Further delineation of Weaver syndrome

Further delineation of Weaver syndrome

Seven new cases of Weaver syndrome are described, including the first reported case in an adult. Overgrowth is usually but not always present. The combination of characteristic facies and developmental delay, with the peculiar radiographic findings of accelerated dysharmonic osseous maturation and splaying of the distal long bones, is diagnostic of Weaver syndrome. (J PEDIATR 1986;108:228-235)

Holly H. Ardinger, M.D., James W. Hanson, M.D., Mary Jo E. Harrod, Ph.D., M. Michael Cohen, Jr., D.M.D., PhlD., John A. R. Tibbles, M.D., J. Philip Welch, M.B., Ch.B,, Ph.D., Theresa Young-Wee, M.D., Annemar ie Sommer, M.D., Rosalie Goldberg, M.S., Robert J. Shprintzen, Ph.D., Eugene J. Sidoti, M.D., Lawrence G. Leichtman, M.D., and H. Eugene Hoyme, M.D.

From the Division of Medical Genetics, Department of Pediatrics, University of Iowa, Iowa City; the Department of Obstetrics and Gynecology, University of Texas, Dallas; Departments of Oral Biology and Pediatrics, Dalhousie University, Halifax, Nova Scotia, Canada; Division/ Section of Genetics, Department of Pediatrics, Ohio State University College of Medicine, Columbus; Center for Craniofacial Disorders, Montefiore Hospital and Medical Center and Albert Einstein College of Medicine, Bronx, New York; Medical Care Associates of Tulsa; and Vermont Regional Genetics Center, University of Vermont, Burlington

Subsequent to the original paper describing Weaver over-

growth syndrome;~ several addit ional cases z-~ have been

described. Questions have been raised as to whether

Weaver syndrome is a dist inct condition. 4,5, ~3

We present what we believe to be seven new cases of

Weaver syndrome, and compare them with previously

reported cases. Our pa t ien t 7 is the first reported adult

believed to have Weaver syndrome. We support this

syndrome as a unique clinical entity.

CASE R E P O R T S

Patient 1. This 3V2-year-old boy was noted to be large at birth. Birth weight was 4800 gm and length 56 cm at 38 weeks gestation. There were no serious neonatal problems. Subsequent growth has been above but parallel to the 97th percentile for height, weight, and head circumference. When first seen at 15 months, he was noted to have a broad forehead, mild ocular hypertelorism, long philtrum, large ears, and micrognathia (Fig. 1, A). His voice was

Submitted for publication June 12, 1985; accepted Aug. 21, 1985.

Reprint requests: Holly H. Ardinger, M.D., Division of Medical Genetics, Department of Pediatrics, University of Iowa Hospitals, Iowa City, IA 52242.

hoarse, and development was moderately delayed. There was no hypertonieity. Other features included limitation of motion at e!bows and knees, mild metatarsus adductus, prominent fingertip pads, broad thumbs, thin deep-set nails, mildly loose and excess skin, a small umbilical hernia, and rectus diastasis. Radiographs a t 15 months of age revealed a carpal bone age of 4 years and splaying of distal femurs (Fig. 2, A). At 23 months, developmental ag e was 23 to 24 months (Bayley Scales of Infant Development), although uncoordination was present. At 41A years, IQ was in the low average range (St anford-Binet Intelligence Scale).

The patient's mother had weighed 3500 gm at birth at 37 weeks gestation. Adult height was 170 cm (90th percentile), and she had a broad forehead and ocular hypertelorism. Intelligence was normal. Her own mother had similar facial features, a height Of 180 cm (>95th percentile), and an umbilical hernia. The patient's father was 185.4 cm tall (90th percentile). Other family members did not have features of Weaver syndrome.

Patient 2. This 5-year-01d girl was the product of an uncomplicated term gestation, labor, and delivery; birth weight was 3295 gm, During the first 10 months, growth accelerated rapidly such that her length was 75 cm (90th to 97th percentile), weight was 10.3 kg (50th to 75th percentile); and head circumference was 47 cm (75th percentile). At 3 months she had a broad forehead, ocular hypertelorism, large ears, long philtrum, and small mandible with apparent glossoptosis, resulting in cyanosis with stridor.

