Arch. Dis. Childh., 1968, 43, 717.

Familial Congenital Adrenal HypoplasiaN. V. O'DONOHOE and P. D. J. HOLLAND

From Our Lady's Hospital for Sick Children, Dublin; and Royal College of Surgeons in Ireland

Adrenal hypoplasia is an invariable finding ininfants with anencephaly. Hypoplastic adrenalglands have been described in infancy associatedwith congenital hypoplasia of the pituitary gland(Mosier, 1956). S;kl (1948) was probably thefirst author to describe congenital adrenal hypo-plasia unassociated with other congenital abnormali-ties, though he mentions some similar cases describedby earlier authors. Mitchell and Rhaney (1959)were the first authors to describe adrenal corticalhypoplasia in sibs, and all the reported cases- werereviewed recently by Roselli and Barbosa (1965)who added a family with 2 affected sibs.

Adrenal failure in early infancy due to congenitaldefect of the adrenal glands is most commonlydue to adrenal hyperplasia, where a variety ofenzymatic abnormalities have been described(Prader, 1967). The rare condition of lipoidadrenal hyperplasia, reviewed by O'Doherty (1964),is associated with adrenal insufficiency in infancyand with male pseudohermaphroditism. Congeni-tal adrenal hypoplasia unassociated with othercongenital anomalies produces an uncomplicateddeficiency of adrenocortical hormones which canbe replaced to restore normal metabolic function.A family with this condition is here described.

Both parents are healthy and unrelated. Themother was an only child and her mother had noother pregnancies. The father was one of fivechildren; his mother had one miscarriage.

Case ReportsCase 1. The first child, a female, was born in

May 1959, after delivery 2 weeks over term; birth-weight 4260 g. Labour was prolonged and deliverywas by forceps. The infant was described as shockedat birth and was nursed in an incubator for 5 days.Some respiratory difficulty occurred and was thoughtto be due to atelectasis. Vomiting after feeds was aproblem in the first 2-3 months but then ceased andthe baby thrived normally. During the exceptionallyfine summer of 1959, the child, who had fair hair,became deeply pigmented, and the mother claimed

Received May 23, 1968.

that she had noticed this in the first month of life.Eventually she became 'almost black' and retained muchof this pigmentation throughout the following winter.She appeared healthy and had no illnesses of noteexcept for acute febrile reactions aftel triple immuniza-tion injections.Her final illness began in September 1960, when she

became suddenly febrile. She was given aspirin, and24 hours later her temperature had fallen to belownormal and she was listless and apathetic. After 36hours she began to vomit and became hyperpyrexial.She was given penicillin and cortisone and was admittedto hospital. Convulsions then occurred and she diedabout 44 hours from the onset of her illness.At necropsy the macroscopical appearances were as

follows. The body was that of a well-formed, flaxen-haired female child, the size corresponding to the statedage. The skin showed a striking degree of pigmentationinvolving the entire body, the exposed parts being moredeeply pigmented than those parts covered by clothing.The skin of the abdominal wall was deeper in colourthan that of the remaining covered surfaces. The lungswere deeply congested and mottled in appearance andshowed multiple subpleural petechial haemorrhages.The smaller bronchi contained thin mucus. Bothlower lobes were firm and partly consolidated. Theheart was normal in size and showed no anatomicaldefect. The gastro-intestinal tract was normal inappearance. The mesenteric lymph nodes weremoderately enlarged and congested. The uterus,ovaries, pancreas, and kidneys appeared normal. Thespleen was slightly enlarged and congested. Theadrenals were located with difficulty but were normalin position. Both were remarkably small but werenormal in outline (Fig. 1). No ectopic adrenal tissuewas found. The brain was not examined.

Histological examination of the lungs showed themas strikingly congested and oedematous, and therewere occasional areas of frank haemorrhage. Theinterstitial tissues contained a lymphocytic inflamma-tory exudate in some areas. The findings suggesteda pneumonitis probably ofviral origin. The skin showeda marked increase in pigmentation, the pigmentedarea extending into the stratum granulosum.Both adrenals (combined weight 0 8 g.) had an identi-

cal histological appearance (Fig. 2). Beneath the cap-sule, a thin rim of adult-type cortex was present inwhich the three layers could be identified. The zonaglomerulosa and zona reticularis were well developed,

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FIG. l.-Case 1. The adrenal glands (below) compared with adrenals from a child of the same age (above).

P.-Y'. 4_

FIG. 2.-Case 1. Section of the adrenal gland, showing narrow rim of cortical tissue. (H. and E. x 22.)

