SNOMEDCT: 1255121003; ORPHA: 536532; DO: 0080732;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 7p13 | Ehlers-Danlos syndrome, classic-like, 2 | 618000 | Autosomal recessive | 3 | AEBP1 | 602981 |
A number sign (#) is used with this entry because of evidence that Ehlers-Danlos syndrome classic-like-2 (EDSCLL2) is caused by homozygous or compound heterozygous mutation in the AEBP1 gene (602981) on chromosome 7p13.
Ehlers-Danlos syndrome classic-like-2 (EDSCLL2) is characterized by severe joint and skin laxity, osteoporosis involving the hips and spine, osteoarthritis, soft redundant skin that can be acrogeria-like, delayed wound healing with abnormal atrophic scarring, and shoulder, hip, knee, and ankle dislocations. Variable features include gastrointestinal and genitourinary manifestations, such as bowel rupture, gut dysmotility, cryptorchidism, and hernias; vascular complications, such as mitral valve prolapse and aortic root dilation; and skeletal anomalies (Blackburn et al., 2018).
See 606408 for another classic-like EDS syndrome. For a discussion of the classification of EDS, see 130000.
Alazami et al. (2016) studied a Saudi sister and brother, born to first-cousin parents (family 1, ID 14DG1601), who presented with severe joint and skin laxity and severe osteopenia. They exhibited facial dysmorphism consisting of bilateral ptosis, sagging cheeks, large ears, soft and redundant skin, narrow palate, and abnormal dental alignment; they also had webbed neck with low posterior hairline as well as dislocated hips, knees, and ankles.
Blackburn et al. (2018) studied 4 patients from 3 families with a suspected connective tissue disorder, including a 35-year-old man of German and Panamanian ancestry (family A), a 41-year-old man of Italian ancestry (family B), and the 2 Saudi sibs (family C) previously reported by Alazami et al. (2016). In addition to severe joint and skin laxity and severe osteopenia, the probands of families A and B also exhibited atrophic widened scars and piezogenic papules of the feet, as well as genitourinary abnormalities (cryptorchidism), gastrointestinal abnormalities (motility problems and bowel rupture), and vascular abnormalities (mitral valve prolapse and aortic dilation). The Beighton score was 8 out of 9 in the 3 patients for whom it was reported. Light microscopy of skin from the proband of family B showed decreased dermal collagen compared to heterozygous carriers and unaffected members of the family. Ultrastructural examination of skin from the proband of family A showed irregular disrupted collagen fibrils or 'collagen flowers,' with moderate variation in collagen size; longitudinal sections showed a ragged or frayed appearance of the fibrils.
Hebebrand et al. (2019) described a 36-year-old woman and her 38-year-old brother with classic-like Ehlers-Danlos syndrome and reviewed their clinical findings and those of 4 previously reported patients. All 6 patients had hyperextensible and redundant skin with atypical scarring, 5 had a predisposition for joint dislocations/subluxations, 4 had a prematurely aged appearance, and 4 had severe osteopenia (the other 2 were not tested for osteopenia, but had no fractures). Mitral valve prolapse and hernias were each seen in 3 of the patients. Cryptorchidism was seen in 2 of the 4 males. The 2 newly reported cases also had features of Marfan syndrome (154700), including tall stature (90-97th centile in both sibs), arachnodactyly, positive wrist sign, positive thumb sign, and pes planus, which had not previously been reported in EDSCLL2.
The transmission pattern of EDSCLL2 in the families reported by Alazami et al. (2016) and Blackburn et al. (2018) was consistent with autosomal recessive inheritance.
In 2 sibs from a consanguineous Saudi family with severe joint and skin laxity and severe osteopenia, Alazami et al. (2016) performed whole-exome sequencing and identified homozygosity for a splice site mutation in the AEBP1 gene (602981.0001) that segregated fully with disease in the family.
In 2 unrelated men with classic-like Ehlers-Danlos syndrome, Blackburn et al. (2018) identified compound heterozygosity and homozygosity, respectively, for mutations in the AEBP1 gene (602981.0002-602981.0004).
By exome sequencing in 2 adult sibs with classic-like Ehlers-Danlos syndrome, Hebebrand et al. (2019) identified homozygosity for a nonsense mutation in the AEBP1 gene (Y306X; 602981.0005). The phenotypically normal mother was heterozygous for the mutation, but the father could not be tested.
Alazami, A. M., Al-Qattan, S. M., Faqeih, E., Alhashem, A., Alshammari, M., Alzahrani, F., Al-Dosari, M. S., Patel, N., Alsagheir, A., Binabbas, B., Alzaidan, H., Alssiddiky, A., and 12 others. Expanding the clinical and genetic heterogeneity disorders of connective tissue. Hum. Genet. 135: 525-540, 2016. [PubMed: 27023906] [Full Text: https://doi.org/10.1007/s00439-016-1660-z]
Blackburn, P. R., Xu, Z., Tumelty, K. E., Zhao, R. W., Monis, W. J., Harris, K. G., Gass, J. M., Cousin, M. A., Boczek, N. J., Mitkov, M. V., Cappel, M. A., Francomano, C. A., Parisi, J. E., Klee, E. W., Faqeih, E., Alkuraya, F. S., Layne, M. D., McDonnell, N. B., Atwal, P. S. Bi-allelic alterations in AEBP1 lead to defective collagen assembly and connective tissue structure resulting in a variant of Ehlers-Danlos syndrome. Am. J. Hum. Genet. 102: 696-705, 2018. [PubMed: 29606302] [Full Text: https://doi.org/10.1016/j.ajhg.2018.02.018]
Hebebrand, M., Vasileiou, G., Krumbiegel, M., Kraus, C., Uebe, S., Ekici, A. B., Thiel, C. T., Reis, A., Popp, B. A biallelic truncating AEBP1 variant causes connective tissue disorder in two siblings. Am. J. Med. Genet. 179: 50-56, 2019. [PubMed: 30548383] [Full Text: https://doi.org/10.1002/ajmg.a.60679]