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Mental retardation plus macrocephaly in a 16-year-old boy
Mental Retardation Plus Macrocephaly in a 16-Year-Old Boy John B. Bodensteiner and Raj D. Sheth The evaluation of mental retardation is a frequent and challenging problem in pediatric neurology. Often clues obtained on history or by physical examination will help to direct the evaluation in the appropriate channel. This 16year-old boy had clinical features which suggested the appropriate diagnostic studies. Copyright 9 1996 by W.B. Saunders Company
E T A R D E D 16-year-old boy (BE),, was A~ rst seen in the pediatric neurologist s office after a consultation request from a local ophthalmologist. The ophthalmologist had seen the boy for severe visual impairment resulting from bilateral cataracts and retinal dystrophy with retinal detachment. She was concerned that there might be an association between the retinal dystrophy and the mental retardation in this child. The referring ophthalmologist also noted striking gaze-induced nystagmus, an old post repair cleft palate, and diabetes mellitus. Although the reason appeared obscure, the patient was also unable to ambulate. The parents believed that the boy was retarded because of an episode of severe cyanosis that occurred while in the hospital as a newborn. Review of the early history revealed that BE was his mother's only child. She had a pregnancy before BE that ended in spontaneous abortion at 3 months gestation and one tubal pregnancy after BE that resulted in a tubal ligation. The pregnancy was uneventful and BE was delived after 39 weeks gestation, weighing 3,693 g with Apgar score of 7 at 1 minute. The mother stated that when the baby was only a few hours of age (when they first brought the child to her) he had an episode of severe cyanosis which she described as follows: "He turned black," I called the nurse, who took him immediately and began "mouth to mouth" and called the doctor. The physician felt the infant was breathing well and did not require further evaluation or treatment. Over the next 12 hours the baby's respirations were somewhat irregular, there were no further changes in color noted. Despite this event, the child was discharged from the nursery after 2 days and had no further events. Described as floppy for the first few years of life, his parents no longer felt he was hypotonic. The cleft palate was repaired in a series of operations between 9 and 14 months of age. He was noted to have cataracts at 1 year and was
followed for these until 10 years of age, when progressive retinal dystrophy was noticed. Several seizures occurred at 1 year of age, for which he had a computed tomography scan and electroencephalogram, both of which were interpreted as normal. He was placed on phenobarbital for 3 years, but he has not had any seizures since the drug was stopped. He developed diabetes mellitus at age 12 and takes two daily doses of insulin with apparently good control. His developmental progress had always been slow, with language development being particularly impaired so that he has no identifiable words and communicates with a variety of vocalizations and gestures. BE had never been toilet-trained or taught to walk, but he was able to support his weight to help in transfer activities. The general review of systems was otherwise unremarkable. EXAMINATION
Physical examination revealed an irritable young man with normal stature (Height, 50th percentile; Weight, 10th percentile), and macrocephaly (FOC 4 SD above the mean for age). The parents had average head circumferences. He was not able to communicate verbally but seemed to have some receptive language. His head appeared large and his ears were deformed by repeated self-inflicated trauma to the pinna. The face moved symmetrically and he was able to swallow without difficulty. His left eye was aphakic and his right eye did not follow a target, but he did reach for a bright flashlight without appendicular dysmetria. He had spontaFrom the Departments of Neurology and Pediatrics, West Virginia University, Robert C. Byrd Health Sciences Center, Morgantown, WV26506-9180. Address reprint requests to John B. Bodensteiner, Departments of Neurology and Pediatrics, West Virginia University, Robert C. Byrd Health Sciences Center, Morgantown, WV 26506-9180. Copyright 9 1996 by WB. Saunders Company 1071-9091/96/0303-000555.00/0
Seminars in Pediatric Neurology, Vol 3, No 3 (September), 1996: pp 177-181
177
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BODENSTEINER AND SHETH
