Progressive muscular dystrophy with congenital adrenal hypoplasia: An unusual autopsy case

Progressive Muscular Dystrophy with Congenital Adrenal Hypoplasia: An Unusual Autopsy Case Teruko Toyofuku, MD, Sachio Takashima, MD, Kenzo Takeshita, MD and Hiroshi Nagafuji, MD

A 3%-year-old child with progressive muscu lar dystro phy (PMD) and congenital adrenal hypoplasia (CAH) is described. Sy mptoms and signs of adren ocortical insufficiency appeared shortly after birth. Despite corticosteroid therapy, the muscular weakness and elevated CK level continued. A diagnosis of Duchenne muscular dystrophy was made on th e basis of clinical signs and characteristic muscle biopsy. The affection of his older broth er suggests an X-linked recessive inheritance. The autopsy revealed a very rare combination of cytomegalic type CAH and PMD. This combination suggests that a small deletion of X-chromosome might be responsible for the two disorders. Toyofuku T, Takashima S, Takeshita K, Nagafuji H. Progressive muscular dystro phy with co ngenital adrenal hypoplasia : an unusual autopsy case. Brain Dev 1986;8:285-9

Duchenne muscular dystrophy is an X-linked condition characterized by progressive degeneration of skeletal muscles and usually pseudohypertrophy of calves. Congenital adrenal hypoplasia (CAH) has two types [1]. The primary form is adrenal hypoplasia unassociated with other congenital abnormalities [6-14], and the second is with anencephaly or ~ypoplasia of the pituitary gland [2-5]. The primary form is very uncommon, and two different modes of inheritance , autosomal and X-linked recessive , have been suggested [l ; 14] . This report describes an autopsy case of

From the Division of Child Neurology, Tottori University School of Medicine, Yonago (TT, ST, KT); and Department of Pediatrics, Matsue Red Cross Hospital, Matsue (HN). Received for publication: October 30 , 1985. Accepted for publication: January 7, 1986.

Key words: Muscular dystrophy, adrenal hypoplasia, muscle. Correspondence address: Dr. Sachio Takashima, Division of Child Neurology , Tottori University School of Medicine, Yonago 683, Tottori, Japan .

progressive muscular dystrophy and a primary form of CAH. The association of Duchenne muscular dystrophy and CAH , very rarely reported in the literature, suggests an X-linked recessive trait of the inheritance. Case Report A 3l-2-year-old Japanese boy was admitted to the Matsue Red Cross Hospital because of generalized seizure, apneic spells and unconsciousness. He died 3 days later despite various medical treatments. There was no consanguinity in the family. His maternal uncle died of unknown cause in the neonatal period . He had a healthy older sister and an affected older brother, who showed the same symptoms (skin pigmentation , vomiting, fatigability, diminished deep tendon reflexes, waddling gait and Gowers' maneuver) and the same laboratory findings (marked elevated serum enzyme activities and abnormal electrolytes) as the present case . The older brother died at age of 3 years and 7 months (Fig 1). The child was born following a normal pregnancy and smooth delivery at 42 weeks

gestation. His birth weight was 3,500 g. He had episodic vomiting shortly after birth, and was admitted to hospital because of feeding difficulty, body weight loss (3,100 g) and fatigability at 23 days of age . There were moderate dehydration and brown pigmentation of the skin but no abnormality of the external genitalia. Laboratory examination showed se-

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rum sodium 116 mEqjL, potassium 7.5 mEqjL, GOT 842 U, GPT 149 U, LDH 3,400 U, CK 2,220 U, and aldolase 125 U. There were 0.2 mg of 17-KS, 0.8 mg of 17-0HCS and 0.25 /J.g of aldosterone in a 24 hr urine sample. Serum ACTH was elevated to 661 pg/dl, ~-MSH 1,085 pg/dl, and angiotensin 2,000 U. Serum CK and aldolase of the parents were normal (Table 1).

Fig 1 Pedigree of the family.

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Table 1 Laboratory examination • Endocrinologic studies Thyroid function PBI

T.

