Tapia et al., Spectrum of faciocardiorenal syndrome GENETIC COUNSELING, Vol. 23,A.J.L. No 1,Brambila 2012, pp 51-56
FACIOCARDIORENAL SYNDROME: A WIDE CLINICAL SPECTRUM? BY A.J.L. BRAMBILA TAPIA 1,2, A.I. VÁSQUEZ VELÁSQUEZ 2, M.G. GONZÁLEZ MERCADO 1,2, A. MACÍAS CHUMACERA 3, B.E. GUTIÉRREZ-AMAVIZCA 1,2, R.A. LARA AGUILAR 1,2, R. PÉREZ JUÁREZ CANTÓN 2, A. MORENO ANDRADE 2, AND L.E. FIGUERA 1,2. Summary: Faciocardiorenal syndrome: a wide clinical spectrum?: Faciocardiorenal syndrome (FCRS), also named Eastman-Bixler syndrome, is an apparent autosomal recessive entity, characterized by endocardial fibroelastosis, unusual facial appearance, renal defects and mental retardation. We report a 7 months male patient, with the diagnosis of endocardial fibroelastosis, an abnormal facial appearance (arched eyebrows, broad nasal root, long philtrum and microretrognathia) and psychomotor delay. Associated anomalies were: plagiocephaly, broad halluces, nail hypoplasia, cryptorchidism, diastasis recti, and adducted thumbs. Focal seizures in the mouth were also observed. The radiographs revealed advanced bone age and metaphyseal widening of femur and tibia. FCRS has an unknown etiology with only three reported cases so far (since 1977). We report a patient with the main features of FCRS but without the renal component, suggesting that this entity can present a wide clinical spectrum. Based on these findings and on the few previously reported cases with a highly variable phenotype when compared with the original report, we suggest that FCRS should be further clinical delineated according to the following leading anomalies: endocardial fibroelastosis, unusual facial appearance and mental retardation, in order to find more cases that allow a wider clinical description and the identification of the genetic defect(s). Key-Words: Faciocardiorenal syndrome – Eastman-Bixler syndrome – Endocardial fibroelastosis.
INTRODUCTION Faciocardiorenal syndrome (FCRS), or Eastman-Bixler syndrome (OMIM 227280), was first described in 1977, by Eastman and Bixler (1), in a family with three affected siblings, as an autosomal recessive entity that included unusual facial appearance: malar hypoplasia, broad nasal root, hypoplastic philtrum, hypodontia, cleft palate, plagiocephaly, prominent and low-set ears, prominent mandible (although Pierre-Robin sequence was also described); heart defects: being endocardial fibroelastosis the typical one, but prolapse of tricuspid valve has also been reported (3), and renal anomalies: the typical anomaly is horseshoe kidneys, although dysplastic kidneys, cyst and pelvicaliceal dilatation have also been found (2). Other physical anomalies considered as a part of the syndrome are: inguinal hernia, cryptorchidism, scoliosis, thumb clinodactyly, syndactyly, symphalangism, broad halluces, hypoplastic nails, multiple nevi
(1) Doctorado en Genética Humana, Instituto de Genética Humana, CUCS, Universidad de Guadalajara, Guadalajara, Jalisco, México. (2) División de Genética, Centro de Investigación Biomédica de Occidente (CIBO), Instituto Mexicano del Seguro Social (IMSS). Guadalajara, Jalisco, México (3) Instituto Nacional de Cardiología “Dr. Ignacio Chávez”, México D.F.
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GENETIC COUNSELING
and severe mental retardation, although Levin et al. reported a child with only language delay (1-3). A case with isolated growth hormone deficiency, with successful response to treatment, was reported. (3). Here, we report a possible case of FCRS with many features of the entity with the exception of the renal defect.
