Clinical Genetics 1975: 8: 269-274
Syndrome of epiphyseal dysplasia, short stature, microcephaly and nystagmus" R. B. LOWRY AND B. J. WOOD The Departments of Medical Genetics, Diagnostic Radiology and Paediatrics, University of British Columbia, and the Vancouver General Hospital, Vancouver, British Columbia, Canada This report describes two brothers with short stature, congenital nystagmus and microcephaly. The radiographic findings disclosed small, irregularly shaped epiphyses, square iliac bones and flattened acetabulae. The humeri and femora were short. The parents were normal. The syndrome is possibly X-linked, or autosomal recessive in origin. Received I0 February, accepted for publication 3 April 1975
Many different forms of short-limbed dwarfism have been described in the past decade (Kaufman et al. 1970, Cremin & Beighton 1974, Dorst et al. 1972, Felson 1973). Prior to that almost all were classified as achondroplasia. The present report concerns two brothers with radiologic features similar to both multiple epiphyseal dysplasia and achondroplasia. Case Reports
Case 1 was born in 1967, the first child of healthy, unrelated parents aged 32 (father) and 26 years (mother). There was one previous miscarriage. Both parents are above normal stature (177 and 170 cm, respectively), neither show nystagmus and the family history discloses no other cases of short stature, or nystagmus. Despite a full-
*
term pregnancy, the birth weight was only 2500 g. An operation for pyloric stenosis was done at 4 months of age. At 1 year, the patient was investigated for repeated chest infections, wheezing and eczema. Horizontal nystagmus was noted; his optic fundi were, however, normal and there did not appear to be any visual defect. The hands, including the nails, were normal; however, the toenails were small and poorly formed. Normal teeth and hair were noted and the only abnormality was limited extension at the elbow joints and abduction of the hip joints. Investigation at this time disclosed an eosinophilia, ranging from 9 % to 1 3 %, but there were no other abnormalities in the white cell count. Immunoglobulin studies disclosed an IgG of 200 mg %, an IgA of 15 mg % and an IgM of 25 mg % (normal range of values, IgG:
This work was supported in part by the Medical Research Council of Canada, Grant NO. MA - 4539.
270
LOWRY AND WOOD Fig. 1. Case 1 at 27 months, showing short stature, limb shortening, slight genu valgum and small cranium.
420-1290 mg %; IgA: 16-96 mg 96; IgM: 30-188 mg %). A Schick Test was negative (previously immunized with D.P.T.P.) and blood typing disclosed that the patient was Group A with normal isohaemagglutinins. At 2 years it was evident that he was short in stature and he was referred to the Genetics Clinic. Examination disclosed a small head (circumference 46.2 cm - below three standard deviations), a height of 74 cm (below the third percentile, height age of 12 months) and short limbs (Fig. 1). Radiographic examination confirmed the
small skull, which was otherwise normal and disclosed square iliac bones with marked flattening of the acetabular roofs, absence of the proximal epiphysis of the femur and short femoral necks (Fig. 2). The spine (Figs. 3 and 4) was normal, although the usual widening of the interpedicular distances in the lower lumbar region was less than average. In the long bones, the epiphyses were smaller than normal (Fig. 5) and there was slight shortening of the shafts of the humeri and femora, but the lengths of the radii, ulnae, tibiae and fibulae were
EPIPHYSEAL DYSPLASIA AND NYSTAGMUS
normal. The following laboratory tests were found to be within normal limits: blood urea nitrogen, serum calcium, phosphate, alkaline phosphatase, electrolytes, total proteins, protein bound iodine, sweat electrolytes and Growth Hormone studies. Mucopolysaccharide and amino acid screening tests on the urine were normal, as was an amino-acid chromatogram and the chromosome karyotype showed a normal 46,XY pattern. At 3 years a review of the patient’s developmental progress revealed that he sat at 10 months, walked at 18 months, but except for a few words was not talking and was immature in behaviour. His height was 83 cm with a lower segment of 36 cm and a span of 78 cm and the head circumference remained unchanged. A repeat Schick test
271
was negative. Further investigation of his asthma and eczema revealed allergy to egg, walnut, peanut, feathers and house-dust mites. The nystagmus was unchanged, but vision was normal. Nystagmography indicated that the vestibular responses were probably normal and the nystagmus was of ocular origin and of a sinusoidal type. At 3 years, 8 months, psychological testing revealed a mental age of 2 years 7 months, giving a full scale I.Q. of approximately 70 on the Stanford-Binet Scale, but his language development was only at 18 months. H e subsequently went to kindergarten and entered Grade 1. His language remains delayed as compared to the rest of his development. His growth has remained below the third percentile and at 6 years 6 months,
Flg. 2. Radiograph of pelvis of Case 1, at 27 months. small square iliac bones with marked flattening of the acetabular roofs, absence of proximal femoral epiphysis and short femoral necks.
