Severe Salt-Losing 3β-Hydroxysteroid Dehydrogenase Deficiency: Treatment and Outcomes of HSD3B2 c.35G>A Homozygotes (original) (raw)

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1Clinic for Special Children (A.R.B., M.Y., D.R., C.H., K.A.S.), Strasburg, Pennsylvania 17579;

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1Clinic for Special Children (A.R.B., M.Y., D.R., C.H., K.A.S.), Strasburg, Pennsylvania 17579;

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1Clinic for Special Children (A.R.B., M.Y., D.R., C.H., K.A.S.), Strasburg, Pennsylvania 17579;

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1Clinic for Special Children (A.R.B., M.Y., D.R., C.H., K.A.S.), Strasburg, Pennsylvania 17579;

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2Department of Pediatric Endocrinology (P.A.L.), Pennsylvania State University Milton S. Hershey Medical Center, Hershey, Pennsylvania 17033;

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1Clinic for Special Children (A.R.B., M.Y., D.R., C.H., K.A.S.), Strasburg, Pennsylvania 17579;

3Franklin and Marshall College (K.A.S.), Lancaster, Pennsylvania 17603;

4Lancaster General Hospital (K.A.S.), Lancaster, Pennsylvania 17602

*Address all correspondence and requests for reprints to: Kevin A. Strauss, MD, Clinic for Special Children, 535 Bunker Hill Road, Strasburg, PA 17579.

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Published:

01 August 2015

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Abigail R. Benkert, Millie Young, Donna Robinson, Christine Hendrickson, Peter A. Lee, Kevin A. Strauss, Severe Salt-Losing 3β-Hydroxysteroid Dehydrogenase Deficiency: Treatment and Outcomes of HSD3B2 c.35G>A Homozygotes, The Journal of Clinical Endocrinology & Metabolism, Volume 100, Issue 8, 1 August 2015, Pages E1105–E1115, https://doi.org/10.1210/jc.2015-2098
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Context:

3-β-hydroxysteroid dehydrogenase (HSD3B2) deficiency accounts for less than 5% of congenital adrenal hyperplasia worldwide, but is relatively common among the Old Order Amish of North America due to a HSD3B2 c.35G>A founder mutation.

Objective:

We review clinical presentation, disease course, treatment, and outcomes of a genetically homogenous population of HSD3B2-deficient patients.

Design and Participants:

This was a retrospective case series: anthropometric, biochemical, and clinical data from 16 (six male) affected subjects (age, 7.2 ± 6.4 y) were compared to reference data from 12 age-matched unaffected siblings.

Setting:

The setting was the Clinic for Special Children, a nonprofit rural community health center in Lancaster, Pennsylvania.

Main Outcome Measures:

The main outcome measures were growth, skeletal maturation, sexual development, blood pressure, glucocorticoid dose, pituitary-adrenal homeostasis, and long-term morbidity.

Results:

Exogenous glucocorticoid requirement was dichotomous: a standard-dose group (n = 9) required 15.4 ± 4.9 mg/m2/d hydrocortisone equivalent, whereas a high-dose group required much larger and more variable doses (hydrocortisone equivalent, 37.8 ± 15.4 mg/m2/d) (P < .0001). Despite glucocorticoid doses 2-fold higher than the standard-dose group, high-dose patients: 1) had ACTH, 17-hydroxypregnenolone, and dehydroepiandrosterone levels that were 10-fold, 20-fold, and 20-fold higher, respectively; 2) were exclusively affected by signs of sex steroid excess; and 3) tended to have more iatrogenic complications.

Conclusions:

Patients with HSD3B2 deficiency and 21-hydroxylase deficiency suffer similar morbid complications from under- and overtreatment, but HSD3B2 deficiency is associated with a distinctive pattern of sex steroid dysmetabolism. Disease- and treatment-related morbidities are almost exclusively observed among subjects who have a high exogenous glucocorticoid requirement.

Congenital adrenal hyperplasia (CAH) results from deficiency of any one of five enzymes that mediate synthesis of cortisol from cholesterol in adrenal cortical cells (1). Absolute cortisol deficiency and loss of its endogenous diurnal rhythm is common to all forms of CAH and predisposes individuals to life-threatening adrenal crises characterized by hypoglycemia, hemodynamic instability, and electrolyte disturbances. Chronic cortisol deficiency drives compensatory hypersecretion of ACTH by pituitary corticotrophs, which results in hyperplasia of the adrenal cortex, skin hyperpigmentation, and in some cases, growth of ectopic adrenal tissue within the gonads. Abnormal sex steroid homeostasis is a common feature of CAH, but the specific pattern and its clinical impact vary depending on the particular enzyme deficiency and its treatment (1).

