Pathological mandibular fracture complicated by osteonecrosis in an adult patient with pycnodysostosis: clinical report and review of the literature.

Pycnodysostosis is an ultra-rare osteosclerotic skeletal disorder characterized by short stature, susceptibly to fractures, acroosteolysis of the distal phalanges, and craniofacial features (frontal bossing, prominent nose, obtuse mandibular angle, micrognathia). Dental abnormalities (delayed eruption of teeth, hypodontia, malocclusion, dental crowding, persistence of deciduous teeth, enamel hypoplasia, and increased caries) are also frequent; due to bone metabolism alteration, the patients have an increased risk for jaw osteomyelitis, especially after tooth extraction or mandible fracture. Other complications are obstructive sleep apnea, endocrine alterations and cytopenia. Pycnodysostosis is caused by biallelic loss of function variants in CTSK gene, coding the lysosomal protease cathepsin K. CTSK is involved in the degradation of bone matrix proteins, such as type I and type II collagen. In pycnodysostosis, this degradation is decreased, leading to increased bone density and bone fragility with pathological fractures and poor healing. We present a clinical report of a female adult patient with typical pycnodysostosis phenotype. At the age of 52 years, she had a pathological spontaneous fracture of the right mandible complicated by osteonecrosis, treated with load bearing osteosynthesis. The direct sequencing of CTSK gene revealed the presence of the pathogenic homozygous variant c.746T>A, (p.Ile249Asn), that confirmed the diagnosis of pycnodysostosis. We also review the literature case series published to date, that suggest to always consider the diagnosis of pycnodysostosis in case of osteosclerosis, even in the absence of brachydactyly or short stature. This report details the natural history of the disease in this patient, from childhood to adulthood, and highlights the importance of a quality of life assessment. In addition, we describe a case of mandibular osteonecrosis and spontaneous fracture in pycnodysostosis, drawing attention on the maxillofacial complications in these patients and on the importance of a personalized follow-up.

Clinical and genetic characterization of three Russian patients with pycnodysostosis due to pathogenic variants in the CTSK gene.

BACKGROUND: Pycnodysostosis (PD, OMIM # 265800) is a rare variant of skeletal dysplasia with an autosomal recessive type of inheritance, characterized by a combination of specific features such as disproportionate nanism, generalized osteosclerosis, and distinct craniofacial dysmorphism. Radiographic features include acro-osteolysis of the distal phalanges in association with sclerosing bone lesions with multiple fractures. The polymorphism of the clinical manifestations of pycnodysostosis and low prevalence of the disorder lead to the difficulties with early. METHODS: The following tests were used for diagnostics: genealogical analysis, clinical examination, neurological examination according to the standard method with an assessment of the psychoemotional sphere, radiological analysis, searching for pathogenic variants in the CTSK gene by the automated Sanger sequencing. RESULTS: We describe first clinical and genetic characteristics of three Russian patients with pycnodysostosis from unrelated families. Two patients have a novel homozygous nucleotide substitution c.746T>A (p. Ile249Asn), and one has a previously described homozygous pathogenic variant c.746T>C (p.Ile249Thr) in the CTSK gene. In all three cases, a transition or transversion was found at nucleotide position 746 in exon 6 of the CTSK gene, leading to two different amino acid substitutions in the polypeptide chain. The obtained results may indicate the presence of a major pathogenic variant in the CTSK gene, leading to the typical manifestation of the disease. CONCLUSION: The data presented in the study enlarge the clinical, radiological, and mutational spectrum of pycnodysostosis. Typical clinical manifestations and the small size of the CTSK gene make the automated Sanger sequencing the optimal method for diagnosis of pycnodysostosis.

The genotypic and phenotypic spectrum of pycnodysostosis in Saudi Arabia: Novel variants and clinical findings.

