Geleophysic Dysplasia 1

A number sign (#) is used with this entry because of evidence that geleophysic dysplasia-1 (GPHYSD1) is caused by homozygous or compound heterozygous mutation in the ADAMTSL2 gene (612277) on chromosome 9q34.

Description

Geleophysic dysplasia-1 is an autosomal recessive disorder characterized by severe short stature, short hands and feet, joint limitations, and skin thickening. Radiologic features include delayed bone age, cone-shaped epiphyses, shortened long tubular bones, and ovoid vertebral bodies. Affected individuals have characteristic facial features including a 'happy' face with full cheeks, shortened nose, hypertelorism, long and flat philtrum, and thin upper lip. Other distinctive features include progressive cardiac valvular thickening often leading to an early death, toe walking, tracheal stenosis, respiratory insufficiency, and lysosomal-like storage vacuoles in various tissues (summary by Le Goff et al., 2011).

Genetic Heterogeneity of Geleophysic Dysplasia

Geleophysic dysplasia-2 (GPHYSD2; 614185) is an autosomal dominant form of the disorder caused by heterozygous mutation in the FBN1 gene (134797) on chromosome 15q21.1. Acromicric dysplasia (102370) and the autosomal dominant form of Weill-Marchesani syndrome (608328) are allelic to geleophysic dysplasia-2 and share overlapping skeletal and joint features.

Geleophysic dysplasia-3 (GPHYSD3; 617809) is caused by heterozygous mutation in the LTBP3 gene (602090) on chromosome 11q13.

Clinical Features

Spranger et al. (1971) suggested the designation 'geleophysic' because of the happy-appearing faces of the affected children (gelios = happy, physis = nature); the typical facies includes upturned corners of the mouth. They further suggested that the disorder is a 'focal' mucopolysaccharidosis. In addition to the facial appearance, 2 unrelated children showed dysostosis multiplex-like changes, predominantly in the hands and feet, and an apparently focal accumulation of acid mucopolysaccharides in the liver and possibly the cardiovascular system. Small hands and feet were evident at birth. The upper lip was long and thick with 'ironing out' of the philtrum. The nasal bridge was depressed. Joint contractures affected particularly the fingers. Hepatomegaly and cardiomegaly were present. Urinary excretion of mucopolysaccharides was normal. Spranger et al. (1971) thought that the patient reported by Vanace et al. (1960) probably had this disorder.

Spranger et al. (1984) gave a follow-up of the male patient described by Spranger et al. (1971) and described the same disorder in of his sibs. The original patient had progressive joint contractures; he walked on his toes and stood bent forward, flexed at the hips and knees. By age 12 he had extensive disease of the aortic and mitral valves. A sister developed heart failure soon after birth and was found to have right ventricular hypertrophy. She was found to have severe mitral stenosis with aortic regurgitation; she died at age 7.5 years during preparation for surgical repair of the valvular lesions. At autopsy all 4 heart valves were strikingly abnormal. The liver and heart as well as the growth plates showed cells with lysosomal inclusions with the staining properties of a neutral glycoprotein. Radiographic changes were most striking in the hands and feet where the tubular bones were short and plump. The other sib was stillborn and was probably affected.

Legare et al. (2018) provided another follow-up on the male patient with GPHYSD1 described by Spranger et al. (1971). On physical examination at 48 years of age, he had a high-pitched voice, round face, low-set hairline, broad nasal bridge, prominent nasal spine, and small mandible. He had a wide mouth, upturned corners of his mouth, and normal teeth. He had thickening of his perioral skin and of the area above his vermilion, resulting in a smooth philtrum. Skin was thick and tight over his chest and joints. His chest was short and broad with pectus excavatum. Extremities were micromelic, with relative acromelia and brachydactyly. He had multiple joint contractures. His hands were short and broad, with short thumbs. He used a walker for balance because of his plantar flexion contractures. Deep tendon reflexes were increased, with clonus in his lower extremities. His clinical course had included slowly progressive decreased joint mobility at shoulders, elbows, wrists, fingers, hips, knees, and ankles, and he eventually developed arthritis in these joints. He had severe restrictive lung disease that had progressed over the past 2 decades, which was thought to be due to his small chest and pectus excavatum. Other comorbidities included irritable bowel syndrome, cholelithiasis, early cataracts, and moderate to severe hearing loss. Cognitive evaluation in childhood revealed an IQ of 74, but in adulthood, his cognitive function appeared close to normal. At age 48 years, he presented with chronic heart failure due to severe aortic regurgitation with severe left outflow tract obstruction and left ventricular dysfunction. He underwent a transcatheter aortic valve replacement, which resulted in resolution of his aortic regurgitation and improvement of his left ventricular outflow tract physiology. A year later, his heart failure symptoms had completely resolved.

