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A probable case of familial Weaver syndrome associated with neoplasia
  1. CHRIS DERRY,
  2. I KAREN TEMPLE
  1. Wessex Clinical Genetics Service, Southampton University Hospitals NHS Trust, The Princess Anne Hospital, Coxford Road, Southampton SO16 5YA
  2. Portsmouth Healthcare NHS Trust, Child Development Centre, 151 Locksway Road, Portsmouth, Hants PO4 8LD
    1. K VENKAT-RAMAN
    1. Wessex Clinical Genetics Service, Southampton University Hospitals NHS Trust, The Princess Anne Hospital, Coxford Road, Southampton SO16 5YA
    2. Portsmouth Healthcare NHS Trust, Child Development Centre, 151 Locksway Road, Portsmouth, Hants PO4 8LD

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      Editor—Overgrowth is a well recognised feature in several dysmorphic syndromes. These conditions often have overlapping clinical pictures and on occasions it can be difficult to fit patients into known categories. In 1974, Weaveret al 1 described a syndrome of accelerated growth and advanced bone age associated with macrocephaly, developmental delay, and distinctive facies with a broad forehead, hypertelorism, large ears, micrognathia, and a long philtrum. Since the original report, over 30 cases have been published.

      An increased incidence of neoplasia has been associated with other overgrowth syndromes, particularly in Beckwith-Wiedemann syndrome, but has been reported in Weaver syndrome only on one previous occasion.2 This low incidence may reflect the relative rarity of the condition.

      We were recently referred a boy at the genetic clinic with probable Weaver syndrome. His mother had mild features of the condition and in addition developed an ovarian endodermal sinus tumour in her teenage years.

      The proband was delivered at term +9 by caesarian section for fetal distress following an otherwise uneventful pregnancy. He had aspirated meconium and at delivery had low Apgar scores of 3, 4, and 8 at one, five, and 10 minutes respectively. Intubation and ventilation was required for five minutes, but the baby recovered well, and after one night on SCBU was returned to the ward and experienced no further difficulties. Birth weight was 4460 g (91st centile), OFC was 39 cm (>99th centile), and length was 58 cm (99th centile). He was not noted to have any dysmorphic features at this time and was discharged.

      The next contact with paediatric services was at the age of 2 years when he was referred for assessment for tiptoe walking. He had poor speech at this time and also a tendency to have very severe tantrums. On examination he was noted to have a large, round face with a prominent forehead, mild hypertelorism, a flat nasal bridge, and large ears. He also had square hands and a large gap between his hallux and second toe. Neurological examination showed increased tone bilaterally in the lower limbs, with upward plantar reflexes and symmetrical but brisk deep tendon reflexes. Upper limbs were normal. Weight, height, and OFC remained greater than the 97th centile. A formal developmental assessment performed at 31 months showed a moderate delay in most areas, but severe delay in speech, performing at a developmental level of 17 months.

      Subsequent review by the clinical genetics service noted, in addition, posteriorly rotated ears, anteverted nares, a deep, broad philtrum, a long, thin tongue and a marked “Cupid’s bow” of the lips (figs 1and 2). His hands were slightly puffy with tapering fingers. His feet were broad, with mild incurving of the fourth and fifth toes bilaterally.

      Figure 1

      Photograph of case 1 in early childhood. Note the flat nasal bridge, broad tip, large ears, broad philtrum, and small pointed chin. (Photographs reproduced with permission.)

      Figure 2

      Case 1 aged 7 years 9 months.

      Chromosome analysis, including fragile X screening, was normal. Urinary mucopolysaccharides were negative. Bone age at age 4 years 10 months was variably advanced in different bones; ulnar and radial epiphyses were estimated at 5 years of age, but the carpal bones were more advanced, with the trapezoid having a 6 year appearance, the trapezium 7 years, and the scaphoid 8 years. The phalangeal epiphyses were also advanced, at a bone age of 6 years.

      The subject has continued to show overgrowth throughout childhood, with his height, weight, and OFC remaining above the 97th centile at 7 years 9 months. He has also continued to show some behavioural abnormalities, although these have changed from major tempers and disruptive behaviour to a tendency to solitude accompanied by some obsessive traits such as an intense fascination with bus routes and trains. He has a short attention span and immature social skills. In terms of intellectual development, his ability in mathematics and reading is reported to be normal, but his fine and gross motor skills are delayed and he has coordination difficulties. He continues to have phonation problems and his speech, though markedly improved, is still somewhat unclear. He attends a school for children with physical disabilities. His gait has improved, although he still has a tendency to tiptoe walking and his reflexes remain brisk.

