ATYPICAL CONGENITAL ADRENAL HYPERPLASIA (CAH) PRESENTATION OF A PATIENT, RESULTING IN A SIMILAR DIAGNOSIS FOR HIS SIBLING

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Introduction
Congenital adrenal hyperplasia (CAH) is the commonest cause of primary adrenal insufficiency with an autosomal recessive inheritance pattern.It is characterized by cortisol deficiency and androgen excess due to a deficiency in the 21-hydroxylase enzyme.21-hydroxylase deficiency is the commonest cause of CAH and occurs in 95% of all CAH cases.It results from a mutation in the encoding gene of CYP21A2.
CAH can be divided into three different categories as according to the spectrum of disease severity.The categories are not only different in its clinical presentation, but also in the biochemical data.The categories include classical salt-wasting CAH, classical simple virilizing CAH (SV CAH) and non-classical CAH (NCCAH).Classical salt-wasting CAH is the most severe form due to severe deficiency of 21hydroxylase enzyme resulting in decreased production of both cortisol and aldosterone.Patients typically present with dehydration, electrolyte imbalances and adrenal crisis which can be lifethreatening.Classical simple virilizing CAH is the less severe disease spectrum of CAH as the deficiency of 21-hydroxylase enzyme is less than the former, resulting in decreased production of cortisol, however with relatively normal aldosterone production.This results in clinical presentation of excess androgen production including atypical genitalia presentation in female infants.NCCAH is the least severe form as the 21-hydroxylase enzyme deficiency is only partial hence the hormonal deficiency is only mild.Patients may present later in life, with virilisation due to androgen excess such as virilized females and precocious puberty in males.Some patients may even be asymptomatic.
A recent meta-analysis summarizing 58 studies and 31 countries reported an overall incidence of classic CAH of 1:9,498 [1].Singapore, a neighbouring country, reported an incidence of 4.5 per 100,000 live births [2].NCCAH is more common, with estimated prevalence of 1 in 200 among Caucasians [3].Malaysia, a developing country in Southeast Asia, has limited data on the incidence of CAH partly due to the absence of newborn screening for CAH.In countries without CAH newborn screening, the diagnosis of CAH is often delayed.It is crucial to train the health care workers on early detection of the clinical features of CAH to avoid complications and mortality of this condition [1].
We describe a pair of CAH siblings, born of a nonconsanguineous union.The elder sibling was diagnosed as classical simple virilizing CAH, as he initially presented with precocious puberty as a sequela of androgen excess, with subsequent stimulation test that was in consistent with CAH.The younger sibling was screened after birth to avoid the possibility of late presentation as the elder sibling.