Pycnodysostosis is characterized by short stature, osteosclerosis, acro-osteolysis, increased tendency of fractures, and distinctive dysmorphic features. It is a rare autosomal recessive disease caused by biallelic CTSK mutations. The clinical details of 18 patients from Saudi Arabia were reviewed. Short stature, osteopetrosis, acro-osteolysis, and distinctive facial dysmorphism were documented in all cases. Our results highlight the significant complications associated with this disease. The large anterior fontanelle is one of the cardinal signs of this disease; however, half of our patients had small fontanelles and a quarter had craniosynostosis, which caused optic nerve compression. Sleep apnea was of the major complications in three patients. Bone fracture can be a presenting symptom, and in our patients it mainly occurred after the age of 3 years. Bone marrow suppression was seen in a single patient of our cohort who was misdiagnosed initially with malignant osteopetrosis. In this study, we also describe two novel (c.5G > A [p.Trp2Ter], c.538G > A [p.Gly180Ser]) and two reported (c.244-29 A > G, c.830C > T [p.Ala277Val]) CTSK mutations. Our results indicate that the recurrent intronic variant, c.244-29 A > G is likely to be a founder mutation, as it was found in 78% (14/18 patients) of our cohort belonging to the same tribe.

Phenotypic and genotypic spectrum of CTSK variants in a cohort of twenty-five Indian patients with pycnodysostosis.

BACKGROUND: Pycnodysostosis is an autosomal recessive skeletal dysplasia with easily recognizable clinical features and marked molecular heterogeneity. In this study, we explored the clinical and molecular spectrum of 25 Indian patients with pycnodysostosis from 20 families. METHODS: Clinical information was collected on a predesigned clinical proforma. Sanger method was employed to sequence all the exons and exon/intron boundaries of the CTSK gene. Novel variants were systematically assessed by prediction softwares and protein modelling. The pathogenicity of variant was established based on ACMG-AMP criteria. An attempt was also made to establish a genotype-phenotype correlation and devise a diagnostic scoring system based on clinical and radiological findings. RESULTS: Consanguinity and positive family history were present in 65% (13/20) and 45% (9/20) of the families respectively. Short stature and fractures were the predominant presenting complaints and was evident in 96% (24/25) and 32% (8/25) of affected individuals respectively. Gestalt facial phenotype and acro-osteolysis were present in 76% (19/25) and 82.6% (19/23) of the individuals respectively. Hepatosplenomegaly was present in 15% (3/20) of the individuals with one of them having severe anaemia. Causative sequence variations were identified in all of them. A total of 19 variants were identified from 20 families amongst which 10 were novel. Homozygous variants were identified in 90% (18/20) families. Amongst the novel variants, there was a considerable proportion (40%) of frameshift variants (4/10). No significant genotype-phenotype correlation was noted. Scoring based on clinical and radiological findings led to the proposal that a minimum of 2 scores in each category is required in addition to high bone density to diagnose pycnodysostosis with certainty. CONCLUSION: This study delineated the genotypic and phenotypic characterisation of Indian patients with pycnodysostosis with identification of 10 novel variants. We also attempted to develop a clinically useful diagnostic scoring system which requires further validation.

Increased Bone Resorption during Lactation in Pycnodysostosis.

Pycnodysostosis, a rare autosomal recessive skeletal dysplasia, is caused by a deficiency of cathepsin K. Patients have impaired bone resorption in the presence of normal or increased numbers of multinucleated, but dysfunctional, osteoclasts. Cathepsin K degrades collagen type I and generates N-telopeptide (NTX) and the C-telopeptide (CTX) that can be quantified. Levels of these telopeptides are increased in lactating women and are associated with increased bone resorption. Nothing is known about the consequences of cathepsin K deficiency in lactating women. Here we present for the first time normalized blood and CTX measurements in a patient with pycnodysostosis, exclusively related to the lactation period. In vitro studies using osteoclasts derived from blood monocytes during lactation and after weaning further show consistent bone resorption before and after lactation. Increased expression of cathepsins L and S in osteoclasts derived from the lactating patient suggests that other proteinases could compensate for the lack of cathepsin K during the lactation period of pycnodysostosis patients.

Clinical and genetic evaluation of Danish patients with pycnodysostosis.