neous lateral nystagmus in his right eye at rest, which was exacerbated by attempted lateral gaze. The right fundus could not be examined. Hearing was grossly intact though his left tympanic membrane was perforated by a drainage tube and his right was red and retracted but intact. Examination of the chest, abdomen and external genitalia were unremarkable and he had a single coffee-colored, tennis ball-sized patch of pigmentation on his right lateral thigh. He had normal strength and no deformities of the extremities. His muscle tone was slightly below the normal range and his reflexes were symmetrically brisk throughout (3 + / 4) with flexor plantar responses. He was able to stand with a broad base and was ataxic in both stance and gait. Detailed sensory examination was not possible, but response to noxious stimulus was appropriate. SUMMARY OF CLINICAL FEATURES
The chief clinical characteristics of this case include: (1) nonprogressive mental retardation with macrocephaly, and without evidence of cortical spinal tract disease (no spasticity, no Babinski responses); (2) evidence of midline cerebellar dysfunction with nystagmus, truncal, and gait ataxia; (3) ocular involvement with retinal dystrophy and cataracts; and (4) diabetes mellitus. Although the parents believed that the cyanotic spell in the newborn period was the cause of the child's mental retardation, there are features that suggest this is not the case. Most children who suffer an hypoxic event severe enough to result in mental retardation have a rather severe encephalopathy and evidence of other organ injury after the event, show failure of the damaged brain to grow normally, and develop marked spasticity (increased tone and reflexes) after the first few months of life. However, this child was macrocephalic, had ataxia, and was hypotonic, not spastic. Furthermore, there was no evidence of encephalopathy following the "cyanotic episode" in the nursery, most clearly documented by the fact that the child was discharged after only 2 days in hospital. Although the cause of BE's mental retardation is obscure at this point, the evidence points to developmental or genetic problems more
than birth injury or any postnatal injury to a previously normal brain. Many investigators have felt that mental retardation alone is sufficient reason to perform a neuroimaging study. However, even with the development of the magnetic resonance imaging (MRI), which increases greatly the number of structural abnormalities of the brain that can be detected, routine imaging of all retarded individuals is a low yield enterprise. 1 Factors which would increase the likelihood of finding an abnormality by neuroimaging include multiple minor somatic anomalies and involvement of other or multiple organ systems. Certainly in patients with abnormalities of head size, an MRI scan is justified. 2 The combination of mental retardation, macrocephaly, hypotonia, and ataxia suggest that neuroimaging is a priority in the evaluation of this child. The possibility that metabolic derangements might be associated with either mental retardation or structural abnormalities of the brain would make at least some metabolic studies appropriate as well. The causes of cataracts, such as Lowe syndrome (with renal tubular acidosis and aminoaciduria), galactosemia, myotonic dystrophy, and so on, may also require some investigation, although the clinical setting eliminates most of these conditions. 3 Infectious causes of cataracts would be hard to identify at this age, but brain imaging might shed some light on this possibility. The significance of the diabetes in the overall picture is not clear at this point, though there are a variety of associations of neurological conditions with diabetes (Freidreich's, myotonic dystrophy, and Wolfram's, for example). Finally, in a child with mental retardation (particularly a male) and a normal or large head, the possibility of chromosomal abnormalities and fragile X syndrome must be considered. Currently DNA testing for the expanding tandem repeats of the fragile X locus is recommended if there is a high degree of suspicion of this diagnosis. High resolution banding chromosome studies should be used to test for other chromosomal anomalies. LABORATORY AND RADIOGRAPHIC EVALUATION
In this case, the urine metabolic screen, organic acid screen, and amino acid screen were
RETARDATION AND MACROCEPHALY
normal. High resolution chromosome banding studies for fragile X syndrome were also normal. The MRI scan revealed several interesting abnormalities (Fig 1) including: (1) absence of
179
the cerebellar vermis (Fig 1A); (2) dilatation of the superior medullary velum (Fig 1D); and (3) irregularity of the lateral ventricular surface (Fig 1B and D).
