American Journal of Medical Genetics 131A:82 – 85 (2004)
Clinical Report Septo-Optic Dysplasia With Digital Anomalies— A Recurrent Pattern Syndrome Iain M. Harrison, Donal Brosnahan, Ethna Phelan, Ray J. Fitzgerald, and William Reardon* Our Lady’s Hospital for Sick Children, Crumlin, Dublin, Ireland
A distinct form of septo-optic dysplasia (SOD) comprises limb malformations in addition to the characteristic CNS and ocular abnormalities. To date, there have been 4 reports, citing 5 affected patients with this combined phenotype. We now add a further case and present neuroradiological images of the CNS findings in this condition. The striking consistency of the limb malformations and their overlap with the Streeter’s band phenotype is emphasized. ß 2004 Wiley-Liss, Inc. KEY WORDS: septo-optic dysplasia; CNS; limb malformations
INTRODUCTION Septo-optic dysplasia (SOD) is a rare developmental anomaly characterized by an absent septum pellucidum, optic nerve hypoplasia, and pituitary abnormalities [de Morsier, 1956; Willnow et al., 1996]. First described by Reeves [1941] in a 7month-old baby with optic nerve abnormalities and absence of the septum pellucidum, SOD is a heterogeneous condition defined loosely by any combination of optic nerve hypoplasia, pituitary hypoplasia, and midline neuroradiological malformations [Dattani and Robinson, 2002]. SOD is usually a sporadically occurring disorder, although familial recurrences indicative of autosomal recessive inheritance have been reported [Blethen and Weldon, 1985; Benner et al., 1990; Wales and Quarrell, 1996]. However, there are reports of SOD in association with cleft lip and palate [Sandri et al., 1990], cleft face [Stewart et al., 1983] as well as microphthalmos [Gunduz et al., 1996] and schizencephaly [Kuban et al., 1989]. Among malformations infrequently observed with SOD have been 5 patients with digital anomalies [van Dalen and Delleman, 1983; Pagon and Stephan, 1984; Faivre et al., 2002; Stevens and Dobyns, 2004]. There is a consistency to the nature of the limb malformations described in that all cases showed a degree of syndactyly with reduction abnormalities of digits associated with constriction bands. We describe a 3month-old boy with SOD and similar digital anomalies.
with a history of juvenile arthritis but who was otherwise healthy. There was no parental consanguinity nor use of medications or recreational drugs during pregnancy although the mother is a known smoker. Apgar score was 9 at 1 min and 10 at 5 min. Birth weight was 3 kg (50th centile), length 50.5 cms (75th centile), and occipito-frontal circumference was 35.2 cm (90th centile). Routine antenatal ultrasound scan at 28 weeks gestation had recognized a disproportion in head circumference with other parameters and dialatation of the ventricular system suggested a diagnosis of hydrocephalus. On examination at age 1 week, he was noted to have dysmorphic features including simple ears, micrognathia, cleft of the soft palate, a pedunculated occipital scalp lesion (Fig. 1) and abnormalities of both hands and feet (Fig. 2). The right hand had syndactyly of digits 1–3 with terminal hypoplasia and ring constriction of the 3rd digit. The 4th and 5th digits were normal. The left thumb was normal; there was fusion and hypoplastic development of digits 2–4 of the left hand. The left 5th digit, unaffected by the syndactyly, was hypoplastic with an absent nail. The right foot had all digits present with no syndactyly but hypoplastic nails. The left foot showed absence of digits 1–3 with 4 and 5 present but without nails. Ophthalmic examination revealed bilateral hypoplastic optic nerves but no other ocular abnormality. Computed tomography (Fig. 3) of the head showed an absent septum pellucidum, colpocephaly, and a defect in the skull vault deep to the occipital lesion. Magnetic resonance imaging (Fig. 4) confirmed the absence of the septum pellucidum and colpocephaly but showed an apparently normal pituitary-hypothalamic axis. At the site of the skin tag there was no obvious connection with the brain itself or local cortical dysplasia suggesting any encephalocoele is atretic. There was no evidence of migration abnormality. At 2 months a VP shunt was inserted to treat progressive hydrocephalus. Routine karyotype is normal.
CLINICAL REPORT This boy was born at 37 weeks gestation by elective lower section caesarian section to a 25-year-old primagravid mother
*Correspondence to: Dr. William Reardon, Our Lady’s Hospital for Sick Children, Crumlin, Dublin 12, Ireland. E-mail:
[email protected] Received 19 January 2004; Accepted 29 May 2004 DOI 10.1002/ajmg.a.30309
ß 2004 Wiley-Liss, Inc.
Fig. 1. The pedunculated occipital lesion is demonstrated.
