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Classical Rett syndrome in sisters: variability of clinical expression
Brain & Development 19 (1997) 492–494
Case report
Classical Rett syndrome in sisters: variability of clinical expression Akie Miyamoto*, Michio Yamamoto, Satoru Takahashi, Junichi Oki Department of Pediatrics, Asahikawa Medical College, Asahikawa, Japan Received 16 December 1996; revised version received 18 June 1997; accepted 4 July 1997
Abstract Familial cases of Rett syndrome (RS) are rare. No significant differences have been reported in the clinical courses of concordant monozygotic twins with RS. We present the variability of clinical expression in two Japanese sisters with classic RS. The younger sister, currently 6 years and 6 months old, never stood or walked alone, showed severe spasticity, growth retardation, and microcephaly and developed sleep-wake rhythm disturbance from age 4 years and seizures from age 5 years. The elder, currently 7 years and 9 months old, walked alone and had mild spasticity, no growth retardation, normal sleep-wakefulness rhythm and no seizures. RS is most likely to be transmitted as an X-linked dominant, male-lethal (XDML) disorder, although this is still contested. If RS is an XDML disorder, lyonization may account for variability of expression in the sisters. 1997 Elsevier Science B.V. Keywords: Rett syndrome; Sisters; Female X-linked disease
1. Introduction It has been postulated that Rett syndrome (RS) is an Xlinked dominant, male lethal (XDML) disorder, but this is not confirmed [1]. A few families with two affected females have been reported and this suggests that the inheritance is through the maternal line [2,3]. No significant differences have been reported in the clinical courses of concordant monozygotic twins with RS, and reports of other familial cases are sparse [4–6]. We describe the variability of clinical expression in two sisters with RS.
2. Case report The patients were two Japanese sisters whose pedigree is shown in Fig. 1. The parents were unrelated and there was no relevant family history but their elder brother (III-1) had
* Corresponding author. Department of Pediatrics, Asahikawa Medical College, 4-5-3-11, Nishikagura, Asahikawa 078, Japan. Tel.: +81 166 68 2483; fax: +81 166 66 0595; e-mail: [email protected]
0387-7604/97/$17.00 1997 Elsevier Science B.V. All rights reserved PII S0387-7604 (97 )0 0052-1
anaphylactoid glomerulonephritis. Their clinical course and signs are shown and compared with the diagnostic criteria of RS [7] in Table 1. The karyotype was 46,XX. The results of neuroimaging in these patients have been previously described: magnetic resonance images were normal and single photon emission computed tomography showed hypoperfusion in the cerebellum [8]. The auditory brain stem responses were normal. 2.1. Case 1 (III–3) The patient was born in October 1990, is currently 6 years and 6 months old, and developed almost normally until 8 months old. However, she could stand with support at 18 months when she showed stereotypic ‘hand-wringing’ movements and ceased speaking. The child was referred to us at 22 months old. She showed poor eye contact. Her height was 81 cm (−0.8 SD), weight was 9.6 kg (−1.1 SD), and her head circumference was 45.5 cm (−1.3 SD). She had convergent strabismus and a submucosal cleft palate. She could not stand and walk alone. There was mild hypotonia and hyperreflexia in PTR. The electrœncephalogram (EEG) showed 3–4 Hz, 200 mV theta waves in the occipital areas
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A. Miyamoto et al. / Brain & Development 19 (1997) 492–494
4 years and 3 months. At 5 years and 10 months old she developed seizures, which occurred weekly and are still intractable to treat. 2.2. Case 2 (III-2)
Fig. 1. Pedigree of the family. III-2 is Case 2 (elder sister) and III-3 is Case 1 (younger sister). Arrow indicates the proband.
