Normal male external genitalia do not rule out CYP11A1 deficiency

Abstract

Defects in the initial steps of steroidogenesis usually present with female external genitalia in both 46,XX and 46,XY. Hence, they are not often considered in the differential diagnosis of primary adrenal insufficiency children with normal male external genitalia. Here, we report a boy with normal male external genitalia who presented with hyperpigmentation since the age of 2 years but diagnosis was delayed till 11 years of age. Evaluation revealed low-serum cortisol with elevated adrenocorticotropic hormone and direct renin level confirming primary adrenal insufficiency. Clinical exome sequencing analysis revealed a homozygous c.1351C>T (p.R451W) mutation in exon 8 of the CYP11A1 gene which was confirmed on Sanger sequencing. Both parents were heterozygous for the variation. To conclude, we report the first case of CYP11A1 deficiency from India. The report reiterates the existence of non-classic CYP11A1 deficiency characterised by primary adrenal insufficiency and normal male external genitalia in 46,XY.

Background

A wide variety of causes lead to adrenal insufficiency in children.^{1 2} Congenital adrenal hyperplasia (CAH) refers to a group of disorders characterised by defects in steroidogenesis and the most common among them is 21α hydroxylase deficiency.³ Other causes of CAH are rare. Defects in the initial steps of steroidogenesis are expected to affect the synthesis of not only glucocorticoids and mineralocorticoids, but also sex steroids leading to female external genitalia in both 46,XX and 46,XY.¹ Hence, these conditions are most often not suspected as a cause of adrenal insufficiency in children who present with normal male external genitalia. However, few recent studies have reported normal male external genitalia in children with STAR and CYP11A1 defects.^{4 5} Here, we report a boy with CYP11A1 deficiency who presented with adrenal insufficiency and normal male external genitalia.

Case presentation

A 11-year-old boy presented with complaints of gradually progressive darkening of skin since the age of 2.5 years. He had a history suggestive of neuro-infection at the age of 6 years for which he was hospitalised for 14 days. At the age of 10 years, he consulted a dermatologist for hyperpigmentation where he was subjected to skin biopsy and a diagnosis of carbon baby syndrome was made. A year later, the patient presented to our institute for evaluation of hyperpigmentation where he was suspected to have primary adrenal insufficiency. There was no history of alacrimia, feeding difficulties, behavioural abnormalities or poor scholastic performance, ambiguous genitalia, candidiasis or tetany. He was born of a third-degree consanguineous marriage, cried immediately after birth and had age-appropriate developmental milestones. The family history is summarised in figure 1.

Figure 1.

Summary of family history.

On examination, the child weighed 19 kg and measured 124 cm. He had generalised hyperpigmentation of skin, lips, tongue and buccal mucosa. No goitre was present. Genital examination revealed normal male genitalia with prepubertal sexual maturity rate (stretched penile length of 5 cm with bilateral testicular volume of 2 mL).

Investigations

Serum 08:00 cortisol was 1.63 µg/dL, plasma 08:00 adrenocorticotropic hormone was >1250 pg/mL whereas plasma direct renin was >500 µIU/mL. Thyroid function testing revealed elevated thyroid-stimulating hormone (TSH; 18.28 µIU/mL) with normal T3 (1.83 ng/mL) and T4 (10.58 µg/dL). Anti-thyroid peroxidase (TPO) antibody was negative. Serum electrolyte testing revealed mild hyponatraemia (serum sodium: 133 mEq/L) and normal serum potassium (4.53 mEq/L). He was diagnosed with primary adrenal insufficiency. Clinical exome sequencing analysis revealed a homozygous c.1351C>T (p.R451W) mutation in exon 8 of the CYP11A1 gene which was confirmed on Sanger sequencing. Both parents were heterozygous for the variation.

Treatment and outcome

Patient was started on oral hydrocortisone 10 mg/day and fludrocortisone 0.1 mg/day along with a stress dose of glucocorticoids. Three months later, patient weighed 22.7 kg and measured 125.5 cm with a moderate decrease in pigmentation. Serum potassium was 3.58 mEq/L and sodium was 143 mEq/L. TSH was reduced to 7.85 µIU/mL with normal T3 (1.24 ng/mL) and T4 (11.84 µg/dL).

