American Journal of Medical Genetics 42724-727 (1992)
Brief Clinical Report Dwarfism, Rhizomelic Limb Shortness, and Abnormal Face: New Short Stature Syndrome Sharing Some Manifestations With Robinow Syndrome ~
Peter D. Turnpenny and Richard J. Thwaites Department of Paediatrics, The Nazareth Hospital, Nazareth, Israel
We describe a child with short stature of prenatal onset, rhizomelic limb shortness affecting the upper limbs particularly, and an unusual face. She had frontal balding, mid-face hypoplasia, a small nose, macrostomia with down-turned corners of the mouth, gingival hypertrophy, and hypoplasia or absence of the clitoris. There was no gross modelling defect of the skeleton and the vertebral column was normal. Some of these manifestations overlap with those of Robinow syndrome. KEY WORDS: rhizomelia, hypoplasia, macrostomia, gingival hypertrophy INTRODUCTION Short stature and disproportionate skeletal growth occur in many syndromes sometimes associated with characteristic radiological changes which help delineation. However, in many, minimal diagnostic criteria are poorly defined and overlap between apparently distinct syndromes is common. This reflects our understanding based on phenotypes rather than genotypes. The subject of this report has characteristics distinct from other dwarfing syndromes known to us, yet some of the findings are the same as seen in Robinow syndrome (RS). First described by Robinow et al. [19691, this syndrome has variable clinical and radiological manifestations [Butler and Wadlington, 19871, and may be heterogeneous. CLINICAL REPORT A female infant weighing 2,080 g was born a t term after an uneventful pregnancy to a 20-year-old priReceived for publication January 31, 1991; revision received July 1, 1991. Dr. P.D. Turnpenny is currently at Medical Genetics, Medical School, Foresterhill, Aberdeen AB9 2ZD, U.K. Address reprint requests there.
0 1992 Wiley-Liss, Inc.
migravid mother and 25-year-old father, the parents being Israeli Arabs and first cousins once removed. Birth length was 41.5 cm and OFC 34.0 cm. A pan-systolicheart murmur, thought to represent a ventricular septa1defect, disappearedby 6 months. Ultrasonography of the heart at 10 months was entirely normal. Her growth data are summarised in Table I and the 50th centile equivalents a t 14 months demonstrate that she has disproportionately short limbs and marked rhizomelic upper limb shortness. The growth chart (Fig. 1) illustrates that she is drifting away from the centile lines in all parameters. Figures 2 and 3 illustrate her general appearance and craniofacial appearance. She has frontal balding, mild telecanthus, mid-face hypoplasia, a small blunt nose, macrostomia, down-turned corners of Lhe mouth, and gingival hypertrophy. Dental eruption began at 6 months and at 18 months her teeth were crowded with notched lower incisors and all four canine teeth were slightly pointed. There was no obvious abnormality of the nails. The clitoris was not visible. Skeletal radiographs are presented in Figures 4-8. The thorax is dome-shaped and there is delayed ossification at the proximal humeral and femoral epiphyses. However, in general there are no gross modelling, metaphyseal, or epiphyseal defects. There is no vertebral dyssegmentation. She was delayed in her gross motor development, not sitting unsupported until the age of 11 months, and by 18 months she had begun to take a few steps. At 18 months fine motor development, vision, and hearing were normal, and she had a vocabulary of approximately 15 words. Karyotyping by G-banding or, peripheral lymphocytes showed normal 46,XX chromosomes on 2 occasions. Results of full blood count, urea, electrolytes, calcium, phosphate, alkaline phosphatase, serum amino acids, thyroid function tests, and a random growth hormone estimation were normal. A paternal first cousin born to consanguineous parents was a male dwarf with proportional short stature and 14 years old when the proposita was born. He had neither craniofacial changes nor rhizomelic shortness of limbs and was considered to have a different condition.
A New Dwarfing Syndrome
725
TABLE I. Growth Parameters of Patient at Various Ages Age
Birth
14 months
50th centile equivalent at llmonths
Weight (g) Length (cm) crown-heel crown-rump Sub-ischial Leg length (cm) Upper arm (cm) (acromion-olecranon)
2,080
4,960
2% months
5,400
41.5
-
59 40
4% months
3 months
60 41.5
-
19
1% months
-
-
8
34-35 weeks gestation Birth < 3 months 6 months
-
-
Span (cm) Hand length (cm) OFC (cm)
I
52 7.0 43.0
34.0
8
8
'
I
~
1 2 3 4 5 678 9
~
'
"
'
'
'
'
~
~
'
~
~
~
1
12 15 18 2124 Month1I
Fie1. 1. Growth chart for head, length, and weight parameters, biirth to 18 moriths.
