Cardiopulmonary and Neurologic Dysfunctions in Fibrodysplasia Ossificans Progressiva

Fibrodysplasia Ossificans Progressiva (FOP) is an ultra-rare but debilitating disorder characterized by spontaneous, progressive, and irreversible heterotopic ossifications (HO) at extraskeletal sites. FOP is caused by gain-of-function mutations in the Activin receptor Ia/Activin-like kinase 2 gene (Acvr1/Alk2), with increased receptor sensitivity to bone morphogenetic proteins (BMPs) and a neoceptor response to Activin A. There is extensive literature on the skeletal phenotypes in FOP, but a much more limited understanding of non-skeletal manifestations of this disease. Emerging evidence reveals important cardiopulmonary and neurologic dysfunctions in FOP including thoracic insufficiency syndrome, pulmonary hypertension, conduction abnormalities, neuropathic pain, and demyelination of the central nervous system (CNS). Here, we review the recent research and discuss unanswered questions regarding the cardiopulmonary and neurologic phenotypes in FOP.

Jarcho-Levin Syndrome: Two Consecutive Cases in the Same Family

Jarcho-Levin Syndrome was first defined in 1938 by Saul Jarcho and Paul Levin. In the medical literature Jarcho-Levin Syndrome has a variety of synonyms such as Spondylocostal dysplasia/Dysostosis, SCD, SCDO, Spondylothoracic dysplasia/Dysostosis and costovertebral dysplasia. For years the SCD and a similar disorder, spondylothoracic dysplasia, were considered the same disorder and referred as Jarcho-Levin Syndrome. Today we know that these two disorders are different clinical entities with different causes and that the term Jarcho-Levin Syndrome should be reserved for individuals with Spondylocostal dysplasia. Affected individuals with SCD have various abnormalities in the development of the spine and ribs. Due to these abnormalities they are more prone to develop thoracic insufficiency syndrome which may eventually lead to early neonatal death. In the current case report we describe two consecutive cases with SCD in the same family. In the case of a strong clinical suspicion from the findings of the ultrasound scan we should proceed to a molecular genetic diagnosis of a mutation in DLL3, MESP2, LFNG and HES7 gene by sequencing the entire coding area of the fetal DNA.

Goldenhar Syndrome

Goldenhar syndrome (also known as oculo-auriculo-vertebral spectrum, facio-auriculo-vertebral syndrome, and Goldenhar-Gorlin syndrome) is caused by fetal growth disturbances of the first two brachial clefts. Diagnostic criteria include eye, ear, mandibular, and/or vertebral anomalies. These patients may also have cardiac and renal malformations with varying degrees of severity. Airway management for Goldenhar patients may include difficult ventilation and intubation, which may become increasingly difficult with age. Vertebral anomalies including fused cervical vertebrae and/or cervical instability further complicate airway management. Pulmonary complications occur due to congenital malformations and scoliosis, which can lead to thoracic insufficiency syndrome. This chapter discusses genetics, presentation, and management of Goldenhar syndrome.