Fig 1. (A) MR! of the brain, T2-weighted image at the level of the upper medulla and cerebellum. Note the complete absence of the midline cerebellar vermis and the somewhat larger than expected cerebellar hemispheres. (B and C) Tl-weighted and T2-weighted images of the brain at the level of the midbody of the lateral ventricles. Note the irregularity of the lateral wall of the ventricles and the variable thickness of the cortical ribbon in the left (right on the photo) frontal region. (D) Tl-weighted image of the brain in the sagittal plane. Note the dilatation of the upper fourth ventricle (superior medullary velum) and the absence of midline structures of the cerebellum.
180
BODENSTEINER AND SHETH
DISCUSSION
The combination of cerebellar vermal hypoplasia, developmental delay/mental retardation, hypotonia, and nystagmus strongly suggest the diagnosis of Joubert Syndrome. The primary features of this unusual syndrome were first described in four members of a family with unrelated parents in 1969.4 Since the original description of Joubert syndrome, there have been several reports of patients with this condition. 4q2 It has been fairly well established as an autosomal recessive disease. The five diagnostic features of Joubert syndrome are: (1) vermal hypoplasia/aplasia; (2) hypotonia; (3) developmental delay/mental retardation; (4) abnormal eye movements; and (5) abnormal breathing patterns (particularly episodic hyperpnea and apnea in infants). 5 Of these diagnostic features, the first three are seen in all Joubert syndrome patients and at least four of the five are necessary for the diagnosis. This patient had four of these five features and it is possible that the "cyanotic spell" he suffered at birth was a manifestation of the irregular respiratory patterns characteristic of this syndrome. Once the diagnosis of Joubert syndrome was considered, the possibility of consanguinity between the parents of BE was more carefully explored, including review of public birth records, and so on. It was eventually determined that the parents were second cousins in two separate ways, making the genetic relationship equivalent to that of first-degree cousins. Although the presence of consanguinity does not directly result in an autosomal recessive condition such as Joubert syndrome, it does indicate a considerably greater risk of these rare conditions. In some of the reported cases of Joubert syndrome there is hypoplasia of the cerebellar hemispheres as well as the vermis, but in many, as in this patient, the cerebellar hemispheres may actually be larger than normal (D.C. Harwood-Nash, M.B., personal communication, August 1995). The dysplasia of the posterior fossa structures may be the most easily recognized of the neuroimaging features, but there are also usually dysplastic changes in the cerebral hemispheres such as heterotopias, anomalies of the
corpus callosum and gyral anomalies. It is the cerebral dysplasia that results in the mental deficiency in these patients. Approximately two thirds of reported Joubert syndrome patients have retinal dystrophy. Multiple renal cysts also occur in approximately 20% of Joubert syndrome patients. However, renal cysts, only occur in those Joubert syndrome patients with retinal dystrophy. 5 Other features of the Joubert syndrome include selfmutilation, coloboma of the optic nerve and/or retina, encephalocele, polydactyly, tumors of the tongue, and duodenal atresia. 6-12 The differential diagnosis of Joubert syndrome may include other syndromes with polydactyly, though none of these characteristically have vermal aplasia, episodic hyperpnea or abnormal eye movements. The oral-facio-digital syndrome may have tongue nodules, cleft lip and palate, and polydactyly, but it is not associated with hyperpnea, mental retardation or vermal aplasia. The Dandy-Walker malformation is mentioned in this context because it is the prototype of conditions with anomalous development of the cerebellar vermis. DandyWalker malformation is not inherited or associated with eye coloboma or retinal dystrophy and Joubert syndrome is not associated with hydrocephalus or encystment of the fourth ventricle. The Dandy-Walker malformation may include vermal aplasia, encephalocele, and a variety of cerebral dysplastic changes as will Joubert syndrome, though mental retardation is not universal in Dandy-Walker malformations. Other posterior fossa anomalies in the differential include collections of cerebrospinal fluid such as arachnoid cysts and the large cisterna magna. Both may be associated with minor degrees of dysplasia of cerebral structures, though none of the other features of Joubert syndrome are common in either condition. 13 A variety of cerebellar degenerations associated with vermal atrophy/hypoplasia could mimic some of the neuroimaging features of Joubert syndrome, including hereditary ataxia (all patterns of inheritance), Machado-Joseph disease, Ramsay Hunt, olivopontocerebellar degenerations (all patterns of inheritance), ataxiatelangiectasia, Friedreich ataxia, Bassen-Kornz-
