American Journal of Medical Genetics 42:320-322 (1992)

Brief Clinical Report Autosomal Dominant Inheritance of Klein-Waardenburg Syndrome Ruth Sheffer and Joel Zlotogora Department of Human Genetics, Hadassah Hebrew University Medical Center, Jerusalem, Israel

We report on 2 sibs with the Klein-Waardenburg syndrome;they had dystopia canthorum, blepharophimosis, and bilateral flexion contractures of the fingers. The children’sfather and paternal aunt are also affected. This report confirms that the Klein-Waardenburg syndrome is an autosomal dominant syndrome. KEY WORDS: Klein-Waardenburg syndrome, joint contractures, autosomal dominant inheritance INTRODUCTION Klein [1947, 19501described a girl with deafmutism, partial albinism of hair and skin and blue irides, dystopia canthorum, a broad nasal root, blepharophimosis, and arthromyodsyplasia of the upper limbs. The ocular, auditory, and pigmentary manifestations in association with musculoskeletal hypoplasia of the upper limbs and pectoral girdle constitute the Klein-Waardenburg syndrome (KWS) [Goodman et al., 1982; Klein, 19831. We report on a family with KWS in 2 generations. These findings support the assumption that the KleinWaardenburg is a separate entity inherited as an autosoma1 dominant trait. FAMILY STUDY The proposita (Fig. 1)was born after a normal pregnancy and delivery, birth weight 2,570 g. After birth, a wide nasal bridge and flexion contractures of the fingers were noted. At 2 months, she was a well developed and alert infant; her length was 54 cm (10th centile) and occipitofrontal head circumference (OFC) 37 cm (2nd centile). Her irides were brown and no pigmentary abnormalities of skin or hair were noted. Physical findings included mild oxycephaly, downward slant of palpebral fissures, blepharophimosis with short palpebral fissures (1.4 cm) and pseudostrabismus, outer canthal distance

5.8 cm (> 10th centile) and inner canthal distance 3.0 cm (> 97th centile), a small nose and narrow nostrils, an umbilical hernia 1 x 1 cm, right simian line, and bilateral flexion contractures of the fingers. On examination at 5 months (Figs. 2,3), psychomotor development was normal for age. Slight residual finger contractures were evident, although much improved by physiotherapy and less severe than those of her father. At 1year, her mental development was normal for age. However, decreased hearing is suspected. Cytogenetic analysis showed normal chromosomes (46,XX). Recently, a brother of the proposita was born; he has similar facial manifestations as well as flexion contractures of the fingers which are more severe than those of the proposita. His irides are brown and no pigmentary abnormalities of the hair or skin are seen. The children’s father has been described in previous reports [Sachs, 1964; Goodman et al., 19821. He is a 34year-old Yemenite Jew of normal intelligence, he works as a driver. His height is 163 cm and weight 60 kg. Eye findings include heavy eyebrows, laterally displaced medial canthi, and residual blepharophimosis after surgical correction. The nasal bridge is high, with deviation of the septum, hypoplastic ala nasi, and a bulbous tip (Fig. 4A, 4B).The palate is high and the upper lip has a pronounced “cupid’s bow7’form. The arms and forearms are hypoplastic and have decreased muscle mass. There is bilateral camptodactyly of the 3rd-5th fingers, and medial “insertion” of the thumbs (Fig. 5 ) . Lower limb length and muscle mass are normal. The irides are brown and no pigmentary abnormalities of skin or hair are evident. He has decreased hearing in the right ear.

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Received for publication February 5, 1991; revision accepted June 3, 1991. Address reprint requests to Ruth Sheffer MD, Department of Human Genetics, Hadassah Hospital, POB 12 000, Jerusalem il-91120, Israel.

0 1992 Wiley-Liss, Inc.

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Fig. 1. The pedigree of the family.

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Fig. 3. Slight residual flexion contractures in the proposita.

The paternal grandparents are nonconsanguinous and were examined by us; they are normal, and do not have facial or limb abnormalities. The children’s mother is a healthy 28-year-old Jewish woman of Russian origin.

