American Journal of Medical Genetics 41:275-278 (1991)
Association of the Robin Sequence With the Fragile X Syndrome Ave M. Lachiewicz, Stanton F. Hoegerman, Gosta Holmgren, Eva Holmberg, and Kristian Arinbjarnarson Child Development Unit, Duke University Medical Center, Durham, North Carolina (A.M.L.),Biology Department, College of William and Mary, Williamsburg, Virginia and Genetics Program, Eastern Virginia Medical School, Norfolk, Virginia (SP.H.), Department of Clinical Genetics, University Hospital, Umed, Sweden (G.H., E.H.), Department of Pediatrics, Skellefted, Sweden (K.A.)
We report on 4 individuals with the fragile X [fra(X)Isyndrome and the Robin sequence (or elements of that sequence).To our knowledge, this association has been described in only one other boy. However, males with the fra(X) syndrome have been reported to have an increased incidence of cleft palate. We recommend that children with a cleft palate or the Robin sequence be assessed for developmental delays and a family history of mental retardation. The fra(X)syndrome may be one of the genetic causes of the Robin sequence and, when indicated, children with the sequence should be tested for fra(X). KEY WORDS: cleft palate, micrognathia, glossoptosis INTRODUCTION Individuals with the fra(X) syndrome are thought to have a connective tissue dysplasia and hypotonia [Opitz et al., 1984;Hagerman, 19871. These abnormalities may cause many of the physical manifestations, including enlarged protuberant ears, an abnormally shaped palate, hyperextensible joints, mitral valve prolapse, and flat feet, seen in individuals with the fra(X) syndrome. Individuals with the syndrome have also been reported to have a high incidence of cleft palate [Partington, 19841.In our work with over 100 individuals with fra(X) syndrome, we have records on 4 individuals with the syndrome and a cleft palate. Three were reported to have the Robin sequence, while the fourth was described as having elements of the Robin sequence. To our knowledge this association has been reported previously in only one other child [Hagerman, 19871.
The Robin sequence has an estimated incidence of 1/8,850 live births [Shefield et al., 19871 and is characterized by micrognathia and glossoptosis with or without cleft palate. In most cases of the Robin sequence, the primary defect is thought to be secondary to hypoplasia of the mandible [Cohen, 1976;Jones, 19881. This causes the tongue to be posteriorly placed, and results in impairment of normal palate formation. The Robin sequence is associated with numerous genetic conditions, including at least 10 monogenic syndromes, trisomy 18, and partial trisomy l l q [Shefield et al., 1987; Cohen, 19851. It is frequently associated with other anomalies, but a diagnosis of underlying cause is not always made. The Robin sequence is often reported in individuals without associated physical abnormalities, but these otherwise apparently normal individuals may comprise less than half of the total cases [Cohen, 19791. Since corrective surgery for the Robin sequence may be performed early in life, the observation of developmental delay or mental retardation may not be made at the time of surgery.
CLINICAL REPORTS Patient 1
P.W. (Fig. 1)was the 3710 g product of a term pregnancy. At birth, he had “a high palate with a midline cleft of the soft palate and most of the hard palate.” The tongue was displaced posteriorly, filling the pharynx. Roentgenograms also showed hypoplasia of the maxilla. At age 3 days, the tongue was sutured to the lower lip because of respiratory distress. At age 8 months, the cleft palate was repaired. According to the history, the infant was hypotonic. Other medical problems included one generalized seizure during infancy and frequent ear infections. At age 31 years, the patient lives at home, is healthy, attends a sheltered workshop, and generally functions in the moderately retarded range. He has macroorchidism and pectus excavatum; 12% of his cells express Received for publication September 8, 1989; revision accepted fra(X). His sister and her two daughters also express the December 24, 1990. Address reprint requests to Stanton F. Hoegerman, Department fragile site, but his mother does not. There are no afof Biology, College of William and Mary, Williamsburg, VA 23185. fected male relatives.