      The mother was born at term weighing 3640 g. She had normal developmental milestones, attended grammar school, and now works as a civil servant. She had no serious childhood illnesses, but was always considered to be a large child and was investigated for this. Complete records of her growth in childhood are not available, but her notes record that she was markedly overweight at the age of 3 years 9 months, with the height of a child of 7 years at this time. In addition, it has been noted that her deciduous dentition had fallen out by the age of 4 years 6 months. By the age of 11 years she was 165 cm tall (>97th centile) and she is now 170 cm (85th centile) with OFC and weight both above the 97th centile. She has a facial appearance similar to that of her son, with a round face, depressed nasal bridge, and broad nasal tip (fig 3). Her philtrum is broad and her chin small and prominent. She has small fingernails and toenails, most marked on the first, second, and third toes, and there is overriding of her fifth toe bilaterally (fig 4). She has mild pes cavus bilaterally.

      Figure 3

      Mother and son. Mother has a similar facial appearance to her son, with broad nasal tip and long, broad philtrum.

      Figure 4

      Feet of mother showing small nails in adulthood.

      At the age of 17, she was found to have a large right sided ovarian cyst. This was excised and found on histology to be a malignant neoplasm, namely an endodermal sinus tumour. She was treated with chemotherapy and has been well since.

      The diagnosis of Weaver syndrome, as distinct from the other known syndromes associated with overgrowth, can be difficult. The overwhelming majority of published reports of Weaver syndrome have described cases in infancy or early childhood, and the characteristic facies with broad forehead, flat nasal bridge, long philtrum, large ears, and micrognathia are observations in this age group. Reports of two adults with the syndrome emphasise the tendency of these features to become less obvious with increasing age.3 4 This makes the diagnosis more difficult in older children and adults. Unfortunately no earlier photos were available in this family. The mother’s final height is a little against the diagnosis being only on the 80th centile in adulthood, as most convincing cases of Weaver syndrome in adulthood are above the 98th centile. However, there is likely to be variation in final adult height in this syndrome and it is possible that treatment of the ovarian tumour affected her growth. Comparison of all features observed in the mother and son of this case report with recognised features of Weaver syndrome makes the diagnosis likely here (table 1). Macrocephaly syndromes, such as Cowden syndrome, were considered in this family. However, none of the skin manifestations often seen in this condition were present in either mother or son and advanced bone age is not a recognised feature of this syndrome.

      Table 1

      Clinical features of present cases

      The majority of published cases of Weaver syndrome to date appear to have been sporadic, but there have been exceptions. Ardingeret al 3 and Majewskiet al 5 both describe cases in which the mothers of boys with Weaver syndrome had a similar facial appearance and growth pattern to their sons, but were of normal intelligence. It has been proposed that either autosomal dominant inheritance with sex limited expression or possibly X linked recessive inheritance, would explain these family histories. Such an inheritance pattern might also explain why the syndrome appears to be more common in males; reports to date suggest the condition is diagnosed almost twice as frequently in males than females.6

      However, Dumic et al 7 reported a case of twins (a boy and a girl) both affected with Weaver syndrome and their mother who was tall and macrocephalic, with large ears, a hoarse voice, and thin, deep set nails. The sibs were equally affected in this case suggesting no sex differences in the expression of the condition. Another report by Fryer et al 8 describes a case of father to daughter transmission in which the daughter is the more markedly affected of the two and recently Proud et al 9reported father to son transmission for the first time. Sex linked expression in the light of these reports seems unlikely and it is now suggested that Weaver syndrome is, in fact, inherited in an autosomal dominant fashion. It is well recognised that ascertainment of adult parental cases is biased towards the milder end of the spectrum, irrespective of sex, and the cases of Ardinger et al 3 and Majewski et al 5 may be a reflection of this tendency.

      A further point of interest raised by this case is the diagnosis of a rare ovarian tumour in the mother, who we believe to have a mild form of Weaver syndrome. Endodermal sinus tumours, otherwise known as yolk sac tumours, are neoplasms exhibiting differentiation towards embryonal endodermal yolk sac structures. The overall incidence of these tumours is rare, but they are the second most common malignant germ cell tumour of the ovary (after dysgerminoma). They generally occur in the second to third decade of life, although about 10% occur before the age of 10 and these childhood endodermal sinus tumours (CESTs) have been linked to deletions on the short arm of chromosome 1 at 1p36.10Yolk sac tumours are very aggressive, rapidly growing tumours which untreated have a three year survival of only 13%. They are, however, extremely responsive to treatment by surgery and chemotherapy and with current treatment many patients now make a full recovery.

      Our case is a second report of neoplasia occurring in Weaver syndrome. In view of this case, and the known association of other syndromes of overgrowth with neoplasia, it would appear that subjects with Weaver syndrome may indeed be at increased risk of such complications. We would therefore agree with the recommendation of Ardingeret al 3 that these subjects should be observed for neoplasia and any cases of such be reported. The diversity of tumours reported, however, render screening impractical.

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