Amish Hair Brain Syndrome

At a glance

Inherited syndrome with mild psychomotor retardation, hypogonadism, short stature, and brittle hair.

Synonyms

Trichothiodystrophy (TTD); Amish Brittle Hair Syndrome; Hair-Brain Syndrome; BIDS Syndrome (Brittle Hair and Nails, Intellectual Deficit, Decreased Fertility, Short Stature Syndrome); PIBIDS (Photosensitivity, Ichthyosis, Brittle Hair and Nails, Intellectual Deficit, Decreased Fertility, Short Stature Syndrome); IBIDS (Ichthyosis, Brittle Hair and Nails, Intellectual Deficit, Decreased Fertility, Short Stature Syndrome); Pollitt Syndrome.

Incidence

Initially described in 25 members of an Amish kindred. To date, more than 100 cases have been reported and the estimated incidence is in the range of 1:1,000,000 live births. Both genders are equally affected.

Genetic inheritance

Autosomal recessive transmission. TTD results from mutations in one of several different DNA repair genes (XPB, XPD, or TTDA) and TTDN1, a gene whose function remains poorly defined.

Clinical aspects

Brittle hair affects all TTD patients, which in the majority of cases is due to markedly reduced cystine content resulting in a lack of sulfur-rich matrix proteins. Almost half of the patients also have sparse hair and alopecia. Electron- and lightmicroscopy examination of the hair show multiple shaft abnormalities with an irregular and grooved surface, transverse fractures (trichoschisis) and occasionally trichorrhexis nodosa or 180° twists similar to pili torti. Polarizing microscopy reveals a diagnostic pattern of alternating light and dark banding, which, due to its appearance, has been called “tiger tail banding” or “zig-zag” pattern. The same underlying defect seems to be responsible for onychodystrophy (brittle, dysplastic, dystrophic nails, with yellowish discoloration). A wide spectrum of other clinical manifestations include intellectual impairment (presenting as failing to achieve developmental milestones, such as sitting, talking, walking) in over 80% of patients, short stature (in 73%) and decreased fertility (in 14%) secondary to gonadal dysgenesis/hypogonadism. The most common skeletal findings are osteosclerosis (in 14%), delayed bone age (in 13%), and osteopenia (in 9%). Joint contractures and dislocations are rare. For unknown reasons, the height and weight in most patients tend to drop off the growth curve as they get older. A minority of patients shows dysmyelination (in 14%), cerebellar atrophy, and dilated ventricles (each in 4%) on neuroimaging scans. Ophthalmologic findings include microcornea (in 44%), microphthalmia (in 8%), cataracts (in 28%), nystagmus (14%), strabismus (10%), and xerophthalmia. Characteristic facial features such as microcephaly (in 50% of patients), micrognathia (in 29%), and prominent ears have been described. Cardiac anomalies are reported in less than 10% of patients and include cardiomyopathy, pulmonary valve stenosis, and ventricular septal defect. Anemia is reported in 12% of patients. About one-third of newborns with TTD are small for gestational age. Short stature and failure to thrive affects more than 70% of cases. TTD has a 20-fold increased incidence of death ...