GRAPHICAL ABSTRACT

INTRODUCTION

Lipoid congenital adrenal hyperplasia (LCAH, Online Mendelian Inheritance in Man [OMIM] #201710) is a rare disorder caused by defects in the steroidogenic acute regulatory (STAR) protein. STAR plays a critical role in transporting cholesterol from the outer to the inner mitochondrial membrane in steroidogenic cells [1]. Defects in STAR result in intracellular cholesterol accumulation, leading to impaired synthesis of cortisol, aldosterone, and androgens or estrogens [2]. The STAR gene is located on chromosome 8p11.23 and has been recognized since 1995 [3]. To date, approximately 104 pathogenic or likely pathogenic variants have been identified.

LCAH represents a rare subtype of congenital adrenal hyperplasia (CAH), as more than 95% of CAH cases are caused by 21-hydroxylase deficiency. Although 11β-hydroxylase deficiency is generally the second most common form worldwide, LCAH is reported more frequently in East Asian populations, including Korea, Japan, and China, where it represents the second most prevalent subtype [4,5]. The only published estimate of the prevalence of lipoid CAH in Japan is 2.1 per 1,000,000 individuals [6]. This regional predominance has been attributed to founder effects, as evidenced by the high frequency of the p.Q258* variant in East Asian populations [4,5,7]. The STAR gene exhibits population-specific variant distributions, with the R182L (c.201_202delCT) variant prevalent in Palestine, the L260P variant in Switzerland, and the p.Q258* variant in East Asia, all of which have been associated with founder effects [7-9].

Depending on the degree of residual STAR function, clinical manifestations of LCAH can vary widely. The classic form of LCAH is characterized by a complete loss of STAR function, resulting in an inability to synthesize steroid hormones and leading to primary adrenal insufficiency (PAI) during the neonatal period. In contrast, the nonclassic form retains partial STAR function, resulting in later disease onset and incomplete steroid deficiency, with clinical severity depending on the specific gene variant involved [10].

Although several single-center studies on LCAH have been reported in Korea [7,11], a multicenter study with long-term follow-up in Korean patients with LCAH has not previously been conducted. In the present study, we investigated clinical manifestations, karyotypes and disease subtypes, genetic and hormonal profiles, treatment patterns, and follow-up outcomes, including growth and pubertal development, in Korean patients with LCAH enrolled in the Multicenter Networks for Ideal Outcomes of Pediatric Rare Endocrine and Metabolic Disease (OUTSPREAD) cohort.

METHODS

This study included patients diagnosed before 18 years of age between January 1980 and August 2022. Data were obtained from a multicenter cohort study, the OUTSPREAD study, which involved 30 medical centers across South Korea [12]. Among the 351 patients with CAH included in the OUTSPREAD study, 31 patients with LCAH were identified from 10 medical centers (Supplemental Table S1), including one pair of twins and 29 individuals from unrelated families.

LCAH was defined by the presence of PAI and pathogenic variants in the STAR gene and was categorized into classic and nonclassic forms. The classic form (C-LCAH) presented with adrenal insufficiency during the neonatal or early infantile period and was characterized by a female phenotype or minimally masculinized external genitalia, irrespective of karyotype. The nonclassic form (NC-LCAH) was defined according to criteria applied in a recent study [6]. Patients were classified as having NC-LCAH if they met at least one of the following criteria: (1) a 46,XY karyotype with fully male external genitalia; (2) absence of salt-wasting adrenal insufficiency or no requirement for fludrocortisone supplementation; or (3) diagnosis after infancy.

Data on age, anthropometric measurements, initial clinical presentations, physical findings (including Quigley grade), karyotype, STAR genotype, surgical data, hormone replacement therapy, and other medical treatments were collected at key time points as part of the overall cohort study [12]. Decisions regarding sex assignment at birth are typically made during the neonatal period, taking into account genital appearance, anticipated functional outcomes, and potential fertility. Hyponatremia was defined as a serum sodium concentration <135 mmol/L, hyperkalemia as a serum potassium concentration ≥7.0 mmol/L, and hypoglycemia as a blood glucose level <54 mg/dL. The collected information included anthropometric data obtained annually from the time of diagnosis up to 3 years post-diagnosis, as well as at the onset of spontaneous puberty, at attainment of adult height, and at the last follow-up. Height, weight, and body mass index z-scores were calculated using the 2017 Korean National Growth Charts for Children and Adolescents [13].

