Hydrocephalus with cleft lip and palate : An overlap between midline malformation syndromes
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《美国医学杂志》
Department of Pediatrics, Karadeniz Technical University Faculty of Medicine, Trabzon, Turkey
Abstract
We present a male infant with hydrocephalus, cleft lip/palate, micrognathia, club foot, laryngeal stenosis and ostium secundum type atrial septal defect. The karyotype was 46 XY. The combination of malformations observed overlaps with the characteristic findings of hydrolethalus syndrome, Meckel syndrome, Smith-Lemli-Opitz syndrome and pseudotrisomy 13. We discussed the differential diagnosis of the case.
Keywords: Hydrocephalus; Atrial septal defect; Cleft lip/palate
The Hydrolethalus syndrome (HS), Meckel syndrome (MS), Smith-Lemli-Opitz syndrome (SLOS) and pseudotrisomy 13 are all characterized by malformations of central nervous system and midline structures.[1] In this manuscript, a case with hydrocephalus associated with anomalies of midline structures is reported, which has the combination of the defects considered as diagnostic for each of these syndromes and we discuss the possible reasons for phenotypic overlap between these syndromes.
Case report
A two-hours-old boy, born at 32 weeks' of gestation to a non-consanguineous couple, was admitted to our hospital for multiple congenital anomalies. According to his parents' report, this was the second pregnancy and the first pregnancy was complicated by polyhydramnios noticed at the 28th week of gestation. Autopsy was not carried out at that time but postmortem examination showed a male fetus with macrocephaly, micrognathia, cleft lip/palate and clubfoot.
Prenatal ultrasonography of this newborn also revealed polyhydramnios and hydrocephalus. Birth weight was 3000 g, length was 50 cm and head circumference was 46 cm (>90 p). He had large fontanelles, midline cleft palate/lip, apparently low-set ears, broad nose, hypertelorism, micrognathia, and clubfeet. The testes were descended and bilateral hydroceles were present. Hypospadias was not noted Figure1. Laboratory findings including complete blood count, urinalysis, renal and liver function tests, arterial pH and bicarbonate levels, lactic acid, ammonia (NH 3 ) and thyroid function tests were within the normal limits. Serologic tests for TORCH panel were negative.
The patient had irregular breathing pattern and tracheal intubation was hardly performed because of the laryngeal stenosis. The chest X-ray showed a "bell-shaped" thorax. He died of respiratory insufficiency on the third day of life. Karyotyping revealed 46 XY. At autopsy; in addition to dysmorphic findings, hydrocephalus with hypoplastic corpus callosum and small secundum type atrial septal defect were noted. Microvesicular hepatic steatosis was detected on microscopic examination. The lungs, spleen, thymus, adrenal glands, pancreas, gastrointestinal tract and urinary tract were anatomically and histologically normal.
Discussion
We presented a male infant with multiple congenital malformations involving the central nervous system and midline structures. He had hydrocephalus, hypoplastic corpus callosum, micrognathia, midline cleft lip/palate, wide set eyes, broad nose, low set ears, club foot, laryngeal stenosis and cardiac defect. These findings show considerable overlap between HS, MS, SLOS, and pseudotrisomy 13 table1.
Hydrolethalus syndrome is an autosomal recessive lethal malformation syndrome, which was first discovered during the course of a study of another lethal malformation syndrome, Meckel syndrome, in Finland.[2] It occurs much more frequently in Finnish population than elsewhere in the world and the locus of the syndrome has been mapped to chromosome 11q23-25 in Finnish families.[2],[3] The term hydrolethalus refers to polyhydramnios, hydrocephalus and lethality. Most of the cases are abortuses, and others were the infants with either stillborn or died within a few hours of birth. The most frequent findings are hydrocephalus, micrognathia, midline cleft lip/palate, low-set ears, polydactyly, club feet, anomalous nose, occipital bone defect and congenital heart and lung defects.[4] Many of these anomalies are midline anomalies that are believed to result from disturbed fusion and division during organogenesis.[4] The combination of hydrocephalus, hypoplastic corpus callosum, micrognathia, midline cleft lip/palate, wide set eyes, broad nose, low-set ears, club foot, laryngeal stenosis, bell-shaped thorax and cardiac defect suggested HS, in our case. However, our case did not have a keyhole occipital bone defect and polydactyly as described in most of the neonates with HS.[5],[6] The diagnosis of HS is generally based on clinical findings. It is not clear that whether mildly affected babies with extended survival, as in our case, have really HS. Ammala P et al[7] reported that hydrocephalus, club foot and polyhydroamnios are suggestive for the prenatal diagnosis, even if other malformations are not seen. Indeed, no anomaly is entirely specific for HS, and other midline malformations overlap with it.
