Trigonocephaly in a boy with paternally inherited deletion 22q11.2 syndrome^†

INTRODUCTION

Deletion 22q11.2 syndrome is well documented and its etiology has been well established. It occurs at a frequency of 1 in 4,000 live births [Emanuel et al., 2001], and has been identified in DiGeorge syndrome, velocardiofacial syndrome, and conotruncal anomaly face syndrome. The list of symptoms is extensive and varies from patient to patient. Homologous recombination events between low copy repeats (LCR) mediate the same 3-Mb deletion in 80%–90% of the patients [Spiteri et al., 2003]. McDonald-McGinn et al. 2005 reported four patients with a deletion 22q11.2 who presented craniosynostosis of the coronal suture. Recently, we encountered a unique patient with a familial deletion 22q11.2 associated with trigonocephaly derived from craniosynostosis of the metopic suture rather than the coronal suture. This is the first report of a relationship between deletion 22q11.2 and trigonocephaly.

CLINICAL REPORT

The patient, a boy, was born to non-consanguineous parents at 36 weeks of gestation, weighing 2,300 g (−0.7 SD), measuring 44.5 cm (−1.1 SD), and with OFC of 31 cm (−0.8 SD). Heart murmurs were noted, and cardiac examination revealed a ventricular septal defect, double-chambered right ventricle, and mitral regurgitation. At age 5 months, he was referred to us because of trigonocephaly. His OFC was 40.5 cm (−1.4 SD). He had a face with almond-shaped palpebral fissures, hypertelorism, edematous eyelids, a low nasal bridge, hypoplastic nasal alae, low-set lop ears, a small mouth, high-arched palate, and micrognathia (Fig. 1A,B). At age 11 months, his OFC was 43 cm (−2.1 SD). When he moved his right hand, his left hand moved in a mirror fashion. A neurological examination showed left hemifacial palsy, left hemiplegia, and left ankle clonus. Radiography demonstrated complete synostosis of the metopic suture (Fig. 1C). Brain MRI showed polymicrogyria of the right hemisphere (Fig. 1D,E). Linear craniectomy of the metopic suture was performed at age 18 months. At age 2 years, he walked with support, and spoke few words. He had febrile convulsions, and his EEG showed spike activities in the right fronto-central region. Sequencing analysis of the fibroblast growth factor receptor 2 (FGFR2) gene detected no mutation [Yamamoto et al., 2001].

The mother was healthy and phenotypically normal. The father was of normal intelligence but had the facial gestalt characteristic of an adult with the deletion 22q11.2 syndrome, including long face, narrow palpebral fissures, square root of the nose, hypoplastic nasal alae, and small mouth. His speech was nasal.

CYTOGENETIC STUDIES

G-banded chromosomes of the boy were 46,XY. Fluorescent in situ hybridization (FISH) analysis using LSI DiGeorge/VCFS Region Probe (Vysis, Inc., Downers Grove, IL) detected a deletion in the patient and the father, but not in the mother (Fig. 1F). FISH using probes spanning the 22q11.21-11.22 region detected a 3-Mb deletion in both the father and son (Table I).

DISCUSSION

The present patient and the father showed the typical gestalt of conotruncal anomaly face syndrome, including a narrow nose with its squared root and narrow ala nasi, and short palpebral fissures [Matsuoka et al., 1994]. These and additional clinical manifestations identified in the patient, including mental and motor developmental delay, microcephaly, seizures, polymicrogyria, and cardiac anomalies were clues for the identification of 3-Mb deletion of 22q11.2 region in this family. This clinical variability from full manifestation to extremely mild clinical anomalies in familial deletion 22q11.2 as seen in this family is a well-known phenomenon [Digilio et al., 2003]. Hemicephalic polymicrogyria revealed in the patient is also a well-known rare complication of deletion 22q11.2 syndrome [Sztriha et al., 2004], but the exception is trigonocephaly.

Trigonocephaly is seen in some chromosomal abnormalities such as monosomy 9p and partial monosomy 11q, as well as in other genetic disorders [Azimi et al., 2003; Jehee et al., 2005; Yatsenko et al., 2005]; a candidate region for monosomy 9p syndrome had recently been narrowed by our group [Kawara et al., 2006]. However, deletion 22q11.2 syndrome has never been listed as the cause of trigonocephaly. Ryan et al. 1997 summarized a spectrum of clinical features of deletion 22q11.2 syndrome, and described five patients with craniosynostosis without descriptions of its type. McDonald-McGinn et al. 2005 reported four patients with deletion 22q11.2 syndrome associated with craniosynostosis, all of whom showed synostosis of the coronal suture but not involving the metopic suture. Therefore, the present report is the first description of a relationship between deletion 22q11.2 syndrome and trigonocephaly.

Although the exact cause of the coexistence of deletion 22q11.2 and trigonocephaly remains unknown, and coincidental occurrence might be the explanation for this. Alternatively, symptoms of trigonocephaly might be a minor complication of deletion 22q11.2. Another possibility, but less likely, is a mutated trigonocephaly gene mapped to 22q11.2 and derived from the mother was unmasked by the deletion in the patient.