American Journal of Medical Genetics 138A:297–299 (2005)

Research LetterKlippel-Feil Anomaly in a boy and DubowitzSyndrome With Vertebral Fusion in his Brother:A new Variant of Dubowitz Syndrome?Shoko Takahira,1 Tatsuro Kondoh,1* Muneichiro Sumi,1 Masato Tagawa,1 Masayuki Obatake,2 Eiichi Kinoshita,1

Osamu Shimokawa,3 Naoki Harada,3 Noriko Miyake,4 Naomichi Matsumoto,5 and Hiroyuki Moriuchi1

1Department of Pediatrics, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan2Department of Pediatric Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan3Department of Human Genetics, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan4Kyushu Medical Science Nagasaki Laboratory, Nagasaki, Japan5Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan

To the Editor:

Dubowitz syndrome, a disorder of unknown cause, is char-acterized by microcephaly, facial anomalies, eczema, high-pitched hoarse voice, and growth retardation [Kuster andMajewski, 1986; Lyonnet et al., 1992].Most cases are sporadic,but some showed an autosomal recessive mode of inheritance.Klippel-Feil anomaly is a disorder with short neck, lowposterior hair line, restriction of neck movement due tosegmentation failure, and occasional spina bifida occulta. Itis classified into types I, II, and III. Among them, type III showscervical fusion plus lumbar or lower thoracic fusion, and mostpatients with the syndrome, the sporadic and familial cases(autosomal recessive inheritance), were also reported.

Wedescribe a family inwhichaboyhasKlippel-Feil anomalytype III with microcephaly and short stature, and his youngerbrother hasDubowitz syndrome associatedwith C4–C5 fusionand tracheostenosis. The elder brother was born at 38weeks ofgestation after an uneventful pregnancy as the first child of a32-year-old mother and a 31-year-old father, both healthy andnon-consanguineous. Themother tooknoalcohol ormedicationduring pregnancy. There was no family history of congenitalmalformations ormental retardation. Birthweightwas 1,938 g(�3.3 SD), length 41 cm (�4.2 SD), and OFC 30 cm (�2.3 SD).His growth was retarded but growth hormone excretion wasnormal as were thyroid hormones. At the age of 5 years, his IQwas at the range of 75–88.Now aged 6 years, heweighs 12.4 kg(�2.6 SD), measures 95 cm (�3.8 SD), and has OFC of 47.6 cm(�2.2 SD). He has C4–C5 and L4–L5 fusion, L4 hemivertebra,Sprengel anomaly (Fig. 1A–C),mild hypertelorism, andmicro-gnathia. Fusion of C4–C5 and L4–L5 is consistent withKlippel-Feil anomaly type III as is Sprengel deformity [Larsonet al., 2001], while short stature and microcephaly areinfrequent in patients with this condition.

The younger brother was born 5 years later at 39 weeks ofgestation with weight of 2,654 g (�1.3 SD), length of 48 cm(�1.3 SD), and OFC of 31.5 cm (�1.0 SD). The mother took noalcohol or medication during pregnancy. The boy developedneonatal respiratory distress, was found to have tracheoste-

nosis, and at the age of 1 month, underwent tracheotomy,followed by repeated baloon dilatation of the stenosis. For2 days of life, he has been on diuretics and digoxin because ofan atrial septal defect and a ventricular septal defect. He hadsparse hair, high and sloping forehead, hypertelorism, ble-pharophymosis, blepharoptosis, depressed nasal bridge, andmicrognathia (Fig. 2A). His voice feature could not be con-firmed because of his tracheotomy. He became progressivelymicrocephalic. At the age of 12 months, he weighed 7.85 kg(�2.4 SD), measured 69 cm (�2.6 SD), and had OFC of 40 cm(�4.3 SD). He developed eczema. He had C2–C3 fusion(Fig. 2B). Now aged 16 months, his DQ is 50. Intrauterinegrowth retardation, short stature, microcephaly, delayeddevelopment, eczema, sparse hair, and characteristic facies,all supported the diagnosis of Dubowitz syndrome.

G-banded chromosomes were 46,XY in both brothers.Microarray-based comparative genomic hybridization (arrayCGH) analysis in the brothers disclosed no abnormalities,using subtelomeric and other BAC/PAC clones [Harada et al.,2004; Kurosawa et al., 2004].

Simultaneous occurrence ofDubowitz syndrome andKlippel-Feil anomaly in a family has never been reported. Theoccurrence of Klippel-Feil in a boy and Dubowitz syndrome inhis brother could be a chance association. Alternatively, theycould be causally related. The clinical manifestations in theelder brother may represent Dubowitz syndrome with normalfacial appearance. Such a situation has been reported in 15 outof the 141 patients with the syndrome [Tsukahara and Opitz,1996]. However, phenotypic patterns of our cases are differentfrom those of the familial cases of Dubowitz syndrome that arereported to be similar within a sibship [Tsukahara and Opitz,1996]. Both brothers shared short stature, microcephaly, andmild tomoderate mental retardation, all of which are themainfeatures of Dubowitz sydnrome, and are not uncommon inKlippel-Feil anomaly. Craniovertebral abnormalities havebeen described in 3 out of the 143 cases of the syndrome[Swartz et al., 2003]. Of these, C2–C3 fusion as was present inthe younger brother has been reported in only one patient[Swartz et al., 2003]. We would like to propose that thecondition in both brothers is possibly the variability of a newvariant of Dubowitz syndrome. It is likely that the inheritancemode of their disorder is autosomal recessive or X-linkedrecessive, because both of their parents are phenotypi-cally normal, although an autosomal dominant fashion withgonadal mosaicism in a parent cannot be excluded. Meioticsegregation of a submicroscopic terminal reciprocal transloca-tion may result in different unbalanced translocations withdifferent phenotypes in siblings [Lukusa et al., 2003]. Thepossibility, however, was effectively ruled out in the brotherswith array CGH.

*Correspondence to: Tatsuro Kondoh, M.D., Ph.D., Departmentof Pediatrics, Nagasaki University Graduate School of BiomedicalSciences, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan.E-mail: kontatsu@net.nagasaki-u.ac.jp

Received 21 February 2005; Accepted 31 May 2005

DOI 10.1002/ajmg.a.30947

� 2005 Wiley-Liss, Inc.

Fig. 1. The elder brother of the patient with Dubowitz syndrome at the age of 6 years, showing C4–C5 fusion (arrow) (A), L4 hemivertebraand L4–L5 fusion (open arrow) (B), and left scapula (arrow) that is smaller and takes higher position than the right one (C).

Fig. 2. The younger brother at the age of 1 year (A), showing C2–C3 fusion (arrow) (B).

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