BACKGROUND: Pycnodysostosis is a rare autosomal recessive osteosclerotic skeletal dysplasia caused by variants in the cathepsin K gene (CTSK). Clinical features include short stature, bone fragility, characteristic facial features and acro-osteolysis of the distal phalanges. Usually, patients suffer from multiple bone fractures. The purpose of this study was to describe the Danish population of pycnodysostosis patients with respect to genotype, phenotype and the prevalence of complications. We collected medical history, performed clinical examination, collected blood- and urine samples, performed dual-energy x-ray absorptiometry scan (DXA) and high-resolution peripheral quantitative computed tomography scan (HRpQCT) and obtained clinical photos. Information about complications, bone mineral density and bone markers in the blood were collected and analysed. RESULTS: Ten patients with a median age of 32 years ranging from five to 51 years participated. The pycnodysostosis phenotype varied with respect to the number of bone fractures and degree of complications. DXA and HRpQCT showed high bone mineral density. A tendency of growth hormone treatment escalating growth and increasing final height was seen. A marker of bone resorption measured in blood was within normal range in nine patients and elevated in one patient. A novel pathogenic variant in CSTK causing pycnodysostosis was detected in two related patients. Moreover information about the patients' own health perception was reported. An example being they rated their mental health to be good despite multiple bone fractures. CONCLUSION: This study provides information about genotypes and phenotypes in a Danish pycnodysostosis population. It reports new data about the complications such as bone fractures and it elucidates the levels of bone turnover markers as well as the density of the bones in one of the biggest cohort of pycnodysostosis patients ever published. An individualised approach to treatment in this patient group is necessary as the phenotype including complications varies between patients. Additional studies are needed to further understand genotype-phenotype correlations.

Pycnodysostosis: Natural history and management guidelines from 27 French cases and a literature review.

Pycnodysostosis is a lysosomal autosomal recessive skeletal dysplasia characterized by osteosclerosis, short stature, acro-osteolysis, facial features and an increased risk of fractures. The clinical heterogeneity of the disease and its rarity make it difficult to provide patients an accurate prognosis, as well as appropriate care and follow-up. French physicians from the OSCAR network have been asked to fill out questionnaires collecting molecular and clinical data for 27 patients issued from 17 unrelated families. All patients showed short stature (mean = -3.5 SD) which was more severe in females (P = .006). The mean fracture rate was moderate (0.21 per year), with four fractures in total average. About 75% underwent at least one surgery, with an average number of 2.1 interventions per patient. About 50% required non-invasive assisted ventilation due to sleep apnea (67%). About 29% showed psychomotor difficulties and 33% needed a school assistant or adapted schooling. No patient had any psychological evaluation or follow-up. Molecular data were available for 14 families. Growth hormone administration was efficient on linear growth in 40% of cases. We propose several axis of management, such as systematic cerebral MRI for Chiari malformation screening at diagnosis and regular psychological follow-up.

Not all pycnodysostosis-related mutants of human cathepsin K are inactive - crystal structure and biochemical studies of an active mutant I249T.

Human cathepsin K (CTSK) is a collagenolytic lysosomal cysteine protease that plays an important role in bone turnover. Mutation in CTSK gene is associated with loss of collagenolytic activity of CTSK leading to an autosomal recessive bone disorder called pycnodysostosis. Although a number of pycnodysostotic missense mutations have been reported, underlying mechanism of the disease is not clear. In this study, we investigated in vitro six recombinant pycnodysostosis-related mutants of human CTSK (G79E, I249T, G243E, G303E, G319C and Q187P). While all the mutants, like wild-type, show similar high levels of expression in Escherichia coli, four of them (G79E, G303E, G319C and Q187P) are inactive, unstable and spontaneously degrade during purification process. In contrast, proteolytic/collagenolytic activity, zymogen activation kinetics and stability of G243E and I249T mutants are nominally affected. Crystal structure of I249T at 1.92 Å resolution shows that the mutation in R-domain causes conformational changes of a surface loop in the L-domain although the catalytic cleft remains unaltered. Molecular simulation, normal mode analysis and fluorescence lifetime measurement eliminated the possibility that the change in L-domain surface loop orientation is a crystallization artefact. CD-based thermal melting profile indicates that stability of I249T is significantly higher than wild-type. Our studies first time reports that pycnodysostosis-related mutations do not always lead to complete loss of general proteolytic activity or specific collagenolytic activity of CTSK. The first crystal structure of a pycnodysostotic mutant (I249T) provides critical information that may pave new avenues towards understanding the disease at molecular level. DATABASE: The atomic co-ordinates and structure factors for I249T mutant of human CTSK (codes 5Z5O) have been deposited in the Protein Data Bank (http://wwpdb.org/).

