Prenatal Diagnosis of Isolated Unilateral Limb Length Discrepancy: A Case Report

Abstract

We report a case of a 32-year-old primigravida referred at 22 weeks' gestation for evaluation of short long bones. Detailed ultrasonography revealed asymmetric shortening of the left tibia and fibula with otherwise normal fetal growth and anatomy. Genetic evaluation identified a heterozygous likely pathogenic variant not typically associated with skeletal dysplasia. Absence of parental testing limited the interpretation of pathogenicity. Despite a favorable orthopaedic prognosis, the couple opted for termination owing to uncertainty regarding phenotypic expression and psychosocial implications. This case highlights the interpretive challenges of prenatal genetic findings in isolated limb length discrepancy and underscores the importance of multidisciplinary counseling in decision-making.

Keywords

fetal ultrasound - limb length discrepancy - prenatal genetics - exome sequencing - skeletal dysplasia

Case Report

A 32-year-old primigravida was referred at 22 weeks of gestation for evaluation of short long bones. This was a spontaneous conception with no family history of genetic disorders. First-trimester combined screening was low risk.

Detailed two-dimensional and three-dimensional ultrasonography (Voluson E22, GE Healthcare) demonstrated asymmetric shortening of the left tibia (25 mm, < 5th centile) and fibula (26.4 mm, 5th centile) ([Figs. 1],[2],[3]), while the right tibia (30 mm) and fibula (30.7 mm) measured at the 50th centile. Biparietal diameter and abdominal circumference were appropriate for gestation. No facial dysmorphism or additional structural anomalies were identified.

Fig. 1 Ultrasound image of bilateral lower limbs showing discrepancy.

Fig. 2 Centiles of measured extremities.

Fig. 3 Centiles of measured extremities.

Differential diagnoses included skeletal dysplasia, isolated limb length discrepancy (LLD), congenital infection, amniotic band syndrome, and vascular insult. After counseling, amniocentesis was performed, and amniotic fluid was sent for clinical exome sequencing (CES) and fluorescence in situ hybridization.

Genetic analysis revealed a likely pathogenic variant not typically linked to skeletal abnormalities. The gene exhibits both autosomal dominant and autosomal recessive inheritance, with variable clinical penetrance ([Fig. 4], [Table 1]). The fetus was heterozygous, making phenotypic expression uncertain. Parental exome testing was not undertaken; had one parent carried the same variant with a normal phenotype, its clinical significance would have been questionable.

Table 1 Possible manifestation of the detected variant

Inheritance
Inheritance	- Autosomal dominant - autosomal recessive
Growth
Subcategory	Features
Height	- Short stature
Weight	- Low weight
Other	- Intrauterine growth retardation - poor growth
Head and neck
Subcategory	Features
Head	- Microcephaly
Face	- Facial dysmorphism (in some patients) - Receding hairline - Triangular face - Long, smooth philtrum - Progeroid appearance (in some recessive patients) - Micrognathia (recessive) - Retrognathia (recessive)
Ears	- Low-set ears (recessive)
Eyes	- Deep-set eyes (recessive) - Strabismus (recessive) - Synophrys (recessive) - Arched eyebrows (recessive) - Upslanting palpebral fissures (recessive) - Prominent epicanthi (recessive) - Rieger anomaly (in one recessive patient)
Nose	- Broad nasal bridge
Mouth	- Thin upper lip - Fleshy lower lip - High-arched palate (recessive) - Small mouth (recessive)
Teeth	- Delayed eruption of dentition (recessive) - Small opalescent teeth (recessive) - Brittle teeth (recessive) - Eroded teeth (recessive)
Neck	- Pterygium colli (recessive)
Cardiovascular
Subcategory	Features
Heart	- Patent foramen ovale (recessive) - Atrial septal defect (recessive) - Ventricular septal defect (recessive)
Vascular	- Narrowing of pulmonary branch arteries (recessive) - Continuation of inferior vena cava to azygos vein (recessive)
Chest
Subcategory	Features
External features	- Pectus excavatum (rare)
Breasts	- Widely spaced nipples (rare)
Skeletal
Subcategory	Features
General	- Delayed bone age
Hands	- Clinodactyly - Short fingers - Small hands
Feet	- Sandal gap (recessive) - Small feet
Skin, nails, and hair
Subcategory	Features
Skin	- Axillary acanthosis nigricans (recessive)
Hair	- Sparse scalp hair (recessive)
Muscle, soft tissues
- Reduced subcutaneous fat (recessive) - Truncal obesity (recessive) - Lipodystrophy (recessive)
Neurologic
Subcategory	Features
Central nervous system	- Delayed motor development - Speech delay - Developmental delay, mild - Global developmental delay - Mental retardation - Underdeveloped cerebral gyri (recessive) - Hypoplastic corpus callosum (recessive)
Behavioral psychiatric manifestations	- Anxious affect - Obsessive tendencies - Agitation
Voice
- High-pitched voice (recessive)
Endocrine features
- Elevated baseline insulin (recessive) - Diabetes mellitus, type 2 (in some heterozygous adults) - Diabetes mellitus, type 1 (in one recessive adolescent patient)

Fig. 4 Clinical exome sequencing (CES) of tested fetus showed IGF1R variant.

