Background: Congenital adrenal hyperplasia (CAH) is an autosomal recessive genetic disorder that causes defects in the adrenal cortex enzymes that impair the biosynthesis of cortisol, aldosterone, or both. The most common type is the 21-hydroxylase enzyme deficiency in approximately 95% of cases resulting from CYP21A2 gene mutations or deletions. Objectives: This study aimed to systematically review the national differences in CAH incidence and analyze the pooled results to determine disparities and whether ethnicity can predispose people to develop CAH. Methods: PubMed, Scopus, and LILACS were used to achieve results until June 22, 2018. Study eligibility criteria included availability of full-text; English, Spanish, or Portuguese languages; incidence or number of new cases; and number of live births or sample population. Only the classic CAH type (salt-wasting and simple-virilizing) was considered, and no distinction was made between the enzyme deficiency types. Results: This study summarizes the findings of 58 studies and 31 countries (from 1969 to 2017), in which the overall CAH incidence was 1:9,498 (95% confidence interval: 1:9,089, 1:9,945). Countries from the Eastern Mediterranean and Southeast Asia revealed the highest CAH incidence. The lowest incidence was reported in countries of the Western Pacific of Asia. No remarkable difference was observed in the Hispanics/Latino and White groups. However, they manifested a higher incidence of CAH than people identified as Black or of African descent. Published studies on CAH incidence in the sub-Saharan African region and parts of Europe were insufficient. Conclusions: This study highlights the at-risk population for CAH and regions that need monitoring for CAH. The highest CAH incidence could be attributed to higher consanguinity, less genetic diversity, or other genetic causes since CAH is an inherited genetic disorder. Cultural practices in some places regarding consanguineous unions or geographic isolation may directly affect the incidence. Newborn screening for CAH may be unavailable in many developing countries, thereby affecting the actual CAH incidence. Therefore, healthcare workers should be trained to recognize CAH at an early stage to reduce its complications and mortality.

Congenital adrenal hyperplasia (CAH) is an autosomal recessive genetic disorder that causes defects in the adrenal cortex enzymes. CAH impairs the biosynthesis of adrenal glucocorticoids, mineralocorticoids, and sex steroid production based on the type of enzyme deficiency [1]. The 21-hydroxylase enzyme deficiency is the most common type in approximately 95% of cases due to CYP21A2 gene mutations or deletions in chromosome 6p [1]. Newborn screening uses dried blood spots to detect 17-OH progesterone levels, a precursor of 21-hydroxylase. Subsequently, the serum 17-OHP concentration is used for the final CAH diagnosis [2]. CAH is classified into classic “severe” (salt-wasting and simple-virilizing) and non-classic “mild” (late-onset) types. Some clinical manifestations include salt-wasting, virilization, dehydration, ambiguous genitalia, menstrual abnormalities, rapid bone growth, hirsutism, premature pubarche, and acne, among others [2].

The overall and individual incidence data are key to identifying populations at risk and improving early detection and management. Previous worldwide studies reported a classic CAH incidence of 1:14,554 live births (95% confidence interval [CI]: 1:11,203–1:19,318) from 1980 to 1988, and 1:5,000 (Saudi Arabia) to 1:23,000 (New Zealand) in 1995 [3, 4]. A high incidence was identified among Alaska Yupik Eskimos, USA (1:282) due to the founder effect and La Reunion, France (1:2,141) due to higher consanguinity rates [3]. Furthermore, the incidence in Japan is relatively low compared to North American and European countries [4]. Meanwhile, a more recent study reported a range from 1:14,000 to 1:18,000 in CAH incidence among 16 countries from published studies in 2008 and later [5]. Similarly, CAH was concluded to be more prevalent in genetically isolated groups and remote geographic regions. This study aimed to examine changes in the worldwide incidence and the presence of updates on the most affected countries.

Alternatively, CAH incidence could be evaluated based on the type of enzyme deficiency. A study reported an incidence for 21-hydroxylase deficiency of 1:10,000 to 1:20,000 classic and 1:200 to 1:1,000 non-classic types [1]. The 11β-hydroxylase deficiency was predominant in Caucasians (1:100,000) and Moroccan Jews (1:6,000). The 17α-hydroxylase deficiency was 1:50,000 with an increased frequency in Brazil. The 3β-hydroxysteroid dehydrogenase deficiency and P450 oxidoreductase deficiency were rare. In addition, ethnic-specific mutations were found in the CYP21A2 gene in different populations. Significant mutations in the Anglo-Saxons, Ashkenazi Jews, Croatians, Iranians, Yupik-speaking Eskimos of Western Alaska, and East Indians have been reported [6]. No distinction was made between the types of enzyme deficiencies in this study. However, emphasizing the fact that certain groups are more affected by mutations or enzyme deficiencies than others is important for understanding the difference in CAH incidence.