0 1991 Wiley-Liss, Inc.
276
Lachiewicz et al. At age 10 years, A.R., as well as 7 male relatives including 3 first cousins, was diagnosed as having the fra(X) syndrome. His maternal grandfather is thought to be a nonpenetrant male; 23% of A X ’ S cells expressed the fragile X chromosome.
Fig. 1. Patient 1as a child and in adulthood. Note early hypotonia
Patient 2 A.R. was the 4160 g product of a term pregnancy. At birth, he was diagnosed as having the Robin sequence with micrognathia, glossoptosis,and cleft palate. On the second day of life, the tongue tip was stitched to the lower lip. At age 4 months, a gastrostomy tube was inserted for a 3-month period because of feeding difficulties and poor weight gain. Other medical problems included an inguinal hernia and frequent ear infections. At age 22 months, the cleft palate was repaired and myringotomy tubes were placed. The palate was described as having an incomplete median cleft involving the soft palate and extending for a short distance into the hard palate area. The cleft was reported to be 4 mm a t the widest. The postoperative period was complicated by a generalized seizure which was treated with diphenylhydantoin. After surgery, A.R. continued to have frequent episodes of otitis media requiring repeated placements of myringotomy tubes. During early childhood, developmental delay was suspected and numerous multidisciplinary evaluations were performed. I& scores declined from 97 on the Stanford Binet a t 32/12 years, to a full scale I& score of 66 on the Wechsler Intelligence Scale for Children-Revised a t 8 V 2 years. At almost 9 years, a speech and language evaluation showed borderline normal language functioning with a wide scatter of skills. Tongue functioning was described as slow and labored with a restricted range of movement. An occupational therapy evaluation documented a 2 to 3112 year delay in acquisition of fine motor skills. Academic skills were at the first grade level, with the exception of general information, which was at the second grade level. Behavior was described as restless, impulsive, and distractible. On physical examination he had an enlarged head (56 cm, >98th centile) and a prominent forehead. Height and weight were a t the 50th centile. Ears were described as well formed. Crowdingof the lower teeth and drooling were reported. Testicles were descended and described as normal in appearance. He also had hypotonia.
Patient 3 F.F. (Fig. 2) was the 3300 g product of a 36-week gestation. At birth, he was described as having the Robin sequence with micrognathia, glossoptosis, and a 3 cm long V-shaped median cleft of his soft palate. He also had bilateral preauricular fistulas. Cleft palate and micrognathia was present in a first cousin of the mother on her maternal side and in the father’s maternal aunt. Neither of these relatives was reported to be mentally retarded. This boy is developmentally delayed, has autistic-like behavior, and was diagnosed as having the fra(X) syndrome a t age 3 years. The fragile site was seen in 8% of peripheral lymphocytes. Patient 4 S.M. (Fig. 3) was the 4560 g product of a 41 week gestation. At birth, he had mild micrognathia and a cleft of the soft palate. He had frequent ear infections and myringotomy tubes were placed at age 5 months and again at 14 months. A V-Ypushback palatoplasty was done at age 17 months to repair the cleft palate. The patient’s airway obstructed immediately post-extubation, requiring emergency reintubation for 7 days. Following surgery, he had persistent serous otitis media and required a third set of myringotomy tubes. S.M. was diagnosed as having the fra(X) syndrome at
Fig. 2. Facial appearance of patient 3
Fig. 3. Appearance of patient 4
Robin Sequence and Fragile X
277
