A recurrent homozygous LMNA missense variant p.Thr528Met causes atypical progeroid syndrome characterized by mandibuloacral dysostosis, severe muscular dystrophy, and skeletal deformities.

Atypical progeroid syndromes (APS) are premature aging syndromes caused by pathogenic LMNA missense variants, associated with unaltered expression levels of lamins A and C, without accumulation of wild-type or deleted prelamin A isoforms, as observed in Hutchinson-Gilford progeria syndrome (HGPS) or HGPS-like syndromes. A specific LMNA missense variant, (p.Thr528Met), was previously identified in a compound heterozygous state in patients affected by APS and severe familial partial lipodystrophy, whereas heterozygosity was recently identified in patients affected by Type 2 familial partial lipodystrophy. Here, we report four unrelated boys harboring homozygosity for the p.Thr528Met, variant who presented with strikingly homogeneous APS clinical features, including osteolysis of mandibles, distal clavicles and phalanges, congenital muscular dystrophy with elevated creatine kinase levels, and major skeletal deformities. Immunofluorescence analyses of patient-derived primary fibroblasts showed a high percentage of dysmorphic nuclei with nuclear blebs and typical honeycomb patterns devoid of lamin B1. Interestingly, in some protrusions emerin or LAP2α formed aberrant aggregates, suggesting pathophysiology-associated clues. These four cases further confirm that a specific LMNA variant can lead to the development of strikingly homogeneous clinical phenotypes, in these particular cases a premature aging phenotype with major musculoskeletal involvement linked to the homozygous p.Thr528Met variant.

Afectación respiratoria en paciente con acrodisostosis: una asociación infrecuente de una enfermedad rara / Respiratory impairment in a patient with acrodysostosis: A rare association of an uncommon pathology

La acrodisostosis es una displasia esquelética rara, de herencia autosómica dominante, que se caracteriza por la presencia de disostosis facial y periférica, talla baja y diferentes grados de obesidad. La acrodisostosis de tipo 1, secundaria a la mutación heterocigota en el gen PRKAR1A (17q24.2), se caracteriza por la asociación de resistencia hormonal múltiple con anomalías esqueléticas. Su incidencia está infradiagnosticada debido a que comparte rasgos clínicos y de laboratorio con otras entidades como el seudohipoparatiroidismo. Presentamos el caso de una niña de 8 años, con acrodisostosis tipo 1, confirmada mediante estudio genético. Además del fenotipo característico descrito, la talla baja y la resistencia hormonal, la paciente presentó una afectación progresiva de la función pulmonar: un patrón pulmonar obstructivo no reversible. En la literatura revisada, no se han encontrado otros casos que describan esta asociación entre acrodisostosis y afectación respiratoria.

Acrodysostosis is a rare skeletal displasia, of autosomal dominant inheritance, characterized by the presence of facial and peripheral dysostosis, short stature and obesity. Type 1 acrodysostosis is secondary to a mutation in the PRKAR1A (17q24.2) gene, which results in multi hormonal resistance and skeletal anomalities. This syndrome is under-diagnosed as it shares analytical and clinical characteristics with other entities, such as pseudohypoparathyroidism. We report the case of an eight-year-old girl with genetically confirmed type 1 acrodysostosis. In addition to the characteristic phenotype described, the short stature and the hormonal resistance, the patient suffered a progressive lung function deterioration: an irreversible pulmonary obstructive pattern. We have not found in previous literature cases reporting an association between acrodysostosis and lung function impairement.

[Respiratory impairment in a patient with acrodysostosis: A rare association of an uncommon pathology]. / Afectación respiratoria en paciente con acrodisostosis: una asociación infrecuente de una enfermedad rara.