Triosorb test TSH

7.8 J.Lg/dl (4-8) 10.3 J.Lg/dl (5.0-13 .7) 28 .6% (25-35) 3 J.Lu/ml « 12)

Adrenal function (before treatment) Urinary 17-0HCS 0.8 mg/day (2.7 ± 0.86) 17-KS 0.2 mg/day (0.8 ± 0.24) U-oxy-17ks 0.1 mg/day ll-deoxy-17ks 0.1 mg/day Androsterone 0.01 mg/day (0.02 ± 0.02) Etiocholanolone 0.01 mg/day (0.01 ± 0.02) DHEA 0.01 mg/day (0.03 ± 0.07) II-OH andro 0.01 mg/day (0.07 ± 0.03) II-OH etio 0.01 mg/day (0.01 ± 0.02) II-K etio 0.03 mg/day (0.05 ± 0.03) Urinary 0.025 ug/day (2-12) Aldosterone 0.26 ug/day Testosterone FSH 0.2 IJ.L/I (0.8-3.2) LH 6.6 IJ.L/I (0.2-2.4) Pregnandiol 0.01 mg/day (0.02 ± 0.01) Pregretriol 0.01 mg/day (0.03 ± 0.02) Plasma 661 pg/ml (50-150) ACTH i3-MSH 1,805 pg/ml « 100) (during treatment) Plasma 2.5 J.Lg/dl (3-22) 11-OHCS Cortisol 0.7 -5.5 ",g/dl(14 ± 0.87) Aldosterone 2.26 ng/dl (2 .8 - 22.4) Angio2,000 pg/ml ten sin I Renin activity 71 ng/ml/hr (632 ± 1.32)

286 Brain & Development, Vol 8, No 3,1986

• Blood chemistry T. protein Alb 0!1 -glob

6.6 g/dl 65.6% 5.2 o!, 12.6 i3 8.9 'Y 7.4 Na 116 mEq/L K 7.5 CI 93 Ca 6.2 Urea-N 10.0 mg/dl Creatinine 0.5 Fasting blood sugar 90 mg/dl T. cholesterol 170 mg/dl GOT « 34) 842 U GPT«29) 147U CK « 35) 2,220 IV ALD « 12) 125 U LDH«400) 3,400U LDH 1 23 .1% LDH 2 50.0% LDH 3 23.1% LDH 4 3.0%

• Parent's examinations Father CK Aldolase Mother CK Aldolase

20.0 IV 8.3 U 20.0 IV 8.8 U

At that time the diagnosis of adrenal insufficiency was made, and treatment was started with predonisone and fludrocortisone. Subsequently his generalized condition and serum electrolyte levels were improved , but serum enzyme activities did not decrease. He held his head up at 3 months and sat at 9 months. There were diminished deep tendon reflexes and hypertrophic calves but no joint contracture. A muscle biopsy showed a marked variation in fiber size, internal nuclei , degenerated muscle fibers with macrophage infiltration , regenerating fibers, adipose and connective tissue proliferation. Adrenal scintigraphy revealed absence of both adrenal glands. He walked at 14 months with a waddling gait and rose from a sitting position using the Gowers' maneuver. At 18 months having measles exanthema, he had vomiting, fever and generalized seizure. The blood glucose concentration was 10 mg/dl , sodium 134 mEq/ L, potassium 4.1 mEqjL and chloride 93 mEqj L. Corticosteroid and anticonvulsant were administered intravenously. He was discharged in good health. One week following discontinuation of medication at age 3 years, he had generalized seizure, apneic spells, developed coma, and died 3 days later in spite of corticosteroid and anticonvul~ sant medication.

Pathological Findings The skin showed generalized hyperpigmentation. His right adrenal gland was not detected in spite of careful examination and the left one was very small in size. Microscopically, the

Fig 2 The atrophic adrenal cortex is very thin, irregularly arranged and nodular. H&E stains, x 200.

adrenal cortical cells were irregularly arranged without any differentiation into zones. There were many large cells of various size with pale granular eosinophilic cytoplasms and large nuclei , which were sometimes vesicular with prominent nucleoli . Other cells showed hyperchromatic nuclei. One area of the cortex showed a nodular pattern. The medulla was reduced to a small island of tissue which contained neurons (Fig 2). The pituitary gland had recent focal ischemic changes with multiple small calcifications. An increase of eosinophilic cells was evident. The other endocrine glands were normal. There were acute bronchopneumonia and atelectasis in the lungs and fatty liver, but the kidneys, pancreas and spleen were normal without calcifica hon. There was not osteopenia in the bones. The histology of the psoas, intercostal and diaphragmatic muscles showed a marked variation in fiber size , type 1 fiber predominancy, internal nuclei, degenerating fibers with opaque or atrophic fibers, adipose and connective tissue proliferation. The muscle degeneration was found multifocally and predominantly in type 2 fibers. These findings were more marked than those of the biopsy (Fig 3). The brain weighed 1,440 g and was edematous. On 1 cm coronal sections, there were neither poly microgyria nor other gross abnormalities. Histologically, there were hypoxicischemic changes with eosinophilia of deep cortical neurons, spongy degeneration of the putamen and thalamus , and loss of cerebellar gran ula r ce Us.

