A Case of Fibular Aplasia-Tibial Campomelia-Oligosyndactyly (FATCO) Syndrome Associated With Split Hand/Foot Syndrome With Long Bone Deficiency (SHFLD) and Review of the Literature

Split hand/foot malformation is a heterogeneous congenital disorder mainly presented with a median cleft of hands or/and feet. It can be associated with long bone aplasia, a syndrome also known as split hand/foot syndrome with long bone deficiency (SHFLD), which is a very rare condition. We report a very rare case of a male fetus with SHFLD syndrome combined with fibular aplasia, tibial campomelia, and oligosyndactyly (FATCO) syndrome. FATCO syndrome is also an extremely infrequent congenital limb defect by itself. Based on our review of the literature, there appears to be no other FATCO case reported in Greece.


Introduction
Congenital limb anomalies are common skeletal birth defects, affecting one in 1,000 births [1], with anomalies in upper limbs clearly dominating [2].It has been estimated that over 15% of all limb defects concern the split-hand foot malformation (SHFM), a congenital distal limb absence mainly observed in the central rays of hands and/or foot [3,4].
In the literature, SHFM has been also described as "ectrodactyly", "cleft hand", "lobster claw hand", "crab claw hand" and "symbrachydactyly" [5].The incidence of SHFM is one in 18,000 newborns.Among those, 80% present with only a single abnormal limb, mainly affecting the upper limbs [6,7].SHFM demonstrates a wide heterogeneity in clinical severity, even among different limbs of an individual, and generally is shown in an asymmetric pattern between left and right limbs [8].
The typical type is defined by the absence of the central rays resulting in a cleft appearance, but also oligodactyly, monodactyly, syndactyly, camptodactyly, clinodactyly, metacarpal or metatarsal, and phalangeal aplasia can occur [3,4,9].This rare condition can be non-syndromic, mostly associated with autosomal dominant inheritance with variable expressivity and reduced penetrance [8], or part of a syndrome involving other extra-limb abnormalities [9], as more than 50 syndromes have been associated with SHFM [10].The most frequent SHFM-associated syndromes are ectrodactyly-ectodermal dysplasia-cleft lip and palate (EEC), acro-derma-to-ungual-lacrimal-tooth (ADULT), lacrimo-auriculo-dento-digital (LADD), and limb-mammary syndrome [3,4].SHFM associated with long bone deficiency has been termed the split hand/foot syndrome with long bone deficiency (SHFLD) syndrome, an extremely rare defect occurring in one in 1,000,000 newborns [11].In this condition, SHFM is almost always accompanied by tibial aplasia or hypoplasia and generally an intact fibula.Less frequent long bone anomalies concern defects of the femur and ulnae [10,12,13].
On the other hand, fibular aplasia-tibial campomelia-oligosyndactyly (FATCO) syndrome was first described by Hetch et al. in 1981 [14].Since then, only a few cases have been reported in the literature as fibular aplasia, tibial campomelia, and oligosyndactyly [15].
In this study, we report the postnatal findings in a fetus 21+6 weeks after elective termination of pregnancy due to multiple limb anomalies and we summarize the literature concerning these uncommon conditions.
A 36-year-old healthy Caucasian primigravida with no exposure to radiation or drug intake, requested a pregnancy termination at 22 weeks after the second-trimester scan, as the fetus was diagnosed with upper and lower limb abnormalities.The parents were nonconsanguineous and family history was referred unremarkable.The fetus was delivered at the Laboratory of Histology-Embryology of Democritus University of Thrace (DUTH), Greece, and clinical examination and X-ray were performed to establish the diagnosis.
Fetal autopsy in upper limbs revealed bilateral split hand malformation with an asymmetric pattern in leftright abnormalities.Absence of both thumbs and bilateral oligosyndactyly were observed.Ectrodactyly of the right hand involved the absence of two digits (thumb and fifth) resulting in a median cleft and soft tissue syndactyly of second and third digits.On the left hand, the thumb and a central digit were missed, whereas the fifth digit was present but dysmorphic and hypoplastic (Figure 1).Clinical examination of the lower limbs showed shortening of the right limb, anterior bowing in the right tibia with skin dimpling, bilateral oligodactyly, and bilateral cutaneous incomplete syndactyly (Figure 1).Radiographic evaluation of upper limbs revealed missing metacarpal bones and digits, bilaterally.Ulnae hypoplasia was detected on the left limb.On the right hand, two metacarpals and three proximal and three distal phalanges were observed.The left hand comprised two metacarpals and two phalanges (Figure 2A).Xray examination of lower limbs showed skeletal malformation on the right side with complete fibular aplasia.The presence of campomelic and shortened right tibia was also confirmed.On each foot, four metatarsal bones and four well-formed digits were observed (Figure 2B).No other anomalies of the spine, pelvis, or skull were detected.External genitalia were normal.No facial malformations or other external abnormalities were detected.Karyotype analysis revealed a normal male karyotype (46, XY).