Acrodysostosis is a rare skeletal displasia, of autosomal dominant inheritance, characterized by the presence of facial and peripheral dysostosis, short stature and obesity. Type 1 acrodysostosis is secondary to a mutation in the PRKAR1A (17q24.2) gene, which results in multi hormonal resistance and skeletal anomalities. This syndrome is under-diagnosed as it shares analytical and clinical characteristics with other entities, such as pseudohypoparathyroidism. We report the case of an eight-year-old girl with genetically confirmed type 1 acrodysostosis. In addition to the characteristic phenotype described, the short stature and the hormonal resistance, the Afectación respiratoria en paciente con acrodisostosis: una asociación infrecuente de una enfermedad rara Respiratory impairment in a patient with acrodysostosis: A rare association of an uncommon pathology patient suffered a progressive lung function deterioration: an irreversible pulmonary obstructive pattern. We have not found in previous literature cases reporting an association between acrodysostosis and lung function impairement.

La acrodisostosis es una displasia esquelética rara, de herencia autosómica dominante, que se caracteriza por la presencia de disostosis facial y periférica, talla baja y diferentes grados de obesidad. La acrodisostosis de tipo 1, secundaria a la mutación heterocigota en el gen PRKAR1A (17q24.2), se caracteriza por la asociación de resistencia hormonal múltiple con anomalías esqueléticas. Su incidencia está infradiagnosticada debido a que comparte rasgos clínicos y de laboratorio con otras entidades como el seudohipoparatiroidismo. Presentamos el caso de una niña de 8 años, con acrodisostosis tipo 1, confirmada mediante estudio genético. Además del fenotipo característico descrito, la talla baja y la resistencia hormonal, la paciente presentó una afectación progresiva de la función pulmonar: un patrón pulmonar obstructivo no reversible. En la literatura revisada, no se han encontrado otros casos que describan esta asociación entre acrodisostosis y afectación respiratoria.

Novel progressive acrodysostosis-like skeletal dysplasia, cerebellar atrophy, and ichthyosis.

Acrodysostosis refers to a rare heterogeneous group of bone dysplasias that share skeletal features, hormone resistance, and intellectual disability. Two genes have been associated with acrodysostosis with or without hormone resistance (PRKAR1A and PDE4D). Severe intellectual disability has been reported with acrodysostosis but brain malformations and ichthyosis have not been reported in these syndromes. Here we describe a female patient with acrodysostosis, intellectual disability, cerebellar hypoplasia, and lamellar ichthyosis. The patient has an evolving distinctive facial phenotype and childhood onset ataxia. X-rays showed generalized osteopenia, shortening of middle and distal phalanges, and abnormal distal epiphysis of the ulna and radius. Brain magnetic resonance imaging showed cerebellar atrophy without other brainstem abnormalities. Genetic workup included nondiagnostic chromosomal microarray and skeletal dysplasia molecular panels. These clinical findings are different from any recognized form of acrodysostosis syndrome. Whole exome sequencing did not identify rare or predicted pathogenic variants in genes associated with known acrodysostosis, lamellar ichthyosis, and other overlapping disorders. A broader search for rare alleles absent in healthy population databases and controls identified two heterozygous truncating alleles in FBNL7 and PPM1M genes, and one missense allele in the NPEPPS gene. Identification of additional patients is required to delineate the mechanism of this unique disorder.

[Genes in the cAMP pathway causing skeletal dysplasia with or without hormonal resistance]. / Gènes de régulation de la voie de l'AMPc, résistance hormonale et dysplasie squelettique.

