American Journal of Medical Genetics 37:516-518 (1990)
Brief Clinical Report Concurrence of Robinow Syndrome and CriglerNajar Syndrome in Two Offspring of First Cousins Hisham Nazer, Thirumazhisai S. Gunasekaran, Nadia A. Sakati, and William L. Nyhan Department of Pediatrics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia (H.N., T.S.G., N.A.S.); Department of Pediatrics, University of California S a n Diego, La Jolla (W.L.N.)
Robinow syndrome and Crigler-Najar syndrome were encountered in 2 Saudi offspring of first cousins. Both died at age 4 months. The parents lost 2 previous children at age 2 months with progressive jaundice but without fetal facial characteristics. KEY WORDS: fetal face syndrome, autosoma1 recessive inheritance ~
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INTRODUCTION Robinow et al. [1969] described a short-limbed syndrome in which the face had the characteristic “fetal” appearance that has led to its ready recognition. It is sometimes referred to as the “fetal face syndrome” [Jones, 19881. The disorder appeared to be inherited in a n autosomal dominant fashion in the initial family, but heterogeneity was recognized by the report [Wadlington et al., 19731 of affected sibs of normal parents. By 1987, 34 patients with this syndrome had been reported [Butler and Wadlington, 19871. Crigler and Najjar 119521 described a n autosomal recessive syndrome of familial nonhemolytic hyperbilirubinemia that results from deficiency of hepatic glucuronyl transferase [Arias et al., 19691. Here we describe 2 sibs with the fetal face syndrome and Crigler-Najjar syndrome. Parental consanguinity indicated that both syndromes in this family were autosomal recessive in inheritance.
CLINICAL REPORTS Patient 1 A 2-month-old boy was referred because of persistent jaundice and facial anomalies. He was the product of a full-term uncomplicated delivery, the seventh born to parents who were first cousins. On the second day of life he was noted to be severely jaundiced. He was treated with 2 exchange transfusions and phototherapy for unconjugated hyperbilirubinemia. Received for publication September 13, 1989; revision received March 5, 1990. Address reprint requests to H. Nazer, M.D., King Faisal Specialist Hospital and Research Centre, P.O. Box 3354, Riyadh 11211, Saudi Arabia.
0 1990 Wiley-Liss, Inc.
Family history included the patient described as patient 2. The first and fifth children were born a t home and died a t 2 months. Both had deepening jaundice which began in the first days of life, but neither had the facial anomalies that characterized patients 1 and 2. Three other children were well. On admission the patient was very icteric. His physical appearance was striking (Fig. 1).The forehead was prominent and the nasal bridge depressed. The nose was small and the nares anteverted. The anterior fontanelle was widely patent. There was apparent hypertelorism and prominence of the eyes. The philtrum was long and the shape of the mouth was triangular with a tendency to eversion of the lower lip. There was an incomplete midline cleft of the lower lip and a bilobed tongue. The mandible was short. The alveolar ridges were strikingly hyperplastic. The ear was malformed and posteriorly rotated. The head circumference was 38.5 cm (50th centile), while the weight of 4.15 kg was just below the 3rd centile, and the length of 43.5 cm was well below the 3rd centile. There were short limbs and brachydactyly of the feet. The shortness of the limbs appeared proportionate rather than mesomelic. There was bilateral clinodactyly, and fifth fingers each lacked one transverse ridge. The distal 2 phalanges of the second and third digits were deviated in the ulnar direction, and those of the fourth and fifth deviated medially. There was mild syndactyly of the second and third toes. CT scan of the brain showed cerebellar hypoplasia and mild dilatation of the lateral ventricles. Chromosomes were normal (46,XY). The liver was palpable 3 cm below the right costal margin. There was a micropenis and a hypoplastic scrotum. The left testis was palpable in the inguinal canal; the right testis was not palpable. The hips were dislocated bilaterally and this was documented roentgenographically. Roentgenograms of the hands and feet showed hypoplastic terminal phalanges, particularly of the toes, and striking hypoplasia of the middle phalanges of the fifth fingers (Fig. 2). Development assessment using Bayley scales a t 6 months found him to be functioning a t a level of less than 2 months. The bilirubin was 16.2 mgidl (1.2 mgidl conjugated). Hemoglobin (Hgb) was 7.7 gidl. The blood smear was normal and the reticulocyte count was less than 1.0%. The blood group was 0 positive; direct Coombs test was negative. Bone marrow aspirate, serum folate, BIZ,TSH,
Robinow Syndrome
517
Fig. 2. Roentgenogram of the left hand (Patient 1) illustrating hypoplasia of the distal phalanges, particularly of the second phalanx of the fifth digit.