Statistical analysis was performed using R version 4.4.0 (R Foundation for Statistical Computing, Vienna, Austria). Data are presented as medians and interquartile ranges (IQRs). Pearson’s chi-square test or Fisher’s exact test was used for categorical variables, and the Kruskal–Wallis test was used to compare continuous variables across groups. Statistical significance was defined as a two-sided P value <0.05.

The study protocol was approved by the Institutional Review Board of Seoul National University Hospital, which waived the requirement for informed consent (IRB No. 2206-211-1336).

RESULTS

Clinical and biochemical presentation at diagnosis

Table 1 summarizes the clinical and biochemical characteristics at diagnosis of patients with C-LCAH (n=29) and NC-LCAH (n=2). The median age at diagnosis was 36.5 days (IQR, 14.6 to 120.5). Among the 29 C-LCAH patients, 12 were diagnosed during the neonatal period, 11 between 31 and 120 days of age, and five between 121 and 210 days of age, while the age at diagnosis was unknown for one patient. The two NC-LCAH patients were diagnosed after 1 year of age. The most common clinical manifestation was skin hyperpigmentation (71.0%), followed by fatigue or lethargy, decreased oral intake, and vomiting.

Chromosome analysis demonstrated a 46,XX karyotype in 17 patients (all C-LCAH-XX, 54.8%) and a 46,XY karyotype in 14 patients (12 C-LCAH-XY and 2 NC-LCAH-XY). Both NCLCAH-XY patients exhibited Quigley grade 1 genitalia, corresponding to completely masculinized external genitalia, whereas all C-LCAH patients showed Quigley grade 6 or 7 genitalia, indicating complete female-type external genitalia, as illustrated in Fig. 1. No family history of LCAH was identified, except for one pair of twins.

A salt-wasting crisis at diagnosis was observed in 17 (58.6%) of the 29 C-LCAH patients. Additionally, hyponatremia was present in 15 patients (60.0%), hyperkalemia in eight patients (32.0%), and hypoglycemia in four patients (22.2%). The median adrenocorticotropic hormone (ACTH) level at diagnosis was highest among patients diagnosed before 30 days of age (3,225 pg/mL; IQR, 1,780 to 5,153), compared with 1,000 pg/mL (IQR, 758 to 2,000) in those diagnosed between 30 and 120 days and 1,214 pg/mL (IQR, 334 to 2,025) in those diagnosed after 120 days. A salt-wasting crisis was noted in six of 12 patients (50.0%) diagnosed before 30 days, seven of 11 patients (63.6%) diagnosed between 30 and 120 days, and four of five patients (80.0%) diagnosed after 120 days. No significant differences were observed in ACTH levels or in the proportion of salt-wasting crises among the three age groups at diagnosis (before 30, 31–120, and 121–210 days).

At diagnosis, all 31 patients were treated with hydrocortisone, and fludrocortisone was administered to 30 patients, excluding one NC-LCAH patient. Sodium chloride supplementation was provided during the infantile period in 13 patients (41.9%). The initial maintenance dose of hydrocortisone was 21.7 mg/m²/day (IQR, 14.9 to 26.5), and the initial dose of fludrocortisone was 0.1 mg/day (IQR, 0.1 to 0.1).

Clinical follow-up of 29 patients with C-LCAH (17 C-LCAH-XX and 12 C-LCAH-XY)

Clinical and biochemical data for the 17 C-LCAH-XX patients are presented in Table 1 (at diagnosis) and Table 2 (follow-up). The median height and weight z-scores at diagnosis were 0.6 (IQR, 0.1 to 1.8) and −0.5 (IQR, −0.8 to −0.2), respectively. STAR gene analysis identified the p.Q258*/p.Q258* variant in 15 patients, p.Q258*/p.Arg182His in one patient, and p.Q258*/p.Arg182Cys in one patient (Table 1).

