Article Text

Cloverleaf skull anomaly and de novo trisomy 4p
  1. D DE BRASI,
  2. L PERONE,
  3. P DI MICCO,
  4. G ANDRIA,
  5. G SEBASTIO
  1. Dipartimento di Pediatria, Università “Federico II”, Via S Pansini 5, I-80131 Naples, Italy
  2. Divisione di Patologia Neonatale, Azienda Ospedaliera “Santobono-Pausilipon”, Naples, Italy
  3. Divisione di Neurochirurgia, Azienda Ospedaliera “Santobono-Pausilipon”, Naples, Italy
    1. E IACCARINO,
    2. L PINTO
    1. Dipartimento di Pediatria, Università “Federico II”, Via S Pansini 5, I-80131 Naples, Italy
    2. Divisione di Patologia Neonatale, Azienda Ospedaliera “Santobono-Pausilipon”, Naples, Italy
    3. Divisione di Neurochirurgia, Azienda Ospedaliera “Santobono-Pausilipon”, Naples, Italy
      1. F ALIBERTI
      1. Dipartimento di Pediatria, Università “Federico II”, Via S Pansini 5, I-80131 Naples, Italy
      2. Divisione di Patologia Neonatale, Azienda Ospedaliera “Santobono-Pausilipon”, Naples, Italy
      3. Divisione di Neurochirurgia, Azienda Ospedaliera “Santobono-Pausilipon”, Naples, Italy

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        Editor—Cloverleaf skull deformity (CS, Kleeblattschaedel, MIM 148800) is a severe form of craniosynostosis rarely associated with chromosomal aberrations.1 2Recently we observed a newborn male presenting with multiple congenital anomalies including a cloverleaf skull and a de novo partial 4p trisomy. He was a 12 day old male, born at 35 weeks of gestation to healthy, non-consanguineous parents. Respiratory distress was present at birth. At 12 days, his weight was 2650 g (5th centile), length 45 cm (<5th centile), and head circumference 30.5 cm (<<5th centile). On clinical evaluation, multiple congenital anomalies were observed, including cloverleaf skull, orbital hypoplasia with proptosis, hypertelorism, right iris coloboma, depressed nasal bridge, anteverted nostrils, low set ears, wide superior alveolar ridge, and pointed chin. Furthermore, inverted nipples, camptodactyly of the hands, club feet, overlapping toes, shawl scrotum, cryptorchidism, and generalised hypertonia were noted. Skeletalx rays showed vertebral anomalies, including hypoplasia of the 5th cervical vertebra, the presence of hemivertebrae of the lumbar spine, and eleven ribs bilaterally. Echocardiography showed a mild atrial septal defect and PDA. Cranial 3D CT scan (fig 1) showed protruding temporal bones and fusion of the coronal, lambdoidal, and temporoparietal sutures with temporoparietal bone ridges. The craniosynostosis partially spared the sagittal and metopic sutures. MRI showed asymmetrically enlarged temporal horns and a hypoplastic corpus callosum. Renal scan was normal; the testes were found by ultrasound inside the inguinal canal bilaterally. EEG was characterised by mild brain electric hypoactivity. Visual evoked potentials were delayed. At 6 months of age, the patient died of cardiac and respiratory failure.

        Figure 1

        Cranial 3D CT scan of the patient, front and lateral view.

        Standard R banding of the patient’s chromosomes disclosed the presence of supernumerary chromosomal bands on 2q. This segment was later identified as part of chromosome 4 by FISH, carried out according to Pinkel et al 3and using a whole chromosome 4 painting library (Oncor) (fig 2, left). Prometaphase RHG banded chromosomes, prepared as described elsewhere,4 defined the extension of the 4p trisomic region as a 4p15.1→pter segment (fig 2, right). No apparent deletion of 2q bands was observed. The patient appeared trisomic for the distal part of 4p, without any apparent deletion of the 2q region apart from the probable loss of the 2q telomere. The patient’s karyotype was 46,XY,−2,+der(2)t(2;4)(q37.3;p15.1). Paternal and maternal karyotypes were normal.