Fig 3 A biceps muscle specimen shows a variation in fiber size, central nuclei, opaque fibers, degenerated and regenerating fibers. H&E stains, x 200.

Toyofuku et al: Muscular dystrophy with congenital adrenal hypoplasia 287

Discussion

of them had an autopsy and revealed nonspeThe marked elevation of serum ACTH without cific osteopenia, mild nephrocalcinosis and congenital abnormality of the pituitary gland small adrenal glands. Microscopic examination in autopsy material suggests that our case was of the adrenals showed nonspecific distortion the primary type of CAH presenting the signs of architecture crowding out of the zona of neonatal adrenal insufficiency. glomerulosa by nodular, hyperplastic zona fasiIn the primary type, two histological forms culata characterized by hypertrophic and occaof CAH have been reported : cytomegalic type sionally necrotic cells. Renier et al [19] also mainly composed of large cells arranged in a described three brothers with CAH, muscular disorderly pattern without architectural zona- dystrophy and GKD. The autopsy of the protion resembling the fetal cortex [8, 11], and band revealed the cytomegalic type of CAH, minimature type similar to the adult adrenal and the muscle biopsy suggested Duchenne architecture. The minimature type is thOUght type muscular dystrophy. The siblings of our to be of an autosomal recessive trait, and the case were not examined for glycerol or glycerol cytomegalic type, of an X-linked recessive trait kinase. Though there were some differences in [1, 10, 14]. The histology of the adrenal gland spasticity, osteoporosis, mental retardation or and the affectation of male siblings in our case adrenal histology between our case and Guggenwere compatible with the cytomegalic type and heim's or Renier's cases, these families had an X-linked recessive inheritance . However, an X-linked trait and adrenomuscular lesions. there is a report of a female case of the primary Therefore , our siblings might have X-linked type, in which the adrenal architecture was of recessive GKD, although cases of GKD present the cytomegalic type [9, 10] . Therefore, there variable clinical features [18-20] including may not be necessarily any correspondence be- autosomal recessive trait. In conclusion, this patient had a rare combitween the histologic appearance and the genetic patterns in adrenal hypoplasia , while the his- nation of cytomegalic type CAH and progressive tological findings of the second type with ab- muscular dystrophy, which showed an X-linked normalities of the central nervous system have trait. A small deletion of the X chromosome might be responsible for the two lesions, but been of the minimature type. On the other hand, muscle weakness and clarification of their physiopathologic mechafatigability are often observed in Addison's nisms needs further studies, because the adrenal disease. These symptoms are due to hypoten- lesion was prenatal and the muscle one postsion, hypokalemia or water imbalance. When natally progressive. these are adequately treated, the symptoms disappear. In our case , muscle weakness and Acknowledgment elevated levels of serum CK never improved We thanks Dr. Nonaka I for his suggestions. despite adequate treatment of adrenal insufficiency. Steroid myopathy and Cushing's synReferences drome also accompany muscular involvement 1. Kissane 1M, Smith MG. Adrenal glands: pathol[15 -1 7 , 19, 21] . However, in our case the ogy of infancy and childhood. StLouis: CV muscle histology and laboratory data were Mosby Co, 1967:613-716. 2. Moister HO . Hypoplasia of the pituitary and not consistent with corticosteroid- or ACTHadrenatal cortex: reports of occurrence in twin induced myopathy, and fit rather well with siblings and autopsy findings. J Pediatr 1956 ; progressive muscular dystrophy, which was 48 :633-9 . demonstrated by muscle biopsy and autopsy 3. Angevine OM. Pathologic anatomy of hypophysis and adrenal in anencephaly. Arch Pathol specimens. 1938;27 :506-18. Recently, the association of CAH with 4. Kerenyi N. Congenital adrenal hypoplasia. Arch muscular dystrophy was found in glycerol PathoI1961;71 :336-43. kinase deficiency (GKD). Guggenheim et al 5. Ehrich RM. Ectopic and hypoplastic pituitary reported two brothers with GKD, who had with adrenal hypoplasia: case report. J Pediatr 1957 ;51:377-84. psychomotor retardation, spasticity, generalized osteoporosis, myopathy with high CK levels, 6. Sikl H. Addison's disease due to congenital hypoplasia of adrenal in an infant aged 33 days. histologically resembling Duchenne muscular J Pathol Bact 1948;60:323-4. dystrophy and adrenal insuffiCiency [18]. One 7. Provenzano RW. Adrenocortical hypoplasia in

