Letter to the Editor

Williams-Beuren Syndrome 35 Years After theDiagnosis in One of the First Beuren Patients

To the Editor:

One of the original patients of Beuren, reexamined at41 years, had supravalvular aortic stenosis, mental re-tardation (IQ 41), characteristic face, and the behaviorof an adult with Williams-Beuren syndrome. Deletionof the ELN and LIMK1 genes at 7q11.23 by fluores-cence in situ hybridization confirmed the diagnosis.

Williams-Beuren syndrome (WBS) is due to deletionof contiguous genes at 7q11.23. One of the original pa-tients of Beuren et al. [1962] at age 41 years had sup-ravalvular aortic stenosis, mental retardation, charac-teristic facial changes [Pankau et al., 1997], and haddeletion of the ELN and LIMK1 genes at 7q11.23. Thepatient is still living and shows the typical behavior ofan adult with WBS [Fryns et al., 1991].

HK was born after uncomplicated pregnancy as thesecond child of nonconsanguineous parents at 42 weeksof gestation by vaginal delivery at home. Birthweightwas 2,500 g, length 50 cm. Early psychomotor develop-ment was retarded. He sat at 9 months. He walkedwithout help at 24 months. Speaking two-word sen-tences was delayed until 5 years. Developmental mile-stones fell within the WBS range reported in the lit-erature [Flehmig et al., 1973; Martin et al., 1984;Morris et al., 1988; Trauner et al., 1989] (Table I). Hehad marked feeding problems in infancy. A herniotomywas performed at age 2 years.

At age 6 years the patient entered a regular primaryschool. After 1 year he had to change to a school for thementally handicapped, where he remained until age16. Diagnostic evaluation at age 5.5 years showed anIQ of 46. At 41 years his IQ was 41 [Morris et al., 1990;Plissart et al., 1994]. His verbal ability was slightlyabove his performance abilities (47 vs. 44, respec-tively). His over-friendly personality and his good em-pathic ability were noted during childhood, as was hislethargy. He had a good recall of persons and locationsand showed a marked sensitivity to noise and a goodsense for music.

At 12 months a heart murmur was noted. At 5 yearstransseptal catheterization showed a supravalvularaortic stenosis with a delta p of 65 mm Hg. He wasoperated on successfully at age 6.5 years. At age 19years a second angiography showed no aortic stenosis;however, a hypoplasia of the abdominal aorta, the su-perior mesenteric artery, and stenoses of the renal ar-teries with poststenotic dilatations and several mildperipheral pulmonary stenoses were noted [Beuren etal., 1963; Wessel et al., 1994]. At 41 years echocardi-ography showed a mild supravalvular aortic stenosis.Results of sonographic evaluation of kidneys and uri-nary tract were normal.

The patient lives in an institution and works in asheltered work center. He is still friendly and open-minded. He loves folk music. His body movements are

Dedicated to Dr. Robert Schulz, Hildesheim, Germany, on theoccasion of his 75th birthday.

*Correspondence to: Carl-Joachim Partsch, M.D., Departmentof Pediatrics, University of Kiel, Schwanenweg 20, D-24105 Kiel,Germany.

Received 26 May 1999; Accepted 6 December 1999

TABLE I. Development of Williams-Beuren Patients*

Milestones of development

Martin et al.[1984]n 4 41

Morris et al.[1988]n 4 42

Trauner et al.[1989]n 4 8

Prospectiveresults Kiel

n 4 218

Denver development scaleFlehmig et al. [1973]

25% 50% 75% 90%

Sitting 10.5 ± 2.5 — 11.8 ± 3.6 11 (6–48) 6.7 7.3 8.0 9.0First words — — 26.2 ± 11.7 20 (7–60) 10.7 12 13.5 14.8Walking 23.4 ± 6.9 21 26.9 ± 7.0 24 (12–60) 12.4 13.8 15.1 16.1Speaking two-word sentences — 21.6a 42.8 ± 12.1 36 (18–84) 19 22.7 27 32Dry — 39 — 48 (24–192) <5 yrs — — —

*Data are presented as mean ± standard deviation or median and range of parentheses.aNot mentioned whether two-word sentences were investigated.

American Journal of Medical Genetics 91:322–324 (2000)

© 2000 Wiley-Liss, Inc.

slow. He has a mild thoracic scoliosis and mild contrac-tures of the large joints. His hypertension is treatedmedically. HK is 159 cm tall (<3rd centile [Reinken andvan Oost 1992]). His height is below his genetic targetheight range (Fig. 1). His syndrome-specific height z-score is −1.33 [Pankau et al., 1992; Partsch et al.,1999]. His body mass index (BMI) is elevated compared

to adult WBS patients (26.1 vs. 21.9 ± 0.44 [Pankau etal., 1994]). He has mild microcephaly (OFC 53.5 cm;<3rd centile [Prader et al., 1988]). Sexual maturation iscomplete. Testicular volumes are slightly subnormal(orchiometry: right 8 ml, left 12 ml). Plasma testoster-one level was normal (20.9 nmol/l). However, a stan-dard GnRH test (100 mg GnRH iv, blood sampling at 0and 30 min) documented increased basal and stimu-lated plasma FSH levels (10.3 → 21.4 IU/L) and anincreased stimulated LH level (3.2 → 20.5 IU/l)[Partsch et al., 1994] in comparison to reference levelsof our laboratory [Partsch et al., 1990]. IGF-I was nor-mal for age (88 ng/ml).

