Introduction

Femoral facial syndrome is a rare congenital disorder, characterised by anomalies that include bilateral femoral hypoplasia and craniofacial dysmorphism. This disorder was first discovered by Daentt et al in 1975¹ and the exact etiology is unknown, but more common in females with a strong association with maternal diabetes.² While the syndrome is primarily defined by lower limb anomalies such as femoral dysplasia or aplasia, the associated craniofacial manifestations significantly impact the patient’s quality of life. These abnormalities can range from mild to severe and have profound implications for patients, affecting both physical appearance and functional aspects of daily living. The complex interplay between craniofacial and skeletal anomalies in femoral facial syndrome highlights the need for a comprehensive understanding of this syndrome to optimise patient care.

Craniofacial manifestations of femoral and facial syndrome

The craniofacial features associated with Femoral-Facial Syndrome (FFS) contribute significantly to the characteristic appearance of affected newborns including cleft palate, bilateral complete cleft lip, micrognathia, a long philtrum, thin upper lip, short nose with broad tip, upslanting palpebral fissures, low set and poorly formed ears/small or virtually absent ears (microtia/anotia), femoral neck anomaly (coxa vara), and cross sided eyes.

Clinical signs are characterized as very frequent, 80-90%

Micrognathia: It is a condition in which the lower jaw is undersized, sometimes called mandibular hypoplasia. It is one of the hallmark signs of femoral facial syndrome. It may interfere with the child’s feeding, speech and breathing.

Cleft lip and cleft palate: Cleft occurs when tissues in the mouth or lip area are not enough and fail to join together properly. The cleft lip is a split or separation of the two sides of the upper lip and appears as a narrow opening or gap in the skin of the upper lip. This separation often extends beyond the base of the nose and maxilla. The cleft palate is a split or opening in the roof of the mouth, involving the hard palate or the soft palate. The cleft lip and palate are frequently observed clinical manifestations, leading to difficulties with feeding, speech and ear infections.

Clinical signs are characterized as relatively frequent, 20-30%

• Upslanting palpebral fissures: The eyes may appear wider due to an upward slant of the eyelid openings
• Short nose with broad tip: The nasal bridge is often underdeveloped, resulting in a short and broad nasal tip
• Long philtrum and thin upper lip: The vertical groove between the nose and upper lip is typically elongated in femoral facial syndrome. A thin upper lip is another common feature, often accentuating the appearance of the long philtrum
• Microtia/anotia: Low set and poorly formed ears, abnormality of the outer ear. The condition can range from minor structural issues to the complete absence of the external ear, which may or may not accompany hearing loss. Anotia is when the external ear is missing completely

Clinical signs are characterized as less frequent, 5-29%

• Strabismus: Both eyes do not line up in the same direction, also known as “crossed eyes” as they do not look at the same object at the same time

Associated anomalies

• Ear malformations: Conductive hearing loss is often present
• Orbital abnormalities: Hypertelorism, increased spacing between the eyes and proptosis, bulging of the eyes may occur
• Dental anomalies: Missing teeth or malocclusion, are common and can impact oral function and aesthetics
• Craniosynostosis: Premature fusion of the skull bones can occur in some cases, leading to abnormal head shape

Potential etiological factors

The exact cause of femoral facial syndrome is unknown; in most cases it occurs randomly. A genetic factor may be the cause in some patients, but in most cases multiple factors are involved. While most cases occur at random, the reported several affected people are in the same family suggesting autosomal dominant inheritance. Genetic involvement is described by Lampert who describes an affected father and daughter and suggests that femoral facial syndrome may be inherited as an autosomal dominant trait.³ The report of Robinow et al also supports the occasional transmission of the femoral facial syndrome as an autosomal dominant with incomplete penetrance.4 Due to the rare nature of femoral facial syndrome, this disease can also occur spontaneously in families with no known history. It seems to be correlated to maternal diabetes mellitus in about a third of patients.5,6 There also have been links to maternal drug exposures, viral infections, radiation, and oligohydramnios, especially in pregnancy terms.⁷

Embryological basis of craniofacial development: The normal embryological development of the face is crucial for comprehending the pathogenesis of craniofacial abnormalities in femoral facial syndrome. The first and second branchial arches give rise to the face, including the maxilla, mandible and other facial structures. Disruptions in these developmental processes, potentially due to genetic or environmental factors, can lead to the characteristic craniofacial features observed in femoral facial syndrome. Ongoing research efforts are focused on identifying the underlying molecular and genetic mechanisms responsible for FFS.

