Overview

Femoral-facial syndrome (FFS) is a rare condition that manifests as thigh bone underdevelopment (hypoplasia), showing asymmetry between both femurs, and specific face features, but also affects other body structures. The causes are still unclear. Reported cases show a genetic root, and there is a range of disturbances that can lead to that. Mother diabetes during pregnancy can cause genetic alteration, for example.¹ It is diagnosed during pregnancy or right after birth. Individuals usually present characteristic physical features:²

Upward-slanting eyes, short nose with a broad tip, long space between the nose and upper lip (philtrum), thin upper lip, small lower jaw (micrognathia), and cleft palate. Other features of FFS may include defects of the spinal bones (vertebrae), extra fingers or toes (polydactyly), ear defects, genitourinary abnormalities, underdeveloped lungs, abnormal kidney development, and patent ductus arteriosus".²

As femoral-facial syndrome is not a common condition and it manifests in a wide range of symptoms, awareness is important, especially for health professionals. A correct diagnosis can guide proper treatments and follow-ups that provide a better quality of life for the patient.³ 

Background information

Initially named femoral hypoplasia-unusual facies syndrome, it was first described in 1975 by an analysis of four distinct cases. They all presented femoral hypoplasia combined with facial anomalies such as cleft palate, micrognathia and long philtrum. Through the years, reports for new cases added new possible abnormalities to the scope of symptoms like scoliosis, femoral agenesis, urogenital and nervous system malformations. Although individuals with FFS mostly don’t share a causing root, maternal diabetes during pregnancy is one of the few conditions observed in many cases. Its rare occurrence might be the reason behind the difficulty in finding a common cause. Not only that, but FFS probably has multiple causes, making it difficult to pinpoint and establish patterns.^4,5

Reports show a few patients sharing a minor genetic alteration. None of them are the result of maternal diabetes during pregnancy. It indicates that, in the absence of that condition, a genetic alteration can be one of the multiple causes of FFS.⁵

Core phenotypic features

The femoral-facial syndrome can affect many organs and structures, giving it heterogeneous characteristics. A high variety of tissues might be affected and each case can present a different combination of them.³ 

Femoral abnormalities 

Femoral abnormality is one of the key features for the diagnosis of FFS. It manifests as femoral hypoplasia or femoral agenesis.³ Femoral hypoplasia refers to the underdevelopment of the thigh bone. Femoral agenesis describes the condition in which there is no development of the bone. Considering all possibilities, the most common conformation is the femoral hypoplasia on both legs.4 The severity of such abnormalities can range from a mild femoral hypoplasia, with a regular appearance, to a complete lack of bone. It can lead to other musculoskeletal disturbances, affecting hips, knees and other structures.⁶

Facial dysmorphisms 

Alterations in facial structure, or facial dysmorphisms, are the other key points for diagnosing FFS; A variety of facial features are connected to the syndrome and manifest in combination, and a high variability of facial presentations is possible. Most common are:^2,4

• Micrognathia: decreased size of the mandible
• Long philtrum: the region between the upper part of the mouth and the nose is elongated
• Thin upper lip
• Short nose
• Cleft palate: a development defect in the orofacial region

Associated anomalies 

A wide variety of clinical presentations are possible for FFS. The majority of the body’s tissues have been reported to be affected by the syndrome. Besides the classical femoral and facial anomalies, other documented manifestations are:^2,3

Other musculoskeletal anomalies 

• Abnormalities in shape, place or structure of bones like ribs, sacrum, fibula, pelvis, tibia
• Fused forearm bones
• Rib fusion
• Abnormal spine segmentation: vertebras not fully separated

Cardiac

• Great vessel abnormality 
• Ventriculomegaly

Renal

• Polycystic kidney dysplasia
• Renal hypoplasia

Neurological

• Underdevelopment of the corpus callosum, a structure that connects the cerebral hemispheres

Other manifestations

• Foot polydactyly: a malformation in which the individual presents additional fingers
• Abnormal localization of kidneys
• Low-set ears: ears are located below the typical place
• Microtia: underdevelopment of the external structures of the ears
• Scoliosis: abnormal spine curvature
• Sprengel anomaly: abnormal scapula placement, one bone is located elevated
• Strabismus

Variability in phenotypic expression

Since its first reports, each new case has been added to the list of clinical presentations (phenotypic expression). Besides femoral anomalies and facial dysmorphisms, a wide range of symptoms can follow the syndrome. 

Real cases described

Several articles have analyzed and followed patients diagnosed with FFS around the world, contributing to the documentation of cases. Briefly described examples of unrelated patients and how their condition manifested, excluding classic features, are listed below (in no particular order):

• Case 1: Shortened tibia, bony prominence, ankle pain, intellectual disability. Mother presented gestational diabetes³
• Case 2: Ventriculomegaly and tethered cord, a malformation of the spinal cord. Mother presented poorly controlled gestational diabetes⁷
• Case 3: Short neck, disproportionate short limbs, overlapping toes, scapula hypoplasia, cardiovascular anomalies, increased islets of Langerhans (endocrine cells within the pancreas). No apparent family history for FFS. mother presented with gestational diabetes. Stillborn⁸
• Case 4: Pelvic bones and sacral hemivertebrae hypoplasia, significantly increased islets of Langerhans (endocrine cells within the pancreas), reproductive organs malformation. Mother presented gestational diabetes⁸
• Case 5: Short neck, slender fingers, tympanic effusion (fluids in the middle ear), left kidney located near the pelvis instead of near the rib cage. Mother did not present gestational diabetes⁵.
• Case 6: Sacral anomalies. The family had no diagnosis of FFS before, but the majority of members presented to be shorter than average, with normal body proportions. The mother did not present gestational diabetes⁹
• Case 7: Ventriculomegaly, foot malformation, thoracic spine anomalies, hydrocephalus. No apparent family history for FFS. Mother presented gestational diabetes¹⁰
• Case 8: No other significant features other than the typical affected femur and facial dysmorphisms. The mother presented a history of diabetes that was under control during pregnancy¹¹
• Case 9: No other significant features other than the typical affected femur and facial dysmorphisms. Mother presented gestational diabetes¹²
• Case 10: The first report on an adult case of FFS (2022). Esophageal stricture (narrowing of the esophageal tube), adenocarcinoma (a type of gland malignancy), shorter than average, spinal malformations. Mother was a heavy smoker, but It is not known whether gestational diabetes occurred¹³

Summary

The femoral-facial syndrome is a condition that mainly affects thigh bone formation and presents a combination of specific facial features. It can manifest alongside a wide variety of other malformations. Disturbances in numerous other tissues have been reported to happen combined with FFS. Since its first reports, it is observed to be a rare syndrome with multiple causes. The low occurrence makes it difficult to gather information and enrich case comparisons. Analyzing patterns is also an obstacle because of the high heterogeneity in clinical presentations. Although the possible rooting causes for FFS are yet to be elucidated, there is an apparent correlation between cases of the syndrome and mothers presenting gestational diabetes. Follow-up during pregnancy can show the typical signs concerning femur and facial features, enabling early diagnosis. Patients with FFS are usually followed to manage their specific complaints on demand. Interventions, especially surgical, are common to improve quality of life.