Fig. 3. General appearance at age 12 months.
Fig. 2. Lateral view a t age 6 months.
18 months
55
-
44.6
Fig. 4. Fig. 5. Fig. 6. Fig. 7.
Antero-posterior radiograph of the thorax and spine at age 18 months. Lateral radiograph of the spine at age 14 months. Lateral radiograph of the skull at age 18 months. Radiograph of arm a t age 18 months.
A New Dwarfing Syndrome
727
phy, and hypoplasia of the clitoris. The overall facial appearance, particularly the absence of hypertelorism, was not typical of RS when she was examined a t birth. It has become less so as she has grown (Fig. 3). She has no hemivertebrae but according to Butler and Wadlington [1987] vertebral anomalies occur in only 66% of RS cases. Nevertheless this case is outstanding for the lack of distinguishing radiological abnormalities. The marked prenatal onset of growth delay and extremely short stature are not common in RS.A positive diagnosis may be possible a t a later stage as craniofacial and skeletal changes evolve. The pedigree status of this case is not helpful since she is a t present the only child of consanguineous parents. The only other dwarfed relative is one of 12 sibs, making it unlikely that he has an autosomal recessive condition. There is evidence for both dominant [Bain et al., 1986; Robinow et al., 1969; Shprintzen et al., 19821and autosoma1 recessive inheritance [Teebi, 1990; Wadia et al., 19781in RS. Difficulties in trying to predict the mode of inheritance on the basis of clinical and radiologicalmanifestations are discussed by Bain et al. [19861, Butler and Wadlington [1987], and Teebi [19901.
ACKNOWLEDGMENTS We thank Dr. Avraham Lorber of Haifa for performing echocardiography on our patient. REFERENCES
Fig. 8. Radiograph of legs a t age 18 months.
DISCUSSION Rhizomelic limb shortness affecting predominantly the upper limbs has been described in a number of rare and apparently distinct syndromes [Barrow and Fitzsimmons, 1984; Kozlowski et al., 1974; Patterson and Lowry, 1975; Reardon et al., 1990; Urbach et al., 1986; Viljoen et al., 19871. Our case differs from all of these on clinical grounds. The only syndrome known to us which bears any resemblance to this case is the Robinow syndrome (RS). Limb shortness in Rs is usually mesomelic in distribution [Butler and Wadlington, 1987;Robinow et al., 1969; Wadlington et al., 19731. One case with rhizomelic shortness has been described [Bain et al., 19861. The findings of our case which are consistent with RS are: relative macrocephaly, short nose, macrostomia with down-turned corners of the mouth, gingival hypertro-
Bain MD, Winter RM, Burn J (1986):Robinow syndrome without mesomelic ‘brachymelia’: a report offive cases. J Med Genet 23:350-354. Barrow M, Fitzsimmons JS (1984):A new syndrome. Short limbs, abnormal facial appearance, and congenital heart defect. Am J Med Genet 18:431-433. Butler MG, Wadlington WB (1987):Robinow syndrome: report of two patients and review of the literature. Clin Genet 31:77-85. Kozlowski KS, Celermajer JM, Tink AR (1974):Humero-spinal dysostosis with congenital heart disease. Am J Dis Child 127:407-410. Patterson C, Lowry RB (1975):A new dwarfhg syndrome with extreme shortening of humeri and severe coxa vara. Radiology 114:341-342. Reardon W, Hurst J, Farag TI, Hall C, Baraitser M (1990):Two brothers with heart defects and limb shortening: case reports and review. J Med Genet 27:746-751. Robinow M, Silverman FN, Smith HD (1969):A newly recognized dwarfing syndrome. Am J Dis Child 117:645-651. Shprintzen RJ, Goldberg RB, Saenger P, Sidoti W (1982): Male-to-male transmission of Robinow’s syndrome. Am J Dis Child 136594-597. Teebi A S (1990):Autosomal recessive Robinow syndrome. Am J Med Genet 3564-68. Urbach D, Hertz M, Shine M, Goodman RM (1986):A new skeletal dysplasia syndrome with rhizomelia of the humeri and other malformations. Clin Genet 2983-87. Viljoen D, Goldblatt J, Wallis C, Beighton P (1987):Familial rhizomelic dysplasia: phenotypic variation or heterogeneity? Am J Med Genet 26941-947. Wadia RS, Shirole DB, Dikshit MS (1978):Recessively inherited costovertebral segmentation defect with mesomelia and peculiar facies (Covesdem syndrome). J Med Genet 15:123-127. Wadlington WB, Tucker VL, Schimke RN (1973):Mesomelic dwarfism with hemivertebrae and small genitalia (the Robinow syndrome). Am J Dis Child 126202-205.