Trisomy 13, presence of an extra copy of chromosome 13, is characterized by central nervous system malformations and extracranial anomalies. Holoprosencephaly, microphthalmia, cleft lip/plate, polydactyly and congenital heart defects are the major features. Sometimes chromosomes may be normal if holoprosencephaly occurs as an isolated anomaly. Microdysplasia of the pancreas is the most specific histopathological change in Trisomy 13.[10] Pseudotrisomy 13 is characterized by holoprosencephaly, postaxial polydactyly, midface hypoplasia, cardiac lesions and normal chromosomes.[6],[10] Our case did not have holoprosencephaly and postaxial polydactyly. Karyotype examination was normal and histopatological examination of the pancreas did not reveal microdysplasia.
Meckel syndrome is an autosomal recessive syndrome and lethal in neonatal period similar to HS. These patients have encephalocele, cystic dysplastic kidneys and a history of oligohydroamnios.[8] The presence of hydrocephalus, absence of renal defect and history of polyhydramnios exclude the diagnosis of MS in our patient.
Smith-Lemli-Opitz syndrome is another autosomal recessive syndrome, which is characterized by hydrocephalus, cerebral hypoplasia, cleft palate and cardiac and genital anomalies. The hydrocephalus is internal and the genital anomalies are generally associated with cryptorchidism and hypospadias.[9] The lack of intrauterine growth retardation and genital and visceral anomalies in our case has made the diagnosis of SLOS unlikely.
In 1992, Verloes A and his colleagues classified central nervous system malformations associated with other system anomalies as Cerebro-Acro-Visceral Early lethality (CAVE) multiplex syndrome.[11] However, there is a still problem to make the differential diagnosis of these phenotypically related syndromes. Based on the clinical findings, we consider that our case has clinical features overlapped between HS, MS, SLOS, and pseudotrisomy 13. Many unclassified cases have been published with more or less similar phenotypes. More case analyses are needed to decide whether these are various expressions of a single entity or a new syndrome.
Finally, we want to emphasize that further comprehensive and detailed examinations are needed in newborns associated with hydrocephalus and extracranial anomalies in order to ovoid for the next mid-trimester terminations or stillborns, and subsequent pregnancies must be closely followed-up by ultrasound beginning at 16th week of gestation for the prenatal early diagnosis.
References
1. Verloes A, Ayme S, Gambarelli D, et al . Holoprosencephaly-polydactyly ('pseudotrisomy 13') syndrome: a syndrome with features of hydrolethalus and Smith-Lemli-Opitz syndromes. A collaborative multicentre study . J Med Genet 1991; 28: 297-303.
2. Salonen R, Herva R, Norio R. The hydrolethalus syndrome: delineation of a "new", lethal malformation syndrome based on 28 patients. Clin Genet 1981; 19: 321-330.
3. Visapaa I, Salonen R, Varilo T, Paavola P, Peltonen L. Assignment of the locus for hydrolethalus syndrome to a highly restricted region on 11q23-25. Am J Hum Genet 1999; 65: 1086-1095.
4. Kivela T, Salonen R, Paetau A. Hydrolethalus: a midline malformation syndrome with optic nerve coloboma and hypoplasia. Acta Neuropathol (Berl) 1996; 91: 511-518.
5. Anyane-Yeboa K, Collins M, Kupsky W et al . Hydrolethalus (Salonen-Herva-Norio) syndrome: further clinicopathological delineation. Am J Med Genet 1987; 26: 899-907.
6. Bachman H, Clark RD, Salahi W. Holoprosencephaly and polydactyly: a possible expression of the hydrolethalus syndrome. J Med Genet 1990; 27: 50-52.
7. Ammala P, Salonen R. First-trimester diagnosis of hydrolethalus syndrome. Ultrasound Obstet Gynecol 1995; 5: 60-62.
8. Opitz JM, Howe JJ. The Meckel syndrome (dysencephalia splachnocystica, the Gruber syndrome). Birth Defects Orig Art Ser 1969; 5: 167-179.
9. Lowry RB: Editorial comment: variability in the Smith-Lemli-Opitz syndrome: overlap with the Meckel syndrome. Am J Med Genet 1983; 14: 429-433.
10. Moerman P, Fryns JP, van der Steen K, et al . The pathology of trisomy 13 syndrome. A study of 12 cases. Hum Genet 1988; 80: 349-356.