No overall updated meta-analysis of variations in incidence between different places was reported, although many studies have documented CAH incidence in various populations. This study systematically reviews CAH incidence results from different countries. The study design was population and outcome: (randomly selected people from a geographical area, nation, race, or ethnicity, with and without CAH) and (incidence or number of new cases and the sample population number). We aimed to determine the disparities in CAH incidence and whether ethnicity or race predisposes people to develop CAH by searching the consulted databases.

This review was conducted in compliance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines [7]. This study followed the PRISMA guidelines and used the CADIMA website (evidence synthesis tool and database), although a registered review protocol was unavailable [8].

Data Source and Search Strategy

Three databases were consulted, including PubMed, Scopus, and LILACS. No filters were applied. The following terms were used in the search box: “(Congenital Adrenal Hyperplasia OR CAH) AND (Epidemiology OR Incidence OR Prevalence OR Frequency) AND (Ethnicity OR Ethnic OR Race OR Asia OR America OR Africa OR Australia OR Europe OR Oceania OR Neonatal Screening OR Newborn Screening).” The search of studies in databases was completed until June 22, 2018. Identified studies through the search were downloaded to EndNoteTM X8.2 (Bld 11343) and uploaded to CADIMA, and both databases were used to remove the duplicates. The systematic review was limited to the identified studies in the databases, and no external studies were included. Therefore, their citations or reference lists were not reviewed to add other potential studies.

Study Selection

The selection was limited to the English, Spanish, or Portuguese languages. Only the classic CAH type (salt-wasting and simple-virilizing) was considered. No distinction was made between the types of enzyme deficiencies (21-hydroxylase, 11β-hydroxylase, 3β-hydroxysteroid, and 17α-hydroxylase, among others). Two-step screening processes were performed, including one with the abstract and one with the full text. The criteria for abstract selection were population and outcome: (randomly selected people from a geographical area, nation, race, or ethnicity, with and without CAH) and (incidence or prevalence or frequency or epidemiology of CAH). One reviewer did the abstract screening using CADIMA, and the other reviewed doubtful abstract information. Studies were included for the full-text review in case of undetermined eligibility from the abstract. The full-text eligibility criteria were as follows: geographical area, incidence or number of new cases, and number of live births or sample population. Full-text review exclusion criteria were as follows: unavailability of full-text; languages other than English, Spanish, or Portuguese; non-classic type; absence of the incidence or number of new cases; and absence of the number of live births or sample population.

Data Extraction and Analysis

Studies were identified and documented using CADIMA. One author extracted the information, and both authors worked on the calculations in the Microsoft Office Excel spreadsheets. The variables extracted were the country, study period, incidence, number of CAH cases, and sample screened or number of live births. This review was conducted at the outcome level, and each study’s methodology parameters for diagnosing CAH were not reviewed, which could cause a potential risk of bias. The incidence was estimated by (number of new CAH cases)/(total numbers of newborns screened or live births). The individual number of cases from the same country was added and divided by the sum of the individual number population sample when more than one study of the same country exists. Some geographical divisions were based on the World Health Organization regions, and the map was created using Datawrapper [9]. Ethnicity or race was assigned according to the described categories in the studies, and others without categories were assigned according to the National Institute of Health categories [10]. The mean and 95% CI were obtained by bootstrapping the results to a value of n = 500 {= INDEX (sample, RANDBETWEEN [1, ROWS (sample)], 1)}. The bootstrapping method was used to achieve a normal distribution by repeatedly resampling the data to create many simulated samples and, ultimately, using the 95% CI Excel functions. 95% CI was calculated using the following equation: (= CONFIDENCE.T [alpha, standard_dev, size]). The standard deviation and standard error were calculated using the following equation: (= STDEV.S) and (= SD/SQRT[n]).

A total of 1,707 articles were identified through the databases of PubMed (n = 807), Scopus (n = 309), and LILACS (n = 591) until June 22, 2018. Duplicates were removed (n = 563), and 130 articles were chosen based on their abstracts. Figure 1 shows the flow diagram. The full-text eligibility criteria were as follows: geographical area, incidence or number of new cases, and number of live births or sample population. A total of 58 articles were selected for the meta-analysis after the full-text evaluation. Some articles have more than one reported incidence due to various study periods, regional divisions, or different populations within their country. Hence, 63 incidence datasets were extracted from the 58 included articles. In summary, this study included results from 31 countries from 1969 to 2017, and the map reflects the incidence variation of n = 100,000 (Fig. 2). A bootstrapping method to a value of n = 500 was performed using the sample of the 31 incidence datasets of the countries, and the obtained mean was 10.81 per 100,000 live births or samples (or 1:9,248). The 95% CIs for the mean were 11.04 (1:9,089) and 10.60 (1:9,945) per 100,000. The standard deviation and standard error per 100,000 were 2.54 and 0.11, respectively.

