American Journal of Medical Genetics 57:620-625 (1995)

Satoyoshi Syndrome: An Unusual Postnatal Multisystemic Disorder

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Mohammad S. Ehlayel and Yves Lacassie Department of Pediatrics (M.S.E., Y.L.) and Center for Molecular and Human Genetics (Y.L.), Louisiana State University Medical Center, and Children’s Hospital (Y.L.), New Orleans, Louisiana

Satoyoshi syndrome is a rare disorder of un- known cause characterized by progressive, painful intermittent muscle spasms, malab- sorption, alopecia, amenorrhea, and skele- tal abnormalities mimicking a skeletal dys- plasia. We describe a 19-year-old Caucasian woman with characteristic manifestations starting at age 9. The report of this patient confirms that this condition is not limited to the Asian population.

KEY WORDS: Satoyoshi syndrome, muscle spasm, alopecia, amenor- rhea, malabsorption, skeletal abnormalities, Caucasian

1995 Wiley-Liss, Inc.

INTRODUCTION Satoyoshi syndrome is a rare disorder of unknown

cause characterized by progressive, painful, intermit- tent muscle spasms, diarrhea or unusual malabsorp- tion, endocrinopathy with amenorrhea, and secondary skeletal abnormalities [Satoyoshi and Yamada, 1967; Satoyoshi, 1978; Ikegawa et al., 1993a,b; Yamagata et al., 19911. Since the first report by Satoyoshi and Yamada [1967] on 2 cases with recurrent spasms, about 27 cases have been reported [Ikegawa et al., 199313; Merello et al., 1994; Aver’ianov et al., 19841. Surpris- ingly, most of them have been reported in Japan. All but 3 patients have been Asian: case 10 in a review of 15 cases [Satoyoshi, 19781 from the United Kmgdom (but no ethnic information was available as the patient was adopted), a Russian patient [Aver’ianov et al., 19841, and an Amerindian male from Argentina [Merello et al., 19941. To the best of our knowledge, our patient is the first Caucasian case ever reported in the

Received for publication September 26, 1994; revision received January 27,1995.

Address reprint requests to Yves Lacassie, M.D., Division of Genetics, Department of Pediatrics, Louisiana State University Medical Center, 1542 Tulane Avenue, New Orleans, LA 70112-2822.

0 1995 Wiley-Liss, Inc.

United States, and probably in the world, confirming that this condition is not limited to the Japanese or Chinese populations [Merello e t al., 19941.

CLINICAL REPORT A 19YL-year-old Caucasian woman was admitted for

diagnostic evaluation of amenorrhea, alopecia, bony de- formities, and short stature. She was born to healthy nonconsanguineous parents. The father is from Louisiana and the mother from Texas. The father was 21 years old and the mother 18 a t the time of birth. The proposita has 2 paternal half-sibs who are healthy. The family history is unremarkable except for the an- tecedent of a paternal second cousin with von Hippel- Lindau syndrome. Prenatal and natal history were unremarkable except for the antecedent of breech pre- sentation. Growth and psychomotor development were normal. At the age of 6 years, when she started school, the patient was considered to be a normal girl. Concern began around age 9y2 years when she started loosing her hair. She noticed progressive loss of scalp hair and eyebrows over a 6-month period (Fig. 1). A few months later, she began to have recurrent and painful cramps in the calves and thighs. They were induced by physi- cal exercise or emotional distress, but not associated with any changes in sensorium. They lasted for a few minutes and on a few occasions the whole day. With time, these cramps became more severe and frequent, involving the whole body musculature, including ab- domen, upper limbs, and the face. Within the last 2 years, she developed problems with swallowing sec- ondary to spasms in the masticatory muscles. Muscle relaxants have not had a favorable effect. Growth re- tardation and progressive skeletal deformities of both knees and wrists, and limitation of movements of the right shoulder became evident after age 10. The defor- mity of both knees caused difficulty in walking. For this reason, she had 5 operations on knees and ankles be- tween the age of 14 and 19 years. In April 1993, the pa- tient sustained a fracture of the right leg with impaired healing. For this reason, an osteotomy of the femur was performed in December 1993, and an electrical bone growth stimulator was placed in March 1994 at another

Satoyoshi Syndrome 621

appearance (Fig. 2e). There were extra finger flexion creases on the left middle and right index fingers. Breast development was normal, but her uterus was hypoplastic; the adnexa were not palpated. Cranial nerves were intact. There were no motor or sensory ab- normalities. Myoclonic jerks were frequent during the examination.