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brother, except for his growth curve, which has remained at the 10th percentile. The radiographic appearances are identical to those of his brother. He crawled at 9 months and walked at 16 months, and at 4 years 6 months his development appears to be within normal limits. His height at this time is 101 cm (10th percentile) with a head circumference of 47.4 cm (below the 3rd percentile). The elbow and hip joints show the same limited degree of movement, although the genu valgum is much milder. Nystagmus with normal vision is present. The same laboratory studies were performed and, except for the absence of eosinophilia, there were no differences between his results and those of his brother. Immunoglobulins Fig. 3. Radiograph of spine of Case 1. at 27 months, showing slight normal widening from LI to LS in interpedicular distances.
his height is 105 cm (height age, 4 years 4 months) and his skull circumference 46.8 cm. Progressive genu valgum is present, with the right being worse than the left, and the spine shows a prominent lumbar lordosis. Over the first 2 years, his immunoglobulins rose to levels just below the lower limit of normal, finally achieving a level above normal, except for the IgA, which has remained below normal. At 4 years, the immunoglobulin levels were as follows: IgG: 700 mg %, IgA: 70 mg %, and IgM: 62 mg %. An intracutaneous Candida (1:10) skin test was positive at 48 h. A biopsy from the chondro-osseous junction of a rib was technically not entirely satisfactory, but did not suggest any abnormality in cartilage growth or maturation, or in enchondral bone formation. The tonsils have always been extremely small. Case 2 was born in 1969, after a full-term
EPIPHYSEAL DYSPLASIA AND NYSTAGMUS
Fig. 5. Radiograph taken at 4 years 8 months showing small fragmented epiphyses, short femoral necks and genu valgum (Case 1).
showed the same slow rise to within normal limits. There are no allergic symptoms and his tonsils are of normal size. Discussion
The radiologic picture fits closely that of multiple epiphyseal dysplasia; however, microcephaly* and nystagmus are not found
* In both our cases, the head circumference measurements were less than three standard deviations below the mean at all ages and thus fulfilled the criterion of microcephaly.
273
in that condition (Jacobs 1973). The pelvis shape is similar to a number of syndromes including achondroplasia, chondroectoderma1 dysplasia and asphyxiating thoracic dystrophy, but the other features in our patients exclude these diagnoses. Congenital nystagmus is frequently due to an autosomal dominant gene; in this family, however, it is not present in either parent, or any other member of the family. While there are similarities in the phenotype, there are also differences, in as much as the younger brother appears more mildly affected in terms of growth. Neither patient has been bothered by persistent bacterial infections, but they did show a delay in the synthesis of immunoglobulins. Several forms of either cell-mediated and/or antibody-mediated immunodeficiency in association with shortlimbed dwarfism have been described (Ammann et al. 1974). Eosinophilia may be seen in patients with lymphopenic agammaglobulinaemia, but the eosinophilia in our first patient is attributed to his allergic diathesis. Apart from the mildly abnormal toenails of Case 1, there is no evidence of any ectodermal dysplasia in either patient. The clinical features together with the family history and laboratory findings suggest a single gene aetiology, either an autosomal or Xlinked recessive trait. Since the parents are divorced, this is a matter of practical importance, since the mother would have the same recurrence risk, namely 25 %, regardless of whom she marries, if it is an X-linked recessive trait, whereas if it were an autosoma1 recessive one, she would be unlikely to marry another heterozygote, and thus her recurrence risk would be negligible. Acknowledgements
The authors would like to acknowledge the help of Drs. R. H. Rogers, A. B. Murray, H. M. Bell and Virginia Wright in the study of these patients.