and no paroxysmal discharge. Subsequently, muscle tone became spastic and her developmental quotient (DQ) declined from 34 at 22 months old to 8 at 5 years old. She developed a severe sleep-wake rhythm disturbance from age
This patient was the elder sister of Case 1. She was born in July 1989, is currently 7 years and 9 months old, and developed almost normally until age 18 months when she ceased speaking. At 34 months of age stereotypic ‘handwringing’ movements were noted. At that time she also showed poor eye contact. Her height was 94.3 cm (−0.2 SD), her weight was 13.5 kg (+0 SD), and her head circumference was 49.6 cm (+0.6 SD). Muscle tone was normal. There was mild hyperreflexia in PTR. The EEG showed 4–7 Hz, 100 mV theta waves in occipital areas and no paroxysmal discharge. Her height stayed within the normal range but head circumference decelerated gradually. Subse-
Table 1 Clinical course and signs Age
Patient 1 (III-3) 6 years 6 months
Patient 2 (III-2) 7 years 9 months
Necessary criteria Apparently normal prenatal and perinatal period Gestational age Birth weight (g) Birth length (cm) Apparently normal psychomotor development throughout the first 6 months Normal head circumference at birth (cm) Deceleration of head growth Head circumference at age 5 years (cm) Loss of acquired purposeful hand skills Development of severely impaired language Stereotypical hand movements Appearance of gait apraxia and truncal apraxia/ataxia
+ 39 weeks 6 days 3300 50.3 + 34.0 ( + 0.4 SD) + 48.0 ( − 1.4 SD) + + 1 year 6 months +
+ 40 weeks 1 day 3190 50.0 + 33.5 ( + 0 SD) + 49.2 ( − 0.8 SD) + + 2 years 10 months +
Supportive criteria Breathing dysfunction EEG abnormalities Seizures Spasticity Peripheral vasomotor disturbances Scoliosis Growth retardation Height at age 5 years (cm) Weight at age 5 years (kg) Hypotrophic small feet
+ + 5 years 10 months Severe + − + 101.3 (−1.2 SD) 12.6 (−2.4 SD) +
− + Never Mild − − − 107.7 (+0.3 SD) 16.2 (−0.5 SD) −
Developmental mile stone First smile Head control Sitting alone Rolling over Crawling Walking
4 months 3 months 8 months 8 months Never Never
3 months 3 months 7 months 7 months Never 12 months
Other observations Strabismus Submucosal cleft palate Sleep disturbance
+ + 4 years 3 months
− − Never
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A. Miyamoto et al. / Brain & Development 19 (1997) 492–494
quently, muscle tone of lower extremities became spastic and her DQ declined from 53 at 3 years of age to 23 at 5 years of age. On examination at age 7 years and 10 months, her sleep-wake rhythm remained normal and she had no seizures.
3. Discussion The history and physical findings of these two sisters satisfied most of the diagnostic criteria of Rett syndrome [7], except for the lack of microcephaly in the elder sister (Table 1). Nomura et al. reported that there were four sets of familial cases out of 211 patients with RS from a nationwide questionnaire study in Japan [9]. The four sets of familial cases were two twins and two sets of sisters (including our cases). Suzuki et al. reported the prevalence of Rett syndrome to be 0.5/10 000 girls in metropolitan Tokyo [10]. As the number of girls born in Japan is about 600 000 a year, the number of the patients with RS aged 0–20 years in Japan is about 600. There are at least four sets of patients from the same family out of 600 patients in Japan. This ratio of less than 1%, is almost the same as in other reports [2,3]. RS is most likely to be transmitted as an XDML, although this is still contested [1]. Detailed documentation of clinical data in familial cases is important for understanding of the genetics. However, there are few studies which describe phenotypical variability of familial cases, except in the case of monozygotic twins. In a set of a maternal aunt and niece [5], the aunt was diagnosed as having a forme fruste of RS and the niece had typical RS. In a mother-daughter pair [6], any difference in the clinical courses was unclear because the daughter was only 2 years and 9 months old. In two sisters [4], the younger had seizures from age 2 months of age and the elder had seizures from age 14 years. Their clinical expression was almost the same except for seizure activity. In our cases, the phenotype of the younger sister (Case 1) was more severe than in the elder
(Case 2). Deterioration of motor and mental development also occurred earlier in the younger sister. Furthermore, seizures and sleep-wake rhythm disturbance developed only in the younger sister. As both sisters were cared for by their mother and they slept in the same room, clinical expression was less influenced by the environment. If RS is an XDML disorder, lyonization may account for variability of expression in the sisters.