14 months, when he and his 2-year-old brother, who is and a cleft palate. F’roster-Iskenius [personal communiautistic and who also has fra(X),received a genetic eval- cation] has also described one male with the fra(X) synuation; 12% of S.M.’s cells showed the fragile site. A drome, a submucous cleft palate, a small tongue, and a younger sister also has developmental delays and is small chin, but the specific diagnosis of the Robin sefra(X) positive. Two of the mother’s sister’s daughters quence had never been made. In our experience, the and one of the mother’s male cousins also have been palate of children with the fra(X) syndrome often apdiagnosed as having fra(X). A maternal second cousin pears to be highly arched or the alveolar ridges may appear broad (Fig. 5). Generally, the tongue and chin has a cleft palate but is not thought to have fra(X). At age 6 years, S.M. has hand-flapping and hand- appear normal. We have also seen one man with an biting with a callus on the right index finger. He makes isolated cleft lip. In one control study of adolescents and poor eye contact, has a short attention span, and is im- adults, abnormal palate dimensions were not found to be pulsive. He has mild tactile defensiveness. His height, a significant manifestation of the fra(X) syndrome weight, and head circumference are at approximately [Shellhart et al., 19861. There are probably several pathological mechanisms the 50th centile. His left ear is between the 25th and 50th centile in length, and his right ear is at the 50th that result in the Robin sequence [Hanson and Smith, centile. The architecture of the ears is normal. The cleft 1975; Cohen, 1976,1979; Carey et al., 19821. A common palate is repaired except for a small fistula (Fig. 4). mechanism may be primary hypoplasia of the mandible Testes measure 2-3 cm using orchidometer beads. which causes the tongue to be posteriorly placed and Joints are hyperextensible at the elbows, and he has flat prevents closure of the posterior palatal shelves [Jones, feet. 19881.This mechanism is generally thought to result in On the Stanford-Binet Intelligence Scale, Form L-M, a U-shaped cleft palate [Hanson and Smith, 19751.None S.M. obtained an I& estimate of less than 52. He has of our patients was described as having a U-shaped cleft mild oral-motor incoordination and his speech is im- palate. Nonetheless, we cannot rule this out since we did paired from the effects of the cleft palate and fra(X) not evaluate these patients at birth. Another important syndrome. primary mechanism may be decreased tongue movements in early fetal development [Carey et al., 19821. DISCUSSION This mechanism may be causal in the fra(X) syndrome The clinical manifestations of these patients sug- since most males with fra(X) have hypotonia and could gested that at least 3 of the 4 patients had the Robin well have decreased tongue movement in utero. We sequence. Patient 4 is similarly affected, but may not think that the combination of hypotonia with decreased have had glossoptosis, which is usually present in the tongue movements and a connective tissue dysplasia Robin sequence. In patients 1 and 2 the tongue was may cause the whole spectrum of palate abnormalities sutured to the lower lip. Patient 3 was reported t o have with micrognathia and glossoptosis seen in fra(X) boys. had clinical glossoptosis. There was no information re- In our experience, individuals with the fra(X) syndrome corded on the size or position of the tongue on patient 4. also have difficulty coordinating oral-motor movements Although there is some information in the literature of the tongue. Perhaps not only decreased but also abon palatal abnormalities in individuals with the fra(X) normal tongue movements in utero contribute to an syndrome, the available information is limited and in- abnormally formed palate. consistent. Partington [19841reviewed minor anomalies Males with the Robin sequence are reported usually to found in 61 males with fra(X) syndrome. He reported have catch up growth of the chin [Jones, 19881.This was that 5 had a history of cleft palate, 7 had a highly arched true of the males in this series and, consistent with a palate, and one had no uvula. Hagerman [19871 de- common finding in the fra(X) syndrome, some even scribed a boy with both the fra(X) syndrome and the seemed to have overgrowth of the mandible (Fig. 1).Two Robin sequence. This child was also reported to have had of our patients (3 and 4) had a family history of cleft a small tumor under his tongue which, it was specu- palate, but neither of the relatives with clefts were diaglated, could have caused a posteriorly displaced tongue nosed as having fra(X). Thus, patients 3 and 4 may have had predisposing genetic mechanisms in addition to fra(X), that led to cleft palates.
Fig. 4. The palate of patient 4 approximately 5 years after repair
Fig. 5. An example of the high-arched palate seen in the fra(X) syndrome
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Lachiewicz et al.