RETARDATION AND MACROCEPHALY
181
weig, and other metabolic conditions. However, the clinical presentation of these conditions is usually one of progressive ataxia, most often with other features that distinguish them from Joubert syndrome. Furthermore, none are associated with retinal dystrophy or the peculiar respiratory patterns that are common features of Joubert syndrome. 14 One interesting feature of this patient was his strikingly large head. Macrocephaly has not been identified as a feature of Joubert syndrome, but a review of the literature shows that many of the patients described in sufficient detail to allow determination of head size have had macrocephaly, including two of the patients in the original case report of the condition.4 BE would more properly be called megalencephalic since the macrocephaly is because of overabun-
dant brain growth, not excessive extracerebral tissues. Familial megalencephaly is the most common cause of megalencephaly, though the parents of this patient did not have large heads, and it is unusual to have severe mental retardation in the context of familial megalencephaly.2 Other causes of megalencephaly include some of the neuronal storage diseases and, more commonly, abnormalities of brain development. A final feature of this patient worth comment is the occurrence of diabetes mellitus. No other descriptions of this association occur although diabetes mellitus has been associated with other neurological conditions such as Friedreich ataxia, myotonic dystrophy, and Wolfram syndrome. Nevertheless, the significance of this finding in Joubert syndrome is unclear at this time.
REFERENCES 1. Schaefer GB, Bodensteiner JB: Evaluation of the child with idiopathic mental retardation. Pediatr Clin North Am 4:929-944, 1992 2. Bodensteiner JB, Chung EO: Macrocrania and megalencephaly in the neonate in neonatal neurology. Semin Neurol 13:84-91, 1993 3. Smith's recognizable patterns of human malformation, in Jones KL (ed): Philadelphia, PA, Saunders, 1988, p 721 4. Joubert M, Eisenring J, Robb JP, et al: Familial agenesis of the cerebellar vermis. A syndrome of episodic hyperpnea, abnormal eye movements, ataxia and retardation. Neurology 19:813-815, 1969 5. Saraiva JM, Baraitser M: Joubert syndrome: A review. Am J Med Genet 43:726-731, 1992 6. Boltshauser E, Isler W: Joubert syndrome: Episodic hyperpnea, abnormal eye movements, retardation and ataxia, associated with dysplasia of the cerebellar vermis. Neuropediatrics 8:57-66, 1977 7. Lindhout D, Barth PG, Valk J, et al: The joubert syndrome associated with bilateral chorioretinal coloboma. Eur J Pediatr 134:173-176, 1980 8. Egger J, Bellman MH, Ross EM, et al: Joubert-
Boltshauser syndrome with polydactyly in siblings. J Neurol Neurosurg Psychiatry 45:737-739, 1982 9. Hartmant-van Rijckevorsel G, Aubert-Tulkens G, Moulin D, et al: Le syndrome de Joubert. Etude clinique et anatomopathologique. Hypotheses etiopathogeniques. Rev Neurol (Paris), 12:715-724, 1983 10. Aicardi J, Castello-Branco ME, Roy CL: Le syndrome de Joubert. Apropos de cinq observations. Arch Fr Pediatr 40:625-629, 1983 11. King MD, Dudgeon J, Stephenson JBP: Joubert's syndrome with retinal dysplasia: Neonatal tachypnoea as the clue to a genetic brain-eye malformation. Arch Dis Child 59:709-718, 1984 12. Lambert SR, Kriss A, Gresty M, et al: Joubert syndrome. Arch Ophthalmol 107:709-713, 1989 13. Bodensteiner JB, Gay CT, Marks WA, et al: The macro cisterna magna: A marker for maldevelopment of the brain? Pediatr Neurol 4:284-286, 1988 14. Fenichel GM: Ataxia, in Clinical Pediatric Neurology: A Signs and Symptoms Approach. Philadelphia, PA, Saunders, 2nd ed, 1993, pp 221-245
