Apert syndrome associated with septo-optic dysplasia

Apert Syndrome Associated with Septo-optic Dysplasia Ru-Jeng Teng, MD, Pen-Jung Wang, MD, Tso-Ren Wang, MD, and Y u - Z e n Shen, M D

Apert syndrome and septo-optic dysplasia are rare congenital structural disorders which have not been associated previously; we report a female infant with this association. Brain sonography and computed tomography revealed agenesis of the septum pellucidum; optic hypoplasia was demonstrated by funduscopic evaluation. We postulate that an embryopathic factor, which manifests at 5-6 weeks gestation, may result in this new association. Transverse craniectomy was performed in the hope of preserving brain development. Neither hypopituitarism nor adrenal insufficiency was observed; however, clinical manifestations and laboratory data provided evidence of inappropriate antidiuretic hormone syndrome. Teng R-J, Wang P-J, Wang T-R, Shen Y-Z. Apert syndrome associated with septo-optic dysplasia. Pediatr Neurol 1989;5:384-8.

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Introduction Baumgartner initially reported a patient with typical acrocephalosyndactylism in 1842. Subsequent patients were also reported by other authors; however, Ihc ~yndrome was not widely accepted until the French pediatrician, Apert, reported 9 patients in 1906 I1/. Malay associated congenital malformations have been reported [2-5 I; however, there have been no reports concernblg the association of Apert syndrome and septo-optic dysplasia. Septo-optic dysplasia had first been described by Reeves in 1941 [6]. By 1956, De Morsier had examined 36 patients with absent septum pellucidum, 9 of whom also had optic hypoplasia; he termed this association septo-optic dysplasia [7]. Only 75 patients were reported be|ore 1986 [8]; the high incidence of associated endocrinopathy has been well documented [9,10]. Both Apert syndrome and septo-optic dysplasia are rare; the reported incidences are 1:1 × 105 - 1.6 x 105 live births [10] and 1:5 x 104, respectively [11]. Their concomitant appearance in a single patient is very rare.

Case Report This 6-month-old female infant was admitted becau~ of acute bronchiolitis. She was born at 40 weeks gestation, weighing < 1 kg, to a G7, P6, SAI mother. Both her parents were aborigines of Taiwan; the father was 42 years of age and the mother 38 years. The patient was delivered by cesarean section due to polyhydramnios and fetal distress at a private obstetric clinic. There was neither consanguinity nor congenital malformation in her family; however, her eldest sister is moderately mentally retarded. On admission, the physical examination revealed antimongoloid palpebral fissure, turribrachycephaly, midface hypoplasia, propt0sis, diver-

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Figure 1. (A,B) General appearance of the patient.

From the Department of Pediatrics; National Taiwan University Hospital; Taipei, Taiwan.

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Communications should be addressed to: Dr. Teng; Department of Pediatrics; National Taiwan University Hospital; No. 1 Chang-Te Street; Taipei, Taiwan. Received May 2, 1989; accepted August 15, 1989.

Orogastric tube feeding was prescribed because of pulmonaryinfection, severe choanal stenosis, and cleft palate. Transversecraniectomy was performed in the hope of decreasing intracranial pressure and maintainingmental development. She was readmitted to our hospital twice within 6 months for repeated lung infection. Syndrome of inappropriate antidiuretic hormone (SIADH) and acneform skin lesion also complicated the clinical course with persistenthyponatremiaand urine osmolality(451 mEq/L) higher than the serum osmolality(245 mEq/L). Auditorybrain responses (ABRs) revealed absence of waves I-III and prolonged wave V latency (Fig 5); these results were compatible with conductivehearing disturbance.

Discussion

Figure 2. Optic disc hypoplasia with double disc margin over the temporal side.

gent hypertelorism,choanal stenosis, cleft uvula and soft palate, saddle nose, and widely open anterior (3 x 3 cm) and posterior (4 × 6 cm) fontanels (Fig 1). There were cervical spine ankylosis, ankylosis of both elbows, mitten hands, syndactylismof both feet, funnel chest, and a 1.5 cm bony spine below the coccyx. A small umbilical hernia and grade 2/6 systolic murmurover the right upper sternal border were also observed. Ophthalmologic evaluation revealed nystagmus and optic hypoplasia (Fig 2). Normal thyroid function and diurnal change of the cortisol level were observed. Brain sonographyrevealed agenesis of the septum pellucidum with mild ventriculomegaly(Fig 3A), whereas severe pulmonary regurgitation, dilated main pulmonary artery, persistent foramen ovale, and pulmonary hypertensionwere demonstrated on echocardiography. Agenesisof the septum pellucidumwas also revealed on computed tomography (CT) (Fig 3B). Cranial radiography demonstrated decreased anterio-posterior diameter, remarkabledigital markings,and maxillaryhypoplasia (Fig 4A). Other roentgenologicfindings included bony ankylosisof both elbows, the first and second metatarsal bone of both feet, the fourth and fifth metacarpal bone, the third and fourth midphalangealbone, and distal phalangeai bone of both hands (Figs 4B-E).

