Pyle disease (ORPHA:3005)
A rare bone dysplasia characterized by long bones with wide and expanded metaphyses, thin cortical bone and bone fragility. The metaphyseal widening and undermodeling extends well into the diaphysis and causes in the distal femur the typical ''Erlenmeyer flask'' or ''paddle'' appearance. Bone undermodeling is also seen in the tubular bones of the hands where there is lack of diaphyseal constriction. Common clinical features include genua valga, big clavicles and dental anomalies. Mild hyperostosis of the skull and mild platyspondyly can also be observed on radiographs.
Epidemiology
To date, less than 30 cases have been reported in the literature.
Clinical description
The disorder is usually not apparent at birth. Genua valga in childhood is a frequently presenting symptom. Dental anomalies are common and may include malocclusion, caries, delayed eruption or prolonged retention of teeth. Prominent clavicles are a characteristic feature that can help in making the diagnosis. Joint pain, muscle weakness and mild scoliosis are occasionally seen. Height is usually in the higher range of normal. Mild sclerosis of the skull base may be present but this does not result in cranial nerve palsy. There is an increased bone fragility but fracturing is usually not a significant problem. The diagnosis can be made incidentally by radiography performed for a fracture.
Etiology
Pyle disease is an autosomal recessive disorder caused by biallelic loss-of-function mutations in the SFRP4 gene, located on chromosome locus 7p14.1. SFRP4 codes for secreted frizzled-related protein 4, a soluble Wnt inhibitor that plays a role in bone remodeling by differential inhibition of the canonical and non-canonical Wnt signaling in cortical and trabecular bone.
Diagnostic methods
The diagnosis is suspected based on clinical presentation and radiographic evaluation and can be confirmed by genetic analysis of the SFRP4 gene.
Differential diagnosis
Pyle disease should be differentiated from other skeletal dysplasias with osteosclerosis and/or bone undermodeling. The ''Erlenmeyer flask'' deformity (usually to a lesser degree) can also be observed in metaphyseal dysplasia, Braun-Tinschert type; craniometaphyseal dysplasia; frontometaphyseal dysplasia; Gaucher disease; and some forms of dysosteosclerosis (CSF1R-related) or osteopetrosis. Prominent clavicles, dental anomalies and bone undermodeling are also features of metaphyseal dysplasia-maxillary hypoplasia-brachydactyly syndrome (RUNX2-related).
Antenatal diagnosis
Antenatal diagnosis is possible in case the biallelic pathogenic variants in SFRP4 have been identified in an affected relative.
Genetic counseling
Inheritance is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy.
Management and treatment
Affected individuals may be asymptomatic. Genu valgum and/or fractures may require orthopedic intervention. Dental and orthodontic care may be necessary when dental anomalies are present. There is no specific or curative treatment available to date.
Prognosis
Life expectancy is normal.

                            Last update: 
                            February 2024


                            - Expert reviewer(s): 
                            Pr Geert MORTIER