Sleep-disordered breathing and its management in children with rare skeletal dysplasias.

Sleep-disordered breathing (SDB) is common in patients with skeletal dysplasias. The aim of our study was to analyze SDB and respiratory management in children with rare skeletal dysplasias. We performed a retrospective analysis of patients with spondyloepiphyseal dysplasia congenita (SEDC), metatropic dysplasia (MD), spondyloepimetaphyseal dysplasia (SEMD), acrodysostosis (ADO), geleophysic dysplasia (GD), acromicric dysplasia (AD), and spondylocostal dysplasia (SCD) between April 2014 and October 2020. Polygraphic data, clinical management, and patients' outcome were analyzed. Thirty-one patients were included (8 SEDC, 3 MD, 4 SEMD, 1 ADO, 4 GD, 3 AD, and 8 SCD). Sixteen patients had obstructive sleep apnea (OSA): 11 patients (2 with SEDC, 1 with SEMD, 1 with ADO, 1 with GD, 2 with AD, and 4 with SCD) had mild OSA, 2 (1 SEMD and 1 GD) had moderate OSA, and 3 (1 SEDC, 1 MD, 1 SEMD) had severe OSA. Adenotonsillectomy was performed in one patient with SCD and mild OSA, and at a later age in two other patients with ADO and AD. The two patients with moderate OSA were treated with noninvasive ventilation (NIV) because of nocturnal hypoxemia. The three patients with severe OSA were treated with adenotonsillectomy (1 SEDC), adeno-turbinectomy and continuous positive airway pressure (CPAP; 1 MD), and with NIV (1 SEMD) because of nocturnal hypoventilation. OSA and/or alveolar hypoventilation is common in patients with skeletal dysplasias, underlining the importance of systematic screening for SDB. CPAP and NIV are effective treatments for OSA and nocturnal hypoventilation/hypoxemia.

Fourteen-year follow-up of a child with acroscyphodysplasia with emphasis on the need for multidisciplinary management: a case report.

BACKGROUND: Acroscyphodysplasia has been described as a phenotypic variant of acrodysostosis type 2 and pseudohypoparathyroidism. In acrodysostosis, skeletal features can include brachydactyly, facial hypoplasia, cone-shaped epiphyses, short stature, and advanced bone age. To date, reports on this disorder have focused on phenotypic findings, endocrine changes, and genetic variation. We present a 14-year overview of a patient, from birth to skeletal maturity, with acroscyphodysplasia, noting the significant orthopaedic challenges and the need for a multidisciplinary team, including specialists in genetics, orthopaedics, endocrinology, and otolaryngology, to optimize long-term outcomes. CASE PRESENTATION: The patient presented as a newborn with dysmorphic facial features, including severe midface hypoplasia, malar flattening, nasal stenosis, and feeding difficulties. Radiologic findings were initially subtle, and a skeletal survey performed at age 7 months was initially considered normal. Genetic evaluation revealed a variant in PDE4D and subsequent pseudohypoparathyroidism. The patient presented to the department of orthopaedics, at age 2 years 9 months with a leg length discrepancy, right knee contracture, and severely crouched gait. Radiographs demonstrated cone-shaped epiphyses of the right distal femur and proximal tibia, but no evidence of growth plate changes in the left leg. The child developed early posterior epiphyseal arrest on the right side and required multiple surgical interventions to achieve neutral extension. Her left distal femur developed late posterior physeal arrest and secondary contracture without evidence of schypho deformity, which improved with anterior screw epiphysiodesis. The child required numerous orthopaedic surgical interventions to achieve full knee extension bilaterally. At age 13 years 11 months, she was an independent ambulator with erect posture. The child underwent numerous otolaryngology procedures and will require significant ongoing care. She has moderate intellectual disability. DISCUSSION AND CONCLUSIONS: Key challenges in the management of this case included the subtle changes on initial skeletal survey and the marked asymmetry of her deformity. While cone-shaped epiphyses are a hallmark of acrodysostosis, posterior tethering/growth arrest of the posterior distal femur has not been previously reported. Correction of the secondary knee contracture was essential to improve ambulation. Children with acroscyphodysplasia require a multidisciplinary approach, including radiology, genetics, orthopaedics, otolaryngology, and endocrinology specialties.

Inactivating PTH/PTHrP Signaling Disorders.