Fig. 2. Facial appearance of the proposita at 5 months with dystopia canthorum, blepharophimosis, pseudostrabismus, and hypoplastic ala nasi.

The paternal aunt, also previously described, was not reexamined by us. She reportedly has microcephaly and severe mental retardation, blepharophimosis and dystopia canthorum, microdactyly, spastic paraplegia, and limb contractures.

DISCUSSION The hallmark of KWS is involvement of the upper limbs and pectoral girdle, in addition to the oculoauditory and pigmentary abnormalities which are typical of the more common Waardenburg syndrome. The upper limb involvement may include hypoplasia of the muscles and bones, flexion contractures, and syndactyly. Prior to this report, the genetic mode of transmission of KWS was unclear. In a previous report, on the basis of the family of the children’s father, autosomal recessive

Fig. 4. (A, B) The proposita’s father with residual blepharophimosis, high nasal bridge, and hypoplastic ala nasi.

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Fig. 5. Flexion contractures of the fingers of the proposita’s father.

inheritance was considered possible, since 2 affected sibs were born to normal parents; dominant inheritance with incomplete penetrance or germinal mosaicism were also considered possible modes of inheritance [Goodman et al., 19821. The 3 other patients affected with KWS [Klein, 1947; Marx and Bertrand, 1968; Mossalam et al., 19741 were each reported as sporadic cases. Later, Klein [19831 reported that the patient described by Marx and Bertrand [19681had had a son with the classical facial defects of Waardenburg syndrome. He also had winging of the scapulae (Sprengel deformity), without abnormalities of the upper limbs. Therefore autosomal dominant inheritance of KWS with varying expressivity seemed likely. However, it was still not clear whether KWS represents a distinct clinical and genetic entity or that the patients with upper limb involvement are in fact affected with a severe form of Waardenburg syndrome. The clinical findings in the children reported here and their father, which include characteristic facial changes, decreased hearing, and upper limb involve-

ment, provide further evidence for autosomal dominant inheritance of KWS and support the delineation of the syndrome as a distinct entity. It is possible that the grandparents of the children were not affected as a result of incomplete penetrance of the mutant allele. More probably, germinal mosaicism for the mutation was present in one of them. Most reported patients with KWS have normal intelligence. There is documentation that the maternal aunt of our proposita may have suffered perinatal asphyxia [Sachs, 19641.Thus, her severe mental retardation and spastic paraplegia may well be attributable to coexistent cerebral palsy, rather than being a more severe presentation of KWS. The proposita’s OFC is in the low normal range, however, a t the age of 1year her mental development appeared to be normal. When evaluating patients with abnormal palpebronasal structures and joint contractures of the upper limbs, the possibility of KWS should be raised and thorough auditory testing and appropriate family investigation are recommended.

REFERENCES Goodman RM, Lewithal I, Solomon A, Klein D (1982): Upper limb involvement in the Klein-Waardenburg Syndrome. Am J Med Genet 11:425-433. Klein D (1947): Albinisme partiel (leucisme) accompagnk de surdimutis, d’ossomyodysplasie, de raideurs articulaires congenitales multiples et dautres malformations conghitales. Arch Klaus Stift Vererb Forsch 22:342-346. Klein D (1950): Albinism partiel (leucisme) avec surdi-mutit.6, blepharophimosis et dysplasies myo-osteoarticulaires. Helv Paediat Acta 538-58. Klein I)(1983):Historical background and evidence for dominant inheritance of the Klein-Waardenburg syndrome (type 111). Am J Med Genet 14:231-239. Marx P, Bertrand J (1968):Un cas de syndrome Waardenburg-Klein. Bull SOCOphtal France 68:444-447. Mossallam I, El-Khodary AF, Temtamy SA (1974): Waardenburg’s syndrome in Egypt. Ain Shams Med J 2543-62. Sachs R (1964):Dystopie du canthus interne associke & une forme fruste du syndrome de Rocher-Sheldon. Ann Ocul (Paris) 197:672-683.

Autosomal dominant inheritance of Klein-Waardenburg syndrome.

We report on 2 sibs with the Klein-Waardenburg syndrome; they had dystopia canthorum, blepharophimosis, and bilateral flexion contractures of the fing...
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