Alternative titles; symbols
SNOMEDCT: 719845008; ORPHA: 2460; DO: 0111699;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 22q11.21 | Van den Ende-Gupta syndrome | 600920 | Autosomal recessive | 3 | SCARF2 | 613619 |
A number sign (#) is used with this entry because of evidence that van den Ende-Gupta syndrome (VDEGS) is caused by homozygous mutation in the SCARF2 gene (613619) on chromosome 22q11.
Van den Ende-Gupta syndrome (VDEGS) is an autosomal recessive disorder characterized by severe contractual arachnodactyly from birth and distinctive facial dysmorphism, including triangular face, malar hypoplasia, narrow nose, everted lips, and blepharophimosis. Skeletal anomalies include slender ribs, hooked clavicles, and dislocated radial head. There is no neurologic involvement (summary by Patel et al., 2014).
In a Brazilian girl born of consanguineous parents, van den Ende et al. (1992) described a Marden-Walker-like disorder, which differed from the usual Marden-Walker syndrome (248700) by the absence of microcephaly, mental retardation, muscular hypotonia, failure to thrive, and joint limitation.
Gupta et al. (1995) described a girl of Pakistani origin, also born to consanguineous parents, with a similar multiple congenital anomaly (MCA) syndrome. The hallmarks of the syndrome included characteristic facies with blepharophimosis, narrow and beaked nose, hypoplastic maxilla with or without cleft palate and everted lower lip, arachnodactyly, self-limiting (i.e., gradual improvement without intervention) congenital joint contractures, peculiar skeletal abnormalities, and normal growth and development. Intelligence was normal, and overall prognosis in the syndrome seemed good. Gupta et al. (1995) suggested that their patient and the patient described by van den Ende et al. (1992) had a 'new' autosomal recessive syndrome, which was not accurately represented clinically by the designation 'Marden-Walker-like syndrome without psychomotor retardation.'
Phadke et al. (1998) reported on 2 unrelated Indian girls with blepharophimosis, arachnodactyly, digital contractures that improved spontaneously, elbow deformity, beaked nose, everted lips, and large ears and pointed out the similarities to the cases reported by van den Ende et al. (1992) and Gupta et al. (1995). Consanguinity in 2 of 4 cases with involvement of both males and females suggested autosomal recessive inheritance. Both cases of Phadke et al. (1998) were Hindu.
Bistritzer et al. (1993) reported as possible cases of congenital contractural arachnodactyly (CAA; 121050) 2 double second cousins born to consanguineous Bedouin parents. Both girls had severe contractural arachnodactyly, and one of them also had ambiguous genitalia. Schweitzer et al. (2003) reviewed the report by Bistritzer et al. (1993) and concluded that the girls were the fourth reported cases of what they termed van den Ende-Gupta syndrome (VDEGS).
In the fifth report of this syndrome, Schweitzer et al. (2003) described 2 Hispanic brothers, born to unrelated parents. The features they considered characteristic were blepharophimosis, narrow nose with hypoplastic alae nasi, hypoplastic maxilla, everted lower lip, slender and elongated hands and feet, arachnodactyly, self-limiting joint contractures, and distinctive skeletal findings. The total number of reported cases was brought to 8, derived from 6 families, 3 of which were consanguineous. Similarities of VDEGS to Marden-Walker syndrome include blepharophimosis, arachnodactyly, and congenital contractures, as well as autosomal recessive inheritance. On the other hand, VDEGS lacks severe mental retardation, serious brain malformations, microcephaly, failure to thrive, and severe joint limitation, which are consistently present in Marden-Walker syndrome. Marden-Walker syndrome may be associated with cerebellar malformations such as Dandy-Walker malformation (220200), whereas the brothers reported by Schweitzer et al. (2003) demonstrated distinctive cerebellar enlargement, a feature not previously described in VDEGS.
Carr et al. (2007) reported 2 African American sisters, 2 years and 5 months of age, respectively, who had been diagnosed with VDEGS and who both developed stridor. Examination revealed large, globular cuneiform cartilages, shortened aryepiglottic folds, a tightly coiled epiglottis, and laryngomalacia; both patients were treated successfully with supraglottoplasty. Carr et al. (2007) noted that respiratory distress had also been reported in a 10-month-old Bedouin patient (Bistritzer et al., 1993) prior to her death from cardiac arrest.
