Short reports
`
`721
`
`REFERENCES
`(1972). A genetic study of infantile and juvenile
`Bundey, S.
`myasthenia gravis.
`journal of Neurology, Neurosurgery and
`Psychiatry, 35, 41.
`Dubowitz, V.
`(1969).
`The Floppy Infant, p. 45.
`I-Ieinemann,
`London.
`Millichap, J. G. , and Dodge, P. R. (1960). Diagnosis and treatment
`of myasthenia gravis in infancy, childhood and adolescence.
`Neurology, 10, 1007.
`Namba, T., Brunner, N. G., Brown, S. B., Muguruma, M., and
`Grob, D.
`(1971). Familial myasthenia gravis. Archives of
`Neurology, 25, 49.
`Rothbart, H. B. (1937). Myasthenia gravis in childrei-i—its familial
`incidence.
`journal of the American Medical Association, 108,
`715.
`
`FRANK OBI-ZRKLAID and IAN J. Hot>xINs*
`Royal Children’: Hospital, Melbourne, and Department of
`Pediatrics, University of Melbourne.
`*Correspondence to Dr. Ian J. Hopkins, Royal Children’s Hospital,
`Melbourne 3052, Australia.
`
`Female phenotype in a male child
`due to 17-oc-_hydroxylase
`deficiency
`The finding of testicles in a normal looking girl
`usually leads to a diagnosis of testicular feminiza-
`tion,
`i.e. congenital
`insensitivity to testosterone
`(due to lack of conversion to dihydrotestosterone).
`
`However, a similar picture may be encountered in
`some patients who have a congenital defect of
`testosterone synthesis (Givens et al., 1974) and in
`whom adrenal
`insufliciency may cause
`severe
`illness. Serious illness in a child wrongly diag-
`nosed as a case of testicular feminization led to
`discovery of 17-at-hydroxylase deficiency.
`Methods
`
`Pregnanediol and pregnanetriol were estimated in
`urine by gas-liquid chromatography after enzymatic
`hydrolysis (Moolenaar and Van Seters, 1971).
`ll-
`Hydroxycorticosteroids in serum were estimated accord-
`ing to Mattingly (1962), cortisol and corticosterone by a
`competitive protein—binding technique (Dr. H.
`J.
`Degenhart, Sophia Children’s Hospital Rotterdam), and
`testosterone, progesterone,
`and follicle
`stimulating
`hormone by radioimmunoassay.
`
`Case report
`in
`A girl of 3 years was admitted to this hospital
`a semicomatose condition.
`6 months earlier she had
`been admitted to another hospital with inguinal hernia.
`A testicle was then found in the hernial sac, and karyo-
`typing showed a 44,XY pattern, a diagnosis of testicular
`feminization being made. The external genitals were of
`normal
`female appearance;
`the vagina was present;
`neither uterus nor ovaries could be felt.
`When admitted to our hospital the child had been
`ill for 24 hours and was found to have otitis media
`
`TABLE
`
`Concentrations of main steroids in blood and urine
`
`1
`
`1
`
`Blood pressure (mmHg)
`
`‘
`
`145/ 100
`
`‘
`
`100/70
`
`Amerigen Exhibit 1167
`Amerigen Exhibit 1167
`Amerigen v. Janssen IPR2016-00286
`Amerigen V. Janssen IPR2016-00286
`
`x
`
`1
`
`‘
`
`‘
`
`\
`
`‘
`
`_
`1
`l
`5
`
`1
`l
`‘
`
`Urine
`17-oxosteroids mg/24 h
`(umol/24 h)
`17-oxogenic steroids mg/24 h
`(umol/24 h)
`Pregnanediol mg/24 h
`(umol/24 h)
`Pregnanetriol mg/24 h
`(umol/24 h)
`Serum
`ll-OH steroids ug/100 ml
`
`Cortisol u.g/ 100 ml (nmol/1)
`Corticosterone ug/I00 ml
`Testosterone ng/100 ml (nmol/1)
`Testosterone after Pregnyl
`ng/100 ml (nmol/1)
`Progesterone ng/ml (nmol/1)
`
`Follicle stimulating hormone
`mIU/ml
`
`Untreated
`
`0-6-1 -2
`(2-1-4-2)
`2-4 (8-3)
`
`0-99 (3-1)
`
`0-04 (0-12)
`
`45-57
`
`<0-3 (8-28)
`47
`<5 (0-17)
`
`<5 (0-17)
`4-3 (13-67)
`
`1
`1
`N
`Treated with dexamethasone
`1-; Prmhafldva “es
`1 mg/d
`0-23 mg/d
`m C
`re“
`for 70 days
`for 2 days
`
`1-0-1-3
`(3-5-4-5)
`3-2-3-9
`(ll-1-13-5)
`0-32 (0-99)
`
`0-02 (0-06)
`
`0-9-1-9
`(3 - 1-6-6)
`1 -2-2-7
`(4-2—94)
`0-37 (1-2)
`
`0-01 (0-03)
`
`4-9
`
`4-6
`
`1
`
`-
`
`.\
`‘
`
`.