CASE REPORT The patient is a boy of 7 months of age, he was hospitalized in the cardiology department because of respiratory distress. He was the product of the first pregnancy, from apparently healthy and non-consanguineous parents, the mother was 21 and the father 23 years old. During pregnancy the mother had an adequate prenatal control, and only a urinary infection was present during the first trimester. The prenatal echosonography showed microcephaly and nuchal cord; he was obtained by caesarean section (because of the nuchal cord) at 38 weeks of gestation; he presented spontaneous breathing and crying with APGAR score of 7-8. The birth weight was 2730 grs and length was 48 cm. PHYSICAL EXAMINATION
The physical examination at present age (7 months) showed the following somatic measures: weight of 7,200 (Pc 30-40), height of 71 cm (Pc 90-97) and occipitofrontal circumference of 37 cm (Pc -3). Dysmorphic facial findings included: plagiocephaly, wide forehead with prominent metopic suture, arched and thick eyebrows with moderate synophrys, up-slanting palpebral fissures, broad nasal root with bulbous nose (Fig. 1A), large ears, high arched palate, and microretrognathia (Figure 1B). The patient also had the eruption of the medial upper and lower incisors. The neck was short, the thorax normal and diastasis recti was present. The hands showed apparently long fingers with adducted thumbs, bilateral clinodactyly of fifth fingers, and hypoplastic nails (Fig. 1C). Bilateral cryptorchidism was present with both testes in the inguinal canal. He had broad halluces with clinodactyly and hypoplastic toe nails (Fig. 1D). At this age, he was not able to gaze and turned his eyes constantly, he was also unable to hold his head. He presented around 3-4 spasms daily, localized in the mouth, with an approximate duration of 1 minute. LABORATORY STUDIES
An echocardiogram showed a hypertrophic and dilated left ventricle, 52
A.J.L. Brambila Tapia et al., Spectrum of faciocardiorenal syndrome
Figure 1: A) The patient face showing a prominent metopic suture, with upslanting palpebral fissures, arched eyebrows, long philtrum, retrognathia and short neck. B) The patients profile showing large and normal implanted ears without malformations. C) Patient´s hand showing adducted thumb, long fingers, fifth finger clinodactyly and hypoplastic nails. D) Broad halluces clinodactyly and nail hypoplasia.
with involvement of lateral wall, anterolateral and apical hypokinesia that affects the global systolic function. A thorax radiograph showed enlargement of the cardiac silhouette. These findings are compatible with endocardial fibroelastosis. Abdomen tomography was normal; the absence of renal anomalies was confirmed with renal echosonography. A cranial magnetic resonance imaging (MRI) showed cerebral tissue agenesis with a left congenital veil that segments part of the left ventricle. Orthopantomography was not performed because of the young age of the proband. An X-ray survey revealed a 1 year-old bone age, and metaphyseal widening of femur and tibia; the skull radiograph confirmed plagiocephaly. Metabolic screening was normal. In order to exclude Pompe disease, the acid alpha glucosidase activity was performed, with normal values. 53
GENETIC COUNSELING
The karyotype, at about 500 band level, showed a normal 46,XY karyotype.
DISCUSSION The reported patient presents the main clinical features of FCRS. The presence of the typical cardiac anomaly, together with facial appearance and severe mental retardation as major features, along with the presence of other minor but rare anomalies, including broad halluces and nail hypoplasia, in addition to other not so rare features such as palgiocephaly and cryptorchidism, makes this syndrome the most probable diagnosis, although the renal component is absent (Table I). Other features not reported previously but present in this case are: microcephaly, diastasis recti, seizures, adducted thumb, advanced bone age and metaphyseal widening of femur and tibia. The advanced bone age is consistent with the patient length at the upper limits (pc90-97) that has not been reported previously. The brain malformations detected in this patient could also be present in the other cases reported; nevertheless, they did not report any cranium tomography or MRI. The main differential diagnosis, according to the rarest syndrome feature (endocardial fibroelastosis), are listed in Table II, and it is evident that none of them is as consistent with our patient as FCRS. So far, only 3 cases of FCRS, including the original one, have been reported, with some phenotypical variations compared with the first report including the heart defect, the facial appearance, the renal malformation and the degree of mental retardation (Table I). It is a small number of cases considering the time since it was discovered. This lack of reports, together with the wide clinical variability of the leading and other minor anomalies, included in the syndrome, is the probable explanation why the syndrome is underdiagnosed and the renal defect may or not be present, and still be part of the same genetic entity. Although the syndrome is more probable to be inherited as an autosomal recessive, de novo autosomal dominant mutations cannot be excluded. So far, the genetic defect is unknown, although Martinet et al. (2) reported a female fetus with a double apparently balanced translocation, karyotype: 46,XX t(17;20)(q21.1;p11.21)mat, t(17;20)(q21.1;p11.21), in a product of first cousins parents; the translocation does not ensure that the genetic defect could be in these breakpoints. Nevertheless, no suggestive genes of FCRS were found at these breakpoints (2). Considering the FCRS as a wide clinical spectrum, and according to our findings; we propose as main features of the syndrome: the unusual facial appearance, the cardiac defect (endocardial fibroelastosis) and 54
A.J.L. Brambila Tapia et al., Spectrum of faciocardiorenal syndrome
Table I: Faciocardiorenal syndrome features shared by this case and by the other 2 previously reported Feature
Eastman and Bixler (1)
Nevin et al. (3)
Martinet et al. (2)
This case
Total
Number of cases (gender)
3 (M, M F)
1 (M)
1(F)
1(M)
4M/3F
Plagiocephaly
3/3
+
-
+
5/6 (83)
Malar hypoplasia
3/3
+
-
-
4/6 (67)
Hypoplastic philtrum
3/3
+
-
-
4/6 (67)
Micrognathia
3/3
+
+
+
6/6 (100)
Stiff prominent pinnae
3/3
-
-
-
3/6 (50)
Microtia
1/3
-
-
-
1/6 (17)
Broad nasal root
3/3
+
-
+
5/6 (83)
Cleft palate
1/3
-
+
-
2/6 (33)
Hypodontia
2/3
+
?