E T A R D E D 16-year-old boy (BE),, was A~ rst seen in the pediatric neurologist s office after a consultation request from a local ophthalmologist. The ophthalmologist had seen the boy for severe visual impairment resulting from bilateral cataracts and retinal dystrophy with retinal detachment. She was concerned that there might be an association between the retinal dystrophy and the mental retardation in this child. The referring ophthalmologist also noted striking gaze-induced nystagmus, an old post repair cleft palate, and diabetes mellitus. Although the reason appeared obscure, the patient was also unable to ambulate. The parents believed that the boy was retarded because of an episode of severe cyanosis that occurred while in the hospital as a newborn. Review of the early history revealed that BE was his mother's only child. She had a pregnancy before BE that ended in spontaneous abortion at 3 months gestation and one tubal pregnancy after BE that resulted in a tubal ligation. The pregnancy was uneventful and BE was delived after 39 weeks gestation, weighing 3,693 g with Apgar score of 7 at 1 minute. The mother stated that when the baby was only a few hours of age (when they first brought the child to her) he had an episode of severe cyanosis which she described as follows: "He turned black," I called the nurse, who took him immediately and began "mouth to mouth" and called the doctor. The physician felt the infant was breathing well and did not require further evaluation or treatment. Over the next 12 hours the baby's respirations were somewhat irregular, there were no further changes in color noted. Despite this event, the child was discharged from the nursery after 2 days and had no further events. Described as floppy for the first few years of life, his parents no longer felt he was hypotonic. The cleft palate was repaired in a series of operations between 9 and 14 months of age. He was noted to have cataracts at 1 year and was
followed for these until 10 years of age, when progressive retinal dystrophy was noticed. Several seizures occurred at 1 year of age, for which he had a computed tomography scan and electroencephalogram, both of which were interpreted as normal. He was placed on phenobarbital for 3 years, but he has not had any seizures since the drug was stopped. He developed diabetes mellitus at age 12 and takes two daily doses of insulin with apparently good control. His developmental progress had always been slow, with language development being particularly impaired so that he has no identifiable words and communicates with a variety of vocalizations and gestures. BE had never been toilet-trained or taught to walk, but he was able to support his weight to help in transfer activities. The general review of systems was otherwise unremarkable. EXAMINATION
Physical examination revealed an irritable young man with normal stature (Height, 50th percentile; Weight, 10th percentile), and macrocephaly (FOC 4 SD above the mean for age). The parents had average head circumferences. He was not able to communicate verbally but seemed to have some receptive language. His head appeared large and his ears were deformed by repeated self-inflicated trauma to the pinna. The face moved symmetrically and he was able to swallow without difficulty. His left eye was aphakic and his right eye did not follow a target, but he did reach for a bright flashlight without appendicular dysmetria. He had spontaFrom the Departments of Neurology and Pediatrics, West Virginia University, Robert C. Byrd Health Sciences Center, Morgantown, WV26506-9180. Address reprint requests to John B. Bodensteiner, Departments of Neurology and Pediatrics, West Virginia University, Robert C. Byrd Health Sciences Center, Morgantown, WV 26506-9180. Copyright 9 1996 by WB. Saunders Company 1071-9091/96/0303-000555.00/0
Seminars in Pediatric Neurology, Vol 3, No 3 (September), 1996: pp 177-181
177
178
BODENSTEINER AND SHETH
neous lateral nystagmus in his right eye at rest, which was exacerbated by attempted lateral gaze. The right fundus could not be examined. Hearing was grossly intact though his left tympanic membrane was perforated by a drainage tube and his right was red and retracted but intact. Examination of the chest, abdomen and external genitalia were unremarkable and he had a single coffee-colored, tennis ball-sized patch of pigmentation on his right lateral thigh. He had normal strength and no deformities of the extremities. His muscle tone was slightly below the normal range and his reflexes were symmetrically brisk throughout (3 + / 4) with flexor plantar responses. He was able to stand with a broad base and was ataxic in both stance and gait. Detailed sensory examination was not possible, but response to noxious stimulus was appropriate. SUMMARY OF CLINICAL FEATURES