The median age at the last follow-up was 12.5 years (IQR, 9.0 to 15.1), and 11 patients were older than 10 years at that time. Fig. 2 illustrates ovarian function-related outcomes in the 17 CLCAH-XX patients. Spontaneous puberty occurred in 11 patients at a median age of 11.0 years (IQR, 8.2 to 12.2). Five patients experienced spontaneous menarche at a median age of 12.4 years (IQR, 11.9 to 13.2). Among eight C-LCAH-XX patients who underwent ultrasonography, unilocular ovarian cysts were identified in three patients, including one patient who experienced ovarian cyst rupture at 15 years of age. At the last follow-up, their luteinizing hormone levels were 5.1, 9.2, and 21 mIU/mL, with corresponding follicle-stimulating hormone levels of 1.0, 3.9, and 7.5 mIU/mL. Three of the five postmenarcheal girls had irregular menstruation, and one of these patients was treated with progesterone after being diagnosed with polycystic ovary syndrome at 19.9 years of age.

At the last follow-up, four patients were classified as overweight and two as obese. The median daily doses of hydrocortisone and fludrocortisone were 17.4 mg/m² (IQR, 13.4 to 24.1) and 0.1 mg (IQR, 0.1 to 0.1), respectively. Three patients reached adult height, with a median height Z-score of −0.8 (IQR, −1.0 to 0.2).

Clinical and biochemical data for the 12 C-LCAH-XY patients are shown in Table 1 (at diagnosis) and Table 2 (follow-up). All patients were found to carry the homozygous p.Q258* mutation. The median height and weight z-scores at diagnosis were 0.4 (IQR, −0.8 to 1.1) and −1.1 (IQR, −2.0 to 0.2), respectively. Gonadectomy was performed in all 12 patients at a median age of 3.3 years (IQR, 1.3–6.4), and one patient was diagnosed with germ cell neoplasia in situ (GCNIS) at 1.3 years of age. The median age at the last follow-up was 11.6 years (IQR, 9.6 to 20.8), with a median follow-up duration of 10.3 years (IQR, 6.7 to 17.8). At the last follow-up, two patients were overweight and four were obese. The median daily doses of hydrocortisone and fludrocortisone were 15.6 mg/m² (IQR, 13.7 to 18.7) and 0.1 mg (IQR, 0.1 to 0.2), respectively. Six patients initiated estrogen replacement therapy at a median age of 11.6 years (IQR, 11.0 to 16.3). Four patients reached adult height, with a median height Z-score of 0.9 (IQR, −0.3 to 1.4).

Clinical follow-up of two patients with NC- LCAH (NC-LCAH-XY)

The two NC-LCAH-XY patients were diagnosed at 1.6 and 3.3 years of age and carried the p.Q258*/p.Val187Met and p.Ala-218Val/p.Gly221Ser variants, respectively (Table 1). Both patients presented with skin hyperpigmentation and were followed until 6.1 and 26.3 years of age. One patient entered puberty at 10.6 years of age and reached adult height, with a height Z-score of 0.1. At the last follow-up, this patient demonstrated adequate hormone levels (luteinizing hormone, 8.5 mIU/mL; follicle-stimulating hormone, 8.4 mIU/mL; and testosterone, 5.4 ng/mL).

DISCUSSION

This study presents comprehensive clinical features and outcomes, including genetic evaluation, of 31 patients with LCAH in Korea. Most patients (93.5%) were classified as having the classic form and were diagnosed at a median age of 36.5 days. Skin hyperpigmentation was the most common presenting feature. Most C-LCAH-XX and NC-LCAH-XY patients who had reached pubertal age experienced spontaneous puberty and demonstrated age-appropriate growth. Ovarian cysts were frequently observed in individuals with a 46,XX karyotype.

Earlier reports defined LCAH as PAI presenting in late infancy or childhood, accompanied by completely masculinized external genitalia in individuals with a 46,XY karyotype. Definitions of LCAH used in previous studies are summarized in Supplemental Table S2. More recently, however, the age at onset of PAI has been shown not to provide a clear distinction between classic and nonclassic forms, as some NC-LCAH patients have been reported to develop PAI during infancy [6]. Consequently, a recent Japanese study incorporated the requirement for mineralocorticoid replacement into the diagnostic criteria, and we adopted the same definition to maintain consistency with that study.