Brief Clinical Report Dwarfism, Rhizomelic Limb Shortness, and Abnormal Face: New Short Stature Syndrome Sharing Some Manifestations With Robinow Syndrome ~
Peter D. Turnpenny and Richard J. Thwaites Department of Paediatrics, The Nazareth Hospital, Nazareth, Israel
We describe a child with short stature of prenatal onset, rhizomelic limb shortness affecting the upper limbs particularly, and an unusual face. She had frontal balding, mid-face hypoplasia, a small nose, macrostomia with down-turned corners of the mouth, gingival hypertrophy, and hypoplasia or absence of the clitoris. There was no gross modelling defect of the skeleton and the vertebral column was normal. Some of these manifestations overlap with those of Robinow syndrome. KEY WORDS: rhizomelia, hypoplasia, macrostomia, gingival hypertrophy INTRODUCTION Short stature and disproportionate skeletal growth occur in many syndromes sometimes associated with characteristic radiological changes which help delineation. However, in many, minimal diagnostic criteria are poorly defined and overlap between apparently distinct syndromes is common. This reflects our understanding based on phenotypes rather than genotypes. The subject of this report has characteristics distinct from other dwarfing syndromes known to us, yet some of the findings are the same as seen in Robinow syndrome (RS). First described by Robinow et al. [19691, this syndrome has variable clinical and radiological manifestations [Butler and Wadlington, 19871, and may be heterogeneous. CLINICAL REPORT A female infant weighing 2,080 g was born a t term after an uneventful pregnancy to a 20-year-old priReceived for publication January 31, 1991; revision received July 1, 1991. Dr. P.D. Turnpenny is currently at Medical Genetics, Medical School, Foresterhill, Aberdeen AB9 2ZD, U.K. Address reprint requests there.
0 1992 Wiley-Liss, Inc.
migravid mother and 25-year-old father, the parents being Israeli Arabs and first cousins once removed. Birth length was 41.5 cm and OFC 34.0 cm. A pan-systolicheart murmur, thought to represent a ventricular septa1defect, disappearedby 6 months. Ultrasonography of the heart at 10 months was entirely normal. Her growth data are summarised in Table I and the 50th centile equivalents a t 14 months demonstrate that she has disproportionately short limbs and marked rhizomelic upper limb shortness. The growth chart (Fig. 1) illustrates that she is drifting away from the centile lines in all parameters. Figures 2 and 3 illustrate her general appearance and craniofacial appearance. She has frontal balding, mild telecanthus, mid-face hypoplasia, a small blunt nose, macrostomia, down-turned corners of Lhe mouth, and gingival hypertrophy. Dental eruption began at 6 months and at 18 months her teeth were crowded with notched lower incisors and all four canine teeth were slightly pointed. There was no obvious abnormality of the nails. The clitoris was not visible. Skeletal radiographs are presented in Figures 4-8. The thorax is dome-shaped and there is delayed ossification at the proximal humeral and femoral epiphyses. However, in general there are no gross modelling, metaphyseal, or epiphyseal defects. There is no vertebral dyssegmentation. She was delayed in her gross motor development, not sitting unsupported until the age of 11 months, and by 18 months she had begun to take a few steps. At 18 months fine motor development, vision, and hearing were normal, and she had a vocabulary of approximately 15 words. Karyotyping by G-banding or, peripheral lymphocytes showed normal 46,XX chromosomes on 2 occasions. Results of full blood count, urea, electrolytes, calcium, phosphate, alkaline phosphatase, serum amino acids, thyroid function tests, and a random growth hormone estimation were normal. A paternal first cousin born to consanguineous parents was a male dwarf with proportional short stature and 14 years old when the proposita was born. He had neither craniofacial changes nor rhizomelic shortness of limbs and was considered to have a different condition.
A New Dwarfing Syndrome
725
TABLE I. Growth Parameters of Patient at Various Ages Age
Birth
14 months
50th centile equivalent at llmonths
Weight (g) Length (cm) crown-heel crown-rump Sub-ischial Leg length (cm) Upper arm (cm) (acromion-olecranon)
2,080
4,960
2% months
5,400
41.5
-
59 40
4% months
3 months
60 41.5
-
19
1% months
-
-
8
34-35 weeks gestation Birth < 3 months 6 months
-
-
Span (cm) Hand length (cm) OFC (cm)
I
52 7.0 43.0
34.0
8
8
'
I
~
1 2 3 4 5 678 9
~
'
"
'
'
'
'
~
~
'
~
~
~
1
12 15 18 2124 Month1I
Fie1. 1. Growth chart for head, length, and weight parameters, biirth to 18 moriths.