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Volume 108 Weaver syndrome 2 2 9 Number 2

She had bilateral clubfoot, and all four extremities were noted to be "extremely stiff." Her hands had prominent fingertip pads, thin, deep-set nails, and camptodactyly. She had two large capillary hemangiomas on the trunk. Radiographic studies showed broadened femoral metaphyses and fragmentation or mottling of some epiphyses. At 26 months her height, weight, and head circumference were at the 95th percentile. Dysmorphic features remained the same (Fig. 1, B). At 28 months, carpal bone age was 5 years 9 months, and phalangeal bone age 3 years 6 months. Development has been moderately delayed. At 10 months, a developmental index was <50 on the Bayley Scales of Infant Development. Family history was negative for Weaver syndrome.

Patient 3. This 8-month-old girl was born after a term gestation with excessive maternal weight gain. Birth weight was 4540 gm, and the infant was hypotonic with poor suck and a small mandible. Subsequently, she had gross motor delay, but growth remained accelerated, with height, weight, and head circumference >97th percentile. At 5 months of age (Fig. 1, C) she had macrocephaly with broad forehead, craniofacial asymmetry, ocular hypertelorism, downslanting palpebral fissures, large ears, and microgna- thin; loose nuchal skin; and crowded toes and deep-set toenails. Her teeth began to erupt at 2 to 3 months of age. Radiographs showed wide metaphyses and vertebral anomalies. Bone age at 4 months was 9 months. Chromosomes and serum somatomedin, insulin, and fasting growth hormone measurements were normal. Family history was negative for Weaver syndrome, except that her father had a broad forehead as an infant, but no other signs as an adult. He was not overgrown at birth, and final adult height was 170 cm (75th percentile). The patient's mother's height was 165 cm (60th percentile).

Patient 4. This 71/z-year-old boy (-Fig. 1, D) was born after an uncomplicated term pregnancy, labor, and delivery; birth weight was 3856 gm. At birth he had a low-pitched cry, mild hypotonia, small ears with folded helices, upslanting palpebral fissures, fiat nasal bridge, redundant nuchal skinfolds, second-degree hypospa- dias, and bilateral clubfoot. His growth curve followed the 90th percentile in weight, and jumped from the 50th to the 90th percentile in height between the ages of 41~ and 7 years. Head circumference was at the 50th percentile at 7 years. In his early years, he was developmentally delayed. He required surgical

procedures to correct alternating exotropia, bilateral inguinal hernias, and an atretic left ear canal. Radiographs at 4y~ years demonstrated a bone age of 8 years (Fig. 2, B), and at 61/2 years bone age was 10 years. Reevaluation at 7 years revealed additional dysmorphic features, including marked hypertelorism and small penis. His hands appeared large, with broad thumbs, deep-set nails, camptodactyly, and prominent fingertip pads. He was in a special education class at school. Family history was unremarkable, and his parents were of average adult height.

Patient 5. This boy had a birth weight of 3657 gm after a 37-week pregnancy complicated by first-trimester bleeding (treated by hormone injection) and maternal use of oral broncho- dilators and antihistamines throughout gestation. By one year he weighed 13.2 kg (>98th percentile); his growth continued at this rate (50th percentile for head circumference). He had an unusual

Fig. t. Facial features characteristic of Weaver syndrome. Note broad forehead, hypertelorism, fiat nasal bridge, long philtrum, large ears, and micrognathia. A, Patient 1 at 15 months of age.

cry at birth, with subsequent speech delay and a "husky" hypernasal voice. He was described as lethargic for the first year of life, and had evidence of psychomotor delay, predominately of gross and fine motor development. At 4 years he passed all the verbal and personal-social landmarks for age, but failed to perform expected graphomotor tasks on the Denver Developmen- tal Screening Test. He obtained IQ scores of 100 on a variety of psychologic tests, with a wide scatter of test results because of his hyperactive and distractable nature. Examination at age 4 years was remarkable for a very broad face with a small mandible, flattened posterior skull, prominent supraorbitat ridge, ocular hypertelorism, large protruberant ears, and a small hemangioma on the left cheek (Fig. 1, E). An umbilical hernia was present. At 6y2 years, bone age was 10 years. Serum thyroid-stimulating hormone, thyroxine, and testosterone values were all normal. No positive family history for similar problems was elicited. His mother's height was 151.7 cm (<5th percentile), and his father's height was 180.3 cm (70th percentile).