Acrodysostosis refers to a heterogeneous group of rare skeletal dysplasia that share characteristic features including severe brachydactyly, facial dysostosis and nasal hypoplasia. The literature describing acrodysostosis cases has been confusing because some reported patients may have had other phenotypically related diseases presenting Albright Hereditary Osteodystrophy (AHO) such as pseudohypoparathyroidism type 1a (PHP1a) or pseudopseudohypoparathyroidism (PPHP). A question has been whether patients display or not abnormal mineral metabolism associated with resistance to PTH and/or resistance to other hormones that bind G-protein coupled receptors (GPCR) linked to Gsa, as observed in PHP1a. Defects in two genes, PRKAR1A and PDE4D, both important players in the GPCR-Gsa-cAMP-PKA signaling, were recently identified in patients affected with acrodysostosis. This has helped clarify some issues regarding the heterogeneity of acrodysostosis, in particular the presence of hormonal resistance. Two different genetic and phenotypic syndromes are now identified, both with a similar bone dysplasia: acrodysostosis type 1 due to PRKAR1A defects, and acrodysostosis type 2, due to PDE4D defects. The existence of hormone resistance is typical of the acrodysostosis type 1 syndrome. We discuss here the PRKAR1A and PDE4D gene defects and phenotypes identified in acrodysostosis syndromes, in particular in regard to phenotypically related diseases caused by Gsa gene defects in the same signaling pathway.

Congenital Spondylolytic Spondylolisthesis of C2 Vertebra Associated With Atlanto-Axial Dislocation, Chiari Type I Malformation, and Anomalous Vertebral Artery: Case Report With Review Literature.

BACKGROUND: Congenital spondylolytic spondylolisthesis of C2 vertebra resulting from deficient posterior element of the axis is rarely described in the literature. CASE DESCRIPTION: We describe a unique case of agenesis of posterior elements of C2 with craniovertebral junction anomalies consisting of osseous, vascular, and soft tissue anomalies. A 26-year-old man presented with symptoms of upper cervical myelopathy of 12 months' duration. A computed tomography scan of the cervical spine including the craniovertebral junction revealed spondylolisthesis of C2 over C3, atlantoaxial dislocation, occipitalization of the atlas, hypoplasia of the odontoid, and cleft posterior C1 arch. Additionally, the axis vertebra was found devoid of its posterior elements except bilaterally rudimentary pedicles. Magnetic resonance imaging revealed tonsilar herniation, suggesting associated Chiari type I malformation. CT angiogram of the vertebral arteries displayed persistent bilateral first intersegmental arteries crossing the posterior aspect of the C1/2 facet joint. This patient underwent foramen magnum decompression, C3 laminectomy with occipito-C3/C4 posterior fusion using screw and rod to maintain the cervical alignment and stability. CONCLUSION: We report this rare constellation of congenital craniovertebral junction anomaly and review the relevant literature.

Cervical subluxation associated with posterior cervical hemivertebra.

PURPOSE: Hemivertebrae, associated with a failure in the formation and fusion of vertebral body ossification nuclei, are a common cause of thoracic or lumbar scoliosis. A cervical location is rare and even rarer as a cause of cervical subluxation in flexion and extension (for which only one previous case has been found). CASE REPORT: We report on the case of a 7-year-old female patient, who was examined for a cervical fusion defect, consisting of a posterior C4 hemivertebra and a left hemiblock from C5 to C7. After performing surgery consisting of a C4 corpectomy and anterior fixation with intersomatic graft and plate, adequate cervical stabilization with only a self-limiting left C6 brachialgia and ipsilateral Horner syndrome occurs in the postoperative period. CONCLUSION: Posterior cervical hemivertebra associated with instability is a very rare finding. The anterior approach with corpectomy and anterior plate enables suitable stabilization.

Multiple cervical hemivertebra resection and staged thoracic pedicle subtraction osteotomy in the treatment of complicated congenital scoliosis.

