Lymphoproliferative disorders in Sotos syndrome: Observation of two cases

American Journal of Medical Genetics 64:588-593 (1996)

Lymphoproliferative Disorders in Sotos Syndrome: Observation of Two Cases

Giovanni Corsello, Mario GiuffrB, Aldo Carcione, Margherita L. Cuzto, Maria Piccione, and Ottavio Ziino Istituto Materno Infantile (G.C., A.C., M.P.) and Istituto di Pediatria (M.G., M.L.C., O.Z.), Universita di Palermo, Palermo, Italy

Sotos syndrome is included among the overgrowth disorders, most of which have an increased risk of neoplasms. Sotos syndrome does not appear to be related to a specific tumor type, but rather to the development of solid tumors of ectodermal or mesodermal origin in general. We report on two Sotos syndrome patients who developed a non- Hodgkin lymphoma and an acute lymphoblastic leukaemia, respectively. Our experience suggests that there may exist a high frequency of lymphoproliferative disorders in Sotos syndrome, and points out the importance of a long-term follow-up of Sotos syndrome patients, to detect a possi- ble neoplastic evolution. 01996 Wiley-Liss, Inc.

KEY WORDS: Sotos syndrome, lymphoproliferative disorders, overgrowth syndromes

INTRODUCTION Sotos syndrome was first described in 1964 by Sotos

et al. [1964] in 5 children with large body size, early ac- celerated growth, advanced bone age, acromegaly, de- velopmental delay and nonprogressive neurological disorder. After this report, many other cases with additional findings were described [Jaeken et al., 19721. Till now, it has been difficult to determine the minimal di- agnostic criteria and the real incidence of this disorder [Cole and Hughes, 19901.

Sotos syndrome belongs t o a group of conditions with prenatal overgrowth. Gigantism, which is evident during infancy, has a tendency to decrease during childhood because the advanced bone maturation declines with age [Karlberg and Wit, 19911. On the other hand, macrocephaly persists, the face becomes longer and thinner, and prognathism becomes more pronounced.

Received for publication March 9, 1995; revision received September 14,1995.

Address reprint requests to Prof. Giovanni Corsello, Istituto Materno Infantile, Via Cardinale Rampolla 1, 90100 Palermo, Italy.

0 1996 Wiley-Liss, Inc.

Psychomotor development is delayed, with an ex- tremely variable I& (18-119), and many patients have behavior (poverty of language, problems of numeration, difficulty of socialization) and coordination disabilities [Morrow et al., 1990; Rutter and Cole, 19911.

Although chromosomes are usually normal in Sotos syndrome, there are several reports of children diagnosed as having Sotos syndrome who were found to have the fragile-X syndrome [Beemer et al., 19861. It is virtu- ally certain that the two conditions are separate, but with a phenotypic overlap [Stengel-Rutkowski et al., 19931.

In most reports, Sotos syndrome appears to be sporadic, although some familial cases have been described [Hansen and Friis, 1976; Lecornu et al., 19761. In familial cases the most likely mode of inheritance is autosomal-dominant with variable expressivity [Zonana et al., 1977; Winship, 19851. In addition, both autosomal- recessive inheritance and male-to-male transmission have been reported. All these data support the genetic heterogeneity of this condition [Boman and Nilsson, 1980; Townes and Scheiner, 19731.

Several reports describe an increased incidence among Sotos syndrome patients of solid ectodermal as well as mesodermal tumors, including Wilms tumor [Maldonado et al., 19841, hepatocarcinoma [Sugarman et al., 19771, vaginal epidermoid carcinoma [Seyed- abadi et al., 19811, parotid tumor, cavernous haeman- gioma [Abraham and Snodgrass, 19691, osteochon- droma [Hook and Reynolds, 19671, neuroectodermal tumor, giant-cell granuloma of the mandible, small-cell lung carcinoma [Cole et al., 19921, neuroblastoma [Nance et al., 19901, non-Hodgkin lymphoma, and acute lymphocytic leukemia [Hersh et al., 19921.