274
LOWRY AND WOOD
References
Ammann, A. J., W. Sutliff & E. Millinchick (1974). Antibody-mediated immunodeficiency in short-limbed dwarfism. J . Pediat. 84, 200203. Cremin, B. J. & P. Beighton (1974). Dwarfism in the newborn: The nomenclature, radiological features and genetic significance. Brit. J . Radiol. 47, 77-93. Dorst, J. P., C. I. Scott & .I. G. Hall (1972). The radiological assessment of short staturedwarfism. Radiof. Clin. N . Amer. 10, 393414. Felson, B. (ed.) (1973). Dwarfs and other little people. Sem. Roentgen. 8, 133-260.
Jacobs, P. (1973). Multiple epiphyseal dysplasia. Progress in Pediatric Radiology, Vol. 4. (ed.) Kaufrnann, H. J. Basel, Karger, pp. 309-324. Kaufman, R. L., D. L. Rirnoin, W. H. McAlister & J. M. Kissane (1970). Thanatophoric dwarfism. Amer. J . Dis. Child. 120, 53-57.
Address: D r . R . B. Lowry Department of Medical Genetics University of British Columbia 855 West 10th Avenue Vancouver, B.C. V5Z l M 9 Canada
Syndrome of epiphyseal dysplasia, short stature, microcephaly and nystagmus" R. B. LOWRY AND B. J. WOOD The Departments of Medical Genetics, Diagnostic Radiology and Paediatrics, University of British Columbia, and the Vancouver General Hospital, Vancouver, British Columbia, Canada This report describes two brothers with short stature, congenital nystagmus and microcephaly. The radiographic findings disclosed small, irregularly shaped epiphyses, square iliac bones and flattened acetabulae. The humeri and femora were short. The parents were normal. The syndrome is possibly X-linked, or autosomal recessive in origin. Received I0 February, accepted for publication 3 April 1975
Many different forms of short-limbed dwarfism have been described in the past decade (Kaufman et al. 1970, Cremin & Beighton 1974, Dorst et al. 1972, Felson 1973). Prior to that almost all were classified as achondroplasia. The present report concerns two brothers with radiologic features similar to both multiple epiphyseal dysplasia and achondroplasia. Case Reports
Case 1 was born in 1967, the first child of healthy, unrelated parents aged 32 (father) and 26 years (mother). There was one previous miscarriage. Both parents are above normal stature (177 and 170 cm, respectively), neither show nystagmus and the family history discloses no other cases of short stature, or nystagmus. Despite a full-
*
term pregnancy, the birth weight was only 2500 g. An operation for pyloric stenosis was done at 4 months of age. At 1 year, the patient was investigated for repeated chest infections, wheezing and eczema. Horizontal nystagmus was noted; his optic fundi were, however, normal and there did not appear to be any visual defect. The hands, including the nails, were normal; however, the toenails were small and poorly formed. Normal teeth and hair were noted and the only abnormality was limited extension at the elbow joints and abduction of the hip joints. Investigation at this time disclosed an eosinophilia, ranging from 9 % to 1 3 %, but there were no other abnormalities in the white cell count. Immunoglobulin studies disclosed an IgG of 200 mg %, an IgA of 15 mg % and an IgM of 25 mg % (normal range of values, IgG:
This work was supported in part by the Medical Research Council of Canada, Grant NO. MA - 4539.