Salt-losing 3-β-hydroxysteroid dehydrogenase (HSD3B2) deficiency (MIM 201810) is a rare form of CAH within outbred populations (2), but occurs frequently among the Old Order Amish of North America due to a c.35G>A founder mutation of HSD3B2. HSD3B2 is expressed in adrenal gland and gonadal tissue (3), where it normally catalyzes the conversion of pregnenolone, 17-hydroxypregnenolone (17OHPreg), and dehydroepiandrosterone (DHEA) into aldosterone, cortisol, and androstenedione, respectively (Figure 1A). Consequently, loss of HSD3B2 activity results in aldosterone, cortisol, and androstenedione deficiencies, as well as accumulation of proximal adrenal hormone intermediates, including the relatively weak androgen, DHEA (2). A second isozyme (HSD3B1) is 93.5% homologous to HSD3B2 and is expressed in peripheral tissues (eg, skin, mammary gland, placenta), where it mediates transformation of circulating DHEA into more potent sex steroids such as testosterone (T) and estradiol (Figure 1A) (4).

Figure 1.

A, Biosynthesis of hormones from cholesterol in adrenal and extraadrenal tissues. The conversion of pregnenolone (Preg), 17OHPreg, and DHEA to progesterone (Prog), 17-hydroxyprogesterone (17-OHP), and androstenedione (AD), respectively, depends on type II HSD3B2. The HSD3B2 c.35G>A founder mutation abrogates enzyme function, and cortisol deficiency releases feedback inhibition on pituitary corticotrophs, which hypersecrete ACTH. High circulating ACTH drives biosynthesis of steroid intermediates and hyperplastic remodeling of the adrenal glands, and can also stimulate formation of ectopic adrenal tissue in the gonads (eg, TARTs). In patients who lack HSD3B2, proximal steroid intermediates such as DHEA can be converted to more potent downstream sex steroids (eg, T, 5-dihydrotestosterone [5-DHT], and estradiol [E2]) via HSD3B1 action in peripheral tissues like skin and mammary gland. Metabolites typically used to monitor HPA axis activity in patients with HSD3B2 deficiency appear in blue font. B and C, We observed strong correlations among the three hormones (ACTH, 17OHPreg, DHEA) used for monitoring HSD3B2 deficiency. D, To improve the convenience and flexibility of monitoring, we developed methodology to measure DHEA from dried filter paper blood spots collected from home with ELISA (x-axis), and validated the results against those from a CLIA-certified endocrine reference laboratory (Esoterix; y-axis). Abbreviations: 11-DOC, 11-deoxycortisol; DHEA-S, DHEA-Sulfate.

Here we present clinical and biochemical data from 16 HSD3B2 c.35G>A homozygotes (ages 0.6 to 22.6 y) managed at a single center between 1992 and 2015. The overall type and prevalence of disease complications were similar to those observed among larger 21-hydroxylase (CYP21A2) deficiency cohorts (5–7), but abnormalities of sexual development, bone maturation, and reproductive health revealed a pattern of sex steroid dysmetabolism particular to HSD3B2 deficiency. Most HSD3B2 c.35G>A homozygotes required glucocorticoid doses similar to published CAH norms, but nearly half (n = 7; 44%) required considerably higher doses to control ACTH secretion and adrenal steroid biosynthesis. Only this latter group suffered morbid complications of both sex steroid excess and glucocorticoid toxicity, raising important questions about medication adherence (8), hypothalamic-pituitary-adrenal (HPA) adaptation (9), and optimal treatment for high-risk patients (10).

Patients and Methods

Patients

We cared for 16 (six male) individuals homozygous for HSD3B2 c.35G>A (age, 7.2 ± 6.4 y; range, 0.6–22.6 y) between 1992 and 2015 (116 cumulative patient-years) using the strategy outlined in Supplemental Table 1. Anthropometric, hemodynamic, and biochemical data were compared to similar measures from 12 age-matched (P = .309) unaffected siblings (age, 8.5 ± 4.0 y). The two oldest patients were lost to follow-up; detailed biochemical profiling was only completed on 14 patients (nine standard dose [SD], five high dose [HD]) in our cohort. The study was approved by the Institutional Review Board of Lancaster General Hospital, and parents consented to research on behalf of their children.