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Familial Congenital Adrenal Hypoplasia

FIG. 3.-Case 1. Section of the adrenal cortex and part of the medulla. (H. and E. x 156.)

but the zona fasciculata was relatively reduced inamount (Fig. 3). Beneath the adult-type cortex andforming the bulk of the cortical tissue was a mass ofirregularly arranged large pale polygonal cells withvesicular nuclei. These cells had little resemblanceto the normal fetal-type cortex. The medulla of theglands appeared histologically normal.

Case 2. The second child, a female, was born inMarch 1960, after a spontaneous delivery 5 days beforeterm; birthweight 3990 g. She was normal at birthand developed normally in the first two years of life.After the death of the third child (Case 3) it was decidedto investigate her adrenal cortical function. She wasadmitted to hospital in May 1962, and remainedfor 24 hours. A 24-hour urinary collection was

obtained with difficulty (vol. 210 ml.), and con-

tained 0 5 mg. 17-ketosteroids. On the admissionday, blood obtained by heel-stab contained sodium136 9 mEq/l. and potassium 7- 6 mEq/l. On thefollowing day, potassium was 7-8 mEq/l. On thatday her ECG was normal. During the followingmonth, three further electrolyte estimations were donewith the following results: on the capillary blood,sodium was 139 and 136 9 mEq/l. and potassiumwas 7 8 and 7- 0 mEq/l., and on a venous sample,potassium was 6* 0 mEq/l. No haemolysis was reportedin any specimen. She was then admitted for an ACTHstimulation test (Clayton, 1961). After an initialcontrol day, ACTH 20 units 12-hourly was given intra-muscularly for a total of six doses and 24-hour urine

collections were obtained. The results obtained werewithin normal limits for her age.

Since 1962 this child has remained perfectly welland has overcome the usual childhood infections withoutany unusual complications occurring. The curiouselectrolyte abnormality remains unexplained, and theparents are not anxious for further investigation ofthis child.

Case 3. The third child, a male, was born in April1962 after labour was induced 2 weeks over term;birthweight 3900 g. Delivery was spontaneous andeasy. Oxygen was administered immediately afterbirth, but his colour quickly became normal and he wastransferred to a cot. No abnormal pigmentation wasnoticed. He fed normally after about 12 hours.After 24 hours he became cyanosed and grey in appear-ance. He was limp and appeared unconscious. Itwas considered that he might have had a cerebralhaemorrhage but, because of the history of the firstborn,hydrocortisone, 50 mg., was given intramuscularlybut without benefit. He died 28 hours after birth.At necropsy, the lungs were congested, and alternating

areas of atelectasis and compensatory emphysema werepresent. The liver was congested. The kidneys,spleen, thyroid, testes, and pancreas were normal.The pituitary was examined and was normal and thebrain was also normal.Both adrenals were tiny (7 x 2 x 20 mm. approx.)

but, unfortunately, were not weighed. Histologicallythey were abnormal and resembled closely the adrenals

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P .R :... x * .

FIG. 4.-Case 3. Section of the adrenal cortex, showing narrowing of the 3 zones of cells, and a pale degen-eratedfetal-type zone. (H. and E. x 156.)

of the other sib, i.e. there was a thin rim of adult-typecortex in which the three zones of cells could be dis-tinguished, the zona fasciculata being relatively reduced.Beneath the adult-type rim of cortex, there was a zoneof degenerated fetal-type cortex, the cells of whichwere not eosinophilic but were vacuolated (Fig. 4). Theadult and fetal type cortices were roughly equal involunme.

Case 4. The fourth child, a male, was born inOctober 1963, after labour was induced two weeks afterterm; delivery spontaneous; birthweight 4320 g. Hecried immediately but was cyanosed and limp. Afteraspiration of the upper respiratory tract, transfer to anincubator and the administration of oxygen, he remainedlimp and no improvement in colour occurred. Hisbreathing was shallow and bradycardia was present.After 30 minutes, intravenous hydrocortisone hemi-succinate, 20 mg., was given intravenously via anumbilical vein catheter. General improvement followedrapidly on this injection. During the next 5hours, he became vigorous and his cry was strong.However, his skin colour remained ashen. He hadno abnormal pigmentation of the scrotum or else-where. Cord blood electrolyte estimations were asfollows: serum sodium 139 mEq/l. and serum potassium5 mEq/l. The plasma cortisol estimation in cordblood was 4 1 ,ug./100 ml. (mean of triplicate estimationsranging from 3-4 to 4-5 ,ug./100 ml.). The cortisol

was measured fluorimetrically. Plasma corticosteronewas not detected. Plasma 17-hydroxycorticosteroidsin a specimen of blood taken from the mother immedi-ately after delivery measured 549 ,ug./100 ml. These wereestimated as Silber-Porter chromogens, predominantlycortisol. The normal non-pregnant adult range bythis method is 5 to 25 ,tg./100 ml. Two months afterdelivery, the mother's serum cortisol level was 36-9,ug./100 ml. and corticosterone was 6-5 pg./100 ml.(B. T. Rudd, Institute of Child Health, Universityof Birmingham).

