Cornelia de lange syndrome associated with a suprasellar germinoma

cance of this finding is not clear.

References 1. Fisher M. An unusual variant of acute idiopathic polyneuritis (syndrome of ophthalmoplegia, ataxia , and areflexia). N Engl J Med 1956;255: 57-65. 2. Derakhshan I, Lotfi l , Kaufman B. Ophthalmoplegia, ataxia and hyporeflexia (Fisher syndrome). With a midbrain lesion demonstrated by CT scanning. Eur Neurol 1979 ;18: 361-6. 3. AI-Din An, Anderson M, Bickerstaff ER, Harvey I. Brainstem encephalitis and the syndrome of Miller Fisher. A clinical study. Brain 1982;105: 481-95. 4. Bell W, van Allen M, Blackman 1. Fisher syndrome in childhood. Dev Med Child Neural 1970;12:758-66. 5 . Davis Ml. A Guillain-Barre variant ophthalmoplegia, ataxia and areflexia. Mt Sinai J Med (NY) 1975 ;42: 167-72. 6. Elizan TS , Spire lP , Andiman RM , Baughaman FA , Lloyd-Smith DL. Syndrome of acute idiopathic ophthalmoplegia with ataxia and areflexia.

Neurology 1977;21:240-3.

7. Price RL , OConnor PS, Rothner AD. Acute ophthalmoplegia, ataxia and areflexia (Fisher syndrome) in childhood. Cleve Clin Q 1978 ;45: 247-52. 8. Marks H, Augustyn P, Allen R. Fisher syndrome in children. Pediatrics 1978 ;60: 726-9. 9. Ropper AH , Shahani B. Proposed mechanism of ataxia in Fisher syndrome. Arch Neurol 1983; 40:537-8. 10. Becker W, Watters G, Humphreys P. Fisher syndrome in childhood. Neurology 1981 ;31 :555-60. 11. Sauron B, Bouche P, Cathala HP, Chain F , Gastaigne P. Miller Fisher syndrome. Clinical and electrophysiologic evidence of peripheral origin in 10 cases. Neurology 1984;34:953-6. 12. Baronitini F, Sita D. The nosological position of Fisher syndrome (ophthalmoplegia, ataxia and areflexia). J Neural 1983;299:33-44. 13. Bickerstaff ER. Brain stem encephalitis. Further observations on a grave syndrome with benign prognosis. Br Med J 1957;1: 1384-7. 14. Bickerstaff ER . Brain stem encephalitis (Bickerstaff's encephalitis. In: Viken Pl , Bruyn GW, eds. Handbook of clinical neurology, Vol 34. Amsterdam: North-Holland Publ Co, 1975:605-9. 15. Tripp l , Brett E. Miller-Fisher polyneuritis. Proc R Soc Med 1975 ;68:301-2.

Cornelia de Lange Syndrome Associated with a Suprasellar Germinoma Katsuo Sugita, MD, Tatsuro Izumi, MD, Kiyoko Yamaguchi, MD, Yukio Fukuyama, MD, Akito Sato, MD and Akira Kajita, MD

A case of Cornelia de Lange syndrome complicated by a suprasellar germinoma is presented. The patient was an 18 years old girl with severe mental retardation and characteristic facial and other malformed features. She was admitted because of polyuria and polydipsia. Endocrine investigation showed defects of hypothalamic-pituitary function. The most striking finding on postmortem examination was the existence of a suprasellar germinoma extending to the optic tract and pituitary lobes. We discussed a diagnostic problem caused by the coexistence of these two uncommon entities.

Sugita K, Izumi T, Yamaguchi K, Fukuyama Y, Sato A, Kajita A. Cornelia de Lange syndrome associated with a suprasellar germinoma. Brain Dev 1986;8:541-6

In 1933 Cornelia de Lange [I] first described two infant girls, in Amsterdam, who had mental retardation associated with a pattern of relative-

Iy minor congenital malformations. There were no specific laboratory examinations to confirm the clinical diagnosis of de Lange syndrome [2]

170 .~~~~~~~~~~~--~~-----~--~~~--~,B.HI. : . (em) : .

Growth · Chart for Girl" (0 ':"'18ye~rs)_;_ :_...