`‘
`
`0-3-0-6
`(0-95-1-9)
`
`0-8 (2-5)
`
`0-1-3-0
`(3-5-10-4)
`1 -5-9-6
`(5 -2-33-3)
`O-01-0-14
`(0-03-0-45)
`0-02-0-16
`(O-06-0-48)
`
`10-20
`(0-28-O-55)
`10-20
`1-2
`14-23
`(48-6-79-8)
`
`<0-5 (1 -59)
`
`4-3-0-8
`
`17-0
`100/70
`
`‘
`
`

`
`722
`
`Short reports
`and mastoiditis. The severity of the symptoms was
`judged to be out of proportion to the severity of the
`infection. Further
`investigation disclosed hyperten-
`sion (blood pressure 145/100 mmHg) and hypokalaemia
`(2-6 mmol/l) with a strongly negative potassium-balance
`and hypoglycaemia (1-6 mmol/1; 29 mg/100 ml).
`After recovery from the infection hormonal studies
`were undertaken. The results are summarized in the
`Table, and are characteristic of 17-ac-hydroxylase
`deficiency, with high levels of progesterone in the blood
`(4-35 ng/ml) and of pregnanediol in the urine (0-99
`mg/24 h). The ratio between pregnanediol
`and
`pregnanetriol in urine was high at 25 (in normal children
`1-3). The excretion of oxogenic steroids and oxo-
`steroids was low ; excretion in normal children may be
`too low to enable subnormal excretion to be recognized.
`The blood level of ll-hydroxycorticosteroids was high
`(45-57 p.g/100 ml), due to increased amounts of corti-
`costerone. The blood level of cortisol was very low at
`<0-3 pg/100 ml (8-28 nmol/l). The very low blood
`testosterone concentration was unaffected by administra-
`tion of chorionic gonadotrophin (Pregnyl); in boys with
`normal testicles testosterone increases markedly after one
`injection (Zachmann, 1972). The high level of follicle
`stimulating hormone, estimated only during treatment
`with dexamethasone, was most likely due to the small
`amounts of circulating testosterone. The decreased levels
`of ll-hydroxycorticosteroids and progesterone, and the
`normalization of blood pressure by dexamethasone
`provided further confirmation of the diagnosis.
`Orchidectomy was performed. Histology showed
`normal infantile testicular tissue, comparable to that of a
`newborn with undifferentiated tubular cells; Leydig
`cells were present.
`In the testicular hilus only rudimen-
`tary epididymal
`tubules were
`encountered (Prof.
`A. Schaberg, Dept. of Pathology) (Fig.).
`
` T‘
`
`.
`
`:~
`
`,..«~
`
`§(—»v~‘.
`
`..
`
`8*
`
`.
`
`r
`
`-
`
`..
`
`(1971), Alvarez,
`4 described by Mantero et al.
`Cloutier, and Hayles (1973), and H. Van Slooten
`(personal communication, 1975), were male (XY).
`The female patients were detected because of
`hypertension and sexual
`infantilism. The male
`patients all presented as females; they also showed
`hypertension and sexual infantilism.
`In none was
`the diagnosis based upon the finding of testicles.
`All the reported cases showed increased produc-
`tion of desoxycorticosterone (DOC) and corticoste-
`rone, and decreased production of cortisol. High
`blood pressure and hypokalaemia are the result of
`the increased levels of DOC and possibly other
`precursors of aldosterone, and these normalize if
`dexamethasone is given. Clinical signs of cortisol
`deficiency have not been mentioned in published
`case
`reports. Low aldosterone
`excretion has
`usually been reported, probably secondary to the
`high level of DOC. Decreased excretion of andro-
`gens and oestrogens have been mentioned in most
`reports.