Patient 6. This boy was the product of an unremarkable term pregnancy, with birth weight 5080 gm (>95th percentile), length 53.5 cm (90th percentile), and head circumference 38 cm (98th percentile). At birth he had camptodactyly, mild arthrogryposis of the knees, hydrocele, an umbilical hernia, and large, low-set ears

2 3 0 Ardinger et al. The Journal of Pediatrics February 1986

Fig. 4. (cont'd). B, Patient 2 at 26 months of age.

with abnormal antihelices. During the first 14 months of life, growth was above but parallel to the 95th percentile for height, weight, and head circumference. He had ocular hypertelorism (inner eanthal distance 3.4 cm), a square shaped head, a harsh, deep cry, bilateral inguinal hernias, and loose skin at the base of his neck and over his forehead. He was also hypotonic. Develop- mental quotient (DQ) was 70 at 14 months (Cattell Infant Intelligence Scale). Bone age was 2y2 years at 1~2 years of age. At 24 months he had a height of 91.5 cm (90th percentile) and weight of 2.0.5 kg (>95th percentile). DQ remained in the 60 to 70 range and was associated with persistent b, ypotonia. No other affected family members were known.

Patient 7. This man had reached adulthood when features of Weaver syndrome were recognized. He was born after an uncomplicated term pregnancy and delivery; birth weight was ~5.2 kg. At birth he was noted to be hypertonic, with flexion contractures of both hands and a very low-pitched cry. He subsequently had markedly accelerated growth, and developmental delay with gross motor incoordination. He first walked and spoke at age 2 years. He required special attention in school, and dropped out in the sixth grade. He has worn corrective lenses for myopia since age 2 years, and had had increasing clumsiness and progressive spastic-

ity. Evaluation at age 39 years revealed a height of 209.5 cm

(>97th percentile), weight 95.4 kg (>97th percentile), and head circumference 6l cm (>97th percentile). He was unable to walk because of spasticity in all extremities (more pronounced in the legs). Facial characteristics included a broad, prominent forehead, large narrow ears (8.5 cm bilaterally), prominent supraorbital ridges, maxillary hypoplasia, downslanting palpebral fissures, and ocular hypertelorism (inner canthal distance 4.0 cm) (Fig. 1, F).

Other findings included mild pectus excavatum, a soft I I /VI systolic ejection murmur with normal chest radiograph and electrocardiogram, left crytorchidism, inability to completely extend his elbows or completely pronate or supinate his arms, large hands and feet (both 97th percentile), camptodactyly with contractures in fingers 3, 4, and 5 and all toes, and inability to

abduct his thumbs completely. Radiographs revealed some prominence of the terminal tufts of

the distal phalanges, diffuse calvarial hyperostosis, somewhat enlarged joints, ocular hypertelorism, widening and splaying of distal ends of femurs, and short fourth metatarsals. CT scan was normal except for a cyst of the septum pellucidum. Myelogram revealed questionable cervical spinal stenosis, prominent vertebral arteries, and a large foramen magnum. There was no improve- ment of spasticity after C2-C7 decompression laminectomy. Results of endocrinologic studies were normal, as were chromosomes. Pyschologic testing revealed a full-scale IQ of 45, memory


Fig. I. (cont'd). D, Patient 4 at 7 years of age.

Fig. t. (cont'd). C, Patient 3 at 5 months of age.

quotient of 50, verbal quotient of 58, and performance quotient of 42. He is currently a resident in a chronic care nursing home. No other family members had similar characteristics.

