Letter to the Editor

Magnetic Resonance Imaging Abnormalities of theBrain in Goldberg-Shprintzen Syndrome(Hirschsprung Disease, Microcephaly, andIris Coloboma)

To the Editor:

Goldberg and Shprintzen [1981] described a brotherand sister with Hirschsprung disease, microcephaly,characteristic facial appearance, short stature, andmental retardation. Up to now, nine patients have beenreported, including two pairs of sibs [Goldberg andShprintzen, 1981; Yomo et al., 1991], two affected boysin separate sibships in a pedigree [Hurst et al., 1988],and three single individuals [Hurst et al., 1988; Halaland Morel, 1990; Tanaka et al., 1993]. Inheritance ofthe syndrome is suggested to be autosomal recessive.Electroencephalogram (EEG) was abnormal in four offive individuals studied. The brain computed tomogra-phy (CT) was abnormal in 9 of 10 individuals and theabnormalities included a small and thick vault, irregu-lar margins of the ventricles, irregular density of thedeep white matter, cerebral atrophy, and ventriculardilatation. We report on a Japanese boy with the syn-drome and describe brain magnetic resonance imaging(MRI) abnormalities.

The patient was born to healthy, nonconsanguineousparents at 40 weeks of gestation after an uncompli-cated pregnancy with a birth weight of 3,190 g, length33.5 cm, and OFC of 33.5 cm. The mother was 29 yearsold and the father 30 years old at the patient’s birth.Hypotonia and poor sucking were noted during the neo-natal period. He underwent an emergency colostomy atage 6 days because of severe constipation, abdominaldistention, and congenital megacolon. Histologicalfindings of a rectal biopsy showed aganglionosis of thesubmucosal plexus in the wall and confirmed short seg-ment Hirschsprung disease. At age 5 months, an endo-rectal pull-through operation was performed with clo-sure of the colostomy. The patient was referred to us atage 15 months with an epileptic status. He had sparsescalp hair, a sloping forehead, sparse eyebrows, tele-canthus, broad nasal bridge, large ears and pointed

chin (Fig. 1), a ventricular septal defect, hypospadiaswith bifid scrotum, cutaneous syndactyly between thesecond and third fingers, and rocker bottom feet. At age28 months, his length was 82.9 cm (−2.0 SD), weight9.7 kg (−1.9 SD), and OFC 46.0 cm (−1.4 SD). His psy-chomotor development was delayed: he lifted his headat age 7 months and spoke meaningful words at 2years. EEG demonstrated 3–4 Hz spike with slowwaves, mainly over the bilateral frontal areas. A brainCT revealed prominent sulci and dilatation of ven-tricles, indicating brain atrophy or hypoplasia. A brainMRI showed loss of parenchymal volume, especially ofthe white matter, a thin and hypoplastic corpus callo-sum with the absent rostrum, genu, and configuration(Fig. 2). The anterior commissure was absent. Chromo-somes were normal.

*Correspondence to: Kiyoshi Imaizumi, M.D., Kanagawa Chil-dren’s Medical Center, Mutsukawa 2-138-4, Minami-ku, Yoko-hama 232, Japan.

Received 15 July 1996; Accepted 9 May 1997

Fig. 1. The patient at age 2 years, showing sparse scalp hair, slopingforehead, sparse eyebrows, telecanthus, broad nasal bridge, large ears, andpointed chin.

American Journal of Medical Genetics 73:230–232 (1997)

© 1997 Wiley-Liss, Inc.

All the 10 reported patients with the syndrome hadHirschsprung disease, craniofacial anomalies, andmental retardation. Brain CT and MRI were studiedonly in our patient, and the findings were compatiblewith disturbed migration and distribution of the neuralcrest cells in early embryonic development. Hirsch-sprung disease, an autosomal dominant disease withincomplete penetrance, involves aganglionosis of themyenteric and submucosal plexus in the wall of thedistal alimentary tract, which is assumed to have re-sulted from abnormal migration of the neural crestcells. Mutation in the RET gene has been reported in

patients with Hirschsprung disease [Angrist et al.,1995]. Waardenburg- Hirschsprung syndrome, an au-tosomal recessive disease, was recently reported to re-sult from a homozygous mutation in the endothelin-Breceptor gene [Attie et al., 1995] or in the endothelin-3gene [Edery et al., 1996]. It is likely that the phenotypeof the syndrome, a combination of Waardenburg syn-drome type 2 and Hirschsprung disease, results fromdisturbed development of the neural crest cells andtheir disturbed migration into target organs duringembryonic development. It is tempting to speculatethat Goldberg-Shprintzen syndrome results from mu-

Fig. 2. CT scan of the brain (A, B) showing prominence of the sulci and dilated ventricles. MRI findings of the brain (C, D) showing hypoplasia of thecorpus callosum, including the absent rostrum, genu, and splenium. The body of the corpus callosum is thin, loss of parenchymal volume in the whitematter.

Letter to the Editor 231

tation of a recessive gene, and in turn from disturbeddevelopment and migration of the neural crest cells.

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Kei OhnumaKiyoshi Imaizumi*Mitsuo MasunoMihoko NakamuraYoshikazu KurokiDivision of Medical GeneticsKanagawa Children’s Medical CenterKanagawa, Japan

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