Genetic study of eight Egyptian patients with pycnodysostosis: identification of novel CTSK mutations and founder effect.

This is the first Egyptian study with detailed clinical and orodental evaluation of eight patients with pycnodysostosis and identification of four mutations in CTSK gene with two novel ones and a founder effect. INTRODUCTION: Pycnodysostosis is a rare autosomal recessive skeletal dysplasia due to mutations in the CTSK gene encoding for cathepsin K, a lysosomal cysteine protease. METHODS: We report on the clinical, orodental, radiological, and molecular findings of eight patients, from seven unrelated Egyptian families with pycnodysostosis. RESULTS: All patients were offspring of consanguineous parents and presented with the typical clinical picture of the disorder including short stature, delayed closure of fontanels, hypoplastic premaxilla, obtuse mandibular angle, and drum stick terminal phalanges with dysplastic nails. Their radiological findings showed increased bone density, acro-osteolysis, and open cranial sutures. Mutational analysis of CTSK gene revealed four distinct homozygous missense mutations including two novel ones, c.164A>C (p. K55T) and c.433G>A (p.V145M). The c.164A>C (p. K55T) mutation was recurrent in three unrelated patients who also shared similar haplotype, suggesting a founder effect. CONCLUSION: Our findings expand the mutational spectrum of CTSK gene and emphasize the importance of full clinical examination of all body systems including thorough orodental evaluation in patients with pycnodysostosis.

Human Genetics of Sclerosing Bone Disorders.

PURPOSE OF REVIEW: The group of sclerosing bone disorders encompasses a variety of disorders all marked by increased bone mass. In this review, we give an overview of the genetic causes of this heterogeneous group of disorders and briefly touch upon the value of these findings for the development of novel therapeutic agents. RECENT FINDINGS: Advances in the next-generation sequencing technologies are accelerating the molecular dissection of the pathogenic mechanisms underlying skeletal dysplasias. Throughout the years, the genetic cause of these disorders has been extensively studied which resulted in the identification of a variety of disease-causing genes and pathways that are involved in bone formation by osteoblasts, bone resorption by osteoclasts, or both processes. Due to this rapidly increasing knowledge, the insights into the regulatory mechanisms of bone metabolism are continuously improving resulting in the identification of novel therapeutic targets for disorders with reduced bone mass and increased bone fragility.

A case report of pycnodysostosis with atypical femur fracture diagnosed by next-generation sequencing of candidate genes.

RATIONALE: Pycnodysostosis is a rare autosomal recessive skeletal dysplasia characterized by short stature, craniofacial dysmorphism, acro-osteolysis, osteosclerosis, and brittle bone with poor healing. Pycnodysostosis results from the deficient activity of cathepsin K, a lysosomal cysteine protease that is encoded by CTSK. PATIENT CONCERNS: We report a Korean adult patient with pycnodysostosis and atypical femur fracture whose diagnosis was confirmed by next-generation sequencing (NGS) of candidate genes. A 41-year-old female patient was presented with a left femur fracture after falling down. Underlying sclerotic bone disease was suspected as a radiographic skeletal survey showed thickened cortical bones, and the total body bone density was increased (T score was 5.3, and Z score was 4.9). DIAGNOSES: We performed candidate gene sequencing of various sclerotic bone diseases for the differential molecular diagnosis of underlying sclerosing bone disease. Two heterozygous variants of CTSK were detected. One was a frameshift variant in exon 5, c.426delT (p.Phe142Leufs*19), which was previously reported, and the other was a novel missense variant in exon 6, c.755G>A (p.Ser252Asn). Sanger sequencing of CTSK confirmed the 2 heterozygous variants and thus the patient was diagnosed with pycnodysostosis. INTERVENTIONS: The patient had emergency surgery for subtrochantic femoral fracture. OUTCOMES: After 4 months of surgery, the patient had almost a full range of hip and knee movements and radiographs show the substantial bridging callus across the fracture. LESSONS: Candidate gene sequencing could be a useful diagnostic tool for the genetically heterogeneous skeletal dysplasia group, especially in cases with a mild or atypical clinical phenotype.

