The physical appearance of the patient can be very helpful in determining a diagnosis.


A high forehead is suggestive of:

  • a peroxisomal disorder (e.g., Zellweger syndrome or neonatal adrenoleukodystrophy)
  • lissencephaly
  • fragile X syndrome

Frontal bossing may suggest:

  • Hurler’s syndrome
  • GM1 gangliosidosis
  • mucolipidosis II (I-cell disease)
  • multiple sulfatase deficiency

Microcephaly is characteristic of:

  • Angelman’s syndrome
  • Cockayne’s syndrome
  • Smith-Lemli-Opitz syndrome
  • Rett syndrome

Other causes of cerebral and somatic dysmorphism associated with epilepsy include:

  • glutaric aciduria type II
  • hypomelanosis of Ito
  • Lowe syndrome
  • molybdenum cofactor deficiency
  • pyruvate dehydrogenase deficiency
  • tuberous sclerosis

Hair and skin defects

Defects in hair and skin are also important clues:

  • Loss of hair: biotinidase deficiency and Cockayne’s syndrome
  • Other anomalies of hair: mucopolysaccharidoses, Menkes’ syndrome, argininosuccinic aciduria
  • Nodular lesions on the face, depigmented macules: tuberous sclerosis
  • Café au lait spots and neurofibromas: neurofibromatosis
  • Streaked, whirled, and mottled areas of hyperpigmentation: hypomelanosis of Ito
  • Thin, atrophic skin: Cockayne’s syndrome

A Wood’s lamp examination of the skin for hypopigmentation should, therefore, be a routine part of the workup of a child who is experiencing seizures.

Growth failure

Growth failure is a common feature of many hereditary metabolic diseases. Short stature is found in patients with:

  • mucopolysaccharidoses
  • mucolipidoses
  • mitochondrial encephalopathies
    • Leigh disease
    • MELAS
    • myoclonic epilepsy with ragged red fibers (MERFF)

Enlarged liver

Hepatomegaly with liver dysfunction may be a sign of:

  • Wilson’s disease
  • Alpers-Huttenlocher syndrome
  • Niemann-Pick disease type C

The liver is enlarged early in the course of Niemann-Pick disease types A and B, but liver failure occurs only as a late sequela. Liver failure is found also in certain mitochondrial disorders and in Zellweger syndrome.

Splenomegaly in an infant with seizures will suggest type 2 Gaucher’s disease. A later onset is typical of type 3 Gaucher’s disease.

Adapted from: Kolodny, EH. Metabolic and genetic disorders. In: Devinsky O and Westbrook LE, eds. Epilepsy and Developmental Disabilities. Boston: Butterworth-Heinemann; 2001;17–22. 
With permission from Elsevier ( 

Reviewed By: 
Steven C. Schachter, MD
Saturday, May 1, 2004