After 6 hours, serum sodium was 128 mEq/l. andserum potassium 6- 6 mEq/l., and after 10 hours,sodium was 132 mEq/l. and potassium 7- 2 mEq/l.(capillary blood). Cortisone 10 mg. was given byintragastric tube 6 hours after birth and fludrocortisone,0-025 mg., was given in the same way 7 hours afterbirth. A dextrose-saline (NaCl 0-450%) intravenousinfusion was started at that stage and subsequentadministration of hydrocortisone on the first day wasby the intravenous route. During the first 24 hourshe received hydrocortisone 60 mg. and fludrocortisone0 075 mg. and, over the next 6 days, the daily doseswere gradually reduced to 20 mg. and 0 05 mg., res-pectively. After 48 hours, he developed generalizedoedema. This was interpreted as an inability to excretea water load as in the Robinson-Power-Kepler test,and the intravenous infusion was stopped. The oedemagradually disappeared duiing the next 3 days.

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Familial Congenital Adrenal HypoplasiaAfter the first week, oral cortisone was substituted

and up to 25 mg. daily was given over the next 4 weeks.Fludrocortisone dosage was increased to 0 2 mg.daily because of serum potassium estimations of upto 7 4 mEq/l. at times. Beginning 5 weeks after birth,dexamethasone was gradually substituted for cortisone,increasing to a dose of 0 25 mg. twice daily. An ACTHstimulation test was carried out, beginning three daysafter stopping cortisone therapy and while the patientwas on dexamethasone and fludrocortisone. ACTHgel, 20 units, 12-hourly, intramuscularly, was givenfor a total of 6 doses. Blood was collected before thetest and daily at the same time during the test. Thehormone assays were performed by Mr. B. T. Rudd,and he reported that neither cortisol nor corticosteronecould be detected in any of the 4 samples.

Cortisone therapy was resumed. BCG vaccinationand immunization against diphtheria, pertussis, tetanus,and poliomyelitis (Salk) were completed while he wasin hospital. He was discharged home 4 months afterbirth and was having cortisone 10 mg. daily and fludro-cortisone 0 25 mg. daily. Serum sodium and potassiumestimations were normal. Other investigations includeda normal urinary amino acid chromatogram, a normalserum protein electrophoretic pattern, and a buccalmucosal smear which showed a normal male pattern.

Since that time, the dosage of fludrocortisone hasbeen progressively reduced to 0 05 mg. daily and corti-sone has been increased to 15 mg. daily. Fludrocorti-sone was reduced because of systolic blood pressuresof up to 170 mm. Hg. Recent blood pressure estima-tions have been normal.Now aged 4 years, he weighs 15 5 kg. and his height is

95 cm. He is a healthy intelligent child. He hasovercome several acute respiratory infections withoutincident, the dosage of cortisone having been increasedto 25 mg. daily during these illnesses. He has not hadany acute infectious fevers so far. Immunizationagainst measles was completed without incident.

Case 5. The fifth child, a male, was born by spon-taneous delivery 2 weeks before term in May 1965;birthweight 3540 g. He was cyanosed at birth butquickly recovered. He remained completely wellduring the first 48 hours of life and subsequently.Repeated serum electrolyte estimations were normal.His progress since birth has been normal. A specimenof the mother's blood, taken at the time of delivery,contained less than 25 ,ug. cortisol/100 ml., and theserum cortisol level in the cord blood was describedas being slightly lower than the level in the mother'sblood, but accurate analysis was not possible becausethe amount of serum available was insufficient. At theage of 21 years, a 30-minute Synacthen test was doneafter the method of Wood et al. (1965). 0 25 mg. ofSynacthen was given intramuscularly. Plasma cortisolbefore the test was 6 4 ,ug./100 ml. and, after 30minutes, the level was 34-7 ,ug./100 ml. This is anormal result.