PURPOSE: To present our experience of staged correction with multiple cervical hemivertebra resection and thoracic pedicle subtraction osteotomy (PSO) treating a rare and complicated congenital scoliosis. METHODS: A 14-year-old male presented with progressive torticollis and spine deformity. The malformation developed since birth, and back pain after long-time sitting or exercise arose since 6 months before, which was unsuccessfully treated by physiotherapy. X-ray showed a right cervical curve of 60° and a left compensatory thoracic curve of 90°. Three-dimensional computed tomography (3-D CT) scan revealed three semi-segmented hemivertebrae (C4, C5 and C6) on the right side. Based on our staged strategy, the three consecutive cervical hemivertebrae, as the major pathology causing the deformity, were firstly resected by the combined posterior and anterior approach. Six months later, T6 PSO osteotomy was used to correct the structural compensatory thoracic curve. RESULTS: The cervical curve was reduced to 23° while the thoracic curve to 60° after the first-stage surgery, and the thoracic curve was further reduced to 30° after the second-stage surgery. The radiograph at 5-year follow-up showed that both the coronal and sagittal balance were well restored and stabilized, with the occipital tilt reduced from 12° to 0°. CONCLUSIONS: Our strategy may provide an option for similar cases with multiple consecutive cervical hemivertebrae and a large structural compensatory thoracic curve, which proved to achieve excellent correction in both the coronal and sagittal planes with acceptable neurologic risk.

Pulgarización en Síndrome de Nager. Caso clínico / Pollicization in Nager Syndrome. A case report

El tratamiento de las hipoplasias del pulgar, independientemente del síndrome clínico en el que estén incluidas, se basa en su severidad. La pulgarización, migración quirúrgica del índice hacia la posición del pulgar para sustituir su función, se reserva para los casos más severos. Presentamos el caso de un varón de 4 años de edad con Síndrome de Nager. Entre las características clínicas más significativas del caso destacamos: paladar hendido, microtia bilateral, fisura palpebral antimongoloide, hipoplasia malar, hipoplasia mandibular, coloboma del párpado inferior, así como hipoplasia severa bilateral de pulgares y ausencia parcial de tibia. Realizamos procedimiento de pulgarización en mano derecha sin complicaciones, con evolución satisfactoria. Tras 18 meses de seguimiento, el paciente presenta prensión esférica y cilíndrica adecuada, prensión lateral, así como oposición al quinto dedo (AU)

Treatment paradigm for a child with thumb deficiency or hypoplasia is based on severity, apart from other clinical features. Pollicization or surgical substitution of the thumb, most commonly using the index finger, is reserved for the most severe cases. We present the case of a 4-year-old male with Nager Syndrome. Among the most notable clinical characteristics we found: cleft palate, bilateral microtia, downslanting palpebral fissure, malar hypoplasia, mandibular hypoplasia, lower eyelid coloboma, partial tibial agenesis as well as bilateral hypoplastic/absent thumbs. Pollicization was performed for the right hand without complications. After 18 months follow-up, adequate cilyndrical and spherical grasp was achieved, as well as lateral prehension and opposition to fifth finger (AU)

Early initiation of enzyme replacement therapy for the mucopolysaccharidoses.

The mucopolysaccharidoses (MPS), a group of rare genetic disorders caused by defects in glycosaminoglycan (GAG) catabolism, are progressive, multi-systemic diseases with a high burden of morbidity. Enzyme replacement therapy (ERT) is available for MPS I, II, and VI, and may improve walking ability, endurance, and pulmonary function as evidenced by data from pivotal trials and extension studies. Despite these demonstrable benefits, cardiac valve disease, joint disease, and skeletal disease, all of which cause significant morbidity, do not generally improve with ERT if pathological changes are already established. Airway disease improves, but usually does not normalize. These limitations can be well understood by considering the varied functions of GAG in the body. Disruption of GAG catabolism has far-reaching effects due to the triggering of secondary pathogenic cascades. It appears that many of the consequences of these secondary pathogenic events, while they may improve on treatment, cannot be fully corrected even with long-term exposure to enzyme, thereby supporting the treatment of patients with MPS before the onset of clinical disease. This review examines the data from clinical trials and other studies in human patients to explore the limits of ERT as currently used, then discusses the pathophysiology, fetal tissue studies, animal studies, and sibling reports to explore the question of how early to treat an MPS patient with a firm diagnosis. The review is followed by an expert opinion on the rationale for and the benefits of early treatment.

