Prenatal diagnosis of achondroplasia, the most common form of dwarfism, is increasingly prevalent, yet inconsistencies in diagnostic pathways and referral systems persist. While most cases are identified before birth or within the first month of life, a streamlined approach is crucial to optimize prenatal detection rates and ensure timely access to specialized care. This article delves into the current landscape of Achondroplasia Diagnosis In Utero, highlighting the importance of early detection, the methodologies employed, and the pathways necessary for improved patient outcomes and family support.
Current data indicates that prenatal diagnosis of achondroplasia is achieved in a significant majority of cases. A European epidemiological study revealed that approximately 63.4% of achondroplasia diagnoses were made prenatally, with a further 24.1% diagnosed within the first week after birth. This data underscores the effectiveness of current screening methods in identifying achondroplasia early in life. However, variations in antenatal diagnostic procedures highlight the necessity for a more standardized and structured approach to diagnosing and managing cases of achondroplasia before birth. Establishing clear diagnostic and referral pathways is paramount to enhancing prenatal diagnostic rates and ensuring consistent care across different regions and healthcare settings.
Molecular confirmation of achondroplasia, while not always mandatory, plays a vital role in specific scenarios. For instance, when prenatal ultrasound findings strongly suggest achondroplasia and termination of pregnancy is not under consideration, molecular testing might be deemed unnecessary. This is particularly relevant when invasive testing poses a risk of miscarriage, or when parents prefer to forgo prenatal genetic confirmation. However, molecular confirmation becomes invaluable in cases where diagnostic uncertainty exists. If a skilled ultrasonographer identifies clear indicators of achondroplasia through prenatal ultrasound, further imaging or FGFR3 gene testing may not be required. The integration of expert ultrasound assessment and molecular diagnostics provides a robust approach to confirming achondroplasia, and discrepancies in the timing of confirmed diagnoses across different centers may be attributed to variations in these diagnostic approaches.
EAF diagnostic pathway for fetal skeletal dysplasia, emphasizing the crucial steps from routine ultrasound screening to specialist referral for suspected achondroplasia.
Non-invasive prenatal testing (NIPT) has emerged as a significant advancement in prenatal diagnosis. The discovery of cell-free fetal DNA in maternal blood paved the way for NIPT, and as early as 2000, successful prenatal diagnosis of achondroplasia using NIPT was reported. A survey at the European Achondroplasia Forum (EAF) meeting indicated that NIPT for achondroplasia was available to a majority of attendees from various European countries. While NIPT for FGFR3, the gene associated with achondroplasia, is validated in countries like the UK and France, its routine availability and use for single-gene mutations vary across Europe. Currently, there is no universal consensus on recommending NIPT as a standard best practice for achondroplasia diagnosis, highlighting an area for further discussion and potential standardization.
Invasive prenatal molecular diagnosis remains a common practice in many countries. Prenatal molecular diagnosis is widely utilized, but the specific type of molecular test employed can differ. In non-specialist settings, comprehensive prenatal panels might present overwhelming information, potentially leading to confusion due to variants of unknown significance. To mitigate this, specialist centers in regions like Spain, Belgium, and the UK utilize targeted skeletal dysplasia panels, limiting incidental findings. Conversely, centers in France and Portugal often favor targeted variant analysis, reserving skeletal dysplasia panels for cases where the common achondroplasia FGFR3 variant is not initially detected. Targeted single variant testing can offer quicker turnaround times, which is particularly crucial in prenatal scenarios where termination of pregnancy is a consideration. Experts in specialized centers generally agree that single gene variant sequencing is the most efficient method for confirming achondroplasia when clinical suspicion is high. Prenatal molecular confirmation eliminates the need for postnatal genetic testing, streamlining the diagnostic process.
For cases where prenatal diagnosis is not achieved, postnatal clinical and radiological evaluation, followed by genetic testing, are recommended to confirm achondroplasia diagnosis. The EAF has established a diagnostic pathway for achondroplasia, emphasizing routine ultrasound screening at local imaging centers. If concerns arise, referral to specialized fetal medicine units for advanced ultrasound investigation is recommended. Systemic genetic testing for isolated shortened femur findings is discouraged. In cases suggesting skeletal dysplasia, referral to a multidisciplinary team (MDT) specializing in skeletal dysplasia diagnosis and management is essential. Expert ultrasonographers can identify specific antenatal indicators of achondroplasia, allowing for targeted gene testing to confirm the diagnosis.
Post-diagnosis, a clear referral pathway to expert centers is crucial, yet often lacking at national and European levels. The EAF recognizes substantial variations in achondroplasia management and referral pathways across countries. While proactive communication exists between patient advocacy groups and expert centers, referral pathways can be unclear in some regions, hindering access to specialized care. Establishing a comprehensive directory of centers managing achondroplasia and conducting regular audits of diagnosis and referral times can help identify effective centers and promote early referral. The EURORDIS rare disease survey emphasizes the importance of establishing Centers of Excellence for rare conditions. Creating or recognizing national or regional reference centers dedicated to achondroplasia or skeletal dysplasias should be prioritized where such centers are not yet established. Enhanced collaboration among European centers, potentially through integration within the European Reference Network on Rare Bone Disorders (ERN-BOND), could also prove beneficial.
Post-referral patient journeys vary significantly. A standardized patient journey for individuals with achondroplasia across Europe is absent, as is standardized information provision. The volume of information can overwhelm parents, and initial interactions with multiple MDT members can be daunting. Providing timely and appropriate information, either through centers or patient advocacy groups, is vital. Direct communication, such as a phone call post-referral, can prepare families for their first specialist center visit. Genetic counseling and psychological support should be readily available following an achondroplasia diagnosis. Specialist centers should offer clear information regarding MDT organization and professional roles. The EAF advocates for a clear point of contact within specialist centers and transparent communication of the MDT structure to families. Future development of standardized patient journey information, adaptable to individual centers, is planned to support patients upon referral.
The EAF management principles emphasize immediate referral to experienced physicians upon suspected or confirmed achondroplasia diagnosis, whether prenatal or postnatal, to discuss prognosis and management. However, audits reveal that immediate referral is not consistently practiced, with a significant portion of patients experiencing delays between diagnosis and referral. Factors contributing to referral delays include parents’ preference to postpone specialist center visits until after birth, delivery at local hospitals instead of specialist centers, internal referral processes, and personal or cultural factors. In cases of prenatal diagnosis, the absence of in utero interventions may lead parents to perceive specialist center interaction as non-urgent until after birth. Furthermore, parental grief responses, shock, and denial upon receiving a diagnosis can contribute to delayed referrals. Despite acknowledging these reasons for delay, the EAF strongly advocates for the earliest possible referral to optimize clinical and psychological outcomes for families affected by achondroplasia.
Further research is warranted to investigate the duration of delays between achondroplasia diagnosis and specialist referral. Regular audits of management pathways at individual centers can identify barriers to diagnosis and referral, facilitating the implementation of targeted strategies. These strategies may include enhanced educational support for ultrasonographers, obstetricians, and gynecologists, and training programs to promote early diagnosis and timely referral upon suspicion of achondroplasia.
Limitations of the EAF Steering Committee audit, including a small cohort size and focus on expert centers, should be addressed in future studies. Repeating the audit with a larger cohort, encompassing centers with varying levels of expertise, and refining question wording would provide a more comprehensive understanding of the European landscape of achondroplasia diagnosis and management. This would particularly benefit centers lacking specialized expertise in achondroplasia, ensuring best practices are more widely disseminated and implemented.
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