Fig. 3. General appearance at age 12 months.
Fig. 2. Lateral view a t age 6 months.
18 months
55
-
44.6
Fig. 4. Fig. 5. Fig. 6. Fig. 7.
Antero-posterior radiograph of the thorax and spine at age 18 months. Lateral radiograph of the spine at age 14 months. Lateral radiograph of the skull at age 18 months. Radiograph of arm a t age 18 months.
A New Dwarfing Syndrome
727
phy, and hypoplasia of the clitoris. The overall facial appearance, particularly the absence of hypertelorism, was not typical of RS when she was examined a t birth. It has become less so as she has grown (Fig. 3). She has no hemivertebrae but according to Butler and Wadlington [1987] vertebral anomalies occur in only 66% of RS cases. Nevertheless this case is outstanding for the lack of distinguishing radiological abnormalities. The marked prenatal onset of growth delay and extremely short stature are not common in RS.A positive diagnosis may be possible a t a later stage as craniofacial and skeletal changes evolve. The pedigree status of this case is not helpful since she is a t present the only child of consanguineous parents. The only other dwarfed relative is one of 12 sibs, making it unlikely that he has an autosomal recessive condition. There is evidence for both dominant [Bain et al., 1986; Robinow et al., 1969; Shprintzen et al., 19821and autosoma1 recessive inheritance [Teebi, 1990; Wadia et al., 19781in RS. Difficulties in trying to predict the mode of inheritance on the basis of clinical and radiologicalmanifestations are discussed by Bain et al. [19861, Butler and Wadlington [1987], and Teebi [19901.
ACKNOWLEDGMENTS We thank Dr. Avraham Lorber of Haifa for performing echocardiography on our patient. REFERENCES
Fig. 8. Radiograph of legs a t age 18 months.
DISCUSSION Rhizomelic limb shortness affecting predominantly the upper limbs has been described in a number of rare and apparently distinct syndromes [Barrow and Fitzsimmons, 1984; Kozlowski et al., 1974; Patterson and Lowry, 1975; Reardon et al., 1990; Urbach et al., 1986; Viljoen et al., 19871. Our case differs from all of these on clinical grounds. The only syndrome known to us which bears any resemblance to this case is the Robinow syndrome (RS). Limb shortness in Rs is usually mesomelic in distribution [Butler and Wadlington, 1987;Robinow et al., 1969; Wadlington et al., 19731. One case with rhizomelic shortness has been described [Bain et al., 19861. The findings of our case which are consistent with RS are: relative macrocephaly, short nose, macrostomia with down-turned corners of the mouth, gingival hypertro-
Bain MD, Winter RM, Burn J (1986):Robinow syndrome without mesomelic ‘brachymelia’: a report offive cases. J Med Genet 23:350-354. Barrow M, Fitzsimmons JS (1984):A new syndrome. Short limbs, abnormal facial appearance, and congenital heart defect. Am J Med Genet 18:431-433. Butler MG, Wadlington WB (1987):Robinow syndrome: report of two patients and review of the literature. Clin Genet 31:77-85. Kozlowski KS, Celermajer JM, Tink AR (1974):Humero-spinal dysostosis with congenital heart disease. Am J Dis Child 127:407-410. Patterson C, Lowry RB (1975):A new dwarfhg syndrome with extreme shortening of humeri and severe coxa vara. Radiology 114:341-342. Reardon W, Hurst J, Farag TI, Hall C, Baraitser M (1990):Two brothers with heart defects and limb shortening: case reports and review. J Med Genet 27:746-751. Robinow M, Silverman FN, Smith HD (1969):A newly recognized dwarfing syndrome. Am J Dis Child 117:645-651. Shprintzen RJ, Goldberg RB, Saenger P, Sidoti W (1982): Male-to-male transmission of Robinow’s syndrome. Am J Dis Child 136594-597. Teebi A S (1990):Autosomal recessive Robinow syndrome. Am J Med Genet 3564-68. Urbach D, Hertz M, Shine M, Goodman RM (1986):A new skeletal dysplasia syndrome with rhizomelia of the humeri and other malformations. Clin Genet 2983-87. Viljoen D, Goldblatt J, Wallis C, Beighton P (1987):Familial rhizomelic dysplasia: phenotypic variation or heterogeneity? Am J Med Genet 26941-947. Wadia RS, Shirole DB, Dikshit MS (1978):Recessively inherited costovertebral segmentation defect with mesomelia and peculiar facies (Covesdem syndrome). J Med Genet 15:123-127. Wadlington WB, Tucker VL, Schimke RN (1973):Mesomelic dwarfism with hemivertebrae and small genitalia (the Robinow syndrome). Am J Dis Child 126202-205.
