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Cathepsin K analysis in a pycnodysostosis cohort: demographic, genotypic and phenotypic features.

Arman A, Bereket A, Coker A, Kiper PÖ, Güran T, Ozkan B, Atay Z, Akçay T, Haliloglu B, Boduroglu K, Alanay Y, Turan S - Orphanet J Rare Dis (2014)

Bottom Line: Seven exons and exon/intron boundaries of CTSK gene for the children and their families were amplified with PCR and sequenced.The mutations were homozygous in all cases, and the families mostly originated from the region where consanguineous marriage rate is the highest.Additionally, none of the previously described hot spot mutations were seen in our cohort; indeed, L7P and R312X were the most frequently detected mutations.

View Article: PubMed Central - HTML - PubMed

Affiliation: The Department of Pediatric Endocrinology, Marmara University, İstanbul, Turkey. serap.turan@marmara.edu.tr.

ABSTRACT

Background: To characterize cathepsin K (CTSK) mutations in a group of patients with pycnodysostosis, who presented with either short stature or atypical fractures to pediatric endocrinology or dysmorphic features to pediatric genetics clinics.

Methods: Seven exons and exon/intron boundaries of CTSK gene for the children and their families were amplified with PCR and sequenced. Sixteen patients from 14 families with pycnodysostosis, presenting with typical dysmorphic features, short stature, frequent fractures and osteosclerosis, were included in the study.

Results: We identified five missense mutations (M1I, I249T, L7P, D80Y and D169N), one nonsense mutation (R312X) and one 301 bp insertion in intron 7, which is revealed as Alu sequence; among them, only L7P and I249 were described previously. The mutations were homozygous in all cases, and the families mostly originated from the region where consanguineous marriage rate is the highest. Patients with M1I mutation had fractures, at younger ages than the other pycnodysostosis cases in our cohort which were most probably related to the severity of mutation, since M1I initiates the translation, and mutation might lead to the complete absence of the protein. The typical finding of pycnodysostosis, acroosteolysis, could not be detected in two patients, although other patients carrying the same mutations had acroosteolysis. Additionally, none of the previously described hot spot mutations were seen in our cohort; indeed, L7P and R312X were the most frequently detected mutations.

Conclusions: We described a large cohort of pycnodysostosis patients with genetic and phenotypic features, and, first Alu sequence insertion in pycnodysostosis.

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Related in: MedlinePlus

Panel A: Typical finding of acro-osteolytic distal phalanges on X-rays and wrinkled skin over the dorsa of distal fingers and flattened and grooved nails in pycnodysostosis detected in patient 4. Panel B: Osteosclerosis without acroosteolysis detected on radiograph of the patient #8.
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Figure 1: Panel A: Typical finding of acro-osteolytic distal phalanges on X-rays and wrinkled skin over the dorsa of distal fingers and flattened and grooved nails in pycnodysostosis detected in patient 4. Panel B: Osteosclerosis without acroosteolysis detected on radiograph of the patient #8.

Mentions: Sixteen patients from 14 families were studied. Patients #1-I and #1-II are distant cousins, while patients #13-II.1 and #13-II.3 are the sisters. Nine patients were evaluated in the Pediatric Endocrinology Clinics in Istanbul and Erzurum due to short stature, while seven patients were referred to a Pediatric Genetic Unit in Ankara for dysmorphic features. The diagnosis was based on their phenotypic and radiographic evaluation. The clinical features of the patients are summarized on Table 1, in which the number of fractures and height standard deviation scores (SDS) are representing data at the time of presentation. Figure 1 shows typical acroosteolysis and osteosclerosis, which are the most prominent radiological and morphological feature of the disease. However, patients #8 and #13.II did not show any acroosteolysis, osteosclerosis and typical facial feature leading to diagnosis. As an additional finding, one of the patients had Arnold Chiari malformation (Patient #6) and patient #8 had craniosynostosis.