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Apert syndrome is an autosomal dominantly transmitted disorder which presents most often as a spontaneous mutation [1]. A few patients were reported to have various chromosomal translocations [12]. Older paternal age was frequently associated with this syndrome [13]. Park and Powers used the Lewis theory to explain the embryologic sequence of Apert syndrome [1 ]. They suggested that 3-5 weeks gestation was the critical period for development. Early reports favored the cranial base origin for acrocephaly, but premature closure of the sutures had also been claimed by some authors [11,16]. Park and Powers reported that Wheaton was the first to describe a patient with underdevelopment of the cranial base [1]. Stewart et al. described a fetus (24 weeks) with Apert syndrome without premature coronal suture closure [14]. Ousterhout and Melsen finally concluded that the basic craniofacial deformity is secondary to the reduced growth potential of the cranial base by histologic examination of the biopsied specimen obtained from facioplasty [ 15]. Hogan and Bauman reported that hydrocephalus often accompanied Apert syndrome and postulated that it may play some role in mental subnormality [16]. Kim et al. described a patient with Apert syndrome who presented with fetal hydrocephalus at 28 weeks gestation [17]; this study strongly supported the findings by Hogan and Bauman [16]. Other reports of associated central nervous

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Figure 3. (A) Brain sonography and (B) cranial CT reveal septum pellucidum agenesis.

Teng et al: Apert Syndrome 385

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Figure 4. (A) Lateral view ~f the skull which reveals oxycephaly and promment digital markings. (B,C) Bony ankylosis of both elbows: (D,E) lnterphalangeal ankylosis and interdigital bony.fusion.

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system anomalies include 4 patients with septal agenesis [18], 1 with agenesis of the corpus callosum [19], and 1 with rhinencephalon maldevelopment [3]. This patient is the first described with septo-optic dysplasia and Apert syndrome. Progressive bony dysplasia in Apert syndrome was first observed by Schauerte and St. Aubin [20] and subsequently by Beligere et al. [21]. The most frequently involved joints are the elbow and shoulder. The elbows were already involved in our patient. Septo-optic dysplasia includes the association of septal agenesis and optic hypoplasia which suggests a developmental disturbance occurring as early as 4-6 weeks gestation [18]. Because our patient had both Apert syndrome and septo-optic dysplasia, it would be reasonable to postulate that the developmental problem occurred within 4-5 weeks gestation. Older paternal age is a frequent finding in Apert syndrome which was true in our patient; however, her mother was not as young as has been reported in most septo-optic dysplasia patients [22]. Our patient was not a first-bom child as most septo-optic dysplasia patients are [9,23,24]. The findings of nystagmus and divergent strabismus were similar to those reported by Hoyt et al. [10]. Septo-optic dysplasia can be easily diagnosed by brain sonography [8] or CT [3], but sometimes may be difficult to differentiate from lobar-type holoprosencephaly [25]. Association of septo-optic dysplasia and holoprosencephaly has been reported by Ellenberger and Runyan [26]; some authors have considered them to be parts of one disease spectrum. Preservation of mental and motor development was the most important issue in the management of our patient. The true incidence of mental retardation is not known because of sampling bias [27]; however, most authors agreed that mental retardation is more prevalent in patients with Apert syndrome than among the general population

[28]. Transverse craniectomy, along the coronal suture, is most often performed. It should be performed as early as possible [19,29,30]; best results are obtained before 2 months of age, primarily to reduce intracranial pressure and allow cerebral expansion with a decrease in the incidence of damage to the brain and optic nerve, as well as for cosmetic reasons [31]. Because bony dysplasia continues into adulthood, the appropriate timing of orthopedoplasty depends on each patient. Most authors agreed with early plastic surgery of the hand to preserve elementary grasping mechanics [19,27], while arthroplasty of other joints should be delayed until adulthood. Facial appearance may be improved by the LeFort III procedure [32]. Normal mental status has been reported [ 19,27]. Endocrinopathy is frequently associated with septo-optic dysplasia; growth hormone should be evaluated in the future. SIADH has never been reported to complicate septo-optic dysplasia which may be due to recurrent lung infection or organic brain disorder. Conductive hearing defect, present in our patient, is another problem that has been frequently mentioned in Apert syndrome [33]. Because there are many handicaps confronting these patients, multidisciplinary cooperation is required for adequate management.

References

[1] Park EA, Powers GF. Acrocephaly and scaphocephaly with symmetricallydistributed malformationsof the extremities. Am J Dis Child 1920;20:235-315. [2] Owen RH. Acrocephalosyndactyly- A case with congenital cardiac abnormalities.Br J Radiol 1952;25:103-6. [3] Maksem JA, Roessmann U. Apert's syndrome with central nervous systemanomalies. Acta Neuropathol 1979;48:59-61. [41 Margolis S, Siegel IM, Choy A, Breinin GM. Oculocutaneous albinism associated with Apert's syndrome. Am J Ophthalmol 1977; 84:830-9. [5] Margolis S, Pachter BR, Breinin GM. Structural alterations of extraocular muscle associated with Apert's syndrome. Br J Ophthalmol 1977;61:683-9.