'+250 - - - -

,. I

..-C-_':--,-_+---+_ :.

~~~;.

i

/..:,;.:........~::::=':....-.-!....~...!....:.~~.-.:...~~_~.....:..._~~~ _________. _!_ - ' - _

I

10

BWI. (kg)

O~~--2~~3-~4--~5----~~~--79--~10~~ll~~1~ 2~1~3--1~4-~15-~16~~17~~180

Fig 1 Growth curves for the patient (i8-yearold girl). Both stature and weigh t curvrs are well below -2SD. The latter shows the remarkable loss

~~e~~~h~ :~~~~s.

Years

From the Departments of Pediatrics, (KS , TI , KY , YF) and Pathology (AS , AK), Tokyo Women's Medical College, Tokyo. Received for publication : May 16 , 1985 . Accepted for publication: March 13, 1986. Key words: Cornelia de Lange syndrome, suprasellar germinoma, diabetes insipidus, hypothyroidism. Correspondence address: Katsuo Sugita, MD, Department of Pediatrics, Chiba University School of Medicine, 1-8-1 Inohana, Chiba 280, Japan.

542 Brain & Development, Vol 8, No 5, 1986

but an etiologic approach has been taken on the basis of genetic, teratologic and epidemiologic considerations [3-5]. We have recently seen a girl with Cornelia de Lange syndrome and a suprasellar germinoma, whose initial endocrinological signs seemed to be a failure to develop a·"growth spurt" on reaching puberty. Three years later, she was admitted to our hospital for amenorrhea and polyuria and poly-

no clinodactyly or syndactyly of the second and third toes. The external genitalia were relatively hypoplastic with little public hair. Cardiovascular examination was normal. Ataxia, tremor, involuntary movement or nystagmus were not seen, but aggressive behavior was present. Funduscopic examination showed no optic atrophy nor papilledema. Case Report Laboratory studies on admission showed the The girl was the second child of healthy, non- following: WBC 7 ,600/cmm, RBC 378 x 10\ consanguineous parents, aged 35 (father) and Ht 31.5%, Na 151 mEq/l, K 3.6 mEq/l, CI 30 (mother) years old. There was no relevant "Ill mEq/l, glucose 60 mg/dl; and plasma osmofamily history. Delivery was normal after larity 310 mOsm/I. Urinalysis revealed specific 38 weeks and 3 days uncomplicated gestation. gravities ranging from 1.003-1.006, pH 6-7 , Her birth weight and height were 2,060 g and and no glucose or albunlin, and no pathologic 45 cm, respectively. She was a poor feeder for findings of sediment. The cerebrospinal fluid 1 year, and her growth and development were was clear with normal cellular and protein significantly delayed. She was able to control contents. her head at 10 months, sit at 4 years and stand The patient underwent anterior and postefirst with support at 6 years. At 3 years, she rior pituitary stimulation tests under continual visited the Tokyo Women's Medical College supervision (Table 1). The method of Sato et Hospital and was diagnosed as Cornelia de Lange syndrome from the facial and other physical findings. Her subsequent course has been one of severe developmental retardation with short stature and low body weight (Fig 1), and frequent respiratory infection. Bone age retardation was not found in this patient. Menstruation began at the age of 12 years but its periods were both irregular and occurring at unduly long intervals. Her growth of height did not accelerate before and during this age. Three years later, polyuria, polydipsia and amenorrhea appeared. At the age of 18 years, she was admitted to our hospital because of a 7 kg loss in weight and polyuria and polydipsia resulting in a daily water intake of from 2,000 to 2,500 mI. On admission, her body weight was 20 kg, 4.8 standard deviations below the mean, and her height was 121 cm, 7 standard deviations below the mean. Her head was microbrachycephalic (circumference 43.5 cm, 10 standard deviations below the mean). She had the characteristic facial features of the Cornelia de Lange syndrome, with synophrys, long curly lashes, anteverted nostrils and thin lips turned down at the corners (Fig 2). Her arms, legs and back were hirsute and she had hypoplastic Fig 2 The patient at the age of 18 years. A characteristic face with bushy eyebrows fused at the midline, nipples and umbilicus. She also had proximal- long and upturned eyelashes, a small nose with a low ly implanted thumbs, bilateral simian creases bridge, anteverted nostrils and a crescent-shaped and flexion contractures of the elbows, but mouth. dipsia. Tllis case may be an example which suggests a possible causal relationship between teratogenesis and oncogenesis [6] . The coexistence of these two rare entities and the resultant diagnostic problems, especially endocrine, are the basis of this report.