        Figure 2

        FISH performed in the patient using chromosome 4 painting library: arrowhead indicates part of chromosome 4 translocated onto chromosome 2 (left). RHG banded partial karyotype of the proband: chromosome translocation 2;4 (right).

        Molecular analysis (data not shown) performed using PCR on DNA from a lymphoblastoid cell line of the proband and from the parents’ peripheral lymphocytes showed that the patient was monosomic for a distal 2q telomeric marker, D2S125 (GDB ID:187994),5 and heterozygous for a (AC)n repeat of the ALPP gene (PLAP, GDB ID:180439),5 which maps to 2q37.1. On the other hand the analysis of the 4p markers disclosed the presence in the patient of three alleles for both a HOX7 (CA)n repeat (GDB ID:176982)5 and D4S126 (GDB ID:197926),5respectively mapping to 4p16.1 and 4p16.3, the extra allele deriving from an error in paternal meiosis I.

        Both environmental and genetic causes have been proposed for the pathogenesis of CS1 but only three cases of CS have been found associated with cytogenetic aberrations so far. The first two cases reported CS associated with partial trisomy of 15q and 13q,1 whereas, more recently, Van Allenet al 2 reported a child with multiple congenital anomalies, including CS, and an unbalanced 2q;15q translocation. This resulted in trisomy for the 15q26→qter region, and the authors hypothesised a cluster of genes crucial for the closure of cranial sutures located on chromosome 15q. Our patient and that reported by Van Allen et al 2seem to share the same deletion of band 2q37. Even if microcephaly has been observed in some patients with 2q terminal deletion, this cytogenetic aberration has never been correlated with cloverleaf skull anomaly.6 7 Furthermore, these patients exhibited a breakpoint more proximal than that found in our patient,6whereas deletions mapped distally to 2q37.1 were associated with normal cranial circumference or even macrocephaly.7

        On physical examination, our patient exhibited many clinical features found in the classical trisomy 4p syndrome,8 including iris coloboma, depressed nasal bridge, pointed chin, vertebral and rib abnormalities, camptodactyly, club feet, cryptorchidism, generalised hypertonia, cardiac defect, and respiratory problems, which can be explained by the presence of trisomy of a large part of the 4p region. However, his overall phenotype appears more severe than that described in the classical trisomy 4p syndrome. Specifically, CS is an extreme form of craniosynostosis compared to the variable pattern of sutural fusion observed in the classical trisomy 4p syndrome, which ranges from protruding glabella (30%) or prominent continuous supraorbital ridge fused across the glabella (23%), to microcephaly, prominent forehead, or other less specific cranial abnormalities, which have been described with a variable degree of severity even within the same family members.8

        Several of the classical findings of the trisomy 4p syndrome can be caused by the duplication of about 2.1 Mb extending from the telomere and involving the 4p16.1→16.3 region.9 In order to understand how cranial involvement is a main feature of the trisomy 4p syndrome, particularly in our patient, some of the genes located in the critical region should be taken into account. The gene encoding the fibroblast growth factor receptor 3 (FGFR3) maps to 4p16.310 and mutations within its different domains have recently been associated with syndromic and non-syndromic craniosynostosis.10 A constitutive FGFR3 activation seems to be the mechanism underlying the craniosynostosis.10 In this respect, three copies of the wild type FGFR3 gene might result in a greater production of protein, thus mimicking the effect of FGFR3 mutations as observed in some craniosynostoses.

        The same activating mechanism could be envisaged for MSX1, which maps to 4p16.1. Even if MSX1 has never been associated with craniosynostosis, MSX2, one of its homologues,11 has been found associated with the Boston type of craniosynostosis through a gain of function mutational mechanism.12 Furthermore, MSX1 deficiency has been recently associated with failure of development of alveolar bone and teeth in man13; overexpression of MSX1 could result in hypertrophy of the alveolar process, as observed in our patient.

        Further studies on both FGFR3 and MSX1 will probably clarify the effective involvement of these genes in the determination of craniosynostosis in the trisomy 4p syndrome.

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