Discussion
In this report, we presented a case of a male fetus with both FATCO and SHFLD syndromes present.To the best of our knowledge, till date, this is the first report of a case with the coexistence of these two extremely rare syndromes in the literature.
SHFLD is defined by the presence of upper or lower limb ectrodactyly and long bone defects.As previously reported, SHFLD is mainly associated with tibial aplasia or hypoplasia [12,16] and ectrodactyly phenotype may show significant heterogeneity, as presented in Figure 3.  Image Credit: Vaya Karapepera SHFLD cases with defective femur, ulnae, or radius have also been reported [13,17,18].To the best of our knowledge, no reported SHFLD case with tibial campomelia has been recorded in the literature [9,16,19].Furthermore, a common locus for SHFLD is that it rarely affects the fibula [12].These findings played a major role in leading us to strongly believe that in this case, two separate clinical syndromes coexist.
The most common long bone agenesis is considered to be fibular aplasia [20], which can occur besides FATCO syndrome, in other conditions like femur-fibula-ulna (FFU) syndrome, Furhmann syndrome, Du Pan syndrome, and thrombocytopenia-absent radius (TAR) syndrome [1].The main diagnostic finding that can differentiate FATCO syndrome from other fibula-related entities is the absence of femoral and radial defects [21].In particular, Furhmann syndrome which has been already presented in the literature to overlap with FATCO syndrome [22], in this case, was ab initio excluded by the confirmation of the straight femora.Normal femora should also rule out the diagnosis of FFU syndrome [1].Fibular aplasia with ectrodactyly has been considered by some as the clinical entity that should include FATCO syndrome [23], but in the literature, there is no agreement [22,12].Isik et al. recently suggested that ectrodactyly with fibular aplasia and no additional findings should be considered as FATCO syndrome [24].However, as the etiology of FATCO remains unclear, the vast majority of cases demonstrating the clinical triad of fibular aplasia, tibial campomelia, and oligosyndactyly are considered FATCO syndrome [1,11,22,24].
It is suggested that the diagnosis of FATCO syndrome should initially be based on abnormalities of lower limbs.Then, all associated syndromes should be ruled out based on phenotypic features.Of course, the scenario of overlapping conditions should be kept in mind, as these clinical entities may share a common genetic basis [25].
In general, FATCO syndrome is an extremely rare condition, with less than 30 cases reported worldwide [1,2,26].After a thorough review of the literature [1,2,11,12,14,15,, we found that the total number of cases increases to 46 if FATCO variants are also included (Table 1) [27][28][29].It is noteworthy to clarify that previous studies included some cases demonstrating the characteristics of FATCO syndrome which, however, had been diagnosed as fibular hemimelia [30,31].On the other hand, two cases of Fuhrmann syndrome were presented by Huber et al. in 2003.Regarding these cases, the authors strongly believe that they should be counted as FATCO syndrome because the femora and pelvis were found normal, thus the diagnosis of Fuhrmann syndrome was excluded [32].For this reason, in the newest studies, these incidents were included as FATCO syndrome [11,33,34].

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References  Among all the reported cases, a wide range of variability has been demonstrated [35,36].However, common findings in FATCO syndrome include the tendency to affect the right side, the anterior bowing of the tibia, and the skin dimpling located in the distal third [21], as observed in our case.
Based on our literature search, almost half of FATCO cases have been recorded in Asia with Turkey and India with the majority of cases.Interestingly, cases in which parental consanguinity was declared were also observed in these countries (Table 1) [37][38][39][40][41][42][43][44][45][46][47][48].Based on clinical and radiographical findings, we report here the first case with FATCO syndrome presented in Greece demonstrating the classic triad in lower extremities: fibular aplasia, tibial campomelia, and bilateral oligosyndactyly.Concurrently, the diagnosis of SHFLD was made with the clinical detection of ectrodactyly of upper limbs and the presence of left ulnae hypoplasia on X-ray imaging.
To date, the majority of published FATCO syndrome cases provided clinical data from the postnatal period.
Our study is one of the few that highlights the fetal phenotypic features, aiming to familiarize fetal physicians with this rare condition, as prenatal diagnosis and counseling could be essential in the management of these cases.Taking into account the above-mentioned cases, it seems that our case is the second FATCO case overlapping with another limb syndrome, the first being reported by Abdalla et al. [22], which in this instance involves the upper limbs.
According to the most recent study, the involvement of the upper limb in FATCO syndrome seems to be rare, as only a few cases were recorded with upper limb defects, exclusively located in the hands [11].For that reason, the presence of exhibited unilateral ulnae hypoplasia, which is a finding that had never been associated with FATCO syndrome (Table 1), raised the suspicion in our case that two distinct abnormal entities concurrently exist.Based on previously reported cases, a male preponderance has been established in FATCO syndrome [2] and the sex ratio (male/female), including our case, is now approximately estimated at 2:1 (Table 1).

Conclusions
In this report, we presented an extremely unusual case of a fetus with a phenotype of FATCO syndrome associated with another rare upper limb disorder, SHFLD.To the best of our knowledge and based on the literature search presented, this is the first case with both FATCO syndrome and SHFLD reported.
Considering the high clinical and genetic heterogeneity of these conditions, the diagnosis often seems to be difficult.Our case may contribute to further understanding of these rare conditions.

FIGURE 1 :
FIGURE 1: Post-abortum photograph of fetus showing bilateral ectrodactyly of upper limbs with right lower limb shortening, anterior bowing, and overlying skin dimpling with associated bilateral feet oligosyndactyly.

FIGURE 2 :
FIGURE 2: (A) Fetal X-ray showing bilateral hand malformations and left ulnae hypoplasia; (B) Radiograph of lower limbs showing right fibular aplasia and tibial campomelia with missing metatarsal bones and digits bilaterally.

FIGURE 3 :
FIGURE 3: Schematic representation of various split hand malformations, including our case.

(
A) Dorsal view of bidactylous with thumb and one digit separating by a cleft; (B) Dorsal view of hand with syndactyly and two mild clefts; (C) Dorsal view of split hand with three malformed digits and large cleft extended to the carpometacarpal joint; (D) Absence of the thumb and one digit, median cleft, and syndactyly (right hand of our case); (E) Palmar view of a hand with the absence of the third digit and median cleft; (F) Dorsal view of ectrodactyly with only two digits present separating by a large cleft; (G) Dorsal view of split hand with thumb and two digits; (H) Ectrodactyly with thumb and a central digit absent, hypoplasia of fifth digit, and syndactyly of two central digits (left hand of our case).