Fig. 1.

Flowchart of the study selection and exclusion criteria. A flowchart diagram was created of the literature search and selection following the PRISMA Flow Diagram [7]. The full-text eligibility criteria were as follows: geographical area, incidence or number of new cases, and number of live births or sample population.

Fig. 1.

Flowchart of the study selection and exclusion criteria. A flowchart diagram was created of the literature search and selection following the PRISMA Flow Diagram [7]. The full-text eligibility criteria were as follows: geographical area, incidence or number of new cases, and number of live births or sample population.

Close modal
Fig. 2.

CAH incidence (n= 100,000). The map reflects the incidence variation per 100,000 live births or samples. Low incidence corresponds to <5/100,000 (∼1:20,000), the mean range is 10/100,000 (∼1:10,000), and high incidence corresponds to >15/100,000 (∼1:6,661). Studies published regarding CAH incidence in the sub-Saharan African region and parts of Europe were insufficient. Countries from the Eastern Mediterranean and Southeast Asia revealed the highest CAH incidence. China has a high CAH incidence as per our results; however, a posterior study (not included) reported that the incidence of CAH in China is 4.34/100,000 newborns [11].

Fig. 2.

CAH incidence (n= 100,000). The map reflects the incidence variation per 100,000 live births or samples. Low incidence corresponds to <5/100,000 (∼1:20,000), the mean range is 10/100,000 (∼1:10,000), and high incidence corresponds to >15/100,000 (∼1:6,661). Studies published regarding CAH incidence in the sub-Saharan African region and parts of Europe were insufficient. Countries from the Eastern Mediterranean and Southeast Asia revealed the highest CAH incidence. China has a high CAH incidence as per our results; however, a posterior study (not included) reported that the incidence of CAH in China is 4.34/100,000 newborns [11].

Close modal

Table 1 shows the characteristics of the included studies. All included studies were based on neonatal screening, except for seven retrospective studies. Information about the newborn screening program establishment was added according to the reported study period, which may differ today. Other studies were reported under newborn screening research studies or pilot programs without an established newborn screening. Countries from the Eastern Mediterranean with the highest incidence were Egypt [24] and Saudi Arabia (the Eastern region had the majority of cases) [22, 60]. Hyderabad and Chennai regions had the highest incidence in India [45, 47]. North America’s highest incidence was found in the population of Yupik Eskimo (1:282 in 1982) in Alaska [19] and The Bahamas (1:5,053) [20]. In Latin America, Argentina had the highest incidence (1:8,937) [61] and in Europe, La Reunion (1:2,654 in 1982) in France [33]. No updated studies were found in our search for previously reported high-risk countries, including Alaska, USA, and La Reunion, France [62]. Meanwhile, the Western Pacific region, including Oceania, appeared to have a low incidence, except for China (1:6,083) [52] and Australia’s Aboriginal community (1:6,594) [58].

Table 1.

Characteristics of included studies of CAH [12‒61, 63‒70]

 Characteristics of included studies of CAH [12‒61, 63‒70]
 Characteristics of included studies of CAH [12‒61, 63‒70]

Table 2 shows the incidence data divided by ethnicity and race. No remarkable difference was observed in Hispanics/Latino and White groups. Nevertheless, our results revealed a higher incidence of CAH in these groups than in people identified as Black or of African descent. Moreover, our results revealed that a higher incidence of CAH was observed in the Asian populations than in those belonging to other regions (Table 2). However, these results are attributed more to Southeast Asia and not to the Western Pacific countries from Asia.

Table 2.

CAH incidence by ethnicity and race

 CAH incidence by ethnicity and race
 CAH incidence by ethnicity and race

This study summarizes the findings of 58 studies and 31 countries from 1969 to 2017, in which the overall classic CAH incidence was 1:9,498 (95% CI: 1:9,089, 1:9,945). This overall incidence is lower than other studies, in which incidence data of 1:15,000 and 1:14,000 to 1:18,000 were reported worldwide [3, 5]. Our study is different from other studies in that we did not exclude studies on a yearly basis as well as the incidence data of countries’ subpopulations that were particularly high while using the bootstrapping method. Unpublished data and the absence of newborn screening programs in many countries also affect the incidence result.