Acknowledgements We thank Professor Akimasa Okuno for reviewing of the manuscript.
References [1] Clarke A. Rett syndrome. J Med Genet 1996; 33: 693–699. [2] Zoghbi H. Genetic aspects of Rett syndrome. J Child Neurol 1988; 3: S76–S78. [3] Percy AK. The Rett syndrome: the recent advances in genetic studies in the USA. Brain Dev 1992; 14 (suppl): S104–S105. [4] Haenggeli CA, Moura-Serra J, DeLozier-Blanchet CD. Brief Report: Two sisters with Rett syndrome. J Autism Dev Disord 1990; 20: 129–138. [5] Anvret M, Wahlstrom J, Skogsberg P, Hagberg B. Segregation analysis of the X chromosome in a family with Rett syndrome in two generations. Am J Med Genet 1990; 37: 31–37. [6] Engerstrom IW, Forslund M. Mother and daughter with Rett syndrome. Dev Med Child Neurol 1992; 34: 1022–1025. [7] The Rett syndrome Diagnostic Criteria Work Group. Diagnostic criteria for Rett syndrome. Ann Neurol 1988; 23: 425–428. [8] Miyamoto A, Yamamoto M, Yanagawa J, et al. Rett syndrome: Truncal ataxia and MRI, SPECT findings of cerebellum (in Japanese). No To Hattatsu (Tokyo) 1993; 25: S180. [9] Nomura Y, Takeuchi Y, Simohira M, Kimura K, Segawa M. Rett syndrome–studies on pathophysiology. In: Study on Aetiology and Prevention of Brain Dysplasia. Annual Report of the Project Team, Japan (in Japanese) 1996: 183–187. [10] Suzuki H, Hirayama Y, Arima M. Prevalence of Rett Syndrome in Tokyo. No To Hattatsu 1989; 21: 430–433.
Case report
Classical Rett syndrome in sisters: variability of clinical expression Akie Miyamoto*, Michio Yamamoto, Satoru Takahashi, Junichi Oki Department of Pediatrics, Asahikawa Medical College, Asahikawa, Japan Received 16 December 1996; revised version received 18 June 1997; accepted 4 July 1997
Abstract Familial cases of Rett syndrome (RS) are rare. No significant differences have been reported in the clinical courses of concordant monozygotic twins with RS. We present the variability of clinical expression in two Japanese sisters with classic RS. The younger sister, currently 6 years and 6 months old, never stood or walked alone, showed severe spasticity, growth retardation, and microcephaly and developed sleep-wake rhythm disturbance from age 4 years and seizures from age 5 years. The elder, currently 7 years and 9 months old, walked alone and had mild spasticity, no growth retardation, normal sleep-wakefulness rhythm and no seizures. RS is most likely to be transmitted as an X-linked dominant, male-lethal (XDML) disorder, although this is still contested. If RS is an XDML disorder, lyonization may account for variability of expression in the sisters. 1997 Elsevier Science B.V. Keywords: Rett syndrome; Sisters; Female X-linked disease
1. Introduction It has been postulated that Rett syndrome (RS) is an Xlinked dominant, male lethal (XDML) disorder, but this is not confirmed [1]. A few families with two affected females have been reported and this suggests that the inheritance is through the maternal line [2,3]. No significant differences have been reported in the clinical courses of concordant monozygotic twins with RS, and reports of other familial cases are sparse [4–6]. We describe the variability of clinical expression in two sisters with RS.