270
LOWRY AND WOOD Fig. 1. Case 1 at 27 months, showing short stature, limb shortening, slight genu valgum and small cranium.
420-1290 mg %; IgA: 16-96 mg 96; IgM: 30-188 mg %). A Schick Test was negative (previously immunized with D.P.T.P.) and blood typing disclosed that the patient was Group A with normal isohaemagglutinins. At 2 years it was evident that he was short in stature and he was referred to the Genetics Clinic. Examination disclosed a small head (circumference 46.2 cm - below three standard deviations), a height of 74 cm (below the third percentile, height age of 12 months) and short limbs (Fig. 1). Radiographic examination confirmed the
small skull, which was otherwise normal and disclosed square iliac bones with marked flattening of the acetabular roofs, absence of the proximal epiphysis of the femur and short femoral necks (Fig. 2). The spine (Figs. 3 and 4) was normal, although the usual widening of the interpedicular distances in the lower lumbar region was less than average. In the long bones, the epiphyses were smaller than normal (Fig. 5) and there was slight shortening of the shafts of the humeri and femora, but the lengths of the radii, ulnae, tibiae and fibulae were
EPIPHYSEAL DYSPLASIA AND NYSTAGMUS
normal. The following laboratory tests were found to be within normal limits: blood urea nitrogen, serum calcium, phosphate, alkaline phosphatase, electrolytes, total proteins, protein bound iodine, sweat electrolytes and Growth Hormone studies. Mucopolysaccharide and amino acid screening tests on the urine were normal, as was an amino-acid chromatogram and the chromosome karyotype showed a normal 46,XY pattern. At 3 years a review of the patient’s developmental progress revealed that he sat at 10 months, walked at 18 months, but except for a few words was not talking and was immature in behaviour. His height was 83 cm with a lower segment of 36 cm and a span of 78 cm and the head circumference remained unchanged. A repeat Schick test
271
was negative. Further investigation of his asthma and eczema revealed allergy to egg, walnut, peanut, feathers and house-dust mites. The nystagmus was unchanged, but vision was normal. Nystagmography indicated that the vestibular responses were probably normal and the nystagmus was of ocular origin and of a sinusoidal type. At 3 years, 8 months, psychological testing revealed a mental age of 2 years 7 months, giving a full scale I.Q. of approximately 70 on the Stanford-Binet Scale, but his language development was only at 18 months. H e subsequently went to kindergarten and entered Grade 1. His language remains delayed as compared to the rest of his development. His growth has remained below the third percentile and at 6 years 6 months,
Flg. 2. Radiograph of pelvis of Case 1, at 27 months. small square iliac bones with marked flattening of the acetabular roofs, absence of proximal femoral epiphysis and short femoral necks.
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LOWRY AND WOOD
brother, except for his growth curve, which has remained at the 10th percentile. The radiographic appearances are identical to those of his brother. He crawled at 9 months and walked at 16 months, and at 4 years 6 months his development appears to be within normal limits. His height at this time is 101 cm (10th percentile) with a head circumference of 47.4 cm (below the 3rd percentile). The elbow and hip joints show the same limited degree of movement, although the genu valgum is much milder. Nystagmus with normal vision is present. The same laboratory studies were performed and, except for the absence of eosinophilia, there were no differences between his results and those of his brother. Immunoglobulins Fig. 3. Radiograph of spine of Case 1. at 27 months, showing slight normal widening from LI to LS in interpedicular distances.