Patient 1
A 4-year-old Malay boy was referred to the clinic with signs of virilization and body odour for 2 months.There was presence of pubic hair and acne.Besides that, he was noted to be taller than his peers with a recent height spurt.
He was born premature at 34 weeks via emergency lower segment caesarean section due to bleeding placenta praevia type II with a birth weight of 2.1 kg.He was transferred to the neonatal intensive care unit (NICU) due to prematurity.During the NICU stay, he had a transient episode of recurrent hypoglycaemia at day 2 of life, that resolved after 1 day.He was discharged home after 1 week.He has been well since then and has not required hospitalisation for any severe illnesses.
The patient has been on regular follow up at the local public health clinic, fully immunized up to age without any complications.On review of his early growth, his height velocity has been above average even between the 1 st and 2 nd year of life at 16.8 cm/year without any clinical suspicion during follow up.There was no significant family history, and his parents were not consanguineous.There was no significant drug history including no history of prolonged or recent steroid medication, as he was previously well.
On physical examination, there was no obvious hyperpigmentation.The standing height was at the 95 th centile, mid-parental height was 167.5 cm (10 th centile), his weight was at the 75 th -90 th centile and his body mass index (BMI) at the 5 th -10 th centile.
There was facial acne with signs of precocious puberty including Tanner II genitalia with stretched penile length of 7 cm, pubic hair, and bilateral testicular volume of 4 mls.
Baseline gonadotropins which were taken at noon was not elevated, therefore stimulation test was done.The luteinizing hormone releasing hormone (LHRH) test using gonadorelin 2.5 mcg/kg confirmed premature activation of the hypothalamic-pituitary gonadal axis.Baseline LH was low (<0.1 IU/L); however, the peak was elevated at 11.4 IU/L.He had a significantly advanced bone age of 11.4 years, which was 7 years more advanced than his chronological age.The clinical findings were initially suspicious of peripheral precocious puberty (PPP), however the LHRH test has confirmed CPP.Other investigations including serum beta-human chorionic gonadotropins (ß-HCG), alpha-fetoprotein (α-FP) and magnetic resonance imaging (MRI) brain were otherwise normal.
Assessments for baseline adrenal function were suspicious of primary adrenal insufficiency with low cortisol and elevated 17-hydroxyprogesterone (17OHP).Testosterone was detected.The adrenocorticotropic hormone (ACTH) level was significantly elevated, at 2.8 times the upper limit of normal.
Short Synacthen test was performed using Synacthen 250 mcg, showed low cortisol level (85.4 nmol/L).The baseline and peak 17OHP (243 nmol/L and 931 nmol/L respectively) were both significantly elevated.The 17OHP:cortisol ratio at 30 minutes was very high at 12.9.For the mineralcorticoid pathway assessment, repeated sodium and potassium remained normal, however, the renin was elevated at 166.5 mU/L (normal range 4.2 -59.7) and the aldosterone was 155 pmol/L (normal range 102 -859).
Financial constraints and parental refusal precluded any genetic analyses to determine the genetic variants of CAH in this case.A diagnosis of simple virilizing CAH and CPP was made, and hydrocortisone, fludrocortisone and GnRH analogue were started.