Ali et al. (2010) reported 3 male and 3 female patients with VDEGS from 4 consanguineous families, 3 of which belonged to the same highly inbred tribe from Qatar. The affected individuals all had a remarkably similar phenotype, with features in common that included blepharophimosis, narrow nasal bridge with convex nasal ridge, malar hypoplasia, and everted lower lip, and most had a small mouth with limited opening. All also showed contractures of the fingers, limited mobility in the elbows, and long halluces that typically showed distal tapering. Radiologic examination of the 4 patients from the 3 families from the same tribe showed hypoplasia of the facial bones with underdeveloped maxillae, as well as small scapulae, small distal clavicular ends, small radial heads, radioulnar subluxation, and bowing of the femora. Ali et al. (2010) noted that these features are all typical for VDEGS, and that these cases suggested autosomal recessive inheritance.
Patel et al. (2014) reported 3 patients from 2 unrelated consanguineous Saudi families with VDEGS confirmed by genetic analysis. Two teenaged brothers had contractural arachnodactyly, craniosynostosis, and abnormal facial features, including blepharophimosis, malar hypoplasia, narrow nose with deviated septum and pseudocleft of the columella, everted lower lip, high-arched palate, and asymmetric face. Radiographs showed several abnormalities, including small anterior cranial fossa and bowed long bones in both, and slender ribs with a hooked clavicle and dislocated radial head in 1 patient. Other features included nonprogressive hydronephrosis and asthma. A 10-year-old boy from an unrelated Saudi family had typical features of VDEGS.
Odeh et al. (2022) identified 3 sibs (2 females, 1 male) with VDEGS. Features seen in these patients included asymmetrical face, blepharophimosis, hypertelorism, downslanting eyebrows, flat and wide nasal bridge, prominent nasal tip, malar hypoplasia, prominent ears, arachnodactyly, and camptodactyly. Motor and mental development were normal in all 3. Asymmetric narrow nose, crowded teeth, cleft palate, macrocephaly, laryngomalacia, tracheal stenosis, and a curved penis were seen in the affected boy. The authors noted that tracheal stenosis and curved penis had not previously been described in VDEGS.
Hildebrandt et al. (2021) described 7 patients and reviewed 29 previously reported patients with features of VDEGS. Cases were divided into those with identified pathogenic variants in the SCARF2 gene (613619) (15, 42%), those with negative SCARF2 testing (6, 16%), and those not tested (15, 42%). Among those who tested positive for SCARF2 pathogenic variants, over 90% had blepharophimosis, midface hypoplasia, narrow nose, everted lower lip, camptodactyly, and arachnodactyly. Common features seen in 40 to 89% of SCARF2 positive and untested patients included triangular face, micrognathia, palatal anomalies, microstomia, beaked nose, and ear anomaly. None of the patients with SCARF2 pathogenic variants had major congenital heart disease or clinically significant aortic root dilation. Three patients with negative SCARF2 testing were found to have heterozygous pathogenic variants in the ABL1 gene (189980), associated with congenital heart defects and skeletal malformations syndrome (CHDSKM; 617602). Given the overlapping features of VDEGS and CHDSKM, Hildebrandt et al. (2021) recommended that patients with arachnodactyly and blepharophimosis undergo echocardiography while awaiting results of molecular testing.
Anastasio et al. (2010) confirmed autosomal recessive inheritance of van den Ende-Gupta syndrome by the identification of homozygous mutations in patients with the disorder.
Leal and Silva (2009) reported a Brazilian kindred with 3 affected individuals, 2 brothers and their half sister. Because the mother had the affected children with 2 partners, who were both unrelated to her and to each other, the authors suggested that the van den Ende-Gupta syndrome in this family was probably transmitted as an autosomal dominant trait in connection with gonadal mosaicism, although incomplete penetrance could not be ruled out. One of the brothers and the sister had asymmetry of the nose due to deviation of the septum, and the sister also had sensorineural hearing loss; Leal and Silva (2009) stated that neither of these features had previously been described in cases of van den Ende-Gupta syndrome.
In 4 patients with van den Ende-Gupta syndrome from 3 consanguineous Qatari families from the same highly inbred Bedouin tribe, previously studied by Ali et al. (2010), Anastasio et al. (2010) performed homozygosity mapping and identified a single 2.4-Mb homozygous segment on 22q11, between positions 16910984 and 19296457 (NCBI36). The regions of homozygosity were of different sizes in each patient, and the haplotypes in that region were not identical: 2 cousins from 1 family shared a common haplotype, whereas the remaining 2 patients were homozygous for a distinct 1.6-Mb haplotype within their individual homozygous regions, delimited by SNPs rs885988 and rs2075277.
