Pycnodysostosis; A Rare Disease Case Report.

Pycnodysostosis is a rare disease with very few reported cased all over the world. It was first described in 1963 by Maroteaux and Lamy. It is also known as Toulouse-Lautrec syndrome, after a French artist, Henri de Toulouse Lautrec. The affected gene, CTSK, was first isolated in 1996. It is an autosomal recessive osteochondrodysplasia, characterized by disrupted function of osteoclasts. Incidence of this disease is 1.7 per 1 million births with a male to female ratio of 1:1 30% cases arise from consanguineous marriages.

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.

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.

Picnodisostosis familiar, reporte de un caso tras 10 años de seguimiento / Family picnodisostosis, report of a case after 10 years of follow-up

Resumen: Introducción: La picnodisostosis es una rara enfermedad secundaria en una mutación en el gen 1q21 que codifica la catepsina K, enzima implicada en el metabolismo de osteonectina, osteopontina y colágeno I. La incidencia mundial es de 1-1.7 casos por millón, sin prevalencia por género, se caracteriza clínicamente por talla baja, deformidades craneales, «cara de pájaro¼ y fragilidad ósea con tendencia a fracturas patológicas, que afectan predominantemente los huesos largos y ocasionalmente en los pedículos vertebrales. Radiológicamente es característica la presencia de osteoesclerosis con canales medulares permeables. Aunque existen numerosos reportes de casos clínicos en la literatura, pocos son los que describen familias con más de un individuo afectado y el seguimiento suele ser a corto plazo. Objetivo: Analizar la evolución clínica de los pacientes afectados. Material y métodos: Se realizó estudio retrospectivo, descriptivo, observacional de tres pacientes con diagnóstico de picnodisostosis, en el período de Julio 2006 a Marzo de 2016. Resultados: Se observaron diferentes formas de afectación de la picnodisostosis, algunas de ellas atípicas como la espondilólisis y una fractura de escápula en una paciente. Conclusiones: El presente estudio podría ser el análisis longitudinal más extenso del que se tenga registro. Conocer la variedad de manifestaciones y complicaciones presentadas permitirá al lector seleccionar el mejor método de tratamiento para cada caso.

Abstract: Introduction: Pycnodysostosis is a rare disease secondary to a mutation in gen 1q21 that codifies the cathepsin K, proteolitic enzyme implicated in the metabolism of osteonectin, osteopontin and type I colagen. Its global incidence is around 1-1.7 cases per million, without genre prevalences, it is clinically caracterized by short stature, craneal deformities, «bird's face¼ and bone fragility with pathological fractures tendency predominantly affecting long bones and occasionally vertebral pedicles. Radiologically is characterized by sclerous bones with permeable medular cannel. Despite there are numerous clinical reports on medical literature, just a litlle describe families with more than one afected member and its followship is usually short-term. Objective: To analize clinical evolution of these afected patients. Material and methods: A retrospective, descriptive, observational study was reelized in three patients with diagnosis of pycnodisostosis, between July 2006 and March 2016. Results: different affection forms of pycnodisostosis where observed, some of them, atipical, as for example spondilolisis and a escapule fracture in one patien. Conclusions: The present study could be the longest longitudinal report ever registered. By knowing the presented variety of manifestations and complications, the reader could select the best treatment method for each case.

Traumatic cervical spine injuries in a patient with pycnodysostosis.

Pycnodysostosis is a rare hereditary disease, characterized by systemic bone sclerosis. Susceptibility to long bone fractures is characteristic, whereas vertebral fractures are extremely rare. We report a case of a 21-year-old man with a past history of pycnodysostosis and spontaneous leg fractures who was admitted in hospital for a neck pain after a banal fall. Radiological examination revealed C1-C2-C3 posterior arch fractures with a C3-C4 left articular fracture dislocation. A surgical stabilization was decided but refused by the patient. To the best of our knowledge, this is the first publication that reports pycnodysostosis with cervical spine traumatic staged injuries.

[Family picnodisostosis, report of a case after 10 years of follow-up]. / Picnodisostosis familiar, reporte de un caso tras 10 años de seguimiento.

INTRODUCTION: Pycnodysostosis is a rare disease secondary to a mutation in gen 1q21 that codifies the cathepsin K, proteolitic enzyme implicated in the metabolism of osteonectin, osteopontin and type I colagen. Its global incidence is around 1-1.7 cases per million, without genre prevalences, it is clinically caracterized by short stature, craneal deformities, «birds face¼ and bone fragility with pathological fractures tendency predominantly affecting long bones and occasionally vertebral pedicles. Radiologically is characterized by sclerous bones with permeable medular cannel. Despite there are numerous clinical reports on medical literature, just a litlle describe families with more than one afected member and its followship is usually short-term. OBJECTIVE: To analize clinical evolution of these afected patients. MATERIAL AND METHODS: A retrospective, descriptive, observational study was reelized in three patients with diagnosis of pycnodisostosis, between July 2006 and March 2016. RESULTS: different affection forms of pycnodisostosis where observed, some of them, atipical, as for example spondilolisis and a escapule fracture in one patien. CONCLUSIONS: The present study could be the longest longitudinal report ever registered. By knowing the presented variety of manifestations and complications, the reader could select the best treatment method for each case.