D I S C U S S I O N

Since Weaver et al. l first reported two boys with this overgrowth syndrome, at least 11 additional probable cases have been reported. 2-n The findings in these cases and the seven new ones we report are summarized in the Table. A distinct pattern of characteristics emerges. Craniofacial features include a broad forehead, large ears, ocular hypertelorism, long philtrum, and relative micrognathia. Alterations of muscle tone, developmental delay, and hoarse voice are usually present. Positional limb deformi- ties and limited joint motility are frequent findings. Excess loose skin and hernias are common. Radiographic features include dysharmonically accelerated osseous maturation and metaphyseal widening.

Overgrowth, previously the major focus of Weaver syndrome, seems to be variable in both onset and duration. The majority of patients are quite large at birth, but in others overgrowth may not be evident until a few months

later. The patient reported by Shimura et al? did not have excessive growth either at birth or by 19 months, but other clinical features were consistent with the diagnosis of Weaver syndrome.

It has been speculated that with acceleration of bony maturation there might be early closure of the epiphyses and normal final adult height. However, our patient 7 continued to grow at an increased rate throughout adoles- cence and attained a final adult height much greater than 2 SD above the mean. In contrast, patient 2 of Roussounis and Crawford 9 grew at an accelerated rate until 3 years, when her growth rate decreased considerably. Endocrine evaluations have yielded normal results in those tested.

It has been suggested that patients with accelerated osseous maturation like that seen in Marshall-Smith syndrome or Weaver syndrome may have a mesenchymal defect resulting in early mineralization of the ossification centers. 11 The presence of other dysmorphic features is consistent with this hypothesis. I3

In addition, the accelerated bony maturation in Weaver syndrome is dysharmonic, with the carpals ahead of the phalanges and metacarpals. This type of dysharmonic maturation is also seen in Marshall-Smith syndrome and in Beckwith-Wiedemann syndrome, whereas Sotos syndrome


Fig. t. (cont'd). E, Patient 5 at 4~A years of age.

Fig. 1. (cont'd). F, Patient 7 as an adult.

has the opposite pattern of dysharmonic maturation, with phalanges and metacarpals ahead of the carpals) 4 Weaver

syndrome can be readily distinguished from Beckwith- Wiedemann syndrome on a clinical basis.

Three previous reports 4, 5. L3 have suggested that Weaver syndrome is simply a morphologie variant of Marshall- Smith syndrome. We and others ~,6, 8,15,16 believe that the disorders are separate entities. The two disorders share dysharmonic osseous maturation, early acceleration of linear growth, and developmental delay, but differ in craniofacial dysmorphism and the presence of failure to thrive in terms of weight. Widened middle and proximal phalanges, problems with respiratory secretions, and early death occur in Marshall-Smith syndrome only.

A second, consistent skeletal finding in patients with Weaver syndrome is the unusual metaphyseal splaying of the long bones, especially the femur. Weisswichert et al. s noted that of all the known diseases and syndromes with accelerated skeletal maturation in infancy, only Weaver syndrome also had distal widening of the long bones. The combination of these two radiographic abnormalities may be useful in confirming suspected Weaver syndrome.

Neurologic examination has been remarkable for abnormalities of tone, the majority of patients being hypertonic.


Fig. 2. Radiographs of patients with Weaver syndrome. A, Femurs of patient 1 show widening of metaphyses. B, Hands of patient 4 at 4~f2 years of age show dysharmonic accelerated osseous maturation (bone age 8 years).

Patient 2 of Roussounis and Crawford 9 was hypotonic as a newborn but developed increased tone by 3 months. Progressive spasticity was especially marked in our patient 7, who lost the ability to walk as an adult.

All individuals with Weaver syndrome have been developmentally delayed to some degree. Although delay of motor skills may be related to rapid growth, structural brain abnormalities have been noted in some patients. Of six head CT scans reported, two were normal (our patients 3 and 4), two showed a small cyst in the septum pellucidum (our patient 7 and the patient reported by Weisswichert et al)), one showed dilation of the ventricles, basal cisterns, sylvian cistern, and interhemispheric fissure consistent with nonspecific cerebral atrophy (patient 2 of Roussounis

and Crawfordg), and one showed somewhat enlarged vessels and hypervascularization in the areas of the middle and left posterior cerebral arteries (patient 1 of Majewski et al.7). The relationship of these findings to the neurologic abnormalities and possibly to the overgrowth remains to be determined.

