Asphyxiating thoracic dystrophy associated with IFT74 pathogenic variant: a case report

Abstract

Background

Asphyxiating Thoracic Dystrophy (ATD) is a rare skeletal ciliopathy characterized by a constricted thoracic cage, short ribs, and pulmonary hypoplasia. While typically linked to pathogenic variants in IFT80 or DYNC2H1, recent genomic advancements have identified biallelic variants in IFT74 as a cause of short-rib thoracic dysplasia type 20 (SRTD20). Due to its rarity, the clinical progression and phenotypic spectrum of IFT74-related ATD remain poorly understood.

Case presentation

We report the case of a term male infant presenting at birth with severe respiratory distress, macrocephaly, and a narrow chest with pectus excavatum. Initial radiographic skeletal surveys were inconclusive for classic dysplasia. Despite intensive neonatal care, the patient experienced persistent respiratory failure, recurrent atelectasis, and profound axial hypotonia. Magnetic resonance imaging (MRI) revealed no structural abnormalities. Whole exome sequencing (WES) identified a homozygous pathogenic copy number loss in the IFT74 gene. The clinical course was complicated by severe oropharyngeal dysphagia and recurrent aspiration pneumonia. Despite gastrostomy placement and maximal supportive care, the infant suffered a fatal cardiopulmonary arrest at four months of age.

Conclusions

This case highlights a lethal neonatal phenotype of IFT74-related SRTD20, reinforcing the critical role of IFT74 in ciliary assembly and axonal guidance. Early WES is essential for diagnosing genetically heterogeneous skeletal dysplasias, providing accurate prognostic counseling, and guiding end-of-life discussions in cases of severe thoracic insufficiency.

Background

Asphyxiating Thoracic Dystrophy (ATD) also known as Jeune syndrome, is a severe skeletal dysplasia characterized by a narrow, bell-shaped thoracic, short ribs and variable degrees of micromelia [1]. The severity of the disease is determined by thoracic restriction, causing secondary pulmonary hypoplasia and respiratory failure [2].

The pathophysiology of ATD is a genetic defect affecting the primary cilium (a microtubule based organelle crucial for embryonic signaling pathways). While pathogenic variants in IFT80, DYNC2H1, and WDR19 are classical in ATD, recent genomic expansions have identified biallelic pathogenic variation in IFT74, a core component of the IFT-B complex as a direct cause of short-rib thoracic dysplasia [3].

Because IFT74 related ATD is exceptionally rare, the clinical progression, optimal management and phenotypic variations remain poorly understood. In this report, we present a case of an infant with a lethal presentation of ATD driven by an IFT74 pathogenic variant.

Case presentation

A term male infant was referred from a local hospital to our Neonatal Intensive Care Unit (NICU) at 2 months and 16 days of age for the management of recurrent, severe respiratory distress.

The patient’s history dates back at birth, when he was born with respiratory distress characterized by grunting. Oxygen therapy via nasal cannula was initiated; however, no clinical improvement was observed. Consequently, the infant was transferred to the NICU at the age of 3 h for further evaluation and management.

The infant was delivered via Cesarean section to a 25-year-old mother (blood group O+). The infant’s birth weight was 3.36 kg (50th percentile), head circumference was 37 cm (above the 90th percentile), and length was 49 cm (approximately at the 50th percentile).

Upon his first NICU admission, physical examination revealed a neonate in respiratory distress characterized by tachypnea, grunting, and subcostal retractions. The chest appeared narrow with pectus excavatum. Macrocephaly, low-set ears, and relatively short limbs were also noted. Otherwise, the examination was unremarkable, with no additional dysmorphic features identified.

Upon admission to our tertiary facility, physical examination revealed a narrow chest with pectus excavatum, macrocephaly, low-set ears, and relatively short limbs. To investigate these features, the initial radiographic skeletal survey performed at birth was retrospectively re-evaluated, and a follow-up chest and abdominal X-ray was obtained.