Acrodysostosis and spinal canal involvement.

BACKGROUND: Acrodysostosis is a rare syndrome characterized by peripheral dysostosis, nasal hypoplasia, and frequently mental retardation. Only two adult cases of acrodysostosis have been reported to have neurological symptoms. CASE DESCRIPTION: We report one additional adult case that presented with signs of spinal cord compression from spinal stenosis, and make the first histologic description in the literature of the bony anomalies seen in acrodysostosis. The patient had a T3 to T5 laminectomy and experienced a complete recovery. CONCLUSIONS: Special attention should be given to these patients to detect signs of spinal stenosis, as early decompression can lead to neurological recovery.

Homozygosity for a novel truncating mutation confirms TBX15 deficiency as the cause of Cousin syndrome.

Cousin syndrome, also called pelviscapular dysplasia (OMIM 260660), is characterized by short stature, craniofacial dysmorphism, and multiple skeletal anomalies. Following its description in two sibs in 1982, no new cases have been observed until the observation of two unrelated cases in 2008 who were homozygous for frameshift mutations in TBX15. We investigated an adult individual with short stature, a complex craniofacial dysmorphism, malformed and rotated ears, short neck, elbow contractures, hypoacusis, and hypoplasia of scapula and pelvis on radiographs. We identified homozygosity for a novel nonsense mutation (c.841C>T) in TBX15 predicted to cause a premature stop (p.Arg281*) with truncation of the protein. This observation confirms that Cousin syndrome is a consistent and clinically recognizable phenotype caused by loss of function of TBX15.

Acrodysostosis associated with hypercalcemia.

An 18-year-old man was admitted to the clinic complaining of deterioration in the function of his hands and feet. The clinical examination revealed that his movements were clumsy and that he had disproportionally short limbs. In addition, he also had facial abnormalities of frontal bossing, hypertelorism, maxillary hypoplasia, broad low nasal bridge, short upturned nose with anteverted nostrils and triangular mouth. All extremities appeared short with stubby fingers and toes and with broad hands and wrinkling of the dorsal skin. Chromosomal analysis showed a normal (46, XY) karyotype. X-ray studies revealed broad, short metacarpals and phalanges with cone-shaped epiphyses and brachycdactyly and a diagnosis of peripheral dysostosis was confirmed by the characteristic radiographic appearance of the hands. Serum calcium and alkaline phosphatase levels were high, parathormone (PTH) was low, but 25 (OH) Vitamin D, albumin, and 24 hour urine calcium levels were in the normal range. Based on these findings, a diagnosis of acrodysostosis associated with hypercalcemia was made. To the best of our knowledge, this represents the first description of this syndrome.

Mucolipidosis type III in an adolescent presenting with atypical facial features and skeletal deformities.

Mucolipidosis type III (MLIII) (MIM# 252600) is an uncommon autosomal recessive disorder that results from deficiency of the multimeric enzyme, UDP-N-acetylglucosamine-1-phosphotransferase. The enzymatic defect results in deficiencies of lysosomal degradative enzymes with concomitant intracellular accumulation of both partly degraded glycosaminoglycans and sphingolipids leading to clinical manifestations such as short stature, developmental delay and other structural abnormalities. The diagnosis is challenging since musculoskeletal presentation may mimic some of the rheumatic and metabolic disorders. We herein report on a 13-year-old adolescent who was admitted to our rheumatology clinic because of progressive joint stiffness and deformities of her hands. The clinical and radiological findings led us to the diagnosis of MLIII despite negative urinary aminoglycosyaminoglycans. Therefore we decided to check for the presence of elevated activities of alpha-mannosidase and beta-hexosaminidase A+B in the plasma which was actually the case and confirmed the clinical diagnosis ofMLIII.

PRKAR1A and PDE4D mutations cause acrodysostosis but two distinct syndromes with or without GPCR-signaling hormone resistance.