The cause of Weaver syndrome is unclear. Males are affected three times as frequently as females. The reasons for this sex difference are not obvious; females may have a milder form of the syndrome. Two of the five reported female patients (our patient 3 and that of Shimura et al)) were normal sized at birth. Shimura's patient never had an accelerated growth rate, 5 and one of the patients described by Roussounis and Crawford 9 had a normal growth rate


Table. Manifestations of Weaver syndrome in all known patients*

Our pat ients LiteratureV~ I Total

Sex Male 5/7 10/13 15/20 Female 2/7 3/13 5/20

Growth Prenatal growth excess 5/7 11 / 13 16/20 Postnatal growth excess 7/7 12/13 19/20 Accelerated skeletal maturation 6/6 l 3/13 19/19

Craniofacial features Broad forehead 6/6 12/13 18/t 9 Flat oceiput 1/2 5/9 6/11 Large ears 6/7 9/10 15 / 17 Ocular hypertel0rism 7/7 12/12 19/19 Prominent or long philtrum 1/3 9/11 1 O/14 Relative. micrognathia 4/6 13/13 17/19

Limb abnormalities Prominen } fingerpads 3/4 3/5 6/9 Camptodactyly 4/6 7/10 11 / 16 Broad thumbs 2/3 2/3 4/6 Thin, deep-set nails 3/3 6/7 9/10 Clinodactyly O/l 4/4 4/5 Limited elbow or knee extension 4/6 6/7 10/13 Widened distal long bones 4/5 1 2/13 16/18 Foot deformity (clubfoot, calcaneovalgus, 4/6 3/4 7/10

metatarsus adductus) Neur01ogic features

Hypertonia 2/7 8/1 1 1 O/18 Hypotonia 3/7 2/1 1 5/18 Developmental delay 7/7 12/1 2 19/19 Hoarse, low-pitched voice 7/7 7/10 14/17

Other Excess loose skin 5/5 6/7 1 ! / 1 2 Umbilical hernia or diastasis recti 3/7 9/1 0 1 2/17 Inguinal hernia 2/7 2/7 4/14 Inverted nipples 1/2 2/2 3/4

*Feature specifically mentioned.

after 3 years. Inasmuch as Weaver syndrome has been classified primarily as an overgrowth syndrome, perhaps some cases have been missed in females, if other clinical features h ave not been considered.

Positive family histories for other individuals with similar characteristics in our patient 1 and in patient 2 of Majewski e t al. 7 suggest the importance of �9 factors in the cause o f Weayer syndrome. In both cases, the mother of a boy with the syndrome had similar facial characteristics and growth patterns, but normal intelligence. Either autosomal dominant inheritance with sex- limited expression, or possibly X-linked recessive inheritance Could be evoked to explain these family histories and milder manifestations in females. The occurrence in a brother and sister of "phenotypieal!y normal" parents 9 makes either of these inheritance patterns more difficult to explain; it is possible that one of the parents had such mild

manifestations as to be missed. We considered the possibil- ity of a dominant fresh gene mutation associated with older paterna! age, beca~hse the father of patient 7 was 43 years at the time of the patient's birth. However, the paternal ages in our patients 1, 5, and 6 were 34, 24, and 34 years, respectively, and those from the literature range from 22 to 41 years (mean 31.3 years)?-"

Because only one adult patient has been identified with Weaver syndrome, it will be important to follow other patients over time to identify the spectrum of the natural history of this syndrome. In addition, potm0rtem studies of the brain may reveal abnormalities not evident on CT scan to account for neurologic abnormalities. Studies of other tissues may provide a clue to the cause of the variable overgrowth.

