Femoral-Facial Syndrome

Description

Femoral-facial syndrome (FFS), also known as femoral hypoplasia-unusual facies syndrome (FHUFS), is a rare and sporadic multiple congenital anomaly syndrome comprising bilateral femoral hypoplasia and characteristic facial features, such as long philtrum, thin upper lip, micrognathia with or without cleft palate, upward-slanting palpebral fissures, and a short nose with broad tip. Other features, such as renal anomalies, are more variable (summary by Nowaczyk et al., 2010).

Clinical Features

Daentl et al. (1975) first called attention to a characteristic syndrome of femoral hypoplasia and unusual facies. The facial features include upslanting palpebral fissures, short nose with broad tip, long philtrum, thin upper lip, micrognathia, and cleft palate. Similarities to the caudal regression syndrome were pointed out by Gleiser et al. (1978). Except for the cases in father and daughter reported by Lampert (1980) and those in infant and maternal great-aunt reported by Kelly (1974), all cases have been sporadic. Of 10 reported cases, all those with the full syndrome (including cleft palate) were female (Burck et al., 1981).

Johnson et al. (1983) reported 3 children with the femoral hypoplasia--unusual facies syndrome who had the characteristic facial pattern of upslanted palpebral fissures, long philtrum with thin upper lip, micrognathia, and hypoplastic alae nasi. The third, an infant girl who died within 24 hours after birth, had cleft lip which distorted some of the other features. She also had a cleft palate, as did 1 of the 2 older boys. All 3 children had ear defects, upper limb involvement, and rib, vertebral, lower limb, and genitourinary tract abnormalities. The infant girl died of lung hypoplasia associated with dysplastic kidneys and widely patent ductus arteriosus (see 607411). All 3 were infants of diabetic mothers, 1 mother having developed overt diabetes in the first trimester of pregnancy. A literature review of 36 reported cases of FH/UFS uncovered 12 individuals who were IDMs (infants of diabetic mothers), establishing a strong relationship. Johnson et al. (1983) suggested multifactorial inheritance and noted some phenotypic similarity of FH/UFS to caudal regression.

Burn et al. (1984) presented a series of 13 patients with bilateral femoral hypoplasia; 6 of them had facial features compatible with the diagnosis of femoral hypoplasia--unusual facies syndrome. One case was attributable to severe fetal constraint secondary to oligohydramnios, 3 were associated with maternal diabetes, as in the cases of Johnson et al. (1983), and 2 were idiopathic. All 13 cases were sporadic.

Sabry et al. (1996) described this syndrome in a male Bedouin baby. The report reemphasized the previously described association of FFS with preaxial polydactyly and suggested that the clinical spectrum could be stretched further to accommodate other unusual traits such as macrophallus and absent tibia.

Luisin et al. (2017) comprehensively reviewed 92 patients (89 from the literature and 3 new patients) with femoral facial syndrome. Both males and females were affected and there was no statistically significant gender difference. The authors stated that apart from 2 familial observations with vertical transmission (Lampert (1980) and Robinow et al., 1995), most cases are sporadic. Maternal diabetes was present in 39 (42.2%) of the cases. The femoral defect was hypoplasia in 72 cases (78.2%), agenesis in 11 (12%), and a combination in 9 (98%). One or more distal limb anomalies were present in 51 cases (55.4%), and additional bone defects were present in 52 cases (56.5%). Vertebral anomalies were recorded in 33 cases (35.9%). In 46 cases (50%), a combination of all 3 following characteristics was observed: short nose, long philtrum, and thin upper lip. The most often associated facial features were micrognathia or retrognathia, ear abnormalities, eyelid abnormalities, and cleft lip or palate. Malformations of internal organs were present in 49 cases (53.3%), and variously affected the genitourinary tract, cardiovascular apparatus, nervous system, gastrointestinal tract, and lungs. Intellectual development was normal in most cases.

Lacarrubba-Flores et al. (2018) reported 14 previously unreported Brazilian patients with femoral-facial syndrome and systematically reviewed the literature. Among 120 previous reported patients with the syndrome, 66 were excluded due to not meeting the inclusion criteria, insufficient data to make the diagnosis, being better aligned with another diagnosis, or being fetuses in the second trimester. Among the 54 remaining patients and their 14 Brazilian patients, femoral hypoplasia was seen in 91.2% and clubfoot was seen in 55.9%. Typical facies included micrognathia (97%), cleft palate (61.8%), and minor dysmorphic features (frontal bossing in 63.6%, short nose in 91.7%, long philtrum in 94.9%, and thin upper lip in 92.3%). Maternal diabetes (preexisting and gestational) was seen in about half (50.8%) of patients. With the exception of 2 patients described in the literature, the syndrome was sporadic. Parental consanguinity was observed in 2 patients in the literature and in 1 Brazilian patient. One of the newly reported Brazilian patients had an unaffected monozygotic twin (zygosity proven by studies of DNA polymorphic markers). No evidence for a monogenic basis was observed.

Diagnosis

Prenatal Diagnosis

Robinow et al. (1995) reported this syndrome in 4 generations with one presumed instance of male-to-male transmission. Fetal micrognathia and short, bowed femora were found on a routine prenatal ultrasonogram. In the proband, at birth, cleft palate and the characteristic facial appearance were thought to confirm the diagnosis of femoral-facial syndrome.

Nowaczyk et al. (2010) presented serial 3-dimensional (3D) sonographic evaluation of 2 unrelated fetuses diagnosed prenatally with femoral-facial syndrome at age 12 and 15 weeks, respectively. Both mothers had poorly controlled type 1 diabetes mellitus. Initial ultrasonography of both fetuses showed micrognathia and short or absent femora, and subsequent imaging showed marked microretrognathia, small mouth, and cleft soft palate. The first patient was delivered at term and had short nose with anteverted nares, narrow mouth, long philtrum, full cheeks, short neck, short proximal arms with absent flexion and extension, humeroradial synostosis, absent right femur, very short left femur, clubfeet with overriding toes, 11 pairs of ribs, and a convex sacrum. The second pregnancy was terminated at 20 weeks' gestation, and the fetus had a small mouth with marked retrognathia and hypoplastic mandible, long philtrum, thin upper vermilion border, and low-set dysplastic ears. There were upper limb contractures, and the legs consisted primarily of tibia and fibula with bilateral clubfeet. Other features included renal hypoplasia, absent uterus and vagina with normal ovaries, bilobed lungs, and hydrocephalus. Radiographs showed humeroradial synostosis, hypoplasia of the femora, and disorganized sacrum. Nowaczyk et al. (2010) also reported an infant born with the disorder whose ultrasound taken at 19 weeks' was reported as 'normal.' Review of the prenatal radiographs showed no diagnostic features in this child. Nowaczyk et al. (2010) noted the difficulties in identifying femoral abnormalities on 2-dimensional (2D) imaging and suggested that 3D imaging is more effective for prenatal diagnosis.

Among 14 previously unreported Brazilian patients with femoral-facial syndrome reported by Lacarrubba-Flores et al. (2018), anomalies on second trimester ultrasound examination were noted in 76.9%, with shortening of the femur being the most commonly observed finding.