Case 6. The sixth child, a female, was born spon-

taneously at term in May 1967; birthweight 2940 g.She was cyanosed after birth but improved after suctionof the upper respiratory passages. She remained wellduring the first 48 hours of life and maintained normalserum levels for sodium and potassium. A specimenof cord blood contained cortisol 21 Fg./100 ml. plasmaA specimen of mother's blood, taken at the time ofdelivery, contained 135 ,g/100 ml. A Synacthen30-minute test was performed at the age of 2 months.The results for plasma cortisol were as follows: 6* 4 ,ug./100 ml. before the intramuscular injection of 0-25 mg.Synacthen and 20- 6 ,ug./100 ml. after 30 minutes.This is a normal result.

Discussion

A study of the literature on congenital adrenalhypoplasia indicates striking differences with respectto the time of onset of symptoms, the nature of thesymptoms, and the microscopical appearance ofthe adrenals in the cases examined at necropsy.In the; reported cases, symptoms have appearedeither at birth or at about the third week of life.The later development of symptoms has been ex-plained as a consequence of the protection providedby maternal adrenal cortical hormones. Theratio of maternal-blood to cord-blood levels of17-hydroxycorticosteroids is usually taken to liebetween 5:1 and 2:1 (Aarskog, 1965). Yet, inthe fourth member of this family, with symptomspresent immediately after birth, the ratio was133:1. The mother's level of 17-hydroxycorti-costeroids was remarkably high, though 2 monthsafter delivery it had fallen to nearly normal levels,and the estimation was not abnormal in the fifthpregnancy where the child was unaffected byadrenal hypoplasia. However, the level was againhigh at term in the sixth pregnancy, though theinfant was normal. The high maternal levels inthe fourth pregnancy may have represented aneffort on the part of the maternal adrenals to com-pensate for severe hypoplasia of the fetal adrenals.Despite this, however, little cortisol was demon-strable in cord blood and symptoms began immedi-ately after birth. Actual weight of the adrenalscannot be correlated with length of survival. In thefirstborn child of this family, dying at 18 months,the combined weight of the adrenals (08 g.) wasconsiderably less than the combined weights inmany cases dying at birth.

Variation in the clinical features of the diseasehas also been notable. In the first two days,collapse, cyanosis, convulsions, apnoeic attacks,and vomiting have been the main complaints,suggesting a diagnosis of cerebral haemorrhage.Vomiting, diarrhoea, and electrolyte disturbances

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O'Donohoe and Hollandare more prominent features after the first 2 days,suggesting a diagnosis of congenital adrenal hyper-plasia, and estimations of pregnanetriol and 17-ketosteroids may be necessary to differentiatethe two conditions. Obviously a family historyof the disorder is the most useful single aid to earlyaccurate diagnosis in the newborn. Melanodermiais a clinical sign which has been observed infre-quently, and may have been present at birth inthe first member of this family, gradually intensi-fying up to the time of her death.The curious electrolyte abnormalities in the second

member of the family are not easy to explain.Electrolyte levels of sodium and potassium in theparents have been normal. A normal responseto ACTH does not rule out a possible defect inthe zona glomerulosa, the area where aldosteroneis formed.There has been considerable variation in the

histological appearances in the cases examinedat necropsy as reported by different authors. Themedulla has been either normal or reduced to smallislands of tissue. The cortex has varied from awell-differentiated, though hypoplastic cortex, to acomplete absence of cortical tissue. Kerenyi (1961)divided the cases on the basis of adrenal morphologyinto a group in which the adrenals were of the typeseen in association with anencephaly, and a groupin which the adrenal cortex was composed mainlyof large cells without any distinct arrangement.In the first group, the structure of the adrenals wasof the miniature adult type, resembling the adrenalsof anencephalic monsters, and the layers of thecortex and medulla were recognizable. He sug-gested that, in this type of hypoplasia, the lesionof the adrenal was always associated with a lesionof the pituitary, usually hypoplasia. In hissecond group, the cortex was composed mainly oflarge cells resembling the cells of the fetal zone ofthe cortex. These cells were often very large indeedand were either arranged haphazardly or in columns,and the characteristic layers of the cortex could notbe identified. The borders of the cells werepoorly defined, the nuclei stained poorly, and thecytoplasm was often eosinophilic and finely granular.The pituitary was normal, as were other endocrineorgans. Our necropsied cases seem to fall intoKerenyi's first group as far as histological appearancesare concerned, and yet we have no evidence ofpituitary abnormality. The first child did nothave histological examination of the pituitaryperformed, but she had grown and developednormally up to the time of death. In the secondcase, the histological appearances of the pituitarywere normal. The boy of 4 years, who is on

