autosomal dominant

There are no systemic abnormalities in this disorder. 

A defect in type I collagen leading to brittle bones and frequent fractures is the systemic hallmark of this group of disorders.  Clinical and genetic heterogeneity is evident. The nosology is as yet not fully established and will likely require more molecular information.  Type I is considered the mildest of the several forms that have been reported.  Relatively minor trauma during childhood and adolescence can lead to fractures while adults have less risk.  Fractures generally heal rapidly without deformities  and with good callous formation in patients with milder disease.  However, those with more serious disease often end up with deformities and bowed bones.

Short stature, hearing loss, easy bruising, and dentinogenesis imperfecta are often seen as well.

Type II is more severe and fractures often occur in utero.  Fractures may involve long bones, skull bones and vertebrae.  At birth the rib case appears abnormally small and the underdeveloped pulmonary system may lead to severe respiratory problems and even death in some newborns.

A variety of defects in facial development have been reported, most involving the ears, eyelids, lower jaw, and zygomatic arch.  The characteristic facial phenotype is usually evident at birth.  One-third of patients have a cleft palate.  Microtia or even anotia may be present and a conductive hearing loss can result, especially when the ossicles are malformed or absent.  The pinnae are often malformed, appearing 'crumpled', low-set, and rotated posteriorly.  There may be ear tags and blind fistulas anywhere between the tragus and angle of the mouth.  The mandible and its rami may be hypoplastic causing severe micrognathia that can result in feeding and speaking difficulties, especially when pharyngeal hypoplasia is also present.  The zygomatic arches are often underdeveloped (or even absent) and the midface is flattened.  Arhinia and cleft palate are sometimes seen.  A low hairline may be present.  Intelligence is usually normal.

Type II neurofibromatosis often presents in the third or fourth decade of life as hearing loss accompanied by tinnitus and dizziness. A significant proportion of children (30%) present with the same symptoms although they are more likely to complain of visual disturbances. Type II accounts for about 10% of neurofibromatosis cases.  Acoustic neurinomas, usually bilateral, are far more common in type II (95%) and are considered diagnostically distinctive by some.  Such schwannomas also occur in other cranial and peripheral nerves.  Neurofibromas are uncommon but meningiomas, ependymomas, and astrocytomas are seen frequently. Schwannomas can form anywhere along peripheral nerves and at least a third of patients require surgical excision of one or more of these lesions.  These account for the majority of skin plaques and lumps and are found in more than half of patients.  Caf√©-au-lait spots are uncommon or even absent in many patients with type II.  Patients with type II neurofibromatosis do not have the cognitive problems sometimes seen in those with type I.

Longevity overall is reduced.  The average patient lives about 15 years after diagnosis and the average age of death is 36 years.

The clinical features of this syndrome are highly variable.  Hair is sparse and the nails are usually dysplastic.  The nose appears small and peaked with underdevelopment of the nasal alae, and the mandible may be broad.  The cranial bones are often hyperostotic and the long bones as well as the ribs and clavicle are widened.  The middle phalanges of the digits are usually hypoplastic or may be absent.  Syndactyly of fingers and toes is often a feature and camptodactyly is common.  The teeth are small and carious with evidence of enamel dysplasia.   Hair often grows slowly and is sparse.  A variety of neurological deficits have been reported but no consistent pattern has been recognized.  However, white matter lesions and basal ganglia changes have been documented on MRI.

This is a late onset form of progressive muscular dystrophy with onset of symptoms during midlife (mean age of onset ~48 years).  Evidence of pharyngeal muscle weakness often occurs concomitantly with the ocular signs (43%).  Ptosis occurs first in 43% and dysphagia first in 14%.    Dysarthria and dysphagia are often associated with facial muscle weakness.  Swallowing times for ice cold water and dry food is usually prolonged.  Evidence of weakness and wasting of neck and limb muscles is usually noted later.  Life expectancy is normal in contrast to some other forms of muscular dystrophy.  Some patients have significant gait problems and generalized disability as a result of muscle weakness.

Microscopic studies of muscle biopsies usually show evidence of myopathy with abnormal fibers and accumulations of sarcoplasmic matter.  Intranuclear inclusions consisting of tubular filaments and mitochondrial abnormalities have also been described.  Serum CK can be significantly elevated in severe cases.