Genetic and Molecular Evaluation: Reporting Three Novel Mutations and Creating Awareness of Pycnodysostosis Disease

Abstract

Pycnodysostosis is a rare autosomal recessive disorder with characteristic diagnostic manifestations. This study aims to phenotype and provide molecular characterization of Egyptian patients, with emphasis on identifying unusual phenotypes and raising awareness about pycnodysostosis with different presentations to avoid a mis- or under-diagnosis and consequent mismanagement. We report on 22 Egyptian pycnodysostosis patients, including 9 new participants, all descending from consanguineous families and their ages ranging from 6 to 15 years. In addition, prenatal diagnosis was performed in one family with affected siblings. They all presented with short stature, except for one patient who presented with pancytopenia as her primary complaint. Moreover, 41.2% of patients had sleep apnea, 14% presented with craniosynostosis, and 44.4% had failure of tooth development. Molecular analysis via direct exome sequencing of the cathepsin K gene revealed three novel mutations ((NM_000396.3) c.761_763delCCT, c.864_865delAA, and c.509G>T) as well as two previously reported mutations among nine new cases. The following is our conclusion: This study expands the molecular spectrum of pycnodysostosis by identifying three novel mutations and adds to the clinical and orodental aspects of the disease. The link between the CTSK gene mutations and the failure of tooth development has not been established, and further studies could help to improve our understanding of the molecular pathology.

Clinical and radiographic characteristics of pycnodysostosis: A systematic review

“…Additionally, brachydactyly was present in 66.0% of cases, and acroosteolysis was noted in 58.1%. While previous studies 10 13 17 31 50 have identified sleep apnea among characteristics of PYCD, it was not commonly observed in this systematic review, appearing in only 13.5% of the reported cases.…”

“…Based on examination of the full texts of these papers, 84 studies 3 4 5 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 ...…”

“…Most patients diagnosed with PYCD were female (55.3%). The mean participant age fell within the second decade of life (14.7 years), with reported ages ranging from 4 months 13 to 58 years. 3 Consanguinity was frequently reported (51.4%), with 26.2% of cases having at least 1 additional family member affected by PYCD.…”

“…Previous research has underscored the high rate of consanguinity among the parents of individuals diagnosed with PYCD, consistent with the autosomal recessive inheritance pattern of the disease. 4 13 37 49 72 87 …”

“…According to Sayed Amr et al, 13 patients with PYCD typically seek medical attention for concerns such as short stature or unusual bone fractures. In this review, short stature was frequently observed as a clinical feature in the analyzed reports, occurring in 86.1% of cases.…”