`In all reported males (XY) with l7-at-hydroxylase
`deficiency the lack of testosterone in early fetal life
`has led to complete female development of the
`external genitals. The case published by New and
`Suvannakul (1970) is the only one with ambiguous
`genitals; however, hormone studies in this patient
`were not compatible with a severe deficiency of
`17-on-hydroxylase
`activity:
`the
`deficiency was
`either partial or another endocrine disorder was
`present.
`The presence of an epididymis has been mentioned
`in a few male patients.
`In our case only a few
`poorly developed epididymal
`tubules were seen.
`Though exploratory laparotomy was not performed,
`investigation under anaesthesia failed to disclose the
`presence of a uterus.
`It may be assumed that the
`fetal testes had produced Miiller-inhibiting-factor.
`The clinical and laboratory findings in our patient
`are very similar to those of other reported patients,
`but the case is remarkable for several reasons.
`In
`the first place the child originally was diagnosed as a
`case of testicular feminization. Secondly, she is
`the only reported patient in whom deficiency of
`17-oc—hydroxylase has been detected in childhood.
`Thirdly, the child exhibited clinical signs of adrenal
`insufficiency during an infection.
`The diagnosis of testicular feminization in a
`child should thus not be made before a defect of
`steroid biosynthesis has been excluded.
`
`FIG.—Rudz'mentary epididymal tubules.
`
`( X85.)
`
`Discussion
`
`Nine cases of 17-at-hydroxylase deficiency have
`been reported, all in adults.
`5 patients described
`by Biglieri, Herron, and Brust (1966), Goldsmith,
`Solomon, and Horton (1967), Mallin (1969), and
`Linquette er al.
`(1971) were female (XX), and
`
`Summary
`The discovery of testicles in a 3-year-old girl
`with XY karyotype led to a diagnosis of testicular
`feminization. Subsequently, however, hypokalaemia,
`
`

`
`Short reports
`
`723
`
`hypertension, and severe prostration during a mild
`infection suggested adrenal
`involvement,
`and
`investigations
`showed a 17-on-hydroxylase defi-
`ciency. Diagnosis of testicular feminization should
`not be made without excluding a defect of testos-
`terone synthesis.
`
`REFERENCES
`
`Alvarez, M. N., Cloutier, M. D., and Hayles, A. B. (1973). Male
`pseudohermaphroditism due to 17-at-hydroxylase deficiency in
`two siblings. Pediatric Research, 7, 325.
`l7-Hydro-
`Biglieri, E. G., Herron, M. E., and Brust, N. (1966).
`xylation deficiency in man.
`Journal of Clinical Investigation,
`45, 1946.
`Givens, 1. R., Wiser, W. L., Summitt, R. L., Kerber, I. J., Andersen,
`R. N., Pittaway, D. E., and Fish, S. (1974). Familial male
`pseudohermaphroditism without gynecomastia due to deficient
`testicular 17-ketosteroid reduetase activity. New England
`journal of Medicine, 291, 938.
`Goldsmith, 0., Solomon, D. H., and Horton, R. (1967). Hypo-
`gonadism and mineralocorticoid excess. New England journal
`of Medicine, 277, 673.
`Linquette, M., Dupont, A., Racadot, A., Lefebvre, J., May, I. P.,
`and Cappoen,
`I. P.
`(1971). Deficit en 17-hydroxylase.
`Annales d'Endocrinologie, 32, 574.
`Mallin, S. R. (1969). Congenital adrenal hyperplasia secondary to
`17-hydroxylase deficiency. Annals of Internal Medicine, 70, 69.
`Mantero, F., Busnardo, B., Riondel, A., Veyrat, R., and Austoni,
`M.
`(1971). Hypertension artérielle, alcalose hypokaliémique
`et pseudohermaphrodisme male par deficit en 17 on-hydroxylase.
`Schweizerische Medizinische Wochenschrift, 101, 38.
`the
`Mattingly, D.
`(1962). A simple fiuorimetric method for
`estimation of free ll-hydroxycorticoids in human plasma.
`Journal of Clinical Pathology, 15, 374.
`Moolenaar, A. J., and van Seters, A. P. (1971). Gaschromatographic
`determination of steroids in the urine of patients with Cushing’s
`syndrome. Acta Endocrinologica, 67, 303.