Over the last 5 years we have cared for 5 children af- fected with Sotos syndrome, and have observed in 2 of them the development of a lymphoproliferative disorder. These 2 patients are described in the present report.

CLINICAL REPORTS Patient 1

This boy was born to healthy, nonconsanguineous parents (mothers age 38 years, fathers age 41 years) a t term of the fourth pregnancy. Delivery was complicated by forceps application. Birth weight was 4,290 g (97th

Lymphoproliferative Disorders in Sotos Syndrome 589

centile). The mother reported excessive growth since the first year of life, in stature and weight.

At 5712 years, clinical examination showed: weight of 29.5 kg (>97th centile), height of 123 cm (>99th centile, +2.7 SD), head circumference (OFC) of 58 cm (>97th centile), macrodolichocephaly, frontal bossing, prognathism, ocular hypertelorism, bilateral strabismus (Fig. lB), highly-arched palate and apparently low-set ears with thick and prominent antehelix. There was a 216 systolic murmur, muscular hypertrophy, especially in limbs (Fig. lA), normal genitalia, left convex scoliosis with mild deformation of the rib cage, ataxic gait, and mild psychomotor and speech delay. Roentgenograms of the left hand showed advanced bone age (TW2 = 7.9 years old) (Fig. 2). Chromosomes were normal (46,XY). Auditory brain stem responses (ABR) showed bilaterally normal auditory threshold, and bilaterally delayed V-wave with increased I-V inter- val suggesting brain stem bioelectrical abnormalities. Electrocardiogram was normal. Thyroid hormone, growth hormone (GH), adrenocorticotropin hormone (ACTH), and cortisol levels were normal. Roentgeno- logically, the volume of the skull was greater than normal (Fig. 3), with subopacity of the sphenoidal sinuses, irregularities of the outlines of iliac crests, squat humeri, radii, and ulnae, small and flattened radial proximal epiphyseal nuclei, absence of the ulnar distal epiphyseal nucleus, squat and short metacarpals, squat and enlarged femora and tibiae, and enlarged first metatarsals and first and second phalanges bilaterally. Analysis of the metacarpophalangeal pattern profile showed a squat and short profile which was not compatible with any of the cases reported in the litera-

ture [Dijkstra, 1985; Butler et al., 19881. Abdominal ultrasonography showed hepatosplenomegaly. A brain CT scan showed enlarged lateral ventricles.

At age 5y1z years, marked laterocervical and medi- astinal lymphoadenopathy was noted, and a T-cell non- Hodgkin lymphoma was diagnosed. The central ner- vous system was not involved. The patient was treated with protocol LSA2-L2, which induced a complete remission. Five months later an intracranial relapse (4,000 cells/ml) led to death within 13 months in spite of chemotherapy and cranial irradiation (24 Gy).

Patient 2 This boy was born to healthy, nonconsanguineous

parents (mothers age 37 years, fathers age 37 years) a t term of the fifth pregnancy. Delivery was performed by cesarean section due to the presence of a malformed bicornuate uterus. In the first pregnancy a preterm polymalformed infant was born, who died soon after birth, while the two following pregnancies ended in spontaneous abortion. The mother has macrocephaly and prognathism, apparently compatible with Sotos syndrome.

Clinical examination at birth showed: weight of 3,450 g (50th centile), length of 49 cm (25th centile), OFC of 38.5 cm (>97th centile), macrocephaly, high forehead, frontal bossing, downslanting palpebral fissures, epicanthic folds, depressed nasal bridge (Fig. 4A1, apparently low-set and posteriorly angulated ears, short neck with prominent occiput (Fig. 4B), normal genitalia, generalized hypotonia, and absence of head control. ABR showed normal auditory threshold on the left and elevated on the right (45 db), suggesting a right mild

Fig. 1. Patient 1, age 53/12 years. A Note body size, muscular hypertrophy in limbs, and left convex scoliosis. B Note macrocephaly with frontal bossing, ocular hypertelorism, and strabismus.