The initial neonatal survey at birth had been reported as showing normal bone morphology and mineralization with symmetric long bones (bilateral femoral length measured 7.2 cm, at the lower limit of normal), lacking the classic “handlebar” clavicles typically associated with Asphyxiating Thoracic Dystrophy (ATD). However, our follow-up evaluation and progress radiography revealed a pronounced, progressive clinical discrepancy: while the long bones lacked severe micromelia, the thoracic cage was profoundly narrow and severely restricted relative to the expanding abdomen (Fig. 3). This indicated that the initial findings at birth were either too subtle for standard radiographic detection or were temporarily masked by early neonatal proportions, highlighting that a normal early skeletal survey should not rule out evolving ATD. Abdominal ultrasound performed at our center demonstrated normal findings with no organomegaly.

Fig. 3.

Portable x-ray of chest and abdomen showing upper lobe pulmonary infiltrates, and a narrow rib cage relative to abdomen

The patient was initially supported with nasal synchronized intermittent mandatory ventilation (N-SIMV), resulting in transient clinical improvement. However, the infant continued to require high FiO₂ levels, and respiratory effort progressively increased. Chest radiography revealed lung atelectasis, necessitating endotracheal intubation and mechanical ventilation.

Multiple attempts at ventilator weaning and extubation were unsuccessful due to recurrent atelectasis. Chest physiotherapy was subsequently initiated, leading to gradual clinical improvement.

Given the presence of macrocephaly, a transfontanelle ultrasound was performed and demonstrated normal findings, with no evidence of intraventricular hemorrhage, midline shift, or hydrocephalus. Ventricular measurements were within normal limits, and the brain parenchyma showed normal echogenicity without focal lesions. Ophthalmologic examination was also normal, revealing positive bilateral red reflexes, normal anterior segments, flat retinas, and normal optic discs.

At the age of one month, routine neurological assessment revealed axial hypotonia with a frog-leg posture, while peripheral tone and deep tendon reflexes were preserved. Moro and sucking reflexes were absent. A pediatric neurologist was consulted, and an extensive metabolic workup was performed, including thyroid function tests, plasma and urine organic acids, serum ammonia, and lactate levels. All results were within normal limits for age. Given the persistent unexplained neurological findings, whole exome sequencing (WES) was performed.

WES identified a homozygous pathogenic copy number loss of at least 120 base pairs in the IFT74 gene (seq[GRCh38] 9p21.2 (26961968_26962087)x0). Pathogenic variants in IFT74 are associated with a spectrum of ciliopathies, most notably Bardet–Biedl syndrome type 22, and have also been linked to Joubert syndrome and other ciliopathy related conditions. This copy number variant (CNV) profile mapped a localized intra-genic structural deletion targeting a specific exonic segment within the core coding region of IFT74. This localized deletion results in an absolute zero-copy state (homozygous loss) that disrupts the open reading frame within essential functional domains of the protein, predicted to cause either a severely truncated, non-functional protein or trigger nonsense-mediated mRNA decay (NMD). There is no consanguinity between parents and no known family history of skeletal dysplasias, unexplained neonatal deaths, or ciliopathies. We consulted parents for further genetic testing for them, nonetheless, the parents declined further testing.

Brain Magnetic Resonance Imaging (MRI) performed at two months of age demonstrated no structural abnormalities involving the cerebral hemispheres, brainstem, or cerebellum. (see Fig. 1) Myelination was appropriate for age. The corpus callosum was present and complete, although detailed assessment of its myelination was limited by age. No intracranial hemorrhage, hydrocephalus, space-occupying lesions, or diffusion restriction were identified. A subtle prominence of the cerebellar folia and extra-axial subarachnoid spaces was noted (Fig. 2); however, this was classified as a benign, non-specific finding secondary to the patient’s clinical macrocephaly rather than a structural hindbrain hypoplasia.

Fig. 1.

Axial MRI at the level of the midbrain showing normal findings

Fig. 2.

Mid-sagittal T2-weighted MRI of the neonatal brain: yellow markings showing a subtle prominence of the cerebellar folia and subarachnoid spaces

By the age of two months, the infant was successfully weaned to room air with acceptable oxygen saturation levels; however, baseline tachypnea and subcostal retractions persisted. The patient remained on ongoing chest physiotherapy and frequent nebulized therapy.