We cannot entirely discount the possibility that the ACKNOWLEDGMENTS concurrence of the fra(X) syndrome and the Robin seThis work was aided by grants from the March of quence in these patients was a chance event. If we accept Dimes Birth Defects Foundation, Social and Behavioral the estimate of Sheffield et al. [1987] of 1/8,850 as the Sciences grant #12-195, the Virginia Academy of Scifrequency of the Robin sequence and that of Webb et al., ence, the Sataholm Foundation, and the Swedish Medi[19861 of 1 4 3 6 0 as the frequency of the fra(X) syndrome cal Research Council (Project No 19X-05445).We thank in males, we would expect, by chance, a joint frequency Dr. David Bixler for providing clinical information on of 1/12,036,000, which would be roughly equal to 10 patient 4. such cases in the United States (US). To date, 3 or 4 US REFERENCES cases are known to us (the case of Hagerman [19871 and cases 1,2, and, perhaps, 4 of this study). It is our subjec- Carey JC, Fineman RM, Ziter FA (1982):The Robin sequence as a consequence of malformation, dysplasia, and neuromuscular syntive opinion that the fra(X) syndrome is underdiagnosed dromes. J Pediatr 101:858-864. in the US and that a diagnosis of “Robin syndrome” may Cohen MM (1976):The Robin anomalad-Its nonspecificity and associpreclude a search for the underlying cause of developated syndromes. J Oral Surg 34587-593. mental delay. If this argument is correct and if there Cohen MM (1979):Cleft palate, micrognathia, and glossoptosis. In actually were only 10 such cases in the US, it would be Bergsma B (ed): “Birth Defects Compendium,” 2nd ed. New York Alan R. Liss, Inc., p 228. unlikely that 3 or 4 of them would have come to our attention. Cohen MM (1985):Dysmorphic growth and development and the study of craniofacial syndromes. J Craniofac Genet and Dev Bio S1:43-55. Patient 3, from Sweden, may well represent a chance Hagerman R J (1987):Fragile X syndrome. Curr Prob Pediatr 17:621association. The family history, with an individual on 674. both sides of the family affected with a cleft palate, JW, Smith DW (1975):U-shaped palatal defect in the Robin suggests the possibility of autosomal recessive or poly- Hanson anomaly: Developmental and clinical relevance. J Pediatr 87:30genic inheritance of the Robin sequence. Also, the possi33. bility of an autosomal dominant with incomplete pene- Jones KL (1988):“Smith’s RecognizablePatterns of Human Malformation,” 4th ed. Philadelphia: W.B. Saunders, pp 196-197. trance and variable expressivity cannot be discounted. In summary, we conclude that an abnormally shaped Opitz JM, Westphal JM, Daniel A (1984).Discovery of a connective tissue dysplasia in the Martin-Bell syndrome. Am J Med Genet palate, cleft palate, and the Robin sequence may all be 17:lOl-109. clinically associated with the fra(X) syndrome. ConPartington MW (1984):The fragile X syndrome 11: Preliminary data on versely, it may be that fra(X) syndrome will be found to growth and development in males. Am J Med Genet 17:175-194. be one of the many significant causes of Robin sequence Sheffield U,h i s s JA, Strohm K, Gilding M (1987):A genetic follow-up and cleft palate. We recommend that individuals with study of 64patients with the Pierre Robin complex. Am J Med Genet 28:25-36. the Robin sequence or a cleft palate be assessed for a family history of mental retardation, for developmental Shellhart WC, Casamassimo PS, Hagerman RJ,Belanger GK (1986): Oral findings in the fragile X syndrome. Am J Med Genet 23:179delay, and for manifestations of the fra(X) syndrome. 187. The fra(X) syndrome should be included in the differenWebb TP, Bundey SE, Thake AI, Todd J (1986):Population incidence tial diagnosis of both the Robin sequence and isolated and segregation ratios in the Martin-Bell syndrome. Am J Med cleft palate. Genet 23573-580.