Reported case studies

Johnson et al reported 3 children with femoral facial syndrome who had the characteristic facial pattern of upslanted palpebral fissures, long philtrum with thin upper lip, and micrognathia. One of the infant girls who died after birth had a cleft lip and other distorted features. A literature review of 36 reported cases, showed 12 individuals who were infants of diabetic mothers, establishing a strong relationship.⁸ Burn et al states that in a series of 13 patients with bilateral femoral hypoplasia, 6 of them had facial features, 3 were associated with maternal diabetes, 2 were idiopathic and one case was due to severe fetal constraint secondary to oligohydramnios.6 Luisin et al literature notes that of the 92 patients reviewed with femoral facial syndrome, apart from 2 familial observations with vertical transmission, maternal diabetes was present in 42.2% of the cases.9 Lacarrubba flores et al reported 14 previously unreported patients with femoral-facial syndrome and systematically reviewed the literature. Among the patients, typical facial abnormalities including micrognathia, were present in 97%, cleft palate was present in 61.8%, and other minor dysmorphic features.¹⁰

Diagnosis

Establishing a definitive diagnosis of Femoral-Facial Syndrome (FFS) often relies on a combination of clinical findings and diagnostic tests, the presence of characteristic lower limb anomalies in conjunction with specific craniofacial features is highly suggestive of femoral facial syndrome.

Key clinical features to assess the syndrome include

• Facial morphology: Facial symmetry, micrognathia, cleft palate, nasal features, and cleft lips
• Oral cavity anomalies: Dental anomalies, palatal structures, and tongue position
• Ear morphology: Ear size, shape and position
• Ocular findings: Hypertelorism, proptosis, and other abnormalities

Radiological investigations

It can provide valuable information about the extent of craniofacial anomalies and associated skeletal abnormalities; 

• Radiographs: To assess mandibular hypoplasia and palate structure.
• Computed tomography (CT): Aiding in the evaluation of craniosynostosis and other complex craniofacial anomalies
• Magnetic resonance imaging (MRI): Assessing soft tissue structures, brain abnormalities, and potential associated anomalies
• Ultrasound examination: It can be detected in utero through ultrasound images that help to see the fetus and can detect skeletal malformations, uplifted cleft, and characteristic low set of ears. Luisin et al states that the prenatal diagnosis via imaging investigation can suggest femoral facial syndrome. Despite advancements in ultrasound, this diagnosis is difficult to make based on defining features in the absence of genetic or biological markers. Thus, the diagnosis is often made after birth⁹

Differential diagnosis

Differentiating femoral facial syndrome from other syndromes with overlapping features is crucial for accurate diagnosis and appropriate management.

Important differential considerations include:

• Treacher Collins syndrome: Characterised by underdevelopment of facial bones, ear anomalies, and cleft palate
• Pierre Robin sequence: Includes micrognathia, cleft palate, and glossoptosis (posteriorly positioned tongue)
• Other craniofacial disorders: Other syndromes may present with similar craniofacial features like cleft lip and palate

Management and treatment

Management of femoral-facial syndrome requires a multidisciplinary approach due to the wide range of affected systems. Surgical intervention is necessary to address craniofacial abnormalities in femoral-facial syndrome like cleft palate repair, mandibular advancements, rhinoplasty, ear reconstruction, and craniosynostosis repair. The determination for surgery was based on the patient's age, severity, and overall health status. Orthodontic treatments play a crucial role in managing malocclusion associated with femoral-facial syndrome. Speech therapy and other tertiary care is essential for patients’ facial abnormalities like cleft lip and palate and associated abnormalities. Individuals with femoral-facial syndrome may experience challenges related to self-esteem and body image, psychological support is needed to develop healthy coping mechanisms.

FAQ’s

Who gets femoral facial syndrome?

Infants are mostly affected.

Who gets affected most, male or female?

There are no sexual differences, both male and female, in fact, all racial and ethnic groups may be affected.

Are there any risk factors for femoral facial syndrome?

Currently, there are no risk factors that are clearly identified.

How common is Femoral facial syndrome?

The femoral facial syndrome is very rare, affecting 0.1-0.2 in every 10,000 children that are born.

Summary

Long-term follow-up is essential to monitor growth and development, address any emerging issues, and evaluate the effectiveness of treatment. Regular assessments by the multidisciplinary team are crucial for optimizing patient outcomes. Increasing public health awareness about craniofacial manifestations by healthcare providers can enhance early diagnosis and provide comprehensive care. Though significant advancements are made in the management of abnormalities, ongoing research is needed to develop novel treatment approaches. Research and collaboration among clinicians and researchers are needed to improve the lives of patients with this rare condition.