Pyle Disease

A number sign (#) is used with this entry because of evidence that Pyle disease (PYL) is caused by homozygous mutation in the SFRP4 gene (606570) on chromosome 7p14.

Description

Pyle disease is characterized by long bones with wide and expanded trabecular metaphyses, thin cortical bone, and bone fragility. Fractures are common in Pyle disease, and fracture lines usually go through the abnormally wide metaphyses, revealing their fragility (summary by Kiper et al., 2016).

Clinical Features

Despite bizarre roentgenographic changes, there are few clinical findings in Pyle disease other than genu valgum. The skull is only mildly affected, thus distinguishing this disorder from the craniometaphyseal dysplasias (see 123000, 218400). The femurs show an Erlenmeyer-flask deformity. The humerus is abnormally broad and 'undermodeled' in its proximal two-thirds, the radius and ulna in their distal two-thirds (Gorlin et al. (1969, 1970)).

Pyle (1931) described this disorder in a 5-year-old boy. Bakwin and Krida (1937) restudied this boy and described his affected sister.

Raad and Beighton (1978) described the disorder in an inbred Afrikaner kindred. Apart from genu valgum of moderate degree, the patients enjoyed good health and their gross radiographic skeletal abnormalities contrasted with the innocuous clinical presentation. Some of the obligatory and potentially heterozygous relatives of the 2 presumed homozygotes showed minor widening of the distal femora on radiographic study.

Kiper et al. (2016) studied 4 patients with Pyle disease. The 16-year-old proband in a consanguineous Turkish family was first noted to have progressive genu valgum at age 7 years. He experienced 2 fractures after minimal trauma, of the left radius and right femur. Radiographic survey showed findings consistent with Pyle disease, including disturbed modeling of long bones, with wide metaphyses and thin cortexes, and an absence of paranasal sinuses. His 14-year-old sister had genu valgum, bilateral cubitus valgus, and limitation of extension in the proximal interphalangeal joints of all fingers except the thumb, but had no bone fractures. Radiographic findings were similar to those of her brother, and neither sib had pain or muscle weakness. Other features included delayed tooth eruption in both sibs, and their deciduous teeth did not shed. Bone mineral densitometry of the lumbar spine revealed Z scores of -2.7 and -2.1, with proximal femur Z scores of -1.1 and -1.4, respectively. Serum levels of calcium, phosphate, alkaline phosphatase, vitamin D, and parathyroid hormone were normal in both sibs; however, elevated levels of bone metabolism markers, including osteocalcin (112260), bone-specific alkaline phosphatase (see 171760), and P1NP, indicated a particularly active bone deposition process, whereas normal levels of carboxy-terminal collagen crosslinks suggested a normal bone resorption rate. Their first-cousin parents were unaffected, and they had an unaffected brother. Kiper et al. (2016) also studied a 58-year-old Japanese man who experienced tibial fractures after a workplace accident, at which time it was noted that the tibia also had a highly abnormal shape and structure; radiographic evaluation was consistent with Pyle disease. The fourth patient was a 3.5-year-old boy from India who had progressive genu valgus deformity after he started walking. He had no history of fractures, and his dentition appeared normal. Radiographs showed the metaphyseal tubulation defect, chalk-like appearance of bone, and lack of cortical bone that are typical of Pyle disease.

Inheritance

Pyle disease is an autosomal recessive disorder. Affected sibs were reported by Bakwin and Krida (1937), Hermel et al. (1953), Feld et al. (1955) and Daniel (1960), among others. Parental consanguinity was present in the cases of Daniel (1960).

In the family described by Komins (1954), a brother and sister were affected as well as the mother and a maternal uncle.

Beighton (1987) found about 20 reported cases; in 7 instances sibs of normal parents were affected, and in 2 instances parental consanguinity was identified.

Molecular Genetics

By exome sequencing in 2 Turkish sibs with Pyle disease, Kiper et al. (2016) identified homozygosity for a 1-bp insertion in the SFRP4 gene (606570.0001), for which their parents and unaffected brother were heterozygous. Analysis of SFRP4 in 2 additional patients with Pyle disease revealed homozygosity for a nonsense mutation in an affected Japanese man (R232X; 606570.0002) and homozygosity for a 7-bp deletion in a 3.5-year-old Indian boy (606570.0003). Radiography of the clinically unaffected Turkish father and brother showed undermodeling of the distal radius and distal tibia, as well as mild incurvation of the tibia, consistent with mild expression in the heterozygous state.

History

Beighton (1987) noted that Edwin Pyle (1891-1961) was an orthopedic surgeon in Waterbury, Connecticut.