?
3/4 (75)
Endocardial fibroelastosis/ other heart defect
3/3
-/+
+
+
5/6 (83)
Cryptorchidism
1/3
+
*
+
3/4 (75)
Horseshoe kidney
3/3
+
-
-
4/6 (67)
Hydroureters
-
+
-
1/6 (17)
Scoliosis
1/3
-
-
-
1/6 (17)
Thumb clinodactyly
1/3
-
-
+
2/6 (33)
Syndactyly (3-4 finger)
2/3
-
-
-
2/6 (33)
Symphalangism
1/3
-
-
-
1/6 (17)
Broad halluces
2/3
-
-
+
3/6 (50)
Syndactyly (2-3 toe)
1/3
-
-
-
1/6 (17)
Multiple nevi
2/3
-
?
-
2/5 (40)
Hypoplastic nail
2/3
-
?
+
3/5 (60)
Decreased muscle mass
3/3
-
-
-
3/6 (50)
Mental retardation, severe
3/3
mild
?
+
4/5 (80)
* Not applicable
the severe mental retardation, which remain constant with the originally reported cases (1) and are the most frequent characteristics of the syndrome (Table I). We suggest that FCRS needs to be further delineated according to the main features previously described in order to find more cases that allow an appropriate diagnosis as well as the identification of the molecular basis of the disease. 55
GENETIC COUNSELING
Table II: Possible diagnosis according endocardial fibroelastosis
Syndrome
Clinical features
OMIM
Inheritance
X-linked endocardial fibroelastosis
Thick endocardium, endocardial fi- 305300 broelastosis, left ventricular hypertrophy
X-linked
Endocardial fibroelastosis EFE
Endocardial fibroelastosis, cardiomy- 226000 opathy, unusual facial appearance, hypothalamic dysfunction, cryptorchidism
AR Heterogeneous
HEC syndrome
Communicating hydrocephalus, endo- 600559 cardial fibroelastosis, congenital cataracts, polyhydramnios
Genetic vs viral
Ulnar agenesis and endocardial fibroelastosis
Endocardial fibroelastosis, absent ul- 276822 nae, oligodactyly, hydrops fetalis, neonatal death
AR ?
Endocardial fibroelastosis and coarctation of abdominal aorta
Mitral regurgitation, cardiomyopathy, 226100 endocardial fibroelastosis, coarctation of abdominal aorta
AR
REFERENCES 1. EASTMAN J.R., BIXLER D.: Facio-cardio-renal syndrome: a newly delineated recessive disorder. Clin. Genet., 1977,11, 424-430. 2. MARTINET D., VIAL Y., THONNEY F., BECKMANN J.S., MEAGHER-VILLEMURE K., UNGER S.: Fetus with two identical reciprocal translocations: description of a rare complication of consanguinity. Am. J. Med. Genet. A., 2006, 140, 769-774. 3. NEVIN N.C., HILL A.E., CARSON D.J.: Facio-cardio-renal (Eastman-Bixler) syndrome. Am. J. Med. Genet., 1991, 40, 31-33 4. Online Mendelian Inheritance in Man, OMIM (TM): Mckusick-Nathans Institute for Genetic Medicine, Johns Hopkins University (Baltimore, MD) and Na-
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tional Center of Biotechnology Information, National Library of Medicine (Bethesda, MD), April 25. 2011. World Wide Web URL: http://www.ncbi.nlm. nih.gov/omim/ ADDRESS FOR CORRESPONDENCE: Luis E. Figuera División de Genética, CIBO-IMSS Sierra Mojada #800 Colonia Independencia, Guadalajara Jalisco, CP 44100 México AP: Postal 1-3838 Tel.: (+52-33) 36-17-00-60, ext. 31930; Fax: (+52-33) 36-18-17-56 E-mail:
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