Patient 2 The sixth child was delivered by cesarean section. Birth weight was 2.8 kg. Facial anomalies (Fig. 3) were similar to those of her brother. The face was flat in profile. The genitalia were normal and the hips were not dislocated. This infant had persistent unconjugated jaundice. She was treated with exchange transfusions, phototherapy, and phenobarbitone. She was transferred to a regional hospital and then home, where she died shortly after 4 months of age.
DISCUSSION The 2 sibs had a n identical skeletal dysplasia and congenital nonhemolytic jaundice. The fetal appearance of their faces placed them in the syndrome referred to as Robinow syndrome, but this is clearly a heterogeneous group of at least 2 disorders. The syndrome in these 2 children included, in addition to the craniofacial appearFig. 1. Patient 1.The alveolar hyperplasia and very small penis are ance, generalized shortness of the limbs, brachydactyly, evident as well as the short limbs and the characteristic facial appearance. The triangular appearance of the mouth was not apparent in this clinodactyly, alveolar hyperplasia, and developmental view in which the mouth was widely opened. When the mouth was retardation. nearly closed the angles turned down. The original report of Robinow et al. [1969] documented a n autosomal dominant mode of inheritance. The limbs were described as brachymelic or as moderately mesomelic at least in the arms, but the shortness and T, levels and results of TORCH screen were normal. appeared similar to the pattern of our patients and Erythrocyte activity of pyruvate kinase was normal, but clearly not rhizomelic. The hands of these patients were activity of glucose-6-phosphate dehydrogenase (G6PD) described as normal. Hypoplastic genitalia were characwas low a t 0.32 u/ml RBC (normal range 1.74-5.19). teristic, and one had a cleft vertebra. In the autosomal The SCOT was 30 units and the SGPT 28 units; the recessive syndrome reported by Wadlington et al. prothrombin time was 10 sec and the PTT 28 sec. The 119731, there were 2 sibs of unaffected parents. The shortness of the arms was more clearly mesomelic, a t histology of biopsied liver was normal. He appeared to respond to phototherapy and phe- least in the roentgenograms; it was not clear in the nobarbitone; with treatment, the bilirubin was main- clinical photographs and certainly not in the legs. The tained a t 14 mgldl. After 4 months, he was transferred to faces had the fetal configuration, and the genitalia were a regional hospital where therapy was continued, but a hypoplastic. The authors emphasized hemivertebrae, but this would not distinguish this syndrome from the month later he developed pneumonia and died.
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Nazer et al.
Fig. 3 Patient 2. She had symmetrical shortness of the limbs and brachydactyly. The forehead was prominent, the nasal bridge depressed, and the nose small and anteverted. The philtrum was long, the mouth triangular, and the jaw micrognathic.