A pediatric orthopaedic consultation suggested that the discrepancy could be surgically correctable with a favorable prognosis, though final limb length prediction at maturity was uncertain. Despite this, the couple opted for termination of pregnancy, citing uncertainty, potential need for multiple surgeries, and psychosocial concerns. They declined genetic counseling and parental testing.

Discussion

Congenital limb anomalies occur in approximately 6 per 10,000 live births, more commonly unilateral and affecting the right side.[1] Limb morphogenesis is tightly regulated by HOX, SHH, FGF, and BMP gene families, and disruption in these pathways results in variable phenotypes.[2] Etiologies range from genetic and vascular to environmental factors, though in many cases they remain undetermined.

Prenatal detection largely depends on imaging quality and operator expertise. Ultrasound can identify femoral or humeral shortening as markers of skeletal dysplasia, but isolated lesions present diagnostic challenges. Pajkrt and Chitty reported that fetuses with dysplasia often demonstrate long bone measurements ≥ 5% below expected values.[3]

Recent advances in genomic testing have improved diagnostic yields. Fu et al demonstrated higher detection rates of chromosomal abnormalities in fetuses with multiple malformations than in isolated defects.[4] Copy number variation analysis and whole exome sequencing now provide diagnostic yields up to 70 to 85% for systemic skeletal abnormalities, though localized lesions such as isolated LLD remain poorly characterized.[5] [6]

Previous reports echo similar diagnostic uncertainty. D'Amato et al described a case of congenital unilateral tibial shortening where prognosis depended on orthopaedic correction.[7] Heussel et al reported fibular hemimelia misdiagnosed prenatally as skeletal dysplasia, emphasizing the limitations of imaging-based differentiation.[8] These reports illustrate that genetic testing may not always explain localized skeletal anomalies, and postnatal orthopaedic evaluation often determines prognosis.

In the present case, interpretation was complicated by the uncertain variant significance, heterozygous state, and absence of parental testing. Consultation with a clinical geneticist might have clarified inheritance and recurrence risk. Additionally, while CES expanded the diagnostic scope, it failed to provide definitive reproductive counseling, leaving the couple with unresolved uncertainty.

Ultimately, the decision to continue the pregnancy remains individual. Although orthopaedic correction was feasible, apprehension regarding genetic expression, recurrence risk, and psychosocial burden influenced the parents' choice. This case underscores the need for multidisciplinary coordination among fetal medicine specialists, geneticists, pediatricians, and orthopaedic surgeons to guide families through complex prenatal findings.

Conclusion

Prenatal diagnosis of isolated unilateral LLD presents unique interpretive and counseling challenges. While CES broadens diagnostic possibilities, its uncertain results particularly in the absence of parental studies can complicate decision-making. A coordinated multidisciplinary approach and comprehensive genetic counseling remain essential to support informed parental choices and optimize clinical outcomes.

Conflict of Interest

None declared.

• References

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• 3 Pajkrt E, Chitty LS. A sonographic approach to the diagnosis of skeletal dysplasias. Prenat Diagn 2004; 24: 652-662
• 4 Fu F, Li R, Li Y. et al. Whole exome sequencing as a diagnostic adjunct to clinical testing in fetuses with structural abnormalities. Ultrasound Obstet Gynecol 2018; 51 (04) 493-502
• 5 Chitty LS, Mason S, Barrett AN. et al. Non-invasive prenatal diagnosis of achondroplasia and thanatophoric dysplasia using next-generation sequencing. Prenat Diagn 2015; 35: 656-662
• 6 Yang Y, Muzny DM, Xia F. et al. Molecular findings among patients referred for clinical whole-exome sequencing. JAMA 2014; 312 (18) 1870-1879
• 7 D'Amato CR, Ho NC, Barfield WR. Congenital unilateral tibial shortening: a case report and review of the literature. J Pediatr Orthop 2000; 20: 672-675
• 8 Heussel CP, Kalache KD, Bolz S. et al. Fibular hemimelia: prenatal diagnosis, differential diagnosis, and review of the literature. Ultrasound Obstet Gynecol 2002; 19: 359-364

Publication History

Article published online:
20 January 2026