Koiffmann et al. (1984) reported the disorder in an 11-year-old Brazilian girl. At birth she was short with small hands and feet. At presentation she had 'tip-toe gait' because of bilateral talipes equinovarus, joint limitation at the elbows, and hepatomegaly to 4 cm below the right costal margin. Aortic systolic and diastolic murmurs were explained by 'important stenosis and mild insufficiency' of the aortic valve found at cardiac catheterization. A sister, who died of heart failure at age 3, was described by the mother as 'a tiny child with small hands.'

Lipson et al. (1987) reported the clinical, radiologic, and pathologic findings in a patient with a typical picture of progressive growth delay, mild facial anomalies, small hands, hepatosplenomegaly, and progressive cardiac valvular lesions. Electron microscopy showed electron-dense, lysosomal-like bodies in hepatocytes, similar to those previously reported. A defect of glycoprotein metabolism had been proposed.

A patient with an acrofacial dysplasia described by Spranger et al. (1984) had many features similar to those in patients with geleophysic dysplasia but the identity was imperfect. Lipson et al. (1987) and Rosser et al. (1995) noted phenotypic similarities to acromicric dysplasia (102370).

Wraith et al. (1990) described 2 patients, one of whom was the offspring of consanguineous parents. One died of heart failure at the age of 5 months. A disturbance in the relations between cell membrane and extracellular matrix was suggested by histologic and ultrastructural changes. Shohat et al. (1990) described 5 patients, 2 of whom were sibs. The facies included long, thin upper lip with flat and long philtrum and inverted vermilion borders. Behavior, development, and intelligence were normal. Growth delay was noted during infancy; 2 patients who completed normal puberty had remarkably short stature (140 and 150 cm) with relatively lean body habitus. The hands and feet were small, with short, plump tubular bones and broad proximal phalanges, associated with marked limitation in motion of fingers and wrists. The liver was enlarged after the age of 3 years. Two patients had mild mitral and tricuspid valve stenosis and 1 had severe aortic stenosis. The most severely affected child died at the age of 3.5 years of airway obstruction resulting from progressive tracheal narrowing. Skin biopsy showed lysosomal storage vacuoles in epithelial cells, and autopsy in the child that died showed similar vacuoles in the cells of the tracheal mucosa, liver, cartilage, and macrophages.

Rosser et al. (1995) reported 3 boys with geleophysic dysplasia, 2 of whom were brothers. Serial ultrasound scans, performed on 2 of the cases during pregnancy, failed to demonstrate short limbs until after 28 weeks of gestation. The facies and small hands with limitation of movement of interphalangeal joints were pictured. Both brothers had bicuspid aortic valve and 1 had aortic stenosis with mild poststenotic dilatation. Because of stiff joints, all 3 patients had a marked tiptoe gait.

Pontz et al. (1996) described clinical and ultrastructural findings in 3 patients with geleophysic dysplasia. They presented electron microscopic evidence supporting the hypothesis that geleophysic dysplasia is indeed a lysosomal storage disease.

Santolaya et al. (1997) suggested that geleophysic dysplasia may have a broader clinical spectrum than initially suspected. They reported the cases of 2 boys with facial anomalies, small hands and feet, joint contractures, thick skin, unusual tiptoe gait, and lysosome-like inclusions in the hepatocytes, compatible with the diagnosis of geleophysic dysplasia. One of them also had fibrosis and fatty degeneration of the liver. Neither had short stature nor progressive cardiac valvular disease. The facial appearance of the 2 cases was thought to be different. The second case had the same 'happy-natured' face as in the cases of Spranger et al. (1984).