viously been reported [Vera-Roman, 19731. Life span is usually normal, but death in infancy has been reported in 10% of patients [Butler and Wadlington, 19871. Of course in our patients the developmental retardation and early demise may have been consequences of the Crigler-Najar syndrome in which kernicterus is the rule and most patients die in infancy [Bloomer and Sharp, 19841. The other 2 sibs with congenital icterus died early in life. Infants with the Crigler-Najar syndrome who present with severe jaundice in the first days of life tend to have virtually complete absence of activity of uridine diphosphateglucuronyl transferase. The occurrence of 2 rare autosomal recessive disorders in 2 sibs is unusual but not inconsistent with the burden of consanguinity. The Crigler-Najar syndrome is rare [Bloomer and Sharp, 19841. Instances of the Robinow syndrome that appear clearly recessive are even rarer. The consanguinity in our family and the occurrence of the 2 disorders clearly indicate autosomal recessive inheritance. A search of the literature failed to find other examples of the combination of these 2 disorders. Nevertheless the concurrence appears to be the chance assortment in a family in which both parents were heterozygotes for 2 rare genes, because the 2 earlier sibs who died doubtless had the same icteric disease as our 2 patients, but did not have the Robinow syndrome. The initial inbred kindred of Crigler and Najar [1952] displayed a similar situation in which one of the affected sibships also included a patient with Morquio syndrome.
REFERENCES dominant syndrome. The hands and feet were broad and short as in our patients, and clinodactyly of the fifth fingers was associated with a hypoplastic fifth middle phalanx, and these might be distinguishing characteristics, but one of the 4 patients of Wadlington et al. 119731 appeared to have the dominant disorder and had a t least the findings in the fifth digit. The teeth were crowded but alveolar hyperplasia, so prominent in our patients, was not described. This feature as well as clefting of the lower lip and tongue and ankyloglossia [Israel and Johnson, 19881 does not distinguish dominant and recessive types. Bain et al. [1986] tried to distinguish the dominant and recessive phenotypes in a report of 5 patients, all of whom had what they called “gum” hypertrophy. They emphasized abnormalities of the ribs and vertebrae in the recessive forms, but these features as well as roentgenographic changes in the bones of the forearm [Robinow and Markert, 19881, which were not observed in our patient, do not appear to discriminate. In fact in the 3 autosomal dominant patients they reported there was no shortness of the limbs a t all. Clearly there is considerable heterogeneity among patients with fetalappearing faces. Intelligence is usually normal [Butler and Waldington, 19871,but mental retardation has pre-
Arias IM, Gartner LM, Cohen M, Ben Ezzer J , Levi AJ (1969):Chronic hemolytic unconjugated hyperbilirubinemia with glucuronyltransferase-deficiency. Clinical, biochemical and genetic evidence. Am J Med 47:395-409. Bain MD, Winter RM, Burn J (1986):Robinow syndrome without mesomelic ‘brachymelia’: A report of five cases. J Med Genet 23:350-354. Bloomer JR, Sharp HL (1984): The liver in Crigler-Najjar syndrome, protoporphyria and other metabolic diseases. Hepatology [Suppll 4:18S-21S. Butler MG, Wadlington WB (1987): Robinow syndrome: Report of two patients and review of literature. Clin Genet 31:77-85. Crigler J, Jr., Najjar V (1952):Congenital familial nonhemolytic jaundice with kernicterus. Pediatrics 10:169-180. Israel H, Johnson GF (1988): Craniofacial pattern similarities and additional orofacial findings in siblings with the Robinow syndrome. J Craniofac Genet Dev Biol 8:63-73. Jones KL (1988): Robinow syndrome (fetal face syndrome). In Smith DW, Jones KL (eds): “Smiths Recognizable Patterns of Human Malformation,” 4th Ed. Philadelphia: WB Saunders Co., pp 112-113.
Robinow M, Markert R J (1988): The fetal face (Robinow) syndrome: Delineation of the dominant and recessive phenotypes. Proc Greenwood Genet Ctr 7:144. Vera-Roman JM (1973): Robinow dwarfing syndrome accompanied by penile agenesis and hemivertebrae. Am J Dis Child 126:206-208. Wadlington WB, Tucker VL, Schimke R (1973):Mesomelic dwarfism with hemivertebrae and small genitalia (the Robinow syndrome). Am J Dis Child 126:202-205.