The chief clinical characteristics of this case include: (1) nonprogressive mental retardation with macrocephaly, and without evidence of cortical spinal tract disease (no spasticity, no Babinski responses); (2) evidence of midline cerebellar dysfunction with nystagmus, truncal, and gait ataxia; (3) ocular involvement with retinal dystrophy and cataracts; and (4) diabetes mellitus. Although the parents believed that the cyanotic spell in the newborn period was the cause of the child's mental retardation, there are features that suggest this is not the case. Most children who suffer an hypoxic event severe enough to result in mental retardation have a rather severe encephalopathy and evidence of other organ injury after the event, show failure of the damaged brain to grow normally, and develop marked spasticity (increased tone and reflexes) after the first few months of life. However, this child was macrocephalic, had ataxia, and was hypotonic, not spastic. Furthermore, there was no evidence of encephalopathy following the "cyanotic episode" in the nursery, most clearly documented by the fact that the child was discharged after only 2 days in hospital. Although the cause of BE's mental retardation is obscure at this point, the evidence points to developmental or genetic problems more
than birth injury or any postnatal injury to a previously normal brain. Many investigators have felt that mental retardation alone is sufficient reason to perform a neuroimaging study. However, even with the development of the magnetic resonance imaging (MRI), which increases greatly the number of structural abnormalities of the brain that can be detected, routine imaging of all retarded individuals is a low yield enterprise. 1 Factors which would increase the likelihood of finding an abnormality by neuroimaging include multiple minor somatic anomalies and involvement of other or multiple organ systems. Certainly in patients with abnormalities of head size, an MRI scan is justified. 2 The combination of mental retardation, macrocephaly, hypotonia, and ataxia suggest that neuroimaging is a priority in the evaluation of this child. The possibility that metabolic derangements might be associated with either mental retardation or structural abnormalities of the brain would make at least some metabolic studies appropriate as well. The causes of cataracts, such as Lowe syndrome (with renal tubular acidosis and aminoaciduria), galactosemia, myotonic dystrophy, and so on, may also require some investigation, although the clinical setting eliminates most of these conditions. 3 Infectious causes of cataracts would be hard to identify at this age, but brain imaging might shed some light on this possibility. The significance of the diabetes in the overall picture is not clear at this point, though there are a variety of associations of neurological conditions with diabetes (Freidreich's, myotonic dystrophy, and Wolfram's, for example). Finally, in a child with mental retardation (particularly a male) and a normal or large head, the possibility of chromosomal abnormalities and fragile X syndrome must be considered. Currently DNA testing for the expanding tandem repeats of the fragile X locus is recommended if there is a high degree of suspicion of this diagnosis. High resolution banding chromosome studies should be used to test for other chromosomal anomalies. LABORATORY AND RADIOGRAPHIC EVALUATION
In this case, the urine metabolic screen, organic acid screen, and amino acid screen were
RETARDATION AND MACROCEPHALY
normal. High resolution chromosome banding studies for fragile X syndrome were also normal. The MRI scan revealed several interesting abnormalities (Fig 1) including: (1) absence of
179
the cerebellar vermis (Fig 1A); (2) dilatation of the superior medullary velum (Fig 1D); and (3) irregularity of the lateral ventricular surface (Fig 1B and D).
Fig 1. (A) MR! of the brain, T2-weighted image at the level of the upper medulla and cerebellum. Note the complete absence of the midline cerebellar vermis and the somewhat larger than expected cerebellar hemispheres. (B and C) Tl-weighted and T2-weighted images of the brain at the level of the midbody of the lateral ventricles. Note the irregularity of the lateral wall of the ventricles and the variable thickness of the cortical ribbon in the left (right on the photo) frontal region. (D) Tl-weighted image of the brain in the sagittal plane. Note the dilatation of the upper fourth ventricle (superior medullary velum) and the absence of midline structures of the cerebellum.