Sugita et al: De Lange syndrome with germinoma 543

Table I Results of anterior and posterior pituitary stimulation tests Anterior pituitary'" GH Cortisol Prolactin LH FSH TSH

T3 T4 Glucose

(ng/dl) (,ug/dl) (ng/ml) (mID/ml) (mID/ml) CuU/ml) (ng/dl) (Jlg/dl) (mg/dl)

0

30

Time (min) 60

90

120

3.9 4.9 69.0 5.3 4.4 1.0 55 5.9 60

3.0 6.7 97.5 6.1 6.1 4.3

4.1 9.0 70.4 4.5 5.1 4.2

5.5 8.1 78.9 5.6 5.6 2.7

6.7 13.1 81.5 5.9 4.2 2.7

22

28

45

49

Posterior pituitary * *

-3.5

-2.5

-1.5

Time (h) -0.5 0

+0.5

+1.5

+2.5

Urine: Volume Osmolarity

(ml) (mOsm/l)

400 135

100 112

90 109

120 110

30 252

25 423

20 440

Plasma: Osmolarity

(mOsm/l)

309

329

287

290

286

289

292

*: Simultaneous intravenous injections of insulin (0.1 p.g/kg), TRH (10 p.g/kg), and LH-RH (3 p.g/kg) in 10 ml saline. Normal values are as follows, GH: 5, Cortisol: 4.5-24, Prolactin: 2-20, LH: 2-20 (follicular phase), 1-16 (luteal phase), FSH: 5-12 (follicular phase), 2-16 (luteal phase), TSH: 4, T3: 90-170, T4; 5.1-11.4. * *: Intramuscular injection of vasopressin 5 Units at time 0 h.

al [7] was used to evaluate anterior pituitary reserve. This investigation confirmed pituitary hypothyroidism and hyposecretion of gonadotropin. Despite adequate hypoglycemia, there was no growth hormone response and a low cortisol response of below 25 Jlgjdl. Plasma prolactin levels remained elevated both before and after TRH stimulation. A water deprivation test indicated impaired posterior pituitary function together with the renal response to the rise in urinary osmolarity after intramuscular injection of vasopressin, conclusively demonstrating the presence of pituitary diabetes insipidus. Renal function tests including both creatinine clearance test and PSP test were also within normal limits. Cranial plain roentgenography and computed tomography of every 5 mm slice without contrast enhancement showed no abnormal fmdings. The polyuria and polydipsia gradually improved after administration of carbamazepine which we chose first for treatment of both diabetes insipidus [8] and behavior disorders [9]. Thereafter, she was followed carefully at the outpatient clinic

544 Brain & Development. Vol 8. No 5. 1986

Fig 3 Photomicrograph showing the characteristic histologic pattern of a germinoma, consisting of isolated spheroidal cells interspersed with lymphocytelike cells.

after discharge. Unexpectedly, she died suddenly at home at the age of 18 years 6 months and an autopsy was carried out. The pathological findings were as follows; the most striking finding on postmortem examination was a suprasellar tumor, which consisted from two types of cells: large polygonal or spheroidal cells and small cells identical in appearance to lymphocytes; these are typical

of a germinal cell tumor (Fig 3). The tumor cells had invaded the optic tract, pituitary stalk and posterior pituitary lobes. The latter were so enlarged that they displaced and compressed the anterior lobes severely. (The pathological finidngs were reported elsewhere in detail [I 0].) Discussion

injury to or removal of the posterior lobe alone did not prevent ADH release in the hypothalamus [15]. So we suspected that not only pituitary but also hypothalamic injury was involved in this case even though elevated prolactin level might be related to increased TRH level secondary to hypothyroidism. To our knowledge, no one has reported a case of the Cornelia de Lange syndrome with a hypothalamic lesion. On the other hand, this girl was evidently "small for gestational age" at birth and remained abnormally small in stature, as usually seen in the Cornelia de Lange syndrome. But it is noteworthy that she had normal bone age and had her menarche at twelve years old , so that her endocrine function may be assumed to have been grossly normal previously. The failure to develop a "growth spurt" on reaching puberty, which was observed even in this syndrome [2] , may have been the first sign of endocrine dysfunction. In order to recognize hypothalamic complication in this syndrome , it is important and necessary to know both the longitudinal growth patterns and the standard endocrine function levels in this syndrome.