Brief Clinical Report Concurrence of Robinow Syndrome and CriglerNajar Syndrome in Two Offspring of First Cousins Hisham Nazer, Thirumazhisai S. Gunasekaran, Nadia A. Sakati, and William L. Nyhan Department of Pediatrics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia (H.N., T.S.G., N.A.S.); Department of Pediatrics, University of California S a n Diego, La Jolla (W.L.N.)
Robinow syndrome and Crigler-Najar syndrome were encountered in 2 Saudi offspring of first cousins. Both died at age 4 months. The parents lost 2 previous children at age 2 months with progressive jaundice but without fetal facial characteristics. KEY WORDS: fetal face syndrome, autosoma1 recessive inheritance ~
~~
~~
~
~
INTRODUCTION Robinow et al. [1969] described a short-limbed syndrome in which the face had the characteristic “fetal” appearance that has led to its ready recognition. It is sometimes referred to as the “fetal face syndrome” [Jones, 19881. The disorder appeared to be inherited in a n autosomal dominant fashion in the initial family, but heterogeneity was recognized by the report [Wadlington et al., 19731 of affected sibs of normal parents. By 1987, 34 patients with this syndrome had been reported [Butler and Wadlington, 19871. Crigler and Najjar 119521 described a n autosomal recessive syndrome of familial nonhemolytic hyperbilirubinemia that results from deficiency of hepatic glucuronyl transferase [Arias et al., 19691. Here we describe 2 sibs with the fetal face syndrome and Crigler-Najjar syndrome. Parental consanguinity indicated that both syndromes in this family were autosomal recessive in inheritance.
CLINICAL REPORTS Patient 1 A 2-month-old boy was referred because of persistent jaundice and facial anomalies. He was the product of a full-term uncomplicated delivery, the seventh born to parents who were first cousins. On the second day of life he was noted to be severely jaundiced. He was treated with 2 exchange transfusions and phototherapy for unconjugated hyperbilirubinemia. Received for publication September 13, 1989; revision received March 5, 1990. Address reprint requests to H. Nazer, M.D., King Faisal Specialist Hospital and Research Centre, P.O. Box 3354, Riyadh 11211, Saudi Arabia.
0 1990 Wiley-Liss, Inc.
Family history included the patient described as patient 2. The first and fifth children were born a t home and died a t 2 months. Both had deepening jaundice which began in the first days of life, but neither had the facial anomalies that characterized patients 1 and 2. Three other children were well. On admission the patient was very icteric. His physical appearance was striking (Fig. 1).The forehead was prominent and the nasal bridge depressed. The nose was small and the nares anteverted. The anterior fontanelle was widely patent. There was apparent hypertelorism and prominence of the eyes. The philtrum was long and the shape of the mouth was triangular with a tendency to eversion of the lower lip. There was an incomplete midline cleft of the lower lip and a bilobed tongue. The mandible was short. The alveolar ridges were strikingly hyperplastic. The ear was malformed and posteriorly rotated. The head circumference was 38.5 cm (50th centile), while the weight of 4.15 kg was just below the 3rd centile, and the length of 43.5 cm was well below the 3rd centile. There were short limbs and brachydactyly of the feet. The shortness of the limbs appeared proportionate rather than mesomelic. There was bilateral clinodactyly, and fifth fingers each lacked one transverse ridge. The distal 2 phalanges of the second and third digits were deviated in the ulnar direction, and those of the fourth and fifth deviated medially. There was mild syndactyly of the second and third toes. CT scan of the brain showed cerebellar hypoplasia and mild dilatation of the lateral ventricles. Chromosomes were normal (46,XY). The liver was palpable 3 cm below the right costal margin. There was a micropenis and a hypoplastic scrotum. The left testis was palpable in the inguinal canal; the right testis was not palpable. The hips were dislocated bilaterally and this was documented roentgenographically. Roentgenograms of the hands and feet showed hypoplastic terminal phalanges, particularly of the toes, and striking hypoplasia of the middle phalanges of the fifth fingers (Fig. 2). Development assessment using Bayley scales a t 6 months found him to be functioning a t a level of less than 2 months. The bilirubin was 16.2 mgidl (1.2 mgidl conjugated). Hemoglobin (Hgb) was 7.7 gidl. The blood smear was normal and the reticulocyte count was less than 1.0%. The blood group was 0 positive; direct Coombs test was negative. Bone marrow aspirate, serum folate, BIZ,TSH,
Robinow Syndrome
517
Fig. 2. Roentgenogram of the left hand (Patient 1) illustrating hypoplasia of the distal phalanges, particularly of the second phalanx of the fifth digit.