INTRODUCCIÓN: La picnodisostosis es una rara enfermedad secundaria en una mutación en el gen 1q21 que codifica la catepsina K, enzima implicada en el metabolismo de osteonectina, osteopontina y colágeno I. La incidencia mundial es de 1-1.7 casos por millón, sin prevalencia por género, se caracteriza clínicamente por talla baja, deformidades craneales, «cara de pájaro¼ y fragilidad ósea con tendencia a fracturas patológicas, que afectan predominantemente los huesos largos y ocasionalmente en los pedículos vertebrales. Radiológicamente es característica la presencia de osteoesclerosis con canales medulares permeables. Aunque existen numerosos reportes de casos clínicos en la literatura, pocos son los que describen familias con más de un individuo afectado y el seguimiento suele ser a corto plazo. OBJETIVO: Analizar la evolución clínica de los pacientes afectados. MATERIAL Y MÉTODOS: Se realizó estudio retrospectivo, descriptivo, observacional de tres pacientes con diagnóstico de picnodisostosis, en el período de Julio 2006 a Marzo de 2016. RESULTADOS: Se observaron diferentes formas de afectación de la picnodisostosis, algunas de ellas atípicas como la espondilólisis y una fractura de escápula en una paciente. CONCLUSIONES: El presente estudio podría ser el análisis longitudinal más extenso del que se tenga registro. Conocer la variedad de manifestaciones y complicaciones presentadas permitirá al lector seleccionar el mejor método de tratamiento para cada caso.

[Pycnodysostosis: about a case]. / Pycnodysostose: à propos d'un cas.

Pycnodysostosis is a very rare genetic disease of the bone characterized by osteocondensation associated with dysmorphic syndrome and growth retardation. This study aims to highlight the phenotypic abnormalities, the radiological signs, the therapeutic and evolutionary features of pycnodysostosis in a 11-year old child. The child was referred by his dentist for clinical evaluation. He was born to first-degree consanguineous parents and had recurrent spontaneous fractures since the age of 3 years. Clinical examination showed dysmorphic syndrome characterized by frontal hump, persistent anterior fontanelle, micrognathia, finger deformities, dental malposition, curved nails, asymmetric chest, lumbar spine scoliosis with severe growth retardation (-4DS). Skeletal X-rays showed bony densification of the skull base, persistent anterior fontanelle, dental malposition, diaphysometaphyseal densification of the long bones mainly at the level of the lower limbs with malunions and tapered phalanges of the hands. Bone densitometry was normal. The diagnosis of pycnodysostosis was retained based on the clinical and radiological signs. Genetic counselling was proposed to the family as well as dental and orthopaedic treatment. Pycnodysostosis is a rare disorder; diagnosis is sometimes difficult and delayed posing diagnostic problem due to its resemblance with osteoporosis. Treatment is essentially based on fractures and dental caries prevention.

Pycnodysostosis at otorhinolaryngology.

AIM: Pycnodysostosis is a rare autosomal, recessive, skeletal dysplasia caused by a mutation in the cathepsin k gene. Pycnodysostosis is characterized by short stature, characteristic facial appearance (delayed closure of fontanelles and cranial sutures, mandibular hypoplasia and angle disorder, blue sclera), and acroosteolysis of the distal phalanges. Our aim was to describe the otorhinolaryngologic findings, differential diagnoses, various treatment options, and followup in eight cases of pycnodysostosis. METHOD: This retrospective clinical study used data from eight patients diagnosed with pycnodysostosis by a single pediatric endocrinologist primarily based on clinical and radiographic findings. All patients were referred to the otorhinolaryngology outpatient clinic by the pediatric endocrinology unit of the Marmara University between February 2013 and March 2015. Detailed medical histories were obtained in all cases and otorhinolaryngologic physical examination, blood assays, electrocardiogram, lateral skull X-rays, chest radiograph, cephalometric investigations, tympanograms, and audiograms were also carried out. Sleep videos of patients were recorded and those with upper airway problems were evaluated for sleep apnea by polysomnography. Informed consent form was obtained from the parents of all patients. RESULTS: Eight patients (7 females and 1 male) displaying proportionate dwarfism were included in the study. They had a mean age of 14.7 years (range: 13-16 y), the mean height of 141.3 cm (range 132-155 cm), and mean weight of 44.4 kg (range: 39.6-49.3 kg). All patients had facial dysmorphism with frontal bossing and the hands and feet had short digits with overlying cutaneous wrinkles that tapered off with large overriding nails. Midfacial hypoplasia and malocclusion were observed in seven of the eight patients (87.5%), four (50%) had micrognathia, and five (62.5%) had proptosis. Tympanograms and audiograms of all patients were type A and normal, and the mean of the pure tone audiogram was 13.3 dB (range: 10-16 dB). All patients had a narrow and grooved palate with disturbed dentition; two of them (25%) had mild markedness of the tongue base, five (62.5%) had grade 3 and three (37.5%) had grade 2 tonsillar hypertrophy, and five (62.5%) had adenoid hypertrophy. One patient (12.5%) had grade 3 Mallampati, four (50%) showed grade 2 Mallampati while three (37.5%) patients displayed grade 1 Mallampati score. Further, while six (75%) patients had no uvular pathology, one (12.5%) patient presented with uvular elongation and another patient had a bifid uvula. Cephalometric measurements such as PAS-UP (mean 5.67 mm; range: 5.0-7.6 mm) and PAS-TP (mean 9.61 mm; range: 8.5-12.2 mm) were lower than that of normal subjects. Video recordings showed that six of the eight patients (75%) had respiratory distress and four (50%) had sleep apnea. Polysomnography in these patients with sleep apnea showed that two had mild OSA (AHI: 18.2 and 20.1 events/hour) and two had severe OSA (AHI: 53.4 and 62.8 events/hour). For upper airway problems, an adenotonsillectomy was performed in two (25%) patients while two others required an adenoidectomy. Positive pressure ventilation was recommended in two patients with persistent sleep apnea after adeno/adenotonsillectomy. However, because of the parental objections, the follow-up polysomnographs could not be obtained. CONCLUSION: Pycnodysostosis is a very rare form of bone dysplasia. Otorhinolaryngologically, proper follow-up of these patients and appropriate treatment of upper airway problems are important to achieve an acceptable quality of life. Adeno/adenotonsillectomy and positive pressure ventilation, used as conservative approaches in treating upper airway problems, are effective and could be used instead of an aggressive surgery such as tracheotomy or maxillomandibular advancement. This study, to the best of our knowledge, is the largest ENT case series on pycnodysostosis.

