Autosomal Dominant Related Disorders

CLINICAL CHARACTERISTICS

The autosomal dominant related disorders include two principal types: neuromuscular disorders and skeletal dysplasias. Affected individuals typically have either neuromuscular or skeletal manifestations, although overlapping phenotypes can occur. There is a wild range of phenotypic severity. In the mildest of the autosomal dominant related disorders life span is normal; in the most severe it is shortened. The three clinically recognized autosomal dominant neuromuscular disorders are Charcot-Marie-Tooth disease type 2C, scapuloperoneal spinal muscular atrophy, and congenital distal spinal muscular atrophy. Clinical overlap between these phenotypes does occur. These neuromuscular disorders are characterized by a motor-predominant, non-length-dependent peripheral neuropathy or motor neuronopathy with a wide range in age of onset, from congenital to late adult. Additional common features include laryngeal dysfunction (i.e., vocal fold paresis causing voice change and/or inspiratory stridor), diaphragm weakness (orthopnea), scoliosis, bilateral sensorineural hearing loss, and joint contractures. The five autosomal dominant skeletal dysplasias are (from mildest to most severe) familial digital arthropathy with brachydactyly, brachyolmia, spondylometaphyseal dysplasia (Kozlowski type), spondyloepimetaphyseal dysplasia (Maroteaux type), and metatropic dysplasia. All -related skeletal dysplasias are characterized by brachydactyly; the four most severe forms have short stature that varies from mild to severe with progressive spinal deformity and involvement of the long bones and pelvis.

DIAGNOSIS/TESTING: The diagnosis of an autosomal dominant -related disorder is established in a proband who has characteristic clinical and neurophysiologic findings, radiographic findings in the skeletal dysplasias, and a heterozygous pathogenic variant identified by molecular genetic testing.

MANAGEMENT

Treatment is focused on symptom management. Affected individuals are often evaluated and managed by a multidisciplinary team that may include neurologists, physiatrists, orthopedic surgeons, otologists/audiologists, laryngologists, pulmonologists, geneticists, and physical and occupational therapists. This multidisciplinary team will determine the best treatment options for supportive care, prevention of obesity, and management of pain and depression. For neuromuscular disorders, additional treatment includes special shoes with good ankle support, shoe orthotics, ankle-foot orthoses / knee-ankle-foot orthoses, surgery for severe foot deformities, mobility devices, and exercise as tolerated; management of kyphoscoliosis per orthopedist; management of tethered spinal cord per neurosurgeon; laryngeal surgery for vocal cord paresis (in some individuals, vocal fold lateralization or tracheostomy); speech therapy; and respiratory therapy including noninvasive ventilatory support as needed. For skeletal dysplasias, additional treatment includes physical therapy/exercise and heel cord stretching to maintain function; surgical intervention when kyphoscoliosis compromises pulmonary function and/or causes pain and/or when upper cervical spine instability and/or cervical myelopathy are present. For neuromuscular disorders, annual neurologic examination, physical therapy assessment, otolaryngology evaluation of laryngeal function, dynamic breathing chest radiograph, pulmonary function tests, sleep study, hearing assessment, and musculoskeletal evaluation; assessment of weight, height, and weight-for-height or body composition to diagnose obesity at each visit. For skeletal dysplasias, annual evaluation for joint pain and scoliosis; assessment for odontoid hypoplasia before a child reaches school age and before surgical procedures involving general anesthesia; annual hearing assessment; and assessment of weight, height, and weight-for-height at each visit. Obesity, as it makes walking more difficult. For neuromuscular disorders, avoid diabetes and neurotoxic medications; upper respiratory tract infections can cause vocal fold swelling and worsen upper airway obstruction. For skeletal dysplasias, avoid extreme neck flexion and extension (in those with odontoid hypoplasia); activities that place undue stress on the spine and weight-bearing joints. Ideally a woman with an autosomal dominant -related disorder would seek consultation from a high-risk obstetrician or maternal-fetal medicine specialist to evaluate risk associated with pregnancy and delivery.

GENETIC COUNSELING

By definition, autosomal dominant -related disorders are inherited in an autosomal dominant manner. Because the most severe related skeletal phenotypes can be lethal in childhood (or in utero), children with these phenotypes typically have a pathogenic variant and unaffected parents. Individuals with less severe skeletal phenotypes or neuromuscular phenotypes often have the disorder as the result of a pathogenic variant inherited from a heterozygous parent ( pathogenic variants have also been described in individuals with these phenotypes). Each child of an individual with an autosomal dominant -related disorder has a 50% chance of inheriting the pathogenic variant. Specific phenotype, age of onset, and disease severity cannot be accurately predicted because of reduced penetrance and highly variable expressivity. However, in general, a child who inherits a pathogenic variant associated with neuromuscular disease or skeletal dysplasia from an affected parent is likely to have a similar overall phenotype as the parent, although the age of onset and severity may be quite distinct. Once the pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.