Patient 2 The sixth child was delivered by cesarean section. Birth weight was 2.8 kg. Facial anomalies (Fig. 3) were similar to those of her brother. The face was flat in profile. The genitalia were normal and the hips were not dislocated. This infant had persistent unconjugated jaundice. She was treated with exchange transfusions, phototherapy, and phenobarbitone. She was transferred to a regional hospital and then home, where she died shortly after 4 months of age.
DISCUSSION The 2 sibs had a n identical skeletal dysplasia and congenital nonhemolytic jaundice. The fetal appearance of their faces placed them in the syndrome referred to as Robinow syndrome, but this is clearly a heterogeneous group of at least 2 disorders. The syndrome in these 2 children included, in addition to the craniofacial appearFig. 1. Patient 1.The alveolar hyperplasia and very small penis are ance, generalized shortness of the limbs, brachydactyly, evident as well as the short limbs and the characteristic facial appearance. The triangular appearance of the mouth was not apparent in this clinodactyly, alveolar hyperplasia, and developmental view in which the mouth was widely opened. When the mouth was retardation. nearly closed the angles turned down. The original report of Robinow et al. [1969] documented a n autosomal dominant mode of inheritance. The limbs were described as brachymelic or as moderately mesomelic at least in the arms, but the shortness and T, levels and results of TORCH screen were normal. appeared similar to the pattern of our patients and Erythrocyte activity of pyruvate kinase was normal, but clearly not rhizomelic. The hands of these patients were activity of glucose-6-phosphate dehydrogenase (G6PD) described as normal. Hypoplastic genitalia were characwas low a t 0.32 u/ml RBC (normal range 1.74-5.19). teristic, and one had a cleft vertebra. In the autosomal The SCOT was 30 units and the SGPT 28 units; the recessive syndrome reported by Wadlington et al. prothrombin time was 10 sec and the PTT 28 sec. The 119731, there were 2 sibs of unaffected parents. The shortness of the arms was more clearly mesomelic, a t histology of biopsied liver was normal. He appeared to respond to phototherapy and phe- least in the roentgenograms; it was not clear in the nobarbitone; with treatment, the bilirubin was main- clinical photographs and certainly not in the legs. The tained a t 14 mgldl. After 4 months, he was transferred to faces had the fetal configuration, and the genitalia were a regional hospital where therapy was continued, but a hypoplastic. The authors emphasized hemivertebrae, but this would not distinguish this syndrome from the month later he developed pneumonia and died.
518
Nazer et al.
Fig. 3 Patient 2. She had symmetrical shortness of the limbs and brachydactyly. The forehead was prominent, the nasal bridge depressed, and the nose small and anteverted. The philtrum was long, the mouth triangular, and the jaw micrognathic.
