Marked phenotypic variability in progressive diaphyseal dysplasia (Camurati–Engelmann disease): Report of a four‐generation pedigree, identification of a mutation in TGFB1, and review

Abstract

Progressive diaphyseal dysplasia (PDD) (Camurati-Engelmann disease) is an autosomal dominant craniotubular dysplasia characterized by hyperostosis and sclerosis of the diaphyses of the long bones and the skull. Mutations in transforming growth factor beta-1 (TGFB1) were recently found in patients with PDD. We report on a four-generation pedigree with seven individuals affected by PDD, linkage and mutational analysis results, and review the literature. This pedigree demonstrates the autosomal dominant inheritance pattern, remarkable variation in expressivity, and reduced penetrance. The most severely affected individual had progression of mild skull hyperostosis to severe skull thickening and cranial nerve compression over 30 years. His carrier father remained asymptomatic into his ninth decade and had no radiographic hyperostosis or sclerosis of the bones. Symptomatic relatives presented with lower limb pain and weakness. They were initially diagnosed with a variety of other conditions. Two of the symptomatic individuals were treated successfully with prednisone. We genotyped 7 markers from chromosome region 19q13.1-13.3 in 15 relatives and confirmed linkage to this region in this family. We screened the TGFB1 gene for mutations and identified a missense mutation resulting in an R218H substitution in the affected individuals, the asymptomatic obligate carrier, and another unaffected relative. We genotyped the family for seven known TGFB1 polymorphisms and a novel TAAA tetranucleotide repeat in intron 1. These polymorphisms did not appear to account for the variability in disease severity in this family. Our review illustrates how the disorder can significantly compromise health. Cranial involvement, which occurs in 61% of patients, can be severe, entrapping cranial nerves or causing increased intracranial pressure. Therapy with corticosteroids should be attempted in all symptomatic patients.

Orthopaedic · Radiology · Pathology Conference: Bilateral Leg Pain in a 4-year-old Girl

“…These anomalies include delayed closure of the fontanel, choanal atresia, mental retardation, proximal symphalangism, joint laxity, prominent cutaneous veins, and severe growth retardation [11]. Kenny-Caffey dysplasia is characterized by dwarfism, delayed fontanel closure, craniofacial anomalies, hypocalcemia, and hypoparathyroidism [11]. As reported, CED does not have any specific laboratory abnormalities, which makes the distinction here straightforward [11].…”

“…Kenny-Caffey dysplasia is characterized by dwarfism, delayed fontanel closure, craniofacial anomalies, hypocalcemia, and hypoparathyroidism [11]. As reported, CED does not have any specific laboratory abnormalities, which makes the distinction here straightforward [11]. Juvenile Paget's disease is characterized by a predisposition to fractures, elevated alkaline phosphatase, and coarse trabeculations observed on radiographs [11].…”

“…The reported incidence of the disorder (also known as progressive diaphyseal dysplasia or Engelmann's disease) is one in 1,000,000 [9]. In 1920, Cockayne first described the disease and in 1922 Camurati proposed the genetic inheritance pattern as autosomal dominant when he treated a father and son with traditional symptoms [11]. In 1929, Engelmann reported the progressive character of the disease when he treated an 8-year-old boy, and since then there have been 199 published cases [11].…”

“…However, few disorders have clinical and radiographic findings specifically resembling those of CED [11]. LenzMajewski dysplasia is similar in the skeletal involvement, but it has additional congenital anomalies not found in patients with CED.…”

“…LenzMajewski dysplasia is similar in the skeletal involvement, but it has additional congenital anomalies not found in patients with CED. These anomalies include delayed closure of the fontanel, choanal atresia, mental retardation, proximal symphalangism, joint laxity, prominent cutaneous veins, and severe growth retardation [11]. Kenny-Caffey dysplasia is characterized by dwarfism, delayed fontanel closure, craniofacial anomalies, hypocalcemia, and hypoparathyroidism [11].…”