]. Management of airway calcification in CDP is challenging, with treatment guided by the severity, location, and extent of stenosis. In cases of critical upper airway narrowing, tracheostomy has historically been the most frequent intervention. Balloon dilation has emerged as a less invasive alternative, especially in cases of focal stenosis. Schweiger et al. reported the first successful balloon dilation of distal tracheal narrowing in a 3-month-old with CDP [5]. More recently, Lee et al. demonstrated that staged balloon dilations temporarily improved tracheal caliber, though a tracheostomy was ultimately required [4]. Despite the typically refractory nature of diffuse tracheobronchial calcification, our patient—the first reported case of CDPX2 with airway anomalies—responded to endoscopic dilation with restoration of airway patency, successful CPAP weaning, and avoidance of tracheostomy. This case represents the first report of airway involvement in Conradi–Hünermann–Happle syndrome (CDPX2), underscoring the importance of considering airway pathology when evaluating infants with this disorder. In cases of localized subglottic stenosis, serial endoscopic dilations can provide sustained improvement in airway patency and obviate the need for tracheostomy. Early recognition and proactive airway management are essential for these medically complex patients. The authors have nothing to report. The authors have nothing to report. This study was exempt from ethics approval by The Hospital for Sick Children Review Ethics Board, as case reports with one or two patients do not meet the Tri-Council Policy Statement definition of research. Informed consent was obtained from the patient(s)’ legal guardian for the publication of this case report. Informed consent was obtained from the patient's legal guardians for the publication of this case series. A copy of the consent is available for review by the Editor-in-Chief of this journal. The authors declare no conflicts of interest. Data sharing not applicable to this article as no datasets were generated or analyzed during the current study. Table S1: Literature Review of Reported Patients with Chondrodysplasia Punctata and Airway Involvement. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.