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9. 10. 11. 12. 13. 14.

the newborn infants: report of a case with replacement therapy. New Engl J Med 1960;242: 87-9. Boyd JF, MacDonald AM. Adrenal cortical hypoplasia in siblings. Arch Dis Child 1960;35: 561-8. Roselli A, Barbosa LT. Congenital hypoplasia of adrenal glands: reports of two cases in sisters with necropsy. Pediatrics 1965 ;35 :70-5. Mitchell RG, Rhancy K. Congenital adrenal hypoplasia in siblings. Lallcet 1959 ;1:488-92. O'Donohoe NY, Molland PDl. familial congenital adrenal hypoplasia. Arch Dis Child 1970;43: 717-23. Backer WC, Weis MG, Mezzer ML. Cytomegalic adrenal hypoplasia in 4'12 year old boy. Am J Dis Child 1967;114: 180-5. Weiss L, Mellinger RC. Congenital adrenal hypoplasia in an X-linked disease. J Med Gellet 1970; 7:27-32. Sperling MA, Wolfsen AR, fisher DA. Congenital adrenal hypoplasia: an isolated defects of organogenesis. J Pediatr 1973;82:444-9.

15. Engel EG. Endocrine myopathies. In: Walton IN, ed . Disorders of voluntary muscle. 4th ed. Edinburgh: Churchill Livingston, 1980:693. 16. Darchman DB, Toyka KY, Myer E. Predonison in Duchenne muscular dystrophy. Lallcet 1974; 2: 1409-12. 17. Muller R, Kugelberg E. Myopathy in Cushing syndrome. J Neurol Neurosurg Psychiatry 1959; 22:314-9 . 18. Guggenheim MA, McCabe ERB , Roig M, et a!. Glycerol kinase deficiency with neuromuscular, skeletal and adrenal abnormalities. Alln Neurol 1980;7:441-9. 19. Renier WO, Nabben FAE , Hustinx TWJ . et a!. Congenital adrenal hypoplasia, progressive muscular dystrophy, and severe mental retardation, in association with glycerol kinase deficiency , in male sibs. CUn Genet 1983;24:243-51. 20. Bartley lA , Miller OK, Hayford 1T, McCabe ERB. Concordance of X-linked glycerol kinase deficiency with X-linked congenital adrenal hypoplasia. Lancet 1982;2:733-6.

Mitochondrial Cytopathy with Lactic Acidosis, Carnitine Deficiency and DeToni- Fanconi-Debre Syndrome Akito Kitano, MD, Soroku Nishiyama, MD, Teruhisa Miike, MD, Shinzaburo Hattori, MD, Yoshinobu Ohtani, MD and rehiro Matsuda, MD

We reported a 6-year-old girl with mitochondrial cytopathy with lactic acidosis. The patient developed hypotonia, hearing loss, mental retardation, short stature, cataracta, hypoparathyroidism, DeToni-Fanconi-Debre syndrome and carnitine deficiency. Histological examination disclosed ragged red fibers and moderate lipid storage in skeletal muscle tissue and several structural abnormalities of mitochondria both in muscle tissue and proximal renal tubules. Biochemical examination of muscle tissue revealed a partial deficiency of pyruvate dehydrogenase complex and normal activities of cytochrome c oxidase, succinate cytochrome c reductase and NADH cytochrome c reductase. This is the first report of mitochondrial cytopathy representing DeToniFanconi-Debre syndrome associated with partial deficiency of pyruvate dehydrogenase complex and normal cytochrome c oxidase activity. Kitano A, Nishiyama S, Miike T, Hattori S, Ohtani Y, Matsuda 1. Mitochondrial cytopathy with lactic acidosis, carnitine deficiency and DeToni-Fanconi-Debre syndrome. Brain Dev 1986;8:289-95

Egger et al [1] ex tended the concept of "mitochondrial myopathy" to "mitochondrial cytopathy" because other organs may also be affected, including the brain and endocrine

organs. The syndrome is almost certainly a heterogenous collection of many different diseases bound together by accumulation of red staining materials in the subsarcolemmal and