Clinical methods

Between 1992 and 2008, all HSD3B2 c.35G>A homozygotes were treated with thrice daily hydrocortisone. Three patients remain on this regimen. Between 2009 and 2010, after favorable longer-term reports (11), we switched several patients to morning dexamethasone. However, two of them developed early morning hypoglycemia, prompting a change to nocturnal dexamethasone dosing as described for CYP21A2 deficiency (12). At present, the majority (81%) of HSD3B2 c.35G>A homozygotes are treated with liquid dexamethasone (0.1 mg/mL) administered between 8 and 10 pm each evening. Based on our longitudinal observations, we estimate the hydrocortisone:dexamethasone glucocorticoid equivalency to be 70:1.

We provided all families with an emergency action plan (Supplemental Data) and instructions about how to deliver intramuscular hydrocortisone acetate and implement hydrocortisone stress-dosing (75–100 mg/m2/d, divided every 6 h) as needed. Fludrocortisone (100 μg) was prescribed twice daily during the first 12–18 months of life and once daily thereafter. Most children, particularly those treated with dexamethasone, received supplemental sodium chloride (2–5 mEq/kg/d) during the first year of life.

Most biochemical measurements were collected at two specific time points: early morning (ie, between 6 and 7 am) after an overnight fast, and early evening (ie, between 5 and 7 pm), just before the evening glucocorticoid dose. This allowed us to capture two physiological peaks of endogenous daily HPA activity, determine hormonal control at “trough” exogenous glucocorticoid levels, and assess the integrity of overnight counter-regulatory physiology. To improve the convenience and flexibility of monitoring, we developed and validated a novel method for measurement of DHEA from dried filter paper blood spots using an ELISA (four-parameter fit logarithmic curve, quantitation range, 0–3000 ng/dL; lower limit of detection, 30 ng/dL; 90% recovery) (Figure 1D).

For subjects of appropriate maturity, we collected 24-hour urine 17-ketosteroids and pregnenetriol. Plasma renin activity (PRA) was used as an index of renal mineralocorticoid receptor activation (13). We obtained radiographs of the left hand to determine skeletal maturity (bone age) according to the method of Greulich and Pyle (14). We used fasting lipoproteins, 25-hydroxyvitamin D, PTH, osteocalcin, and the homeostatic model assessment (HOMA) index as markers of lipid, bone, and insulin dysmetabolism.

Optimal glucocorticoid dosing

Glucocorticoid doses were adjusted based on clinical indices of undertreatment (eg, hyperpigmentation, acne, hirsutism, premature thelarche, accelerated linear growth, advanced skeletal maturation, testicular adrenal rest tumors [TARTs]) or overtreatment (eg, obesity, slow linear growth, delayed skeletal maturation) (Supplemental Table 1). Serum concentrations of ACTH, DHEA, and 17OHPreg were used to determine HPA axis control in response to exogenous glucocorticoids. Among these, 17OHPreg was most volatile and proved least useful as a monitoring variable, but it was deemed acceptable within 10 times the age-adjusted upper limit. Glucocorticoid doses were primarily adjusted to maintain ACTH and/or DHEA levels between the mean and two times the age-adjusted upper limit of normal (15–17). The more potent sex steroids—androstenedione, T, and estradiol—were measured selectively among patients who had clinical signs of delayed sexual development or sex steroid excess.

Statistical methods

We used one-way ANOVA followed by Tukey pairwise post-testing to compare hemodynamic and biochemical data among three groups: unaffected sibling controls, CAH SD glucocorticoid, and CAH HD glucocorticoid. Fisher's exact test was used to determine differences in morbid outcomes between SD and HD groups. For continuous variables compared between two groups (eg, age, exogenous glucocorticoid dose), we used the unpaired t test with Welch's correction (not assuming equal variances). All statistical analyses were performed with Prism 6 (GraphPad Software, Inc).

Results

The constellation of morbidities associated with severe HSD3B2 deficiency changes with age. Risk for adrenal crisis begins immediately after birth and persists for life. Infants can also have growth failure, salt wasting, hyperkalemic acidosis, and hypospadias (males). Complications of endogenous sex steroid excess (undertreatment) and exogenous glucocorticoid toxicity (overtreatment) become more problematic with advancing age. Four case studies detailed in the Supplemental Data represent the most serious complications of HSD3B2 deficiency.

Clinical presentation of HSD3B2 c.35G>A homozygotes

17-Hydroxyprogresterone levels from filter paper blood spots of HSD3B2 c.35G>A homozygotes were 106.8 ± 25.9 ng/mL (range, 1.3–302.8 ng/mL). Five newborns (31%) had a 17-hydroxyprogresterone level below the state cutoff for referral (<19 ng/mL) and thus were not detected by newborn screening. Affected children with false-negative newborn screening results came to clinical attention because of perinatal adrenal crisis (n = 1), hypospadias (n = 2), or high-risk molecular screening prompted by an affected older sibling (n = 2). We did not observe ambiguous genitalia among 10 newborn females with HSD3B2 deficiency. All males were born with hypospadias requiring surgical repair.