his height is 105 cm (height age, 4 years 4 months) and his skull circumference 46.8 cm. Progressive genu valgum is present, with the right being worse than the left, and the spine shows a prominent lumbar lordosis. Over the first 2 years, his immunoglobulins rose to levels just below the lower limit of normal, finally achieving a level above normal, except for the IgA, which has remained below normal. At 4 years, the immunoglobulin levels were as follows: IgG: 700 mg %, IgA: 70 mg %, and IgM: 62 mg %. An intracutaneous Candida (1:10) skin test was positive at 48 h. A biopsy from the chondro-osseous junction of a rib was technically not entirely satisfactory, but did not suggest any abnormality in cartilage growth or maturation, or in enchondral bone formation. The tonsils have always been extremely small. Case 2 was born in 1969, after a full-term
EPIPHYSEAL DYSPLASIA AND NYSTAGMUS
Fig. 5. Radiograph taken at 4 years 8 months showing small fragmented epiphyses, short femoral necks and genu valgum (Case 1).
showed the same slow rise to within normal limits. There are no allergic symptoms and his tonsils are of normal size. Discussion
The radiologic picture fits closely that of multiple epiphyseal dysplasia; however, microcephaly* and nystagmus are not found
* In both our cases, the head circumference measurements were less than three standard deviations below the mean at all ages and thus fulfilled the criterion of microcephaly.
273
in that condition (Jacobs 1973). The pelvis shape is similar to a number of syndromes including achondroplasia, chondroectoderma1 dysplasia and asphyxiating thoracic dystrophy, but the other features in our patients exclude these diagnoses. Congenital nystagmus is frequently due to an autosomal dominant gene; in this family, however, it is not present in either parent, or any other member of the family. While there are similarities in the phenotype, there are also differences, in as much as the younger brother appears more mildly affected in terms of growth. Neither patient has been bothered by persistent bacterial infections, but they did show a delay in the synthesis of immunoglobulins. Several forms of either cell-mediated and/or antibody-mediated immunodeficiency in association with shortlimbed dwarfism have been described (Ammann et al. 1974). Eosinophilia may be seen in patients with lymphopenic agammaglobulinaemia, but the eosinophilia in our first patient is attributed to his allergic diathesis. Apart from the mildly abnormal toenails of Case 1, there is no evidence of any ectodermal dysplasia in either patient. The clinical features together with the family history and laboratory findings suggest a single gene aetiology, either an autosomal or Xlinked recessive trait. Since the parents are divorced, this is a matter of practical importance, since the mother would have the same recurrence risk, namely 25 %, regardless of whom she marries, if it is an X-linked recessive trait, whereas if it were an autosoma1 recessive one, she would be unlikely to marry another heterozygote, and thus her recurrence risk would be negligible. Acknowledgements
The authors would like to acknowledge the help of Drs. R. H. Rogers, A. B. Murray, H. M. Bell and Virginia Wright in the study of these patients.
274
LOWRY AND WOOD
References
Ammann, A. J., W. Sutliff & E. Millinchick (1974). Antibody-mediated immunodeficiency in short-limbed dwarfism. J . Pediat. 84, 200203. Cremin, B. J. & P. Beighton (1974). Dwarfism in the newborn: The nomenclature, radiological features and genetic significance. Brit. J . Radiol. 47, 77-93. Dorst, J. P., C. I. Scott & .I. G. Hall (1972). The radiological assessment of short staturedwarfism. Radiof. Clin. N . Amer. 10, 393414. Felson, B. (ed.) (1973). Dwarfs and other little people. Sem. Roentgen. 8, 133-260.
Jacobs, P. (1973). Multiple epiphyseal dysplasia. Progress in Pediatric Radiology, Vol. 4. (ed.) Kaufrnann, H. J. Basel, Karger, pp. 309-324. Kaufman, R. L., D. L. Rirnoin, W. H. McAlister & J. M. Kissane (1970). Thanatophoric dwarfism. Amer. J . Dis. Child. 120, 53-57.
Address: D r . R . B. Lowry Department of Medical Genetics University of British Columbia 855 West 10th Avenue Vancouver, B.C. V5Z l M 9 Canada