Pycnodysostosis with novel gene mutation and sporadic medullary thyroid carcinoma: A case report.

RATIONALE: Pycnodysostosis is a rare autosomal recessive skeletal dysplasia caused by a mutation in the cathepsin K encoded by cathepsin K gene (CTSK). Medullary thyroid carcinoma (MTC) is also a relatively rare type of primary thyroid carcinoma. PATIENT CONCERNS: A 31-year-old woman presenting a short stature and a palpable nodule in the front of her neck that had gradually increased in size during the last 2 years was referred to our department. She has experienced multiple fractures at lower limbs in the last 2 decades. DIAGNOSES: The patient's clinical examination revealed short stature, underweight, a prominent forehead, stubby fingers, and a fixed nodule in the right thyroid lobe. Intraoral examination revealed multiple clinically malposed and missing teeth, as well as chronic periodontitis with a narrow and grooved palate. Radiographic examination revealed typical widely separated cranial sutures and an open anterior/posterior fontanel with an obtuse gonial angle, acroosteolysis, and osteosclerosis with narrowed medullary cavities. Ultrasonography of the thyroid gland showed a marked hypoechoic solid nodule in the right lobe in which tumor cell clusters were confirmed by ultrasound-guided fine needle aspiration biopsy and was suspected to be MTC. Laboratory tests revealed dramatically elevated serum calcitonin >2000 pg/L (reference range: 0-5 pg/L) and carcinoembryonic antigen (CEA) 134.37 ng/mL (reference range: 0-5 ng/mL). Genotypic screening revealed compound heterozygous mutations in the CTSK gene (c.158delA, P.Asn53Thr/c.C830T, P.Ala277Val) but no mutation associated with the familial forms of MTC. INTERVENTIONS: The patient underwent a total thyroidectomy with right-sided functional neck dissection. OUTCOMES: CEA and serum calcitonin decreased significantly postthyroidectomy, and no further fracture has been reported by the patient so far. LESSONS: The present study is the first to report a rare case of the coexistence of pycnodysostosis with a compound CTSK gene mutation and sporadic MTC. Radiological techniques and gene analysis play key roles in the definitive diagnosis.

Inherited diseases caused by mutations in cathepsin protease genes.

Lysosomal cathepsins are proteolytic enzymes increasingly recognized as prognostic markers and potential therapeutic targets in a variety of diseases. In those conditions, the cathepsins are mostly overexpressed, thereby driving the respective pathogenic processes. Although less known, there are also diseases with a genetic deficiency of cathepsins. In fact, nowadays 6 of the 15 human proteases called 'cathepsins' have been linked to inherited syndromes. However, only three of these syndromes are typical lysosomal storage diseases, while the others are apparently caused by defective cleavage of specific protein substrates. Here, we will provide an introduction on lysosomal cathepsins, followed by a brief description of the clinical symptoms of the various genetic diseases. For each disease, we focus on the known mutations of which many have been only recently identified by modern genome sequencing approaches. We further discuss the effect of the respective mutation on protease structure and activity, the resulting pathogenesis, and possible therapeutic strategies.

Molecular analysis of the CTSK gene in a cohort of 33 Brazilian families with pycnodysostosis from a cluster in a Brazilian Northeast region.