CONTEXT: Acrodysostosis is a rare skeletal dysplasia that is associated with multiple resistance to G protein-coupled receptor (GPCR) signaling hormones in a subset of patients. Acrodysostosis is genetically heterogeneous because it results from heterozygous mutations in PRKAR1A or PDE4D, two key actors in the GPCR-cAMP-protein kinase A pathway. OBJECTIVE: Our objective was to identify the phenotypic features that distinguish the two genotypes causing acrodysostosis. PATIENTS AND METHODS: Sixteen unrelated patients with acrodysostosis underwent a candidate-gene approach and were investigated for phenotypic features. RESULTS: All patients had heterozygous de novo mutations. Fourteen patients carried a PRKAR1A mutation (PRKAR1A patients), five each a novel PRKAR1A mutation (p.Q285R, p.G289E, p.A328V, p.R335L, or p.Q372X), nine the reported PRKAR1A p.R368X mutation; two patients harbored a mutation in PDE4D (PDE4D patients) (one novel mutation, p.A227S; one reported, p.E590A). All PRKAR1A, but none of the PDE4D mutated patients were resistant to PTH and TSH. Two PRKAR1A patients each with a novel mutation presented a specific pattern of brachydactyly. One PDE4D patient presented with acroskyphodysplasia. Additional phenotypic differences included mental retardation in PDE4D patients. In addition, we report the presence of pigmented skin lesions in PRKAR1A and PDE4D patients, a feature not yet described in the acrodysostosis entity. CONCLUSIONS: All PRKAR1A and PDE4D patients present similar bone dysplasia characterizing acrodysostosis. Phenotypic differences, including the presence of resistance to GPCR-cAMP signaling hormones in PRKAR1A but not PDE4D patients, indicate phenotype-genotype correlations and highlight the specific contributions of PRKAR1A and PDE4D in cAMP signaling in different tissues.

Development of anaplastic Wilms tumor and subsequent relapse in a child with diaphanospondylodysostosis.

Diaphanospondylodysostosis (DSD) is a rare skeletal dysplasia syndrome resulting from disordered mesenchymal differentiation. Children with DSD generally die in utero or during the first month of life from severe thoracic insufficiency syndrome. An association of DSD with nephroblastomatosis has been observed, but the natural history of such nephroblastomatosis remains poorly characterized due to the rarity of the underlying condition. We describe a patient with DSD who developed bilateral hyperplastic nephroblastomatosis that ultimately evolved into therapy-resistant anaplastic Wilms tumor (nephroblastoma).

Fracture management in pycnodysostosis: 27 years of follow-up.

Pycnodysostosis is a rare hereditary disease, characterized by systemic bone sclerosis, which is often brought to the orthopedic surgeon's attention because of repeated fractures. The operative treatment of the patient with a fracture is a real challenge for the orthopedic surgeon because of the unusual problems imposed by the hard but-brittle bone characteristics of the disease. We report a 27-year follow-up of a patient treated for fractures of both femurs and tibia with intramedullary nailing. According to our experience and literature review, we recommend the use of an internal fixation, preferably intramedullary nailing as the treatment of choice for these rare cases. Once the fractures are healed, the removal of the hardware is not recommended, as these keep the bones from further fractures.

Mandibular osteomyelitis and fracture in a patient with pyknodysostosis.

Pyknodysostosis is a rare, recessive, hereditary, autosomal disease belonging to the group of bone dysplasias. Complications such as osteomyelitis and fractures of the mandible are not uncommon and appear in the most varied forms. We report a case of chronic osteomyelitis with subsequent mandible fracture, which was successfully treated with the use of a reconstruction plate and antibiotic therapy. This article outlines the clinical and radiographic characteristics of this condition based on the clinical case described and proposes an approach regarding the best form of treatment. Considering the risks of fracture subsequent to removal of the graft from long bones as well as the presence of chronic infection, difficult-to-defeat infection, and bone contact on the compression band, the best choice is a more conservative treatment.