Patient 2
After 2 years of follow up, the parents had another child.A male newborn who was born at late premature at 36 weeks' gestation, via emergency lower segment caesarean section due to premature rupture of membrane, born with a birth weight of 2.7 kg.The baby was born vigorous, with no complications during the intrapartum and postnatal period and was discharged to mum after birth.
The parents brought the child to our clinic, at 2 months old.On our review, the baby appeared healthy, with no signs of obvious hyperpigmentation.The parents were offered to do baseline laboratory screening of CAH for the newborn, in view of the late presentation of his elder brother with simple virilizing CAH complicated with CPP.The result of the baby showed a normal baseline cortisol however the 17OHP was markedly raised (Table1).Serum sodium and potassium were borderline low and high respectively.Testosterone was measurable, however not suspicious considering the mini-puberty period.
A short Synachten test using a Synacthen dose of 36 mcg/kg for age less than 6 months showed normal baseline cortisol with a suboptimal cortisol peak (223.1 nmol and 430.6 nmol/L respectively).The levels of 17OHP at baseline and peak were markedly elevated (427.8 and 787.8 nmol respectively), with a high 17OHP:Cortisol ratio at 30 minutes with a value of 2.3.The renin was markedly elevated with normal range of aldosterone.
In view of the abnormal short Synachten test, borderline serum sodium and potassium and elevated renin, this patient was also diagnosed as simple virilizing CAH.Hydrocortisone and fludrocortisone were started soon after.The parents once again were advised on genetic testing in view of having two offspring with clinically diagnosed CAH.However, this time, the parents were not keen for genetic testing as they have completed their family.[4,6].
Patient 1 illustrates presentation of a male patient who was investigated for clinical signs of PPP, including Tanner 2 genitalia, growth spurt and significantly advanced bone age.Further workup for PPP confirmed the primary cause to be simple virilizing CAH.Stimulation test for precocious puberty however confirmed CPP with elevated stimulated LH (>5 IU/L).CPP has occurred in this case as a result of chronic androgen excess from untreated CAH, that has activated the central puberty [7].CPP can be triggered in this situation because of virilization that has occurred for several years, that has matured the hypothalamic-pituitary-gonadal axis.This can be due to due to late commencement of corticosteroid, or due to its poor compliance [8].CPP as a presentation of classical SV CAH is uncommon, however there were studies that have shown that the patients who developed this complication would benefit from GnRH analogue therapy [8,9].Treatment aims to control the CAH as well as suppress puberty with GnRHa.GnRHa therapy may slow the advancement of bone age that will result in slight improvement in predicted adult height.Treatment is recommended to be commenced immediately once these CAH patients have features consistent with CPP [9].
Clinical suspicion due to family history is important in this case.In the absence of the family history, this case would probably been missed.Clinical features of CAH in the younger sibling were lacking, including with the absence of any obvious hyperpigmentation.Hyperpigmentation is a common clinical finding in CAH.In CAH, ACTH level is elevated as body tries to stimulate cortisol production.This would concurrently result in hyperpigmentation due to increased melanin.In our patients, the ACTH levels were elevated however, there was no obvious hyperpigmentation, likely due to their own skin colour which is slightly tanned as they are both of Malay ethnicity.Furthermore, patient 2 exhibits mild disease with only suboptimal cortisol level in the short Synacthen test, therefore obvious hyperpigmentation was not observed.
On review of the baseline mineralcorticoid assessment, patient 2 was noted to have subtle saltwasting with the borderline sodium and potassium balance.SV CAH may demonstrate disturbance in aldosterone synthesis; therefore, overstimulation of renin will result in production of normal aldosterone.This explains why mineralcorticoid therapy must be considered in SV CAH [10].
In consideration of the late diagnosis of simple virilizing CAH complicated with CPP in patient 1, the parents were offered screening for their newborn (Patient 2), to avoid a similar sequela as the elder sibling.Individual screening was considered in our case, due to the absence of newborn screening in Malaysia.Newborn screening for CAH has the advantage of preventing newborns from presenting with life-threatening adrenal crisis, implementing early treatment and assisting in appropriate genderassignment for affected female infants [11].Newborn screening should implement the detection of 17OHP [4].Newborn screening has been implemented in many countries, as recommended by international endocrine societies [12,13].In Japan, the newborn screening has been successful with significantly improved clinical outcomes of 21OHD CAH with earlier first visit to hospitals with no fatal cases identified [11].Early diagnosis of CAH is important as late diagnosis results in physical, psychological and neurological damage to patients which are the results of delayed treatment, hence the severe sequelae [14].
Treatment of classical CAH requires glucocorticoid and mineralocorticoid replacement if necessary.It is important to note that CAH children requires not only early diagnosis, but also good clinical and biochemical control of the disease to achieve normal final adult height [15].Management of CAH in developing countries is challenging extending from newborn screening, early diagnosis, treatment, limited availability of paediatric endocrinologists and not forgetting the socioeconomic and cultural issues [13].Improvement of growth, final adult height, fertility, bone health & metabolic parameters can be achieved with early diagnosis and lifelong treatment, along with multidisciplinary team management [16].

Conclusion
This pair of cases highlights that all young children who present with clinical signs of peripheral precocious puberty must be investigated for CAH.CAH can present with PPP that can progress to CPP which requires appropriate evaluation and treatment to preserve the bone age and height potential.Finally, these cases highlight the fact that siblings of affected children with CAH must be screened early for the possibility of CAH, especially in countries where newborn screening for CAH is not offered.It is important to implement education among health care workers on early recognition of CAH in the population in the absence of newborn screening as early diagnosis and treatment lead to better outcome for the patients.

Disclosure
Part of this case report has been presented at the Malaysian Endocrine & Metabolic Society Annual Congress (MAC13) and the abstract has been published in Journal of The ASEAN Federation of Endocrine Societies, in July 2023.