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[6] Reeves DL. Congenital absence of the septum pellucidum. Bull Johns Hopkins Hosp 1941;69:61-71. [7] Morishima A, Aranoff GS. Syndrome of septo-optic-pituitary dysplasia. The clinical spectrum. Brain Dev 1986;8:233-9. [8] Nowell M. Ultrasound evaluation of septo-optic dysplasia in the newborn - - report of a case. Neuroradiology 1986;28:491-2. [9] Huseman CA, Kelch RP, Hopwood NJ, Zipf WB. Sexual precocity in association with septo-optic dysplasia and hypothalamic hypopituitarism. J Pediatr 1978;92:748-53. [10] Hoyt WF, Kaplan SL, Grumbach MM, Glaser JS. Septo-optic dysplasia and pituitary dwarfism. Lancet 1970;1:893-4. [11] Cohen MM. An etiologic and nosologic overview of craniosynostosis syndromes. Birth Defects 1975;11:137-89. [12] Dodson WE, Museles M, Kennedy JL Jr, AI-Aish M. Acrocephalosyndactylia associated with a chromosomal translocation: 46,XX,t (2p-;Cq+). Am J Dis Child 1970;120:360-2. [13] Weech AA. Combined acrocephaly and syndactylism occurring in mother and daughter. Bull Johns Hopkins Hosp 1927;40:73-5. [14] Stewart RE, Dixon G, Cohen A. The pathogenesis of premature craniosynostosis in acrocephalosyndactyly (Apert's syndrome). Plast Reconstr Surg 1977;59:699-707. [15] Ousterhout DK, Melsen B. Cranial base deformity in Apert's syndrome. Plast Reconstr Surg 1982;69:254-63. [16] Hogan GR, Bauman ML. Hydrocephalus in Apert's syndrome. J Pediatr 1971;79:782-7. [17] Kim H, Uppal V, Wallach R. Apert syndrome and fetal hydrocephalus. Hum Genet 1986;73:93-5. [18] Bruyn GW. Agenesis and cavum septi pellucidi. In: Vinken RJ, Bruyn GW, eds. Handbook of neurology, vol. 30. Amsterdam: North-Holland, 1977;313-21. [19] Musalam SS, Poley JR, Riley HD. Apert's syndrome (acrocephalosyndactyly) I A description and a report on seven cases. Clin Pediatr 1947;74:213-7.

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[20] Schauerte EW, St. Aubin PM. Progrc~i'.,: kxm~slo~i-, m Apert's syndrome (acrocephalosyndactyly) with a description ~f roenl. genographic changes in the feet. Am J Roentgenol !9(~6"~)7%7 '3 [21] Beligere N, Harris V, Pruzansky S. Progressixc b~m} ttysplasi~l in Apert syndrome. Radiology 1981;139:5~,~3-7. [221 Lippe B, Kaplan SA. La Franchi S. Septo-optic dysplasia. ] Pediatr 1979:94:162-3. [23] Elster AB, McAuarney ER. Maternal age rc septo-optic dysplasia. J Pediatr 1979;94:162-3. [24] Purdy F, Friend JCM. Matemat factors in seplo-optic dysplasia. J Pediatr 1979;95:661. [25] Leech RW, Shiman RM. Holoprosencephaly and relatcd midline cerebral anomalies: A review. J Child Neurol 1986;1:3-18. [26] Ellenberger C, Runyan TE. Holoprosencephaly with hypoplasia of the optic nerve, dwarfism, and agenesis of the sepmm pellucidum. Am J Ophthalmol 1970;70:960-7. [27] Dunn FH. Apert's acrocephalosyndactylism. Radiology t962; 78:738-43. I28] Kahn A Jr, Fulmer J. Acrocephalosyndactylism. N Engt J Med 1955;252:379-82. [29] Gray H, Dickey LB. Acrocephalosyndactyly. Am J Dis Child 1947;74:213-7. [30] Shillito J Jr, Matson DD. Craniosynostosis: A review of 591 surgical patients. Pediatrics 1968;41:829-53. [31] Abe H, Itoka T, Akino M, Kitami K, Tsuru M. Functional prognosis of surgical treatment of craniosynostosis. Childs Nerv Syst 1985; 1:53-61. [32] Tessier P. Total osteotomy of the middle third of the face for faciostenosis or for sequelae of the LeFort III fracture, Plast Reconstr Surg 1971;48:533-41. [33] Gould HJ, Caldarelli DD. Hearing and otopathology in Apert syndrome. Arch Otolaryngol Head Neck Surg 1982;108:347-9.