American Journal of Medical Genetics 47:797-799 (1993)

Brief Clinical Report

Provisionally Unique Autosomal Recessive Chondrodysplasia Punctata Syndrome Helga V. Toriello, James V. Higgins, and Theodore Miller Butterworth Hospital, Grand Rapids (H.V.T., J.V.H., T.M.) and Department of PediatricslHuman Development, Michigan State University, East Lansing (H.V.T.), Michigan

Stippled epiphyses occur in several mono- genic, teratogenic, or aneuploidy syndromes. We describe two sibs with a provisionally unique chondrodysplasia punctata syndrome, who have, in addition to stippled epiphyses, minor facial anomalies, short stature, and oc- ular colobomata. Inheritance of this condition is likely autosomal recessive. 0 1993 Wiley-Liss, Inc.

KEY WORDS: stippled epiphyses, short stat- ure, ocular colobomata

INTRODUCTION Recently, Wulfsberg et al. [19921 and Bennett et al.

119921 reviewed the group of syndromes which include chondrodysplasia punctata (CDP) as one of the phe- notypic manifestations. We describe sibs with a previ- ously unrecognized CDP syndrome which is likely in- herited as an autosomal recessive trait.

CLINICAL REPORTS Patient 1

Patient 1 is a female born to nonconsanguineous par- ents with unremarkable family history. Pregnancy length was 42 weeks; delivery was by cesarean section because of breech position. Birth weight was 3,500 g (40th centile) and length was 57 cm 0 9 0 t h centile); occipito-frontal circumference (OFC) is unknown to us. Torticollis, dislocated jaw, bilateral hip dislocation, and iris colobomata were noted soon after birth. Radiographs demonstrated stippled proximal humeral epiphyses. The patient had Hemophilus influenzae meningitis a t age 10 weeks, resulting in mild left hemiparesis.

At age 5 months, the patient was seen in Genetics

Received for publication April 30, 1993; revision received May 18, 1993.

Address reprint requests to Dr. Helga V. Toriello, Genetic Ser- vices, 221 Michigan Street N.E., Suite 301, Grand Rapids, MI 49503.

0 1993 Wiley-Liss, Inc.

Clinic. In addition to the above mentioned features, we noted brachycephaly, iris colobomata with no evidence of cataracts, flat facial profile, mild synophyrs, small nose with anteverted nares, and apparently lowset, small ears (Figs. 1, 2). Unilateral deafness was diag- nosed in early childhood. At age 6 years, height was 109.6 cm (<5th centile), weight was 20.5 kg (25th cen- tile), and OFC was 51.5 cm (50th centile). Physical find- ings were essentially unchanged with the additions of malocclusion and hepatosplenomegaly. Hand and wrist radiographs demonstrated retarded bone age and dys- plastic distal phalanges. Previous evaluations done to determine the cause of hepatosplenomegaly have in- cluded determinations of alpha-1-antitrypsin and sweat chloride, barium swallow, metabolic screen, and hepa- titis B antigen studies which were all normal; a liver biopsy simply showed hepatic fibrosis. Banded chromo- somes, studied on two occasions, were both normal, as were evaluations for possible peroxisomal disorders. At age 10 years, physical findings remained unchanged (Fig. 3); height was 122 cm ( 4 t h centile) and weight was 27.5 kg (25th centile). Development is delayed.

Patient 2 Patient 2 is the younger brother born 9 years later.

Pregnancy length was 40 weeks; birth weight was 3.4 kg (50th centile) and length was 51 cm (50th centile). At 5.5 months of age, weight was 7.5 kg (25th centile), length was 63 cm ( 4 t h centile), and OFC was 41.6 cm (90th centile). He had numerous physical findings similar to those of his sister, including brachycephaly, midface hypoplasia, iris colobomata (as well as optic nerve col- oboma on the right), small nose with anteverted nares, apparently lowset ears, and cutis marmorata. In addi- tion, he had epicanthal folds; deep, long philtrum; thin upper lip; mild pectus excavatum; diastasis recti; deep palmar creases; malimplanted second toe; and toenail hypoplasia (Figs. 4,5). Liver edge was not palpable. At 2 years, development is delayed, with no intelligible speech. Hearing has been tested and is apparently normal.

