Grange Syndrome

A number sign (#) is used with this entry because of evidence that Grange syndrome (GRNG) is caused by homozygous or compound heterozygous mutation in the YY1AP1 gene (607860) on chromosome 1q22.

Clinical Features

Grange et al. (1998) reported a family in which 4 of 9 sibs had a seemingly unique syndrome of stenosis or occlusion of multiple arteries, including renal, abdominal, cerebral and probably coronary arteries, congenital heart defects, brachydactyly, syndactyly, bone fragility, and learning disabilities. The arterial occlusive disease was similar in distribution and clinical consequences to fibromuscular dysplasia. The bone fragility resembled a mild form of osteogenesis imperfecta. Both parents and 2 offspring of 1 of the affected sibs were clinically normal. The proposita, aged 29 years, had a patent ductus arteriosus (see 607411) ligated at age 14 months. She was later found to have a bicuspid aortic valve with mild to moderate insufficiency, along with persistence of a small perimembranous ventricular septal defect. She had had several fractures, and bone densitometry showed reduced mineralization. Narrowing or occlusion of several cerebral arteries was found at the age of 26 years. Later abdominal arteriograms showed complete occlusion of the celiac artery and 75% occlusion of the superior mesenteric artery near its origin. Her brother, aged 27 years, also had bicuspid aortic valve and a gradient across the pulmonic valve consistent with mild pulmonic stenosis. Bilateral renal artery stenosis was demonstrated and hypertension was a problem. Cerebral arteriograms showed a pattern of severe moyamoya disease (see 252350). The next younger affected member of the sibship had died suddenly at the age of 18 years. She had had numerous fractures and was considered to have osteogenesis imperfecta. She also had a history of chronic hypertension, initially diagnosed at age 5 years. The youngest affected sib was found to be hypertensive at the age of 3 years and likewise had had multiple fractures.

Weymann et al. (2001) described a 15-year-old boy who had stenosis and occlusion of multiple cranial, renal, and celiac arteries, aneurysm of the basilar artery, bilateral cutaneous syndactyly between fingers 4 and 5, partial cutaneous syndactyly between fingers 3 and 4 on the right hand, brachydactyly, and borderline mental retardation. The clinical course was characterized by recurrent abdominal pain, gastritis, and hypertension. The pattern of the clinical and radiologic findings was different from that in fibromuscular dysplasia and moyamoya disease and considered highly suggestive of Grange syndrome.

Wallerstein et al. (2006) reported a 3-year-old girl with hypertension, bilateral renal artery stenosis, brachydactyly, bilateral cutaneous syndactyly of fingers 4 and 5, bone fragility with multiple fractures, and failure to thrive. Echocardiogram showed no structural heart disease or cardiomyopathy. She was born of nonconsanguineous parents and had 2 unaffected sibs. Wallerstein et al. (2006) noted that this was the third reported patient with features of Grange syndrome without congenital cardiac anomalies, suggesting that congenital cardiac abnormalities may not be essential for the diagnosis.

Guo et al. (2017) restudied the family originally reported by Grange et al. (1998), designating the family 'DVD047.' The proband, now 47 years of age, had developed coronary artery disease involving branches of the left anterior descending artery at age 32 years. She was also diagnosed with long QT syndrome (see 192500) and had undergone implantation of a cardioverter-defibrillator. Her affected 46-year-old brother was noted to have hyperintense lesions within the periventricular white matter that were suggestive of small vessel ischemic disease. Recent imaging in their 34-year-old affected sister showed narrowing near the origin of the celiac axis and external iliac arteries bilaterally. Their 67-year-old mother had refractory hypertension, chronic renal insufficiency, and stenosis of the proximal left renal artery. Guo et al. (2017) also provided follow-up on the girl previously described by Wallerstein et al. (2006) (DVD097), in whom brain imaging at 15 years of age showed stenoses of the internal carotid arteries, collateral vessel formation, and multiple periventricular hyperintense lesions. In addition, Guo et al. (2017) reported a girl (DVD112) with borderline intellectual disability who exhibited features of Grange syndrome, including mild facial dysmorphism (hypertelorism), brachydactyly, fifth-finger clinodactyly, and mild cutaneous syndactyly of the second and third toes. There was no evidence of bone fragility, echocardiography was normal, and CT angiography showed no stenoses of the cerebral, renal, or other arteries.

Molecular Genetics

In 2 of the affected sibs from the family (DVD047) originally described by Grange et al. (1998), Guo et al. (2017) performed exome sequencing and identified compound heterozygosity for 2 nonsense mutations in the YY1AP1 gene, Q242X (607860.0001) and L797X (607860.0002). Sanger sequencing confirmed that a third affected child in that family was also compound heterozygous for Q242X and L797X. Sanger sequencing of YY1AP1 in the 2 probands (DVD093 and DVD097) with Grange syndrome previously reported by Weymann et al. (2001) and Wallerstein et al. (2006), respectively, revealed homozygous mutations in both: a nonsense mutation in the former (E801X; 607860.0003) and a 4-bp deletion in the latter (607860.0004). Another patient (DVD112) with features of Grange syndrome was determined to be homozygous for a nonsense mutation (Q222X; 607860.0005). Noting that the heterozygous mother of the sibs from the original Grange syndrome kindred (DVD047) had refractory hypertension due to left renal artery stenosis, and that a sporadic patient with fibromuscular dysplasia (FMDA; 135580) involving the renal and extracranial carotid arteries was heterozygous for a frameshift mutation in the YY1AP1 gene, Guo et al. (2017) suggested that heterozygous YY1AP1 mutations might be associated with susceptibility to FMDA in the general population.