2. Case report The patients were two Japanese sisters whose pedigree is shown in Fig. 1. The parents were unrelated and there was no relevant family history but their elder brother (III-1) had
* Corresponding author. Department of Pediatrics, Asahikawa Medical College, 4-5-3-11, Nishikagura, Asahikawa 078, Japan. Tel.: +81 166 68 2483; fax: +81 166 66 0595; e-mail: [email protected]
0387-7604/97/$17.00 1997 Elsevier Science B.V. All rights reserved PII S0387-7604 (97 )0 0052-1
anaphylactoid glomerulonephritis. Their clinical course and signs are shown and compared with the diagnostic criteria of RS [7] in Table 1. The karyotype was 46,XX. The results of neuroimaging in these patients have been previously described: magnetic resonance images were normal and single photon emission computed tomography showed hypoperfusion in the cerebellum [8]. The auditory brain stem responses were normal. 2.1. Case 1 (III–3) The patient was born in October 1990, is currently 6 years and 6 months old, and developed almost normally until 8 months old. However, she could stand with support at 18 months when she showed stereotypic ‘hand-wringing’ movements and ceased speaking. The child was referred to us at 22 months old. She showed poor eye contact. Her height was 81 cm (−0.8 SD), weight was 9.6 kg (−1.1 SD), and her head circumference was 45.5 cm (−1.3 SD). She had convergent strabismus and a submucosal cleft palate. She could not stand and walk alone. There was mild hypotonia and hyperreflexia in PTR. The electrœncephalogram (EEG) showed 3–4 Hz, 200 mV theta waves in the occipital areas
493
A. Miyamoto et al. / Brain & Development 19 (1997) 492–494
4 years and 3 months. At 5 years and 10 months old she developed seizures, which occurred weekly and are still intractable to treat. 2.2. Case 2 (III-2)
Fig. 1. Pedigree of the family. III-2 is Case 2 (elder sister) and III-3 is Case 1 (younger sister). Arrow indicates the proband.
and no paroxysmal discharge. Subsequently, muscle tone became spastic and her developmental quotient (DQ) declined from 34 at 22 months old to 8 at 5 years old. She developed a severe sleep-wake rhythm disturbance from age
This patient was the elder sister of Case 1. She was born in July 1989, is currently 7 years and 9 months old, and developed almost normally until age 18 months when she ceased speaking. At 34 months of age stereotypic ‘handwringing’ movements were noted. At that time she also showed poor eye contact. Her height was 94.3 cm (−0.2 SD), her weight was 13.5 kg (+0 SD), and her head circumference was 49.6 cm (+0.6 SD). Muscle tone was normal. There was mild hyperreflexia in PTR. The EEG showed 4–7 Hz, 100 mV theta waves in occipital areas and no paroxysmal discharge. Her height stayed within the normal range but head circumference decelerated gradually. Subse-
Table 1 Clinical course and signs Age
Patient 1 (III-3) 6 years 6 months
Patient 2 (III-2) 7 years 9 months
Necessary criteria Apparently normal prenatal and perinatal period Gestational age Birth weight (g) Birth length (cm) Apparently normal psychomotor development throughout the first 6 months Normal head circumference at birth (cm) Deceleration of head growth Head circumference at age 5 years (cm) Loss of acquired purposeful hand skills Development of severely impaired language Stereotypical hand movements Appearance of gait apraxia and truncal apraxia/ataxia
+ 39 weeks 6 days 3300 50.3 + 34.0 ( + 0.4 SD) + 48.0 ( − 1.4 SD) + + 1 year 6 months +
+ 40 weeks 1 day 3190 50.0 + 33.5 ( + 0 SD) + 49.2 ( − 0.8 SD) + + 2 years 10 months +
Supportive criteria Breathing dysfunction EEG abnormalities Seizures Spasticity Peripheral vasomotor disturbances Scoliosis Growth retardation Height at age 5 years (cm) Weight at age 5 years (kg) Hypotrophic small feet
+ + 5 years 10 months Severe + − + 101.3 (−1.2 SD) 12.6 (−2.4 SD) +
− + Never Mild − − − 107.7 (+0.3 SD) 16.2 (−0.5 SD) −
Developmental mile stone First smile Head control Sitting alone Rolling over Crawling Walking
4 months 3 months 8 months 8 months Never Never
3 months 3 months 7 months 7 months Never 12 months
Other observations Strabismus Submucosal cleft palate Sleep disturbance
+ + 4 years 3 months
− − Never
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A. Miyamoto et al. / Brain & Development 19 (1997) 492–494
quently, muscle tone of lower extremities became spastic and her DQ declined from 53 at 3 years of age to 23 at 5 years of age. On examination at age 7 years and 10 months, her sleep-wake rhythm remained normal and she had no seizures.