590 Corsello et al.

Fig. 2. Bone age of patient 1: TW2 = 7.9 years old.

sensorineural hypoacusia. Cerebral ultrasonography was normal. A brain CT scan at age 3 years demonstrated macrocephaly and a slight enlargement of the ventricular system, cisterna magna, and subarachnoid spaces in the frontal region.

At age 31/12 years his weight was 15.2 kg (30th centile), height 105 cm (94th centile), and OFC 57 cm (>97th centile); the child had fever and anemia, and an acute lymphoblastic leukemia was diagnosed. The im- munophenotypical analysis demonstrated an early pre- B acute lymphoblastic leukemia (ALL). The patient started the therapeutic protocol AIEOP LAL 9101 for standard-risk ALL and achieved a complete remission; therefore, the therapy was stopped 2 years after diagnosis. The treatment was tolerated without any partic- ular comp~ication, and the patient is free of disease 8 months after termination of therapy. Growth velocity

Fig. 4. Patient 2 at birth. A: Frontal view. Note macrocephaly, high forehead, downslanting palpebral fissures, epicanthic folds, and depressed nasal bridge. B: Profile. Note apparently low-set and posteriorly angulated ears, and short neck.

stopped during the induction antiblastic chemotherapy; afterwards, linear growth restarted following the 90th centile.

At age 5l%2 years (Fig. 5) his weight was 21 kg (65th centile), height 121 cm (92nd centile), and OFC 58 cm (>97th centile), and a mild lumbar left convex scoliosis was noted. Bone age (TW2) was 4.3, with a maturation of the metacarpophalangeal axis more advanced than the carpal bones (radius-ulna score [RUS] = 5.5) (Fig. 6). Mild speech delay and behavioral disabilities (insta- bility, hyperreactivity) were present.

DISCUSSION The main clinical findings in the present 2 cases are

mmmarized in Table I, in comparison with the phenotype of the other 3 Sotos syndrome patients observed during the last 5 years.

In our experience, macrocephaly and psychomotor delay were the most common findings, present in all cases. Other frequent manifestations were frontal bossing and prognathism. The delay in psychomotor development was usually characterized by nonprogressive Fig. 3. Patient 1. Skull roentgenogram. Note macrodolichocephaly.


Fig. 5. Patient 2, age ~ ' Y u years. A Frontal view. Note excessive size of head and downslanting palpebral fissures. B: Profile. Note high and prominent forehead.

incoordination, especially expressed with ataxic gait, and mild-to-severe mental retardation. ABR were abnormal in both patients, showing elevated auditory threshold, long latency of V wave, and increased I-V in- terval. Some phenotypical traits observed in patient 1 (large fleshy ear lobes and prominent mandible) also oc- cur in Weaver syndrome, in which the overgrowth pattern is associated with specific skeletal findings such as camptodactyly, limited elbow and knee extension, foot deformities, and relative micrognathia.

Patient 1 was sporadic, while patient 2 showed pos- sible inheritance of the syndrome from the mother. Concerning the other 3 patients without neoplasia, in 2 of them (who are brothers) inheritance from the father was quite probable, and the other was sporadic.

Sotos syndrome is included among the overgrowth disorders, conditions in which the tissues overreact to as yet unidentified hyperplastic stimuli. Most of these syndromes, listed in Table 11, have an increased risk of neoplasms.

Various malignancies have been reported in the literature in association with Sotos syndrome, and it appears that the risk of tumor in these patients is greater

Fig. 6. Bone age of patient 2: TW2 = 4.3 years old (RUS = 5.5) .

than in the general pediatric population, with a wide distribution of tumor sites and types. In addition, the syndrome does not appear to be related to a specific tumor type, but rather to solid tumors of ectodermal or mesodermal origin in general [Hersh et al., 19921.

Non-Hodgkin lymphoma and lymphoblastic leukemia, observed in patients 1 and 2, respectively, are two different disorders affecting the same cell lineage. Clinical presentation of disease and evolution were different in the 2 patients (relapse and demise in case 1, and 31 months of disease-free survival in case 2). Pro- longed chemotherapy may be responsible for the rela- tively delayed carpal bone development in patient 2.

