Macrocephaly, Benign Familial

Clinical Features

Asch and Myers (1976) described 5 males in 2 generations of a family with occipitofrontal head circumferences greater than 2 SD above the mean. All were neurologically and mentally normal. A maternal uncle of the first generation was said to have a large head. All were dolichocephalic. By sonographic studies the ventricular system was enlarged in 3 of the 5. Similar families were reported by Platt and Nash (1972) and by Day and Shutt (1979).

Arbour et al. (1996) measured head size in the parents and sibs of 23 patients with a head circumference more than 2 SD above the mean and with no evidence of hydrocephalus or syndromic associations. In 12 of the 23, some degree of psychomotor impairment was present. It was found that head circumference of parents and sibs had a mean significantly greater than the population norm and a unimodal distribution. Probands with psychomotor impairment had bigger heads, and more had a history of birth difficulty than did unimpaired probands. They noted that macrocephaly in a parent or sib of an unborn child may present a risk for birth injury to that child.

In the course of a clinical study of Sotos syndrome (117550), Cole and Hughes (1991) found that 6 of 79 probands who failed to fit that phenotype showed remarkable similarities to each other and to some of their first- and second-degree relatives. In addition to macrocephaly, clinical features included typical facies characterized by square outline with frontal bossing, 'dished-out' midface, biparietal narrowing, and long philtrum. Birth weight and length were normal or near normal with subsequent obesity. Cole and Hughes (1991) were uncertain as to whether this represented a new entity or benign familial macrocephaly; see 605309.

Diaz-Rodriguez et al. (2010) reported a mother and son with benign familial macrocephaly who displayed the characteristic square facial appearance with frontal bossing and dished-out midfacies. There was also an unaffected sister.

Inheritance

The pedigree pattern in the family with macrocephaly described by Asch and Myers (1976) suggested male-limited autosomal dominant inheritance.

Arbour et al. (1996) concluded that the usual genetic basis for nonsyndromic macrocephaly is multifactorial with a polymorphic genetic basis, rather than autosomal dominance. A risk of recurrence appeared to be much more lower than it would be on the assumption of autosomal dominant inheritance.