Bilateral short legs and rotation of both feet
The left and right femur were not recognized
The left fibula and left tibia seemed to be absent
The right tibia and right fibula were measured with difficulty. The upper extremities were seen with difficulty.
The brain was also abnormal. The posterior fossa was normal. A large arachnoid cyst was diagnosed.
The thalami were present and not fused
The spine was distorsed
The face profile was abnormal with severe retrognathia
The ears were also abnormal
The study of the heart anatomy revealed a mesocardia
The left kidney was not seen and the bladder was small
There was polyhydramnios, but the stomach was seen.
A left abdominal hernia
After the parents were counseled, they decided to interrupt the pregnancy at 31 weeks. Pathological examination confirmed the diagnosis. The gross examination revealed a male fetus (weighing 1300g) with abnormalities including shortened lower extremities, bilateral clubfeet, micrognathia, a long philtrum, a thin upper lip and short nose.
Postmortem radiographs showed complete absence of the femur, tibia and fibulae on the left and absence of the femur on the right. There was no evidence of spina bifida. The fetal karyotype was normal (46 XY). Autopsy was accepted by the parents. The brain anomaly confirmed to be an arachnoid cyst. The skeletal anomalies were confirmed. There was left abdominal eventration.
Note the anechoic cyst
The abdominal hernia and the irregular appearance of the vertebrae
3D of the face showing the micrognathia
Postmortem skeletal radiograph at day one confirming bilateral femoral agenesis and absence of left fibula and tibia.
Postnatal pictures. Note the micrognatia and the abnormal ears
Definition: Femoral hypoplasia-unusual facies syndrome (FH-UFS) or Femoral-Facial Syndrome (FFS) is characterized by femoral hypoplasia and a distinct facies, including upturned nose with a broad tip, elongated philtrum, thin upper lip and micrognathia.
History: Femoral-Facial Syndrome has been underestimated in the obstetrical literature (1-2-3). Franz and O’Rahilly reported the first case in 1961 (3) but it was not described as a distinct syndrome until 1975 when Daentl et al. reported their cases (4).
Prevalence: The prevalence and the recurrence risk are unknown. Females are more commonly affected than males. While most reported cases have been sporadic, Lampert reported a case of father and daughter with Femoral-Facial Syndrome (1980), suggesting, an autosomal dominant inheritance (3).
Etiology: The etiology is unknown but maternal diabetes has frequently been reported (4). Indeed one third of reported cases have occurred in infants of diabetic mothers (3) as compared to 16% in the commonly considered caudal regression syndrome (5).
Pathogenesis: The pathogenesis is multifactorial and it has been suggested that a disruption of normal carbohydrate homeostasis at a critical point of embryogenesis may be important in the development of Femoral-Facial Syndrome as well in the development of Caudal Regression Syndrome (4). Indeed, in humans, limb buds grow and differentiate during the 4th and 8th weeks of gestation.
Inadequate control of maternal diabetes mellitus (particularly hyperglycemia) and viral infection, irradiation, focal ischemia or drug exposure during this early critical embryonic phase, may account for the subsequent developmental anomalies (6). Although most cases are usually unexplained, the degree and pattern of malformations in Femoral-Facial Syndrome clearly reflect an insult occurring during early embryogenesis before the 7th weeks of gestation (6). Landauer in the 1940’s showed that some anomalies similar to those of Femoral-Facial Syndrome could be induced in chickens by injections of insulin into the yolk sac (3). The timing of the insult was also important since injections performed in early embryological period produced anomalies similar to Caudal Regression Syndrome while those performed a little bit later produced anomalies related to Femoral-Facial Syndrome. However in humans, maternal insulin does not cross the placenta and fetal insulin is not detectable until 10 weeks of gestation, which is after this critical period of embryologic long bone formation. This raises the possibility of maternal hyperglycemia being a teratogenic factor in Femoral-Facial Syndrome (7-8).
Sonographic Findings: The important criteria for diagnosis of Femoral-Facial Syndrome include significant femoral hypoplasia and at least two of the following four facial features:
Nevertheless other malformations may be present, including skeletal defects and visceral abnormalities (9-10). The list of associated anomalies is long and includes hypoplasia or absence fibulas, dysplasia of the hips, clubfeet, shortening of humeri, and restricted motion of elbows, lower spine abnormalities and posterior tapering of the ribs.
Associated Anomalies: A review of the literature in 1993 disclosed 55 previously published cases, none of them were diagnosed prenatally (7). Tadmor in 1993 described the first antenatal diagnosis of Femoral-Facial Syndrome (9). Since then few cases have been reported (3-5-6-7-10). In 1997, Gillerot et al. reported a case of Femoral-Facial Syndrome with anomalies in the central nervous system that died at four hours of life (heterotopia of the brain, partial agenesis of the corpus callosum) (7). Leal described another case with colpocephaly, partial agenesis of corpus callosum, hypoplasia of the falx cerebri and absent septum pellucidum (4).
Differential Diagnosis: The main differential diagnosis to be considered in our fetus includes Caudal Regression Syndrome or aneuploidy. The differentiation between Femoral-Facial Syndrome from Caudal Regression Syndrome (both of them have been associated with maternal diabetes) may be difficult since they have overlapping features (8). According to some authors, Femoral-Facial Syndrome may be classified as a form of Caudal Regression Syndrome and not as a separate entity. The features recognized only in the Femoral-Facial Syndrome are essentially the facial characteristics.
Caudal Regression Syndrome is characterized by structural abnormalities of the caudal end adherent structure due to a disruption in the caudal portion of the neural tube early in pregnancy (agenesis or dysgenesis of the sacrum, abnormal vertebral bodies of the lumbar spine, pelvic deformities). Femoral hypoplasia, club feet, flexion contractures of the lower extremities and decreased movements of the lower extremities are possible. Renal, gastro-intestinal and genital anomalies can be associated. The differentiation between Femoral-Facial Syndrome and Caudal Regression Syndrome can also be made if facial and upper extremity abnormalities are detected. The patients with Caudal Regression Syndrome often suffer from extensive neurologic, orthopedic and urologic disabilities (8).
Another differential diagnosis include thanatophoric dysplasia, achondrogenesis and achondroplasia.
Femur Fibula Ulna syndrome is an asymmetrical abnormality of upper and lower limbs, including hypoplasia and aplasia of the femur and fibula, absence of fingers or arms, para-axial hemimelia of the ulna and fibula of the humerus (12-13-14). However, the facies is normal. Camptomelic dysplasia is characterized by abnormal curvature of the long bones, mimicking fractures particularly of the lower extremities such as femur and tibia. Other features are micrognathia, hypertelorism, cleft palate, short ribs, bell-shaped thorax, absence or hypoplasia of the fibula and scapulae (15).
Management: The prognosis of Femoral-Facial Syndrome is related to complications due to physical limitations. Infants with the disease have normal intelligence (8). Most complications arise from small stature and limited function of the lower limbs. Problems with feeding and speech development may also arise due to facial abnormalities. Other complications as recurrent urinary tract infection and incontinence have also been reported (6). However, in cases without serious complications, the life span is usually normal. Nevertheless when detected before viability, the option of termination of pregnancy should be offered.
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