180
BODENSTEINER AND SHETH
DISCUSSION
The combination of cerebellar vermal hypoplasia, developmental delay/mental retardation, hypotonia, and nystagmus strongly suggest the diagnosis of Joubert Syndrome. The primary features of this unusual syndrome were first described in four members of a family with unrelated parents in 1969.4 Since the original description of Joubert syndrome, there have been several reports of patients with this condition. 4q2 It has been fairly well established as an autosomal recessive disease. The five diagnostic features of Joubert syndrome are: (1) vermal hypoplasia/aplasia; (2) hypotonia; (3) developmental delay/mental retardation; (4) abnormal eye movements; and (5) abnormal breathing patterns (particularly episodic hyperpnea and apnea in infants). 5 Of these diagnostic features, the first three are seen in all Joubert syndrome patients and at least four of the five are necessary for the diagnosis. This patient had four of these five features and it is possible that the "cyanotic spell" he suffered at birth was a manifestation of the irregular respiratory patterns characteristic of this syndrome. Once the diagnosis of Joubert syndrome was considered, the possibility of consanguinity between the parents of BE was more carefully explored, including review of public birth records, and so on. It was eventually determined that the parents were second cousins in two separate ways, making the genetic relationship equivalent to that of first-degree cousins. Although the presence of consanguinity does not directly result in an autosomal recessive condition such as Joubert syndrome, it does indicate a considerably greater risk of these rare conditions. In some of the reported cases of Joubert syndrome there is hypoplasia of the cerebellar hemispheres as well as the vermis, but in many, as in this patient, the cerebellar hemispheres may actually be larger than normal (D.C. Harwood-Nash, M.B., personal communication, August 1995). The dysplasia of the posterior fossa structures may be the most easily recognized of the neuroimaging features, but there are also usually dysplastic changes in the cerebral hemispheres such as heterotopias, anomalies of the
corpus callosum and gyral anomalies. It is the cerebral dysplasia that results in the mental deficiency in these patients. Approximately two thirds of reported Joubert syndrome patients have retinal dystrophy. Multiple renal cysts also occur in approximately 20% of Joubert syndrome patients. However, renal cysts, only occur in those Joubert syndrome patients with retinal dystrophy. 5 Other features of the Joubert syndrome include selfmutilation, coloboma of the optic nerve and/or retina, encephalocele, polydactyly, tumors of the tongue, and duodenal atresia. 6-12 The differential diagnosis of Joubert syndrome may include other syndromes with polydactyly, though none of these characteristically have vermal aplasia, episodic hyperpnea or abnormal eye movements. The oral-facio-digital syndrome may have tongue nodules, cleft lip and palate, and polydactyly, but it is not associated with hyperpnea, mental retardation or vermal aplasia. The Dandy-Walker malformation is mentioned in this context because it is the prototype of conditions with anomalous development of the cerebellar vermis. DandyWalker malformation is not inherited or associated with eye coloboma or retinal dystrophy and Joubert syndrome is not associated with hydrocephalus or encystment of the fourth ventricle. The Dandy-Walker malformation may include vermal aplasia, encephalocele, and a variety of cerebral dysplastic changes as will Joubert syndrome, though mental retardation is not universal in Dandy-Walker malformations. Other posterior fossa anomalies in the differential include collections of cerebrospinal fluid such as arachnoid cysts and the large cisterna magna. Both may be associated with minor degrees of dysplasia of cerebral structures, though none of the other features of Joubert syndrome are common in either condition. 13 A variety of cerebellar degenerations associated with vermal atrophy/hypoplasia could mimic some of the neuroimaging features of Joubert syndrome, including hereditary ataxia (all patterns of inheritance), Machado-Joseph disease, Ramsay Hunt, olivopontocerebellar degenerations (all patterns of inheritance), ataxiatelangiectasia, Friedreich ataxia, Bassen-Kornz-
