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.

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.

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).

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.

The clinical spectrum and pathophysiology of skeletal complications in lysosomal storage disorders.

Lysosomal storage disorders affect multiple organs including the skeleton. Disorders with prominent skeletal symptoms are type 1 and 3 Gaucher disease, the mucopolysaccharidoses, the glycoproteinoses and pycnodysostosis. Clinical manifestations range from asymptomatic radiographical evidence of bone pathology to overt bone crises (Gaucher), short stature with typical imaging features known as dysostosis multiplex (MPS), with spine and joint deformities (mucopolysaccharidoses, mucolipidosis), or osteopetrosis with pathological fractures (pynodysostosis). The pathophysiology of skeletal disease is only partially understood and involves direct substrate storage, inflammation and other complex alterations of cartilage and bone metabolism. Current treatments are enzyme replacement therapy, substrate reduction therapy and hematopoietic stem cell transplantation. However, effects of these interventions on skeletal disease manifestations are less well established and outcomes are highly dependent on disease burden at treatment initiation. It is now clear that adjunctive treatments that target skeletal disease are needed and should be part of future research agenda.

Pycnodysostosis: review and case report.

AIM: Aim of the present study was to present a case report of a patient suffering from pycnodysostosis and assess how it may manifest and affect the dental/ orthodontic treatment. METHODS: An 11-year-old patient who was diagnosed with pycnodysostosis at the age of 18 months, attended the orthodontics department requiring treatment for extensive carious lesions, periodontal disease and severe crowding. RESULTS: After an accurate radiographic, clinical and orthodontic assessment of the patient taking into consideration the severity of the condition and the patient's necessities, we have formulated a treatment plan, which was accepted by both the patient and parents. We took into consideration the risks and benefits of the options available and the requests of the patient. CONCLUSION: We have decided to opt for the extraction of teeth to relieve the crowding as this was impeding good oral hygiene and hence increasing the risk of caries and periodontal disease. Such patients must be placed under an oral hygiene prevention scheme, a treatment plan must be accurately designed and the patient must be constantly motivated.

Challenges in the orthodontic treatment of a patient with pycnodysostosis.

Pycnodysostosis is a rare, autosomal recessive syndrome characterized by osteosclerosis, brittle bones, stunting, and significant craniofacial changes. The objective of this study was to report a case of a 6-year-old patient with pycnodysostosis orthodontically treated and followed up until age 10 years and to discuss the risk factors, options for orthodontic treatment, and limitations involving this type of treatment, which has not yet been performed. Prevention through counseling and periodic follow-up visits is essential in eliminating factors that predispose patients to infections and fractures. New studies are necessary to establish safe and efficient orthodontic treatment plans.

[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.

Pycnodysostosis with novel gene mutation and severe obstructive sleep apnoea: management of a complex case.

Pycnodysostosis is a rare genetic disease. Impaired osteoclastic function is the basis for typical phenotypic features and bone fragility. The main differential diagnosis is osteopetrosis, also associated with altered bone remodelling, but with a more severe prognosis. We describe the case of an 8-year-old boy who presented life-threatening obstructive sleep apnoea successfully managed with non-invasive ventilation. Haematological overlap phenotype included anaemia and altered bone marrow, more common in osteopetrosis. Molecular analysis of the CTSK gene revealed a mutation not previously described in the literature.

Pycnodysostosis with extreme sleep apnea: a possible alternative to tracheotomy.

PURPOSE: Pycnodysostosis (OMIM:265800) is an autosomal recessive genetic disorder due to a mutation in the cathepsin K gene, which causes a decrease of the bone turnover and a deterioration of the bone structure. Our aim was to describe a 5 year-old patient affected by pycnodysostosis, associated with an extremely severe obstructive sleep apnea syndrome, who was treated effectively with a combination of upper airway surgery and positive pressure ventilation. METHODS: A 5 year-old child affected by pycnodysostosis was referred to us for failure to thrive, facial dysmorphisms and respiratory disorders, and who developed an extremely severe sleep apnea syndrome. RESULTS: Polysomnography showed extremely severe OSAS (AHI = 81.6 events/hour). The child was treated successfully with a combination of adenotonsillectomy, uvulo-palato-pharingo plasty (UPPP), followed by positive pressure ventilation. Polysomnographic recordings confirmed the striking reduction of obstructive respiratory events during sleep (from 81.6 to 12.3 events/hour). Lateral skull Rx and cephalometric measures showed that the Posterior Airway Space (PAS) increased from 3 to 19 mm. The decision to perform UPPP in association with adeno-tonsillectomy was motivated by the presence of palatal obstruction, caused by hypertrophic and prolapsed soft tissue. CONCLUSIONS: Our observations suggest that a conservative surgical treatment, consisting of adenotonsillectomy plus UPPP, may increases the patency of the upper airway, both at palatal and pharyngeal level. The combination of adenotonsillectomy plus UPPP, followed by CPAP ventilation, may avoid tracheotomy in very severe OSAS patients.