Cathepsin K analysis in a pycnodysostosis cohort: demographic, genotypic and phenotypic features.

Arman A, Bereket A, Coker A, Kiper PÖ, Güran T, Ozkan B, Atay Z, Akçay T, Haliloglu B, Boduroglu K, Alanay Y, Turan S - Orphanet J Rare Dis (2014)

Panel A: Typical finding of acro-osteolytic distal phalanges on X-rays and wrinkled skin over the dorsa of distal fingers and flattened and grooved nails in pycnodysostosis detected in patient 4. Panel B: Osteosclerosis without acroosteolysis detected on radiograph of the patient #8.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4022088&req=5

Figure 1: Panel A: Typical finding of acro-osteolytic distal phalanges on X-rays and wrinkled skin over the dorsa of distal fingers and flattened and grooved nails in pycnodysostosis detected in patient 4. Panel B: Osteosclerosis without acroosteolysis detected on radiograph of the patient #8.
Mentions: Sixteen patients from 14 families were studied. Patients #1-I and #1-II are distant cousins, while patients #13-II.1 and #13-II.3 are the sisters. Nine patients were evaluated in the Pediatric Endocrinology Clinics in Istanbul and Erzurum due to short stature, while seven patients were referred to a Pediatric Genetic Unit in Ankara for dysmorphic features. The diagnosis was based on their phenotypic and radiographic evaluation. The clinical features of the patients are summarized on Table 1, in which the number of fractures and height standard deviation scores (SDS) are representing data at the time of presentation. Figure 1 shows typical acroosteolysis and osteosclerosis, which are the most prominent radiological and morphological feature of the disease. However, patients #8 and #13.II did not show any acroosteolysis, osteosclerosis and typical facial feature leading to diagnosis. As an additional finding, one of the patients had Arnold Chiari malformation (Patient #6) and patient #8 had craniosynostosis.

Bottom Line: Seven exons and exon/intron boundaries of CTSK gene for the children and their families were amplified with PCR and sequenced.The mutations were homozygous in all cases, and the families mostly originated from the region where consanguineous marriage rate is the highest.Additionally, none of the previously described hot spot mutations were seen in our cohort; indeed, L7P and R312X were the most frequently detected mutations.

View Article: PubMed Central - HTML - PubMed

Affiliation: The Department of Pediatric Endocrinology, Marmara University, İstanbul, Turkey. serap.turan@marmara.edu.tr.

ABSTRACT

Background: To characterize cathepsin K (CTSK) mutations in a group of patients with pycnodysostosis, who presented with either short stature or atypical fractures to pediatric endocrinology or dysmorphic features to pediatric genetics clinics.

Methods: Seven exons and exon/intron boundaries of CTSK gene for the children and their families were amplified with PCR and sequenced. Sixteen patients from 14 families with pycnodysostosis, presenting with typical dysmorphic features, short stature, frequent fractures and osteosclerosis, were included in the study.

Results: We identified five missense mutations (M1I, I249T, L7P, D80Y and D169N), one nonsense mutation (R312X) and one 301 bp insertion in intron 7, which is revealed as Alu sequence; among them, only L7P and I249 were described previously. The mutations were homozygous in all cases, and the families mostly originated from the region where consanguineous marriage rate is the highest. Patients with M1I mutation had fractures, at younger ages than the other pycnodysostosis cases in our cohort which were most probably related to the severity of mutation, since M1I initiates the translation, and mutation might lead to the complete absence of the protein. The typical finding of pycnodysostosis, acroosteolysis, could not be detected in two patients, although other patients carrying the same mutations had acroosteolysis. Additionally, none of the previously described hot spot mutations were seen in our cohort; indeed, L7P and R312X were the most frequently detected mutations.

Conclusions: We described a large cohort of pycnodysostosis patients with genetic and phenotypic features, and, first Alu sequence insertion in pycnodysostosis.

Show MeSH
Related in: MedlinePlus