Metaphase spreads for G-banded karyotyping andFISH were prepared from PHA-stimulated peripheralblood lymphocytes of the patient according to standardprotocols. For FISH, the commercially available Willi-ams-syndrome-probe (Oncor, Gaithersburg, MD) con-taining the elastin (ELN) gene and the LSI-Williamssyndrome region DNA FISH Probe (Vysis, DownersGrove, IL) containing the ELN and the LIMK1 genes aswell as D7S613 were applied. FISH was performed asdescribed recently [Schlegelberger et al., 1999].

FISH showed a constitutional microdeletion withinthe Williams syndrome critical region on one chromo-some 7 with both probes applied. Therefore, the karyo-type of the patient is: 46, XY. ish del (7)(q11.23q11.23)(ELN-, ELN/LIMK1/D7S613-, D7S486/D7S522+,D7S427+) confirming the clinical diagnosis originallymade by Beuren et al. [1962].

Figure 2 shows the patient at the age of the originalpublication by Beuren et al. [1962] and at the presenttime.

REFERENCESBeuren AJ, Apitz J, Harmjanz D. 1962. Supravalvular aortic stenosis in

association with mental retardation and a certain facial appearance.Circulation 26:1235–1240.

Beuren AJ, Schulze D, Eberle P, Harmjanz D, Apitz J. 1963. The syndromeof supravalvular aortic stenosis, peripheral pulmonary stenosis, men-tal retardation and similar facial appearance. Am J Cardiol 13:471–482.

Flehmig I, Schloon M, Uhde J, von Bernuth H. 1973. Denver Entwick-lungsskalen, Testanweisung. Hamburg: Hamburger Spastikerverein.

Fryns JP, Borghgraef M, Volcke P, van den Berghe H. 1991. Adults withWilliams syndrome. Am J Med Genet 40:253.

Martin NDT, Snodgrass GJAI, Cohen RD. 1984. Idiopathic infantile hy-percalcaemia — a continuing enigma. Arch Dis Child 59:605–613.

Morris CA, Demsey SA, Leonard CO, Dilts C, Blackburn BL. 1988. Naturalhistory of Williams syndrome. Physical characteristics. J Pediatr 113:318–326.

Morris CA, Leonard CO, Dilts C, Demsey SA. 1990. Adults with Williamssyndrome. Am J Med Genet 6(Suppl.):102–107.

Pankau R, Partsch C-J, Gosch A, Oppermann HC, Wessel A. 1992. Staturalgrowth in Williams-Beuren syndrome. Eur J Pediatr 151:751–755.

Pankau R, Partsch CJ, Gosch A, Winter M, Wessel A. 1997. Picture of themonth. Arch Pediatr Adolesc Med 151:203–204.

Partsch C-J, Hummelink R, Sippell WG. 1990. Reference ranges for lutro-pin and follitropin in the luliberin test in prepubertal and pubertalchildren using a monoclonal immunoradiometric assay. J Clin ChemClin Biochem 28:49–52.

Partsch C-J, Pankau R, Blum WF, Gosch A, Wessel A. 1994. Hormonalregulation in children and adults with Williams-Beuren syndrome. AmJ Med Genet 51:251–257.

Partsch C-J, Dreyer G, Gosch A, Winter M, Schneppenheim R, Wessel A,Pankau R. 1999. Longitudinal evaluation of growth, puberty, and bonematuration in children with Williams syndrome. J Pediatr 134:82–89.

Plissart L, Borghgraef M, Volcke P, van den Berghe H, Fryns JP. 1994.Adults with Williams-Beuren syndrome: evaluation of the medical,psychological and behavioral aspects. Clin Genet 46:161–167.

Fig. 1. Growth chart of the patient; 3rd, 50th, and 97th centiles fromGerman longitudinal standards [Reinken and van Oost 1992]. The squareon the right-hand side marks the genetic target height. The vertical linedepicts the target height range.

Fig. 2. The patient at the age of 5.5 years (left) and at age 41 (right).Note the characteristic facial appearance of an adult with WBS [Fryns etal., 1991; Pankau et al., 1997].

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Prader A, Largo RH, Molinari L, Issler C. 1988. Physical growth of Swisschildren from birth to 20 years of age. Helv Paediatr Acta 43(Suppl.52):1–125.

Reinken L, van Oost G. 1992. Longitudinale Korperentwicklung gesunderKinder von 0 - 18 Jahren. Klin Padiatr 204:129–133.

Schlegelberger B, Metzke S, Harder S, Zuhlke-Jenisch R, Zhang Y, SiebertR. 1999. Classical and molecular cytogenetics of tumor cells. In: Weg-ner R-D, editor. Diagnostic cytogenetics. Berlin, Heidelberg: Springer-Verlag. p 151–185.

Trauner DA, Bellugi U, Chase C. 1989. Neurologic features of Williamssyndrome and Down syndrome. Pediatr Neurol 5:166–168.

Wessel A, Pankau R, Kececioglu D, Ruschewski W, Bursch JH. 1994. Threedecades of follow-up of aortic and pulmonary vascular lesions in theWilliams-Beuren syndrome. Am J Med Genet 52:297–301.

Rainer PankauChildren’s HospitalSt. Bernward KrankenhausHildesheim, Germany

Carl-Joachim Partsch*Angela GoschDepartment of PediatricsChristian-Albrechts-UniversitatKiel, Germany

Reiner SiebertManfred SchneiderDepartment of Human GeneticsChristian-Albrechts-UniversitatKiel, Germany

Reinhard SchneppenheimDepartment of Pediatric OncologyUniversity of HamburgHamburg, Germany

Martin WinterDepartment of OphthalmologyChristian-Albrechts-UniversitatKiel, Germany

Armin WesselDepartment of Pediatric CardiologyUniversity of GottingenGottingen, Germany

324 Pankau et al.