viously been reported [Vera-Roman, 19731. Life span is usually normal, but death in infancy has been reported in 10% of patients [Butler and Wadlington, 19871. Of course in our patients the developmental retardation and early demise may have been consequences of the Crigler-Najar syndrome in which kernicterus is the rule and most patients die in infancy [Bloomer and Sharp, 19841. The other 2 sibs with congenital icterus died early in life. Infants with the Crigler-Najar syndrome who present with severe jaundice in the first days of life tend to have virtually complete absence of activity of uridine diphosphateglucuronyl transferase. The occurrence of 2 rare autosomal recessive disorders in 2 sibs is unusual but not inconsistent with the burden of consanguinity. The Crigler-Najar syndrome is rare [Bloomer and Sharp, 19841. Instances of the Robinow syndrome that appear clearly recessive are even rarer. The consanguinity in our family and the occurrence of the 2 disorders clearly indicate autosomal recessive inheritance. A search of the literature failed to find other examples of the combination of these 2 disorders. Nevertheless the concurrence appears to be the chance assortment in a family in which both parents were heterozygotes for 2 rare genes, because the 2 earlier sibs who died doubtless had the same icteric disease as our 2 patients, but did not have the Robinow syndrome. The initial inbred kindred of Crigler and Najar [1952] displayed a similar situation in which one of the affected sibships also included a patient with Morquio syndrome.
REFERENCES dominant syndrome. The hands and feet were broad and short as in our patients, and clinodactyly of the fifth fingers was associated with a hypoplastic fifth middle phalanx, and these might be distinguishing characteristics, but one of the 4 patients of Wadlington et al. 119731 appeared to have the dominant disorder and had a t least the findings in the fifth digit. The teeth were crowded but alveolar hyperplasia, so prominent in our patients, was not described. This feature as well as clefting of the lower lip and tongue and ankyloglossia [Israel and Johnson, 19881 does not distinguish dominant and recessive types. Bain et al. [1986] tried to distinguish the dominant and recessive phenotypes in a report of 5 patients, all of whom had what they called “gum” hypertrophy. They emphasized abnormalities of the ribs and vertebrae in the recessive forms, but these features as well as roentgenographic changes in the bones of the forearm [Robinow and Markert, 19881, which were not observed in our patient, do not appear to discriminate. In fact in the 3 autosomal dominant patients they reported there was no shortness of the limbs a t all. Clearly there is considerable heterogeneity among patients with fetalappearing faces. Intelligence is usually normal [Butler and Waldington, 19871,but mental retardation has pre-
Arias IM, Gartner LM, Cohen M, Ben Ezzer J , Levi AJ (1969):Chronic hemolytic unconjugated hyperbilirubinemia with glucuronyltransferase-deficiency. Clinical, biochemical and genetic evidence. Am J Med 47:395-409. Bain MD, Winter RM, Burn J (1986):Robinow syndrome without mesomelic ‘brachymelia’: A report of five cases. J Med Genet 23:350-354. Bloomer JR, Sharp HL (1984): The liver in Crigler-Najjar syndrome, protoporphyria and other metabolic diseases. Hepatology [Suppll 4:18S-21S. Butler MG, Wadlington WB (1987): Robinow syndrome: Report of two patients and review of literature. Clin Genet 31:77-85. Crigler J, Jr., Najjar V (1952):Congenital familial nonhemolytic jaundice with kernicterus. Pediatrics 10:169-180. Israel H, Johnson GF (1988): Craniofacial pattern similarities and additional orofacial findings in siblings with the Robinow syndrome. J Craniofac Genet Dev Biol 8:63-73. Jones KL (1988): Robinow syndrome (fetal face syndrome). In Smith DW, Jones KL (eds): “Smiths Recognizable Patterns of Human Malformation,” 4th Ed. Philadelphia: WB Saunders Co., pp 112-113.
Robinow M, Markert R J (1988): The fetal face (Robinow) syndrome: Delineation of the dominant and recessive phenotypes. Proc Greenwood Genet Ctr 7:144. Vera-Roman JM (1973): Robinow dwarfing syndrome accompanied by penile agenesis and hemivertebrae. Am J Dis Child 126:206-208. Wadlington WB, Tucker VL, Schimke R (1973):Mesomelic dwarfism with hemivertebrae and small genitalia (the Robinow syndrome). Am J Dis Child 126:202-205.