Association of the Robin Sequence With the Fragile X Syndrome Ave M. Lachiewicz, Stanton F. Hoegerman, Gosta Holmgren, Eva Holmberg, and Kristian Arinbjarnarson Child Development Unit, Duke University Medical Center, Durham, North Carolina (A.M.L.),Biology Department, College of William and Mary, Williamsburg, Virginia and Genetics Program, Eastern Virginia Medical School, Norfolk, Virginia (SP.H.), Department of Clinical Genetics, University Hospital, Umed, Sweden (G.H., E.H.), Department of Pediatrics, Skellefted, Sweden (K.A.)
We report on 4 individuals with the fragile X [fra(X)Isyndrome and the Robin sequence (or elements of that sequence).To our knowledge, this association has been described in only one other boy. However, males with the fra(X) syndrome have been reported to have an increased incidence of cleft palate. We recommend that children with a cleft palate or the Robin sequence be assessed for developmental delays and a family history of mental retardation. The fra(X)syndrome may be one of the genetic causes of the Robin sequence and, when indicated, children with the sequence should be tested for fra(X). KEY WORDS: cleft palate, micrognathia, glossoptosis INTRODUCTION Individuals with the fra(X) syndrome are thought to have a connective tissue dysplasia and hypotonia [Opitz et al., 1984;Hagerman, 19871. These abnormalities may cause many of the physical manifestations, including enlarged protuberant ears, an abnormally shaped palate, hyperextensible joints, mitral valve prolapse, and flat feet, seen in individuals with the fra(X) syndrome. Individuals with the syndrome have also been reported to have a high incidence of cleft palate [Partington, 19841.In our work with over 100 individuals with fra(X) syndrome, we have records on 4 individuals with the syndrome and a cleft palate. Three were reported to have the Robin sequence, while the fourth was described as having elements of the Robin sequence. To our knowledge this association has been reported previously in only one other child [Hagerman, 19871.
The Robin sequence has an estimated incidence of 1/8,850 live births [Shefield et al., 19871 and is characterized by micrognathia and glossoptosis with or without cleft palate. In most cases of the Robin sequence, the primary defect is thought to be secondary to hypoplasia of the mandible [Cohen, 1976;Jones, 19881. This causes the tongue to be posteriorly placed, and results in impairment of normal palate formation. The Robin sequence is associated with numerous genetic conditions, including at least 10 monogenic syndromes, trisomy 18, and partial trisomy l l q [Shefield et al., 1987; Cohen, 19851. It is frequently associated with other anomalies, but a diagnosis of underlying cause is not always made. The Robin sequence is often reported in individuals without associated physical abnormalities, but these otherwise apparently normal individuals may comprise less than half of the total cases [Cohen, 19791. Since corrective surgery for the Robin sequence may be performed early in life, the observation of developmental delay or mental retardation may not be made at the time of surgery.
CLINICAL REPORTS Patient 1
P.W. (Fig. 1)was the 3710 g product of a term pregnancy. At birth, he had “a high palate with a midline cleft of the soft palate and most of the hard palate.” The tongue was displaced posteriorly, filling the pharynx. Roentgenograms also showed hypoplasia of the maxilla. At age 3 days, the tongue was sutured to the lower lip because of respiratory distress. At age 8 months, the cleft palate was repaired. According to the history, the infant was hypotonic. Other medical problems included one generalized seizure during infancy and frequent ear infections. At age 31 years, the patient lives at home, is healthy, attends a sheltered workshop, and generally functions in the moderately retarded range. He has macroorchidism and pectus excavatum; 12% of his cells express Received for publication September 8, 1989; revision accepted fra(X). His sister and her two daughters also express the December 24, 1990. Address reprint requests to Stanton F. Hoegerman, Department fragile site, but his mother does not. There are no afof Biology, College of William and Mary, Williamsburg, VA 23185. fected male relatives.
0 1991 Wiley-Liss, Inc.