Glucocorticoid treatment and monitoring

Patients homozygous for HSD3B2 c.35G>A fell into two distinct groups (P < .0001) (Table 1) with regard to exogenous glucocorticoid requirement. A SD group (n = 9; age, 3.7 ± 3.0 y) required glucocorticoid doses comparable to those reported for most salt-wasting CYP21A2-deficient patients (dexamethasone, 0.22 ± 0.07 mg/m2/d; hydrocortisone equivalent, 15.4 ± 4.9 mg/m2/d) (1, 18, 19), whereas a HD group (n = 7; age, 5.6 ± 4.0 y) required considerably larger and more variable doses (dexamethasone, 0.54 ± 0.22 mg/m2/d; hydrocortisone equivalent, 37.8 ± 15.4 mg/m2/d) to control corticotroph ACTH secretion and sex steroid excess (Table 1 and Figure 2).

Table 1.

Hemodynamic and Biochemical Measurements of HSD3B2 c.35G>A Homozygotes and Sibling Controls

Abbreviations: BP, blood pressure; LDL, low-density lipoprotein; HDL, high-density lipoprotein; na, not applicable.

*

, P < .05;

**

, P < .01;

***

, P < .001;

****

, P < .0001.

a

The two oldest HSD3B2-deficient patients were lost to follow-up and did not participate in this detailed biochemical profiling study.

b

Measured in pubertal males only (n = 2).

c

HOMA insulin resistance index is calculated as [(insulin in μIU/mL) (glucose in mg/dL)]/405. Values >2.77 are an index of tissue insulin resistance.

Table 1.

Hemodynamic and Biochemical Measurements of HSD3B2 c.35G>A Homozygotes and Sibling Controls

Abbreviations: BP, blood pressure; LDL, low-density lipoprotein; HDL, high-density lipoprotein; na, not applicable.

*

, P < .05;

**

, P < .01;

***

, P < .001;

****

, P < .0001.

a

The two oldest HSD3B2-deficient patients were lost to follow-up and did not participate in this detailed biochemical profiling study.

b

Measured in pubertal males only (n = 2).

c

HOMA insulin resistance index is calculated as [(insulin in μIU/mL) (glucose in mg/dL)]/405. Values >2.77 are an index of tissue insulin resistance.

Figure 2.

Patients homozygous for HSD3B2 c.35G>A fell into two distinct groups with regard to exogenous glucocorticoid requirements (P < .0001).

A, A SD (blue circles) group (n = 9; age, 3.7 ± 3.0 y) required mean dexamethasone doses of 0.22 ± 0.07 mg/m2/d (hydrocortisone equivalent, 15.4 ± 4.9 mg/m2/d), comparable to those reported for most salt-wasting CYP21A2-deficient patients (gray shaded area). A HD (green squares) group (n = 7; age, 5.6 ± 4.0 y) required considerably larger and more variable doses (dexamethasone, 0.54 ± 0.22 mg/m2/d; hydrocortisone equivalent, 37.8 ± 15.4 mg/m2/d) to control corticotroph ACTH secretion and overproduction of adrenal intermediates. B, A shift in the relationship between prescribed dexamethasone and DHEA levels suggests either medication nonadherence or altered homeostatic control of the HPA axis.

At all timepoints, significant correlations were observed between 17OHPreg and DHEA (rs = 0.73; P < .0001), ACTH and DHEA (rs = 0.60; P < .0001), and ACTH and 17OHPreg (rs = 0.80; P < .0001) among both groups (Figure 1, B and C). We thus implemented streamlined testing using quantification of DHEA from dried filter paper blood spots collected from home at 7 am and 5 pm (Figure 1D). In aggregate, ACTH, 17OHPreg, and DHEA were elevated in patients relative to their unaffected siblings and published reference intervals, but this difference was largely attributable to the HD group (Table 1 and Figures 2 and 3).

Figure 3.

A–C, Aggregate biochemical monitoring data from HSD3B2 c.35G>A homozygotes during the first 14 years of life show elevated ACTH (A), 17OHPreg (B), and DHEA (C) relative to age-matched unaffected siblings (white diamonds).