Due to persistent respiratory distress and the inability to safely initiate oral feeding, the infant was initially fed via an orogastric tube. A swallow therapist was consulted for feeding assessment. Evaluation revealed weak and poorly sustained non-nutritive suck with rapid fatigability and poor intra-oral suction. No clinically observable swallow reflex was elicited during oral stimulation, and coordinated suck–swallow–breath patterns were absent, indicating a high risk of aspiration. Swallow and oral-motor therapy were initiated, resulting in gradual improvement.

The infant was discharged at approximately two and a half months of age. At discharge, he was stable on room air, although baseline tachypnea persisted. Feeding had transitioned to oral feeding, and the infant remained on frequent nebulized therapy and proton pump inhibitor treatment. The family received counseling regarding aspiration risk and appropriate anti-reflux positioning.

Five days after discharge, the infant was readmitted following clinical deterioration. On the third day at home, he developed increasing respiratory distress, hypoactivity, and poor oral intake. The family initially managed the symptoms with nebulized therapy at home for two days. However, on the fifth day, the infant developed cyanosis and was brought to the emergency department.

Laboratory investigations revealed elevated C-reactive protein levels, and chest x-ray shown in Fig. 3 showed pulmonary infiltrates. The infant was admitted to the pediatric intensive care unit and treated as a case of aspiration pneumonia with intravenous antibiotics. After five days of treatment, clinical improvement was noted and the patient was discharged home.

On the same day of discharge, the infant returned to the emergency department with recurrent cyanosis and severe respiratory distress requiring urgent endotracheal intubation. During intubation, milk was observed emerging from the endotracheal tube, strongly suggesting aspiration. The infant was therefore readmitted with a diagnosis of aspiration pneumonia.

After stabilization, the family was counseled regarding gastrostomy placement to reduce the risk of recurrent aspiration. The family consented, and a gastrostomy tube was subsequently inserted. Enteral feeding was initiated via gastrostomy; however, the infant remained ventilator-dependent from a respiratory standpoint.

Unfortunately, at the age of four months, the infant developed a sudden cardiopulmonary arrest. Cardiopulmonary resuscitation was initiated immediately; however, return of spontaneous circulation was not achieved, and the patient was subsequently pronounced dead.

Discussion and conclusions

This case represents a severe neonatal presentation of ATD associated with bilallelic IFT74 pathogenic variants. The clinical features of thoracic constriction, respiratory failure and early lethality aligns with the most severe end of IFT74 related ciliopathy spectrum and highlights the critical prognostic significance of variant class and neonatal respiratory status.

The pathogenicity of IFT74 variants is determined by the residual function of intraflagellar transport protein. Splice-sites that abolish IFT74 expression lead to profound disruptions in ciliary assembly and function [3, 4].

Patients who have severe loss of function alleles present with lethal skeletal chondrodysplasia classified as short-rib thoracic dysplasia type 20 (SRTD20, OMIM #617866). This genotype-phenotype correlation is based on the role of IFT74 N-terminus in tubulin binding and transport, while partial loss may permit limited primary cilium function [3].

The clinical presentation of immediate neonatal respiratory failure and early lethality is suggestive of severe or total loss of function of IFT74 alleles. This severe phenotype contrasts with hypomorphic cases, where patients often survive infancy but develop chronic respiratory disease and progressive retinal degeneration over time [4].

Although Bardet-Biedl syndrome type 2 (BBS22) has been proposed as a designation for IFT74 disorders, the literature lacks robust evidence linking this gene to the classic BBS pentad of obesity, polydactyly, and cognitive impairment. Instead, IFT74 pathogenic variant appear to define a spectrum ranging from combined motile and primary ciliopathies to isolated, severe skeletal dysplasia [3, 4].

SRTD20 represents the most severe skeletal end of the IFT74 spectrum, mirroring the cardinal features of Jeune syndrome, such as a narrow thorax, shortened tubular bones and trident acetabular roofs [4–6]. While Jeune syndrome is genetically heterogenous with DYNC2H1 pathogenic variants accounting for approximately 59% of families, the extraskeletal manifestations, including renal and hepatic complications, occur in about 30% of cases overall [7–9]. However, the precise frequency of these complications specifically in IFT74 related SRTD20 remains poorly characterized due to high neonatal mortality rates [6, 8].