276
Lachiewicz et al. At age 10 years, A.R., as well as 7 male relatives including 3 first cousins, was diagnosed as having the fra(X) syndrome. His maternal grandfather is thought to be a nonpenetrant male; 23% of A X ’ S cells expressed the fragile X chromosome.
Fig. 1. Patient 1as a child and in adulthood. Note early hypotonia
Patient 2 A.R. was the 4160 g product of a term pregnancy. At birth, he was diagnosed as having the Robin sequence with micrognathia, glossoptosis,and cleft palate. On the second day of life, the tongue tip was stitched to the lower lip. At age 4 months, a gastrostomy tube was inserted for a 3-month period because of feeding difficulties and poor weight gain. Other medical problems included an inguinal hernia and frequent ear infections. At age 22 months, the cleft palate was repaired and myringotomy tubes were placed. The palate was described as having an incomplete median cleft involving the soft palate and extending for a short distance into the hard palate area. The cleft was reported to be 4 mm a t the widest. The postoperative period was complicated by a generalized seizure which was treated with diphenylhydantoin. After surgery, A.R. continued to have frequent episodes of otitis media requiring repeated placements of myringotomy tubes. During early childhood, developmental delay was suspected and numerous multidisciplinary evaluations were performed. I& scores declined from 97 on the Stanford Binet a t 32/12 years, to a full scale I& score of 66 on the Wechsler Intelligence Scale for Children-Revised a t 8 V 2 years. At almost 9 years, a speech and language evaluation showed borderline normal language functioning with a wide scatter of skills. Tongue functioning was described as slow and labored with a restricted range of movement. An occupational therapy evaluation documented a 2 to 3112 year delay in acquisition of fine motor skills. Academic skills were at the first grade level, with the exception of general information, which was at the second grade level. Behavior was described as restless, impulsive, and distractible. On physical examination he had an enlarged head (56 cm, >98th centile) and a prominent forehead. Height and weight were a t the 50th centile. Ears were described as well formed. Crowdingof the lower teeth and drooling were reported. Testicles were descended and described as normal in appearance. He also had hypotonia.
Patient 3 F.F. (Fig. 2) was the 3300 g product of a 36-week gestation. At birth, he was described as having the Robin sequence with micrognathia, glossoptosis, and a 3 cm long V-shaped median cleft of his soft palate. He also had bilateral preauricular fistulas. Cleft palate and micrognathia was present in a first cousin of the mother on her maternal side and in the father’s maternal aunt. Neither of these relatives was reported to be mentally retarded. This boy is developmentally delayed, has autistic-like behavior, and was diagnosed as having the fra(X) syndrome a t age 3 years. The fragile site was seen in 8% of peripheral lymphocytes. Patient 4 S.M. (Fig. 3) was the 4560 g product of a 41 week gestation. At birth, he had mild micrognathia and a cleft of the soft palate. He had frequent ear infections and myringotomy tubes were placed at age 5 months and again at 14 months. A V-Ypushback palatoplasty was done at age 17 months to repair the cleft palate. The patient’s airway obstructed immediately post-extubation, requiring emergency reintubation for 7 days. Following surgery, he had persistent serous otitis media and required a third set of myringotomy tubes. S.M. was diagnosed as having the fra(X) syndrome at
Fig. 2. Facial appearance of patient 3
Fig. 3. Appearance of patient 4
Robin Sequence and Fragile X
277