Discussion

We report the first case of CYP11A1 deficiency from India. CYP11A1 deficiency leads to defective synthesis of mineralocorticoids, glucocorticoids and sex steroids. In classical presentation, 46,XY children with CYP11A1 deficiency present during neonatal period with female external genitalia or ambiguous genitalia and primary adrenal insufficiency with both glucocorticoid deficiency and mineralocorticoid deficiency.² The boy in the present report presented with adrenal insufficiency without ambiguous genitalia. Although all cases of 46XY CYP11A1 deficiency reported before 2011 had either female or severely ambiguous external genitalia,^6–11 many cases with normal or slightly ambiguous (micropenis or hypospadias) male external genitalia have been reported since 2011.^{4 5}

The genetic variation observed in our patient has been reported previously in 11 patients so far. First, it was reported in two 46,XY siblings with CYP11A1 deficiency from Germany who had relatively late onset adrenal insufficiency (2.1–4.5 years) with normal male genitalia.⁴ In fact, these were the first report of 46,XY children with CYP11A1 deficiency having normal male external genitalia. The same mutation is a hot spot mutation in eastern Turkey and has been reported in nine patients (five 46,XX girls, three 46,XY boys with normal male genitalia and one boy with micropenis and cryptorchidism) with primary adrenal insufficiency (diagnosed between 1 and 6 years of age) from Turkey.¹ Five of the 11 patients reported to have this mutation so far, had adequate aldosterone synthesis and presented as isolated glucocorticoid deficiency which may confuse the diagnosis with familial glucocorticoid deficiency.^{1 4} However, such patients should be closely monitored for evolving mineralocorticoid deficiency which may become apparent later as noted in a patient.¹ In 46,XX later presentation of adrenal insufficiency may be the presentation of nonclassic (mild) CYP11A1 deficiency.¹

Although in majority of the cases, there was a correlation of external genital development and onset of adrenal failure with enzyme activity level, it was not perfect.^4–16 Few patients with 46,XY and relatively lower enzyme activity level had normal external genitalia whereas few patients with normal enzyme activity or heterozygous mutation had abnormal genitalia. Similar discordance was also observed between enzyme activity and age at onset of adrenal failure in few patients. However, there was better correlation between age at onset of adrenal failure and genital phenotype among 46,XY CYP11A1 deficiency children.^{1 4–16} 46,XY children with normal or slightly ambiguous male external genitalia had later onset of adrenal insufficiency when compared to those with female or severely ambiguous external genitalia who had their presentation in neonatal or early infancy period.^{1 4–16} Recent studies have identified a large number of CYP11A1 deficiency patients among those with apparent primary adrenal insufficiency without disorder of sex development.^{1 17–20} The studies have also suggested a pathogenic role for few predicted benign (most commonly for p.E341K) and synonymous variants in CYP11A1 by causing aberrant splicing.^18–20

Normal genital appearance does not ensure normal pubertal development or eugonadism in the adulthood.⁵ Hence, all CYP11A1 children should be evaluated for possible hypergonadotropic hypogonadism irrespective of the genital appearance. However, in our child FSH and LH were in the prepubertal range and he has been advised to be under surveillance for pubertal development.

It is also not clear whether the two siblings were 46,XX with normal female external genitalia or 46,XY with female external genitalia due to more severe phenotype. However, it is less likely to have severe phenotype with the described genotype which is associated with relatively well-preserved enzyme activity (30%) and apparent male external genitalia in all the reported 46,XY cases including the index case of the present report.⁴ A previous study has also reported a sibling of CYP11A1 deficiency boy who had female external genitalia but unrecognised karyotype and died at the age of 6.3 years.⁵

It was likely that the two siblings who had hyperpigmentation since around the age of 2 years also had adrenal insufficiency. One sibling died due to presumed neuro-infection is likely to be a missed case of hypoglycaemia due to glucocorticoid deficiency during a febrile illness with infection elsewhere. Death in another sibling during an episode of acute gastroenteritis is most likely due to unrecognised and untreated adrenal crisis precipitated by acute gastroenteritis. Even in the index case, despite an episode suggestive of neuro-infection the diagnosis of primary adrenal insufficiency was missed, and hyperpigmentation was wrongly attributed to carbon baby syndrome. It was unfortunate that both the siblings died probably due to unrecognised adrenal insufficiency despite definitive history of hyperpigmentation. Hence, it is highly essential to increase the awareness of adrenal insufficiency among paediatricians and dermatologists.

High TSH suggested the possibility of autoimmune polyglandular syndrome. However, anti-TPO was negative suggesting against this possibility. Moreover, there was no goitre. Hence, possibility of high TSH due to cortisol deficiency was suspected and it was decided not to start on thyroxine. TSH level decreased during the follow-up suggesting elevation of TSH due to glucocorticoid deficiency. However, the possibility of recovery phase of sick euthyroid syndrome (less likely since there was no history of acute illness in the preceding 6 months) or subacute thyroiditis cannot be disregarded.

Learning points.

• We report the first case of CYP11A1 deficiency from India.

• The report reiterates the existence of non-classic CYP11A1 deficiency, characterised by primary adrenal insufficiency and normal male external genitalia in 46,XY.

• There is a great need to increase awareness of adrenal insufficiency among paediatricians and dermatologists.

• Glucocorticoid deficiency may lead to elevated TSH which normalises with glucocorticoid replacement.