One interesting aspect of overgrowth syndromes, such as Beckwith-Wiedemann and Sotos syndromes and hemihy-


pertrophy, is their association with neoplasia. 17 However, none of the 20 cases of Weaver syndrome now reported have shown this association. A presumed case of Weaver syndrome possibly associated with neuroblastoma has been reported to one of us (M.M.C.), but no diagnostic confir- mation is available. Because both overgrowth and neoplasia represent an increase in the number of Cell divisions, it seems reasonable to recommend that individuals with Weaver syndrome be observed for neoplasia and any cases

of Such be reported. Our findings indicate that Weaver syndrome may be

more common than has been thought. The criteria for

diagnosis suggested by previous investigators have included facial dysmorphism, accelerated growth and skeletal maturation, long bone abnormalities~ and deveiopmental delay. We believe that this diagnosis should be considered not only in those with overgrowth but also in individuals who have the characteristic facial features, developmental delay, accelerated dysharmonic carpophalangeal maturation; and distal Splaying of the long bones, with or without

overgrowth.

R E F E R E N C E S

1 . . . . . . . . . . Graham CB, Thomas IT, Smith DW. A new overgrowth syndrome with accelerated skeletal maturation, unusual facies, and camptodactyly. J PEDIATR 1974i84:547.

2. M0reno H, Kirkland R. Another candidate for the overgrowth syndrome [Letter]. J PEDJATR 1974;85:583.

3. Moreno HD, Zachai E, Kaufman H J, Mellman WJ. Case report 18. Syndrome ldent 1974;2:22.

4. Bosch-Banyeras JM, Sakedo S, Lucaya J, Laverde R, Boronat M, Marti-Henneberg C. Acceleration du development postnatal, hypertonie, elargissement des phalanges medianes et des metaphyses distales du femur, facies particu- lier: s'agit-it d'un syndrome de Weaver? Arch Fr Pediatr 1978;35:177.

5. Shimura T, Utsumi Y, Fujikawa S, Nakamura H, Baba K. Marshal!-Smith syndrome with large bifrontal diameter, broad distal femora, camptodactyly, and without broad middle phalanges. J PED1ATt~ 1979;94:93.

6. Gemme' G, Bonioli E, Ruffa G, Lagorio V. The Weaver- Smith syndrome. J PEDIATR 1980;97:962.

7. Majewski F, Ranke M, Kemperdick H, Schmidt E. The Weaver syndrome: a rare type of primordial overgrowth. Eur J Pediatr ]981;137:277.

8. Weisswichert PH, Knapp G, Wiliich E. Accelerated bone maturation syndrome of the Weaver type. Eur J Pediatr 198l;137:329.

9. Roussounis MB, Crawford JJ. Siblings with Weaver syndrome. J PED[ATR 1983;102:595.

10. Meinecke P; Schaefer E, Englebrecht R. The Weaver syndrome in a girl. Eur J Pediatr 1983;141:58.

11. Amir N, Gross-Kieselstein E, Hirsch H J, Lax E, Silverberg- Shalev R. Weaver Smith. syndrome: a case study with long-term follow-up. AmJ Dis Child t984;138:111.3.

12. Marshall RE, Graham CBI Scott CR, Smith DW. Syndrome Of accelerated skeletal maturation and relative failure to thrive: a newly recognized clinical growth disorder. J PEDIATR 1971;78:95.

13. Hassan M, Sutton.Ti Mage K, Limal JM, Rappaport R. The syndrome of accelerated bone maturation in the newborn infant with dysmorphism and congenital malformations. Pedi- atr Radiol 1976.;5:53.

14. Poznanski AK, Garn SM, Kuhns LR, Shaw HA. Disharmon- ic skeletal maturation in the congenital malformation syndromes. Birth Defects ! 977;13(3c):45.

15. Fitch N. The syndromes of Marshall and Weaver. J Med Genet 1980;17:174.

16. Cohen M. Overgrowth syndromes. In: Elshafie M, Klippel CH, eds. Associated congenital anomalies. Baltimore: Wil- liams &Wilkins, 1981:71.

17. Cohen MM. The large-for-gestational-age (LGA). infant in dysmorphic perspective. In: Willey AM, Carter TP, Kelly S, Porter IH, eds. Clinical genetics: problems in diagnosis and counseling. New York: Academic Press, 1982:153.

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Further delineation of Weaver syndrome