The development of a lymphoproliferative disorder in both patients draws attention to the frequency of this kind of neoplasm in Sotos syndrome. Although only a few cases of leukemia or lymphoma associated with So- tos syndrome have been reported, most of the patients with Sotos syndrome often do not receive prolonged follow- up for malignancies, distorting the evaluation of cancer risk in this condition [Hersh et al., 19921. In addition, even now we cannot say whether increased cancer risk is related to overgrowth pattern, or to some specific characteristic of the syndrome [Daling et al., 19841.

Sotos syndrome shows both clinical variability and genetic heterogeneity. Our experience shows that clinical evaluation as well as long-term follow-up are ex-

592 Corsello et al.

TABLE I. Clinical Evaluation of Patients With Sotos Syndrome*

Additionally Patient 2 observed patients Patient 1

m + + + +

-

-

m + + + -

m + + + -

Sex Macrocephaly Frontal bossing Prognathism Abnormalities of external ears Hypertelorism Downslanting palpebral fissures Strabismus Depressed nasal bridge Highly-arched palate Cardiac murmur Kyphoscoliosis Advanced bone age Hypotonia Psychomotor delay Ataxic gait Mental retardation Cerebral imaging (CT, US) B R Inheritance Tumors

m + + + + + + + + + + -

+ + + -

-

+ + + + + +

+ A A F +

+ A N S

+ A N F

* N, normal; A, abnormal; S, sporadic; F, familial; CT, computerized tomography; US, ultrasonography.

TABLE 11. More Frequent Tumors in Some Overgrowth Syndromes

Prenatal onset Postnatal onset

Svndrome Tumors Syndrome Tumors

Sotos syndrome Solid ectodermal and mesodermal tumors

Wiedemann-Beckwith Wilms tumor, adrenal syndrome carcinoma, gonado

blastoma, hepatoblastoma Ruvalcaba-Myhre- Mesodermal hamartomas

Smith syndrome (lipomas,hemangiomas, lymphangiomas)

Weaver Neuroblastoma”

Neurofibromatosis Neurofibromas, astrocytomas, cutaneous angiomas, subcutaneous leiomyomas, carcinoid tumors, xanthogranulomas, acoustic neurinomas

Proteus syndrome Subcutaneous hamartomas, fibroadenomas

Klippel-Trenaunay- Cavernous hemangiomas Weber syndrome

Diagnosis not confirmed LGorlin et al., 19901

tremely important in patients with Sotos syndrome. Considering the development of tumors in the patients reported here and in other cases from the literature, the risk of neoplastic evolution in Sotos syndrome seems to be quite high, although additional data are necessary to establish its exact value.

Butler MG, Dijkstra PF, Meaney FJ, Gale DD (1988): Metacarpopha- langeal pattern profile analysis in Sotos syndrome: A follow-up report on 34 subjects. Am J Med Genet 29:143-147.

Cole TRP, Hughes HE (1990): Sotos syndrome. J Med Genet 27571- 576.

Cole TRP, Hughes HE, Jeffrey MJ, Williams AT, Arnold MM (1992): Small cell lung carcinoma in a patient with Sotos syndrome: Are genes a t 3p21 involved in both conditions? J Med Genet 29:338-341.

Daling JR, Starzyk P, Olshan AF, et al. (1984): Birth weight and the incidence of childhood cancer. JNCI 72:1039-1041.

Dijkstra PF (1985): Cerebral gigantism (Sotos syndrome). Metacar- pophalangeal pattern profiles. Fortschr Geb Rontgenstr Nuk- learmed Ergangzungsband 143:183-185.

Gorlin RJ, Cohen MM, Levin LS (1990): “Syndromes of the Head and Neck,” 3rd ed. New York: Oxford University Press, pp 332-336.

Hansen FJ, Friis B (1976): Familial occurrence of cerebral gigantism, Sotos syndrome. Acta Paediatr Scand 65:387-389.

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Lymphoproliferative disorders in Sotos syndrome: Observation of two cases