Macro-, normo-, and microcephaly have been described in these patients. A depressed nasal
bridge, often combined with midface and maxillary hypoplasia are typical. Sensorineural
hearing loss, optic nerve atrophy, and mental delay may be present. Electroencephalography
may document a diffuse cerebral disturbance with epileptiform discharges, and scattered
punctate foci of calcification in the subcortical white matter and cortex have been
demonstrated. Calcification of cartilage may affect the ears, nose, epiglottis, larynx,
trachea (see below), and ribs. Stippled epiphyses, which represent calcifications of the
knees and elbows, may occur as early signs of the disease. Brachytelephalangism (short
terminal phalanges) with short nails results in a drumstick-like shape of the fingers,
which is often combined with mild-to-moderate distal interphalangeal stiffness. Most of
these patients have cardiac issues, typically increased right ventricular pressures and
pulmonary artery hypertension either due to pulmonary (valvular or supravalvular) stenosis
or cor pulmonale as a consequence of calcification of tracheal, paratracheal, bronchial,
and rib cartilages. These calcifications may lead to significant obstruction of the
tracheobronchial tree down to the level of the lobular bronchi. Renal calcifications and
bilateral hydronephrosis as a result of narrowing of the urethrovesicular junction or
bladder outlet obstruction with vesicoureteral reflux have also been reported.