Septo-Optic Dysplasia With Digital Anomalies
Baseline studies of pituitary function are normal at age 2 months. The only other malformation observed was an atrial septal defect, not requiring active management. At age 3 months, the baby was not smiling, was profoundly hypotonic and developmental delay seems likely. DISCUSSION Reports of SOD associated with digital anomalies have been rare. To our knowledge there have only been 5 cases previously reported [van Dalen and Delleman, 1983; Pagon and Stephan, 1984; Faivre et al., 2002; Stevens and Dobyns, 2004]. All have
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had optic nerve hypoplasia. Absence of the septum pellucidum was seen in both cases of Pagon and Stephan [1984] but the septum pellucidum was present in the case of Stevens and Dobyns [2004] and not mentioned in the other 2 cases. Isolated growth hormone deficiency has been documented in 3 of the 5 patients with the other 2 not having had investigation recorded (Table I). Hand abnormalities have invariably involved hypoplasia of the distal and middle phalanges, syndactyly, and areas of constriction akin to amniotic bands. The abnormalities in the feet are generally confined to phalangeal absence or hypoplasia, although are more severe in the case reported by Stevens and Dobyns [2004], wherein complete
Fig. 2. The digital abnormalities are shown. A: Note syndactyly 1–3 of right hand with constriction ring. B: On the left hand there is fusion and hypoplasia of digits 2–4. The 5th digit is hypoplastic and nailless. C: The left foot shows absence of digits 1–3.
Fig. 4. MRI scan showing absence of the septum pellucidum and colpocephaly.
Optic nerve hypoplasia Absent septum pellucidum Ventricles dilated Dev delay Growth hormone deficient Syndactyly Digital hypoplasia Constriction ring Other
Fig. 3. CT scan showing the soft tissue lesion at the occiput with underlying bony defect in the skull vault.
Pagon Case 2 þ þ þ þ þ þ þ þ Hypospadias
Pagon and Stephan [1984] Case 1 þ þ þ þ Not known þ þ þ Nil
þ Not known Not known Not known Not known þ þ Not known Not known
van Dalen and Delleman [1983]
þ Not known Not known þ þ þ þ þ Haemangiomas
Faivre et al. [2002]
TABLE I. Features of Reported Cases to Date
þ þ þ þ þ þ Haemangiomas Polymicrogyria and heterotopias on MRI
Stevens and Dobyns [2004]
þ þ þ þ Not known þ þ þ Atrial septal defect Occipital pedunculated lesion
Harrison et al.
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Septo-Optic Dysplasia With Digital Anomalies
syndactyly of the toes bilaterally was observed with variable absence of the nails. A possible further case of the same phenomenon may be the patient reported by Orrico et al. [2002], in which a 16-year-old girl is recorded with severe mental retardation, seizures, optic nerve hypoplasia, growth hormone deficiency documented at age 9 years and digital malformations confined to the feet, comprising metatarsals asymmetrically but bilaterally. No hand malformations are recorded. Neither are constriction rings remarked upon. A confirmed history of maternal use of multiple recreational drugs, including cocaine, is recorded antenatally in regard of this patient. The pathogenesis of SOD is not yet fully understood. Dattani et al. [1998] showed that in some patients SOD is caused by a single gene defect in the homeobox gene HESX1. Subsequent work has established a few other mutations of likely pathogenic significance at this locus in patients with isolated growth hormone deficiency or combined growth hormone deficiency and pituitary malformation [Dattani and Robinson, 2002]. However, the great majority of patients with diagnostic features suggestive of SOD do not have mutations or deletions at the HESX1 locus and the molecular basis of the clinical abnormality remains to be established. Stevens and Dobyns [2004] have argued that the limb features in this group of patients represent amniotic band disruption, with which hypothesis the clinical findings are entirely consistent. Moreover they argue for a vascular pathogenesis to the SOD, the amniotic band disruption and other features noted in this group of patients (Table I). They find evidence to support this hypothesis in the youthfulness of mothers giving birth to babies with SOD, in the vascular basis of some cases of polymicrogyria, from pathological studies in humans and from animal studies [Stevens and Dobyns, 2004]. This is an attractive hypothesis, but not conclusive. The constriction rings seen in conjunction with the limb malformations in this group of patients are of particular interest. Though reminiscent of amniotic bands, there is little evidence that the other features in these affected individuals are likely to be related to amniotic band constriction. Rather, we take the view that the constriction rings and associated limb malformations constitute part of this recognizable recurrent pattern syndrome, the genetic and pathogenic basis of which are not yet understood. It is noteworthy that amniotic bandlike clinical features have been observed in single gene disorders, Adams–Oliver syndrome being a case in point [Winter and Baraitser, 2003]. The hypothesis of Streeter [1930] that band constrictions and other limb malformations might emanate from primary abnormality of the amniotic cavity and embryo may well explain the association of the specific limb malformations which have been observed in the subgroup of cases with SOD to which we refer.
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