The exact prevalence of NC-LCAH remains unknown. However, in East Asian populations, where the overall frequency of LCAH is relatively high, reported proportions of nonclassic cases range from approximately 11.1% to 19.3% [2,6,14], as summarized in Supplemental Table S2. Moreover, a recent review identified 47 genetically confirmed cases worldwide, encompassing 14 distinct STAR mutations [15].

Our finding that 87.1% of patients with LCAH in this Korean multicenter study carried the p.Q258*/p.Q258* variant was consistent with previous Korean reports [7,11]. The p.Q258* allele is also prevalent in other East Asian regions due to a founder effect, with reported frequencies of 45% in China [14] and 86.1% in Japan [6]. Patients harboring p.Q258* mutations associated with loss of STAR protein function, as well as those with p.Arg182His or p.Arg182Cys mutations resulting in minimal pregnenolone production, exhibited a classic phenotype [16]. In contrast, two patients with the p.Q258*/p.Val187Met and p.Ala218Val/p.Gly221Ser genotypes were diagnosed with NCLCAH-XY and presented with fully masculinized external genitalia after 1 year of age. In vitro functional analyses of the p. Gly221Ser variant demonstrated 30%–50% pregnenolone production compared with the wild type [10]. Similarly, the p.Val-187Met variant retained 21.6% activity [17], whereas the p.Ala-218Val variant showed approximately 6% to 20% residual STAR activity [17,18].

LCAH should be suspected in phenotypic female neonates presenting with adrenal insufficiency, normal 17-hydroxyprogesterone levels, and no evidence of virilization. Accurate diagnosis requires prompt hormonal evaluation and genetic testing. Although hyperpigmentation due to elevated adrenocorticotropic hormone levels is a common presenting feature, it may be overlooked in the absence of overt salt-wasting. Nevertheless, given that only 58.6% of patients in our cohort presented with salt-wasting, hyperpigmentation should raise suspicion of LCAH, even in its absence. This finding highlights skin hyperpigmentation as an important diagnostic clue that should prompt further hormonal and genetic evaluation. In contrast, large-scale studies have reported higher frequencies of electrolyte disturbances, with hyponatremia observed in 82.4% of patients in Japan [6], and salt-wasting reported in 80.8% of patients in China [14]. Other case series have described salt-wasting frequencies ranging from 66% to 80% [19,20].

In C-LCAH-XY patients, Leydig cells, which are primarily responsible for testicular steroidogenesis, display a characteristic foamy appearance. This feature likely reflects chronic impairment of steroidogenesis beginning in the fetal period and culminating in lipid accumulation within these cells [21,22]. Although testicular pathology was not comprehensively assessed in our study, one patient was found to have GCNIS. Similar findings of GCNIS and pre-GCNIS have been reported previously [2,23]. Nevertheless, because the testes are structurally preserved at birth, gonadectomy is typically deferred until later in childhood following female sex assignment.

Most C-LCAH-XX patients undergo spontaneous puberty and menarche, as reported in previous studies (Table 3). Fetal ovarian cells remain dormant until gonadotropin stimulation, allowing pubertal development to proceed. After puberty, however, progressive lipid accumulation occurs due to the initiation of autonomous cholesterol synthesis in the ovaries [21,24], which may lead to ovarian cyst formation, menstrual irregularities, and infertility in adulthood [19]. Elevated luteinizing hormone levels, particularly in the setting of low or normal follicle-stimulating hormone and estradiol levels, may indicate persistent anovulation and an increased risk of ovarian cyst development [25,26]. In our study, three patients were identified with ovarian cysts, one of whom experienced cyst rupture. In previous reports, among 32 pubertal 46,XX patients, 14 developed ovarian cysts following spontaneous menarche, 10 of whom were receiving oral contraceptives (Table 3) [6,19,25-28]. Pregnancy was achieved in two cases using in vitro fertilization [19], and in one case following clomiphene induction and progesterone supplementation [27]. Therefore, monitoring luteinizing hormone levels in conjunction with pelvic ultrasonography is recommended after menarche in patients with C-LCAH to detect ovarian cysts and other reproductive complications. Adult height outcomes in C-LCAH-XX patients have been reported to be comparable to mid-parental height and similar to population norms [6,19,27].