14 months, when he and his 2-year-old brother, who is and a cleft palate. F’roster-Iskenius [personal communiautistic and who also has fra(X),received a genetic eval- cation] has also described one male with the fra(X) synuation; 12% of S.M.’s cells showed the fragile site. A drome, a submucous cleft palate, a small tongue, and a younger sister also has developmental delays and is small chin, but the specific diagnosis of the Robin sefra(X) positive. Two of the mother’s sister’s daughters quence had never been made. In our experience, the and one of the mother’s male cousins also have been palate of children with the fra(X) syndrome often apdiagnosed as having fra(X). A maternal second cousin pears to be highly arched or the alveolar ridges may appear broad (Fig. 5). Generally, the tongue and chin has a cleft palate but is not thought to have fra(X). At age 6 years, S.M. has hand-flapping and hand- appear normal. We have also seen one man with an biting with a callus on the right index finger. He makes isolated cleft lip. In one control study of adolescents and poor eye contact, has a short attention span, and is im- adults, abnormal palate dimensions were not found to be pulsive. He has mild tactile defensiveness. His height, a significant manifestation of the fra(X) syndrome weight, and head circumference are at approximately [Shellhart et al., 19861. There are probably several pathological mechanisms the 50th centile. His left ear is between the 25th and 50th centile in length, and his right ear is at the 50th that result in the Robin sequence [Hanson and Smith, centile. The architecture of the ears is normal. The cleft 1975; Cohen, 1976,1979; Carey et al., 19821. A common palate is repaired except for a small fistula (Fig. 4). mechanism may be primary hypoplasia of the mandible Testes measure 2-3 cm using orchidometer beads. which causes the tongue to be posteriorly placed and Joints are hyperextensible at the elbows, and he has flat prevents closure of the posterior palatal shelves [Jones, feet. 19881.This mechanism is generally thought to result in On the Stanford-Binet Intelligence Scale, Form L-M, a U-shaped cleft palate [Hanson and Smith, 19751.None S.M. obtained an I& estimate of less than 52. He has of our patients was described as having a U-shaped cleft mild oral-motor incoordination and his speech is im- palate. Nonetheless, we cannot rule this out since we did paired from the effects of the cleft palate and fra(X) not evaluate these patients at birth. Another important syndrome. primary mechanism may be decreased tongue movements in early fetal development [Carey et al., 19821. DISCUSSION This mechanism may be causal in the fra(X) syndrome The clinical manifestations of these patients sug- since most males with fra(X) have hypotonia and could gested that at least 3 of the 4 patients had the Robin well have decreased tongue movement in utero. We sequence. Patient 4 is similarly affected, but may not think that the combination of hypotonia with decreased have had glossoptosis, which is usually present in the tongue movements and a connective tissue dysplasia Robin sequence. In patients 1 and 2 the tongue was may cause the whole spectrum of palate abnormalities sutured to the lower lip. Patient 3 was reported t o have with micrognathia and glossoptosis seen in fra(X) boys. had clinical glossoptosis. There was no information re- In our experience, individuals with the fra(X) syndrome corded on the size or position of the tongue on patient 4. also have difficulty coordinating oral-motor movements Although there is some information in the literature of the tongue. Perhaps not only decreased but also abon palatal abnormalities in individuals with the fra(X) normal tongue movements in utero contribute to an syndrome, the available information is limited and in- abnormally formed palate. consistent. Partington [19841reviewed minor anomalies Males with the Robin sequence are reported usually to found in 61 males with fra(X) syndrome. He reported have catch up growth of the chin [Jones, 19881.This was that 5 had a history of cleft palate, 7 had a highly arched true of the males in this series and, consistent with a palate, and one had no uvula. Hagerman [19871 de- common finding in the fra(X) syndrome, some even scribed a boy with both the fra(X) syndrome and the seemed to have overgrowth of the mandible (Fig. 1).Two Robin sequence. This child was also reported to have had of our patients (3 and 4) had a family history of cleft a small tumor under his tongue which, it was specu- palate, but neither of the relatives with clefts were diaglated, could have caused a posteriorly displaced tongue nosed as having fra(X). Thus, patients 3 and 4 may have had predisposing genetic mechanisms in addition to fra(X), that led to cleft palates.
Fig. 4. The palate of patient 4 approximately 5 years after repair
Fig. 5. An example of the high-arched palate seen in the fra(X) syndrome
278
Lachiewicz et al.