The incidence in countries in North America and Europe was similar to previous studies [4, 62]. Likewise, the incidence for Hispanic/Latino and White groups was similar. Otherwise, countries from Eastern Mediterranean revealed a high CAH incidence, including the North of Africa. Additionally, a high rate of consanguinity is observed in these regions, according to the Global Consanguinity 2015 website [71]; particularly, Saudi Arabia had 30–39%, Kuwait had 40–49%, the UAE had 30–39%, and Egypt had 20–29%. Therefore, a possible cause of the high incidence in the Eastern Mediterranean is the higher consanguinity, which correlates with the higher expression of autosomal recessive diseases.

Asian countries were divided into Southeast Asia and Western Pacific countries. India has the highest incidence of Southeast Asia, and high consanguinity rates (30–39%) are reported in the southern parts of India, which may be a reason for the high CAH incidence [71]. Regardless of the high CAH incidence, full implementation of newborn screening faced obstacles and was not a high public health priority in 2018 [72]. Contrastingly, Asian-Pacific countries in our study have a low incidence (e.g., Singapore with 1:22,371 and Japan with 1:21,264) and a low rate of consanguinity (1–5%). The major contributor to the high CAH incidence in the Western Pacific in our study was China (1:6,084) as reported in 2013, with 18.9–19.9% of CAH coverage [52]. Subsequently, an updated comprehensive study of China published in 2021 reported that the CAH incidence in China is 1:23,024, including approximately 7.85 million newborns [11]. The study also pointed out that under-developed healthcare regions could have a high incidence, which could contribute to the results of the previous study in 2013. Thus, these new findings support the low incidence of CAH in the Asian countries of the Western Pacific region.

Newborn screening in sub-Saharan Africa is reported to be minimal [72], and consanguinity rates are unknown [71]. Hence, we could not find sufficient published studies regarding CAH incidence in the sub-Saharan African region. Therefore, we looked for studies with African ancestry in other countries to learn about this population. Studies from North America revealed a low CAH incidence (1:24,838 and 1:41,968) in people identified as Black or of African descent [13, 16, 17]. This information agrees with a study in KwaZulu-Natal Durban, South Africa, which revealed that CAH is not common among black children in that area despite being the third most common diagnosis of sex development-related diagnosis [73, 74]. However, they reported that newborns are not routinely screened for CAH, and missed or delayed diagnosis may result in high mortality, thereby affecting the number of reported cases. Meanwhile, a study in The Bahamas (with 85% African ancestry) showed a high CAH incidence (1:5,053) [20]. These differences may be explained by under-reporting cases in the sub-Saharan African region or other genetic causes in The Bahamian population, although more research is needed.

The limitations of this systematic review were due to insufficiently published studies in databases and screening programs for CAH. Furthermore, some published articles’ results did not meet the inclusion criteria. This review was conducted at the outcome level, which could lead to a possible bias in the results because of each country’s diagnostic parameters. Additionally, more published research is necessary to update the existing incidence and identify other at-risk populations, particularly in countries or ethnicities identified with a high incidence. Therefore, a more comprehensive study should include results from each country’s health databases or websites.

This study reviewed the incidence of CAH worldwide and highlighted the regions that need monitoring. The highest CAH incidence could be attributed to higher consanguinity, less genetic diversity, or other genetic causes (e.g., hotspots for mutations) because CAH is an inherited genetic disorder. Cultural practices in some places regarding consanguineous unions or geographic isolation may directly affect the incidence of CAH. Newborn screening for CAH may not be available in many developing countries, thereby affecting the number of reported cases and the actual CAH incidence. Therefore, healthcare workers should be trained to have early CAH recognition to reduce complications and mortality in the absence of newborn screening.

This study is based exclusively on published literature, and an ethics statement is not applicable. However, this study was conducted in compliance with the research ethics norms established by the Biomedical Responsible Conduct of Research online modules certified by the Collaborative Institutional Training Initiative (CITI) Program. Also, the Introduction to Publication Ethics module by the Committee on Publication Ethics (COPE) guidelines was completed.

The authors have no conflicts of interest to declare.

This research was conducted in the Summer Research Internship in Medical Sciences funded by the University of Missouri School of Medicine.

Both authors participated in the design and methodology. Andrea N. Navarro-Zambrana searched and extracted the information. Both authors worked with the statistical data. Andrea N. Navarro-Zambrana wrote the manuscript, while Lincoln R. Sheets reviewed and approved the manuscript.

All data generated or analyzed during this study are included in this article. Further inquiries can be directed to the corresponding author.

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