`New, M. I., and Suvannakul, L. (1970). Male pseudohermaphro-
`ditism due to 17 or-hydroxylase deficiency.
`journal of Clinical
`Investigation, 49, 1930.
`Zachmann, M.
`(1972). The evaluation of testicular endocrine
`function before and in puberty. Acta Endocrinologica, Suppl.
`164, 20.
`
`G. F. P. HEREMANS, A. J. MOOLENAAR, and H. H.
`VAN GELDEREN*
`Departments of Paediatrics and Pathological Chemis-
`try, University Hospital, Leiden.
`‘Correspondence to Prof. H. H. van Gelderen, Department of
`Paediatrics, University Hospital, Leiden, The Netherlands.
`
`Acute renal failure and gout as
`presenting features of acute
`lymphoblastic leukaemia
`The ‘preleukaemic’ syndrome of pancytopenia
`and hypoplastic bone marrow has been described
`(Melhorn, Gross, and Newman, 1970). Hyper-
`uricaemia (Sinks et al., 1966), gout
`(Whitaker
`et al., 1963), and uric acid nephropathy (Pochedly,
`1973) are recognized complications of treating leuk-
`aemia.
`In our patient all these symptoms preceded
`the clinical onset of frank leukaemia. This has
`6:
`
`only been described once before (Appleyard, 1971).
`In this latter case renal failure was not the presenting
`feature but a later complication.
`
`Case report
`A 2;-year-old girl had been well until 6 months before
`admission. During this period she was
`fractious,
`developed polyuria and nocturia. Before admission her
`right foot and left wrist became painful, she vomited,
`became dehydrated, lethargic, and two bruises appeared.
`On admission she was pale,
`febrile,
`irritable, and
`dehydrated with Kussmaul respirations and hypotension.
`There was no lymphadenopathy, hepatosplenomegaly,
`renal enlargement, and the nervous system was normal.
`Her right foot, left ankle, left wrist, right third proximal
`interphalangeal joint were warm, swollen, and tender.
`She was oliguric. Her blood urea was 91 mmol/1
`(548 mg/100 ml), sodium 128 mmol/1 (128 mEq/1),
`chloride 93 mmol/1 (93 mEq/1), potassium 5-6 mmol/1
`(5-6 mEq/1), and bicarbonate 5 mmol/l
`(5 rr.‘Eq/l).
`Treatment with intravenous saline and sodium bicar-
`bonate corrected her dehydration and the renal failure
`improved without dialysis (Fig. 1). The joint symptoms
`resolved as the renal failure improved and the serum
`uric acid levels fell (Fig. 1).
`Thrombocytopenia had been noted earlier, but within
`4 days pancytopenia developed (Fig. 2). A bone marrow
`smear showed generalized hypocellularity with a relative
`increase in lymphoid and reticulum cells. There was no
`evidence of lymphoblastic change or malignancy. She
`was treated with blood transfusion and antibiotics and
`the pancytopenia gradually resolved (Fig. 2). The
`progress of the haematological and renal changes are
`shown in Figs. 1 and 2.
`Other investigations were normal. Urine contained
`no crystals and was sterile. No viruses were isolated
`and blood cultures were sterile. X—rays showed no
`evidence of leukaemia and no abnormalities.
`Intra-
`venous pyelogram on day 4 was normal. Renal biopsy
`on day 17 showed changes compatible with recovering
`tubular necrosis and two granulomata identical in ap-
`pearance with those described in uric acid nephropathy.
`She remained well until day 52 when she developed
`pains in several distal
`joints. She became restless,
`lethargic, vomited, and was readmitted on day 58 in
`acute renal failure (Fig. 1). She was
`reluctant
`to
`move either elbow, the left wrist, the proximal interpha-
`langeal joints of the right 4th and 5th fingers and the
`left 5th toe. All were swollen and inflamed. Both
`kidneys were palpable and the liver was slightly enlarged.
`There was no splenomegaly,
`lymphadenopathy, or
`bruising. The acute renal failure and acidaemia were
`managed conservatively with dietary restriction and
`intravenous fluids (Fig. 1) and the serum uric acid levels
`fell.
`Fig. 2 shows the results of blood tests at this time.
`The differential white cell count on day 60 showed
`immature red and white cells. Bone marrow examination
`on day 63 showed changes of acute undifferentiated
`leukaemia. On day 66 treatment was started with
`prednisolone 40 mg/m2 per day and allopurinol; the