BACKGROUND: Pycnodysostosis is an autosomal recessive skeletal dysplasia, the prevalence of which is estimated to be low (1 per million). Nevertheless, in recent years we have found 27 affected individuals from 22 families in Ceará State, a region of the Brazilian Northeast, giving a local prevalence of 3 per million. This local prevalence associated with a high parental consanguinity, suggesting a possible founder effect, prompted us to perform a molecular investigation of these families to test this hypothesis. METHODS: The CTSK gene was sequenced by the Sanger method in the patients and their parents. In addition to 18 families from Ceará, this study also included 15 families from other Brazilian regions. We also investigated the origin of each family from the birthplace of the parents and/or grandparents. RESULTS: We have studied 39 patients, including 33 probands and 6 sibs, from 33 families with pycnodysostosis and identified six mutations, five previously described (c.436G>C, c.580G>A, c.721C>T, c.830C>T and c.953G>A) and one novel frameshift (c.83dupT). This frameshift variant seems to have a single origin in Ceará State, since the haplotype study using the polymorphic markers D1S2344, D1S442, D1S498 and D1S2715 suggested a common origin. Most of the mutations were found in homozygosity in the patients from Ceará (83.3 %) while in other states the mutations were found in homozygosity in half of patients. We have also shown that most of the families currently living outside of Ceará have northeastern ancestors, suggesting a dispersion of these mutations from the Brazilian Northeast. CONCLUSIONS: The high frequency of pycnodysostosis in Ceará State is the consequence of the high inbreeding in that region. Several mutations, probably introduced a long time ago in Ceará, must have spread due to consanguineous marriages and internal population migration. However, the novel mutation seems to have a single origin in Ceará, suggestive of a founder effect.

The role of cathepsin K in oral and maxillofacial disorders.

Cathepsin K (CTSK) was thought to be a collagenase, specifically expressed by osteoclasts, and played an important role in bone resorption. However, more and more research found that CTSK was expressed in more extensive cells, tissues, and organs. It may not only participate in regulating human physiological activity, but also be closely related to a variety of disease. In this review, we highlight the relationship between CTSK and oral and maxillofacial disorders on the following three aspects: oral and maxillofacial abnormities in patients with pycnodysostosis caused by CTSK mutations, oral and maxillofacial abnormities in Ctsk(-/-) mice, and the role of CTSK in oral and maxillofacial diseases, including periodontitis, peri-implantitis, tooth movement, oral and maxillofacial tumor, root resorption, and periapical disease.

Miscellaneous Bone Disorders.

This chapter deals with a few of the important childhood bone disorders associated with high bone mass as well as conditions associated with fragility fractures and limb deformities that have not been addressed in previous chapters. A couple of skeletal dysplasias that can sometimes be confused with rickets are also dealt with in this chapter.

A Mutation in CTSK Gene in an Autosomal Recessive Pycnodysostosis Family of Chinese Origin.

Pycnodysostosis is a rare autosomal recessive skeletal dysplasia characterized by short stature, osteosclerosis, acro-osteolysis, frequent fractures, and skull deformities. Mutation in the gene encoding cathepsin K (CTSK), which is a lysosomal cysteine protease, has been found to be responsible for this disease. Here we reported a consanguineous Chinese family with 1 affected individual demonstrating autosomal recessive pycnodysostosis with recurrent kidney stone, a new clinical manifestation which has not been reported in patients of pycnodysostosis before. To identify the pathogenic mutation, we evaluated the patient clinically, biochemically, and radiographically. To screen for mutations in the CTSK gene of the patient and his family members, all of its exons and exon-intron junctions were PCR amplified from genomic DNA and sequenced. Sequence analysis of the patient's CTSK gene revealed homozygosity for a missense mutation (c.746T>C) in exon 6, which leads to amino change (p.Ile249Thr) in the mature CTSK protein. This mutation was firstly reported by Michela Donnarumma and his colleagues in 2007 in a Spanish family. Our study strengthens the role of this particular mutation in the pathogenesis of pycnodysostosis.

Dental Abnormalities Caused by Novel Compound Heterozygous CTSK Mutations.