Males with NC-LCAH retain partial STAR function, which allows some steroidogenic capacity in fetal Leydig cells and enables spontaneous pubertal development [15]. Consequently, as shown in Table 4, most patients with NC-LCAH exhibited age-appropriate pubertal onset, with the exception of one case. NC-LCAH usually presents with male-type external genitalia; however, seven of 14 NC-LCAH-XY patients showed genital abnormalities at diagnosis (Table 4), with hypospadias reported in up to 21.5% of cases in a previous study [15]. Theoretically, individuals with NC-LCAH may develop hypogonadism and impaired fertility, often accompanied by testicular atrophy and vacuolated Sertoli and Leydig cells [17,29]. As shown in Table 4, four of eight patients with available data on both external genitalia and adult fertility demonstrated hypogonadism or testicular abnormalities, including one patient with typical male external genitalia. These findings indicate that, although spontaneous puberty generally occurs in patients with NC-LCAH, the risk of infertility persists, underscoring the importance of ongoing evaluation. Meanwhile, adult height in NC-LCAH-XY patients does not differ from population norms [6,10,14,30]. Despite the absence of NC-LCAH-XX cases in our study, normal pubertal development and regular menstruation have been reported in such cases, as summarized in Table 4. In addition, five cases of spontaneous pregnancy and one case achieved with ovulation induction using clomiphene have been reported [6,31,32].

Our study has several limitations. First, the sample size was limited because of the rarity of LCAH. Second, the relatively young age of patients at the time of last follow-up limited the ability to conduct a comprehensive evaluation of pubertal development and reproductive outcomes, highlighting the need for future prospective studies. Third, due to the retrospective design, clinical parameters such as mid-parental height, bone mineral density, and metabolic outcomes were not consistently collected from diagnosis through the last follow-up. Given the importance of these parameters for understanding long-term prognosis, future prospective studies should incorporate systematic data collection to better elucidate long-term outcomes, including fertility prognosis, through extended follow-up. Fourth, hormone measurements were not standardized across participating centers, and assay kits may have changed within individual centers over the extended study period, potentially affecting data comparability. Although direct numerical comparisons may therefore be limited, these variations are unlikely to have influenced the interpretation of overall increasing or decreasing trends. Despite these limitations, this study is meaningful, as it represents the largest multicenter study conducted in Korea to date.

This study represents the first large-scale multicenter investigation to report long-term outcomes of LCAH stratified by classic and nonclassic forms. LCAH should be suspected in phenotypic female neonates presenting with adrenal insufficiency or skin hyperpigmentation and normal 17-hydroxyprogesterone levels. Along with appropriate adjustment of adrenal hormone replacement therapy, continued follow-up focusing on pubertal development, including ovarian cyst formation in 46,XX patients, and reproductive outcomes is warranted.

Supplementary Material

Article information

CONFLICTS OF INTEREST

No potential conflict of interest relevant to this article was reported.

ACKNOWLEDGMENTS

This research was supported and funded by Seoul National University Hospital Lee Kun-hee Child Cancer & Rare Disease Project, Republic of Korea (grant number: 22C-007-0100).

AUTHOR CONTRIBUTIONS

Conception or design: Y.L., M.K., Y.J.L., S.Y.C., J.S., M.B.A., C.K.C., C.J.K., H.H.L., S.C., W.K.C., E.G.Y., C.H.S., H.W.Y., Y.A.L. Acquisition, analysis, or interpretation of data: Y.L., Y.A.L. Drafting the work or revising: Y.L., M.K., Y.J.L., S.Y.C., J.S., M.B.A., C.K.C., C.J.K., H.H.L., S.C., W.K.C., E.G.Y., C.H.S., H.W.Y., Y.A.L. Final approval of the manuscript: Y.L., M.K., Y.J.L., S.Y.C., J.S., M.B.A., C.K.C., C.J.K., H.H.L., S.C., W.K.C., E.G.Y., C.H.S., H.W.Y., Y.A.L.

Fig. 1.

Clinical classification of lipoid congenital adrenal hyperplasia (LCAH) patients. The age at diagnosis for one 46,XX classic-type patient was unavailable. Age at diagnosis was available in 16 patients with C-LCAH-XX.

Fig. 2.

Pubertal status in classic lipoid congenital adrenal hyperplasia-XX patients. PCOS, polycystic ovary syndrome.

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