Complete blood count (CBC) was normal as was he- moglobin AX, erythrocyte sedimentation rate (ESR), urinalysis test, serum electrolytes (including serum calcium and phosphorus), serum aldolase, liver func- tion tests, and urine myoglobin. Creatine phospho- kinase was mildly elevated at 241 IU/1 (normal range: 24-235 IU/l). Serum T3, T4, and thyroid-stimulating hormone (TSH), serum cortisol, progesterone, estra- diol, prolactin, somatomedin C, IGF binding protein, and follicle-stimulating hormone (FSH) were normal. Luteinizing hormone (LH) was low (0.18 mIU/ml). Im- munological work-up showed normal levels of serum immunoglobulins (IgM, IgG, and IgA), IgG subclasses, total complement activity, C3 and C4. Autoantibodies, such as antinuclear antibodies (ANA), anticholine es- terase antibodies, antithyroid microsomal antibodies, antithyroglobulin antibodies, anti-intrinsic factor anti- bodies, antireticulin antibodies, and antiovary antibod- ies were absent. Serum IgE was elevated, at 342 IU/ml (normal < 158 IU/ ml). Candida intradermal skin test was nonreactive. Lymphocyte subpopulation study showed decreased natural killer cells (CD56) and ele- vated CD4/CD8 ratio. D-xylose, lactose breath hydro- gen test, 3-day stool fat, and upper gastrointestinal (GI) endoscopy and biopsies were all normal.

Radiological examination demonstrated multiple metaphyseal lesions with striking slipping of epiphyses on proximal humeri and femora, distal radii and ulnae (different from a Madelung deformity), left knee (the right knee was recently operated on), and both ankles (Fig. 3). The skull and spine radiographs were normal. Head computed tomographic (CT) scan was normal. U1- trasonography of the pelvis showed hypoplastic uterus.

With the diagnosis of Satoyoshi syndrome, treatment with prednisone [Yamagata et al., 1991; Kuru et al., 19921 was initiated with a dose of 60 mg/m2 every other day. Muscle spasms improved after 4 weeks and totally disappeared by the 8th week of treatment; hair growth was noticed after 6 weeks of treatment, and 2 episodes of light vaginal bleeding were observed during the first 3 months of treatment.

Fig. 1. a,b: The patient at age of 7% and 9Yu years, respectively. c,d: The patient a t 9 % ~ years with incipient alopecia.

hospital. Between the age of 14 and 15, she underwent normal breast development but had no periods. After age 18, because of primary amenorrhea, her mother provided birth control pills for 4 months during which time the patient had normal cycles. In previous genetic and endocrinological evaluations, a small uterus, non- identifiable ovaries, and low growth hormone levels were reported. A prometaphase chromosomal study was done in 1993 with normal results.

Examination a t age of 19Y~ years showed a n alert, in- telligent woman with normal facial appearance, alo- pecia, and short stature (137 cm, 4 t h centile) with de- creased arm span (128.5 cm) and rhizomesomelic shortness of limbs (Fig. 2a-c). Weight was 43.6 kg (<5th centile) and head circumference 50.5 cm (<2nd centile). She presented marked deformities of wrists with appearance of Madelung deformity (Fig. 2d), lim- itation of movements of the right shoulder, increased lumbar lordosis, minor hip deformity, deformation of knees with slight varus deformity, surgical scars in the legs, and a long cast on the right leg due to the un- healed fracture (Fig. 2b). Fingers presented drumstick

DISCUSSION In spite of the increasing number of cases diagnosed

with Komuragaeri disease [Yamagata et al., 19911 (in Japanese, komura means calf and gaeri means turn over or spasm) or Satoyoshi syndrome, its cause is unknown. All cases have been sporadic even in large families [Satoyoshi, 19781. Its pathogenesis seems to involve an autoimmune mechanism [Yamagata et al., 1991; Kuru et al., 1992; Wang and Fu, 1985; Satoh

