Femoral hypoplasia-unusual facies syndrome (FH-UFS), is also known as femoral-facial syndrome. The main findings are micrognathia associated with femoral agenesis or hypoplasia of different degrees. Its pathogenesis is unknown. The prenatal diagnosis is possible also in the first trimester of pregnancy. It has been associated with insulindependent diabetes mellitus during pregnancy, where early ultrasound scan diagnosis would be beneficial given its prognosis.

A 39-year-old woman, with a previous miscarriage, was referred to the present unit at 12 weeks of gestation for fetal micrognathia. She had type-2 diabetes with a 17-year disease course and obesity with a body mass index of 32. The family history was unremarkable. Pregnancy was achieved spontaneously without preconceptional care. On week 9 of her pregnancy, her blood level of glycosylated hemoglobin was 11.6% (HBA1c) in laboratory tests was assessed on week 9 of pregnancy. The first-trimester screening ultrasound study revealed a female fetus with marked micrognathia and low-set ears (Figure 1A); the nuchal translucency was 1.5 mm and other anatomical findings were unremarkable. Laboratory results showed βhCG level of 0.3 MoM and PAPP-A level of 0.5 MoM. A chorionic villous sample was performed and the study showed a normal fetal karyotype, 46 XX.

Figure 1.

— Micrognathia. A: 3D reconstruction of the micrognatia and the low set ears in the first trimester. B and C: Micrognathia at 22 weeks.

The patient failed to attend pregnancy control visits and ultrasound studies planned for weeks 16 and 20-22. She returned on week 22+4 of pregnancy for an ultrasound study, which showed severe fetal micrognathia (Figures 1B, C) and right femur agenesis. The left femur was difficult to examine, although it seemed to be hypoplasic (13 mm); the remaining of the long bones were normal (Figures 2A and B).

Figure 2.

— A: 22 weeks, fetal pelvis with female external genitalia (short arrow) and no visualization of bilateral fetal femur (long arrow). B: 3D reconstruction of the fetal limbs, bilateral absent of thighs, and both femurs. C: Sacral hemivertebra. D, E: sacral skin defect and 3D reconstruction.

Feet were normal, except for both fifth toes, which was in a wrong position towards the external side. A sacral hemivertebra was observed at the S3-S4 level, associated with a skin defect at that level, without neural tube defects (Figures 2C-E). All other anatomical findings were normal. Femoral hypoplasia-unusual facies syndrome was diagnosed. The patient decided to proceed with legal termination of pregnancy. Fetal postmortem anatomopathological and X-ray studies confirmed agenesis of the right femur and severe hypoplasia of the left femur, presence of only three sacral vertebrae including one hemivertebra in the S2-S3 segment, micrognathia, low-set ears, and a sacral bone profusion, which appeared like a truncated spine associated with partial caudal regression syndrome (Figure 3).

Figure 3.

— Postnatal findings. The fetus presented micrognathia, thin upper lip, short nose with broad tip, upstanding palpebral fissures (A), absent thigh (B), skin defect with a bone protrusion (C). Fetal X-ray: micrognathia and absent bilateral femurs, sacral hemivertebra with only three sacral vertebrae.

FH-UFS (OMIM 134780), also known as femoral-facial syndrome, is an extremely rare entity[1].

Its main characteristics are: micrognathia associated with unilateral or bilateral femoral hypoplasia or aplasia of different degrees. This deficiency occurs in 0.1-0.2/10,000 births with the bilateral form corresponding to only 10- 15% of cases [2].

Is a rare anomaly syndrome of unknown etiology, although it is known to be associated with maternal type 1 diabetes mellitus [3]. Insulin dependent diabetic mothers are known to have two- to three-fold higher risk of congenital anomalies than the general population [4, 5].

In most cases of FH-UFS, the type of inheritance is sporadic, although cases of family background have been described with dominant autosomal inheritance [6, 7]. Recently, the duplication 22q37.2 has been proposed as a genetic cause for the femur phenotype in a girl affected by FH-USFS, but only one case is reported in the literature [8]. Other contributing factors described are exposure to drugs (thalidomide), viral infections, radiation, and focal ischemia or trauma [1, 2] as well as severe fetal constraint secondary to oligohydramnios [9].

A review of the literature in PubMed database for prenatally diagnosed cases with absent or hypoplasic femur and micrognathia, or characteristic facial findings of this condition was performed.

Micrognathia and shortened femur can be demonstrated by ultrasonographic imaging in early stage of pregnancy (Table 1). Thirteen cases are published prenatally and only three cases have been reported in the first trimester [10, 12, 17].

The present authors propose that it is important to perform early ultrasound imaging studies to diabetic pregnant women, due to the increased risk of fetal malformations. In the present case, even when micrognathia was found in the first-trimester ultrasound study, femoral hypoplasia was not detected that early.

Prenatal diagnosis is possible but generally, only the femoral defect is detected and most cases are diagnosed postnatally [17-29].

The associated facial dysmorphism include: micrognathia, cleft lip and cleft palate, small nose with a broad tip, long philtrum, thin upper lip, and upslanting palpebral fissures. Other associated are detailed in Table 2. This is the third reported case of prenatal finding of a hemivertebra associated with this syndrome.

The use of 3D ultrasound imaging could enhance the diagnostic capacity of ultrasonography for minor facial dimorphisms such as epicanthus, short nose with a wide tip, pronounced lip philtrum or thin upper lip.

Differential diagnosis include: anophthalmia syndrome, focal femoral dysplasia, femur-tibia-fibula syndrome, caudal regression syndrome, campomelic dysplasia kypomelic dysplasia, and Antley Bixler syndrome and are detailed in Table 3.

The authors thank Marta Pakovich for the contribution of the pictures. Pathology Department of the Complejo Hospitalario Universitario Insular Materno Infantil de Canarias.