In this issue


Observations by Kim et al (DOI: 10.1002/ajmg.a.36024, p. 1970) may drive more prompt recognition of osteogenesis imperfecta (OI) type V and direct-targeted molecular study.

The OI type V phenotype includes interosseous membrane calcification of the forearm and hyperplastic callus formation as typical features. While the majority of patients with OI show heterozygous mutations of either COL1A1 or COL1A2, individuals with OI type V have a specific heterozygous mutation of a recently identified gene, IFITM5.

To review the clinical and radiographic characteristics of mutation-confirmed OI type V in detail, the researchers studied 16 patients diagnosed with the disorder. While they found no evidence of blue sclera and dentinogenesis imperfecta in any patient, they did observe hypodontia in the permanent teeth, ectopic eruption, and short roots in molars in 11 patients.

Of the radiographic abnormalities, cortical thickening and bony excrescence of interosseous margin of the ulna was the most common finding, followed by overgrowth of the olecranon and/or coronoid process of the ulna. Slender ribs and sloping of the posterior ribs with or without fractures were also a consistent finding. The researchers detected hyperplastic callus, often at the femur in 75% of patients. Four patients had heterotopic ossification in the muscles and tendon insertion sites, resulting in bony ankylosis or contracture of joints.

Figure 1.

Scoliosis in a 12-year-old patient shows a pyramidal shape of the thoracic cage with down slanting ribs (A); AP spine radiograph in a 50-year-old man displays thoracic deformity ensuing from severe scoliosis of the spine (B).


Findings by Kalish et al (DOI: 10.1002/ajmg.a.36045, p. 1927) highlight the importance of considering mosaic genome-wide paternal uniparental isodisomy (GWpUPD) in patients who present with severe Beckwith-Wiedemann Syndrome (BWS) phenotype and emphasize vigilant tumor screening in these individuals.

The authors describe three patients with mosaic GWpUPD, all with features of BWS including hyperinsulinism (HI), hemihyperplasia (HH), prematurity, tumorigenesis, and a range of clinical phenotypes.

Single nucleotide polymorphism (SNP) array testing demonstrated mosaic GWpUPD in these patients. By comparing them with 10 other liveborn patients, the researchers determined that the predominant phenotype is paternal uniparental isodisomy for chromosome 11p15 (pUPD11) with a very high incidence of tumor development.

The patients developed non-metastatic tumors of the adrenal gland, kidney, and liver. All three had pancreatic hyperplasia resulting in HI. Both children who survived the neonatal period displayed near-normal cognitive development, likely due to favorable tissue distribution of the mosaicism. The researchers studied multiple tissues with SNP array analysis and detected mosaicism levels of 5% to 95%, roughly correlating with the extent of tissue involvement.

Figure 2.

Subject shows left leg hemihyperplasia at 14 months (A), and mosaic skin pigmentation (B). Arrows indicate the darker skin pigmentation.


Detweiler et al (DOI: 10.1002/ajmg.a.36047,p. 1938) recommend routine orthopedic referrals and hip and spine screening protocols for patients with Costello syndrome.

Costello syndrome is a rare genetic condition caused by heterozygous alterations in HRAS. It usually involves severe feeding difficulties in infancy, short stature, coarse facial features, increased tumor risks, intellectual disability, and cardiac, neurological, and orthopedic complications.

The researchers reviewed medical records, conducted clinical exams, and performed orthopedic inquiries for 43 patients. They completed hip and/or spinal imaging assessments in 23 participants and analyzed serial radiographs.

They identified 25 orthopedic manifestations, 10 of which were seen in the majority of participants and included (in order of prevalence): hypotonia, ligamentous laxity, scoliosis, kyphosis, characteristic hand deformities, ulnar deviation of the wrist, elbow and shoulder contractures, tight Achilles tendon, and pes planus. Unilateral or bilateral hip dysplasia was congenital in some patients, while it developed throughout childhood in others. Spinal involvement included scoliosis, kyphosis, lordosis, and curvature reversal.