Hormone levels were more elevated in HD (green squares) as compared to SD (blue circles) patients. Published reference intervals are represented as gray shaded areas; lighter gray shaded regions delimit target ranges two times, 10 times, and two times the upper limit of normal for ACTH, 17OHPreg, and DHEA, respectively. Symbols for HD and SD groups depict mean value ± 1 standard deviation above the mean binned by age group. Note that all y-axes are log10 scale. D–F, Body mass index (D), length (E), and bone age (F) measurements from HSD3B2 c.35G>A homozygotes in the HD (green squares) and SD (blue circles) groups are compared to similar measures from age-matched unaffected siblings (white diamonds) and published reference standards (gray shaded areas, mean ± 2 standard deviations).

Early morning glucose levels were 8% lower in HSD3B2 c.35G>A homozygotes compared to their unaffected siblings (Table 1) but never reached dangerously low levels in patients treated with nocturnal dexamethasone. Morning insulin, glycohemoglobin, and β-hydroxybutyrate levels did not differ among groups, indicating intact counter-regulatory physiology.

Hyperlipidemia and insulin resistance (HOMA index > 2.77) were present in 47% and 15% of patients, respectively, but did not differ from sibling controls (Tables 1 and 3). Serum osteocalcin levels were low in patients compared to unaffected siblings (P = .0021), with a greater reduction observed in HD patients. PTH and 25-hydroxyvitamin D levels did not differ among groups (Table 1).

SD and HD group differences

Despite HD glucocorticoid doses 2-fold higher than the SD group, patients had ACTH, 17OHPreg, and DHEA levels 10-fold, 20-fold, and 20-fold higher, respectively (Table 1). Urinary 24-hour pregnenetriol, a marker of integrated 17OHPreg production, was 50-fold higher in HD relative to SD patients.

Complications of adrenal insufficiency (adrenal crisis, hypoglycemia, hyperkalemic acidosis, and failure to thrive) were similar between SD and HD groups (Table 2). In contrast, HD patients were exclusively affected by complications of ACTH and sex steroid excess, including advanced skeletal maturation (57%), hirsutism/acne (71%), TARTs (33% of males), and polycystic ovary syndrome (29% of females). Testosterone was detectable in two pubertal age males—one from the SD group (age, 12.3 y; total T, 53 ng/dL), and one from the HD group (age, 12.4 y; total T, 269 ng/dL)—and estradiol was present in both SD and HD subjects (mean, 8 ± 24 and 16 ± 19 pg/mL, respectively) (Table 1 and Figure 1A).

Table 2.

Complications Among 16 HSD3B2 c.35G>A Homozygotes

Abbreviations: na, not applicable; OR, odds ratio; CI, confidence interval.

a

In two of three cases resulting in early morning seizure.

b

All males (n = 6) were born with hypospadias requiring surgical repair.

c

Among females of reproductive age.

Table 2.

Complications Among 16 HSD3B2 c.35G>A Homozygotes

Abbreviations: na, not applicable; OR, odds ratio; CI, confidence interval.

a

In two of three cases resulting in early morning seizure.

b

All males (n = 6) were born with hypospadias requiring surgical repair.

c

Among females of reproductive age.

There was a trend toward more iatrogenic complications in the HD group, but this was only significant for obesity, which was not observed among SD patients but was present in 71% of those treated with HD glucocorticoid (Table 2). It was not uncommon to observe simultaneous signs of overtreatment (Cushingoid appearance, delayed skeletal maturation, hypertension) and undertreatment (high ACTH, hyperpigmentation, TARTs, hirsutism) in affected individuals from the HD group, particularly after age 8 years.

Morbidity

Complications among 16 HSD3B2 c.35G>A homozygotes are summarized in Table 2. The most common electrolyte abnormality during infancy was hyperkalemic acidosis, detected in 38% of patients during the first year of life. For two children, routine outpatient monitoring revealed hypokalemic alkalosis, an indication of iatrogenic hyperaldosteronism.

Growth disturbances were common during infancy and adolescent-adult life; 31% of infants had slow weight gain, whereas 50% of patients ≥ 4 years old were obese. Advanced skeletal maturation and precocious puberty were observed in 80% of patients older than 8 years. Both adult females (ages, 18.5 and 22.3 y) developed polycystic ovary syndrome and morbid obesity (body mass indices, 40.7 and 43.8 kg/m2).

