Exome sequencing identifies CTSK mutations in patients originally diagnosed as intermediate osteopetrosis

Abstract

Autosomal Recessive Osteopetrosis is a genetic disorder characterized by increased bone density due to lack of resorption by the osteoclasts. Genetic studies have widely unraveled the molecular basis of the most severe forms, while cases of intermediate severity are more difficult to characterize, probably because of a large heterogeneity. Here, we describe the use of exome sequencing in the molecular diagnosis of 2 siblings initially thought to be affected by “intermediate osteopetrosis”, which identified a homozygous mutation in the CTSK gene. Prompted by this finding, we tested by Sanger sequencing 25 additional patients addressed to us for recessive osteopetrosis and found CTSK mutations in 4 of them. In retrospect, their clinical and radiographic features were found to be compatible with, but not typical for, Pycnodysostosis. We sought to identify modifier genes that might have played a role in the clinical manifestation of the disease in these patients, but our results were not informative. In conclusion, we underline the difficulties of differential diagnosis in some patients whose clinical appearance does not fit the classical malignant or benign picture and recommend that CTSK gene be included in the molecular diagnosis of high bone density conditions.

Pycnodysostosis: mutation spectrum in five unrelated Indian children

“…Characteristic phenotype is believed to make clinical diagnosis possible for pycnodysostosis, but with the advent of exome sequencing, detection of CTSK mutations in children presenting with intermediate severity of osteopetrosis has been reported (Pangrazio et al, 2014).…”

Cathepsin K osteoporosis trials, pycnodysostosis and mouse deficiency models: Commonalities and differences

“…In general, it is difficult to describe genotype-phenotype correlations regarding disease severity with respect to height, fracture frequency, or additional anomalies such as craniosynostosis and Arnold-Chiari malformation. [120,[123][124][125][126][127] However, there is evidence that the more severe the genotype is, the earlier in age bone fractures occur. [22,123,126] Patients are usually presented in their childhood to the clinics with short stature and atypical fractures.…”

“…Dysmorphic features can be overlooked and acroosteolysis is not universal in all cases with pycnodysostosis. [123,125] In the absence of acroosteolysis, the patient could be misdiagnosed with osteopetrosis if hematological abnormalities are present. [125] Normally, patients with pycnodysostosis rarely have hematological abnormalities or they are transient.…”

“…[123,125] In the absence of acroosteolysis, the patient could be misdiagnosed with osteopetrosis if hematological abnormalities are present. [125] Normally, patients with pycnodysostosis rarely have hematological abnormalities or they are transient. With the exception of a single case of transient thrombocytopenia, none of the other nine patients had hematological problems in our clinic.…”

“…[123] Others described cases with mild to severe anemia requiring transfusion. [125] Another main issue of misdiagnosing osteopetrosis is optic atrophy. [125] Optic atrophy could be related to craniosynostosis and intracranial pressure elevation in pycnodysostosis, or to optic canal stenosis as in osteopetrosis.…”