The primary cause of mortality in SRTD is respiratory failure secondary to thoracic insufficiency [5, 6, 8]. A constricted thorax restricts lung expansion leading to pulmonary hypoplasia and restrictive lung disease. In severe cases, respiratory failure is immediate and incompatible with life despite maximal intervention [3]. Conversely, patients surviving neonatal period may experience gradual improvement as the thoracic cage grows, though they remain susceptible to chronic infections [6, 8]. The presence of immediate neonatal failure serves as a critical prognostic indicator of near-complete loss of protein function [3].

Furthermore, recent functional studies by Fassad et al. have demonstrated that IFT74 localizes to the cytoplasm of respiratory motile cilia, and its deficiency induces a phenotype mimicking Primary Ciliary Dyskinesia (PCD). In our patient, while thoracic restriction and secondary pulmonary hypoplasia were the primary drivers of restrictive lung disease, the clinical course was notably complicated by recurrent, severe atelectasis and a complete inability to wean from mechanical ventilation. It is highly probable that an underlying PCD-like clearance defect severely compounded the mechanical thoracic insufficiency, rendering the patient exceptionally vulnerable to mucus stagnation and lethal aspiration pneumonia [4].

Given this genetic heterogeneity, comprehensive genomic approaches such as WES are essential for accurate diagnosis and management. WES can distinguish between hypomorphic alleles and lethal loss of function variants thereby informing prognosis, natural history expectations and genetic counselling for recurrence risks [7, 10]. in cases of rapid clinical deterioration, rapid WES should be considered a first-line diagnostic tool to clarify the molecular basis of the phenotype and guide parental discussions [11].

Our patient’s severe phenotype directly solidifies emerging genotype-phenotype correlations in IFT74-related ciliopathies. Hypomorphic, missense mutations or partial splicing variants in IFT74 typically preserve residual intraflagellar transport function, leading to milder, non-lethal phenotypes such as adult-onset Bardet-Biedl Syndrome (BBS22) or slowly progressive retinal degeneration [1]. Conversely, our patient harbored a homozygous exonic copy number loss, a severe loss-of-function (null) allele. The absolute structural disruption of this essential IFT-B complex component completely breaks down retrograde and anterograde ciliary axonemal transport during crucial stages of chondrogenesis [3, 4]. This explains why our patient presented with immediate, severe thoracic insufficiency and neuromuscular hypotonia, reinforcing that homozygous structural null deletions in IFT74 dictate a lethal, non-survival skeletal presentation.

A limitation of this report is the lack of parental segregation testing. While parental genetic screening was strongly recommended to confirm heterozygous carrier status and aid future reproductive counseling, the family declined further testing. Consequently, we cannot entirely rule out a rare de novo genomic rearrangement on one allele masking as homozygosity, though true homozygosity remains highly probable in the context of rare recessive disorders.

Future research must address the rarity of IFT74 related SRTD20 to better delineate survival rates and the natural history of the disorder. Establishing clear genotype-phenotype correlations and exploring therapeutic strategies to support respiratory function remain high priorities. Furthermore, advancements in prenatal diagnosis through fetal ultrasound and early WES may provide families with earlier opportunities for informed reproductive decision making regarding these devastating skeletal ciliopathies [11, 12].

Abbreviations

ATD

Asphyxiating Thoracic Dystrophy

NICU

Neonatal Intensive Care Unit

N-SIMV

Nasal synchronized intermittent mandatory ventilation

WES

Whole exome sequencing

MRI

Magnetic Resonance Imaging

SRTD20

Short-rib thoracic dysplasia type 20

BBS22

Bardet-Biedl syndrome type 2

Authors’ contributions

A.A: manuscript writing and editing, data collection, conceptualization.B.A: manuscript writing.H.K: manuscript writing.U.G: Manuscript writing and editing.R.A: conceptualization, reviewing, and supervisionAll authors have read and approved the final manuscript.

Funding

None.

Data availability

Data is available upon request from the corresponding author.

Declarations

Ethics approval and consent to participate

Ethical approval was not needed. Consent to participate was obtained from the patient’s guardian.

Consent for publication

The consent for publication of this case details along with images were obtained from the patient’s guardian and is available upon request.

Competing interests

The authors declare no competing interests.