RETARDATION AND MACROCEPHALY
181
weig, and other metabolic conditions. However, the clinical presentation of these conditions is usually one of progressive ataxia, most often with other features that distinguish them from Joubert syndrome. Furthermore, none are associated with retinal dystrophy or the peculiar respiratory patterns that are common features of Joubert syndrome. 14 One interesting feature of this patient was his strikingly large head. Macrocephaly has not been identified as a feature of Joubert syndrome, but a review of the literature shows that many of the patients described in sufficient detail to allow determination of head size have had macrocephaly, including two of the patients in the original case report of the condition.4 BE would more properly be called megalencephalic since the macrocephaly is because of overabun-
dant brain growth, not excessive extracerebral tissues. Familial megalencephaly is the most common cause of megalencephaly, though the parents of this patient did not have large heads, and it is unusual to have severe mental retardation in the context of familial megalencephaly.2 Other causes of megalencephaly include some of the neuronal storage diseases and, more commonly, abnormalities of brain development. A final feature of this patient worth comment is the occurrence of diabetes mellitus. No other descriptions of this association occur although diabetes mellitus has been associated with other neurological conditions such as Friedreich ataxia, myotonic dystrophy, and Wolfram syndrome. Nevertheless, the significance of this finding in Joubert syndrome is unclear at this time.
REFERENCES 1. Schaefer GB, Bodensteiner JB: Evaluation of the child with idiopathic mental retardation. Pediatr Clin North Am 4:929-944, 1992 2. Bodensteiner JB, Chung EO: Macrocrania and megalencephaly in the neonate in neonatal neurology. Semin Neurol 13:84-91, 1993 3. Smith's recognizable patterns of human malformation, in Jones KL (ed): Philadelphia, PA, Saunders, 1988, p 721 4. Joubert M, Eisenring J, Robb JP, et al: Familial agenesis of the cerebellar vermis. A syndrome of episodic hyperpnea, abnormal eye movements, ataxia and retardation. Neurology 19:813-815, 1969 5. Saraiva JM, Baraitser M: Joubert syndrome: A review. Am J Med Genet 43:726-731, 1992 6. Boltshauser E, Isler W: Joubert syndrome: Episodic hyperpnea, abnormal eye movements, retardation and ataxia, associated with dysplasia of the cerebellar vermis. Neuropediatrics 8:57-66, 1977 7. Lindhout D, Barth PG, Valk J, et al: The joubert syndrome associated with bilateral chorioretinal coloboma. Eur J Pediatr 134:173-176, 1980 8. Egger J, Bellman MH, Ross EM, et al: Joubert-
Boltshauser syndrome with polydactyly in siblings. J Neurol Neurosurg Psychiatry 45:737-739, 1982 9. Hartmant-van Rijckevorsel G, Aubert-Tulkens G, Moulin D, et al: Le syndrome de Joubert. Etude clinique et anatomopathologique. Hypotheses etiopathogeniques. Rev Neurol (Paris), 12:715-724, 1983 10. Aicardi J, Castello-Branco ME, Roy CL: Le syndrome de Joubert. Apropos de cinq observations. Arch Fr Pediatr 40:625-629, 1983 11. King MD, Dudgeon J, Stephenson JBP: Joubert's syndrome with retinal dysplasia: Neonatal tachypnoea as the clue to a genetic brain-eye malformation. Arch Dis Child 59:709-718, 1984 12. Lambert SR, Kriss A, Gresty M, et al: Joubert syndrome. Arch Ophthalmol 107:709-713, 1989 13. Bodensteiner JB, Gay CT, Marks WA, et al: The macro cisterna magna: A marker for maldevelopment of the brain? Pediatr Neurol 4:284-286, 1988 14. Fenichel GM: Ataxia, in Clinical Pediatric Neurology: A Signs and Symptoms Approach. Philadelphia, PA, Saunders, 2nd ed, 1993, pp 221-245