Relative to age-matched sibling controls, 63% of affected subjects were hypertensive regardless of treatment strategy (Table 1). In aggregate, mean PRA was 3.75 ± 8.26 ng/mL/h; 67% of PRA values were within the reference range (0.25–5.82 ng/mL/h). PRA values were 87% lower in hypertensive (mean, 0.073 ± 0.019 ng/mL/h) as compared to nonhypertensive CAH patients (mean, 0.573 ± 0.318 ng/mL/h; P = .02). Mean serum creatinine was reduced in CAH patients (0.30 mg/dL in total cohort; 0.228 mg/dL in hypertensive patients; 0.365 mg/dL in nonhypertensive patients; P < .0001) relative to sibling controls (0.42 mg/dL; P = .004), despite similar 24-hour urine creatinine excretion.

There were a total of 10 urgent hospitalizations for CAH-related illness, and the average length of stay was 4.2 ± 8.1 days (range, 1–27 d; mean, 0.4 hospital days per patient per year). Six patients (38%) were hospitalized for adrenal crises at an average age of 32 months (range, 0 to 111 mo). Two crises manifested as life-threatening hypoglycemic seizures after an overnight fast (ages 16 and 33 mo). One child developed refractory hyponatremia, hyperkalemia, and hypotension 4 hours after birth, remained in extremis for 30 hours, and suffered neurological sequelae of severe ischemic encephalopathy (Supplemental Data, case 1).

Discussion

Glucocorticoid selection

CAH is most often treated with short-acting hydrocortisone (5, 20, 21), but more potent, long-acting glucocorticoids have been successfully used to manage children with CYP21A2 deficiency (11). Dexamethasone at bedtime quells the adrenal sex steroid production that typically occurs 6 hours after the preceding hydrocortisone dose (12). This early morning adrenal “escape” likely contributes to complications of sex steroid excess in children who otherwise appear under good biochemical control when monitored during normal “clinic hours.”

Dexamethasone therapy is associated with lower adrenal sex steroid production but is not without risks (22). Cushingoid effects and deceleration of bone maturation can develop quickly in dexamethasone-treated patients from the HD group, and chronic dexamethasone therapy may also increase their long-term risks for insulin resistance, decreased vitality, and mental health complications (5, 20). However, dosing convenience is critical to long-term medication adherence (23–25), and parents consistently preferred dexamethasone, which could be given together with fludrocortisone just once per 24 hours. As new therapeutic options emerge (26), such practical considerations will continue to shape the specifics of treatment in each clinical context (27).

Glucocorticoid dose

The normal endogenous cortisol production rate in children is 6–8 mg/m2/d, but most children with CAH require higher exogenous glucocorticoid doses (ie, 10–20 mg/m2/d) to adequately suppress corticotroph ACTH release (1, 16). Even on such doses, however, optimal biochemical control is only achieved in 33–41% of CYP21A2-deficient patients (Table 3) (5, 6, 22), some of whom continue to produce large quantities of adrenal androgens and suffer the attendant complications. Such was the case for our HSD3B2-deficient patients, for whom morbidities associated with both under- and overtreatment were common (Table 2), and biochemical criteria indicated optimal glucocorticoid dosing for only 33% of monitoring events (Table 3).

Table 3.

Four CAH Cohorts: Patients, Treatments, and Outcomes

Abbreviations: CaHASE, Congenital adrenal Hyperplasia Adult Study Executive; NIH, National Institutes of Health; CSC, Clinic for Special Children.

a

Mean ± SD hydrocortisone equivalent dose for these groups assumes a dexamethasone:hydrocortisone glucocorticoid potency of 70:1 and excludes distinct outliers within the Tunisia (n = 4 [19%]; mean hydrocortisone equivalent dose, 24.4 ± 3.8 mg/m2/d) and CSC (n = 7 [44%]; mean hydrocortisone equivalent dose, 37.8 ± 15.4 mg/m2/d) cohorts.

b

In patients treated with fludrocortisone, optimization of therapy is determined by PRA within the normal reference range of 0.25–5.82 ng/mL/h.

c

Percentages expressed for females only.

d

Percentage for all females (n = 10); both females of reproductive age had polycystic ovary syndrome.

e

Percentage among females seeking pregnancy.

f

Percentage among women of reproductive age (n = 2).

g

Percentage among males; in CaHASE cohort, TARTs were identified in 69% by ultrasound; only 36% of these were clinically palpable.

Table 3.