11. Verloes A, Gillerot Y, Langhendries JP, et al . Variability versus heterogeneity in syndromal hypothalamic hamartoblastoma and related disorders: review and delineation of the cerebro-acro-visceral early lethality (CAVE) multiplex syndrome. Am J Med Genet 1992; 43 : 669-677.(Cakir Murat, Mungan Ilke,)
Abstract
We present a male infant with hydrocephalus, cleft lip/palate, micrognathia, club foot, laryngeal stenosis and ostium secundum type atrial septal defect. The karyotype was 46 XY. The combination of malformations observed overlaps with the characteristic findings of hydrolethalus syndrome, Meckel syndrome, Smith-Lemli-Opitz syndrome and pseudotrisomy 13. We discussed the differential diagnosis of the case.
Keywords: Hydrocephalus; Atrial septal defect; Cleft lip/palate
The Hydrolethalus syndrome (HS), Meckel syndrome (MS), Smith-Lemli-Opitz syndrome (SLOS) and pseudotrisomy 13 are all characterized by malformations of central nervous system and midline structures.[1] In this manuscript, a case with hydrocephalus associated with anomalies of midline structures is reported, which has the combination of the defects considered as diagnostic for each of these syndromes and we discuss the possible reasons for phenotypic overlap between these syndromes.
Case report
A two-hours-old boy, born at 32 weeks' of gestation to a non-consanguineous couple, was admitted to our hospital for multiple congenital anomalies. According to his parents' report, this was the second pregnancy and the first pregnancy was complicated by polyhydramnios noticed at the 28th week of gestation. Autopsy was not carried out at that time but postmortem examination showed a male fetus with macrocephaly, micrognathia, cleft lip/palate and clubfoot.
Prenatal ultrasonography of this newborn also revealed polyhydramnios and hydrocephalus. Birth weight was 3000 g, length was 50 cm and head circumference was 46 cm (>90 p). He had large fontanelles, midline cleft palate/lip, apparently low-set ears, broad nose, hypertelorism, micrognathia, and clubfeet. The testes were descended and bilateral hydroceles were present. Hypospadias was not noted Figure1. Laboratory findings including complete blood count, urinalysis, renal and liver function tests, arterial pH and bicarbonate levels, lactic acid, ammonia (NH 3 ) and thyroid function tests were within the normal limits. Serologic tests for TORCH panel were negative.
The patient had irregular breathing pattern and tracheal intubation was hardly performed because of the laryngeal stenosis. The chest X-ray showed a "bell-shaped" thorax. He died of respiratory insufficiency on the third day of life. Karyotyping revealed 46 XY. At autopsy; in addition to dysmorphic findings, hydrocephalus with hypoplastic corpus callosum and small secundum type atrial septal defect were noted. Microvesicular hepatic steatosis was detected on microscopic examination. The lungs, spleen, thymus, adrenal glands, pancreas, gastrointestinal tract and urinary tract were anatomically and histologically normal.
Discussion
We presented a male infant with multiple congenital malformations involving the central nervous system and midline structures. He had hydrocephalus, hypoplastic corpus callosum, micrognathia, midline cleft lip/palate, wide set eyes, broad nose, low set ears, club foot, laryngeal stenosis and cardiac defect. These findings show considerable overlap between HS, MS, SLOS, and pseudotrisomy 13 table1.
Hydrolethalus syndrome is an autosomal recessive lethal malformation syndrome, which was first discovered during the course of a study of another lethal malformation syndrome, Meckel syndrome, in Finland.[2] It occurs much more frequently in Finnish population than elsewhere in the world and the locus of the syndrome has been mapped to chromosome 11q23-25 in Finnish families.[2],[3] The term hydrolethalus refers to polyhydramnios, hydrocephalus and lethality. Most of the cases are abortuses, and others were the infants with either stillborn or died within a few hours of birth. The most frequent findings are hydrocephalus, micrognathia, midline cleft lip/palate, low-set ears, polydactyly, club feet, anomalous nose, occipital bone defect and congenital heart and lung defects.[4] Many of these anomalies are midline anomalies that are believed to result from disturbed fusion and division during organogenesis.[4] The combination of hydrocephalus, hypoplastic corpus callosum, micrognathia, midline cleft lip/palate, wide set eyes, broad nose, low-set ears, club foot, laryngeal stenosis, bell-shaped thorax and cardiac defect suggested HS, in our case. However, our case did not have a keyhole occipital bone defect and polydactyly as described in most of the neonates with HS.[5],[6] The diagnosis of HS is generally based on clinical findings. It is not clear that whether mildly affected babies with extended survival, as in our case, have really HS. Ammala P et al[7] reported that hydrocephalus, club foot and polyhydroamnios are suggestive for the prenatal diagnosis, even if other malformations are not seen. Indeed, no anomaly is entirely specific for HS, and other midline malformations overlap with it.