In 4 patients from 3 consanguineous Qatari families with van den Ende-Gupta syndrome, Anastasio et al. (2010) analyzed candidate genes and identified homozygosity for mutations in the SCARF2 gene: a missense mutation in 2 cousins from 1 kindred (613619.0001) and a 2-bp deletion in 2 unrelated patients (613619.0002). In addition to the characteristic features of VDEGS, the 2 cousins had scaphocephaly and partial skin syndactyly of toes 2 and 3; 1 had abnormal development of the proximal radius, with evidence of radioulnar subluxation and no clear demonstration of osseous fusion, whereas the other had a sacral dimple. One of the remaining patients displayed hypoplastic scapulae, clavicles, and ribs, and the other had bilateral renal pelvis dilation on renal ultrasound.
In 3 patients from 2 unrelated consanguineous Saudi families with VDEGS, Patel et al. (2014) identified 2 different homozygous mutations in the SCARF2 gene (613619.0003 and 613619.0004). The mutations segregated with the disorder in the families. Functional studies of the variants were not performed.
In a 23-year-old man with typical features of VDEGS, who also exhibited bilateral sclerocornea and was negative for mutation in genes known to be associated with congenital corneal opacification, Migliavacca et al. (2014) identified homozygosity for a 17-bp deletion in the SCARF2 gene (613619.0005). Noting that sclerocornea had been previously observed in 1 patient with VDEGS (Bedeschi et al., 2010), Migliavacca et al. (2014) suggested that the full VDEGS phenotype may include sclerocornea.
In 3 sibs with VDEGS, who were born to first-cousin Jordanian parents, Odeh et al. (2022) identified a homozygous nonsense mutation in the SCARF2 gene (E74X; 613619.0006). The parents and 3 unaffected sibs were heterozygous for the mutation.
In 3 patients with VDEGS, Hildebrandt et al. (2021) reported homozygosity for mutations in the SCARF2 gene: 2 missense mutations, including one that had previously been reported in a Saudi family (613619.0003), and a 6-bp deletion (613619.0007). The authors also reported 3 patients with features of VDEGS that had heterozygous mutations in the ABL1 gene (189980), consistent with congenital heart defects and skeletal malformations syndrome (CHDSKM; 617602). In addition, 3 patients with features of VDEGS had extensive genetic testing (2 brothers who underwent genome sequencing and targeted long-range sequencing of both SCARF2 and ABL1, and a third who had exome sequencing and RNA sequencing for SCARF2) that was all negative, suggesting genetic heterogeneity.
Ali, R., Almureikhi, M., Al-Musaifri, F., Bhat, V., Teebi, A., Ben-Omran, T. Further delineation of the van den Ende-Gupta syndrome. Am. J. Med. Genet. 152A: 3095-3100, 2010. [PubMed: 21108395] [Full Text: https://doi.org/10.1002/ajmg.a.33725]
Anastasio, N., Ben-Omran, T., Teebi, A., Ha, K. C. H., Lalonde, E., Ali, R., Almureikhi, M., Der Kaloustian, V. M., Liu, J., Rosenblatt, D. S., Majewski, J., Jerome-Majewska, L. A. Mutations in SCARF2 are responsible for van den Ende-Gupta syndrome. Am. J. Hum. Genet. 87: 553-559, 2010. [PubMed: 20887961] [Full Text: https://doi.org/10.1016/j.ajhg.2010.09.005]
Bedeschi, M. F., Colombo, L., Mari, F., Hofmann, K., Rauch, A., Gentilin, B., Renieri, A., Clerici, D. Unmasking of a recessive SCARF2 mutation by a 22q11.12 de novo deletion in a patient with Van den Ende-Gupta syndrome. Molec. Syndromol. 1: 239-245, 2010. [PubMed: 22140376] [Full Text: https://doi.org/10.1159/000328135]