622 Ehlayel and Lacassie

Fig. 2. a: The patient a t age of 14 years wearing a wig and showing short stature with short limbs. b, c: Patient at 19 years. d: Wrist deformity. e: Fingers presenting drumstick deformity.

et al., 1982, 19831. The response of the muscular spasms [Samagata et al., 1991; Kuru et al., 19921, amenorrhea, and alopecia to glucocorticoids [Samagata et al., 19911, the association of some cases with myas- thenia gravis [Satoh et al., 1982, 19831, nephritis [Satoyoshi, 19781, idiopathic thrombocytopenia [Sama- gata et al., 19911, and the deposition of immune com- plexes a t the motor end plate of biceps muscle [Satoh et al., 19831, low IgG [Kuru et al., 19921, and positive ANA of speckled pattern [Samagata et al., 19911 fur- ther support this hypothesis [Yamagata et al., 1991; Kuru et al., 19921. However, an extensive immunologi- cal evaluation in our patient did not show any de- tectable autoimmune abnormality. The muscle spasms seem to play a role in the production of skeletal abnor- malities [Ikegawa et al., 1993b1. The spasms have been associated with the presence of diarrhea, raising the possibility that this disease is a variety of malabsorp- tion syndrome [Satoyoshi and Samada, 1967; Sato- yoshi, 1978; Merello et al., 19941. However, in our patient, an extensive GI evaluation ruled out malab- sorption.

Since most patients have been reported in the Japan- ese literature with only a few references in non-Asian

journals, this syndrome is not included in most genet- ics, neurology, and orthopedic references despite its striking anomalies [Jones, 1988; Swaiman, 1989; Tachdjian, 1990; Baraitser and Winter, 19931. Patients with this condition are considered normal a t birth and infancy, The characteristic phenotype usually appears after the first decade of life.

The Phenotype Clinically this syndrome is characterized by:

1. Progressive painful intermittent muscle spasms starting between the ages of 6-15 years with an av- erage age of onset of 10.6 years [Satoyoshi, 19781. However, in the patient recently reported by Merello et al. [1994], the spasms only started at age 36. These intermittent muscle spasms occur while the patient is fully conscious.

2. Alopecia universalis, also appearing around age 10 [Satoyoshi and Samada, 1967; Satoyoshi, 19781.

3. Unusual malabsorption, preferentially of carbohy- drates, with diarrhea evident in approximately 50% of the patients [Satoyoshi and Samada, 1967;

Satoyoshi Syndrome 623

Fig. 3. dysplasia.

Roentgenograms showing the peculiar deformations suggestive of a metaphyseal chondro-

Satoyoshi, 1978; Wang and Fu, 1985; Merello e t al., 19941.

4. Skeletal abnormalities mimicking a metaphyseal chondrodysplasia. Slipping of multiple epiphyses, cystic lesions, acro-osteolysis and osteolysis, bone fragmentation at tendinous insertions, fatigue frac- tures, and early osteoarthrosis have been reported [Ikegawa et al., 1993133. The skeletal abnormalities seem to be secondary to the muscular spasms [Satoyoshi, 1978; Ikegawa et al., 19931.

5. Endocrine disorders, mainly primary amenorrhea with tendency to hypoplastic uterus and ovaries in most women, probably secondary to hypothalamic dysfunction [Satoyoshi and Yamada, 1967; Satoyoshi, 1978; Yamagata et al., 1991; Aver’ianov et al., 19841.

6. Other secondary manifestations. If the muscular spasms start before age 12, deformities and growth retardation become strikingly evident [Satoyoshi, 1978; Ikegawa et al., 1993133. Generalized emacia- tion may occur after several years secondary to feed- ing difficulties due to spasms of the masticatory muscles [Satoyoshi, 1978; Merello et al., 19941. Therapy with several drugs has been unsuccessful [Satoyoshi, 1978; Merello et al., 19941. Recently, the successful response of masticatory muscle spasm to botulinum toxin directly injected in the muscles in-

volved has been reported [Merello et al., 19941. How- ever, the treatment of choice seems to be glucocorti- coids, since not only the spasms but also the alope- cia and amenorrhea improve after a few months [Yamagata et al., 1991; Kuru et al., 19921. The promising response to steroid treatment in our pa- tient confirms the previous reports [Yamagata et al., 1991; Kuru et al., 19921.