The Cornelia de Lange syndrome is a clinical entity in which several major diagnostic features are present from birth. This patient demonstrated many of the stigmata of the syndrome with a characteristic face, totally consistent with 16/24 of the anomalies described by Ptacek et al [3]. The etiology remained unknown while some authors have elaborated some genetic, teratologic and epidemiologic considerations [3-5]. We happened to experience the case of this syndrome complicated by a germinoma. With respect to the association with neoplasm, there has been only one reported case of the Cornelia de Lange syndrome and a Wilms tumor being present in the same patient [11] . On the other hand, Bolande described the relationship between teratogenesis and oncogenesis [6]. The presence of these two rare entities may be a chance occurrence References 1. De Lange C. Sur un type nouveau de degenerabut the possibility that the two are a sequence tion (Typus Amstelodamensis). Arch Med Enf of closely related events may not ruled out 1933 ;36 :713-9. definitely. 2. McArthur RG, Edwards JH. de Lange syndrome; report of 20 cases. Can Med Assoc J 1967 ;96 : Furthermore, this malformation syndrome 1185-98. shows various physical and endocrine abnormal3. Ptacek LJ, Opitz JM, Smith DW, Gerritsen T, ities. Hillman et al [12] and Schlesinger et al Waisman HA. The Cornelia de Lange syndrome. [13] reported reduced thyroid function and J Pediatr 1963;63 :1000-20. evidence of hypopituitarism in this syndrome, 4. Beck B. Epidemiology of Cornelia de Lange's syndrome. Acta Paediotr Scand 1976 ;65 :631-8. respectively. Ptacek et al [3] described a 5. Jervis GA, Stimson CWo De Lange syndrome. J transient inability to concentrate urine in one Pediatr 1963 ;63:634-45 . of 6 patients. We investigated endocrine func6. Bolande RP. Relationships between teratogenesis tion in our patient. Anterior pituitary function and oncogenesis. In: Perrin EVD, Feingold MJ, eds. Pathobiology of development. Baltimore: tests showed secondary hypothyroidism, hypoWilliams Wilkins, 1973 : 114-34. secretion of gonadotropin and little response 7 . Sato T, Inoue M, Masuyama T, et al. Simultaneof GH and cortisol after insulin-induced hypoous evaluation of the pituitary reserve of GH, glycemia. On the other hand, serum prolactin TSII, ACTH and LH in children. J Gin Endolevels remained elevated. The results of poscrinol Metab 1974;39:595-9. 8. Wales JK. Treatment of diabetes insipidus with terior pituitary function tests showed that carbamazepine. Lancet 1975 ;ii: 948-51. the urine concentration did not increase after 9. Swaiman KF, Wright FS. The practice ofpediwater deprivation but responded to injection atric neurology, vol 2. St Louis·Toronto·London : of vasopressin. CV Mosby, 1982. Previous studies have shown that hypo- 10. Sato A, Kajita A, Sugita K, et al. Cornelia de Lange syndrome with intracranial germinoma. thalamic-pituitary disorders or section of the Acta Pathol Jpn 1986 ;36: 143-9. pituitary stalk resulted in elevated plasma 11. Cohen MM JI. The child with multiple birth prolactin levels [I 4] and also showed that defects. New York : Raven Press, 1982.

Sugita et al: De Lange syndrome with germinoma 545

12. Hillman JC, Hammond J, NOll 0, Reiss M. Endocrine investigations in de Lange's and Seckel's syndrome. AmJ Ment Defee 1968;73 :30-3. 13. Schlesinger B, Clayton B, Bodian M, Jones KV. Typus degenerativus amstelodamensis. Arch Dis Child 1963;38:349-57. 14. Reichlin S. Neuroendocrinology: prolactin re-

546 Brain & Development, Vol 8, No 5, 1986

gulation. In : Williams RH, ed. Textbook of I crino!ogy. 6th ed. Phiiadelphia-London·ToH WB Saunders, 1981:616-8. 15. Kleeman CR, Berl T. The neurohypopl hormones: Vasopressin. In: DeGroot LJ , ( GF, Odell WD, eds. Endocrinology. New' Grune and Stratton Inc, 1979:253-75.