DISCUSSION The chondrodysplasia punctata syndromes are a het-

erogeneous group of syndromes which can clearly be

798 Toriello et al.

Fig. 1. Patient 1 at 5 months. Note especially co!ohoma.

Fig. 3. Patient 1 at 10 years. caused in a number of ways. Wulfsberg et al. [19921 classify these syndromes as either primary chondro- dysplasias or disorders with secondary punctate cal- cification. Among the primary chondrodysplasias are five conditions, including rhizomelic CDP (autosomal recessive), X-linked dominant CDP, X-linked recessive CDP, the Shefield mild type of CDP, and the tibia- metacarpal type. Other disorders such as embryopa- thies, chromosome disorders, and other syndromes are included in the group with secondary calcifications. Bennett et al. [1992] list the conditions differently, and sort them by cause in an outline form. Although the

Fig. 2. Patient 1 at 5 months. Note flat profile. Fig. 4. Patient 2. Note pectus excavatum, facial appearance.

Chondrodysplasia Punctata Syndrome 799

Fig. 5. Hand of patient 2. Note deep palmar creases.

entities included in their table are similar to those listed by Wulfsberg et al. [19921, Bennett et al. list Conradi Hunermann syndrome as an autosomal dominant trait which is distinct from the X-linked dominant CDP (XLDCDP). Although most familial cases of Conradi- Hiinermann syndrome are also consistent with XLDCDP, there is a report by Bergstrom et al. 119721 describing an affected woman and her similarly affected son, thus “leaving the door open” for an autosomal dominant form of CDP distinct from XLDCDP.

In addition to the conditions listed in these tables, there are other reports of single cases or of entities difficult to classify. Kozlowski and Majewski [1990] re- ported two children with a provisionally unique form of CDP, termed acro-spondylar variant. The punctate cal- cifications were confined to hands, feet, and spine; hand films also demonstrated hypoplastiddysplastic tubular bones. The authors also refer to two patients with simi- lar findings described by Lawrence et al. [19891. The sex

of three of these children was male; the sex of the fourth was not specified; therefore it is possible that these chil- dren have the X-linked recessive form described by Mar- oteaux [1989], although the boys in that report had no vertebral stippling.

In the same paper by Lawrence et al. [19893 there is mention of another male with CDP, who also had macro- cephaly, “dysplastic” ears, joint contractures, and excess skin folds. Britton [19841 described an “unknown” case of a boy with upslanting palpebral fissures, epicanthal folds, microcorneae, flat facial profile, micrognathia, sparse hair, imperforate anus, and on X-ray, punctate calcifications of hips, ankles, and sacrum. It is clear that syndromes with CDP constitute a large and hetero- geneous group. We suggest the sibs described in this report have yet another provisionally unique syndrome with CDP as a phenotypic trait.

REFERENCES Bennett CP, Berry AC, Maxwell DJ, Seller MJ (1992): Brief clinical

report Chondrodysplasia punctata: Another possible X-linked re- cessive case. Am J Med Genet 41:795-799.

Bergstrom K, Gustavson KH, Jorulf H (1972): Chondrodystrophia cal- cificans congenita (Conradi‘s disease) in a mother and her child. Clin Genet 3:158-161.

Britton JR (1984): Syndrome Identification Case Report 121.8: Epi- physeal stippling, coronal clefts of vertebrae, imperforate anus, congenital heart defect, and unusual facies. J Clin Dysmorphol 2:16-19.

Kozlowski K, Majewski F (1990): Acro-spondylar variant of punctate epiphyseal dysplasia (Report of two cases). Fortschr Rijntgenstr

Lawrence JJ, Schlesinger AE, Kozlowski K, Poznanski AK, Bacha L, Dreyer GI, Barylak A, Sillence DO, Rager K (1989): Unusual radio- graphic manifestations of chondrodysplasia punctata. Skel Radio1

Maroteaux P (1989): Brachytelephalangic chondrodysplasia punctata: A possible X-linked recessive form. Hum Genet 82:167-170.

Wulfsberg EA, Curtis J, Jayne CH (1992): Chondrodysplasia punctata: A boy with X-linked recessive chondrodysplasia punctata due to an inherited X-Y translocation with a current classification of these disorders. Am J Med Gent 43:823-828.

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