Our patient presents most of the cardinal manifesta- tions making the diagnosis unquestionable. Differen- tial diagnoses are presented in Table I. Geneticists, neurologists, endocrinologists, gastroenterologists, or- thopedists, dermatologists, and pediatricians should be aware of this unusual condition, since, although rare, i t probably exists in all different ethnic groups and its early diagnosis and treatment are crucial for the pre- vention of the most striking complications.

ACKNOWLEDGMENTS The authors wish to thank Drs. R. Sanders, S.

Khouri, and J. Rao for the referral, Drs. M.I. Arriaza and M. Burke for their assistance in the evaluation, Ms. L. LeBoeuf, Children’s Hospital librarian, for bibli- ographic research, and Ms. C. McElveen and Ms. P. A. Giangrosso for editing. Supported in part by a grant from Welch’s Corporation.

624 Ehlayel and Lacassie

TABLE I. Differential Diagnosis of Satoyoshi Syndrome A. Muscular spasm 1. Abnormal serum electrolytes [Warlow, 19911: e.g.,

hyponatremia, hypocalcemia (tetany), hypomagnesemia, uremia

2. Hypothyroid myopathy [Warlow, 19911 3 . Hypoparathyroidism 4. Addison’s disease [Warlow, 19911 5. Idiopathic generalized myokymia [Jamieson and Katirji,

19943: Isaac’s syndrome [Fenichel, 19883, stiff-man syndrome [Warlow, 19911, Schwartz-Jampel syndrome [Fenichel, 19881, myokymia of Kny and Schultze

6. Myotonic dystrophy [Josefowicz and Griggs, 19881 7. Disorders of glycogen metabolism of muscle [Servidei and

DiMauro, 19891: e.g., McArdle disease, Tarui’s disease, and phosphorylase b kinase disease

cimetidine, bumetanide, and danazol

chondrodysplasia

8. Drugs [Warlow, 19911: e.g., phenothiazines, salbutamol,

B Progressive short stature and metaphyseal

1. Rickets 2. Renal osteodystrophy [McCarthy and Kumar, 19901 3. Hepatic osteodystrophy [Chesney, 19841 4. Skeletal dysplasias: e.g., metaphyseal

chondrodysplasia[McKusick et al., 19651 and cartilage- hair hypoplasia disease [McKusick et al., 1965; van der Burgt et al., 19911

5. Whyte syndrome [Whyte et al., 19901 6. Hypophosphatasia [Seshia et al., 1989; Whyte, 19901 C Endocrinopathies presenting hypothalamic dysfunction 1. Behrman et al. [19921: e.g., hypopituitary disorders,

hypothyroid states, parathyroid disorders, adrenal disorders, and gonadal disorders

2. Autoimmune polyglandular syndromes [Ahonen et al., 1990; Garty and Kauli, 1990; Imam et al., 1988; Riley, 19921

D Alopecia 1. Some ectodermal dysplasias [Freire-Maia and Pinheiro,

19841 2. Nutritional deficiencies [Spencer and Callen, 19871: e.g.,

protein-calorie malnutrition [Albers et al., 1993; Fitzpatrick et al., 19871, essential fatty acids [Spencer and Callen, 19871, zinc [Slomin et al., 1992; Spencer and Callen, 19871, and biotin [Spencer and Callen, 19871

3 . Associated with insulin-dependent diabetes mellitus [Rabinowe, 1990; Taniyama e t al., 19911

4. Systemic lupus erythematosus [Laman and Provost, 19941

5. Autoimmune polyglandular syndromes [Ahonen et al., 1990; Garty and Kauli, 1990; Imam et a]., 1988; Riley, 19921

E Chronic malabsorption and diarrhea syndromes: Ulshen [1985]: e.g., disaccharidase deficiency, celiac disease

F Miscellaneous Hennekam syndrome [Hennekam et al., 19901

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