Trisomy 13, presence of an extra copy of chromosome 13, is characterized by central nervous system malformations and extracranial anomalies. Holoprosencephaly, microphthalmia, cleft lip/plate, polydactyly and congenital heart defects are the major features. Sometimes chromosomes may be normal if holoprosencephaly occurs as an isolated anomaly. Microdysplasia of the pancreas is the most specific histopathological change in Trisomy 13.[10] Pseudotrisomy 13 is characterized by holoprosencephaly, postaxial polydactyly, midface hypoplasia, cardiac lesions and normal chromosomes.[6],[10] Our case did not have holoprosencephaly and postaxial polydactyly. Karyotype examination was normal and histopatological examination of the pancreas did not reveal microdysplasia.
Meckel syndrome is an autosomal recessive syndrome and lethal in neonatal period similar to HS. These patients have encephalocele, cystic dysplastic kidneys and a history of oligohydroamnios.[8] The presence of hydrocephalus, absence of renal defect and history of polyhydramnios exclude the diagnosis of MS in our patient.
Smith-Lemli-Opitz syndrome is another autosomal recessive syndrome, which is characterized by hydrocephalus, cerebral hypoplasia, cleft palate and cardiac and genital anomalies. The hydrocephalus is internal and the genital anomalies are generally associated with cryptorchidism and hypospadias.[9] The lack of intrauterine growth retardation and genital and visceral anomalies in our case has made the diagnosis of SLOS unlikely.
In 1992, Verloes A and his colleagues classified central nervous system malformations associated with other system anomalies as Cerebro-Acro-Visceral Early lethality (CAVE) multiplex syndrome.[11] However, there is a still problem to make the differential diagnosis of these phenotypically related syndromes. Based on the clinical findings, we consider that our case has clinical features overlapped between HS, MS, SLOS, and pseudotrisomy 13. Many unclassified cases have been published with more or less similar phenotypes. More case analyses are needed to decide whether these are various expressions of a single entity or a new syndrome.
Finally, we want to emphasize that further comprehensive and detailed examinations are needed in newborns associated with hydrocephalus and extracranial anomalies in order to ovoid for the next mid-trimester terminations or stillborns, and subsequent pregnancies must be closely followed-up by ultrasound beginning at 16th week of gestation for the prenatal early diagnosis.
References
1. Verloes A, Ayme S, Gambarelli D, et al . Holoprosencephaly-polydactyly ('pseudotrisomy 13') syndrome: a syndrome with features of hydrolethalus and Smith-Lemli-Opitz syndromes. A collaborative multicentre study . J Med Genet 1991; 28: 297-303.
2. Salonen R, Herva R, Norio R. The hydrolethalus syndrome: delineation of a "new", lethal malformation syndrome based on 28 patients. Clin Genet 1981; 19: 321-330.
3. Visapaa I, Salonen R, Varilo T, Paavola P, Peltonen L. Assignment of the locus for hydrolethalus syndrome to a highly restricted region on 11q23-25. Am J Hum Genet 1999; 65: 1086-1095.
4. Kivela T, Salonen R, Paetau A. Hydrolethalus: a midline malformation syndrome with optic nerve coloboma and hypoplasia. Acta Neuropathol (Berl) 1996; 91: 511-518.
5. Anyane-Yeboa K, Collins M, Kupsky W et al . Hydrolethalus (Salonen-Herva-Norio) syndrome: further clinicopathological delineation. Am J Med Genet 1987; 26: 899-907.
6. Bachman H, Clark RD, Salahi W. Holoprosencephaly and polydactyly: a possible expression of the hydrolethalus syndrome. J Med Genet 1990; 27: 50-52.
7. Ammala P, Salonen R. First-trimester diagnosis of hydrolethalus syndrome. Ultrasound Obstet Gynecol 1995; 5: 60-62.
8. Opitz JM, Howe JJ. The Meckel syndrome (dysencephalia splachnocystica, the Gruber syndrome). Birth Defects Orig Art Ser 1969; 5: 167-179.
9. Lowry RB: Editorial comment: variability in the Smith-Lemli-Opitz syndrome: overlap with the Meckel syndrome. Am J Med Genet 1983; 14: 429-433.
10. Moerman P, Fryns JP, van der Steen K, et al . The pathology of trisomy 13 syndrome. A study of 12 cases. Hum Genet 1988; 80: 349-356.
11. Verloes A, Gillerot Y, Langhendries JP, et al . Variability versus heterogeneity in syndromal hypothalamic hamartoblastoma and related disorders: review and delineation of the cerebro-acro-visceral early lethality (CAVE) multiplex syndrome. Am J Med Genet 1992; 43 : 669-677.(Cakir Murat, Mungan Ilke,)