Titomanlio et al. (1999) reported a new case of geleophysic dysplasia. Born to consanguineous parents, the patient was first observed at age 8 months and was followed for 7 years.

Ben-Salem et al. (2013) reported patients with geleophysic dysplasia from 2 unrelated consanguineous Arab families. The patient in family 1 was a 2-year-old girl with short stature, small hands and feet with stubby fingers and toes, and dysmorphic features including upslanting palpebral fissures, short nose, long smooth philtrum, and thin upper lip. She had limited movement of the elbow and ankle joints. Skeletal survey showed mild shortening of the long bones and small iliac wings. Echocardiography was normal. The proband in the second family was a 2-year-old boy with similar dysmorphic and skeletal features. He had respiratory difficulties from birth. Echocardiography showed severe pulmonary stenosis, mild aortic stenosis and tricuspid regurgitation, and thickened interventricular septum. He had 2 sibs with similar features who died at ages 4 months and 1 year.

Mapping

Le Goff et al. (2008) performed homozygosity mapping in 4 consanguineous geleophysic dysplasia families of French Polynesian, Moroccan, Algerian, and Pakistani origins and showed linkage of the underlying gene to chromosome 9q34.2-q34.3 in a 619-kb interval (Zmax = 4.52 at theta = 0.0 at the gt-AL590710 locus). A recombination event in family 4 defined the proximal boundary of the region (gt-AL593848), and a second recombinant in the same family defined the distal boundary (gt-AL593186).

Molecular Genetics

Because geleophysic dysplasia belongs to the group of acromelic dysplasias that also includes the autosomal recessive form of Weill-Marchesani syndrome (277600), which is caused by mutations in ADAMTS10 (608990), Le Goff et al. (2008) considered the ADAMTSL2 gene (612277) as the likely candidate among the 7 genes located within the critical interval. Among affected members of 6 families with geleophysic dysplasia, Le Goff et al. (2008) detected 5 different mutations in ADAMTSL2 (612277.0001-612277.0005). In 2 families the same mutation was found (R113H; 612277.0002).

Allali et al. (2011) analyzed the ADAMTSL2 gene in an additional 33 GD patients from 30 families and identified mutations in 14 patients (see, e.g., 612277.0003 and 612277.0006-612277.0007). Comparison of the 20 patients with mutations in ADAMTSL2 (including 6 patients previously reported by Le Goff et al., 2008) and the 19 patients without ADAMTSL2 mutations revealed that while tiptoe walking was consistently reported in patients with ADAMTSL2 mutations, it was rarely reported in the patients without mutations in ADAMTSL2 (88% vs 18%). Facial dysmorphism was also more frequent in the patients with ADAMTSL2 mutations, whereas short stature was much more severe in the patients without mutation in ADAMTSL2. No differences were found regarding heart involvement, skin thickness, recurrent respiratory and ear infections, bronchopulmonary insufficiency, laryngotracheal stenosis, deafness, or radiologic features, and long-term follow-up did not reveal any differences in the course of the disease. Allali et al. (2011) concluded that GD is a genetically heterogeneous condition.

In affected members of 2 unrelated consanguineous Arab families with geleophysic dysplasia-1, Ben-Salem et al. (2013) identified homozygous missense mutations (see, e.g., 612277.0008) that segregated with the disorder in the families. The mutations were not found in the NHLBI EVS database or in ethnically matched controls.

In a 48-year-old man with GPHYSD1, originally described by Spranger et al. (1971), Legare et al. (2018) identified compound heterozygous mutations in the ADAMTSL2 gene (NM_014694.3): the previously identified D167N mutation and a 1-bp deletion (c.31delG) resulting in a frameshift and premature termination (Ala11ProfsTer10). The frameshift was predicted to be pathogenic based on ACMG criteria. The parents were not tested so there was a small possibility that the mutations occurred in cis; the authors considered this unlikely because the patient had 2 affected sibs.