Nestor-Guillermo Progeria Syndrome

A number sign (#) is used with this entry because of evidence that Nestor-Guillermo progeria syndrome is caused by homozygous mutation in the BANF1 gene (603811) on chromosome 11q13.

Clinical Features

Puente et al. (2011) studied a consanguineous Spanish family in which the 31-year-old male proband exhibited an atypical form of progeria. Born to third-cousin healthy parents, the proband showed normal development until 2 years of age, when he experienced failure to thrive and his skin became dry and atrophic with small light-brown spots over the thorax, scalp, and limbs. He also developed generalized lipoatrophy, severe osteoporosis, and marked osteolysis. The atrophic facial subcutaneous fat pad and the marked osteolysis of the maxilla and mandible resulted in a typical pseudosenile facial appearance with micrognathia, prominent subcutaneous venous patterning, convex nasal ridge, and proptosis. Cognitive development was completely normal. Features that differed from other forms of progeria included his age, height of 145 cm (underestimated due to severe scoliosis), presence of eyebrows and eyelashes, persistence of scalp hair to 12 years of age, very severe osteolysis involving the mandible, clavicles, ribs, distal phalanges, and radius, and the absence of coronary dysfunction, atherosclerosis, or metabolic anomalies. A 24-year-old unrelated Spanish man with an almost identical phenotype was also studied. Despite thorough cardiovascular examination, neither patient showed signs of ischemia or atherosclerosis, and neither had insulin resistance, diabetes mellitus, or hypertriglyceridemia.

Cabanillas et al. (2011) described in detail the 2 patients from unrelated Spanish families who were originally studied by Puente et al. (2011), noting that the phenotype was designated 'Nestor-Guillermo' progeria syndrome using the names of these 2 patients. In addition to other progeric features, the 32-year-old index patient had severe progressive scoliosis from 18 years of age and developed secondary pulmonary hypertension by 27 years of age. On examination he had dyspnea upon minor exertion, with a severe restrictive spirometry pattern. Echocardiography showed moderate tricuspid insufficiency, severe mitral regurgitation, and pulmonary hypertension. Electrocardiogram showed sinus tachycardia, with dilation of both atria and right bundle branch block, without signs of ischemia. Doppler ultrasound of the carotid arteries showed no arteriosclerosis, and computed angiography of the coronary arteries showed no coronary calcification or stenosis; his blood pressure was normal. Examination of the second patient revealed a progeria phenotype almost identical to the index case; however, this patient had only mild scoliosis without impact on cardiovascular function. Cardiovascular examination showed no signs of ischemia or atherosclerosis, and blood pressure was normal; electrocardiogram revealed sinus tachycardia and right bundle branch block. Laboratory values in both patients were normal except for low 25-OH-vitamin D and very low leptin; in addition, the index patient had a low fasting glucose. Cabanillas et al. (2011) defined NGPS as a chronic progeria because of the patients' slow clinical course and relatively long survival, despite early onset of disease.

Mapping

In a consanguineous Spanish family in which the proband had an atypical progeroid syndrome and was negative for mutations in the LMNA (150330) and ZMPSTE24 (606480) genes, Puente et al. (2011) performed exon enrichment followed by massively parallel sequencing on DNA samples from the proband and both parents under an assumption of an autosomal recessive mode of inheritance. They identified 4 variants that were heterozygous in the parents and homozygous in the proband, 3 of which were located in a long contiguous stretch of homozygosity on chromosome 11q13.

Molecular Genetics

In a consanguineous Spanish family in which the proband had an atypical progeroid syndrome, Puente et al. (2011) analyzed 4 candidate genes and identified homozygosity for a missense mutation in the BANF1 gene (A12T; 603811.0001) on chromosome 11 that was also found to be present in homozygosity in an unrelated Spanish patient with a nearly identical phenotype. The unaffected parents in both families were heterozygous for the mutation. The presence of a common homozygous haplotype in the 2 patients, who were from geographically distant regions of Spain, suggested that A12T represented a founder mutation.