Cathepsin K (CTSK) is an important protease responsible for degrading type I collagen, osteopontin, and other bone matrix proteins. The mutations in the CTSK gene can cause pycnodysostosis (OMIM 265800), a rare autosomal recessive bone dysplasia. Patients with pycnodysostosis have been reported to present specific dental abnormalities; however, whether these dental abnormalities are related to dysfunctional CTSK has never been reported. Here we investigated the histologic changes of cementum and alveolar bone in a pycnodysostosis patient, caused by novel compound heterozygous mutations in the CTSK gene (c.87 G>A p.W29X and c.848 A>G p.Y283C). The most impressive manifestations in tooth were extensive periradicular high-density clumps with unclear periodontal space by orthopantomography examination and micro-computed tomography scanning analysis. Hematoxylin/eosin and toluidine blue staining and atomic force microscopy analysis showed that the cementum became significantly thickened, softened, and full of cementocytes. The disorganized bone structure was the main character of alveolar bone. The p.W29X mutation may represent the loss-of-function allele with an earlier termination codon in the precursor CTSK polypeptide. Residue Y283 is highly conserved among papain-like cysteine proteases. Three-dimensional structure modeling analysis found that the loss of the hydroxybenzene residue in the Y283C mutation would interrupt the hydrogen network and possibly affect the self-cleavage of the CTSK enzyme. Furthermore, p.Y283C mutation did not affect the mRNA and protein levels of overexpressed CTSK in COS-7 system but did reduce CTSK enzyme activity. In conclusion, the histologic and ultrastructural changes of cementum and alveolar bone might be affected by CTSK mutation via reduction of its enzyme activity (clinical trial registration: ChiCTR-TNC-10000876).

[Rickets-like genetic diseases].

This paper summarizes the clinical features, causative genes and treatment progress of patients with rickets-like genetic diseases, including X-linked hypophosphatemic rickets (XLH), hypophosphatasia, achondroplasia, vitamin D-dependent rickets, pycnodysostosis and ectodermal dysplasia, who visited the pediatric or child health clinic due to the symptoms of rickets, including bow legs, delayed closure of the anterior fontanelle, and sparse hair. Children with XLH usually go to hospital for bow legs and short stature, and biochemical evaluation reveals significantly low serum phosphorus so it is easily diagnosed. This disease is treated using phosphate mixture and 1,25(OH)2D3, which is different from the treatment of nutritional vitamin D deficiency rickets. Hypophosphatasia is characterized by a significant decrease in serum alkaline phosphatase, as well as normal serum calcium and phosphorus. The disease is caused by mutations in TNSALP gene. Patients with achondroplasia show short-limbed dwarfism and special face in addition to bow legs, but with normal serum calcium, phosphorus and alkaline phosphatase. Bone X-ray and FGFR3 gene test contribute to the diagnosis. Vitamin D-dependent rickets is an autosomal recessive disease, and active vitamin D supplement is effective in treatment of the disease. Patients with pycnodysostosis may be first seen at hospital because of large anterior fontanelle; in addition, they also show obtuse mandibular angle, dental abnormalities and dysplastic nails, which are caused by mutations in TSK gene. Children with ectodermal dysplasia may see a doctor for sparse hair, and they are easily misdiagnosed with nutritional vitamin D deficiency rickets. Ectodermal dysplasia is related to EDA, EDAR, EDARADD and WNT 10A genes.

Novel CTSK mutation resulting in an entire exon 2 skipping in a Thai girl with pycnodysostosis.

Pycnodysostosis is a rare autosomal recessive skeletal dysplasia characterized by osteosclerosis, short stature, acro-osteolysis of the distal phalanges, bone fragility and skull deformities. Mutations in the cathepsin K (CTSK) gene, which encodes a lysosomal cysteine protease highly expressed in osteoclasts, have been found to be responsible for the disease. We identified a Thai girl with pycnodysostosis. Her parents were first cousins. Polymerase chain reaction sequencing of the entire coding regions of CTSK of the proband's complementary DNA revealed that the whole exon 2 was skipped. We subsequently amplified exon 2 using genomic DNA, which showed that the patient was homozygous for a c.120G>A mutation. The mutation was located at the last nucleotide of exon 2. Its presence was confirmed by restriction enzyme analysis using BanI. The skipping of exon 2 eliminates the normal start codon. The mutation has never been previously reported, thus the current report expands the CTSK mutational spectrum.