substitution therapy, shows no clinical evidenceof pituitary hypofunction.One of the most interesting features of the present

family has been the presentation of two of the casesin the immediate neonatal period and the successfultreatment of one of them as a result of the necropsyinformation available from his dead sibs. Thediagnosis in the newborn may be extremely difficultwithout such prior knowledge, since the clinicalmanifestations of collapse, cyanosis, and apnoeicspells are non-specific and since excessive pig-mentation may not be a feature. Any infant withsigns of circulatory failure, lethargy, vomiting,dehydration, and failure to thrive should besuspected of adrenal insufficiency, particularlyif there is a history of unexplained vascular collapseor sudden death in sibs.

Treatment of the surviving case in this familyhas been unexpectedly uneventful. It seemsunlikely that it will be possible to withdraw hiscortisone acetate in the future. Mitchell andRhaney (1963) attempted to do this when theirpatient was aged 5 years, but he became listless,and pigmentation of his skin appeared. His ACTHstimulation test elicited no adrenal response,cortisol being undetectable in his plasma on days2 and 3 of the test. However, it may be possibleto withdraw fludrocortisone in our patient at alater date. There is evidence that disturbancesof electrolyte balance may be present in earlyinfancy but lessen or disappear later on. This isknown to occur in some cases of congenital adrenalhyperplasia with the salt-losing syndrome. Stemp-fel and Engel (1960) described a family with asyndrome of adrenocortical insufficiency similarto that occurring in the family here described.One boy, who was closely studied, had a salt-losing state during the neonatal period whichrequired treatment with cortisone and desoxy-corticosterone acetate (DOCA). DOCA was dis-continued at the age of 22 months and no furtherdisturbance of electrolyte regulation occurred,treatment being maintained with cortisone alone.Urinary aldosterone determinations were carriedout at that stage and fell within the normal range.An interesting feature of the affected children

has been that, in each case, delivery has takenplace past term and labour was induced in twoinstances. The unaffected children have beenborn spontaneously at or before term. Themother has commented that she knows that herchild will be affected if her pregnancy goes overterm. Prolonged pregnancy can occur where thefetus is anencephalic, and anencephalic monstershave hypoplastic pituitary and adrenal glands.

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Familial Congenital Adrenal Hypoplasia 723One may speculate that a disturbance in the relationbetween pituitary and adrenal during pregnancyin cases of adrenal hypoplasia may also account forthe prolongation of pregnancy.

Summary

A family of 6 children is described in which 3members, 2 girls and 1 boy, had congenital adrenalhypoplasia.

REFERENCES

Aarskog, D. (1965). Cortisol in the newborn infant. Acta paediat.(Uppsala), 54, Suppl. 158.

Clayton, B. (1961). Adrenocortical disorders in children. InThe Adrenal Cortex (a Symposium organized by the Associationof Clinical Pathologists), p. 180. Ed. by G. K. McGowan andM. Sandler. Pitman, London.

Kerenyi, N. (1961). Congenital adrenal hypoplasia. Report of acase with extreme adrenal hypoplasia and neurohypophysealaplasia, drawing attention to certain aspects of etiology andclassification. Arch. Path., 71, 336.

Mitchell, R. G., and Rhaney, K. (1959). Congenital adrenalhypoplasia in siblings. Lancet, 1, 488.

-, and- (1963). Congenital adrenal hypoplasia. ibid., 2,1065.

Mosier, H. D. (1956). Hypoplasia of the pituitary and adrenalcortex. J. Pediat., 48, 633.

O'Doherty, N. J. (1964). Lipoid adrenal hyperplasia. Guy'sHosp. Rep., 113,368.

Prader, A. (1967). The adrenal cortex in childhood and adolescence.In The Human Adrenal Cortex: Its Function Throughout Life.pp. 29-47. Ed. by G. E. W. Wolstenholme and R. Porter.Churchill, London.

Roselli, A., and Barbosa, L. T. (1965). Congenital hypoplasia ofthe adrenal glands. Pediatrics, 35, 70.

Sikl, H. (1948). Addison's disease due to congenital hypoplasiaof the adrenals in an infant aged 33 days. J. Path. Bact.,60, 323.

Stempfel, R. S., Jr., and Engel, F. L. (1960). A congenital, familialsyndrome of adrenocortical insufficiency without hypoaldo-steronism. J. Pediat., 57, 443.

Wood, J. B., Frankland, A. W., James, V. H. T., and Landon,J. (1965). A rapid test of adrenocortical function. Lancet, 1,243.

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