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.

Oral Lesions in Pycnodysostosis Syndrome: Eleven Years of Follow-Up.

Pycnodysostosis is a rare genetic disease that is characterized by osteosclerosis, short stature, and bone fragility. There are not cases of gnathic bones lesions reported on the international literature. This study aims to describe a clinical case of a 10-year-old girl with pycnodysostosis syndrome and an uncommon association with 4 distinct lesions (dentigerous cyst, central giant cell lesions, and 2 fibro-osseous lesions).

Orthopaedic disorders of pycnodysostosis: a report of five clinical cases.

PURPOSE: Pycnodysostosis is a rare autosomal recessive genetic disorder usually diagnosed at an early age. The few previously published case series have generally focused on maxillofacial manifestations and genetic considerations. The purpose of this study was to evaluate the clinical characteristics and differential diagnosis of pycnodysostosis focusing on its orthopaedic manifestations, which have been poorly described in the literature. METHODS: We evaluated clinical and radiographic characteristics of five patients with pycnodysostosis. RESULTS: Three male and two female patients were included in the study. One patient had consanguineous parents and two had a family history of pycnodysostosis. One patient was of normal height; four with short stature underwent growth hormone treatment. Most patients had bone fractures. All had typical cranial and orofacial manifestations, partial dysplasia of the terminal phalanges and increased bone density. Aplastic acromial ends and spondylolysis were not seen in any patient. Some patients had genu valgus, ankle valgus or sleep apnea; two required tympanic drains for serous otitis media. Two patients experienced nonunion. CONCLUSIONS: Short stature is a consistent feature of pycnodysostosis that can be treated with growth hormone. To our knowledge, serous otitis media, nonunion and other orthopaedic manifestations have not been previously described in pycnodysostosis patients. Intramedullary nailing osteosynthesis can be difficult in these patients because of skeletal sclerosis; therefore, other surgical options should be considered. Nonunion is common in this population. Pycnodysostosis is a poorly described disease, but clinicians should be aware of its potential manifestations in order to appropriately diagnose, manage and follow-up patients.

Pycnodysostosis presenting as atypical stridor.

OBJECTIVES: Pycnodysostosis is a rare genetic disorder caused by a mutation of the cathepsin K gene involved in bone turnover. It is responsible, in particular, for a combination of dwarfism and bone fragility. Upper airway obstruction may be observed, but associated stridor has never been previously described. MATERIALS AND METHODS: Single-centre retrospective study over a period of 15 years with review of the literature. RESULTS: Three children (aged 2-18 months) were managed for stridor and obstructive sleep apnoea syndrome confirmed by polysomnography. Physical examination of these children revealed stridor with laryngomalacia, characteristic dysmorphic features and failure to thrive. Patient 1 presented typical laryngomalacia treated by surgical section of the aryepiglottic folds. Patient 2 presented upper airway obstruction with a narrow nasopharynx and long soft palate, treated by surgery and noninvasive ventilation. Patient 3 presented moderate laryngomalacia and nasal obstruction, treated by surgery and noninvasive ventilation. CONCLUSION: The diagnosis of pycnodysostosis must be considered in the presence of atypical laryngomalacia associated with multifactorial upper airway obstruction, failure to thrive and dysmorphic syndrome. A genetics consultation is essential in these patients.

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.