Bistritzer, T., Fried, K., Lahat, E., Dvir, M., Goldberg, M. Congenital contractural arachnodactyly in two double second cousins: possible homozygosity. Clin. Genet. 44: 15-19, 1993. [PubMed: 8403449] [Full Text: https://doi.org/10.1111/j.1399-0004.1993.tb03835.x]
Carr, C. W., Carron, J. D., Lachman, R. S., Abdul-Rahman, O. A. Van Den Ende-Gupta syndrome: laryngeal abnormalities in two siblings. Am. J. Med. Genet. 143A: 2706-2711, 2007. [PubMed: 17937442] [Full Text: https://doi.org/10.1002/ajmg.a.32007]
Gupta, A., Hall, C. M., Ransley, Y. F., Murday, V. A. A new autosomal recessive syndrome of characteristic facies, joint contractures, skeletal abnormalities, and normal development: second report with further clinical delineation. J. Med. Genet. 32: 809-812, 1995. [PubMed: 8558561] [Full Text: https://doi.org/10.1136/jmg.32.10.809]
Hildebrandt, C. C., Patel, N., Graham, J. M., Bamshad, M., Nickerson, D. A., White, J. J., Marvin, C. T., Miller, D. E., University of Washington Center for Mendelian Genomics, Grand, K. L., Sanchez-Lara, P. A., Schweitzer, D., Al-Zaidan, H. I., Al Masseri, Z., Alkuraya, F. S., Lin, A. E. Further delineation of van den Ende-Gupta syndrome: genetic heterogeneity and overlap with congenital heart defects and skeletal malformations syndrome. Am. J. Med. Genet. 185A: 2136-2149, 2021. [PubMed: 33783941] [Full Text: https://doi.org/10.1002/ajmg.a.62194]
Leal, G. F., Silva, E. O. Van den Ende-Gupta syndrome: evidence for genetic heterogeneity. Am. J. Med. Genet. 149A: 1293-1295, 2009. [PubMed: 19449421] [Full Text: https://doi.org/10.1002/ajmg.a.32871]
Migliavacca, M. P., Sobreira, N. L. M., Antonialli, G. P. M., Oliveira, M. M., Melaragno, M. I. S. A., Casteels, I., de Ravel, T., Brunoni, D., Valle, D., Perez, A. B. A. Sclerocornea in a patient with Van Den Ende-Gupta syndrome homozygous for a SCARF2 microdeletion. Am. J. Med. Genet. 164A: 1170-1174, 2014. [PubMed: 24478002] [Full Text: https://doi.org/10.1002/ajmg.a.36425]
Odeh, O., Barqawi, T., Rashid, H., Almashhdi, S., Shboul, M. Identification of a novel variant of SCARF2 in a Jordanian family with a van den Ende-Gupta syndrome and literature review. Clin. Dysmorph. 31: 157-161, 2022. [PubMed: 35256560] [Full Text: https://doi.org/10.1097/MCD.0000000000000415]
Patel, N., Salih, M. A., Alshammari, M. J., Abdulwahhab, F., Adly, N., Alzahrani, F., Elgamal, E. A., El Khashab, H. Y., Al-Qattan, M., Alkuraya, F. S. Expanding the clinical spectrum and allelic heterogeneity in van den Ende-Gupta syndrome. (Letter) Clin. Genet. 85: 492-494, 2014. [PubMed: 23808541] [Full Text: https://doi.org/10.1111/cge.12205]
Phadke, S. R., Gulati, R., Agarwal, S. S. Further delineation of a new (van den Ende-Gupta) syndrome of blepharophimosis, contractural arachnodactyly, and characteristic face. Am. J. Med. Genet. 77: 16-18, 1998. [PubMed: 9557887] [Full Text: https://doi.org/10.1002/(sici)1096-8628(19980428)77:1<16::aid-ajmg4>3.0.co;2-j]
Schweitzer, D. N., Lachman, R. S., Pressman, B. D., Graham, J. M., Jr. Van den Ende-Gupta syndrome of blepharophimosis, arachnodactyly, and congenital contractures: clinical delineation and recurrence in brothers. Am. J. Med. Genet. 118A: 267-273, 2003. [PubMed: 12673658] [Full Text: https://doi.org/10.1002/ajmg.a.10143]
van den Ende, J. J., van Bever, Y., Rodini, E. S. O., Richieri-Costa, A. Marden-Walker-like syndrome without psychomotor retardation: report of a Brazilian girl born to consanguineous parents. Am. J. Med. Genet. 42: 467-469, 1992. [PubMed: 1609830] [Full Text: https://doi.org/10.1002/ajmg.1320420411]