We cannot entirely discount the possibility that the ACKNOWLEDGMENTS concurrence of the fra(X) syndrome and the Robin seThis work was aided by grants from the March of quence in these patients was a chance event. If we accept Dimes Birth Defects Foundation, Social and Behavioral the estimate of Sheffield et al. [1987] of 1/8,850 as the Sciences grant #12-195, the Virginia Academy of Scifrequency of the Robin sequence and that of Webb et al., ence, the Sataholm Foundation, and the Swedish Medi[19861 of 1 4 3 6 0 as the frequency of the fra(X) syndrome cal Research Council (Project No 19X-05445).We thank in males, we would expect, by chance, a joint frequency Dr. David Bixler for providing clinical information on of 1/12,036,000, which would be roughly equal to 10 patient 4. such cases in the United States (US). To date, 3 or 4 US REFERENCES cases are known to us (the case of Hagerman [19871 and cases 1,2, and, perhaps, 4 of this study). It is our subjec- Carey JC, Fineman RM, Ziter FA (1982):The Robin sequence as a consequence of malformation, dysplasia, and neuromuscular syntive opinion that the fra(X) syndrome is underdiagnosed dromes. J Pediatr 101:858-864. in the US and that a diagnosis of “Robin syndrome” may Cohen MM (1976):The Robin anomalad-Its nonspecificity and associpreclude a search for the underlying cause of developated syndromes. J Oral Surg 34587-593. mental delay. If this argument is correct and if there Cohen MM (1979):Cleft palate, micrognathia, and glossoptosis. In actually were only 10 such cases in the US, it would be Bergsma B (ed): “Birth Defects Compendium,” 2nd ed. New York Alan R. Liss, Inc., p 228. unlikely that 3 or 4 of them would have come to our attention. Cohen MM (1985):Dysmorphic growth and development and the study of craniofacial syndromes. J Craniofac Genet and Dev Bio S1:43-55. Patient 3, from Sweden, may well represent a chance Hagerman R J (1987):Fragile X syndrome. Curr Prob Pediatr 17:621association. The family history, with an individual on 674. both sides of the family affected with a cleft palate, JW, Smith DW (1975):U-shaped palatal defect in the Robin suggests the possibility of autosomal recessive or poly- Hanson anomaly: Developmental and clinical relevance. J Pediatr 87:30genic inheritance of the Robin sequence. Also, the possi33. bility of an autosomal dominant with incomplete pene- Jones KL (1988):“Smith’s RecognizablePatterns of Human Malformation,” 4th ed. Philadelphia: W.B. Saunders, pp 196-197. trance and variable expressivity cannot be discounted. In summary, we conclude that an abnormally shaped Opitz JM, Westphal JM, Daniel A (1984).Discovery of a connective tissue dysplasia in the Martin-Bell syndrome. Am J Med Genet palate, cleft palate, and the Robin sequence may all be 17:lOl-109. clinically associated with the fra(X) syndrome. ConPartington MW (1984):The fragile X syndrome 11: Preliminary data on versely, it may be that fra(X) syndrome will be found to growth and development in males. Am J Med Genet 17:175-194. be one of the many significant causes of Robin sequence Sheffield U,h i s s JA, Strohm K, Gilding M (1987):A genetic follow-up and cleft palate. We recommend that individuals with study of 64patients with the Pierre Robin complex. Am J Med Genet 28:25-36. the Robin sequence or a cleft palate be assessed for a family history of mental retardation, for developmental Shellhart WC, Casamassimo PS, Hagerman RJ,Belanger GK (1986): Oral findings in the fragile X syndrome. Am J Med Genet 23:179delay, and for manifestations of the fra(X) syndrome. 187. The fra(X) syndrome should be included in the differenWebb TP, Bundey SE, Thake AI, Todd J (1986):Population incidence tial diagnosis of both the Robin sequence and isolated and segregation ratios in the Martin-Bell syndrome. Am J Med cleft palate. Genet 23573-580.