Four CAH Cohorts: Patients, Treatments, and Outcomes

Abbreviations: CaHASE, Congenital adrenal Hyperplasia Adult Study Executive; NIH, National Institutes of Health; CSC, Clinic for Special Children.

a

Mean ± SD hydrocortisone equivalent dose for these groups assumes a dexamethasone:hydrocortisone glucocorticoid potency of 70:1 and excludes distinct outliers within the Tunisia (n = 4 [19%]; mean hydrocortisone equivalent dose, 24.4 ± 3.8 mg/m2/d) and CSC (n = 7 [44%]; mean hydrocortisone equivalent dose, 37.8 ± 15.4 mg/m2/d) cohorts.

b

In patients treated with fludrocortisone, optimization of therapy is determined by PRA within the normal reference range of 0.25–5.82 ng/mL/h.

c

Percentages expressed for females only.

d

Percentage for all females (n = 10); both females of reproductive age had polycystic ovary syndrome.

e

Percentage among females seeking pregnancy.

f

Percentage among women of reproductive age (n = 2).

g

Percentage among males; in CaHASE cohort, TARTs were identified in 69% by ultrasound; only 36% of these were clinically palpable.

We found glucocorticoid requirements among HSD3B2 c.35G>A homozygotes to be dichotomous: 56% required standard replacement, and the remainder required much higher and more variable doses (Figure 2). A similar phenomenon appeared in a recent paper about treatment and outcome of 26 Tunisian patients (age, 27.4 ± 8.2 y; 15 female) with CYP21A2 deficiency (7). Although the authors do not draw specific attention to this fact, their data indicate two distinct groups with regard to hydrocortisone requirement: one group (n = 17) requiring 15.0 ± 2.0 mg/m2/d, and a second group (n = 4) requiring 60% higher doses of 24.4 ± 3.8 mg/m2/d (P = .0138).

In both the Tunisian CYP21A2 and Amish HSD3B2 cohorts, the SD/HD distinction might simply be a consequence of variable medication adherence. Data suggest that only 12–50% of children with a chronic medical condition adhere to prescribed therapy (8), and this is known to be an obstacle in long-term management of CAH (28, 29). Differences in glucocorticoid requirement might also reflect differing homeostatic set points for HPA axis control. Exogenous glucocorticoid requirement varies considerably among CAH patients (16, 21). Interindividual differences are most obviously a function of how genotype affects residual enzyme activity (30) but also likely depend on genetic and nongenetic factors that influence hypothalamic responsiveness to circulating hormones, binding activity at tissue glucocorticoid receptors, and extraadrenal/extragonadal metabolism of adrenal hormone intermediates. Intraindividual variation occurs during puberty as a result of age- and gender-related changes of cortisol pharmacokinetics (28, 29). This is the first study to demonstrate that differences in glucocorticoid requirement can be relatively distinct rather than graded and emerge from a homogenous genetic background independent of age and gender.

Homeostatic set points for HPA axis control can also shift in response to extreme physiological circumstances (31, 32). This was certainly true for the child represented in case 1 (Supplemental Data) who, after catastrophic neurological injury as a neonate, continued to have extraordinary pituitary ACTH secretion, adrenal hormone output, and glucocorticoid requirements during observed medication adherence in a neonatal intensive care unit. Such a phenomenon must represent remodeling of pituitary-adrenal interactions and underscores how key life events can influence a system evolved to respond to stress (9).

Glucocorticoid monitoring

Extant CYP21A2 deficiency guidelines emphasize glucocorticoid dose adjustments to optimize growth, prevent adrenal crises, support skeletal maturation, and minimize clinical signs of both under- and overtreatment (17). However, there are comparatively few data to direct the specific glucocorticoid dosing adjustments that occur in everyday practice, and no current regimen perfectly mimics the endogenous cortisol rhythm or fully protects affected children from the dual dangers of systemic cortisol deficiency and sex steroid excess. New controlled-release preparations of cortisol approximate the circadian rhythm and hold promise (26), but they are not yet widely available and are sure to be prohibitively expensive for uninsured populations.

To facilitate monitoring, we used timed filter paper DHEA samples collected from home. This increased the flexibility of testing, reduced turnaround from 6 days to 1 day, and lowered per-test cost by 80%. It also engaged parents more deeply in management and increased treatment adherence. Although not a perfect marker for control of HSD3B2 deficiency, DHEA appears closely linked to disease morbidity and highlights the clinical relevance of “intracrine” tissue dynamics (4, 33). In HSD3B2 c.35G>A homozygotes, we found evidence that DHEA produced by the adrenal glands is converted to estradiol and more potent androgens via HSD3B1 action in extraadrenal/extragonadal tissues such as skin (34). Excess estradiol produced in this way likely contributes to age- or sex-inappropriate breast tissue development and accelerated bone maturation in both females and males (35). Overproduction of androgens such as androstenedione and T likely plays a more prominent role in cutaneous manifestations (eg, acne, virilization) and in polycystic ovary syndrome.