Pseudohypoparathyroidism (PHP), pseudo-PHP, acrodysostosis, and progressive osseous heteroplasia are heterogeneous disorders characterized by physical findings, differently associated in each subtype, including short bones, short stature, a stocky build, ectopic ossifications (features associated with Albright's hereditary osteodystrophy), as well as laboratory abnormalities consistent with hormone resistance, such as hypocalcemia, hyperphosphatemia, and elevated parathyroid hormone (PTH) and thyroid-stimulating hormone levels. All these disorders are caused by impairments in the cAMP-mediated signal transduction pathway and, in particular, in the PTH/PTHrP signaling pathway: the main subtypes of PHP and related disorders are caused by de novo or autosomal dominantly inherited inactivating genetic mutations, and/or epigenetic, sporadic, or genetic-based alterations within or upstream of GNAS, PRKAR1A, PDE4D, and PDE3A. Here we will review the impressive progress that has been made over the past 30 years on the pathophysiology of these diseases and will describe the recently proposed novel nomenclature and classification. The new term "inactivating PTH/PTHrP signaling disorder," iPPSD: (1) defines the common mechanism responsible for all diseases, (2) does not require a confirmed genetic defect, (3) avoids ambiguous terms like "pseudo," and (4) eliminates the clinical or molecular overlap between diseases.

Neonatal umbilical cord blood transplantation halts skeletal disease progression in the murine model of MPS-I.

Umbilical cord blood (UCB) is a promising source of stem cells to use in early haematopoietic stem cell transplantation (HSCT) approaches for several genetic diseases that can be diagnosed at birth. Mucopolysaccharidosis type I (MPS-I) is a progressive multi-system disorder caused by deficiency of lysosomal enzyme α-L-iduronidase, and patients treated with allogeneic HSCT at the onset have improved outcome, suggesting to administer such therapy as early as possible. Given that the best characterized MPS-I murine model is an immunocompetent mouse, we here developed a transplantation system based on murine UCB. With the final aim of testing the therapeutic efficacy of UCB in MPS-I mice transplanted at birth, we first defined the features of murine UCB cells and demonstrated that they are capable of multi-lineage haematopoietic repopulation of myeloablated adult mice similarly to bone marrow cells. We then assessed the effectiveness of murine UCB cells transplantation in busulfan-conditioned newborn MPS-I mice. Twenty weeks after treatment, iduronidase activity was increased in visceral organs of MPS-I animals, glycosaminoglycans storage was reduced, and skeletal phenotype was ameliorated. This study explores a potential therapy for MPS-I at a very early stage in life and represents a novel model to test UCB-based transplantation approaches for various diseases.

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.

Rare monogenetic syndromes in rheumatology practice.

The EULAR Executive Committee defined eight overall objectives for EULAR to achieve by 2012. The first of these objectives is to strengthen activities in areas that are currently less prioritized, such as non-inflammatory and orphan diseases. This study aims to increase awareness of rheumatologists towards rare hereditary musculoskeletal disorders, by describing their genetics, pathogenesis, and typical clinical and radiological features. We analyzed patient charts from the recent 5 years from the Rheumatology Outpatient Department of the University Erlangen-Nuremberg and of two rheumatologic practices, all joined in a regional network ("Rheumazentrum Erlangen") retrospectively for hereditary musculoskeletal disorders other than hemochromatosis, autoinflammatory syndromes, lysosomal storage diseases, and hypermobility syndromes. We were able to identify four patients with trichorhinophalangeal syndrome type I, multiple exostoses, Kirner's deformity, and osteopoikilosis. In addition, a PubMed and OMIM ("Online Mendelian Inheritance in Man") database search was carried out using these as key words and all relevant articles were reviewed for each of these diseases. Our findings show that rare hereditary musculoskeletal disorders occur in a routine rheumatological setting and that rheumatologists should know the clinical and radiological features of these diseases in order to adequately counsel the patient.

Spondylocostal dysostosis: thirteen new cases treated by conservative and surgical means.

STUDY DESIGN: Prospective assessment of a cohort of patients affected by spondylocostal dysostosis. OBJECTIVE: To report on the results of conservative and operative management of spondylocostal dysostosis and, based on this, to propose an assessment and treatment protocol for the condition. SUMMARY OF BACKGROUND DATA: Spondylocostal dysostosis and spondylothoracic dysostosis are subtypes of Jarcho-Levin syndrome, a hereditary condition manifested by vertebral body and related rib malformations. Mortality prevails in spondylothoracic dysostosis because of more severe respiratory compromise. METHODS: Details of prenatal and postnatal diagnosis, history, and management of 13 patients with spondylocostal dysostosis are presented. All patients were treated postnatally with repeated chest physiotherapy. Two patients refractory to conservative treatment underwent surgical intervention: the first had a chest wall reconstruction via a latissimus dorsi flap, the second a posterior spinal instrumented fusion for progressive scoliosis. RESULTS: Prenatal ultrasound in 4 of 13 cases showed full details of vertebral and rib anomalies. Thoracic and lumbar hemivertebrae were most common, leading to congenital scoliosis in 10 of 13 cases. A number of extraskeletal abnormalities were also identified. At an average follow-up of 4.5 years, the survival rate was 100% with a remarkable decrease of the rate of respiratory complications. Surgical treatment in selected cases led to satisfactory results. CONCLUSIONS: Prenatal diagnosis of spondylocostal dysostosis allows exclusion of spondylothoracic dysostosis and aids genetic counseling in quantifying the risk to siblings. Postnatally, prompt management of these patients with physiotherapy leads to prolonged survival. Surgical intervention may then be indicated to stabilize chest wall or spine deformities, with promising results.