3. Discussion The history and physical findings of these two sisters satisfied most of the diagnostic criteria of Rett syndrome [7], except for the lack of microcephaly in the elder sister (Table 1). Nomura et al. reported that there were four sets of familial cases out of 211 patients with RS from a nationwide questionnaire study in Japan [9]. The four sets of familial cases were two twins and two sets of sisters (including our cases). Suzuki et al. reported the prevalence of Rett syndrome to be 0.5/10 000 girls in metropolitan Tokyo [10]. As the number of girls born in Japan is about 600 000 a year, the number of the patients with RS aged 0–20 years in Japan is about 600. There are at least four sets of patients from the same family out of 600 patients in Japan. This ratio of less than 1%, is almost the same as in other reports [2,3]. RS is most likely to be transmitted as an XDML, although this is still contested [1]. Detailed documentation of clinical data in familial cases is important for understanding of the genetics. However, there are few studies which describe phenotypical variability of familial cases, except in the case of monozygotic twins. In a set of a maternal aunt and niece [5], the aunt was diagnosed as having a forme fruste of RS and the niece had typical RS. In a mother-daughter pair [6], any difference in the clinical courses was unclear because the daughter was only 2 years and 9 months old. In two sisters [4], the younger had seizures from age 2 months of age and the elder had seizures from age 14 years. Their clinical expression was almost the same except for seizure activity. In our cases, the phenotype of the younger sister (Case 1) was more severe than in the elder
(Case 2). Deterioration of motor and mental development also occurred earlier in the younger sister. Furthermore, seizures and sleep-wake rhythm disturbance developed only in the younger sister. As both sisters were cared for by their mother and they slept in the same room, clinical expression was less influenced by the environment. If RS is an XDML disorder, lyonization may account for variability of expression in the sisters.
Acknowledgements We thank Professor Akimasa Okuno for reviewing of the manuscript.
References [1] Clarke A. Rett syndrome. J Med Genet 1996; 33: 693–699. [2] Zoghbi H. Genetic aspects of Rett syndrome. J Child Neurol 1988; 3: S76–S78. [3] Percy AK. The Rett syndrome: the recent advances in genetic studies in the USA. Brain Dev 1992; 14 (suppl): S104–S105. [4] Haenggeli CA, Moura-Serra J, DeLozier-Blanchet CD. Brief Report: Two sisters with Rett syndrome. J Autism Dev Disord 1990; 20: 129–138. [5] Anvret M, Wahlstrom J, Skogsberg P, Hagberg B. Segregation analysis of the X chromosome in a family with Rett syndrome in two generations. Am J Med Genet 1990; 37: 31–37. [6] Engerstrom IW, Forslund M. Mother and daughter with Rett syndrome. Dev Med Child Neurol 1992; 34: 1022–1025. [7] The Rett syndrome Diagnostic Criteria Work Group. Diagnostic criteria for Rett syndrome. Ann Neurol 1988; 23: 425–428. [8] Miyamoto A, Yamamoto M, Yanagawa J, et al. Rett syndrome: Truncal ataxia and MRI, SPECT findings of cerebellum (in Japanese). No To Hattatsu (Tokyo) 1993; 25: S180. [9] Nomura Y, Takeuchi Y, Simohira M, Kimura K, Segawa M. Rett syndrome–studies on pathophysiology. In: Study on Aetiology and Prevention of Brain Dysplasia. Annual Report of the Project Team, Japan (in Japanese) 1996: 183–187. [10] Suzuki H, Hirayama Y, Arima M. Prevalence of Rett Syndrome in Tokyo. No To Hattatsu 1989; 21: 430–433.