Mineralocorticoid therapy

Mild diastolic hypertension was documented in 63% of HSD3B2 c.35G>A homozygotes independent of age, gender, and glucocorticoid dosing range. We found that serum creatinine was approximately 38 and 46% lower in hypertensive patients relative to nonhypertensive patients and age-matched sibling controls, respectively, despite similar 24-hour creatinine excretion rates. This likely indicates higher whole-body sodium and extracellular fluid volumes as a consequence of excess mineralocorticoid receptor activation by fludrocortisone. In addition, PRA values for hypertensive patients (mean, 0.073 ± 0.019 ng/mL/h) were below the reference range of 0.25–5.82 ng/mL/h, which is indicative of iatrogenic hypertension due to overtreatment with fludrocortisone.

Attention to this problem becomes critical during the transition from infancy to childhood. Plasma aldosterone levels decrease from approximately 100 ng/dL in newborns to less than 16 ng/dL in young adults (36). The largest change occurs over the first year of life, during which a 50% decrease of circulating aldosterone parallels increasing tissue responsiveness to mineralocorticoid action (36, 37). To accommodate this physiological change, we reduced the fludrocortisone dose from 200 to 100 μg daily between 12 and 18 months of age and weaned supplemental sodium chloride beyond infancy. Nevertheless, our aggregate data suggest that over the longer term, most HSD3B2 c.35G>A homozygotes are overtreated with fludrocortisone. Together, these observations indicate that many CAH patients might benefit from closer attention to mineralocorticoid replacement therapy, which can have an important influence on long-term cardiovascular risk in patients taking concomitant exogenous glucocorticoids (38, 39).

HSD3B2 and CYP21A2 deficiencies: common challenges and opportunities

Table 3 summarizes three large cohorts of CYP21A2-deficient patients (5–7) and compares treatment metrics and morbid outcomes to Amish patients with salt-wasting HSD3B2 deficiency. Our patients are younger, and a larger proportion are treated with dexamethasone, but the prevalence of certain morbid complications among the four cohorts is remarkably consistent, including adrenal crisis (31–33%), short stature (20–38%), hirsutism (27–60%), and obesity (31–41%). Although there are key differences in genital complications (eg, all males but no females with HSD3B2 deficiency had genital surgery, whereas surgery was used to manage genital complications in 69–100% of females with CYP21A2 deficiency), data in Table 3 underscore the serious reproductive health problems faced by all CAH patients, who are at high risk for irregular menses (27–45%), sexual inactivity (57%), erectile dysfunction (41%), TARTs (44–69%), and infertility (25–40% of females, 33% of males) (5, 6, 18, 20, 22). Chronic exogenous glucocorticoid therapy can result in iatrogenic toxicities such as hypercholesterolemia (38–47%) and insulin resistance (15–37%), which together predispose to increased cardiovascular morbidity and mortality (5, 6, 18, 20, 22). Osteopenia and osteoporosis (32–40%) may also reflect lifetime glucocorticoid use.

Collectively, the chronic sequelae of exogenous glucocorticoid toxicity and sex steroid excess reduce quality of life for CAH patients, who have more physical limitations, bodily pain, and emotional problems than their age-matched counterparts. As many as 33% of adult CAH patients are unemployed as a result of such complications (38), and 50% or more are ultimately lost to medical follow-up (40). Thus, current medical therapy for CAH is far from optimal, leaving at least one-third of patients with serious physical, emotional, and social disabilities attributable to their illness or its treatment (7, 20). This presents a seemingly insurmountable dilemma for medical management and demands critical reassessment of treatment options.

Acknowledgments

We thank Dr D. Holmes Morton for his clinical management and advice regarding this cohort of patients. We thank Dr Joseph Majzoub, who provided valuable guidance and expertise for the design and execution of the study, as well as Dr Joan Fallon and Curemark, LLC, who provided funding for the project. We are grateful to the children with HSD3B2 deficiency and their parents, who participated in the research, gave invaluable insights into the practical aspects of treatment and monitoring, and guided our efforts to improve medical care.

This work was funded by Curemark, LLC. The nonprofit Clinic for Special Children is supported by charitable donations from the Amish and Mennonite communities it serves.

Disclosure Summary: The authors have no conflicts of interest to disclose.

Abbreviations

• CAH
  congenital adrenal hyperplasia
• DHEA
• HD
• HOMA
  homeostatic model assessment
• HPA
  hypothalamic-pituitary-adrenal
• HSD3B2
  3-β-hydroxysteroid dehydrogenase
• 17OHPreg
• PRA
• SD
• T
• TART
  testicular adrenal rest tumor.

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