[Pycnodysostosis--common ancestor of some Danish patients. Examination and diagnosis based on molecular genetics]. / Pyknodysostose--faelles stamfar til en del af danske patienter. Udredning og molekylaergenetisk diagnostik.

Eight patients with pycnodysostosis from six Danish families were examined for mutations in the cathepsin K gene. Three different mutations are the cause of pycnodysostosis in the six families--five of whom come from Ringkøbing County and one from Vejle County. One mutation has a high frequency in the families from Ringkoebing County. The five families are related through a common ancestor, who introduced the mutation around the year 1100. The disease is described with respect to aetiology, symptoms, prognosis, diagnosis, and symptomatic treatment. Research in pycnodysostosis may bring important knowledge to the understanding of related diseases, such as osteoporosis.

Effect of early orthopedic intervention on hemifacial microsomia patients: an approach to a cooperative evaluation of treatment results.

The purpose of the present study was to analyze the effects of early orthopedic intervention in patients with hemifacial microsomia, clinically as well as radiologically, by computed tomographic examination to assess soft and hard tissue temporomandibular joint changes. Five patients, one with mandibular dysostosis, one with otomandibular dysostosis, two with Goldenhar syndrome, and one with a surgically revised fibroma of the right mandible that was reconstructed by a costochondral graft, were treated by means of an activator functional appliance. During functional appliance treatment, all patients showed improvement of function and occlusion, and facial asymmetry was reduced. Spiral computed tomographic examination before and during treatment provided data on the bony and muscular deficiencies. The volume and density of the lateral pterygoid muscle was measured with the standard computed tomography software. Evaluation of soft and hard tissue conditions before treatment has shown that the most important factor "lack of soft tissues" can be compensated by excellent cooperation during functional therapy. Pretreatment volume of the affected lateral pterygoid muscle in all patients was significantly smaller than on the unaffected side. In three patients, volume measurements between 4 and 8 years demonstrated that the lateral pterygoid muscle on the affected side had a third, less than a third, and a fifth of the volume of the unaffected side. Although increase, stability, and decrease of the ratio of left and right condylar dimension, muscular volume, and density were found, long-term prognosis cannot be given in the cases with extreme muscular deficiencies after cessation of growth. Prepubertal orthopedic treatment success is a desirable and feasible presurgical or nonsurgical treatment goal for the interdisciplinary team approach. From a study of the pathologic, we learn much about the normal.

[Shwachman syndrome. Exocrine pancreatic insufficiency, growth retardation, peripheral dysostoses and neutropenia]. / Shwachman-Syndrom. Exokrine Pankreasinsuffizienz, Minderwuchs, periphere Dysostosen, Neutropenie.

Since the second year of her life a now 32-year-old woman had growth retardation and recurrent diarrhoea, caused by exocrine pancreatic insufficiency. During intermittent treatment with pancreatic enzymes the diarrhoea ceased and she gained weight. In the course of the illness she had to undergo several orthopaedic operations. Radiological examinations had revealed metaphyseal dysostoses. At the age of 14 years the marked growth retardation stimulated further clinical investigation. The growth retardation, compensated exocrine pancreatic insufficiency and peripheral dysostoses established the diagnosis of Shwachman syndrome, although there was no neutropenia. The severe exocrine pancreatic insufficiency, confirmed by pancreatic function tests, was probably compensated by extrapancreatic lipases, and pancreatic enzyme substitution therefore was unnecessary.

[Dysostoses and postural limb abnormalities in rapidly growing dogs]. / Dysostosen und Stellungsfehler der Gliedmassen bei Hunden mit hoher Wachstumsintensität.

Congenital and acquired dysostosis was studied on two litters of Great Danes. One litter of puppies were descendants of dogs with normal hips, the other of dysplastic animals. Both litters were fed according to NCR standards, the second however ad libitum. One puppy of parents with normal hips demonstrated already with 6 weeks epi- and metaphyseal dysostosis and severe angular deformities of the thoracic and pelvic limbs. Hip dysplasia was diagnosed in three of five puppies from dysplastic dogs. In addition, one puppy showed Wobbler symptoms. The extent and frequency of the alterations were, in comparison to earlier investigations, unexpectedly high. It can be assumed that the examined dogs were genetically predisposed for dysostosis. Our therapeutic procedures are presented.