Physical Features. Males. Females

A. Males. Males who are affected by the fragile X syndrome usually demonstrate a triad of physical features, including macroorchidism, large or prominent ears, and a long narrow face.

Large or prominent ears are seen in approximately 80% of fragile X males at all ages. The ears are almost never malformed. However, they may demonstrate a cupping of the upper part of the pinna. In the prepubertal male, prominent ears are the most common feature that can be detected on physical examination (Fig. 3). Prepubertal individuals only occasionally demonstrate a long narrow face, but this finding is more common in postpubertal males. Prognathism or a prominence of the lower jaw is a frequent finding in older fragile X males. A high-arched palate is also commonly seen in males and this may be associated with crowding of the teeth or malocclusion.

Macroorchidism is seen in approximately 80% of adult fragile X males and it is quantified by a testicular volume of 30 ml or larger. Typically adult fragile X males have a testicular volume of 50 to 60 ml, although individuals with a volume as large as 100 ml have been reported. Macroorchidism is much more difficult to diagnose in the prepubertal male and only one-third of prepubertal individuals have a testicular volume that is larger than normal. The testicle increases most dramatically in size during the early pubertal years, perhaps related to gonadotrophin stimulation.

Approximately 60% of prepubertal fragile X males demonstrate hyperextensibility of the finger joints, most easily detected by bending the fingers back at the knuckles. Hyperextensibility is defined by having the fingers bend to a 90° or greater extension at the knuckle (Fig. 4). Double-jointed thumbs and loose ness of other joints, such as the elbow or ankle, are also commonly seen. Flat feet often with pronation are seen in over 50% of fragile X children and adults.

FIGURE 4. Hyperextensible finger joints. Note that the fingers extend >90° from the neutral position

Other features that occur in 25 to 50% of fragile X males include a pectus deformity of the chest (a pushed-in appearance to the chest), a weak eye muscle causing an in-turning or out-turning of one of the eyes, a single palmar or simian crease, and a large head circumference particularly in early childhood. CT scans are usually normal in fragile X males; however, more recent studies of brain structure using MRI scans have documented a small size of the cerebellar vermis, particularly the posterior region, and enlarged lateral ventricles in fragile X males and significantly affected females. The cerebellar finding appears to be related to the motor and sensory processing problems in fragile X syndrome.

Individuals who are carriers of the premutation usually do not have typical physical features of fragile X syndrome, although some may have prominent ears. It has been postulated that a connective tissue abnormality or dysplasia is associated with the fragile X syndrome because of the physical findings of flat feet, loose joints, and large or prominent ears. Other disorders of connective tissue such as Marfan syndrome and Ehlers-Danlos syndrome also demonstrate similar physical features.

Because these other disorders commonly have cardiac problems associated with connective tissue abnormalities, fragile X patients have also been studied for cardiac abnormalities. Approximately 50% of adult fragile X males demonstrate mitral valve prolapse, which is a floppiness of the mitral valve, sometimes leading to regurgitation of blood through the mitral valve during systole. Mitral regurgitation, however, is only occasionally seen in males with fragile X syndrome.

B. Females. Females who are intellectually impaired because of the fragile X syndrome are most likely to demonstrate the typical physical features. A long narrow face and prominent ears are commonly seen in retarded or learning disabled females (Fig. 3D). Other findings, such as hyperextensible finger joints, a high-arched palate, and mitral valve prolapse, have also been documented in fragile X females. An occasional female is reported with large ovaries but it is unclear whether this is a common finding. Unaffected carrier females sometimes demonstrate physical features of fragile X.